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1.  Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons (e–Pub ahead of print)  
Neurology  2010;75(10):864-873.
Objective:
To determine factors associated with baseline neurocognitive performance in HIV-infected participants enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) neurology substudy.
Methods:
Participants from Australia, North America, Brazil, and Thailand were administered a 5-test neurocognitive battery. Z scores and the neurocognitive performance outcome measure, the quantitative neurocognitive performance z score (QNPZ-5), were calculated using US norms. Neurocognitive impairment was defined as z scores <−2 in two or more cognitive domains. Associations of test scores, the QNPZ-5, and impairment with baseline factors including demographics and risk factors for HIV-associated dementia (HAD) and cardiovascular disease (CVD) were determined in multiple regression.
Results:
The 292 participants had a median CD4 cell count of 536 cells/mm3, 88% had an HIV viral load ≤400 copies/mL, and 92% were taking antiretrovirals. Demographics, HIV, and clinical factors differed between locations. The mean QNPZ-5 score was −0.72; 14% of participants had neurocognitive impairment. For most tests, scores and z scores differed significantly between locations, with and without adjustment for age, sex, education, and race. Prior CVD was associated with neurocognitive impairment. Prior CVD, hypercholesterolemia, and hypertension were associated with poorer neurocognitive performance but conventional HAD risk factors and the CNS penetration effectiveness rank of antiretroviral regimens were not.
Conclusions:
In this HIV-positive population with high CD4 cell counts, neurocognitive impairment was associated with prior CVD. Lower neurocognitive performance was associated with prior CVD, hypertension, and hypercholesterolemia, but not conventional HAD risk factors. The contribution of CVD and cardiovascular risk factors to the neurocognition of HIV-positive populations warrants further investigation.
GLOSSARY
= Alzheimer disease;
= antiretroviral therapy;
= blood pressure;
= Center for Epidemiologic Studies-Depression scale;
= Color Trails;
= cardiovascular disease;
= Finger Tapping Test;
= Grooved Pegboard;
= HIV-associated dementia;
= neurocognitive impairment;
= quantitative neurocognitive performance z score;
= Strategies for Management of Antiretroviral Therapy;
= Timed Gait.
doi:10.1212/WNL.0b013e3181f11bd8
PMCID: PMC2938971  PMID: 20702792
2.  Chronic cigarette smoking and heavy drinking in human immunodeficiency virus: consequences for neurocognition and brain morphology 
Alcohol (Fayetteville, N.Y.)  2007;41(7):489-501.
Alcohol use disorders (AUD) and chronic cigarette smoking are common among individuals with human immunodeficiency virus infection (HIV). Concurrent AUD in HIV is related to greater abnormalities in brain morphology and neurocognition than either condition alone. However, the potential influence of chronic smoking on brain morphology and neurocognition in those concurrently afflicted with AUD and HIV has not been examined. The goal of this retrospective analysis was to determine if chronic smoking affected neurocognition and brain morphology in a subsample of HIV-positive non–treatment-seeking heavy drinking participants (HD+) from our earlier work. Regional volumetric and neurocognitive comparisons were made among age-equivalent smoking HD+(n = 17), nonsmoking HD+(n = 27), and nonsmoking HIV-negative light drinking controls (n = 27) obtained from our original larger sample. Comprehensive neuropsychological assessment evaluated multiple neurocognitive domains of functioning and for potential psychiatric comorbidities. Quantitative volumetric measures of neocortical gray matter (GM), white matter (WM), subcortical structures, and sulcal and ventricular cerebral spinal fluid (CSF) were derived from high-resolution magnetic resonance images. The main findings were (1) smoking HD+ performed significantly worse than nonsmoking HD+ on measures of auditory-verbal (AV) learning, AV memory, and cognitive efficiency; (2) relative to controls, smoking HD+ demonstrated significantly lower neocortical GM volumes in all lobes except the occipital lobe, while nonsmoking HD+ showed only lower frontal GM volume compared with controls; (3) in the HD+ group, regional brain volumes and neurocognition were not influenced by viremia, highly active antiretroviral treatment, or Center for Disease Control symptom status, and no interactions were apparent with these variables or smoking status. Overall, the findings suggested that the direct and/or indirect effects of chronic cigarette smoking created an additional burden on the integrity of brain neurobiology and neurocognition in this cohort of HIV-positive heavy drinkers.
doi:10.1016/j.alcohol.2007.07.007
PMCID: PMC2443733  PMID: 17923369
HIV; Alcohol use disorders; Chronic cigarette smoking; Neuroimaging; Neurocognition
3.  Aging, Neurocognition, and Medication Adherence in HIV Infection 
Objective
To evaluate the hypothesis that poor adherence to highly active antiretroviral treatment (HAART) would be more strongly related to cognitive impairment among older than among younger HIV-seropositive adults.
Setting and Participants
A volunteer sample of 431 HIV-infected adult patients prescribed self-administered HAART was recruited from community agencies and university-affiliated infectious disease clinics in the Los Angeles area.
Measurements
Neurocognitive measures included tests of attention, information processing speed, learning/memory, verbal fluency, motor functioning, and executive functioning. Medication adherence was measured using microchip-embedded pill bottle caps (Medication Event Monitoring System) and self-report. Latent/structural analysis techniques were used to evaluate factor models of cognition and adherence.
Results
Mean adherence rates were higher among older (≥50 years) than younger (<50 years) HIV-positive adults. However, latent/structural modeling demonstrated that neurocognitive impairment was associated with poorer medication adherence among older participants only. When cognitive subdomains were examined individually, executive functioning, motor functioning, and processing speed were most strongly related to adherence in this age group. CD4 count and drug problems were also more strongly associated with adherence among older than younger adults.
Conclusions
Older HIV-positive individuals with neurocognitive impairment or drug problems are at increased risk of suboptimal adherence to medication. Likewise, older adults may be especially vulnerable to immunological and neurocognitive dysfunction under conditions of suboptimal HAART adherence. These findings highlight the importance of optimizing medication adherence rates and evaluating neurocognition in the growing population of older HIV-infected patients.
doi:10.1097/JGP.0b013e31819431bd
PMCID: PMC2679810  PMID: 19307857
HIV; AIDS; aging; cognition; medication adherence; executive functions
4.  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
5.  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
6.  Supervised and Unsupervised Self-Testing for HIV in High- and Low-Risk Populations: A Systematic Review 
PLoS Medicine  2013;10(4):e1001414.
By systematically reviewing the literature, Nitika Pant Pai and colleagues assess the evidence base for HIV self tests both with and without supervision.
Background
Stigma, discrimination, lack of privacy, and long waiting times partly explain why six out of ten individuals living with HIV do not access facility-based testing. By circumventing these barriers, self-testing offers potential for more people to know their sero-status. Recent approval of an in-home HIV self test in the US has sparked self-testing initiatives, yet data on acceptability, feasibility, and linkages to care are limited. We systematically reviewed evidence on supervised (self-testing and counselling aided by a health care professional) and unsupervised (performed by self-tester with access to phone/internet counselling) self-testing strategies.
Methods and Findings
Seven databases (Medline [via PubMed], Biosis, PsycINFO, Cinahl, African Medicus, LILACS, and EMBASE) and conference abstracts of six major HIV/sexually transmitted infections conferences were searched from 1st January 2000–30th October 2012. 1,221 citations were identified and 21 studies included for review. Seven studies evaluated an unsupervised strategy and 14 evaluated a supervised strategy. For both strategies, data on acceptability (range: 74%–96%), preference (range: 61%–91%), and partner self-testing (range: 80%–97%) were high. A high specificity (range: 99.8%–100%) was observed for both strategies, while a lower sensitivity was reported in the unsupervised (range: 92.9%–100%; one study) versus supervised (range: 97.4%–97.9%; three studies) strategy. Regarding feasibility of linkage to counselling and care, 96% (n = 102/106) of individuals testing positive for HIV stated they would seek post-test counselling (unsupervised strategy, one study). No extreme adverse events were noted. The majority of data (n = 11,019/12,402 individuals, 89%) were from high-income settings and 71% (n = 15/21) of studies were cross-sectional in design, thus limiting our analysis.
Conclusions
Both supervised and unsupervised testing strategies were highly acceptable, preferred, and more likely to result in partner self-testing. However, no studies evaluated post-test linkage with counselling and treatment outcomes and reporting quality was poor. Thus, controlled trials of high quality from diverse settings are warranted to confirm and extend these findings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (most living in resource-limited countries) are currently infected with HIV, the virus that causes AIDS, and about 2.5 million people become infected with HIV every year. HIV is usually transmitted through unprotected sex with an infected partner. HIV infection is usually diagnosed by looking for antibodies to HIV in blood or saliva. Early during infection, the immune system responds to HIV by beginning to make antibodies that recognize the virus and target it for destruction. “Seroconversion”—the presence of detectable amounts of antibody in the blood or saliva—usually takes 6–12 weeks. Rapid antibody-based tests, which do not require laboratory facilities, can provide a preliminary result about an individual's HIV status from a simple oral swab or finger stick sample within 20 minutes. However preliminary rapid positive results have to be confirmed in a laboratory, which may take a few days or weeks. If positive, HIV infection can be controlled but not cured by taking a daily cocktail of powerful antiretroviral drugs throughout life.
