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1.  Pretreatment CD4 Cell Slope and Progression to AIDS or Death in HIV-Infected Patients Initiating Antiretroviral Therapy—The CASCADE Collaboration: A Collaboration of 23 Cohort Studies 
PLoS Medicine  2010;7(2):e1000239.
Analyzing data from several thousand cohort study participants, Marcel Wolbers and colleagues find that the rate of CD4 T cell decline is not useful in deciding when to start HIV treatment.
Background
CD4 cell count is a strong predictor of the subsequent risk of AIDS or death in HIV-infected patients initiating combination antiretroviral therapy (cART). It is not known whether the rate of CD4 cell decline prior to therapy is related to prognosis and should, therefore, influence the decision on when to initiate cART.
Methods and Findings
We carried out survival analyses of patients from the 23 cohorts of the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) collaboration with a known date of HIV seroconversion and with at least two CD4 measurements prior to initiating cART. For each patient, a pre-cART CD4 slope was estimated using a linear mixed effects model. Our primary outcome was time from initiating cART to a first new AIDS event or death. We included 2,820 treatment-naïve patients initiating cART with a median (interquartile range) pre-cART CD4 cell decline of 61 (46–81) cells/µl per year; 255 patients subsequently experienced a new AIDS event or death and 125 patients died. In an analysis adjusted for established risk factors, the hazard ratio for AIDS or death was 1.01 (95% confidence interval 0.97–1.04) for each 10 cells/µl per year reduction in pre-cART CD4 cell decline. There was also no association between pre-cART CD4 cell slope and survival. Alternative estimates of CD4 cell slope gave similar results. In 1,731 AIDS-free patients with >350 CD4 cells/µl from the pre-cART era, the rate of CD4 cell decline was also not significantly associated with progression to AIDS or death (hazard ratio 0.99, 95% confidence interval 0.94–1.03, for each 10 cells/µl per year reduction in CD4 cell decline).
Conclusions
The CD4 cell slope does not improve the prediction of clinical outcome in patients with a CD4 cell count above 350 cells/µl. Knowledge of the current CD4 cell count is sufficient when deciding whether to initiate cART in asymptomatic patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
More than 30 million people are currently infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). Most people who become infected with HIV do not become ill immediately although some develop a short flu-like illness shortly after infection. This illness is called “seroconversion” illness because it coincides with the appearance of antibodies to HIV in the blood. The next stage of HIV infection has no major symptoms and may last up to 10 years. During this time, HIV slowly destroys immune system cells (including CD4 cells, a type of lymphocyte). Without treatment, the immune system loses the ability to fight off infections by other disease-causing organisms and HIV-positive people then develop so-called opportunistic infections, Kaposi sarcoma (a skin cancer), or non-Hodgkin lymphoma (a cancer of the lymph nodes) that determine the diagnosis of AIDS. Although HIV-positive people used to die within 10 years of infection on average, the development in 1996 of combination antiretroviral therapy (cART; cocktails of powerful antiretroviral drugs) means that, at least for people living in developed countries, HIV/AIDS is now a chronic, treatable condition.
Why Was This Study Done?
The number of CD4 cells in the blood is a strong predictor of the likelihood of AIDS or death in untreated HIV-positive individuals and in people starting cART. Current guidelines recommend, therefore, that cART is started in HIV-positive patients without symptoms when their CD4 cell count drops below a specified cutoff level (typically 350 cells/µl.) In addition, several guidelines suggest that clinicians should also consider cART in symptom-free HIV-positive patients with a CD4 cell count above the cutoff level if their CD4 cell count has rapidly declined. However, it is not actually known whether the rate of CD4 cell decline (so-called “CD4 slope”) before initiating cART is related to a patient's outcome, so should clinicians consider this measurement when deciding whether to initiate cART? In this study, the researchers use data from CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe), a large collaborative study of 23 groups of HIV-positive individuals whose approximate date of HIV infection is known, to answer this question.
What Did the Researchers Do and Find?
The researchers undertook survival analyses of patients in the CASCADE collaboration for whom at least two CD4 cell counts had been recorded before starting cART. They calculated a pre-cART CD4 cell count slope from these counts and used statistical methods to investigate whether there was an association between the rate of decline in CD4 cell count and the time from initiating cART to the primary outcome—a first new AIDS-defining event or death. 2820 HIV-positive patients initiating cART were included in the study; the average pre-cART CD4 cell decline among them was 61 cells/µl/year. 255 of the patients experienced a new AIDS-related event or died after starting cART but the researchers found no evidence for an association between the primary outcome and the pre-cART CD4 slope or between survival and this slope. In addition, the rate of CD4 cell count decline was not significantly associated with progression to AIDS or death among 1731 HIV-positive, symptom-free patients with CD4 cell counts above 350 cells/µl who were studied before cART was developed.
What Do These Findings Mean?
These findings suggest that knowledge of the rate of CD4 cell count decline will not improve the prediction of clinical outcome in HIV-positive patients with a CD4 cell count above 350 cells/µl. Indeed, the findings show that the rate of CD4 cell decline in individual patients is highly variable over time. Consequently, a rate measured at one time cannot be used to reliably predict a patient's future CD4 cell count. Because this was an observational study, patients with the greatest rate of decline in their CD4 cell count might have received better care than other patients, a possibility that would lessen the effect of the rate of CD4 cell count decline on outcomes. Nevertheless, the findings of this study strongly suggest that knowledge of the current CD4 cell count and an assessment of other established risk factors for progression to AIDS are sufficient when deciding whether to initiate cART in symptom-free HIV-positive patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000239.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including information on treatments and treatment guidelines
Information is available from Avert, an international AIDS charity, on all aspects of HIV/AIDS, including information on treatments for HIV and AIDS, when to start treatment, and the stages of HIV infection (in English and Spanish)
Information on CASCADE is available
doi:10.1371/journal.pmed.1000239
PMCID: PMC2826377  PMID: 20186270
2.  Mass HIV Treatment and Sex Disparities in Life Expectancy: Demographic Surveillance in Rural South Africa 
PLoS Medicine  2015;12(11):e1001905.
Background
Women have better patient outcomes in HIV care and treatment than men in sub-Saharan Africa. We assessed—at the population level—whether and to what extent mass HIV treatment is associated with changes in sex disparities in adult life expectancy, a summary metric of survival capturing mortality across the full cascade of HIV care. We also determined sex-specific trends in HIV mortality and the distribution of HIV-related deaths in men and women prior to and at each stage of the clinical cascade.
Methods and Findings
Data were collected on all deaths occurring from 2001 to 2011 in a large population-based surveillance cohort (52,964 women and 45,688 men, ages 15 y and older) in rural KwaZulu-Natal, South Africa. Cause of death was ascertained by verbal autopsy (93% response rate). Demographic data were linked at the individual level to clinical records from the public sector HIV treatment and care program that serves the region. Annual rates of HIV-related mortality were assessed for men and women separately, and female-to-male rate ratios were estimated in exponential hazard models. Sex-specific trends in adult life expectancy and HIV-cause-deleted adult life expectancy were calculated. The proportions of HIV deaths that accrued to men and women at different stages in the HIV cascade of care were estimated annually.
Following the beginning of HIV treatment scale-up in 2004, HIV mortality declined among both men and women. Female adult life expectancy increased from 51.3 y (95% CI 49.7, 52.8) in 2003 to 64.5 y (95% CI 62.7, 66.4) in 2011, a gain of 13.2 y. Male adult life expectancy increased from 46.9 y (95% CI 45.6, 48.2) in 2003 to 55.9 y (95% CI 54.3, 57.5) in 2011, a gain of 9.0 y. The gap between female and male adult life expectancy doubled, from 4.4 y in 2003 to 8.6 y in 2011, a difference of 4.3 y (95% CI 0.9, 7.6). For women, HIV mortality declined from 1.60 deaths per 100 person-years (95% CI 1.46, 1.75) in 2003 to 0.56 per 100 person-years (95% CI 0.48, 0.65) in 2011. For men, HIV-related mortality declined from 1.71 per 100 person-years (95% CI 1.55, 1.88) to 0.76 per 100 person-years (95% CI 0.67, 0.87) in the same period. The female-to-male rate ratio for HIV mortality declined from 0.93 (95% CI 0.82–1.07) in 2003 to 0.73 (95% CI 0.60–0.89) in 2011, a statistically significant decline (p = 0.046). In 2011, 57% and 41% of HIV-related deaths occurred among men and women, respectively, who had never sought care for HIV in spite of the widespread availability of free HIV treatment. The results presented here come from a poor rural setting in southern Africa with high HIV prevalence and high HIV treatment coverage; broader generalizability is unknown. Additionally, factors other than HIV treatment scale-up may have influenced population mortality trends.
Conclusions
Mass HIV treatment has been accompanied by faster declines in HIV mortality among women than men and a growing female–male disparity in adult life expectancy at the population level. In 2011, over half of male HIV deaths occurred in men who had never sought clinical HIV care. Interventions to increase HIV testing and linkage to care among men are urgently needed.
Jacob Bor and colleagues use demographic data from a longitudinal surveillance cohort to identify increased gains in life expectancy among women compared to men in the years following antiretroviral therapy scale-up in rural South Africa.
Editors' Summary
Background.
AIDS has killed 39 million people over the past three decades, and about 35 million people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the retrovirus that causes AIDS. HIV destroys immune system cells, leaving HIV-positive individuals susceptible to other serious infections. Early in the AIDS epidemic, most HIV-positive individuals died within ten years of infection. Then, in 1996, effective antiretroviral therapy (ART) became available. For people living in high-income countries, HIV infection became a chronic condition, but HIV/AIDS remained largely untreated and fatal in resource-limited countries. In 2003, the international community began to work towards achieving universal access to ART. Now, at least a third of people living with HIV have access to ART, the global rate of AIDS-related deaths has fallen by more than a third from its 2005 peak, and the life expectancy (how long a person is likely to live based on their year of their birth, their current age, and other demographic factors) of HIV-positive adults has markedly increased.
Why Was This Study Done?
Although ART has been provided without charge to patients in South African public clinics since 2004, HIV/AIDS remains the leading cause of death in many parts of South Africa. Reducing the lingering burden of HIV mortality is a policy priority. Prior studies have found worse outcomes among men in HIV care and treatment. Here, the researchers assess the evolution of sex disparities in life expectancy and HIV mortality rates at the population level with the scale-up of ART in a rural region of KwaZulu-Natal, South Africa, where 29% of the population is HIV-positive. Different trends in life expectancy for men and women following ART scale-up may reflect differences in the underlying burden of HIV disease—women tend to be infected and die at younger ages—as well as differences in access to HIV testing, care, and treatment. The researchers also assess where in the cascade of HIV care and treatment HIV mortality occurs for men and women. Knowing more about sex-specific trends in population life expectancy and where the lingering burden of HIV mortality occurs could help experts design strategies to further reduce HIV mortality in regions where free ART is widely available.
What Did the Researchers Do and Find?
The researchers linked demographic data obtained through regular household surveys, including all deaths occurring between 2001 and 2011, for nearly 100,000 adults living in rural KwaZulu-Natal to clinical records held by the public sector HIV treatment and care program. In addition, trained nurses visited households where there had been a death and collected data that were used to determine the probable cause of death (verbal autopsy). Analysis of these data indicated that, between 2003 and 2011, female adult life expectancy increased by 13.2 years (from 51.3 years to 64.5 years), whereas male life expectancy increased by only 9 years (from 46.9 years to 55.9 years). Thus, the gap between female and male adult life expectancy doubled between 2003 and 2011. Moreover, although HIV-related mortality among women and men was similar in 2003, in 2011 women were 27% less likely to die from HIV than men. With the scale-up of ART, male sex has emerged as a risk factor for HIV mortality at the population level. Finally, in 2011, 55% of all male HIV-related deaths and 40% of all female HIV-related deaths occurred among men and women who had never sought care for HIV/AIDS.
What Do These Findings Mean?
These findings suggest that although the mass provision of free ART in South Africa has coincided with a reduction in HIV-related mortality among both men and women, ART scale-up has been accompanied by faster declines in HIV-related deaths among women than men and by a growing female–male disparity in adult life expectancy. Notably, these findings also indicate that despite the wide availability of ART, about half of all HIV-related deaths in the study population occurred among people who had never sought care for HIV. The use of verbal autopsy to determine the probable cause of death may limit the accuracy of these findings, and factors other than the scale-up of ART may have influenced the population mortality trends. Moreover, these findings may not be generalizable to other populations. However, these results highlight the need for further research to understand why men are not as likely as women to seek and adhere to HIV care and treatment, and to design effective interventions to increase the uptake of HIV services among men. Without better outreach to men, the researchers conclude, the full benefits of mass ART provision will not be realized.
Additional Information.
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001905.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on universal access to ART and on HIV/AIDS in South Africa; Avert also provides personal stories about living with HIV/AIDS
The World Health Organization (WHO) provides information on all aspects of HIV/AIDS (in several languages), including its Consolidated Guidelines on the Use of Antiretroviral Therapy for Treating and Preventing HIV Infection and information on the WHO/UNAIDS Treatment 2.0 strategy, an initiative to expand access to HIV testing and ART
The UNAIDS Fast-Track Strategy to End the AIDS Epidemic by 2030 provides up-to-date information about the AIDS epidemic and efforts to halt it, including progress towards universal access to antiretroviral therapy; UNAIDS also provides detailed information about HIV/AIDS in South Africa
More information about the population-based surveillance cohort that provided the data for this study is available from the Africa Centre for Population Health website
doi:10.1371/journal.pmed.1001905
PMCID: PMC4658174  PMID: 26599699
3.  Gender Differences in Survival among Adult Patients Starting Antiretroviral Therapy in South Africa: A Multicentre Cohort Study 
PLoS Medicine  2012;9(9):e1001304.
Morna Cornell and colleagues investigate differences in mortality for HIV-positive men and women on antiretroviral therapy in South Africa.
Background
Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART.
Methods and Findings
Analyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population.
Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22–1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12–1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86–1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located.
Conclusions
HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
About 34 million people (most living in low- and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of becoming infected. Then, in 1996, antiretroviral therapy (ART)—cocktails of drugs that keep HIV in check—became available. For people living in affluent countries, HIV/AIDS became a chronic condition. However, ART was expensive and, for people living in poorer countries, HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global emergency, and governments and international agencies began to implement plans to increase ART coverage in resource-limited countries. Since then, ART programs in these countries have grown rapidly. In South Africa, for example, about 52% of the 3.14 million adults in need of ART were receiving an ART regimen recommended by the World Health Organization by the end of 2010.
Why Was This Study Done?
The outcomes of ART programs in resource-limited countries need to be evaluated thoroughly so that these programs can be optimized. One area of concern to ART providers is that of gender differences in survival among patients receiving treatment. In sub-Saharan Africa, for example, men are more likely to die than women while receiving ART. This gender difference in mortality may arise because men initiating ART in many African ART programs have more advanced HIV disease than women (early ART initiation is associated with better outcomes than late initiation) or because men are more likely to be lost to follow-up than women (failure to continue treatment is associated with death). Other possible explanations for gender differentials in mortality on ART include gender differences in immunologic and virologic responses to treatment (increased numbers of immune system cells and reduced amounts of virus in the blood, respectively). In this multicenter cohort study, the researchers examine the size of, and risk factors for, gender differences in mortality on ART in South Africa by examining data collected from adults starting ART at International Epidemiologic Databases to Evaluate AIDS South Africa (IeDEA-SA) collaboration sites.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 46,201 ART-naïve adults who started ART between 2002 and 2009 in eight IeDEA-SA ART programs. At ART initiation, men had a lower CD4 count on average and were more likely to have advanced HIV disease than women. During the study, after allowing for factors likely to affect mortality such as HIV disease stage at initiation, men on ART had a 31% higher risk of dying than women. Men were more likely to be lost to follow-up than women, but men and women who were lost to follow-up were equally likely to die. Women had a slightly better immunological response to ART than men but virologic suppression was similar in both genders. Importantly, in analyses of mortality limited to individuals who were virologically suppressed at 12 months and to patients who had a good immunological response to ART, men still had a higher risk of death than women. However, the gender differences in mortality on ART were smaller than the gender differences in age-standardized mortality in the HIV-negative South African population.
What Do These Findings Mean?
These analyses show that among South African patients initiating ART between 2002 and 2009, men were more likely to die than women but that this gender difference in mortality on ART cannot be completely explained by gender differences in baseline characteristics, loss to follow-up, or virologic and/or immunologic responses. Instead, the observed gender differences in mortality can best be explained by background gender differences in mortality in the whole South African population. Because substantial amounts of data were missing in this study (for example, HIV disease stage was not available for all the patients), these findings need to be interpreted cautiously. Moreover, similar studies need to be done in other settings to investigate whether they are generalizable to the South African national ART program and to other countries. If confirmed, however, these findings suggest that the root causes of gender differences in mortality on ART may be unrelated to HIV/AIDS or to the characteristics of ART programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001304.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information on the treatment of HIV/AIDS in South Africa is available from the Southern African HIV Clinicians Society
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care, and on HIV/AIDS in South Africa (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in several languages); its 2010 ART guidelines can be downloaded
Information about the IeDEA-SA collaboration is available
The Treatment Action Campaign provides information on antiretroviral therapy and South African HIV statistics
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs
doi:10.1371/journal.pmed.1001304
PMCID: PMC3433409  PMID: 22973181
4.  Mortality of HIV-Infected Patients Starting Antiretroviral Therapy in Sub-Saharan Africa: Comparison with HIV-Unrelated Mortality 
PLoS Medicine  2009;6(4):e1000066.
Comparing mortality rates between patients starting HIV treatment and the general population in four African countries, Matthias Egger and colleagues find the gap decreases over time, especially with early treatment.
Background
Mortality in HIV-infected patients who have access to highly active antiretroviral therapy (ART) has declined in sub-Saharan Africa, but it is unclear how mortality compares to the non-HIV–infected population. We compared mortality rates observed in HIV-1–infected patients starting ART with non-HIV–related background mortality in four countries in sub-Saharan Africa.
Methods and Findings
Patients enrolled in antiretroviral treatment programmes in Côte d'Ivoire, Malawi, South Africa, and Zimbabwe were included. We calculated excess mortality rates and standardised mortality ratios (SMRs) with 95% confidence intervals (CIs). Expected numbers of deaths were obtained using estimates of age-, sex-, and country-specific, HIV-unrelated, mortality rates from the Global Burden of Disease project. Among 13,249 eligible patients 1,177 deaths were recorded during 14,695 person-years of follow-up. The median age was 34 y, 8,831 (67%) patients were female, and 10,811 of 12,720 patients (85%) with information on clinical stage had advanced disease when starting ART. The excess mortality rate was 17.5 (95% CI 14.5–21.1) per 100 person-years SMR in patients who started ART with a CD4 cell count of less than 25 cells/µl and World Health Organization (WHO) stage III/IV, compared to 1.00 (0.55–1.81) per 100 person-years in patients who started with 200 cells/µl or above with WHO stage I/II. The corresponding SMRs were 47.1 (39.1–56.6) and 3.44 (1.91–6.17). Among patients who started ART with 200 cells/µl or above in WHO stage I/II and survived the first year of ART, the excess mortality rate was 0.27 (0.08–0.94) per 100 person-years and the SMR was 1.14 (0.47–2.77).