Why Was This Study Done?
To reduce the spread of HIV, it is essential that HIV-positive individuals get tested, change behaviors avoid transmitting the virus to other people by, for example, always using a condom during sex, and if positive get on to treatment that is available worldwide. Treatment also reduces transmission of virus to the partner and controls the virus in the community. However, only half the people currently living with HIV know their HIV status, a state of affairs that increases the possibility of further HIV transmission to their partners and children. HIV positive individuals are diagnosed late with advanced HIV infection that costs health care services. Although health care facility-based HIV testing has been available for decades, people worry about stigma, visibility, and social discrimination. They also dislike the lack of privacy and do not like having to wait for their test results. Self-testing (i.e., self-test conduct and interpretation) might alleviate some of these barriers to testing by allowing individuals to determine their HIV status in the privacy of their home and could, therefore, increase the number of individuals aware of their HIV status. This could possibly reduce transmission and, through seeking linkages to care, bring HIV under control in communities. In some communities and countries, stigma of HIV prevents people from taking action about their HIV status. Indeed, an oral (saliva-based) HIV self-test kit is now available in the US. But how acceptable, feasible, and accurate is self-testing by lay people, and will people who find themselves self-test positive seek counseling and treatment? In this systematic review (a study that uses pre-defined criteria to identify all the research on a given topic), the researchers examine these issues by analyzing data from studies that have evaluated supervised self-testing (self-testing and counseling aided by a health-care professional) and unsupervised self-testing (self-testing performed without any help but with counseling available by phone or internet).
What Did the Researchers Do and Find?
The researchers identified 21 eligible studies, two-thirds of which evaluated oral self-testing and a third of which evaluated blood-based self-testing. Seven studies evaluated an unsupervised self-testing strategy and 14 evaluated a supervised strategy. Most of the data (89%) came from studies undertaken in high-income settings. The study populations varied from those at high risk of HIV infection to low-risk general populations. Across the studies, acceptability (defined as the number of people who actually self-tested divided by the number who consented to self-test) ranged from 74% to 96%. With both strategies, the specificity of self-testing (the chance of an HIV-negative person receiving a negative test result is true negative) was high but the sensitivity of self-testing (the chance of an HIV-positive person receiving a positive test result is indeed a true positive) was higher for supervised than for unsupervised testing. The researchers also found evidence that people preferred self-testing to facility-based testing and oral self-testing to blood-based self testing and, in one study, 96% of participants who self-tested positive sought post-testing counseling.
What Do These Findings Mean?
These findings provide new but limited information about the feasibility, acceptability, and accuracy of HIV self-testing. They suggest that it is feasible to implement both supervised and unsupervised self-testing, that both strategies are preferred to facility-based testing, but that the accuracy of self-testing is variable. However, most of the evidence considered by the researchers came from high-income countries and from observational studies of varying quality, and data on whether people self-testing positive sought post-testing counseling (linkage to care) were only available from one evaluation of unsupervised self-testing in the US. Consequently, although these findings suggest that self-testing could engage individuals in finding our their HIV status and thereby help modify behavior thus, reduce HIV transmission in the community, by increasing the proportion of people living with HIV who know their HIV status. The researchers suggested that more data from diverse settings and preferably from controlled randomized trials must be collected before any initiatives for global scale-up of self-testing for HIV infection are implemented.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001414.
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 testing, and on HIV transmission and testing (in English and Spanish)
The UK National Health Service Choices website provides information about all aspects of HIV and AIDS; a “behind the headlines” article provides details about the 2012 US approval for an over-the-counter HIV home-use test
The 2012 World AIDS Day Report provides information about the percentage of people living with HIV who are aware of their HIV status in various African countries, as well as up-to-date information about the AIDS epidemic
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 getting a diagnosis
doi:10.1371/journal.pmed.1001414
PMCID: PMC3614510  PMID: 23565066
7.  Male Circumcision at Different Ages in Rwanda: A Cost-Effectiveness Study 
PLoS Medicine  2010;7(1):e1000211.
Agnes Binagwaho and colleagues predict that circumcision of newborn boys would be effective and cost-saving as a long-term strategy to prevent HIV in Rwanda.
Background
There is strong evidence showing that male circumcision (MC) reduces HIV infection and other sexually transmitted infections (STIs). In Rwanda, where adult HIV prevalence is 3%, MC is not a traditional practice. The Rwanda National AIDS Commission modelled cost and effects of MC at different ages to inform policy and programmatic decisions in relation to introducing MC. This study was necessary because the MC debate in Southern Africa has focused primarily on MC for adults. Further, this is the first time, to our knowledge, that a cost-effectiveness study on MC has been carried out in a country where HIV prevalence is below 5%.
Methods and Findings
A cost-effectiveness model was developed and applied to three hypothetical cohorts in Rwanda: newborns, adolescents, and adult men. Effectiveness was defined as the number of HIV infections averted, and was calculated as the product of the number of people susceptible to HIV infection in the cohort, the HIV incidence rate at different ages, and the protective effect of MC; discounted back to the year of circumcision and summed over the life expectancy of the circumcised person. Direct costs were based on interviews with experienced health care providers to determine inputs involved in the procedure (from consumables to staff time) and related prices. Other costs included training, patient counselling, treatment of adverse events, and promotion campaigns, and they were adjusted for the averted lifetime cost of health care (antiretroviral therapy [ART], opportunistic infection [OI], laboratory tests). One-way sensitivity analysis was performed by varying the main inputs of the model, and thresholds were calculated at which each intervention is no longer cost-saving and at which an intervention costs more than one gross domestic product (GDP) per capita per life-year gained. Results: Neonatal MC is less expensive than adolescent and adult MC (US$15 instead of US$59 per procedure) and is cost-saving (the cost-effectiveness ratio is negative), even though savings from infant circumcision will be realized later in time. The cost per infection averted is US$3,932 for adolescent MC and US$4,949 for adult MC. Results for infant MC appear robust. Infant MC remains highly cost-effective across a reasonable range of variation in the base case scenario. Adolescent MC is highly cost-effective for the base case scenario but this high cost-effectiveness is not robust to small changes in the input variables. Adult MC is neither cost-saving nor highly cost-effective when considering only the direct benefit for the circumcised man.
Conclusions
The study suggests that Rwanda should be simultaneously scaling up circumcision across a broad range of age groups, with high priority to the very young. Infant MC can be integrated into existing health services (i.e., neonatal visits and vaccination sessions) and over time has better potential than adolescent and adult circumcision to achieve the very high coverage of the population required for maximal reduction of HIV incidence. In the presence of infant MC, adolescent and adult MC would evolve into a “catch-up” campaign that would be needed at the start of the program but would eventually become superfluous.
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 31 million people (22 million in sub-Saharan Africa alone) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. There is no cure for HIV/AIDS and no vaccine against HIV infection. Consequently, prevention of HIV transmission is extremely important. HIV is most often spread through unprotected sex with an infected partner. Individuals can reduce their risk of HIV infection, therefore, by abstaining from sex, by having one or a few sexual partners, and by always using a male or female condom. In addition, male circumcision—the removal of the foreskin, the loose fold of skin that covers the head of penis—can halve HIV transmission rates to men resulting from sex with women. Thus, as part of its HIV prevention strategy, the World Health Organization (WHO) recommends that male circumcision programs be scaled up in countries where there is a generalized HIV epidemic and where few men are circumcised.
Why Was This Study Done?
One such country is Rwanda. Here, 3% of the adult population is infected with HIV but only 15% of men are circumcised—worldwide, about 30% of men are circumcised. Demand for circumcision is increasing in Rwanda but, before policy makers introduce a country-wide male circumcision program, they need to identify the most cost-effective way to increase circumcision rates. In particular, they need to decide the age at which circumcision should be offered. Circumcision soon after birth (neonatal circumcision) is quick and simple and rarely causes any complications. Circumcision of adolescents and adults is more complex and has a higher complication rate. Although several studies have investigated the cost-effectiveness (the balance between the clinical and financial costs of a medical intervention and its benefits) of circumcision in adult men, little is known about its cost-effectiveness in newborn boys. In this study, which is one of several studies on male circumcision being organized by the National AIDS Control Commission in Rwanda, the researchers model the cost-effectiveness of circumcision at different ages.
What Did the Researchers Do and Find?
The researchers developed a simple cost-effectiveness model and applied it to three hypothetical groups of Rwandans: newborn boys, adolescent boys, and adult men. For their model, the researchers calculated the effectiveness of male circumcision (the number of HIV infections averted) by estimating the reduction in the annual number of new HIV infections over time. They obtained estimates of the costs of circumcision (including the costs of consumables, staff time, and treatment of complications) from health care providers and adjusted these costs for the money saved through not needing to treat HIV in males in whom circumcision prevented infection. Using their model, the researchers estimate that each neonatal male circumcision would cost US$15 whereas each adolescent or adult male circumcision would cost US$59. Neonatal male circumcision, they report, would be cost-saving. That is, over a lifetime, neonatal male circumcision would save more money than it costs. Finally, using the WHO definition of cost-effectiveness (for a cost-effective intervention, the additional cost incurred to gain one year of life must be less than a country's per capita gross domestic product), the researchers estimate that, although adolescent circumcision would be highly cost-effective, circumcision of adult men would only be potentially cost-effective (but would likely prove cost-effective if the additional infections that would occur from men to their partners without a circumcision program were also taken into account).