Conclusions
Mortality of HIV-infected patients treated with combination ART in sub-Saharan Africa continues to be higher than in the general population, but for some patients excess mortality is moderate and reaches that of the general population in the second year of ART. Much of the excess mortality might be prevented by timely initiation of ART.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981 and more than 30 million people (22 million in sub-Saharan Africa alone) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-positive people died within ten years of infection. Then, in 1996, highly active antiretroviral therapy (ART)—combinations of powerful antiretroviral drugs—was developed and the life expectancy of HIV-infected people living in affluent countries improved dramatically. Now, in industrialized countries, all-cause mortality (death from any cause) among HIV-infected patients treated successfully with ART is similar to that of the general population and the mortality rate (the number of deaths in a population per year) among patients with HIV/AIDS is comparable to that among patients with diabetes and other chronic conditions.
Why Was This Study Done?
Unfortunately, combination ART is costly, so although HIV/AIDS quickly became a chronic disease in industrialized countries, AIDS deaths continued unabated among the millions of HIV-infected people living in low- and middle-income countries. Then, in 2003, governments, international agencies and funding bodies began to implement plans to increase ART coverage in developing countries. By the end of 2007, nearly three million people living with HIV/AIDS in these countries were receiving ART—nearly a third of the people who urgently need ART. In sub-Saharan Africa more than 2 million people now receive ART and mortality in HIV-infected patients who have access to ART is declining. However, no-one knows how mortality among HIV-infected people starting ART compares with non-HIV related mortality in sub-Saharan Africa. This information is needed to ensure that appropriate health services (including access to ART) are provided in this region. In this study, the researchers compare mortality rates among HIV-infected patients starting ART with non-HIV related mortality in the general population of four sub-Saharan countries.
What Did the Researchers Do and Find?
The researchers obtained estimates of the number of HIV-unrelated deaths and information about patients during their first two years on ART at five antiretroviral treatment programs in the Côte d'Ivoire, Malawi, South Africa, and Zimbabwe from the World Health Organization Global Burden of Disease (GBD) project and the International epidemiological Databases to Evaluate AIDS (IeDEA) initiative, respectively. They then calculated the excess mortality rates among the HIV-infected patients (the death rates in HIV-infected patients minus the national HIV-unrelated death rates) and the standardized mortality rate (SMR; the number of deaths among HIV-infected patients divided by the number of HIV-unrelated deaths in the general population). The excess mortality rate among HIV-infected people who started ART when they had a low CD4 cell count and clinically advanced disease was 17.5 per 100 person-years of follow-up. For HIV-infected people who started ART with a high CD4 cell count and early disease, the excess mortality rate was 1.0 per 100 person-years. The SMRs over two years of ART for these two groups of HIV-infected patients were 47.1 and 3.4, respectively. Finally, patients who started ART with a high CD4 cell count and early disease who survived the first year of ART had an excess mortality of only 0.27 per 100 person-years and an SMR over two years follow-up of only 1.14.
What Do These Findings Mean?
These findings indicate that mortality among HIV-infected people during the first two years of ART is higher than in the general population in these four sub-Saharan countries. However, for patients who start ART when they have a high CD4 count and clinically early disease, the excess mortality is moderate and similar to that associated with diabetes. Because the researchers compared the death rates among HIV-infected patients with estimates of national death rates rather than with estimates of death rates for the areas where the ART programs were located, these findings may not be completely accurate. Nevertheless, these findings support further expansion of strategies that increase access to ART in sub-Saharan Africa and suggest the excess mortality among HIV-infected patients in this region might be largely prevented by starting ART before an individual's HIV infection has progressed to advanced stages.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000066.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS including HIV and AIDS in Africa, providing AIDS drug treatment for millions, and on the stages of HIV infection
The World Health Organization provides information about universal access to HIV treatment and about the Global Burden of Disease project (in several languages)
More information about the International epidemiological Databases to evaluate AIDS initiative is available on the IeDEA Web site
doi:10.1371/journal.pmed.1000066
PMCID: PMC2667633  PMID: 19399157
5.  Cause-Specific Life Expectancies After 35 Years of Age for Human Immunodeficiency Syndrome-Infected and Human Immunodeficiency Syndrome-Negative Individuals Followed Simultaneously in Long-term Cohort Studies, 1984–2008 
American Journal of Epidemiology  2013;177(2):116-125.
Parametric and semiparametric competing risks methods were used to estimate proportions, timing, and predictors of acquired immune deficiency syndrome (AIDS)-related and non-AIDS-related mortality among individuals both positive and negative for the human immunodeficiency syndrome (HIV) in the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) from 1984 to 2008 and 1996 to 2008, respectively. Among HIV-positive MACS participants, the proportion of deaths unrelated to AIDS increased from 6% before the introduction of highly active antiretroviral therapy (HAART) (before 1996) to 53% in the HAART era (P < 0.01); the median age of persons who died from non-AIDS-related causes after age 35 years increased from 49.0 to 66.0 years (P < 0.01). In both cohorts during the HAART era, median ages at time of non-AIDS-related death were younger for HIV-positive individuals than for comparable HIV-negative individuals (8.7 years younger in MACS (P < 0.01) and 7.6 years younger in WIHS (P < 0.01)). In a multivariate proportional cause-specific hazards model, unemployment (for non-AIDS death, hazard ratio (HR) = 1.8; for AIDS death, HR = 2.3), depression (for non-AIDS death, HR = 1.4; for AIDS death, HR = 1.4), and hepatitis B or C infection (for non-AIDS death, HR = 1.8, for AIDS death; HR = 1.4) were significantly (P < 0.05) associated with higher hazards of both non-AIDS and AIDS mortality among HIV-positive individuals in the HAART era, independent of study cohort. The results illuminate the changing face of mortality among the growing population infected with HIV.
doi:10.1093/aje/kws321
PMCID: PMC3590031  PMID: 23287403
acquired immunodeficiency syndrome; antiretroviral therapy, highly active; cohort studies; competing risks; HIV; mixture model; mortality; proportional hazards models
6.  Incident HIV during Pregnancy and Postpartum and Risk of Mother-to-Child HIV Transmission: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(2):e1001608.
Alison Drake and colleagues conduct a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy and the postpartum period and to compare mother-to-child HIV transmission risk among women with incident versus chronic infection.
Please see later in the article for the Editors' Summary
Background
Women may have persistent risk of HIV acquisition during pregnancy and postpartum. Estimating risk of HIV during these periods is important to inform optimal prevention approaches. We performed a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy/postpartum and to compare mother-to-child HIV transmission (MTCT) risk among women with incident versus chronic infection.
Methods and Findings
We searched PubMed, Embase, and AIDS-related conference abstracts between January 1, 1980, and October 31, 2013, for articles and abstracts describing HIV acquisition during pregnancy/postpartum. The inclusion criterion was studies with data on recent HIV during pregnancy/postpartum. Random effects models were constructed to pool HIV incidence rates, cumulative HIV incidence, hazard ratios (HRs), or odds ratios (ORs) summarizing the association between pregnancy/postpartum status and HIV incidence, and MTCT risk and rates. Overall, 1,176 studies met the search criteria, of which 78 met the inclusion criterion, and 47 contributed data. Using data from 19 cohorts representing 22,803 total person-years, the pooled HIV incidence rate during pregnancy/postpartum was 3.8/100 person-years (95% CI 3.0–4.6): 4.7/100 person-years during pregnancy and 2.9/100 person-years postpartum (p = 0.18). Pooled cumulative HIV incidence was significantly higher in African than non-African countries (3.6% versus 0.3%, respectively; p<0.001). Risk of HIV was not significantly higher among pregnant (HR 1.3, 95% CI 0.5–2.1) or postpartum women (HR 1.1, 95% CI 0.6–1.6) than among non-pregnant/non-postpartum women in five studies with available data. In African cohorts, MTCT risk was significantly higher among women with incident versus chronic HIV infection in the postpartum period (OR 2.9, 95% CI 2.2–3.9) or in pregnancy/postpartum periods combined (OR 2.3, 95% CI 1.2–4.4). However, the small number of studies limited power to detect associations and sources of heterogeneity.
Conclusions
Pregnancy and the postpartum period are times of persistent HIV risk, at rates similar to “high risk” cohorts. MTCT risk was elevated among women with incident infections. Detection and prevention of incident HIV in pregnancy/postpartum should be prioritized, and is critical to decrease MTCT.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.4 million children younger than 15 years old (mostly living in sub-Saharan Africa) are infected with HIV, the virus that causes AIDS by gradually destroying immune system cells, thereby leaving infected individuals susceptible to other serious infections. In 2012 alone, 230,000 children (more than 700 every day) were newly infected with HIV. Most HIV infections among children are the result of mother-to-child HIV transmission (MTCT) during pregnancy, delivery, or breastfeeding. The rate of MTCT (and deaths among HIV-positive pregnant women from complications related to HIV infection) can be greatly reduced by testing women for HIV infection during pregnancy (antenatal HIV testing), treating HIV-positive women with antiretroviral drugs (ARVs, powerful drugs that control HIV replication and allow the immune system to recover) during pregnancy, delivery, and breastfeeding, and giving ARVs to their newborn babies.
Why Was This Study Done?
The World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have developed a global plan that aims to move towards eliminating new HIV infections among children by 2015 and towards keeping their mothers alive. To ensure the plan's success, the incidence of HIV (the number of new infections) among women and the rate of MTCT must be reduced by increasing ARV uptake by mothers and their infants for the prevention of MTCT. However, the risk of HIV infection among pregnant women and among women who have recently given birth (postpartum women) is poorly understood because, although guidelines recommend repeat HIV testing during late pregnancy or at delivery in settings where HIV infection is common, pregnant women are often tested only once for HIV infection. The lack of retesting represents a missed opportunity to identify pregnant and postpartum women who have recently acquired HIV and to prevent MTCT by initiating ARV therapy. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a study that uses statistical methods to combine the results of several studies), the researchers estimate maternal HIV incidence during pregnancy and the postpartum period, and compare the risk of MTCT among women with incident (new) and chronic (long-standing) HIV infection.
What Did the Researchers Do and Find?
The researchers identified 47 studies (35 undertaken in Africa) that examined recent HIV acquisition by women during pregnancy and the 12-month postpartum period. They used random effects statistical models to estimate the pooled HIV incidence rate and cumulative HIV incidence (the number of new infections per number of people at risk), and the association between pregnancy/postpartum status and HIV incidence and MTCT risk and rates. The pooled HIV incidence rate among pregnant/postpartum women estimated from 19 studies (all from sub-Saharan Africa) that reported HIV incidence rates was 3.8/100 person-years. The pooled cumulative HIV incidence was significantly higher in African countries than in non-African countries (3.6% and 0.3%, respectively; a “significant” difference is one that is unlikely to arise by chance). In the five studies that provided suitable data, the risk of HIV acquisition was similar in pregnant, postpartum, and non-pregnant/non-postpartum women. Finally, among African women, the risk of MTCT was 2.9-fold higher during the postpartum period among those who had recently acquired HIV than among those with chronic HIV infection, and 2.3-fold higher during the pregnancy/postpartum periods combined.
What Do These Findings Mean?
These results suggest that women living in regions where HIV infection is common are at high risk of acquiring HIV infection during pregnancy and the postpartum period and that mothers who acquire HIV during pregnancy or postpartum are more likely to pass the infection on to their offspring than mothers with chronic HIV infections. However, the small number of studies included in this meta-analysis and the use of heterogeneous research methodologies in these studies may limit the accuracy of these findings. Nevertheless, these findings have important implications for the global plan to eliminate HIV infections in children. First, they suggest that women living in regions where HIV infection is common should be offered repeat HIV testing (using sensitive methods to enhance early detection of infection) during pregnancy and in the postpartum period to detect incident HIV infections, and should be promptly referred to HIV care and treatment. Second, they suggest that prevention of HIV transmission during pregnancy and postpartum should be prioritized, for example, by counseling women about the need to use condoms to prevent transmission during this period of their lives.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001608.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children and HIV/AIDS and on the prevention of mother-to-child transmission of HIV (in English and Spanish)
The 2013 UNAIDS World AIDS Day Report provides information about the AIDS epidemic and efforts to halt it; the 2013 UNAIDS Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children; the UNAIDS Believe it. Do it website provides information about the campaign to support the UNAIDS global plan
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, NAM/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001608
PMCID: PMC3934828  PMID: 24586123
7.  CD4 Cell Count and the Risk of AIDS or Death in HIV-Infected Adults on Combination Antiretroviral Therapy with a Suppressed Viral Load: A Longitudinal Cohort Study from COHERE 
PLoS Medicine  2012;9(3):e1001194.
Using data from the Collaboration of Observational HIV Epidemiological Research Europe, Jim Young and colleagues show that in successfully treated patients the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression.
Background
Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load.
Methods and Findings
Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements <50 copies/µl and ending with either a measurement >500 copies/µl, the first of two consecutive measurements between 50–500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30–0.40) for counts <200 cells/µl, 0.81 (0.71–0.92) for counts 200 to <350 cells/µl, 0.74 (0.66–0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92–0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl.
Conclusions
Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 34 million people are infected with HIV and every year nearly 3 million people are newly infected with this virus, which causes AIDS. Most people do not become ill immediately after infection with HIV although some develop a short, flu-like illness (a “seroconversion” illness). The next stage of HIV infection, which may last up to 10 years, also has no major symptoms but, during this stage, HIV slowly destroys immune system cells (including CD4 cells, a type of lymphocyte). Eventually, the immune system can no longer fight off infections by other disease-causing organisms and HIV-positive people then develop one or more AIDS-defining condition(s), including severe but unusual infections, Kaposi sarcoma (a skin cancer), and non-Hodgkin lymphoma (a cancer of the lymph nodes). Many of these AIDS-defining conditions are life-threatening and, in the past, HIV-positive people died on average within 10 years of infection. Nowadays, although there is still no cure for HIV infection, combination antiretroviral therapy (cART; a cocktail of powerful antiretroviral drugs) has turned HIV/AIDS into a chronic, treatable condition, at least in developed countries.
Why Was This Study Done?
Most HIV-positive adults achieve viral suppression within a year of starting cART. That is, the number of copies of the virus in their blood drops to below 50 copies/ml. But what is the likely clinical outcome for patients who achieve viral suppression and what is their risk of developing a new AIDS-defining condition or of dying? For people starting cART for the first time, the number of CD4 cells in the blood when cART is initiated provides a strong indication of an individual's likely clinical outcome. Specifically, people who start cART when they have a high CD4 cell count tend to do better than people who start treatment when they have a low CD4 cell count. In this study, the researchers use data collected by the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) to estimate the association between CD4 cell count and progression to a new AIDS-defining event or death among patients who have achieved viral suppression while on cART.
What Did the Researchers Do and Find?
The researchers identified more than 75,000 patients in the COHERE database who, between them, had had more than 104,000 episodes (periods) of viral suppression while on cART and who had had their CD4 cell count determined shortly before or during their viral suppression episodes. The researchers then used stratified multivariate Cox models (a type of statistical analysis method) to estimate the association between CD4 cell counts and the occurrence of a new AIDS-defining event or death. Among the patients included in the study, the mortality (death) rate was 4.8 per 1,000 years of viral suppression. The highest rates of new AIDS-defining events or death were seen in those patients with less than 50 CD4 cells/µl blood and a higher CD4 cell count was associated with a reduced risk of a new AIDS-defining event or death. Finally, among those patients with a CD4 cell count below 200 cells/µl, the risk of progression decreased over time for those patients with higher CD4 cell counts.
What Do These Findings Mean?
These findings suggest that, although new AIDS-defining events and death are uncommon among patients whose viral load is suppressed by cART, the risk of a new AIDS-defining event or death follows a CD4 cell count gradient with the patients with the highest CD4 cell counts having the lowest risk of a new AIDS-defining event or death. The findings also suggest that higher CD4 cell counts provide the greatest benefit for patients with a CD4 cell count below 200 cells/µl blood. These findings have two main clinical implications. First, they add to the evidence that suggests that, to facilitate immune system recovery, cART should be started when a patient's CD4 cell count is between 350 and 500 cells/µl blood, the current recommended range for cART initiation. Unfortunately, most patients in resource-limited settings only start cART when their CD4 cell count is below 200 cells/µl. Second, these findings suggest that patients with sustained viral suppression but low CD4 cell counts should be monitored regularly to ensure that any life-threatening AIDS-defining events are dealt with quickly and effectively.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001194.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including detailed information on HIV treatment and care (in English and Spanish)
The World Health Organization's 2010 antiretroviral therapy guidelines provide recommendations on when to initiate cART
Information about COHERE is available
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001194
PMCID: PMC3308938  PMID: 22448150
8.  Estimating Incidence from Prevalence in Generalised HIV Epidemics: Methods and Validation 
PLoS Medicine  2008;5(4):e80.
Background
HIV surveillance of generalised epidemics in Africa primarily relies on prevalence at antenatal clinics, but estimates of incidence in the general population would be more useful. Repeated cross-sectional measures of HIV prevalence are now becoming available for general populations in many countries, and we aim to develop and validate methods that use these data to estimate HIV incidence.
Methods and Findings
Two methods were developed that decompose observed changes in prevalence between two serosurveys into the contributions of new infections and mortality. Method 1 uses cohort mortality rates, and method 2 uses information on survival after infection. The performance of these two methods was assessed using simulated data from a mathematical model and actual data from three community-based cohort studies in Africa. Comparison with simulated data indicated that these methods can accurately estimates incidence rates and changes in incidence in a variety of epidemic conditions. Method 1 is simple to implement but relies on locally appropriate mortality data, whilst method 2 can make use of the same survival distribution in a wide range of scenarios. The estimates from both methods are within the 95% confidence intervals of almost all actual measurements of HIV incidence in adults and young people, and the patterns of incidence over age are correctly captured.
Conclusions
It is possible to estimate incidence from cross-sectional prevalence data with sufficient accuracy to monitor the HIV epidemic. Although these methods will theoretically work in any context, we have able to test them only in southern and eastern Africa, where HIV epidemics are mature and generalised. The choice of method will depend on the local availability of HIV mortality data.
Timothy Hallett and colleagues develop and test two user-friendly methods to estimate HIV incidence based on changes in cross-sectional prevalence, using either mortality rates or survival after infection.
Editors' Summary
Background.
More than 25 million people have died from AIDS and about 33 million people are currently infected with human immunodeficiency virus (HIV, the virus that causes AIDS). Faced with this threat to human health, governments and international agencies are working together to halt the AIDS epidemic. An important part of this effort is HIV surveillance. The spread of HIV needs to be monitored to assess the impact of interventions (for example, the provision of antiretroviral drugs) and to plan for current and future health care needs. HIV surveillance in countries where the epidemic has spread beyond specific groups into the whole population (a generalized epidemic) has mainly relied on determining the prevalence of HIV infection (the fraction of the population that is infected) among women attending antenatal clinics. Recently, however, household health surveys (for example, the Demographic and Health Surveys) have begun to use blood testing for antibodies to the AIDS virus (serological testing) to provide more accurate estimates of HIV prevalence in the general adult population.
Why Was This Study Done?
Although prevalence estimates provide useful information about the HIV epidemic, another important indicator is incidence—the number of new infections occurring during a specific time period. Incidence measurements provide more information about temporal changes in the epidemic and transmission patterns and allow public-health experts to make better predictions of future health care needs. But, whereas prevalence can be measured with anonymized serological surveys, individuals would have to be identified and followed up in repeat serological surveys to provide a direct measurement of incidence. This is expensive and hard to achieve in many settings. In this study, therefore, the researchers develop and validate two mathematical methods to estimate HIV incidence in generalized HIV epidemics from prevalence data.
What Did the Researchers Do and Find?
Changes in the fraction of the population living with HIV (prevalence) can occur not only because of changes in the rate of new infections (incidence), but also because mortality rates are much higher for infected individuals than others. The researchers' methods disentangle the contributions to HIV prevalence (as measured in serological surveys) made by new infections from those due to deaths from AIDS and other causes. Their first method incorporates information on death rates collected in cohort studies of HIV infection (cohort studies investigate outcomes in groups of people); their second method uses information on survival after HIV infection, also collected in long-running cohort studies. The accuracy of both methods was assessed using computer-simulated data and actual data on HIV prevalence and incidence collected in three community-based cohort studies in Zimbabwe and Uganda (countries with generalized but declining HIV epidemics) and Tanzania (a country with a generalized, stable epidemic). Both methods provided accurate estimates of HIV incidence from the simulated data. Using the data collected in Africa, the mean difference between actual measurements of incidence and the estimate provided by method 1 was 19%; for method 2 it was 14%. In addition, the measured and estimated incidences were in good agreement for all age groups.
What Do These Findings Mean?
These findings suggest HIV incidence rates can be estimated from repeat surveys of prevalence with sufficient accuracy to monitor the HIV epidemic. The accuracy of the estimates across all age groups is particularly important because knowledge of the age-related risk pattern provides the information on transmission patterns that is needed to design effective intervention programs. Because these methods were tested using data only from southern and eastern Africa where the HIV epidemic is mature and generalized, they may not work as well in regions where the epidemic is restricted to subsets of the population. Other factors that might affect their accuracy include the amount of international migration and the uptake of antiretroviral therapies. Nevertheless, with the increased availability of serial measurements of serological prevalence, these new methods for estimating HIV incidence from HIV prevalence could prove extremely useful for monitoring the progress of national HIV epidemics and for guiding HIV control programs. The authors include spreadsheets that can be used to calculate incidence by either method from consecutive survey data.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050080.
The US National Institute of Allergy and Infectious Diseases provides information on HIV infection and AIDS
The US Centers for Disease Control and Prevention provides information on global HIV/AIDS topics (in English and Spanish)
The HIV InSite provides comprehensive and up-to-date information on all aspects of HIV/AIDS from the University of California San Francisco, including country reports on the AIDS epidemic in 195 countries, including Uganda, Zimbabwe, and Tanzania
Avert, an international AIDS charity, provides information on all aspects of HIV/AIDS, including fact sheets on understanding HIV and AIDS statistics, and on HIV and AIDS in Africa
The Demographic and Health Surveys program collects, analyzes, and disseminates information on health and population trends in countries around the world
doi:10.1371/journal.pmed.0050080
PMCID: PMC2288620  PMID: 18590346
9.  Emergence of Drug Resistance Is Associated with an Increased Risk of Death among Patients First Starting HAART 
PLoS Medicine  2006;3(9):e356.
Background
The impact of the emergence of drug-resistance mutations on mortality is not well characterized in antiretroviral-naïve patients first starting highly active antiretroviral therapy (HAART). Patients may be able to sustain immunologic function with resistant virus, and there is limited evidence that reduced sensitivity to antiretrovirals leads to rapid disease progression or death. We undertook the present analysis to characterize the determinants of mortality in a prospective cohort study with a median of nearly 5 y of follow-up. The objective of this study was to determine the impact of the emergence of drug-resistance mutations on survival among persons initiating HAART.
Methods and Findings
Participants were antiretroviral therapy naïve at entry and initiated triple combination antiretroviral therapy between August 1, 1996, and September 30, 1999. Marginal structural modeling was used to address potential confounding between time-dependent variables in the Cox proportional hazard regression models. In this analysis resistance to any class of drug was considered as a binary time-dependent exposure to the risk of death, controlling for the effect of other time-dependent confounders. We also considered each separate class of mutation as a binary time-dependent exposure, while controlling for the presence/absence of other mutations. A total of 207 deaths were identified among 1,138 participants over the follow-up period, with an all cause mortality rate of 18.2%. Among the 679 patients with HIV-drug-resistance genotyping done before initiating HAART, HIV-drug resistance to any class was observed in 53 (7.8%) of the patients. During follow-up, HIV-drug resistance to any class was observed in 302 (26.5%) participants. Emergence of any resistance was associated with mortality (hazard ratio: 1.75 [95% confidence interval: 1.27, 2.43]). When we considered each class of resistance separately, persons who exhibited resistance to non-nucleoside reverse transcriptase inhibitors had the highest risk: mortality rates were 3.02 times higher (95% confidence interval: 1.99, 4.57) for these patients than for those who did not exhibit this type of resistance.
Conclusions
We demonstrated that emergence of resistance to non-nucleoside reverse transcriptase inhibitors was associated with a greater risk of subsequent death than was emergence of protease inhibitor resistance. Future research is needed to identify the particular subpopulations of men and women at greatest risk and to elucidate the impact of resistance over a longer follow-up period.
Emergence of resistance to both non-nucleoside reverse transcriptase inhibitors and protease inhibitors was associated with a higher risk of subsequent death, but the risk was greater in patients with NNRTI-resistant HIV.
Editors' Summary
Background.
In the 1980s, infection with the human immunodeficiency virus (HIV) was effectively a death sentence. HIV causes AIDS (acquired immunodeficiency syndrome) by replicating inside immune system cells and destroying them, which leaves infected individuals unable to fight off other viruses and bacteria. The first antiretroviral drugs were developed quickly, but it soon became clear that single antiretrovirals only transiently suppress HIV infection. HIV mutates (accumulates random changes to its genetic material) very rapidly and, although most of these changes (or mutations) are bad for the virus, by chance some make it drug resistant. Highly active antiretroviral therapy (HAART), which was introduced in the mid-1990s, combines three or four antiretroviral drugs that act at different stages of the viral life cycle. For example, they inhibit the reverse transcriptase that the virus uses to replicate its genetic material, or the protease that is necessary to assemble new viruses. With HAART, the replication of any virus that develops resistance to one drug is inhibited by the other drugs in the mix. As a consequence, for many individuals with access to HAART, AIDS has become a chronic rather than a fatal disease. However, being on HAART requires patients to take several pills a day at specific times. In addition, the drugs in the HAART regimens often have side effects.
Why Was This Study Done?
Drug resistance still develops even with HAART, often because patients don't stick to the complicated regimens. The detection of resistance to one drug is usually the prompt to change a patient's drug regimen to head off possible treatment failure. Although most patients treated with HAART live for many years, some still die from AIDS. We don't know much about how the emergence of drug-resistance mutations affects mortality in patients who are starting antiretroviral therapy for the first time. In this study, the researchers looked at how the emergence of drug resistance affected survival in a group of HIV/AIDS patients in British Columbia, Canada. Here, everyone with HIV/AIDS has access to free medical attention, HAART, and laboratory monitoring, and full details of all HAART recipients are entered into a central reporting system.
What Did the Researchers Do and Find?
The researchers enrolled people who started antiretroviral therapy for the first time between August 1996 and September 1999 into the HAART Observational Medical Evaluation and Research (HOMER) cohort. They then excluded anyone who was infected with already drug-resistant HIV strains (based on the presence of drug-resistance mutations in viruses isolated from the patients) at the start of therapy. The remaining 1,138 patients were followed for an average of five years. All the patients received either two nucleoside reverse transcriptase inhibitors and a protease inhibitor, or two nucleoside and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Nearly a fifth of the study participants died during the follow-up period. Most of these patients actually had drug-sensitive viruses, possibly because they had neglected taking their drugs to such an extent that there had been insufficient drug exposure to select for drug-resistant viruses. In a quarter of the patients, however, HIV strains resistant to one or more antiretroviral drugs emerged during the study (again judged by looking for mutations). Detailed statistical analyses indicated that the emergence of any drug resistance nearly doubled the risk of patients dying, and that people carrying viruses resistant to NNRTIs were three times as likely to die as those without resistance to this class of antiretroviral drug.
What Do These Findings Mean?
These results provide new information about the emergence of drug-resistant HIV during HAART and possible effects on the long-term survival of patients. In particular, they suggest that clinicians should watch carefully for the emergence of resistance to NNRTIs in their patients. Because this type of resistance is often due to poor adherence to drug regimens, these results also suggest that increased efforts should be made to ensure that patients comply with the prescribed HAART regimens, especially those whose antiretroviral therapy includes NNRTIs. As with all studies in which a group of individuals who share a common characteristic are studied over time, it is possible that some other, unmeasured difference between the patients who died and those who didn't—rather than emerging drug resistance—is responsible for the observed differences in survival. Additional studies are needed to confirm the findings here, and to investigate whether specific subpopulations of patients are at particular risk of developing drug resistance and/or dying during HAART.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030356.
US National Institute of Allergy and Infectious Diseases fact sheet on HIV infection and AIDS
US Department of Health and Human Services information on AIDS, including details of approved drugs for the treatment of HIV infection
US Centers for Disease Control and Prevention information on HIV/AIDS
Aidsmap, information on HIV and AIDS provided by the charity NAM, which includes details on antiretroviral drugs
doi:10.1371/journal.pmed.0030356
PMCID: PMC1569883  PMID: 16984218
10.  Proceedings of The 8th Romanian National HIV/AIDS Congress and The 3rd Central European HIV Forum 
Alexiev, Ivailo | Dimitrova, Reneta | Gancheva, Anna | Kostadinova, Asya | Stoycheva, Mariyana | Nikolova, Daniela | Elenkov, Ivaylo | Tilișcan, Cătălin | Predescu, Mioara | Păunescu, Bogdan | Streinu-Cercel, Anca | Săndulescu, Oana | Șchiopu, Claudiu Mihai | Hristache, Mădălina | Brîndușe, Lăcrămioara Aurelia | Streinu-Cercel, Adrian | Todorovic, Marija | Siljic, Marina | Salemovic, Dubravka | Nikolic, Valentina | Pesic-Pavlovic, Ivana | Ranin, Jovan | Jevtovic, Djordje | Stanojevic, Maja | Tudor, Ana Maria | Vlad, Delia | Mărdărescu, Mariana | Petrea, Sorin | Petre, Cristina | Neagu-Drăghicenoiu, Ruxandra | Ungurianu, Rodica | Cibea, Alina | Chirilă, Odette | Anghelina, Cristian | Coserea, Ileana | Krikelli, Pantelia-Amalia | Pavlitina, Eirini | Psichogiou, Mina | Lamnisos, Demetris | Williams, Leslie | Korobchuk, Anya | Skaathun, Britt | Smyrnov, Pavlo | Schneider, John | Sypsa, Vana | Paraskevis, Dimitrios | Hatzakis, Angelos | Friedman, Samuel R. | Nikolopoulos, Georgios K. | Dragović, Gordana | Srdić, Danica | Khawla, Al Musalhi | Soldatović, Ivan | Nikolić, Jelena | Jevtović, Djordje | Nair, Devaki | Temereanca, Aura | Rosca, Adelina | Ene, Luminita | Soontornniyomkij, Benchawa | Diaconu, Carmen | Dita, Claudia | Achim, Cristian | Ruta, Simona | Benea, Șerban | Moroti, Ruxandra | Jipa, Raluca | Manea, Eliza | Stan, Andrada | Benea, Elisabeta | Oțelea, Dan | Hristea, Adriana | Hristea, Adriana | Lăpădat, Irina | Jipa, Raluca | Moroti, Ruxandra | Benea, Șerban | Antonică, Doina | Panait, Irina | Petre, Roxana | Kowalska, Justyna D. | Pietraszkiewicz, Ewa | Grycner, Ewa | Firlag-Burkacka, Ewa | Horban, Andrzej | Vlaicu, Ovidiu | Bănică, Leontina | Paraschiv, Simona | Tudor, Ana-Maria | Moroti, Ruxandra | Oțelea, Dan | Dimitrijević, Bojana | Soldatović, Ivan | Jevtović, Đorđe | Kusić, Jovana | Salemović, Dubravka | Ranin, Jovan | Dragović, Gordana | Florea, Dragoș | Bădicuț, Ioana | Rafila, Alexandru | Camburu, Cornel | Histrea, Adriana | Frățilă, Mihaela | Oțelea, Dan | Gmizic, Ivana | Salemovic, Dubravka | Pesic-Pavlovic, Ivana | Siljic, Marina | Nikolic, Valentina | Djonin-Nenezic, Miljana | Milosevic, Ivana | Brmbolic, Branko | Stanojevic, Maja | Streinu-Cercel, Anca | Săndulescu, Oana | Neguț, Alina Cristina | Predescu, Mioara | Mărdărescu, Alexandra | Săndulescu, Mihai | Streinu-Cercel, Adrian | Pérez, Ana Belen | Chueca, Natalia | Álvarez, Marta | Alados, Juan Carlos | Rivero, Antonio | Vera, Francisco | Delgado, Marcial | Salmeron, Javier | Jiménez, Miguel | Blanco, Maria José | Diago, Moises | Garcia-deltoro, Miguel | Alvarez, Marta | Téllez, Francisco | García, Federico | Tănase, Diana | Manea, Eliza | Bacruban, Rodica | Florea, Dragoș | Oțelea, Dan | Rafila, Alexandru | Mărdărescu, Mariana | Hristea, Adriana | Grgic, Ivana | Planinic, Ana | Santak, Maja | Gorenec, Lana | Lepej, Snjezana Zidovec | Vince, Adriana | Manea, Eliza | Hristea, Adriana | Benea, Șerban | Moroti, Ruxandra | Tănase, Diana | Niculae, Cristian M. | Merisor, Simona | Jipa, Raluca | Paraskevis, Dimitrios | Kostaki, Evangelia | Nikolopoulos, Georgios K. | Sypsa, Vana | Psichogiou, Mina | Paraskeva, Dimitra | Skoutelis, Athanassios | Malliori, Meni | Friedman, Samuel R. | Hatzakis, Angelos | Hackiewicz, Malgorzata | Zabek, Piotr | Firlag-Burkacka, Ewa | Horban, Andrzej | Kowalska, Justyna Dominika | Lunar, Maja M. | Mlakar, Jana | Poljak, Mario | Bănică, Leontina | Martin, Eliza | Gheorghiță, Valeriu | Petrescu, Andrei | Oțelea, Dan | Popescu, Costin-Ioan | Paraschiv, Simona | Neaga, Emil | Ovidiu, Vlaicu | Juncu, Andrei | Bănică, Leontina | Paraschiv, Simona | Oțelea, Dan | Popescu, Costin-Ioan | Luca, Adrian | Lazăr, Florin | Luca, Anca Elena | Ene, Luminița | Achim, Cristian | Gingăraş, Cosmina | Anton, Ștefan Adrian | Rădoi, Roxana | Tetradov, Simona | Țârdei, Grațiela | Nica, Maria | Capşa, Razvan Alexandru | Achim, Cristian L. | Oprea, Cristiana | Ene, Luminița | Szymańska, Bogna | Gawron, Natalia | Pluta, Agnieszka | Łojek, Emilia | Firląg-Burkacka, Ewa | Horban, Andrzej | Bornstein, Robert | Burcoș, Olivia | Erscoiu, Simona Manuela | Cojanu, Filofteia Bănicioiu | Toderan, Andreea | Nica, Maria | Popa, Ionuț Cristian | Ceaușu, Emanoil | Calistru, Petre Iacob | Arbune, Manuela | Alexandrache, Mirela | Arbune, Anca-Adriana | Voinescu, Doina-Carina | Diaconu, Ioan-Alexandru | Stratan, Laurențiu | Aramă, Victoria | Nichita, Luciana | Diaconu, Alexandra | Negru, Anca | Orfanu, Alina | Leuștean, Anca | Ion, Daniela Adriana | Ianache, Irina | Oprea, Cristiana | Leuștean, Anca | Popescu, Cristina | Orfanu, Alina | Negru, Anca | Catana, Remulus | Murariu, Cristina | Diaconu, Ioan-Alexandru | Rădulescu, Mihaela | Tilișcan, Cătălin | Aramă, Victoria | Marincu, Iosif | Poptelecan, Patricia | Bică, Valeria | Lazăr, Florin | Tirnea, Livius | Ianache, Irina | Rădoi, Roxana | Nica, Manuela | Țârdei, Grațiela | Ene, Luminița | Ceaușu, Emanoil | Calistru, Petre | Oprea, Cristiana | Osoianu, Iurie | Halacu, Ala | Stoian, Andreea Cristina | Dumitrescu, Florentina | Diaconescu, Iulian | Cupșa, Augustin | Giubelan, Lucian | Ionescu, Loredana | Niculescu, Irina | Chiriac, Carmen | Șincu, Nina | Kezdi, Iringo Zaharia | Georgescu, Anca | Țilea, Brândușa | Girbovan, Cristina | Incze, Andrea | Fodor, Andrea | Cibea, Alina | Mărdărescu, Mariana | Petre, Cristina | Drăghicenoiu, Ruxandra | Ungurianu, Rodica | Tudor, Ana Maria | Vlad, Delia | Matei, Carina | Dumea, Elena | Petcu, Lucian Cristian | Cambrea, Simona Claudia | Dumitrescu, Florentina | Cupsa, Augustin | Stoian, Andreea Cristina | Giubelan, Lucian | Niculescu, Irina | Diaconescu, Iulian | Hurezeanu, Dan | Dragonu, Livia | Cotulbea, Mioara | Erscoiu, Simona Manuela | Popa, Ionuț Cristian | Stroie, Denisa | Ionescu, Petronela | Duță, Nedeea | Dobrea, Camelia | Voican, Irina | Ceaușu, Emanoil | Calistru, Petre Iacob | Lazăr, Florin | Giubelan, Lucian | Cupșa, Augustin | Diaconescu, Iulian | Dumitrescu, Florentina | Hurezeanu, Dan | Dragonu, Livia | Niculescu, Irina | Stoian, Andreea Cristina | Obretin, Oana | Stănescu, Mariana | Jianu, Mihai | Gorenec, Lana | Lepej, Snjezana Zidovec | Grgic, Ivana | Planinic, Ana | Bes, Janja Iscic | Vince, Adriana | Begovac, Josip | Horga, Luminița Elena | Itu, Corina | Horga, Luminița Elena | David-Aldea, Laura Augusta | Ciorogar, Anca | Jianu, Cristian | Lupșe, Mihaela | Caramangiu, Iuliana | Roșca, Ovidiu | Cialma, Monica | Ardeleanu, Andreea | Marincu, Iosif | Jipa, Raluca | Manea, Eliza | Benea, Șerban | Lăpădat, Irina | Irimescu, Nicoleta | Panait, Irina | Niculae, Cristian | Hristea, Adriana | Kusic, Jovana | Jevtovic, Djordje | Salemovic, Dubravka | Ranin, Jovan | Dimitrijevic, Bozana | Dragovic, Gordana | Aldea-David, Laura-Augusta | Manciuc, Carmen | Nicolau, Cristina | Prisăcariu, Liviu | Largu, Alexandra | Mărdărescu, Mariana | Streinu-Cercel, Adrian | Petre, Cristina | Iancu, Marieta | Vintilă, Sanda | Vitelaru, Daniela | Ionel, Iosif | Șchiopu, Claudiu Mihai | Mărdărescu, Alexandra-Henriette | Micsanschi, Pavel | Holban, Tiberiu | Bîstrițchi, Ina | Pârțână, Lucia | Nagîț, Angela | Popovici, Svetlana | Talmaci, Maria | Cucerova, Irina | Mitrescu, Sorina Georgiana | Mihalcea, Dana | Caramangiu, Iulia | Roșca, Ovidiu | Maricu, Iosif | Negru, Anca | Munteanu, Daniela | Aramă, Victoria | Mihăilescu, Raluca | Diaconu, Ioan | Catana, Remulus | Popescu, Cristina | Orfanu, Alina | Leuștean, Anca | Rădulescu, Mihaela | Tilișcan, Cătălin | Năstase, Raluca | Molagic, Violeta | Duport, Irina | Dragomirescu, Cristina | Aramă, Ștefan Sorin | Negruț, Nicoleta M. | Niță, Violeta Elena | Munteanu, Daniela Ioana | Mihăilescu, Raluca | Diaconu, Ioan | Negru, Anca | Popescu, Cristina | Aramă, Victoria | Orfanu, Alina | Popescu, Cristina | Leuștean, Anca | Negru, Anca | Catana, Remulus | Diaconu, Ioan | Tilișcan, Cătălin | Aramă, Victoria | Aramă, Sorin Ștefan | Pavlovia, Ivana Pesic | Salemovic, Dubravka | Ranin, Jovan | Jevtovic, Djordje | Roșca, Ovidiu | Ardeleanu, Andreea | Caramangiu, Iulia | Desaga, Daniela | Bică, Valerica | Mitrescu, Sorina | Marincu, Iosif | Siljic, Marina | Salemovic, Dubravka | Nikolic, Valentina | Jevtovic, Djordje | Pesic-Pavlovic, Ivana | Ranin, Jovan | Todorovic, Marija | Stanojevic, Maja | Șincu, Nina-Ioana | Georgescu, Anca | Țilea, Brândușa | Kezdi, Iringo Zaharia | Incze, Andrea | Gârbovan, Cristina | Chiriac, Carmen Lucia | Luca, Anca Elena | Lazăr, Florin | Luca, Adrian | Ene, Luminița | Rădoi, Roxana | Talnariu, Adina | Suciu, Silvia | Achim, Cristian | Iacob, Diana Gabriela | Florea, Dragoș | Iacob, Simona | Arbune, Manuela | Drăgănescu, Miruna | Iancu, Alina | Moroti, Ruxandra | Niculae, Cristian M. | Merisor, Simona | Manea, Eliza | Benea, Serban | Stan, Andrada | Hrisca, Raluca | Jipa, Raluca | Tanase, Diana | Hristea, Adriana | Grgic, Ivana | Planinic, Ana | Gorenec, Lana | Lepej, Snjezana Zidovec | Vince, Adriana
BMC Infectious Diseases  2016;16(Suppl 3):290.