What Do These Findings Mean?
As with all modeling studies, the accuracy of these findings depends on the many assumptions included in the model. However, the findings suggest that male circumcision for infants for the prevention of HIV infection later in life is highly cost-effective and likely to be cost-saving and that circumcision for adolescents is cost-effective. The researchers suggest, therefore, that policy makers in Rwanda and in countries with similar HIV infection and circumcision rates should scale up male circumcision programs across all age groups, with high priority being given to the very young. If infants are routinely circumcised, they suggest, circumcision of adolescent and adult males would become a “catch-up” campaign that would be needed at the start of the program but that would become superfluous over time. Such an approach would represent a switch from managing the HIV epidemic as an emergency towards focusing on sustainable, long-term solutions to this major public-health problem.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000211.
This study is further discussed in a PLoS Medicine Perspective by Seth Kalichman
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information is available from the Joint United Nations Programme on HIV/AIDS (UNAIDS) on HIV infection and AIDS and on male circumcision in relation to HIV 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 HIV and AIDS in Africa, and on circumcision and HIV (some information in English and Spanish)
More information about male circumcision is available from the Clearinghouse on Male Circumcision
The National AIDS Control Commission of Rwanda provides detailed information about HIV/AIDS in Rwanda (in English and French)
doi:10.1371/journal.pmed.1000211
PMCID: PMC2808207  PMID: 20098721
8.  HIV-1 Transmission during Early Infection in Men Who Have Sex with Men: A Phylodynamic Analysis 
PLoS Medicine  2013;10(12):e1001568.
Erik Volz and colleagues use HIV genetic information from a cohort of men who have sex with men in Detroit, USA to dissect the timing of onward transmission during HIV infection.
Please see later in the article for the Editors' Summary
Background
Conventional epidemiological surveillance of infectious diseases is focused on characterization of incident infections and estimation of the number of prevalent infections. Advances in methods for the analysis of the population-level genetic variation of viruses can potentially provide information about donors, not just recipients, of infection. Genetic sequences from many viruses are increasingly abundant, especially HIV, which is routinely sequenced for surveillance of drug resistance mutations. We conducted a phylodynamic analysis of HIV genetic sequence data and surveillance data from a US population of men who have sex with men (MSM) and estimated incidence and transmission rates by stage of infection.
Methods and Findings
We analyzed 662 HIV-1 subtype B sequences collected between October 14, 2004, and February 24, 2012, from MSM in the Detroit metropolitan area, Michigan. These sequences were cross-referenced with a database of 30,200 patients diagnosed with HIV infection in the state of Michigan, which includes clinical information that is informative about the recency of infection at the time of diagnosis. These data were analyzed using recently developed population genetic methods that have enabled the estimation of transmission rates from the population-level genetic diversity of the virus. We found that genetic data are highly informative about HIV donors in ways that standard surveillance data are not. Genetic data are especially informative about the stage of infection of donors at the point of transmission. We estimate that 44.7% (95% CI, 42.2%–46.4%) of transmissions occur during the first year of infection.
Conclusions
In this study, almost half of transmissions occurred within the first year of HIV infection in MSM. Our conclusions may be sensitive to un-modeled intra-host evolutionary dynamics, un-modeled sexual risk behavior, and uncertainty in the stage of infected hosts at the time of sampling. The intensity of transmission during early infection may have significance for public health interventions based on early treatment of newly diagnosed individuals.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since the first recorded case of AIDS in 1981, the number of people infected with HIV, the virus that causes AIDS, has risen steadily. About 34 million people are currently HIV-positive, and about 2.5 million people become newly infected with HIV every year. Because HIV is usually transmitted through unprotected sex with an infected partner, individuals can reduce their risk of infection by abstaining from sex, by having only one or a few partners, and by always using condoms. Most people do not become ill immediately after infection with HIV, although some develop a short flu-like illness. The next stage of HIV infection, which may last more than ten years, also has no major symptoms, but during this stage, HIV slowly destroys immune system cells. Eventually, the immune system can no longer fight off infections by other disease-causing organisms, and HIV-positive people then develop one or more life-threatening AIDS-defining conditions, including unusual infections and specific types of cancer. HIV infection can be controlled, but not cured, by taking a daily cocktail of antiretroviral drugs.
Why Was This Study Done?
The design of effective programs to prevent the spread of HIV/AIDS depends on knowing how HIV transmissibility varies over the course of HIV infection. Consider, for example, a prevention strategy that focuses on increasing treatment rates: antiretroviral drugs, in addition to reducing illness and death among HIV-positive people, reduce HIV transmission from HIV-positive individuals. “Treatment as prevention” can only block transmissions that occur after diagnosis and entry into care. However, the transmissibility of HIV per sexual contact depends on a person's viral load, which peaks during early HIV infection, when people are often unaware of their HIV status and may still be following the high-risk patterns of sexual behavior that caused their own infection. Epidemiological surveillance data (information on HIV infections within populations) can be used to estimate how many new HIV infections occur within a population annually (HIV incidence) and the proportion of the population that is HIV-positive (HIV prevalence), but cannot be used to estimate the timing of transmission events. In this study, the researchers use “phylodynamic analysis” to estimate HIV incidence and prevalence and the timing of HIV transmission during infection. HIV, like many other viruses, rapidly accumulates genetic changes. The timing of transmission influences the pattern of these changes. Viral phylodynamic analysis—the quantitative study of how epidemiological, immunological, and evolutionary processes shape viral phylogenies (evolutionary trees)—can therefore provide estimates of transmission dynamics.
What Did the Researchers Do and Find?
The researchers obtained HIV sequence data (collected for routine surveillance of antiretroviral resistance mutations) and epidemiological surveillance data (including information on the stage of infection at diagnosis) for 662 HIV-positive men who have sex with men living in the Detroit metropolitan area of Michigan. They constructed a phylogenetic tree from the sequences using a “relaxed clock” approach and then fitted an epidemiological model (a mathematical model that represents the progress of individual patients through various stages of HIV infection) to the sequence data. Their approach, which integrates surveillance data and genetic data, yielded estimates of HIV incidence and prevalence among the study population similar to those obtained from surveillance data alone. However, it also provided information about HIV transmission that could not be obtained from surveillance data alone. In particular, it allowed the researchers to estimate that, in the current HIV epidemic among men who have sex with men in Detroit, 44.7% of HIV transmissions occur during the first year of infection.
What Do These Findings Mean?
The robustness of these findings depends on the validity of the assumptions included in the researchers' population genetic model and on the accuracy of the data fed into the model, and may not be generalizable to other cities or to other risk groups. Nevertheless, the findings of this analysis, which can be repeated in any setting where HIV sequence data for individual patients can be linked to patient-specific clinical and behavioral information, have important implications for HIV control strategies based on the early treatment of newly diagnosed individuals. Because relatively few infected individuals are diagnosed during early HIV infection, when the HIV transmission rate is high, it is unlikely, suggest the researchers, that the “treatment as prevention” strategy will effectively control the spread of HIV unless there are very high rates of HIV testing and treatment.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001568.
This study is further discussed in a PLOS Medicine Perspective by Timothy Hallett
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 treatment as prevention (in English and Spanish)
The PLOS Medicine Collection Investigating the Impact of Treatment on New HIV Infections provides more information about HIV treatment as prevention
A PLOS Computational Biology Topic Page (a review article that is a published copy of record of a dynamic version of the article as found in Wikipedia) about viral phylodynamics is available
The US National Institute of Health–funded HIV Sequence Database contains HIV sequences and tools to analyze these sequences
Patient stories about living with HIV/AIDS are available through Avert; the charity website Healthtalkonline also provides personal stories about living with HIV
doi:10.1371/journal.pmed.1001568
PMCID: PMC3858227  PMID: 24339751
9.  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
10.  Motor Function and Human Immunodeficiency Virus-Associated Cognitive Impairment in a Highly Active Antiretroviral Therapy-Era Cohort 
Archives of neurology  2008;65(8):1096-1101.
Background
Cognitive impairment has long been recognized as a manifestation of human immunodeficiency virus (HIV) infection. However, highly active antiretroviral therapy (HAART) has altered the neurologic manifestations of HIV.
Objectives
To develop a measure to quantify the motor abnormalities included in the original descriptions of HIV-associated dementia (HAD); to determine whether motor, affective, and behavioral dysfunction predict cognitive impairment; and to determine whether quantitative motor testing is a helpful adjunct in the diagnosis of HAD in a complex population from the HAART era.