O1 HIV-1 diversity in Bulgaria (current molecular epidemiological picture)
Ivailo Alexiev, Reneta Dimitrova, Anna Gancheva, Asya Kostadinova, Mariyana Stoycheva, Daniela Nikolova, Ivaylo Elenkov
O2 Knowledge, attitudes and practices of the general population on HIV/AIDS, hepatitis B and C in Romania
Cătălin Tilișcan, Mioara Predescu, Bogdan Păunescu, Anca Streinu-Cercel, Oana Săndulescu, Claudiu Mihai Șchiopu, Mădălina Hristache, Lăcrămioara Aurelia Brîndușe, Adrian Streinu-Cercel
O3 The prevalence of human leukocyte antigen-B*57:01 allele carriers and CXCR4 tropism among newly diagnosed HIV infected patients in Serbia
Marija Todorovic, Marina Siljic, Dubravka Salemovic, Valentina Nikolic, Ivana Pesic-Pavlovic, Jovan Ranin, Djordje Jevtovic, Maja Stanojevic
O4 HIV transmission among stable serodiscordant couples from the former Pediatric Cohort follow up in the National Institute of Infectious Diseases
Ana Maria Tudor, Delia Vlad, Mariana Mărdărescu, Sorin Petrea, Cristina Petre, Ruxandra Neagu-Drăghicenoiu, Rodica Ungurianu, Alina Cibea, Odette Chirilă, Cristian Anghelina, Ileana Coserea
O5 Unemployment is associated with syringe sharing among people who inject drugs in Greece
Pantelia-Amalia Krikelli, Eirini Pavlitina, Mina Psichogiou, Demetris Lamnisos, Leslie Williams, Anya Korobchuk, Britt Skaathun, Pavlo Smyrnov, John Schneider, Vana Sypsa, Dimitrios Paraskevis, Angelos Hatzakis, Samuel R. Friedman, Georgios K. Nikolopoulos
O6 Correlation of adipocytokine levels in different types of lipodystrophy in HIV/AIDS patients
Gordana Dragović, Danica Srdić, Al Musalhi Khawla, Ivan Soldatović, Jelena Nikolić, Djordje Jevtović, Devaki Nair
O7 IP10 – a possible biomarker for the progression of HIV infection
Aura Temereanca, Adelina Rosca, Luminita Ene, Benchawa Soontornniyomkij, Carmen Diaconu, Claudia Dita, Cristian Achim, Simona Ruta
O8 A permanent challenge: persistent low viremia in HIV positive patients on ART
Șerban Benea, Ruxandra Moroti, Raluca Jipa, Eliza Manea, Andrada Stan, Elisabeta Benea, Dan Oțelea, Adriana Hristea
O9 Infections in IDUs according to their HIV status
Adriana Hristea, Irina Lăpădat, Raluca Jipa, Ruxandra Moroti, Șerban Benea, Doina Antonică, Irina Panait, Roxana Petre
O10 Trends in combined antiretroviral therapy used in methadone program integrated with HIV care - 20 years of experience
Justyna D. Kowalska, Ewa Pietraszkiewicz, Ewa Grycner, Ewa Firlag-Burkacka, Andrzej Horban
O11 Extracellular cyclophilin A – inflammatory mediator in HIV infected patients
Ovidiu Vlaicu, Leontina Bănică, Simona Paraschiv, Ana-Maria Tudor, Ruxandra Moroti, Dan Oțelea
O12 High cardiovascular disease risk in Serbian population, an issue of concern
Bojana Dimitrijević, Ivan Soldatović, Đorđe Jevtović, Jovana Kusić, Dubravka Salemović, Jovan Ranin, Gordana Dragović
O13 Genotypic rifampicin resistance in HIV/ tuberculosis coinfected patients from a tertiary level infectious diseases hospital
Dragoș Florea, Ioana Bădicuț, Alexandru Rafila, Cornel Camburu, Adriana Histrea, Mihaela Frățilă, Dan Oțelea
O14 Occurrence of residual HCV RNA in liver and peripheral blood mononuclear cells among patients with chronic hepatitis C infection and/or HCV/HIV coinfection after IFN-based therapy
Ivana Gmizic, Dubravka Salemovic, Ivana Pesic-Pavlovic, Marina Siljic, Valentina Nikolic, Miljana Djonin-Nenezic, Ivana Milosevic, Branko Brmbolic, Maja Stanojevic
O15 Romanian nationwide screening for infection with HIV and hepatitis B and C viruses
Anca Streinu-Cercel, Oana Săndulescu, Alina Cristina Neguț, Mioara Predescu, Alexandra Mărdărescu, Mihai Săndulescu, Adrian Streinu-Cercel
O16 Treatment emergent variants to combined direct antiviral agents therapy against hepatitis C virus
Ana Belen Pérez, Natalia Chueca, Marta Álvarez, Juan Carlos Alados, Antonio Rivero, Francisco Vera, Marcial Delgado, Javier Salmeron, Miguel Jiménez, Maria José Blanco, Moises Diago, Miguel Garcia-deltoro, Marta Alvarez, Francisco Téllez, Federico García
O17 Clinical and epidemiological aspects in tuberculosis/HIV coinfected patients
Diana Tănase, Eliza Manea, Rodica Bacruban, Dragoș Florea, Dan Oțelea, Alexandru Rafila, Mariana Mărdărescu, Adriana Hristea
O18 Resistance to NS3 protease inhibitors in persons with chronic hepatitis C infected with hepatitis C virus subtype 1a from Croatia
Ivana Grgic, Ana Planinic, Maja Santak, Lana Gorenec, Snjezana Zidovec Lepej, Adriana Vince
O19 Analysis of a simplified diagnostic score for tuberculous meningitis in HIV-infected adults with meningitis
Eliza Manea, Adriana Hristea, Șerban Benea, Ruxandra Moroti, Diana Tănase, Cristian M. Niculae, Simona Merisor, Raluca Jipa
O20 Molecular tracing of the origin of HIV-1 infection among persons who inject drugs in Athens: a phyloethnic study
Dimitrios Paraskevis, Evangelia Kostaki, Georgios K. Nikolopoulos, Vana Sypsa, Mina Psichogiou, Dimitra Paraskeva, Athanassios Skoutelis, Meni Malliori, Samuel R. Friedman, Angelos Hatzakis
O21 The dynamics of virological response to HIV-1 infection and antiretroviral therapy initiation in patients with and without HLA-B*5701 Allele
Malgorzata Hackiewicz, Piotr Zabek, Ewa Firlag-Burkacka, Andrzej Horban, Justyna Dominika Kowalska
O22 Increase in the numbers of non-B subtypes and potential recombinant forms circulating among Slovenian MSM in the recent years
Maja M. Lunar, Jana Mlakar, Mario Poljak
O23 Genotyping intrahost polymorphisms in hepatitis C virus E2 protein associated with resistance to antibody neutralization
Leontina Bănică, Eliza Martin, Valeriu Gheorghiță, Andrei Petrescu, Dan Oțelea, Costin-Ioan Popescu, Simona Paraschiv
O24 Genotyping of HCV NS3 protease inhibitors resistance and phenotyping of rare double resistance mutations in HCV cell culture system
Emil Neaga, Vlaicu Ovidiu, Andrei Juncu, Leontina Bănică, Simona Paraschiv, Dan Oțelea, Costin-Ioan Popescu
O25 Employment status controls the relationship between neurocognitive impairment and depression in a cohort of young HIV-infected adults since childhood
Adrian Luca, Florin Lazăr, Anca Elena Luca, Luminița Ene, Cristian Achim
O26 Predictors of survival in parenterally-infected HIV positive children and youth diagnosed with progressive multifocal leukoencephalopathy
Cosmina Gingăraş, Ștefan Adrian Anton, Roxana Rădoi, Simona Tetradov, Grațiela Țârdei, Maria Nica, Razvan Alexandru Capşa, Cristian L. Achim, Cristiana Oprea, Luminița Ene
O27 Neurocognitive and brain functioning in HIV-infected young MSM treated with cART
Bogna Szymańska, Natalia Gawron, Agnieszka Pluta, Emilia Łojek, Ewa Firląg – Burkacka, Andrzej Horban, Robert Bornstein, et HARMONIA3 Study Group
O28 Clinical value of RT-PCR detection of Toxoplasma gondii DNA in cerebrospinal fluid
Olivia Burcoș, Simona Manuela Erscoiu, Filofteia Bănicioiu Cojanu, Andreea Toderan, Maria Nica, Ionuț Cristian Popa, Emanoil Ceaușu, Petre Iacob Calistru
O29 Characteristics of sleep disorders in Romanian adults infected with human immunodeficiency virus
Manuela Arbune, Mirela Alexandrache, Anca-Adriana Arbune, Doina-Carina Voinescu
O30 Diagnosing neuroHIV: the rift between clinicians and pathologists
Ioan-Alexandru Diaconu, Laurențiu Stratan, Victoria Aramă, Luciana Nichita, Alexandra Diaconu, Anca Negru, Alina Orfanu, Anca Leuștean, Daniela Adriana Ion
O31 A challenging neurological complication in a HIV-infected young woman with multiple opportunistic infections
Irina Ianache, Cristiana Oprea
O32 Brain abscess with uncertain etiology in a late-presenter HIV infected patient
Anca Leuștean, Cristina Popescu, Alina Orfanu, Anca Negru, Remulus Catana, Cristina Murariu, Ioan-Alexandru Diaconu, Mihaela Rădulescu, Cătălin Tilișcan, Victoria Aramă
O33 Cerebral toxoplasmosis and left crural monoparesis with fatal evolution in a noncompliant patient with AIDS C3
Iosif Marincu, Patricia Poptelecan, Valeria Bică, Florin Lazăr, Livius Tirnea
O34 Opportunistic infections still a problem in HIV-infected patients in cART era: a Romanian single center experience
Irina Ianache, Roxana Rădoi, Manuela Nica, Grațiela Țârdei, Luminița Ene, Emanoil Ceaușu, Petre Calistru, Cristiana Oprea
P1: Epidemiological aspects of co-infection of HIV/TB in Moldova
Iurie Osoianu, Ala Halacu
P2 Perinatal exposure at HIV infection in Oltenia region
Andreea Cristina Stoian, Florentina Dumitrescu, Iulian Diaconescu, Augustin Cupșa, Lucian Giubelan, Loredana Ionescu, Irina Niculescu
P3 Women living with HIV in Mureș county
Carmen Chiriac, Nina Șincu, Iringo Zaharia Kezdi, Anca Georgescu, Brândușa Țilea, Cristina Girbovan, Andrea Incze, Andrea Fodor
P4 Late diagnosis of HIV infection in children - a challenge for Romania
Alina Cibea, Mariana Mărdărescu, Cristina Petre, Ruxandra Drăghicenoiu, Rodica Ungurianu, Ana Maria Tudor, Delia Vlad, Carina Matei
P5 Cirrhosis Assessment in Patients Co-infected HIV-Hepatitis B Virus
Elena Dumea, Lucian Cristian Petcu, Simona Claudia Cambrea
P6 HIV late presenters in Craiova Regional Center, Romania
Florentina Dumitrescu, Augustin Cupsa, Andreea Cristina Stoian, Lucian Giubelan, Irina Niculescu, Iulian Diaconescu, Dan Hurezeanu, Livia Dragonu, Mioara Cotulbea
P7 Some aspects of malignancies in patients HIV / AIDS
Simona Manuela Erscoiu, Ionuț Cristian Popa, Denisa Stroie, Petronela Ionescu, Nedeea Duță, Camelia Dobrea, Irina Voican, Emanoil Ceaușu, Petre Iacob Calistru
P8 Factors associated with resilience among people living with HIV in Romania
Florin Lazăr
P9 Fever in HIV-infected patients: a thorny problem to be solved by the clinicians
Lucian Giubelan, Augustin Cupșa, Iulian Diaconescu, Florentina Dumitrescu, Dan Hurezeanu, Livia Dragonu, Irina Niculescu, Andreea Cristina Stoian, Oana Obretin, Mariana Stănescu, Mihai Jianu
P10 Th1, Th2, Th9, Th17 and Th22 cytokines in acute and chronic HIV-1 infection
Lana Gorenec, Snjezana Zidovec Lepej, Ivana Grgic, Ana Planinic, Janja Iscic Bes, Adriana Vince, Josip Begovac
P11 Dyslipidemia in HIV-infected patients treated with protease inhibitors – case report
Luminița Elena Horga
P12 Why use less treatment for the metabolic abnormalities in HIV patients-too many drugs?
Corina Itu, Luminița Elena Horga, Laura Augusta David-Aldea, Anca Ciorogar, Cristian Jianu, Mihaela Lupșe
P13 Sacral Herpes Zoster, with hyperalgesic form, in a patient with C3 stage HIV infection
Iuliana Caramangiu, Ovidiu Roșca, Monica Cialma, Andreea Ardeleanu, Iosif Marincu
P14 Factors associated with in-hospital mortality in tuberculous and cryptococcal meningitis
Raluca Jipa, Eliza Manea, Șerban Benea, Irina Lăpădat, Nicoleta Irimescu, Irina Panait, Cristian Niculae, Adriana Hristea
P15 Lipodystrophy: still present adverse event in resource-limited settings
Jovana Kusic, Djordje Jevtovic, Dubravka Salemovic, Jovan Ranin, Bozana Dimitrijevic, Gordana Dragovic
P16 TB and HIV coinfected patient, an emergent challenge - case report
Laura-Augusta Aldea-David
P17 Efficacy of prophylactic antiretroviral treatment in new-born infants from HIV-positive mothers in 2012-2014, for the North-Eastern part of Romania
Carmen Manciuc, Cristina Nicolau, Liviu Prisăcariu, Alexandra Largu
P18 Surveillance of mother to child transmission of HIV in Romania – 31 December 2015
Mariana Mărdărescu, Adrian Streinu-Cercel, Cristina Petre, Marieta Iancu, Sanda Vintilă, Daniela Vitelaru, Iosif Ionel, Claudiu Mihai Șchiopu, Alexandra-Henriette Mărdărescu
P19 The antiretroviral therapy failure and the need to select the effective treatment in the Republic of Moldova
Pavel Micsanschi, Tiberiu Holban, Ina Bîstrițchi, Lucia Pârțână, Angela Nagîț, Svetlana Popovici, Maria Talmaci, Irina Cucerova
P20 Disseminated cryptococcosis in a patient with C3 HIV stage and multiresistant to antiretroviral therapy with lethal evolution
Sorina Georgiana Mitrescu, Dana Mihalcea, Iulia Caramangiu, Ovidiu Roșca, Iosif Maricu
P21 Aspects of tuberculosis infection in HIV-positive patients from Romania – our experience
Anca Negru, Daniela Munteanu, Victoria Aramă, Raluca Mihăilescu, Ioan Diaconu, Remulus Catana, Cristina Popescu, Alina Orfanu, Anca Leuștean, Mihaela Rădulescu, Cătălin Tilișcan, Raluca Năstase, Violeta Molagic, Irina Duport, Cristina Dragomirescu, Ștefan Sorin Aramă
P22 Dyslipidemia in HIV-infected patients
Nicoleta M Negruț
P23 Challenges in the management of an HIV seropositive patient with psoriasis undergoing immunomodulator therapy
Violeta Elena Niță, Daniela Ioana Munteanu, Raluca Mihăilescu, Ioan Diaconu, Anca Negru, Cristina Popescu, Victoria Aramă
P24 Acute peritonitis as a sign of IRIS in an HIV-infected patient with MAC latent infection
Alina Orfanu, Cristina Popescu, Anca Leuștean, Anca Negru, Remulus Catana, Ioan Diaconu, Cătălin Tilișcan, Victoria Aramă, Sorin Ștefan Aramă
P25 The virologic outcome of the treatment of chronic hepatitis B among HIV co-infected patients on HAART
Ivana Pesic Pavlovia, Dubravka Salemovic, Jovan Ranin, Djordje Jevtovic
P26 A case of HIV encephalopathy with aphasia, agnosia, apraxia and right homonymous hemianopsia
Ovidiu Roșca, Andreea Ardeleanu, Iulia Caramangiu, Daniela Desaga, Valerica Bică, Sorina Mitrescu, Iosif Marincu
P27 Molecular footprints on human immunodeficiency virus -1 genome and association with phylogenetic clustering among subtype B infected patients in Serbia
Marina Siljic, Dubravka Salemovic, Valentina Nikolic, Djordje Jevtovic, Ivana Pesic-Pavlovic, Jovan Ranin, Marija Todorovic , Maja Stanojevic
P28 Neurosyphilis and human immunodeficiency virus infection: double challenge
Nina-Ioana Șincu, Anca Georgescu, Brândușa Țilea, Iringo Zaharia Kezdi, Andrea Incze, Cristina Gârbovan, Carmen Lucia Chiriac
P29 Differences between HIV-infected adults since childhood and non HIV-infected persons on managing everyday life
Anca Elena Luca, Florin Lazăr, Adrian Luca, Luminița Ene, Roxana Rădoi, Adina Talnariu, Silvia Suciu, Cristian Achim
P30 Molecular detection of Bartonella quintana in a HIV immunodepressed patient with fever and isolated lymphadenopathy - Case report
Diana Gabriela Iacob, Dragoș Florea, Simona Iacob
P31 Present epidemiological characteristics of HIV/AIDS newly diagnosed cases in South-Eastern Romania
Manuela Arbune, Miruna Drăgănescu, Alina Iancu
P32 The gender’s preferences among opportunists?