Design
Neurologic and neuropsychological data were collected from the Manhattan HIV Brain Bank, a longitudinal cohort study of patients with advanced HIV. The HIV-Dementia Motor Scale (HDMS) was developed and validated and cognitive and affective or behavioral function was quantified using global neuropsychological T scores, the Beck Depression Inventory (BDI), and an independent assessment of apathy. Relationships among cognitive, motor, affective, and behavioral performance were examined using correlation, linear regression, and analyses of variance.
Setting
An urban AIDS research center.
Participants
A total of 260 HIV-positive, predominantly minority patients.
Main Outcome Measures
The HDMS scores and global neuropsychological T scores.
Results
The HDMS and BDI scores were independent predictors of cognitive impairment. Significant cognitive impairment was found in patients with motor dysfunction. Patients diagnosed as having HAD had a greater degree of motor impairment than those with other neurocognitive diagnoses.
Conclusions
Motor, affective, and behavioral abnormalities predict cognitive impairment in HIV-positive patients in this HAART-era cohort. The HDMS may be useful in the assignment of HIV-associated neurocognitive impairment in HIV populations in which normative data or neuropsychological test design is not optimal.
doi:10.1001/archneur.65.8.1096
PMCID: PMC2696223  PMID: 18695060
11.  Predicting Patterns of Long-Term CD4 Reconstitution in HIV-Infected Children Starting Antiretroviral Therapy in Sub-Saharan Africa: A Cohort-Based Modelling Study 
PLoS Medicine  2013;10(10):e1001542.
Using data from the ARROW trial, Joanna Lewis and colleagues investigate the CD4 cell count recovery profiles of children infected with HIV starting antiretroviral therapy in Sub-Saharan Africa.
Please see later in the article for the Editors' Summary
Background
Long-term immune reconstitution on antiretroviral therapy (ART) has important implications for HIV-infected children, who increasingly survive into adulthood. Children's response to ART differs from adults', and better descriptive and predictive models of reconstitution are needed to guide policy and direct research. We present statistical models characterising, qualitatively and quantitatively, patterns of long-term CD4 recovery.
Methods and Findings
CD4 counts every 12 wk over a median (interquartile range) of 4.0 (3.7, 4.4) y in 1,206 HIV-infected children, aged 0.4–17.6 y, starting ART in the Antiretroviral Research for Watoto trial (ISRCTN 24791884) were analysed in an exploratory analysis supplementary to the trial's pre-specified outcomes. Most (n = 914; 76%) children's CD4 counts rose quickly on ART to a constant age-corrected level. Using nonlinear mixed-effects models, higher long-term CD4 counts were predicted for children starting ART younger, and with higher CD4 counts (p<0.001). These results suggest that current World Health Organization–recommended CD4 thresholds for starting ART in children ≥5 y will result in lower CD4 counts in older children when they become adults, such that vertically infected children who remain ART-naïve beyond 10 y of age are unlikely ever to normalise CD4 count, regardless of CD4 count at ART initiation. CD4 profiles with four qualitatively distinct reconstitution patterns were seen in the remaining 292 (24%) children. Study limitations included incomplete viral load data, and that the uncertainty in allocating children to distinct reconstitution groups was not modelled.
Conclusions
Although younger ART-naïve children are at high risk of disease progression, they have good potential for achieving high CD4 counts on ART in later life provided ART is initiated following current World Health Organization (WHO), Paediatric European Network for Treatment of AIDS, or US Centers for Disease Control and Prevention guidelines. In contrast, to maximise CD4 reconstitution in treatment-naïve children >10 y, ART should ideally be considered even if there is a low risk of immediate disease progression. Further exploration of the immunological mechanisms for these CD4 recovery profiles should help guide management of paediatric HIV infection and optimise children's immunological development.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.3 million children under 15 years old are infected with HIV, the virus that causes AIDS. More than 90% of these children live in sub-Saharan Africa, where nearly 600 children become infected with HIV every day, usually acquiring the virus from their mother during pregnancy, birth, or breastfeeding. HIV gradually reduces the numbers of CD4 lymphocytes in the immune system, leaving infected individuals susceptible to other infections. HIV infection can be kept in check but not cured with antiretroviral therapy (ART)—cocktails of drugs that have to be taken every day throughout life. ART reduces the amount of virus in the blood (viral load), which allows the immune system to recover (long-term immune reconstitution). Unfortunately, ART is very expensive, but concerted international efforts over the past decade mean that about a third of children who need ART are now receiving it, including half a million children in sub-Saharan Africa.
Why Was This Study Done?
World Health Organization (WHO) guidelines recommend initiation of ART at age-related CD4 cell count thresholds based on the risk of short-term disease progression. The guidelines recommend that all HIV-positive children under two years old begin ART as soon they receive a diagnosis of HIV infection. For children aged 2–5 years, ART initiation is recommended once the CD4 count drops below 750 cells/µl blood, whereas for older children the threshold for ART initiation is 350 CD4 cells/µl. Because of improved ART coverage, many more HIV-infected children now survive into adulthood than in the past. It is therefore important to know how the timing of ART initiation in childhood affects long-term immune reconstitution. Unfortunately, although several studies have examined the effect of ART on immune reconstitution in adults, the results of these studies cannot be extrapolated to children because of age-related differences in immune reconstitution. In this cohort-based modelling study, the researchers investigate long-term CD4 recovery in a cohort (group) of HIV-infected children initiating ART in Uganda and Zimbabwe, and present statistical models that predict patterns of long-term CD4 status based on age and CD4 count at ART initiation.
What Did the Researchers Do and Find?
To investigate long-term CD4 reconstitution in children, the researchers used CD4 counts collected during the ARROW trial, a study designed to investigate monitoring strategies during first-line ART in 1,206 HIV-positive children. In three-quarters of the children, CD4 reconstitution following ART initiation was asymptotic—CD4 counts increased rapidly immediately after ART initiation, then slowed before eventually reaching a constant level of about 80% of the CD4 count expected in an uninfected child of the same age. Using a nonlinear mixed-effects statistical model that fitted this pattern of immune reconstitution, the researchers predicted CD4 trajectories for children starting ART at different ages and with different CD4 counts. Higher long-term counts were predicted for children starting ART earlier and with higher CD4 counts. Thus, to achieve a CD4 count greater than 700 cells/µl at age 20 years, CD4 counts of at least 96 cells/µl, 130 cells/µl, and 557 cells/µl are needed for children aged two, five, and 12 years, respectively, when they initiate ART. Qualitatively distinct reconstitution patterns were seen in the remaining children in the study.
What Do These Findings Mean?
These findings suggest that young HIV-positive, ART-naïve children can achieve high CD4 counts in later life, provided ART is initiated as recommended in the current WHO guidelines. However, the recommended CD4 count thresholds for ART initiation are unlikely to maximize immune reconstitution in treatment-naïve children over ten years old. Rather, these findings suggest that ART initiation should be considered in these older children when their CD4 count is still high—even though they have a low risk of immediate disease progression—in order to achieve higher long-term CD4 levels. The omission of viral load measurements in the researchers' model may limit the accuracy of these findings. Moreover, although the predictions made by the model apply to children who will go on to experience asymptotic recovery, they are less relevant to those with different recovery profiles, who cannot currently be accurately identified. Further exploration of the immunological mechanisms underlying the CD4 recovery profiles described here should improve our understanding of the factors that determine the response of HIV-positive children to ART and provide information to guide the management of HIV infections in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001542.
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 HIV infection in children (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 UNAIDS's 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 can be downloaded
Information about the ARROW trial is available
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.1001542
PMCID: PMC3812080  PMID: 24204216
12.  The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial 
PLoS Medicine  2010;7(8):e1000321.
In a double-blind trial, Rajesh Gandhi and colleagues detect no significant reduction in viral load after people with low-level HIV viremia added an integrase inhibitor to their treatment regimen.
Background
Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients.
Methods and Findings
Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median −0.2 and −0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus −44 cells/mm3, p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood.
Conclusion
In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection.
Trial Registration
ClinicalTrials.gov NCT00515827
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed about 25 million people since 1981 and more than 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV is a retrovirus—its genetic blueprint is made of ribonucleic acid (RNA). HIV infects human immune system cells and destroys them, leaving infected individuals susceptible to other infections. Early during the AIDS epidemic, most HIV-positive people died within ten years of infection. Then, in 1996, effective antiretroviral therapy (ART) was developed. ART consists of combinations of drugs that prevent viral replication by inhibiting essential viral enzymes such as reverse transcriptase (the enzyme that makes a DNA copy of the viral RNA; a viral enzyme called integrase inserts this DNA copy into the host cell DNA where it remains dormant until the host cell is activated) and protease (an enzyme needed for the production of new viral particles, which are released into the blood stream). Now, in industrialized countries, the life expectancy of HIV-infected patients treated with ART is similar to that of people with diabetes and other chronic conditions.
Why Was This Study Done?
Although ART can reduce the number of viral RNA copies in the plasma (the liquid portion of blood) of HIV-positive patients to less than 50 copies/mL (the limit of detection of commercial assays), it is does not eradicate HIV. When very sensitive assays are used to detect viral RNA (for example, the “single copy assay” or SCA), most patients on ART have one copy or more of HIV RNA per mL of plasma. The origin of this low-level residual viremia (virus in the blood) is controversial. Residual viremia could arise from ongoing cycles of viral replication, in which case intensification of ART should reduce it. Alternatively, residual viremia could be due to HIV release from stable reservoirs such as latently infected resting immune system cells, in which case intensification of ART should have no effect on residual viremia. In this randomized, controlled trial (a study in which randomly selected groups of patients are given different treatments and the effects of these treatments compared), the researchers assess whether the addition of raltegravir (a drug that inhibits HIV integrase) to standard ART has any effect on residual viremia.
What Did the Researchers Do and Find?
The researchers enrolled 53 HIV-positive patients who had been receiving ART containing several reverse transcriptase inhibitors and, in some cases, a protease inhibitor for at least 12 months and who had a plasma HIV RNA level below 50 copies/mL but detectable viremia by SCA. The patients were randomly assigned to receive either raltegravir or a dummy drug (placebo) in addition to their normal ART for 12 weeks. They were then crossed-over (swapped) to the other therapy for a further 12 weeks. At baseline, the trial participants had an average plasma HIV RNA level of 1.7 copies/mL. The HIV RNA level at weeks 10/12 (the average of SCA results at 10 and 12 weeks) was similar in the raltegravir group and in the placebo group and did not differ significantly from this baseline level. There was also no significant change in plasma HIV RNA levels from weeks 10/12 to weeks 22/24 after the patients crossed-over between treatment groups.
What Do These Findings Mean?
In this randomized, cross-over study, raltegravir intensification of ART for 12 weeks did not demonstrably reduce low-level residual viremia in HIV-positive patients receiving standard ART. It is possible that 12 weeks is too short a time to see an effect of raltegravir on residual viremia. Furthermore, although this is one of the biggest trials of this type done to date, it might be that insufficient patients were included in the trial to detect a subtle effect of raltegravir on residual viremia. Nevertheless, these findings argue against the hypothesis that residual viremia arises from ongoing cycles of viral replication and the infection of new cells. Instead, they suggest that residual viremia might be due to the release of HIV from stable reservoirs. If so, new therapeutic strategies designed to eliminate these reservoirs of latently infected cells will be required to cure HIV infection.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000321.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS, and on the treatment of HIV
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including information on antiretroviral therapies
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including the treatment of HIV and AIDS (in English and Spanish)
MedlinePlus has links to further resources on AIDS and on AIDS medicines (in English and Spanish)
doi:10.1371/journal.pmed.1000321
PMCID: PMC2919424  PMID: 20711481
13.  CCL3L1 gene copy number in individuals with and without HIV-associated neurocognitive disorder 
Current biomarker findings  2012;2012(2):1-6.
Background
CCL3L1 copy number variation has been implicated as a marker for susceptibility and immunity to human immunodeficiency virus (HIV)-1 infection and its pathogenic sequelae. Some of these findings have been confirmed in several, but not all, subsequent independent cohort studies. A three-fold risk for the development of HIV-associated dementia was reported in individuals possessing a CCL3L1 copy number below the ethnic group median combined with a detrimental CCR5 genotype. With the availability of antiretroviral therapy since 1996, there has been a significant decline in HIV-associated dementia, and milder forms of HIV-associated neurocognitive impairment (HAND) are now most prevalent. Moreover, patients are living longer with HIV-1 infection and it is recognized that aging may be a contributory factor to the development of cognitive disorder. Thus, the need for biomarkers that can be used in clinical practice to identify and provide optimal treatment for those at increased risk for HAND is great. HAND affects 20%–30% of HIV-infected individuals, and several genetic loci which have been shown to confer susceptibility to HIV infection may also modulate the development of neurocognitive disorder. The aim of this study was to determine whether CCL3L1 chemokine gene copy number in self-defined ethnic groups could differentiate HIV-infected individuals with and without HAND.
Methods
Genomic DNA was isolated from buccal swabs or peripheral blood mononuclear cells obtained from HIV-infected patients with or without a diagnoses of neurocognitive dysfunction in the Northeast AIDS Dementia Cohort and National NeuroAIDS Tissue Consortium. To maintain a uniform standard, a quantitative polymerase chain reaction design similar to previous studies using Taqman probes and fixed input DNA between 2 ng and 10 ng was used to determine a CCL3L1 copy number. Standard curves with two-fold dilutions from 25 ng to 1.56 ng were generated. CCL3L1 copy number was determined in triplicate in 262 subjects using quantitative polymerase chain reaction and the relative quantitation method. Data were analyzed using analysis of variance, with significance defined as P < 0.05 and Bonferroni post hoc tests.
Results
Significant differences as determined by analysis of variance in CCL3L1 copy number between African-Americans and Caucasians (P < 0.0001) were found, highlighting ethnic group differences in the copy number of this gene. However, there were no differences in CCL3L1 copy number across the neurocognitive groups within each ethnic group. The median CCL3L1 copy number in African-Americans of two and Caucasians of one in this study was significantly lower than the previously reported ethnic group means of two and four copies, respectively. A higher prevalence of abnormal cognition with a relative risk of four was seen in African-Americans versus Caucasians.
Conclusion
Based on this nested case-control study, CCL3L1 copy number alone may not be useful for distinguishing between individuals at risk for mild or severe neurocognitive disorder. Additional larger cohort studies are required to determine whether CCL3L1 copy number in combination with polymorphisms in other genes known to contribute to HIV risk will be useful in identifying those at increased risk for HAND.
doi:10.2147/CBF.S27685
PMCID: PMC3693394  PMID: 23814703
neurological; HIV-associated dementia; HAND; chemokine; copy number; African-American; Caucasian
14.  Prioritizing CD4 Count Monitoring in Response to ART in Resource-Constrained Settings: A Retrospective Application of Prediction-Based Classification 
PLoS Medicine  2012;9(4):e1001207.
Luis Montaner and colleagues retrospectively apply a potential capacity-saving CD4 count prediction tool to a cohort of HIV patients on antiretroviral therapy.
Background
Global programs of anti-HIV treatment depend on sustained laboratory capacity to assess treatment initiation thresholds and treatment response over time. Currently, there is no valid alternative to CD4 count testing for monitoring immunologic responses to treatment, but laboratory cost and capacity limit access to CD4 testing in resource-constrained settings. Thus, methods to prioritize patients for CD4 count testing could improve treatment monitoring by optimizing resource allocation.
Methods and Findings
Using a prospective cohort of HIV-infected patients (n = 1,956) monitored upon antiretroviral therapy initiation in seven clinical sites with distinct geographical and socio-economic settings, we retrospectively apply a novel prediction-based classification (PBC) modeling method. The model uses repeatedly measured biomarkers (white blood cell count and lymphocyte percent) to predict CD4+ T cell outcome through first-stage modeling and subsequent classification based on clinically relevant thresholds (CD4+ T cell count of 200 or 350 cells/µl). The algorithm correctly classified 90% (cross-validation estimate = 91.5%, standard deviation [SD] = 4.5%) of CD4 count measurements <200 cells/µl in the first year of follow-up; if laboratory testing is applied only to patients predicted to be below the 200-cells/µl threshold, we estimate a potential savings of 54.3% (SD = 4.2%) in CD4 testing capacity. A capacity savings of 34% (SD = 3.9%) is predicted using a CD4 threshold of 350 cells/µl. Similar results were obtained over the 3 y of follow-up available (n = 619). Limitations include a need for future economic healthcare outcome analysis, a need for assessment of extensibility beyond the 3-y observation time, and the need to assign a false positive threshold.
Conclusions
Our results support the use of PBC modeling as a triage point at the laboratory, lessening the need for laboratory-based CD4+ T cell count testing; implementation of this tool could help optimize the use of laboratory resources, directing CD4 testing towards higher-risk patients. However, further prospective studies and economic analyses are needed to demonstrate that the PBC model can be effectively applied in clinical settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS has killed nearly 30 million people since 1981, and about 34 million people (most of them living in low- and middle-income countries) are now infected with HIV, the virus that causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte and one of the body's white blood cell types), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within ten years of infection. Then, in 1996, antiretroviral therapy (ART) became available, and for people living in affluent countries, HIV/AIDS became a chronic condition. However, ART was expensive, and for people living in developing countries, HIV/AIDS remained a fatal illness. In 2003, HIV was declared a global health emergency, and in 2006, the international community set itself the target of achieving universal access to ART by 2010. By the end of 2010, only 6.6 million of the estimated 15 million people in need of ART in developing countries were receiving ART.
Why Was This Study Done?
One factor that has impeded progress towards universal ART coverage has been the limited availability of trained personnel and laboratory facilities in many developing countries. These resources are needed to determine when individuals should start ART—the World Health Organization currently recommends that people start ART when their CD4 count drops below 350 cells/µl—and to monitor treatment responses over time so that viral resistance to ART is quickly detected. Although a total lymphocyte count can be used as a surrogate measure to decide when to start treatment, repeated CD4 cell counts are the only way to monitor immunologic responses to treatment, a level of monitoring that is rarely sustainable in resource-constrained settings. A method that optimizes resource allocation by prioritizing who gets tested might be one way to improve treatment monitoring. In this study, the researchers applied a new tool for prioritizing laboratory-based CD4 cell count testing in resource-constrained settings to patient data that had been previously collected.