Ruxandra Moroti, Cristian M Niculae, Simona Merisor, Eliza Manea, Serban Benea, Andrada Stan, Raluca Hrisca, Raluca Jipa, Diana Tanase, Adriana Hristea
P33 Polymorphism of interleukin-28B gene in persons with chronic hepatitis C from Croatia
Ivana Grgic, Ana Planinic, Lana Gorenec, Snjezana Zidovec Lepej, Adriana Vince
doi:10.1186/s12879-016-1480-8
PMCID: PMC4928154  PMID: 27356504
11.  Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial 
PLoS Medicine  2012;9(5):e1001217.
Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial.
Background
Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure.
Methods and Findings
Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models.
382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens.
Conclusions
Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.
Trial registration
www.controlled-trials.com ISRCTN13968779
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 34 million people (mostly in low- and middle-income countries) are infected with HIV, the virus that causes AIDS. At the beginning of the epidemic, more men than women were infected with HIV but now about half of all people living with HIV/AIDS are women, most of who became infected through unprotected sex with an infected partner. In sub-Saharan Africa alone, 12 million women are HIV-positive. Worldwide, HIV/AIDS is the leading cause of death among women of child-bearing age. Moreover, most of the 400,000 children who become infected with HIV every year acquire the virus from their mother during pregnancy or birth, or through breastfeeding, so-called mother-to-child transmission (MTCT). Combination antiretroviral therapy (ART)—treatment with cocktails of powerful antiretroviral drugs—reduces HIV-related illness and death among women, and ART given to HIV-positive mothers during pregnancy and delivery and to their newborn babies greatly reduces MTCT.
Why Was This Study Done?
Because of ongoing international efforts to increase ART coverage, more HIV-positive women in Africa have access to ART now than ever before. However, little is known about pregnancy outcomes among HIV-infected African women taking ART throughout pregnancy for their own health or about the long-term outcomes of their offspring. In particular, few studies have examined the effect of taking tenofovir (an antiretroviral drug that is now recommended as part of first-line ART) throughout pregnancy. Tenofovir readily crosses from mother to child during pregnancy and, in animal experiments, high doses of tenofovir given during pregnancy caused bone demineralization (which weakens bones), kidney problems, and impaired growth among offspring. In this study, the researchers analyze data collected on pregnancy and infant outcomes among Ugandan and Zimbabwean HIV-positive women who took ART throughout pregnancy in the Development of AntiRetroviral Therapy in Africa (DART) trial. This trial was designed to test whether ART could be safely and effectively delivered in Africa without access to the expensive laboratory tests that are routinely used to monitor ART toxicity and efficacy in developed countries.
What Did the Researchers Do and Find?
The pregnancy outcomes of 302 women who became pregnant during the DART trial and information on birth defects among their babies were collected as part of the DART protocol; information on the survival, growth, and development of the infants born to these women was collected in a separate infant study. Most of the women who became pregnant were taking tenofovir-containing ART before and throughout their pregnancies. 58% of the pregnancies resulted in a live birth, 7% resulted in a stillbirth (birth of a dead baby at any time from 22 weeks gestation to the end of pregnancy), and 35% resulted in a termination or miscarriage (before 22 weeks gestation). Of the 226 live births, seven infants died within 2 weeks and seven had birth defects. Similar proportions of the infants exposed and not exposed to tenofovir during pregnancy died soon after birth or had birth defects. Of the 182 surviving infants who were enrolled in the infant study, 14 subsequently died at an average age of 9 months, giving a 1-year mortality of 5%. None of the surviving children who were tested (172 infants) were HIV infected. No bone fractures or major kidney problems occurred during follow-up and prebirth exposure to tenofovir in utero had no effect on growth or weight gain at 2 years (in contrast to a previous US study).
What Do These Findings Mean?
By showing that prebirth tenofovir exposure does not affect pregnancy outcomes or increase birth defects, growth abnormalities, or kidney problems, these findings support the use of tenofovir-containing ART during pregnancy among HIV-positive African women, and suggest that it could also be used to prevent women of child-bearing age acquiring HIV-infection heterosexually. Notably, the observed 5% 1-year infant mortality is similar to the 2%–4% infant mortality normally seen in the region. The absence of HIV infection among the infants born to the DART participants is also encouraging. However, this is a small study (only 111 infants were exposed to tenofovir throughout pregnancy) and women were not randomly assigned to receive tenofovir-containing ART. Consequently, more studies are needed to confirm that tenofovir exposure during pregnancy does not affect pregnancy outcomes or have any long-term effects on infants. Such studies are essential because the use of tenofovir as a treatment for women who are HIV-positive is likely to increase and tenofovir may also be used in the future to prevent HIV acquisition in HIV-uninfected women.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001217.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS nonprofit on many aspects of HIV/AIDS, including detailed information on HIV/AIDS treatment and care, women, HIV and AIDS, children, HIV and AIDS, and on HIV/AIDS and pregnancy (some information in English and Spanish); personal stories of women living with HIV are available
More information about the DART trial is available
Additional patient stories about living with HIV/AIDS are available through the nonprofit website Healthtalkonline
doi:10.1371/journal.pmed.1001217
PMCID: PMC3352861  PMID: 22615543
12.  Switching HIV Treatment in Adults Based on CD4 Count Versus Viral Load Monitoring: A Randomized, Non-Inferiority Trial in Thailand 
PLoS Medicine  2013;10(8):e1001494.
Using a randomized controlled trial, Marc Lallemant and colleagues ask if a CD4-based monitoring and treatment switching strategy provides a similar clinical outcome compared to the standard viral load-based strategy for adults with HIV in Thailand.
Please see later in the article for the Editors' Summary
Background
Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand.
Methods and Findings
The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50–250/mm3) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm3. The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6–11.4) in VL versus 7.4% (5.1–10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2–8.4) in VL versus 7.5% (5.0–11.1) in CD4 (p = 0.097). Median time from treatment initiation to switch was 11.7 months (7.7–19.4) in VL and 24.7 months (15.9–35.0) in CD4 (p = 0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8–8.0) in VL versus 15.8 months (8.5–20.4) in CD4 (p = 0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported.
Conclusions
The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings.
Trial registration
ClinicalTrials.gov NCT00162682
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (most of them living in low-and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV infection leads to the destruction of immune system cells (including CD4 cells, a type of white blood cell), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (HAART)—combined drugs regimens that suppress viral replication and allow restoration of the immune system—became available. For people living in affluent countries, HIV/AIDS became a chronic condition but, because HAART was expensive, HIV/AIDS remained a fatal illness for people living in resource-limited countries. In 2003, the international community declared HIV/AIDS a global health emergency and, in 2006, it set the target of achieving universal global access to HAART by 2010. By the end of 2011, 8 million of the estimated 14.8 million people in need of HAART in low- and middle-income countries were receiving treatment.
Why Was This Study Done?
At the time this trial was conceived, national and international recommendations were that HIV-positive individuals should start HAART when their CD4 count fell below 200 cells/mm3 and should have their CD4 count regularly monitored to optimize HAART. In 2013, the World Health Organization (WHO) recommendations were updated to promote expanded eligibility for HAART with a CD4 of 500 cells/mm3 or less for adults, adolescents, and older children although priority is given to individuals with CD4 count of 350 cells/mm3 or less. Because HIV often becomes resistant to first-line antiretroviral drugs, WHO also recommends that viral load—the amount of virus in the blood—should be monitored so that suspected treatment failures can be confirmed and patients switched to second-line drugs in a timely manner. This monitoring and switching strategy is widely used in resource-rich settings, but is still very difficult to implement for low- and middle-income countries where resources for monitoring are limited and access to costly second-line drugs is restricted. In this randomized non-inferiority trial, the researchers compare the performance of a CD4-based treatment monitoring and switching strategy with the standard viral load-based strategy among HIV-positive adults in Thailand. In a randomized trial, individuals are assigned different interventions by the play of chance and followed up to compare the effects of these interventions; a non-inferiority trial investigates whether one treatment is not worse than another.
What Did the Researchers Do and Find?
The researchers assigned about 700 HIV-positive adults who were beginning HAART for the first time to have their CD4 count (CD4 arm) or their CD4 count and viral load (VL arm) determined every 3 months. Participants were switched to a second-line therapy if their CD4 count declined by more than 30% from their peak CD4 count (CD4 arm) or if a viral load of more than 400 copies/ml was recorded (VL arm). The 3-year cumulative risk of clinical failure (defined as death, a new AIDS-defining event, or a CD4 count of less than 50 cells/mm3) was 8% in the VL arm and 7.4% in the CD4 arm. This difference in clinical failure risk met the researchers' predefined criterion for non-inferiority. The probability of a treatment switch was similar in the two arms, but the average time from treatment initiation to treatment switch and the average duration of a high viral load after treatment switch were both longer in the CD4 arm than in the VL arm. Finally, the future-drug-option score, a measure of viral drug resistance profiles, was similar in the two arms at the time of treatment switch.
What Do These Findings Mean?
These findings suggest that, in Thailand, a CD4 switching strategy is non-inferior in terms of clinical outcomes among HIV-positive adults 3 years after beginning HAART when compared to the recommended viral load-based switching strategy and that there is no difference between the strategies in terms of viral suppression and immune restoration after 3-years follow-up. Importantly, however, even though patients in the CD4 arm spent longer with a high viral load than patients in the VL arm, the emergence of HIV mutants resistant to antiretroviral drugs was similar in the two arms. Although these findings provide no information about the long-term outcomes of the two monitoring strategies and may not be generalizable to routine care settings, they nevertheless provide reassurance that using CD4 counts alone to monitor HAART in HIV treatment programs in resource-limited settings is an appropriate strategy to use as viral load measurement becomes more affordable and feasible in these settings.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001494.
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); its 2010 recommendations for antiretroviral therapy for HIV infection in adults and adolescents are available as well as the June 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the global HIV/AIDS epidemic, on HIV and AIDS in Thailand, on universal access to AIDS treatment, and on starting, monitoring and switching HIV treatment (in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about HIV and AIDS
More information about this trial (the PHPT-3 trial) is available
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about HIV treatment
doi:10.1371/journal.pmed.1001494
PMCID: PMC3735458  PMID: 23940461
13.  Creating and Validating an Algorithm to Measure AIDS Mortality in the Adult Population using Verbal Autopsy 
PLoS Medicine  2006;3(8):e312.
Background
Vital registration and cause of death reporting is incomplete in the countries in which the HIV epidemic is most severe. A reliable tool that is independent of HIV status is needed for measuring the frequency of AIDS deaths and ultimately the impact of antiretroviral therapy on mortality.
Methods and Findings
A verbal autopsy questionnaire was administered to caregivers of 381 adults of known HIV status who died between 1998 and 2003 in Manicaland, eastern Zimbabwe. Individuals who were HIV positive and did not die in an accident or during childbirth (74%; n = 282) were considered to have died of AIDS in the gold standard. Verbal autopsies were randomly allocated to a training dataset (n = 279) to generate classification criteria or a test dataset (n = 102) to verify criteria. A rule-based algorithm created to minimise false positives had a specificity of 66% and a sensitivity of 76%. Eight predictors (weight loss, wasting, jaundice, herpes zoster, presence of abscesses or sores, oral candidiasis, acute respiratory tract infections, and vaginal tumours) were included in the algorithm. In the test dataset of verbal autopsies, 69% of deaths were correctly classified as AIDS/non-AIDS, and it was not necessary to invoke a differential diagnosis of tuberculosis. Presence of any one of these criteria gave a post-test probability of AIDS death of 0.84.
Conclusions
Analysis of verbal autopsy data in this rural Zimbabwean population revealed a distinct pattern of signs and symptoms associated with AIDS mortality. Using these signs and symptoms, demographic surveillance data on AIDS deaths may allow for the estimation of AIDS mortality and even HIV prevalence.
Based on verbal autopsy from patients in rural Zimbabwe, 69% of deaths were correctly classified as AIDS/non-AIDS. The authors say the method can be used in demographic surveillance on AIDS deaths.
Editors' Summary
Background.
The worldwide epidemic of HIV/AIDS is at its most severe in poor countries—for example, in Africa, where over 25 million people are estimated to have been infected with HIV. Such countries generally lack the kind of health system that is able to record the cause of death for each person who dies. This makes it very hard to know the number of people whose deaths are related to AIDS. The uncertainty over the AIDS death rates in these countries causes many problems. For example, it will be hard to establish how effective the introduction of AIDS treatment drugs is proving to be in reducing the number of AIDS deaths. A new approach is needed to determine and record the causes of deaths in these countries. It is not enough to rely on knowing whether the person who has died has been found to be HIV positive; many people in poor countries who have AIDS have never been tested, and, in any case, the cause of death in a person with HIV may not necessarily be related to the virus.
Why Was This Study Done?
The researchers wanted to investigate the use of the technique called “verbal autopsy.” This involves asking those who were with the deceased person before they died—usually close family members—a series of standard questions about the symptoms the person had. This is now a recognized technique, but the researchers wanted to know specifically how effective it can be in identifying AIDS as the cause of death. It is also important to “validate” the set of questions chosen to be used in a verbal autopsy, to see how likely they are to produce the correct explanation for the cause of death.
What Did the Researchers Do and Find?
The researchers drew up a list of what they considered appropriate questions and used them in interviews (conducted by nurses) with the caregivers of 381 adults who died between 1998 and 2003 in Manicaland, a rural area of eastern Zimbabwe. For all of these people, it was known whether they were HIV positive or HIV negative. (This information is not known for most deaths in rural Zimbabwe.) The 282 people who were HIV positive and did not die in an accident or during childbirth were considered by the researchers to have died of AIDS. (They argue this was a reasonable assumption to make, based on what is already known about death rates in HIV-positive and HIV-negative people in Zimbabwe.)
The questions the caregivers were asked about the condition of the person who died included whether or not they had any of the following signs or symptoms that are common among patients with AIDS: moderate or severe weight loss, jaundice, herpes zoster, presence of abscesses or sores, oral candidiasis, acute respiratory tract infections, and vaginal tumours. Explanations of what these conditions looked like were given to the caregivers. There were also questions on the circumstances surrounding each death. Using the answers to the questions, it was possible in 69% of cases to make a correct decision as to whether the death was the result of AIDS.
What Do These Findings Mean?
A verbal autopsy using the signs and symptoms selected by these authors can be used to make reasonable estimates of the number of AIDS deaths. The authors believe that, with the same set of questions, it might also be possible to produce estimates of the number of people living with HIV/AIDS. Validation of the questions used should, however, be carried out separately in each country that adopts this technique.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030312.
• MedlinePlus has many pages providing information about HIV/AIDS.
• Information about the global epidemic of HIV/AIDS and international efforts to fight it can be found on the Web site of the Joint United Nations Programme on HIV/AIDS (UNAIDS).
• Of particular relevance is UNAIDS' country-by-country analysis of the situation in Africa.
• The World Health Organization's pages on HIV/AIDS. A recent discussion on verbal autopsies has been published by WHO.
• The Manicaland HIV/STD Prevention Study.
doi:10.1371/journal.pmed.0030312
PMCID: PMC1526767  PMID: 16881730
14.  Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection 
PLoS Medicine  2008;5(10):e203.
Background
In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).
We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.
Methods and Findings
Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0–4.1; p = 0.05), 8.3 (95% CI, 3.3–20.8; p < 0.0001), and 12.4 (95% CI, 4.2–37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case–control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1–3.1; p = 0.02) to 1.5 (95% CI, 0.8–2.8) and 1.4 (95% CI, 0.8–2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.
Conclusions
IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.
Trial Registration: ClinicalTrials.gov (NCT00027352).
Analyzing biomarker data from participants in a previous randomized controlled trial of continuous versus interrupted HIV treatment (the SMART trial), James Neaton and colleagues find that mortality was related to IL-6 and fibrin D-dimers.
Editors' Summary
Background.
Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). HIV infects and destroys immune system cells (including CD4 cells, a type of lymphocyte). The first stage of HIV infection can involve a short flu-like illness but in the second stage, which can last many years, HIV replicates in the lymph glands (small immune system organs throughout the body) without causing any symptoms. Eventually, however, the immune system becomes so damaged that HIV-infected individuals begin to succumb to “opportunistic” infections (for example, bacterial pneumonia) and cancers (in particular, Karposi sarcoma) that the immune system would normally prevent. AIDS itself is characterized by one or more severe opportunistic infections or cancers (so-called AIDS-related diseases) and by a low blood CD4 cell count. HIV infections cannot be cured but antiretroviral therapy (ART)—combinations of powerful antiretroviral drugs—can keep them in check, so many HIV-positive people now have substantially improved life expectancy.
Why Was This Study Done?
Unfortunately, the effectiveness of ART sometimes wanes over time and prolonged ART can cause unpleasant side effects. Consequently, alternative ART regimens are continually being tested in clinical trials. In the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, for example, HIV-positive patients received either continuous ART (the viral suppression or VS arm), or ART only when their CD4 cell counts were below 250 cells/mm3 (the drug conservation or DC arm; the normal adult CD4 cell count is about 1,000 cells/mm3). Unexpectedly, more people died in the DC arm than in the VS arm from non-AIDS diseases (including heart and circulation problems), a result that led to the trial being stopped early. One possible explanation for these excess deaths is that increased HIV levels following ART interruption might have induced an inflammatory response (a non-specific immune response that occurs with infection or wounding) and/or a hypercoagulable state (a condition in which blood clots form inside undamaged blood vessels) and that these changes increased the risk of death from non-AIDS diseases. In this study, the researchers test this hypothesis.
What Did the Researchers Do and Find?
The researchers measured the levels of proteins that indicate the presence of inflammation or increased coagulation (biomarkers) in stored blood samples from the 85 people who died during the SMART trial (55 and 30 of the participants assigned to receive DC and VS, respectively) and from 170 survivors who served as comparison (control) participants. (Two control participants were “matched” to each participant who had died (cases). In this “case-control” study, an increased risk of death was associated with higher levels at study entry of the inflammation biomarkers high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) and of the coagulation biomarker D-dimer. The risk of death among people with hsCRP values in the highest quarter of measured values was twice that among people with hsCRP values in the lowest quarter (this is expressed as an odds ratio of 2). For IL-6 and D-dimer, the equivalent odds ratios were 8.3 and 12.4, respectively. Furthermore, increases in hsCRP, IL-6 and D-dimer after study entry were associated with an increased risk of death. The researchers also measured blood levels of the same biomarkers in 250 randomly chosen patients from each of the two treatment arms. IL-6 levels increased by 30% over the first month of the trial in the DC arm but were unchanged in the VS arm. Over the same period, D-dimer levels increased by 16% and 5% in the DC and VS arms, respectively. Increases in both markers in the DC arm were related to HIV RNA levels after one month.
What Do These Findings Mean?
Taken together, these findings suggest that HIV-induced activation of inflammation and coagulation increases the risk of death among HIV-positive patients and that interrupting ART further increases this risk, possibly by increasing IL-6 and D-dimer levels. Because only a small number of people died in this study, the relationship between these biomarkers and death and illness among treated and untreated HIV-positive individuals needs to be confirmed in further studies. However, these findings suggest that the development of therapies that reduce the effect that HIV replication has on inflammation and blood coagulation, or that reduce IL-6 and D-dimer levels, might extend the life-expectancy of HIV-positive people.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050203.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and about the SMART trial
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is also available from Avert, an international AIDS charity, on HIV/AIDS
More information about the SMART trial is available on ClinicalTrials.gov, a database of clinical trials maintained by the US National Institutes of Health
doi:10.1371/journal.pmed.0050203
PMCID: PMC2570418  PMID: 18942885
15.  Impact of Risk Factors for Specific Causes of Death in the First and Subsequent Years of Antiretroviral Therapy Among HIV-Infected Patients 
Among HIV-infected patients who initiated antiretroviral therapy (ART), patterns of cause-specific death varied by ART duration and were strongly related to age, sex, and transmission risk group. Deaths from non-AIDS malignancies were much more frequent than those from cardiovascular disease.
Background. Patterns of cause-specific mortality in individuals infected with human immunodeficiency virus type 1 (HIV-1) are changing dramatically in the era of antiretroviral therapy (ART).
Methods. Sixteen cohorts from Europe and North America contributed data on adult patients followed from the start of ART. Procedures for coding causes of death were standardized. Estimated hazard ratios (HRs) were adjusted for transmission risk group, sex, age, year of ART initiation, baseline CD4 count, viral load, and AIDS status, before and after the first year of ART.
Results. A total of 4237 of 65 121 (6.5%) patients died (median, 4.5 years follow-up). Rates of AIDS death decreased substantially with time since starting ART, but mortality from non-AIDS malignancy increased (rate ratio, 1.04 per year; 95% confidence interval [CI], 1.0–1.1). Higher mortality in men than women during the first year of ART was mostly due to non-AIDS malignancy and liver-related deaths. Associations with age were strongest for cardiovascular disease, heart/vascular, and malignancy deaths. Patients with presumed transmission through injection drug use had higher rates of all causes of death, particularly for liver-related causes (HRs compared with men who have sex with men: 18.1 [95% CI, 6.2–52.7] during the first year of ART and 9.1 [95% CI, 5.8–14.2] thereafter). There was a persistent role of CD4 count at baseline and at 12 months in predicting AIDS, non-AIDS infection, and non-AIDS malignancy deaths. Lack of viral suppression on ART was associated with AIDS, non-AIDS infection, and other causes of death.
Conclusions. Better understanding of patterns of and risk factors for cause-specific mortality in the ART era can aid in development of appropriate care for HIV-infected individuals and inform guidelines for risk factor management.
doi:10.1093/cid/ciu261
PMCID: PMC4073781  PMID: 24771333
HIV; cause-specific mortality; antiretroviral therapy
16.  Cotrimoxazole Prophylaxis Discontinuation among Antiretroviral-Treated HIV-1-Infected Adults in Kenya: A Randomized Non-inferiority Trial 
PLoS Medicine  2016;13(1):e1001934.
Background
Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organization (WHO) for HIV-1-infected individuals in settings with high infectious disease prevalence. The WHO 2006 guidelines were developed prior to the scale-up of antiretroviral therapy (ART). The threshold for CTX discontinuation following ART is undefined in resource-limited settings.
Methods and Findings
Between 1 February 2012 and 30 September 2013, we conducted an unblinded non-inferiority randomized controlled trial of CTX prophylaxis cessation versus continuation among HIV-1-infected adults on ART for ≥18 mo with CD4 count > 350 cells/mm3 in a malaria-endemic region in Kenya. Participants were randomized and followed up at 3-mo intervals for 12 mo. The primary endpoint was a composite of morbidity (malaria, pneumonia, and diarrhea) and mortality. Incidence rate ratios (IRRs) were estimated using Poisson regression.
Among 538 ART-treated adults screened, 500 were enrolled and randomized, 250 per arm. Median age was 40 y, 361 (72%) were women, and 442 (88%) reported insecticide-treated bednet use. Combined morbidity/mortality was significantly higher in the CTX discontinuation arm (IRR = 2.27, 95% CI 1.52–3.38; p < 0.001), driven by malaria morbidity. There were 34 cases of malaria, with 33 in the CTX discontinuation arm (IRR = 33.02, 95% CI 4.52–241.02; p = 0.001). Diarrhea and pneumonia rates did not differ significantly between arms (IRR = 1.36, 95% CI 0.82–2.27, and IRR = 1.43, 95% CI 0.54–3.75, respectively). Study limitations include a lack of placebo and a lower incidence of morbidity events than expected.
Conclusions
CTX discontinuation among ART-treated, immune-reconstituted adults in a malaria-endemic region resulted in increased incidence of malaria but not pneumonia or diarrhea. Malaria endemicity may be the most relevant factor to consider in the decision to stop CTX after ART-induced immune reconstitution in regions with high infectious disease prevalence. These data support the 2014 WHO CTX guidelines.
Trial registration
ClinicalTrials.gov NCT01425073
In a randomized controlled non-inferiority trial, Christina Polyak and colleagues assess whether CTX prophylaxis remains important among HIV+ adults on ART in a malaria-endemic setting.
Editors' Summary
Background
AIDS has killed 39 million people over the past three decades, and 35 million people (mostly living in resource-limited countries) are currently infected with HIV, the virus that causes AIDS. HIV, which is usually transmitted through unprotected sex with an infected individual, gradually destroys CD4 lymphocytes and other immune system cells. Because destruction of the immune system leaves HIV-infected individuals susceptible to “opportunistic” infections, early in the AIDS epidemic, most HIV-positive individuals died within ten years of infection. In 1996, effective antiretroviral therapy (ART)—drug regimens that stop HIV replicating and allow the immune system to recover its ability to fight infections—became available. For people living in affluent countries, HIV/AIDS became a chronic condition, but because ART was expensive, HIV/AIDS remained fatal in resource-limited countries. In 2003, the international community began to work towards achieving universal access to ART. Now, at least a third of people living with HIV have access to ART, and the global mortality (death) rate from HIV/AIDS is falling.
Why Was This Study Done?
To prevent opportunistic infections, the World Health Organization (WHO) recommends cotrimoxazole (CTX) prophylaxis for HIV-infected individuals. CTX is a combination of two antimicrobial drugs that is active against a range of bacterial, fungal, and parasitic infections; prophylactic antimicrobials are taken to prevent infection. CTX decreases morbidity (illness) and mortality among HIV-infected individuals primarily by reducing the rates of malaria, pneumonia, diarrhea, and severe bacterial infections. The 2006 WHO guidelines for CTX prophylaxis recommend that, in resource-limited countries, HIV-infected patients whose CD4 count is ≤350 cells/mm3 blood should take CTX and that, in settings with a high prevalence of HIV infection and limited health infrastructure, all HIV-infected adults should take CTX. However, these guidelines were developed before access to ART was scaled-up, and CTX prophylaxis has risks (for example, drug toxicity) as well as benefits. In this unblinded non-inferiority randomized controlled trial, the researchers investigate the effects of CTX discontinuation among ART-treated HIV-infected adults in Kenya. A randomized controlled trial compares the outcomes of individuals randomly assigned to different treatments; in an unblinded trial, everyone involved in the trial knows who is taking which treatment; a non-inferiority trial investigates whether one treatment is not worse than another treatment.
What Did the Researchers Do and Find?
The researchers enrolled 500 HIV-infected adults living in a malaria-endemic region of Kenya (an area where malaria is always present) who had been treated with ART for ≥18 months, who had a CD4 count of >350 cells/mm3, and who were taking CTX. Half the participants continued to take CTX; the remainder stopped taking CTX. After 12 months of follow-up, the combined rate of morbidity (malaria, pneumonia, and diarrhea) and mortality was significantly higher in the CTX discontinuation arm than in the CTX continuation arm (a significant difference is one that is unlikely to have happened by chance). The difference in this primary outcome between the trial arms was driven by malaria morbidity—there were 33 cases of malaria in the CTX discontinuation arm but only one case in the CTX continuation arm. By contrast, the rates of pneumonia and diarrhea did not differ significantly between the trial arms.
What Do These Findings Mean?
Because the difference between the two trial arms in terms of the primary endpoint was greater than the researchers’ predefined non-inferiority limit, these findings suggest that CTX discontinuation is inferior to CTX continuation among ART-treated, immune-reconstituted HIV-infected adults living in a malaria-endemic region. The accuracy of these findings may be affected by the lack of blinding—the clinicians’ care decisions and the patients’ threshold for seeking care may have been influenced by their knowledge of their trial arm assignment. Overall, however, these findings suggest that malaria endemicity should be considered when making decisions about whether to stop CTX after ART-driven immune reconstitution. Indeed, in December 2014, following the release of preliminary data from this trial and the completion of an independent trial on CTX discontinuation, WHO issued supplemental guidelines on CTX prophylaxis. These state that CTX prophylaxis can be discontinued for HIV-infected adults who are clinically stable on ART and have evidence of immune recovery and viral suppression but recommend that CTX prophylaxis be continued regardless of CD4 cell count or HIV/AIDS clinical stage in settings where malaria is endemic and/or severe bacterial infections are common.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001934.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, information on opportunistic infections and on CTX prophylaxis, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV/AIDS in Kenya, on ART, and on opportunistic infections and CTX prophylaxis: Avert also provides personal stories about living with HIV/AIDS
WHO provides information on all aspects of HIV/AIDS, including its 2013 guidelines on using ART to treat HIV infection and its December 2014 supplement to these guidelines, which contains updated recommendations on CTX prophylaxis; a factsheet about CTX prophylaxis is also available
The 2015 World AIDS Day Report provides up-to-date information about the AIDS epidemic, including progress towards universal access to ART
More information about this trial is available
doi:10.1371/journal.pmed.1001934
PMCID: PMC4701407  PMID: 26731191
17.  Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection among Women in Africa: A Randomized Trial 
PLoS Medicine  2012;9(6):e1001236.
In a randomized control trial, Shahin Lockman and colleagues compare nevirapine-based therapy with lopinavir/ritonavir-based therapy for HIV-infected women without previous exposure to antiretroviral treatment.
Background
Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART.
Methods and Findings
In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm3 were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log10 below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm3, HIV RNA = 5.2 log10copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56–1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2–2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF.
Conclusions
Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm3.
Trial registration
ClinicalTrials.gov NCT00089505
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (mostly living in low- or middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of infection. Then, in 1996, antiretroviral therapy (ART)—cocktails of drugs that attack different parts of HIV—became available. For people living in affluent countries, HIV/AIDS became a chronic condition. But, because ART was expensive, for people living in developing countries, HIV/AIDS remained a fatal illness. In 2006, the international community set a target of achieving universal access to ART by 2010 and, although this target has not been reached, by the end of 2010, 6.6 million of the estimated 15 million people in need of ART in developing countries were receiving one of the ART regimens recommended by the World Health Organization (WHO) in its 2010 guidelines.
Why Was This Study Done?
A widely used combination for the initial treatment of HIV-infected people (particularly women) in resource-limited settings is tenofovir and emtricitabine (both nucleotide reverse transcriptase inhibitors; reverse transcriptase is essential for HIV replication) and nevirapine (NVP, a non-nucleoside reverse transcriptase inhibitor). However, little is known about the efficacy of this NVP-based ART combination. Moreover, its efficacy and toxicity has not been compared with regimens containing lopinavir/ritonavir (LPV/r). LPV/r, which inhibits the viral protease that is essential for HIV replication, is available in resource-limited settings but is usually reserved for second-line treatment. LPV/r-based ART is more expensive than NVP-based ART but if it were more effective or better tolerated than NVP-based ART, then first-line treatment with LPV/r-based ART might be cost-effective in resource-limited settings. Conversely, evidence of the clinical equivalence of NVP-based and LPV/r-based ART would provide support for NVP-based ART as an initial therapy. In this randomized equivalence trial, the researchers compare the efficacy and toxicity of NVP-based and LVP/r-based initial therapy for HIV infection among antiretroviral-naïve African women. In a randomized trial, patients are assigned different treatments by the play of chance and followed to compare the effects of these treatments; an equivalence trial asks whether the effects of two treatments are statistically equivalent.
What Did the Researchers Do and Find?
The researchers followed 500 antiretroviral-naïve HIV-infected women with a low CD4 cell count living in seven African countries, half of whom received NVP-based ART and half of whom received LPV/r-based ART, for an average of 118 weeks and recorded the time to virologic failure (the presence of virus in the blood above pre-specified levels) or death among the participants. Forty-two women in the NVP arm reached this primary endpoint (37 virologic failures and five deaths) compared to 50 women in the LPV/r arm (43 virologic failures and seven deaths), a result that indicates equivalent virologic efficacy according to preset statistical criteria. During the initial assigned treatment, similar proportions of women in both treatment arms developed serious drug-related signs and symptoms and laboratory abnormalities. However, whereas 14% of the women in the NVP arm discontinued treatment because of adverse effects, none of the women in the LPV/r arm discontinued treatment. Finally, nearly half of the women tested in the NVP arm but only 15% of the women tested in the LVP/r arm had developed any drug resistance at the time of virologic failure.
What Do These Findings Mean?
These findings indicate that, among HIV-infected, treatment-naïve African women, initial NVP-based ART is as effective as LPV/r-based ART in terms of virologic failure and death although more women in the NVP arm discontinued treatment or developed new drug resistance than in the LPV/r arm. Several limitations of this study may affect the accuracy of these findings. In particular, some of the study participants may have been exposed to single-dose NVP during childbirth to prevent mother-to-child transmission of HIV; in a parallel randomized trial, the researchers found that LPV/r-based ART was superior to NVP-based ART among women with prior exposure to single-dose NVP. Moreover, the duration of the current study means the long-term effects of the two treatments cannot be compared. Nevertheless, these findings support the WHO recommendation of NVP-based ART with careful early toxicity monitoring as an initial affordable and effective HIV treatment regiment in resource-limited settings, until access to better-tolerated and more potent regimens is possible.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001236.
Information is available from the US National Institute of Allergy and Infectious Diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including detailed information on HIV treatment and care (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in English, French and Spanish); its 2010 ART guidelines can be downloaded
More information about this trial, the OCTANE trial, is available
MedlinePlus provides detailed information about nevirapine and lopinavir/ritinovir (in English and Spanish)
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs
doi:10.1371/journal.pmed.1001236
PMCID: PMC3373629  PMID: 22719231
18.  Mortality in Patients with HIV-1 Infection Starting Antiretroviral Therapy in South Africa, Europe, or North America: A Collaborative Analysis of Prospective Studies 
PLoS Medicine  2014;11(9):e1001718.
Analyzing survival in HIV treatment cohorts, Andrew Boulle and colleagues find mortality rates in South Africa comparable to or better than those in North America by 4 years after starting antiretroviral therapy.
Please see later in the article for the Editors' Summary
Background
High early mortality in patients with HIV-1 starting antiretroviral therapy (ART) in sub-Saharan Africa, compared to Europe and North America, is well documented. Longer-term comparisons between settings have been limited by poor ascertainment of mortality in high burden African settings. This study aimed to compare mortality up to four years on ART between South Africa, Europe, and North America.
Methods and Findings
Data from four South African cohorts in which patients lost to follow-up (LTF) could be linked to the national population register to determine vital status were combined with data from Europe and North America. Cumulative mortality, crude and adjusted (for characteristics at ART initiation) mortality rate ratios (relative to South Africa), and predicted mortality rates were described by region at 0–3, 3–6, 6–12, 12–24, and 24–48 months on ART for the period 2001–2010. Of the adults included (30,467 [South Africa], 29,727 [Europe], and 7,160 [North America]), 20,306 (67%), 9,961 (34%), and 824 (12%) were women. Patients began treatment with markedly more advanced disease in South Africa (median CD4 count 102, 213, and 172 cells/µl in South Africa, Europe, and North America, respectively). High early mortality after starting ART in South Africa occurred mainly in patients starting ART with CD4 count <50 cells/µl. Cumulative mortality at 4 years was 16.6%, 4.7%, and 15.3% in South Africa, Europe, and North America, respectively. Mortality was initially much lower in Europe and North America than South Africa, but the differences were reduced or reversed (North America) at longer durations on ART (adjusted rate ratios 0.46, 95% CI 0.37–0.58, and 1.62, 95% CI 1.27–2.05 between 24 and 48 months on ART comparing Europe and North America to South Africa). While bias due to under-ascertainment of mortality was minimised through death registry linkage, residual bias could still be present due to differing approaches to and frequency of linkage.
Conclusions
After accounting for under-ascertainment of mortality, with increasing duration on ART, the mortality rate on HIV treatment in South Africa declines to levels comparable to or below those described in participating North American cohorts, while substantially narrowing the differential with the European cohorts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS has killed about 36 million people since the first recorded case of the disease in 1981, and a similar number of people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other serious infections. Early in the AIDS epidemic, HIV-positive people usually died within 10 years of becoming infected. In 1996, effective antiretroviral therapy (ART) became available and, for people living in high-income countries, HIV infection became a chronic condition. But ART was expensive, so HIV/AIDS remained largely untreated and fatal in resource-limited countries. Then, in 2003, the international community began to work towards achieving universal access to ART. By the end of 2012, nearly two-thirds of HIV-positive people (nearly 10 million individuals) living in low- and middle-income countries who were eligible for treatment because their CD4 cell count had fallen below 350/mm3 blood or because they had developed an AIDS-defining condition were receiving treatment.
Why Was This Study Done?
It is known that a larger proportion of HIV-positive patients starting ART die during the first year of treatment in sub-Saharan Africa than in Europe and North America. This difference arises in part because patients in resource-limited settings tend to have lower CD4 counts when they start treatment than patients in wealthy countries. However, the lack of reliable data on mortality (death) in resource-limited settings has made it hard to compare longer-term outcomes in different settings. Information on the long-term outcomes of HIV-positive patients receiving ART in resource-limited countries is needed to guide the development of appropriate health systems and treatment regimens in these settings. In this collaborative analysis of prospective cohort studies, the researchers compare mortality up to 4 years on ART in South Africa, Europe, and North America. A prospective cohort study follows a group of individuals over time to see whether differences in specific characteristics at the start of the study affect subsequent outcomes. A collaborative analysis combines individual patient data from several studies.
What Did the Researchers Do and Find?
The researchers combined data from four South Africa cohorts of HIV-positive patients starting ART included in the International Epidemiologic Databases to Evaluate AIDS South African (IeDEA-SA) collaboration with data from six North American cohorts and nine European cohorts included in the ART Cohort Collaboration (ART-CC). The South African cohorts were chosen because unusually for studies undertaken in countries in sub-Saharan Africa the vital status of patients (whether they had died) who had been lost to follow-up in these cohorts could be obtained from the national population register. Patients in South Africa began treatment with more advanced disease (indicated by a lower average CD4 count) than patients in Europe or North America. Notably, high early mortality after starting ART in South Africa occurred mainly in patients starting ART with a CD4 count below 50 cells/mm3. The cumulative mortality after 4 years of ART was 16.6%, 4.7%, and 15.3% in South Africa, Europe, and North America, respectively. After adjusting for patient characteristics at ART initiation, the mortality rate among patients beginning ART was initially lower in Europe and North American than in South Africa. However, although the adjusted mortality rate in Europe remained lower than the rate in South Africa, the rate in North America was higher than that in South Africa between 24 and 48 months on ART.