What Did the Researchers Do and Find?
The researchers fitted a mixed-effects statistical model to repeated CD4 count measurements from HIV-infected individuals from seven sites around the world (including some resource-limited sites). They then used model-derived estimates to apply a mathematical tool for predicting—from a CD4 count taken at the start of treatment, and white blood cell counts and lymphocyte percentage measurements taken later—whether CD4 counts would be above 200 cells/µl (the original threshold recommended for ART initiation) and 350 cells/µl (the current recommended threshold) for up to three years after ART initiation. The tool correctly classified 91.5% of the CD4 cell counts that were below 200 cells/µl in the first year of ART. With this threshold, the potential savings in CD4 testing capacity was 54.3%. With a CD4 count threshold of 350 cells/µl, the potential savings in testing capacity was 34%. The results over a three-year follow-up were similar. When applied to six representative HIV-positive individuals, the tool correctly predicted all the CD4 counts above 200 cells/µl, although some individuals who had a predicted CD4 count of less than 200 cells/µl actually had a CD4 count above this threshold. Thus, none of these individuals would have been exposed to an undetected dangerous CD4 count, but the application of the tool would have saved 57% of the CD4 laboratory tests done during the first year of ART.
What Do These Findings Mean?
These findings support the use of this new tool—the prediction-based classification (PBC) algorithm—for predicting a drop in CD4 count below a clinically meaningful threshold in HIV-infected individuals receiving ART. Further studies are now needed to demonstrate the feasibility, clinical effectiveness, and cost-effectiveness of this approach, to find out whether the tool can be used over extended periods of time, and to investigate whether the accuracy of its predictions can be improved by, for example, adding in periodic CD4 testing. Provided these studies confirm its early promise, the researchers suggest that the PBC algorithm could be used as a “triage” tool to direct available laboratory testing capacity to high-priority individuals (those likely to have a dangerously low CD4 count). By optimizing the use of limited laboratory resources in this and other ways, the PBC algorithm could therefore help to maintain and expand ART programs in low- and middle-income countries.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001207.
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/AIDS treatment and care and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment (in several languages)
More information about universal access to HIV treatment, prevention, care, and support is available from UNAIDS
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001207
PMCID: PMC3328436  PMID: 22529752
15.  Changes in HIV Incidence among People Who Inject Drugs in Taiwan following Introduction of a Harm Reduction Program: A Study of Two Cohorts 
PLoS Medicine  2014;11(4):e1001625.
Kenrad Nelson and colleagues report on the association between HIV incidence and exposure to a national harm-reduction program among people who inject drugs in Taiwan.
Please see later in the article for the Editors' Summary
Background
Harm reduction strategies for combating HIV epidemics among people who inject drugs (PWID) have been implemented in several countries. However, large-scale studies using sensitive measurements of HIV incidence and intervention exposures in defined cohorts are rare. The aim of this study was to determine the association between harm reduction programs and HIV incidence among PWID.
Methods and Findings
The study included two populations. For 3,851 PWID who entered prison between 2004 and 2010 and tested HIV positive upon incarceration, we tested their sera using a BED HIV-1 capture enzyme immunoassay to estimate HIV incidence. Also, we enrolled in a prospective study a cohort of 4,357 individuals who were released from prison via an amnesty on July 16, 2007. We followed them with interviews at intervals of 6–12 mo and by linking several databases. A total of 2,473 participants who were HIV negative in January 2006 had interviews between then and 2010 to evaluate the association between use of harm reduction programs and HIV incidence. We used survival methods with attendance at methadone clinics as a time-varying covariate to measure the association with HIV incidence. We used a Poisson regression model and calculated the HIV incidence rate to evaluate the association between needle/syringe program use and HIV incidence. Among the population of PWID who were imprisoned, the implementation of comprehensive harm reduction programs and a lower mean community HIV viral load were associated with a reduced HIV incidence among PWID. The HIV incidence in this population of PWID decreased from 18.2% in 2005 to 0.3% in 2010. In an individual-level analysis of the amnesty cohort, attendance at methadone clinics was associated with a significantly lower HIV incidence (adjusted hazard ratio: 0.20, 95% CI: 0.06–0.67), and frequent users of needle/syringe program services had lower HIV incidence (0% in high NSP users, 0.5% in non NSP users). In addition, no HIV seroconversions were detected among prison inmates.
Conclusions
Although our data are affected by participation bias, they strongly suggest that comprehensive harm- reduction services and free treatment were associated with reversal of a rapidly emerging epidemic of HIV among PWID.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 35 million people worldwide are currently infected with HIV, the virus that causes AIDS, and about 2.3 million people become newly infected every year. HIV is mainly transmitted through unprotected sex with an infected partner. However, people who inject drugs (PWID) have a particularly high risk of HIV infection because blood transfer through needle and syringe sharing can transmit the virus. It is estimated that 5%–10% of all people living with HIV are PWID. Indeed, in some regions of the world the primary route of HIV transmission is through shared drug injection equipment and the prevalence (the proportion of a population that has a specific disease) of HIV infection among PWID is very high. In Asia, for example, more than a quarter of PWID are HIV positive. Because the high prevalence of HIV among PWID poses a global health challenge, bodies such as the Joint United Nations Programme on HIV/AIDS endorse harm reduction strategies to prevent risky injection behaviors among PWID. These strategies include the provision of clean needles and syringes, opioid substitution therapy such as methadone maintenance treatment, and antiretroviral treatment for HIV-positive PWID.
Why Was This Study Done?
Although harm reduction strategies for combating HIV epidemics among PWID have been implemented in several countries, few large-scale studies have examined the association between HIV incidence (the proportion of new cases of HIV in a population per year) and exposure to harm reduction programs among PWID. In this cohort study (an investigation that determines the characteristics of a group of people and then follows them over time), the researchers determine the association between harm reduction programs and HIV incidence among PWID in Taiwan. HIV infections used to be rare among the 60,000 PWID living in Taiwan, but after the introduction of a new HIV strain into the country in 2003, an HIV epidemic spread rapidly. In response, the Taiwanese government introduced a pilot program of harm reduction that included the provision of clean needles and syringes and health education in July 2005. The program was expanded to include methadone maintenance treatment in early 2006 and implemented nationwide in June 2006.
What Did the Researchers Do and Find?
The researchers enrolled two study populations. The first cohort comprised 3,851 PWID who were incarcerated for illicit drug use between 2004 and 2010 and who tested positive for HIV upon admission into prison. By using the BED assay, which indicates whether an HIV infection is recent, the researchers were able to determine the HIV incidence among the prisoners. In 2004, the estimated HIV incidence among prisoners with a history of drug injection was 6.44%. The incidence peaked in 2005 at 18.2%, but fell to 0.3% in 2010.
The second study population comprised 2,473 individuals who were HIV negative on January 1, 2006, and who had been incarcerated for drug use crimes but were released on July 16, 2007, during an amnesty. The researchers regularly interviewed these participants between their release and 2010 about their use of harm reduction interventions, and obtained other data about them (for example, diagnosis of HIV infection) from official databases. Analysis of all these data indicated that, in this cohort, attendance at methadone maintenance treatment clinics and frequent use of needle and syringe services were both associated with a significantly lower HIV incidence.
What Do These Findings Mean?
These findings suggest that the introduction of a comprehensive harm reduction program in Taiwan was associated with a significant reduction in the HIV incidence rate among PWID. These findings must be interpreted with caution, however. First, because the participants in the study were selected from PWID with histories of incarceration, the findings may not be representative of all PWID in Taiwan or of PWID in other countries. Second, PWID who chose to use needle and syringe services or methadone maintenance treatment clinics might have shared other unknown characteristics that affected their risk of HIV infection. Finally, some of the reduction in HIV incidence seen during the study is likely to be associated with the availability of free treatment, which has been offered to all HIV-positive individuals in Taiwan since 1997. Despite these limitations, these findings suggest that countries with a high prevalence and incidence of HIV among PWID should provide comprehensive harm reduction services to their populations to reduce risky drug injection behaviors.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001625.
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 injecting drug users and HIV/AIDS and on harm reduction and HIV prevention (in English and Spanish)
The US National Institute on Drug Abuse also provides information about drug abuse and HIV/AIDS (in English and Spanish)
The 2013 UNAIDS World AIDS Day report provides up-to-date information about the AIDS epidemic and efforts to halt it
Personal stories about living with HIV/AIDS are available through Avert, Nam/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001625
PMCID: PMC3979649  PMID: 24714449
16.  Cost-Effectiveness of Pooled Nucleic Acid Amplification Testing for Acute HIV Infection after Third-Generation HIV Antibody Screening and Rapid Testing in the United States: A Comparison of Three Public Health Settings 
PLoS Medicine  2010;7(9):e1000342.