What Do These Findings Mean?
Although the linkage to national vital registration systems (databases of births and deaths) undertaken in this collaborative analysis is likely to have greatly reduced bias due to under-ascertainment of mortality, the accuracy of these findings may still be limited by differences in how this linkage was undertaken in different settings. Nevertheless, these findings suggest that mortality among HIV-infected patients receiving ART in South Africa, although initially higher than in Europe and North America, rapidly declines with increasing duration on ART and, after 4 years of treatment, approaches the rate seen in high-income settings. Intriguingly, these findings also highlight the relatively higher late mortality in North America compared to either Europe or South Africa, a result that needs to be investigated to explore the extent to which differences in mortality ascertainment, patient characteristics and comorbidities, or health systems and treatment regimens contribute to variations in outcomes among HIV-positive patients in various settings.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001718.
This study is further discussed in a PLOS Medicine Perspective by Agnes Binagwaho and colleagues
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on universal access to ART, on HIV and AIDS in sub-Saharan Africa, and on HIV and AIDS in South Africa (in English and Spanish)
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); its 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infections: recommendations for a public health approach are available
The 2013 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
Information about the International Epidemiologic Databases to Evaluate AIDS South African (IeDEA-SA) collaboration and about the ART Cohort Collaboration is available
Personal stories about living with HIV/AIDS are available through Avert, Nam/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001718
PMCID: PMC4159124  PMID: 25203931
19.  When to Start Antiretroviral Therapy in Children Aged 2–5 Years: A Collaborative Causal Modelling Analysis of Cohort Studies from Southern Africa 
PLoS Medicine  2013;10(11):e1001555.
Michael Schomaker and colleagues estimate the mortality associated with starting ART at different CD4 thresholds among children aged 2–5 years using observational data collected in cohort studies in Southern Africa.
Please see later in the article for the Editors' Summary
Background
There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2–5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS–Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2–5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count <750 cells/mm3 or CD4 percentage (CD4%) <25%.
Methods and Findings
ART-naïve children enrolling in HIV care at IeDEA-SA sites who were between 24 and 59 mo of age at first visit and with ≥1 visit prior to ART initiation and ≥1 follow-up visit were included. We estimated mortality for ART initiation at different CD4 thresholds for up to 3 y using g-computation, adjusting for measured time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score. Confidence intervals were constructed using bootstrapping.
The median (first; third quartile) age at first visit of 2,934 children (51% male) included in the analysis was 3.3 y (2.6; 4.1), with a median (first; third quartile) CD4 count of 592 cells/mm3 (356; 895) and median (first; third quartile) CD4% of 16% (10%; 23%). The estimated cumulative mortality after 3 y for ART initiation at different CD4 thresholds ranged from 3.4% (95% CI: 2.1–6.5) (no ART) to 2.1% (95% CI: 1.3%–3.5%) (ART irrespective of CD4 value). Estimated mortality was overall higher when initiating ART at lower CD4 values or not at all. There was no mortality difference between starting ART immediately, irrespective of CD4 value, and ART initiation at the WHO 2010 recommended threshold of CD4 count <750 cells/mm3 or CD4% <25%, with mortality estimates of 2.1% (95% CI: 1.3%–3.5%) and 2.2% (95% CI: 1.4%–3.5%) after 3 y, respectively. The analysis was limited by loss to follow-up and the unavailability of WHO staging data.
Conclusions
The results indicate no mortality difference for up to 3 y between ART initiation irrespective of CD4 value and ART initiation at a threshold of CD4 count <750 cells/mm3 or CD4% <25%, but there are overall higher point estimates for mortality when ART is initiated at lower CD4 values.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Infection with HIV, the virus that causes AIDS, contributes substantially to the burden of disease in children. Worldwide, more than 3 million children younger than 15 years old (90% of whom live in sub-Saharan Africa) are HIV-positive, and every year around 330,000 more children are infected with HIV. Children usually acquire HIV from their mother during pregnancy, birth, or breastfeeding. The virus gradually destroys CD4 lymphocytes and other immune system cells, leaving infected children susceptible to other potentially life-threatening infections. HIV infection can be kept in check, with antiretroviral therapy (ART)—cocktails of drugs that have to be taken daily throughout life. ART is very effective in children but is expensive, and despite concerted international efforts over the past decade to provide universal access to ART, in 2011, less than a third of children who needed ART were receiving it.
Why Was This Study Done?
For children diagnosed as HIV-positive between the ages of two and five years, the 2010 World Health Organization (WHO) guidelines for the treatment of HIV infection recommended that ART be initiated when the CD4 count dropped below 750 cells/mm3 blood or when CD4 cells represented less than 25% of the total lymphocyte population (CD4 percent). Since June 2013, however, WHO has recommended that all HIV-positive children in this age group begin ART immediately, irrespective of their CD4 values. Earlier ART initiation might reduce mortality (death) and morbidity (illness), but it could also increase the risk of toxicity and of earlier development of drug resistance. In this causal modeling analysis, the researchers estimate the mortality associated with starting ART at different CD4 thresholds among children aged 2–5 years using observational data collected in cohort studies of ART undertaken in southern Africa. Specifically, they compared the estimated mortality associated with the WHO 2010 and WHO 2013 guidelines. Observational studies compare the outcomes of groups (cohorts) with different interventions (here, the timing of ART initiation). Data from such studies are affected by time-dependent confounding: CD4 count, for example, varies with time and is a predictor of both ART initiation and the probability of death. Causal modeling techniques take time-dependent confounding into account and enable the estimation of the causal effect of an intervention on an outcome from observational data.
What Did the Researchers Do and Find?
The researchers used g-computation (a type of causal modeling) adjusting for time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score (a measure of whether a child is underweight for their age that provides a proxy indicator of the clinical stage of HIV infection) to estimate mortality for ART initiation at different CD4 thresholds in 2,934 ART-naïve, HIV-positive children aged 2–5 years old at their first visit to one of eight study sites in southern Africa. The average initial CD4 values of these children were a CD4 count of 592 cells/mm3 and a CD4 percent of 16%. The estimated cumulative mortality after three years was 3.4% in all children if ART was never started. If all children had started ART immediately after diagnosis irrespective of CD4 value or if the 2010 WHO-recommended threshold of a CD4 count below 750 cells/mm3 or a CD4 percent below 25% was followed, the estimated cumulative mortalities after three years were 2.1% and 2.2%, respectively (a statistically non-significant difference).
What Do These Findings Mean?
These findings suggest that, among southern African children aged 2–5 years at HIV diagnosis, there is no difference in mortality for up to three years between children in whom ART is initiated immediately and those in whom ART initiation is deferred until their CD4 value falls below a CD4 count of 750 cells/mm3 or a CD4 percent of 25%. Although causal modeling was used in this analysis, the accuracy of these results may be affected by residual confounding. For example, the researchers were unable to adjust for the clinical stage of HIV disease at HIV diagnosis and instead had to use weight-for-age z-scores as a proxy indicator of disease severity. Other limitations of the study include the large number of children lost to follow-up and a possible lack of generalizability—most of the study participants were from urban settings in South Africa. Importantly, however, these findings suggest that the recent change in the WHO guidelines for ART initiation in young children is unlikely to increase or reduce mortality, with the proviso that the long-term effects of earlier ART initiation such as toxicity and the development of resistance to ART need to be explored further.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001555
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Africa and on children and HIV/AIDS (in English and Spanish)
The UNAIDS World AIDS Day Report 2012 provides up-to-date information about the AIDS epidemic and efforts to halt it; the 2013 Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children by 2015
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 guidelines for ART in infants and children and its 2013 consolidated guidelines on the use of ART can be downloaded
The researchers involved in this study are part of the International Epidemiologic Databases to Evaluate AIDSSouthern Africa collaboration, which develops and implements methodology to generate the large datasets needed to address high-priority research questions related to HIV/AIDS
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001555
PMCID: PMC3833834  PMID: 24260029
20.  Causes of Acute Hospitalization in Adolescence: Burden and Spectrum of HIV-Related Morbidity in a Country with an Early-Onset and Severe HIV Epidemic: A Prospective Survey 
PLoS Medicine  2010;7(2):e1000178.
Rashida Ferrand and colleagues show that HIV infection is the commonest cause of hospitalization among adolescents in a high HIV prevalence setting.
Background
Survival to older childhood with untreated, vertically acquired HIV infection, which was previously considered extremely unusual, is increasingly well described. However, the overall impact on adolescent health in settings with high HIV seroprevalence has not previously been investigated.
Methods and Findings
Adolescents (aged 10–18 y) systematically recruited from acute admissions to the two public hospitals in Harare, Zimbabwe, answered a questionnaire and underwent standard investigations including HIV testing, with consent. Pre-set case-definitions defined cause of admission and underlying chronic conditions. Participation was 94%. 139 (46%) of 301 participants were HIV-positive (median age of diagnosis 12 y: interquartile range [IQR] 11–14 y), median CD4 count = 151; IQR 57–328 cells/µl), but only four (1.3%) were herpes simplex virus-2 (HSV-2) positive. Age (median 13 y: IQR 11–16 y) and sex (57% male) did not differ by HIV status, but HIV-infected participants were significantly more likely to be stunted (z-score<−2: 52% versus 23%, p<0.001), have pubertal delay (15% versus 2%, p<0.001), and be maternal orphans or have an HIV-infected mother (73% versus 17%, p<0.001). 69% of HIV-positive and 19% of HIV-negative admissions were for infections, most commonly tuberculosis and pneumonia. 84 (28%) participants had underlying heart, lung, or other chronic diseases. Case fatality rates were significantly higher for HIV-related admissions (22% versus 7%, p<0.001), and significantly associated with advanced HIV, pubertal immaturity, and chronic conditions.
Conclusion
HIV is the commonest cause of adolescent hospitalisation in Harare, mainly due to adult-spectrum opportunistic infections plus a high burden of chronic complications of paediatric HIV/AIDS. Low HSV-2 prevalence and high maternal orphanhood rates provide further evidence of long-term survival following mother-to-child transmission. Better recognition of this growing phenomenon is needed to promote earlier HIV diagnosis and care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981, and more than 30 million people are now infected with the human immunodeficiency virus (HIV) that causes AIDS. HIV destroys the cells in the immune system that normally provide protection against disease-causing organisms. Consequently, people infected with HIV are susceptible to so-called opportunistic infections, including tuberculosis and pneumonia. HIV is most commonly spread through unprotected sex with an infected partner but another major route of transmission is mother-to-child (vertical transmission) during pregnancy or delivery or during breast feeding. Mother-to-child transmission can be prevented by giving antiviral drugs to HIV-positive mothers during their pregnancy and to their newborn children. But, although most mothers in developed countries have access to this intervention, fewer than half of HIV-positive mothers in low- and middle-income countries receive this treatment and, every year, nearly half a million children become infected with HIV.
Why Was This Study Done?
It is generally thought that HIV infections in infants progress rapidly and that half of the children who acquire HIV from their mothers will die before their second birthday if not treated with antiretroviral drugs. However, as the AIDS epidemic matures, more children are surviving to adolescence with untreated, vertically acquired HIV infection in sub-Saharan Africa, the region where most children with HIV/AIDS live. Little is known about the burden of HIV infection and its contribution to illness and death in adolescents in sub-Saharan Africa but this information is needed to help health care providers prepare for this new aspect of the AIDS epidemic. In this study, the researchers examine the causes of acute hospital admissions (admissions for conditions with a sudden onset and usually a short course) among adolescents in Zimbabwe, a country where the HIV epidemic started early and where one in seven adults is HIV-positive and more than 17,000 children are infected with HIV every year, mainly through vertical transmission.
What Did the Researchers Do and Find?
The researchers recruited 301 10–18-year olds who were admitted to each of the two public hospitals in Harare (Zimbabwe) for acute illnesses between September 2007 and April 2008. Each patient completed a questionnaire about themselves and their health and underwent standard investigations, including HIV testing. Nearly half the participants were HIV positive; about a quarter of these HIV-positive individuals only found out about their status during the study. HIV-positive participants were more likely to be stunted, to have pubertal delay, and to be maternal orphans or have an HIV-infected mother than HIV-negative participants. 69% of HIV-positive participants were admitted to hospital because of infections, often tuberculosis or pneumonia whereas only 19% of the HIV-negative participants were admitted for infections. More than a quarter of all the participants had underlying heart, lung, or other chronic conditions. Finally, 22% of the HIV-positive participants died while in hospital compared to only 7% of the HIV-negative participants. Factors that increased the risk of death among all the participants were advanced HIV infection, pubertal immaturity, and chronic conditions.
What Do These Findings Mean?
These findings indicate that HIV infection is the commonest cause of acute adolescent admission to hospital in Harare (and probably elsewhere in Zimbabwe). Most of these admissions are due to opportunistic infections similar to those seen in HIV-positive adults and to long-term complications of having HIV/AIDS as an infant such as delayed puberty. Other findings indicate that most of the HIV-positive adolescents who participated in this study were infected via vertical transmission, which supports the idea that long-term survival after vertical infection is possible. Because the AIDS epidemic started early in Zimbabwe, there is likely to be a lag before adolescent survivors of vertical HIV transmission become common elsewhere. Nevertheless, all African countries and other places where HIV infection in adults is common need to recognize that the burden of HIV in their acutely unwell adolescents is likely to increase over the next few years. To deal with this emerging aspect of the AIDS epidemic, measures must be introduced to ensure early diagnosis of HIV in this previously neglected age group so that treatment can be started before HIV-positive adolescents become critically ill.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000178.
This study is further discussed in a PLoS Medicine Perspective by Glenda Gray
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including a list of articles and other sources of information about the primary care of adolescents with HIV
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV and AIDS in Zimbabwe, and on children, HIV, and AIDS (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
doi:10.1371/journal.pmed.1000178
PMCID: PMC2814826  PMID: 20126383
21.  Risk Factors and Outcomes for Late Presentation for HIV-Positive Persons in Europe: Results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE) 
PLoS Medicine  2013;10(9):e1001510.
Amanda Mocroft and colleagues investigate risk factors and health outcomes associated with diagnosis at a late stage of infection in individuals across Europe.
Please see later in the article for the Editors' Summary
Background
Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality.
Methods and Findings
LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm3 or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95–0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19–20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55–12.43).
Conclusions
LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year about 2.5 million people become newly infected with HIV, the virus that causes AIDS. HIV can be transmitted through unprotected sex with an infected partner, from an HIV-positive mother to her unborn baby, or through injection of drugs. Most people do not become ill immediately after infection with HIV although some develop a short influenza-like illness. The next stage of the HIV infection, which may last up to 10 years, also has no major symptoms but, during this stage, HIV slowly destroys immune system cells, including CD4 cells, a type of lymphocyte. Eventually, when the immune system is unable to fight off infections by other disease-causing organisms, HIV-positive people develop AIDS-defining conditions—unusual viral, bacterial, and fungal infections and unusual tumors. Progression to AIDS occurs when any severe AIDS-defining condition is diagnosed, when the CD4 count in the blood falls below 200 cells/mm3, or when CD4 cells account for fewer than 15% of lymphocytes.
Why Was This Study Done?
People need to know they are HIV positive as soon as possible after they become infected because antiretroviral therapy, which controls but does not cure HIV infection, works best if it is initiated when people still have a relatively high CD4 count. Early diagnosis also reduces the risk of onward HIV transmission. However, 40%–60% of HIV-positive individuals in developed countries are not diagnosed until they have a low CD4 count or an AIDS-defining illness. Reasons for such late presentation include fear of discrimination or stigmatization, limited knowledge about HIV risk factors, testing, and treatment together with missed opportunities to offer an HIV test. Policy makers involved in national and international HIV control programs need detailed information about patterns of late presentation before they can make informed decisions about how to reduce this problem. In this study, therefore, the researchers use data collected by the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) to analyze trends in late presentation over time across Europe and in different groups of people at risk of HIV infection and to investigate the clinical consequences of late presentation.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 84,524 individuals participating in more than 20 observational studies that were undertaken in 35 European countries and that investigated outcomes among HIV-positive people. Nearly 54% of the participants were late presenters—individuals who had a CD4 count of less than 350 cells/mm3 or an AIDS-defining illness within 6 months of HIV diagnosis. Late presentation was highest among heterosexual males, in Southern European countries, and among people originating in Africa. Overall, late presentation decreased from 57.3% in 2000 to 51.7% in 2010/11. However, whereas late presentation decreased over time among men having sex with men in Central and Northern Europe, for example, it increased over time among female heterosexuals in Southern Europe. Finally, among the 8,000 individuals who developed a new AIDS-defining illness or died during follow-up, compared to non-late presentation, late presentation was associated with an increased incidence of AIDS/death in all regions of Europe during the first and second year after HIV diagnosis (but not in later years); the largest increase in incidence (13-fold) occurred during the first year after diagnosis in Southern Europe.
What Do These Findings Mean?
These findings indicate that, although late presentation with HIV infection has decreased in recent years, it remains an important issue across Europe and in all groups of people at risk of HIV infection. They also show that individuals presenting late have a worse clinical outlook, particularly in the first and second year after diagnosis compared to non-late presenters. Several aspects of the study design may affect the accuracy and usefulness of these findings, however. For example, some of the study participants recorded as late presenters may have been people who were aware of their HIV status but who chose not to seek care for HIV infection, or may have been seen in the health care system prior to HIV diagnosis without being offered an HIV test. Delayed entry into care and late presentation are likely to have different risk factors, a possibility that needs to be studied further. Despite this and other study limitations, these findings nevertheless suggest that HIV testing strategies that encourage early testing in all populations at risk, that ensure timely referrals, and that improve retention in care are required to further reduce the incidence of late presentation with HIV infection in Europe.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001510.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including detailed information on the stages of HIV infection and on HIV and AIDS in Europe (in English and Spanish)
The HIV in Europe Initiative has information about strategies to improve earlier diagnosis and access to care in Europe
Information about COHERE, which was established in 2005 to conduct epidemiological research on the prognosis and outcome of HIV-infected people from across Europe, is available; more information on the consensus definition of late presentation used in this study is available through the HIV in Europe initiative
Patient stories about living with HIV/AIDS are available through Avert and through the nonprofit website Healthtalkonline
doi:10.1371/journal.pmed.1001510
PMCID: PMC3796947  PMID: 24137103
22.  Impact of Round-the-Clock, Rapid Oral Fluid HIV Testing of Women in Labor in Rural India 
PLoS Medicine  2008;5(5):e92.
Background
Testing pregnant women for HIV at the time of labor and delivery is the last opportunity for prevention of mother-to-child HIV transmission (PMTCT) measures, particularly in settings where women do not receive adequate antenatal care. However, HIV testing and counseling of pregnant women in labor is a challenge, especially in resource-constrained settings. In India, many rural women present for delivery without any prior antenatal care. Those who do get antenatal care are not always tested for HIV, because of deficiencies in the provision of HIV testing and counseling services. In this context, we investigated the impact of introducing round-the-clock, rapid, point-of-care HIV testing and counseling in a busy labor ward at a tertiary care hospital in rural India.
Methods and Findings
After they provided written informed consent, women admitted to the labor ward of a rural teaching hospital in India were offered two rapid tests on oral fluid and finger-stick specimens (OraQuick Rapid HIV-1/HIV-2 tests, OraSure Technologies). Simultaneously, venous blood was drawn for conventional HIV ELISA testing. Western blot tests were performed for confirmatory testing if women were positive by both rapid tests and dual ELISA, or where test results were discordant. Round-the-clock (24 h, 7 d/wk) abbreviated prepartum and extended postpartum counseling sessions were offered as part of the testing strategy. HIV-positive women were administered PMTCT interventions. Of 1,252 eligible women (age range 18 y to 38 y) approached for consent over a 9 mo period in 2006, 1,222 (98%) accepted HIV testing in the labor ward. Of these, 1,003 (82%) women presented with either no reports or incomplete reports of prior HIV testing results at the time of admission to the labor ward. Of 1,222 women, 15 were diagnosed as HIV-positive (on the basis of two rapid tests, dual ELISA and Western blot), yielding a seroprevalence of 1.23% (95% confidence interval [CI] 0.61%–1.8%). Of the 15 HIV test–positive women, four (27%) had presented with reported HIV status, and 11 (73%) new cases of HIV infection were detected due to rapid testing in the labor room. Thus, 11 HIV-positive women received PMTCT interventions on account of round-the-clock rapid HIV testing and counseling in the labor room. While both OraQuick tests (oral and finger-stick) were 100% specific, one false-negative result was documented (with both oral fluid and finger-stick specimens). Of the 15 HIV-infected women who delivered, 13 infants were HIV seronegative at birth and at 1 and 4 mo after delivery; two HIV-positive infants died within a month of delivery.
Conclusions
In a busy rural labor ward setting in India, we demonstrated that it is feasible to introduce a program of round-the-clock rapid HIV testing, including prepartum and extended postpartum counseling sessions. Our data suggest that the availability of round-the-clock rapid HIV testing resulted in successful documentation of HIV serostatus in a large proportion (82%) of rural women who were unaware of their HIV status when admitted to the labor room. In addition, 11 (73%) of a total of 15 HIV-positive women received PMTCT interventions because of round-the-clock rapid testing in the labor ward. These findings are relevant for PMTCT programs in developing countries.
Nitika Pant Pai and colleagues report the results of offering a round-the-clock rapid HIV testing program in a rural labor ward setting in India.
Editors' Summary
Background.
Since the first reported case of AIDS (acquired immunodeficiency syndrome) in 1981, the number of people infected with the human immunodeficiency virus (HIV), which causes AIDS, has risen steadily. Now, more than 33 million people are infected, almost half of them women. HIV is most often spread through unprotected sex with an infected partner, but mother-to-child transmission (MTCT) of HIV is also an important transmission route. HIV-positive women often pass the virus to their babies during pregnancy, labor and delivery, and breastfeeding, if nothing is done to prevent viral transmission. In developed countries, interventions such as voluntary testing and counseling, safe delivery practices (for example, offering cesarean delivery to HIV-positive women), and antiretroviral treatment of the mother during pregnancy and labor and of her newborn baby have minimized the risk of MTCT. In developing countries, the prevention of MTCT (PMTCT) is much less effective, in part because pregnant women often do not know their HIV status. Consequently, in 2007, nearly half a million children became infected with HIV mainly through MTCT.
Why Was This Study Done?
In many developing countries, women do not receive adequate antenatal care. In India, for example, nearly half the women living in rural areas do not receive any antenatal care until they are in labor. This gives health care providers very little time in which to counsel women about HIV infection, test them for the virus, and start interventions to prevent MTCT. Furthermore, testing pregnant women in labor for HIV and counseling them is a challenge, particularly where resources are limited. In this study, therefore, the researchers investigate the feasibility and impact of introducing round-the-clock, rapid HIV testing and counseling in a busy labor ward in a rural teaching hospital in Sevagram, India.
What Did the Researchers Do and Find?
Women admitted to the labor ward between January and September 2006 were offered two rapid HIV tests—one that used a saliva sample and the other that used blood taken from a finger prick. Blood was also taken from a vein for conventional HIV testing. All the women were given a 15-minute counseling session about how HIV is transmitted, the importance of HIV testing, and information on PMTCT before their child was born (prepartum counseling), and a longer postpartum counseling session. HIV-positive women were given a cesarean delivery where possible and antiretroviral drug treatment to reduce MTCT. 1,222 women admitted to the labor ward during the study period (1,003 of whom did not know their HIV status) accepted HIV testing. Of 15 study participants who were HIV positive, 11 learnt of their HIV status in the labor room. Two babies born to these HIV-positive women were HIV positive and died within a month of delivery; the other 13 babies were HIV negative at birth and at 1 and 4 months after delivery. Finally, the rapid HIV tests missed only one HIV-positive woman (no false-positive results were given), and the time from enrolling a woman into the study through referring her for PMTCT intervention where necessary averaged 40–60 minutes.
What Do These Findings Mean?
These findings show the feasibility and positive impact of the introduction of round-the-clock pre- and postpartum HIV counseling and rapid HIV testing into a busy rural Indian labor ward. Few of the women entering this ward knew their HIV status previously but the introduction of these facilities in this setting successfully informed these women of their HIV status. In addition, the round-the-clock counseling and testing led to 11 women and their babies receiving PMTCT interventions who would otherwise have been missed. These findings need to be confirmed in other settings and the cost-effectiveness and sustainability of this approach for the improvement of PMTCT in developing countries needs to be investigated. Nevertheless, these findings suggest that round-the-clock rapid HIV testing might be an effective and acceptable way to reduce MTCT of HIV in many developing countries.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050092.
Read a related PLoS Medicine Perspective article
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and on HIV infection in women
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Women, Children, and HIV provides extensive information on the prevention of mother-to-child transmission of HIV in developing countries
Information is available from Avert, an international AIDS charity, on HIV and AIDS in India, on women, HIV, and AIDS, and on HIV and AIDS prevention, including the prevention of mother-to-child transmission
AIDSinfo, a service of the US Department of Health and Human Services provides health information for HIV-positive pregnant women (in English and Spanish)
doi:10.1371/journal.pmed.0050092
PMCID: PMC2365974  PMID: 18462011
23.  Early and Late Direct Costs in a Southern African Antiretroviral Treatment Programme: A Retrospective Cohort Analysis 
PLoS Medicine  2009;6(12):e1000189.
Gary Maartens and colleagues describe the direct heath care costs and identify the drivers of cost over time in an HIV managed care program in Southern Africa.
Background
There is a paucity of data on the health care costs of antiretroviral therapy (ART) programmes in Africa. Our objectives were to describe the direct heath care costs and establish the cost drivers over time in an HIV managed care programme in Southern Africa.
Methods/Findings
We analysed the direct costs of treating HIV-infected adults enrolled in the managed care programme from 3 years before starting non-nucleoside reverse transcriptase inhibitor-based ART up to 5 years afterwards. The CD4 cell count criterion for starting ART was <350 cells/µl. We explored associations between variables and mean total costs over time using a generalised linear model with a log-link function and a gamma distribution. Our cohort consisted of 10,735 patients (59.4% women) with 594,497 mo of follow up data (50.9% of months on ART). Median baseline CD4+ cell count and viral load were 125 cells/µl and 5.16 log10 copies/ml respectively. There was a peak in costs in the period around ART initiation (from 4 mo before until 4 mo after starting ART) driven largely by hospitalisation, following which costs plateaued for 5 years. The variables associated with changes in mean total costs varied with time. Key early associations with higher costs were low baseline CD4+ cell count, high baseline HIV viral load, and shorter duration in HIV care prior to starting ART; whilst later associations with higher costs were lower ART adherence, switching to protease inhibitor-based ART, and starting ART at an older age.
Conclusions
Drivers of mean total costs changed considerably over time. Starting ART at higher CD4 counts or longer pre-ART care should reduce early costs. Monitoring ART adherence and interventions to improve it should reduce later costs. Cost models of ART should take into account these time-dependent cost drivers, and include costs before starting ART.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 30 million people (22 million people in sub-Saharan Africa alone) are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, on average HIV-positive people died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART; combinations of powerful antiretroviral drugs) was developed. For people living in affluent, developed countries HIV/AIDS became a chronic, treatable condition, but for the millions of HIV-infected people living in low- and middle-income countries, effective treatment was unavailable and HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global health emergency and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in developing countries. By the end of 2008, of the 9.5 million people in need of ART in low- and middle-income countries, more than 4 million people were receiving treatment.
Why Was This Study Done?
Good progress is being made towards achieving universal access to ART, partly because the cost of antiretroviral drugs has plummeted in developing countries. But the provision of antiretroviral drugs is not the only direct cost associated with ART. General practitioner, specialist, and maternity-related care for patients receiving ART, hospital accommodation when necessary, and the investigations that are needed to monitor the progress of HIV infection such as CD4 cell counts and viral load measurements all incur considerable costs. To use their limited resources effectively, public-health officials in developing countries need to know as much as possible about the direct costs of HIV health care but few studies have investigated these costs, particularly those incurred before an individual starts taking ART. In this study, the researchers explore health care costs in a South African private-sector HIV/AIDS program and examine the variables that drive the costs of HIV health care around the time of ART initiation and during later phases of ART.
What Did the Researchers Do and Find?
The researchers analyzed the direct costs of treating more than 100,000 HIV-infected adults enrolled in a private HIV care program in South Africa from 3 years before they started ART until up to 5 years after ART initiation; within this program, individuals began to receive ART when their CD4 cell count fell below 350 cells/µl of blood. The researchers found a peak in direct health costs from 4 months before to 4 months after starting ART (the “peri-ART” period), which was driven mainly by hospital costs. After the peri-ART period, costs dropped (although not to the levels seen before this period) and stabilized at an intermediate level for the next 5 years. Detailed statistical analyses suggest that the key variables associated with higher costs in the peri-ART period were a low baseline CD4 cell count, a high baseline HIV viral load, and a shorter time in HIV care before ART initiation. The key variable associated with higher costs later in ART was lower adherence to the drug therapy. That is, costs were higher among patients who did not take their antiretroviral drugs regularly.
What Do These Findings Mean?
This study involved patients enrolled in a private health care program in which the criteria for initiating ART differed somewhat from those recommended by the World Health Organization for ART initiation in resource-limited settings. Thus, the absolute mean total costs calculated by the researchers are unlikely to be generalizable to public HIV care systems in South Africa and in other resource-poor settings. However, the finding that the drivers of mean total costs change considerably over time may be generalizable and provides some useful information for public-health planners that can now be tested in other, more resource-limited patient populations. In particular, the findings of this study suggest that the high early costs of ART programs could be reduced by starting ART at higher CD4 cell counts or by providing longer pre-ART care. In addition, the findings suggest that monitoring ART adherence and introducing interventions to improve ART adherence could reduce the later direct costs of ART programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000189.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV and AIDS in Africa, and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment, including the September 2009 progress report (in English and French)
The US Centers for Disease Control and Prevention also provides information on global efforts to deal with the HIV/AIDS epidemic
doi:10.1371/journal.pmed.1000189
PMCID: PMC2777319  PMID: 19956658
24.  Mortality rates and causes of death in a cohort of HIV-infected and uninfected women, 1993–1999 
HIV/AIDS-associated and non-HIV/AIDS-associated death rates and causes of death between 1993 and 1999 were examined in 885 HIV-infected women and 425 uninfected women of the HIV Epidemiology Research Study cohort. Causes of death were determined by review of death certificates and the National Death Index. Adjusted bazard ratios were calculated for mortality risk factors. In the 885 HIV-infected women and 425 uninfected women, 234 deaths and 8 deaths, respectively, occurred by December 31, 1999. All-cause death rates in the HIV-infected women were unchanged between the pre-HAART (1993–1996) and HAART eras (1997–1999) —5.1 versus 5.4 deaths per 100 person-years (py). AIDS as a cause of death decreased from 58% of all deaths in 1996 to 19% in 1999, while HAART use increased to 42% by the end of 1999. In spite of the modest proportion ever using HAART, HIV-related mortality rates did decline, particularly in women with CD4+cell counts less than 200/mm3. Drug-related factors were prominent: for the 129 non-AIDS-defining deaths, hepatitis C positivity (relative bazard [RH] 2.6, P<0.001) and injection drug use (RH 1.7, P=0.02) were strong predictors of mortality, but were not significant in the Cox model for 105 AIDS-defining deaths (RH 0.9, P>30 and RH 0.7, P>.30, respectively. The regression analysis findings, along with the high percentage of non-AIDS deaths attributable to illicit drug use, suggest that high levels of drug use in this population offset improvements in mortality from declining numbers of deaths due to AIDS.
doi:10.1093/jurban/jtg074
PMCID: PMC3456216  PMID: 14709715
Women; Mortality; Cause of death; HIV; AIDS; Injection drug use
25.  Projections of Global Mortality and Burden of Disease from 2002 to 2030 
PLoS Medicine  2006;3(11):e442.
Background
Global and regional projections of mortality and burden of disease by cause for the years 2000, 2010, and 2030 were published by Murray and Lopez in 1996 as part of the Global Burden of Disease project. These projections, which are based on 1990 data, continue to be widely quoted, although they are substantially outdated; in particular, they substantially underestimated the spread of HIV/AIDS. To address the widespread demand for information on likely future trends in global health, and thereby to support international health policy and priority setting, we have prepared new projections of mortality and burden of disease to 2030 starting from World Health Organization estimates of mortality and burden of disease for 2002. This paper describes the methods, assumptions, input data, and results.
Methods and Findings
Relatively simple models were used to project future health trends under three scenarios—baseline, optimistic, and pessimistic—based largely on projections of economic and social development, and using the historically observed relationships of these with cause-specific mortality rates. Data inputs have been updated to take account of the greater availability of death registration data and the latest available projections for HIV/AIDS, income, human capital, tobacco smoking, body mass index, and other inputs. In all three scenarios there is a dramatic shift in the distribution of deaths from younger to older ages and from communicable, maternal, perinatal, and nutritional causes to noncommunicable disease causes. The risk of death for children younger than 5 y is projected to fall by nearly 50% in the baseline scenario between 2002 and 2030. The proportion of deaths due to noncommunicable disease is projected to rise from 59% in 2002 to 69% in 2030. Global HIV/AIDS deaths are projected to rise from 2.8 million in 2002 to 6.5 million in 2030 under the baseline scenario, which assumes coverage with antiretroviral drugs reaches 80% by 2012. Under the optimistic scenario, which also assumes increased prevention activity, HIV/AIDS deaths are projected to drop to 3.7 million in 2030. Total tobacco-attributable deaths are projected to rise from 5.4 million in 2005 to 6.4 million in 2015 and 8.3 million in 2030 under our baseline scenario. Tobacco is projected to kill 50% more people in 2015 than HIV/AIDS, and to be responsible for 10% of all deaths globally. The three leading causes of burden of disease in 2030 are projected to include HIV/AIDS, unipolar depressive disorders, and ischaemic heart disease in the baseline and pessimistic scenarios. Road traffic accidents are the fourth leading cause in the baseline scenario, and the third leading cause ahead of ischaemic heart disease in the optimistic scenario. Under the baseline scenario, HIV/AIDS becomes the leading cause of burden of disease in middle- and low-income countries by 2015.
Conclusions
These projections represent a set of three visions of the future for population health, based on certain explicit assumptions. Despite the wide uncertainty ranges around future projections, they enable us to appreciate better the implications for health and health policy of currently observed trends, and the likely impact of fairly certain future trends, such as the ageing of the population, the continued spread of HIV/AIDS in many regions, and the continuation of the epidemiological transition in developing countries. The results depend strongly on the assumption that future mortality trends in poor countries will have a relationship to economic and social development similar to those that have occurred in the higher-income countries.
The presented projections suggest a dramatic shift in the distribution of deaths from younger to older ages and from communicable, maternal, perinatal, and nutritional causes to non-communicable disease causes. HIV/AIDS and tobacco remain major killers and possible targets for intervention.
Editors' Summary
Background.
For most of human history, little has been known about the main causes of illness in different countries and which diseases kill most people. But public-health officials need to know whether heart disease kills more people than cancer in their country, for example, or whether diabetes causes more disability than mental illness so that they can use their resources wisely. They also have to have some idea about how patterns of illness (morbidity) and death (mortality) are likely to change so that they can plan for the future. In the early 1990s, the World Bank sponsored the 1990 Global Burden of Disease study carried out by researchers at Harvard University and the World Health Organization (WHO). This study provided the first comprehensive, global estimates of death and illness by age, sex, and region. It also provided projections of the global burden of disease and mortality up to 2020 using models that assumed that health trends are related to a set of independent variables. These variables were income per person (as people become richer, they, live longer), average number of years of education (as this “human capital” increases, so does life expectancy), time (to allow for improved knowledge about various diseases), and tobacco use (a major global cause of illness and death).
Why Was This Study Done?
These health projections have been widely used by WHO and governments to help them plan their health policies. However, because they are based on the 1990 estimates of the global burden of disease, the projections now need updating, particularly since they underestimate the spread of HIV/AIDS and the associated increase in death from tuberculosis. In this study, the researchers used similar methods to those used in the 1990 Global Burden of Disease study to prepare new projections of mortality and burden of disease up to 2030 starting from the 2002 WHO global estimates of mortality and burden of disease.
What Did the Researchers Do and Find?
As before, the researchers used projections of socio-economic development to model future patterns of mortality and illness for a baseline scenario, a pessimistic scenario that assumed a slower rate of socio-economic development, and an optimistic scenario that assumed a faster rate of growth. Their analysis predicts that between 2002 and 2030 for all three scenarios life expectancy will increase around the world, fewer children younger than 5 years will die, and the proportion of people dying from non-communicable diseases such as heart disease and cancer will increase. Although deaths from infectious diseases will decrease overall, HIV/AIDS deaths will continue to increase; the exact magnitude of the increase will depend on how many people have access to antiretroviral drugs and the efficacy of prevention programs. But, even given the rise in HIV/AIDS deaths, the new projections predict that more people will die of tobacco-related disease than of HIV/AIDS in 2015. The researchers also predict that by 2030, the three leading causes of illness will be HIV/AIDS, depression, and ischaemic heart disease (problems caused by a poor blood supply to the heart) in the baseline and pessimistic scenarios; in the optimistic scenario, road-traffic accidents will replace heart disease as the third leading cause (there will be more traffic accidents with faster economic growth).
What Do These Findings Mean?
The models used by the researchers provide a wealth of information about possible patterns of global death and illness between 2002 and 2030, but because they include many assumptions, like all models, they can provide only indications of future trends, not absolute figures. For example, based on global mortality data from 2002, the researchers estimate that global deaths in 2030 will be 64.9 million under the optimistic scenario. However, the actual figure may be quite a bit bigger or smaller because accurate baseline counts of deaths were not available for every country in the world. Another limitation of the study is that the models used assume that future increases in prosperity in developing countries will affect their population's health in the same way as similar increases affected health in the past in countries with death registration data (these are mostly developed countries). However, even given these and other limitations, the projections reported in this study provide useful insights into the future health of the world. These can now be used by public-health officials to plan future policy and to monitor the effect of new public-health initiatives on the global burden of disease and death.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030442.
World Health Organization, provides information on the Global Burden of Disease Project and links to other related resources Global Burden of Disease Project
Harvard School of Public Health, Burden of Disease Unit, offers information on the 1990 Global Burden of Disease study and its projections Harvard School of Public Health
doi:10.1371/journal.pmed.0030442
PMCID: PMC1664601  PMID: 17132052

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