Angela Hutchinson and colleagues conducted a cost-effectiveness analysis of pooled nucleic acid amplification testing following HIV testing and show that it is not cost-effective at recommended antibody testing intervals for high-risk persons except in very high-incidence settings.
Background
Detection of acute HIV infection (AHI) with pooled nucleic acid amplification testing (NAAT) following HIV testing is feasible. However, cost-effectiveness analyses to guide policy around AHI screening are lacking; particularly after more sensitive third-generation antibody screening and rapid testing.
Methods and Findings
We conducted a cost-effectiveness analysis of pooled NAAT screening that assessed the prevention benefits of identification and notification of persons with AHI and cases averted compared with repeat antibody testing at different intervals. Effectiveness data were derived from a Centers for Disease Control and Prevention AHI study conducted in three settings: municipal sexually transmitted disease (STD) clinics, a community clinic serving a population of men who have sex with men, and HIV counseling and testing sites. Our analysis included a micro-costing study of NAAT and a mathematical model of HIV transmission. Cost-effectiveness ratios are reported as costs per quality-adjusted life year (QALY) gained in US dollars from the societal perspective. Sensitivity analyses were conducted on key variables, including AHI positivity rates, antibody testing frequency, symptomatic detection of AHI, and costs. Pooled NAAT for AHI screening following annual antibody testing had cost-effectiveness ratios exceeding US$200,000 per QALY gained for the municipal STD clinics and HIV counseling and testing sites and was cost saving for the community clinic. Cost-effectiveness ratios increased substantially if the antibody testing interval decreased to every 6 months and decreased to cost-saving if the testing interval increased to every 5 years. NAAT was cost saving in the community clinic in all situations. Results were particularly sensitive to AHI screening yield.
Conclusions
Pooled NAAT screening for AHI following negative third-generation antibody or rapid tests is not cost-effective at recommended antibody testing intervals for high-risk persons except in very high-incidence settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since 1981, acquired immunodeficiency syndrome (AIDS) has killed about 25 million people and about 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV, which is most often transmitted through unprotected sex with an infected partner or injection drug use, infects and kills immune system cells, leaving infected individuals susceptible to other infectious diseases. The first, often undiagnosed stage of HIV infection—acute HIV infection (AHI)—lasts a few weeks and sometimes involves a flu-like illness. During AHI, the immune system responds to HIV by beginning to make antibodies that recognize the virus but seroconversion—the appearance of detectable amounts of antibody in the blood—takes 6–12 weeks. During the second, symptom-free stage of HIV infection, which can last many years, the virus gradually destroys the immune system so that by the third stage of infection unusual infections (for example, persistent yeast infections) begin to occur. The final stage of infection (AIDS) is characterized by multiple severe infections and by the development of unusual cancers.
Why Was This Study Done?
Antiretroviral drugs control HIV infections but don't cure them. It is very important, therefore, to prevent HIV transmission by avoiding HIV risk behaviors that increase the risk of HIV infection such as having sex without a condom or with many partners. Individuals with AHI in particular need to avoid high-risk behaviors because these people are extremely infectious. However, routine tests for HIV infection that measure antibodies in the blood often give false-negative results in people with AHI because of the time lag between infection and seroconversion. Nucleic acid amplification testing (NAAT), which detects HIV genetic material in the blood, is a more accurate way to diagnose AHI but is expensive. In this study, the researchers investigate whether pooled NAAT screening (specimens are pooled before testing to reduce costs) for AHI in clinic settings after third-generation antibody testing is a cost-effective HIV prevention strategy. That is, does the gain in quality-adjusted life years (QALY, a measure of the quantity and quality of life generated by healthcare interventions) achieved by averting new HIV infections outweigh the costs of pooled NAAT screening?
What Did the Researchers Do and Find?
The researchers combined effectiveness data from a US study in which AHI was detected using pooled NAAT in three settings (sexually transmitted disease [STD] clinics, a community clinic serving men who have sex with men [MSM], and HIV counseling/testing sites) with a “micro-costing” study of NAAT and a mathematical model of HIV transmission. They then calculated the costs per QALY gained (the cost-effectiveness ratio) as a result of HIV prevention by identification and notification of people with AHI through pooled NAAT screening compared with repeat antibody testing. Pooled NAAT for AHI screening following annual antibody testing (the recommended testing interval for high-risk individuals), they estimate, would cost US$372,300 and US$484,400 per QALY gained for the counseling/testing sites and STD clinics, respectively, whereas pooled NAAT for AHI screening was cost-saving for the community clinic serving MSM. The cost-effectiveness ratio increased for the counseling/testing sites and STD clinics when the antibody testing interval was decreased to 6 months but remained cost-saving for the community clinic. With an antibody testing interval of 5 years, pooled NAAT was cost-saving in all three settings.
What Do These Findings Mean?
Cost-effectiveness ratios of US$100,000–US$200,000 are considered acceptable in the US. These results suggest therefore, that the cost of pooled NAAT screening for AHI following negative third-generation antibody testing is not acceptable at the recommended testing interval for high-risk individuals except in settings where HIV infection is very common such as clinics serving MSM. The researchers reach a similar conclusion in a separate cost-effectiveness analysis of pooled NAAT screening following a negative rapid HIV test. Although the accuracy of these results depends on numerous assumptions made in the cost-effectiveness analyses (for example, the degree to which awareness of HIV status affects the behavior of people with AHI), sensitivity analyses (investigations of the effect of altering key assumptions) show that these findings are not greatly affected by changes in many of these assumptions. Thus, the researchers conclude, NAAT screening should be reserved for settings that serve populations in which there are very high levels of new HIV infection.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000342.
The US Centers for Disease Control and Prevention provides information on HIV infection and AIDS and on HIV testing and diagnosis
HIV InSite has information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS nonprofit organization on many aspects of HIV/AIDS, including HIV testing (in English and Spanish)
MedlinePlus has links to further resources on AIDS (in English and Spanish)
The UK National Institute of Health and Clinical Excellence has a page on measuring effectiveness and cost-effectiveness
doi:10.1371/journal.pmed.1000342
PMCID: PMC2946951  PMID: 20927354
17.  Factors in AIDS Dementia Complex Trial Design: Results and Lessons from the Abacavir Trial 
PLoS Clinical Trials  2007;2(3):e13.
Objectives:
To determine the efficacy of adding abacavir (Ziagen, ABC) to optimal stable background antiretroviral therapy (SBG) to AIDS dementia complex (ADC) patients and address trial design.
Design:
Phase III randomized, double-blind placebo-controlled trial.
Setting:
Tertiary outpatient clinics.
Participants:
ADC patients on SBG for ≥8 wk.
Interventions:
Participants were randomized to ABC or matched placebo for 12 wk.
Outcome Measures:
The primary outcome measure was the change in the summary neuropsychological Z score (NPZ). Secondary measures were HIV RNA and the immune activation markers β-2 microglobulin, soluble tumor necrosis factor (TNF) receptor 2, and quinolinic acid.
Results:
105 participants were enrolled. The median change in NPZ at week 12 was +0.76 for the ABC + SBG and +0.63 for the SBG groups (p = 0.735). The lack of efficacy was unlikely related to possible limited antiviral efficacy of ABC: at week 12 more ABC than placebo participants had plasma HIV RNA ≤400 copies/mL (p = 0.002). There were, however, other factors. Two thirds of patients were subsequently found to have had baseline resistance to ABC. Second, there was an unanticipated beneficial effect of SBG that extended beyond 8 wk to 5 mo, thereby rendering some of the patients at baseline unstable. Third, there was an unexpectedly large variability in neuropsychological performance that underpowered the study. Fourth, there was a relative lack of activity of ADC: 56% of all patients had baseline cerebrospinal fluid (CSF) HIV-1 RNA <100 copies/mL and 83% had CSF β-2 microglobulin <3 nmol/L at baseline.
Conclusions:
The addition of ABC to SBG for ADC patients was not efficacious, possibly because of the inefficacy of ABC per se, baseline drug resistance, prolonged benefit from existing therapy, difficulties with sample size calculations, and lack of disease activity. Assessment of these trial design factors is critical in the design of future ADC trials.
Editorial Commentary
Background: AIDS dementia complex (ADC) was first identified early in the HIV epidemic and at that time affected a substantial proportion of patients with AIDS. Patients with ADC experience dementia as well as disordered behavior and problems with movement and balance. ADC is now much less common in locations where patients have access to HAART (highly active antiretroviral therapy), consisting of combinations of several drugs that attack the virus at different stages of its life cycle. At present, however, there are no generally accepted guidelines for the best treatment of people with ADC. It has been thought for some time that the best treatment regimens for people with ADC would include drugs that cross the barrier between blood and brain well. Shortly following the introduction of HAART, a trial was carried out to find out whether adding one particular drug, abacavir, to existing combinations of drugs would be beneficial in people with ADC. This drug is known to cross the barrier between the blood and brain. The trial enrolled HIV-positive individuals with mild to moderate ADC and who were already receiving antiretroviral drug treatment. 105 participants were assigned at random to receive either high-dose abacavir or a placebo, in addition to their existing therapy. The primary outcome of the trial was a summary of performance on a set of different tests, designed to evaluate cognitive, behavior, and movement skills, at 12 weeks. Other outcomes included levels of HIV RNA (viral load) in fluid around the brain, as well as other neurological evaluations, and the level of HIV RNA and CD4+ T cells (the cells infected by HIV) in blood.
What this trial shows: When comparing the change in performance scores for individuals randomized to either abacavir or placebo, the results showed an improvement in scores for both groups, but no significant difference in improvement between the two groups. Similarly, the levels of HIV RNA in the cerebrospinal fluid did not differ between the two groups being compared, and other neurological tests did not show any differences between the two groups. However, at 12 weeks, patients receiving abacavir were more likely to have low levels of HIV RNA in their blood, suggesting that abacavir was active against the virus, but this did not translate into an additional improvement of these patients' dementia. The overall rates of adverse events were roughly comparable between the two groups in the trial, although participants receiving abacavir were more likely to experience certain types of events, such as nausea.
Strengths and limitations: The trial was appropriately randomized and controlled, using central telephone procedures for randomizing participants and subsequent blinding of patients and trial investigators. These procedures help minimize the chance of bias in assigning participants to the different arms as well as in the subsequent performance of individuals within the trial and the assessment of their outcomes. Limitations in the study design have been identified. One limitation is that individuals enrolled into the trial may not in fact have been receiving their existing HAART regimen for long enough to experience its optimal effect, and therefore the improvement seen in both groups could have resulted from an ongoing response to their existing regimen. It is also possible that patients improved in their test scores over the course of the trial simply because they became more familiar with the tests and not because their condition improved. This is a problem in all such trials that try to improve mental function. Finally, a limitation may have been the inclusion of patients who did not have active disease leading to worsening dementia.
Contribution to the evidence: The findings from this trial suggest that adding high-dose abacavir to existing HAART is not beneficial for patients with ADC. However, the trial provides several insights into the way that future studies of this type can be done, and which typically pose a number of challenging design problems. In particular, sensitive markers are needed that will allow researchers to monitor progression of ADC and patients' response to therapy.
doi:10.1371/journal.pctr.0020013
PMCID: PMC1845158  PMID: 17401456
18.  HIV-associated neurocognitive disorders (HAND) in a South Asian population - contextual application of the 2007 criteria 
BMJ Open  2012;2(1):e000662.
Objectives
To estimate the prevalence of HIV-associated neurocognitive disorders (HAND) among HIV patients in a multiethnic South Asian population, describe the pattern of neurocognitive impairment in HAND and the factors associated with HAND.
Design
A cross-sectional survey of HIV-positive outpatients and inpatients.
Setting
The sole referral centre for HIV/AIDS treatment in Singapore.
Participants
Inclusion criteria were HIV positive, age between 21 and 80 years old and at least 3 years of education. Exclusion criteria included concomitant delirium, serious systemic disease or major psychiatric illness. 265 patients did not meet criteria or declined to participate. The final sample size was 132.
Outcome measures
The primary outcome measure was cognitive impairment based on performance on the Montreal Cognitive Assessment, International HIV Dementia Scale and Instrumental Activities of Daily Living. The secondary outcome measure was the classification of impairment based on the 2007 updated research nosology for HAND.
Results
The prevalence of HAND was 22.7% of which 70% (15.9% of total) were asymptomatic neurocognitive impairment, 23.3% (5.3% of total) were mild neurocognitive disorder and 6.7% (1.5% of total) were HIV-associated dementia. Increasing age (OR 1.104, 95% CI 1.054 to 1.155, p<0.001), less education (OR 0.78, 95% CI 0.69 to 0.89, p<0.001) and low baseline CD4 count (OR 0.15, 95% CI 0.03 to 0.74, p=0.019) were associated with HAND. Delayed recall, language and abstract thinking were the domains most commonly affected, but impairment in visuospatial ability (RC 3.013, 95% CI 1.954 to 4.073, p<0.001) and attention (RC 2.205, 95% CI 1.043 to 3.367, p<0.001) were most strongly associated with HAND.
Conclusion
HAND is common among HIV patients in a South Asian sample, most of whom are asymptomatic. Older patients with less education and severe illness at diagnosis are at highest risk of HAND. Delayed recall is most commonly affected, but visuospatial dysfunction is most strongly associated with prevalent HAND.
Article summary
Article focus
What is the prevalence of HIV-associated neurocognitive disorders (HAND) in South Asia?
What are the demographic and clinical characteristics of South Asian individuals with HAND?
Key messages
The estimated prevalence of HAND in South Asia is high.
Older patients with less education and more severe HIV illness at diagnosis are at highest risk for HAND.
Early diagnosis of HIV and access to care and treatment is essential.
Strengths and limitations of this study
The article's strengths are it is the first study on HAND in a representative multiethnic South Asian population and it used a method of detection that is applicable to local clinical practice.
The limitations are the small sample size and non-comparability with other HAND studies due to different methods used in detection of HAND cases.
Another major limitation is the lack of published local normative data on the tools used.
doi:10.1136/bmjopen-2011-000662
PMCID: PMC3282293  PMID: 22331389
19.  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
20.  Assessment of Recent HIV-1 Infection by a Line Immunoassay for HIV-1/2 Confirmation 
PLoS Medicine  2007;4(12):e343.
Background
Knowledge of the number of recent HIV infections is important for epidemiologic surveillance. Over the past decade approaches have been developed to estimate this number by testing HIV-seropositive specimens with assays that discriminate the lower concentration and avidity of HIV antibodies in early infection. We have investigated whether this “recency” information can also be gained from an HIV confirmatory assay.
Methods and Findings
The ability of a line immunoassay (INNO-LIA HIV I/II Score, Innogenetics) to distinguish recent from older HIV-1 infection was evaluated in comparison with the Calypte HIV-1 BED Incidence enzyme immunoassay (BED-EIA). Both tests were conducted prospectively in all HIV infections newly diagnosed in Switzerland from July 2005 to June 2006. Clinical and laboratory information indicative of recent or older infection was obtained from physicians at the time of HIV diagnosis and used as the reference standard. BED-EIA and various recency algorithms utilizing the antibody reaction to INNO-LIA's five HIV-1 antigen bands were evaluated by logistic regression analysis. A total of 765 HIV-1 infections, 748 (97.8%) with complete test results, were newly diagnosed during the study. A negative or indeterminate HIV antibody assay at diagnosis, symptoms of primary HIV infection, or a negative HIV test during the past 12 mo classified 195 infections (26.1%) as recent (≤ 12 mo). Symptoms of CDC stages B or C classified 161 infections as older (21.5%), and 392 patients with no symptoms remained unclassified. BED-EIA ruled 65% of the 195 recent infections as recent and 80% of the 161 older infections as older. Two INNO-LIA algorithms showed 50% and 40% sensitivity combined with 95% and 99% specificity, respectively. Estimation of recent infection in the entire study population, based on actual results of the three tests and adjusted for a test's sensitivity and specificity, yielded 37% for BED-EIA compared to 35% and 33% for the two INNO-LIA algorithms. Window-based estimation with BED-EIA yielded 41% (95% confidence interval 36%–46%).
Conclusions
Recency information can be extracted from INNO-LIA-based confirmatory testing at no additional costs. This method should improve epidemiologic surveillance in countries that routinely use INNO-LIA for HIV confirmation.
Jörg Schüpbach and colleagues show that a second-generation Western blot antibody test used to confirm HIV infection can also be used to determine rates of recent HIV infection.
Editors' Summary
Background.
Since the first diagnosed cases of AIDS (acquired immunodeficiency syndrome) in 1981, the AIDS epidemic has spread rapidly. Now, 40 million people are infected with HIV (human immunodeficiency virus), the cause of AIDS. HIV infects and kills immune system cells, leaving infected individuals susceptible to other infectious diseases and tumors. The first, often undiagnosed, stage of HIV infection (primary HIV infection) lasts a few weeks and often involves a flu-like illness. During this stage, the immune system begins to respond to HIV by producing antibodies (proteins that recognize viral molecules called antigens). The time needed for these antibodies to appear on testing “seroconversion” (usually 6–12 weeks) is called the window period of the test; HIV antibody tests done during this period give false negative results. During the second, symptom-free stage of HIV infection, which can last many years, the virus gradually destroys the immune system so that by the third stage of infection unusual infections (for example, persistant yeast infections of the mouth) begin to occur. The fourth stage is characterized by multiple AIDS-indicator conditions such as severe bacterial, fungal, or viral infections, and cancers such as Kaposi sarcoma.
Why Was This Study Done?
To monitor the AIDS/HIV epidemic and HIV prevention programs, it is necessary to know how many people in a population have been recently infected with HIV. Serologic testing algorithms for recent HIV seroconversion (STARHS) provide a way to get this information. Early during seroconversion, low levels of antibodies that bind only weakly to their viral antigens (low-affinity antibodies) are made. Later on, antibody concentrations and tightness of binding increase. STARHS calculate the number of recently infected people by analyzing data from special “detuned” HIV antibody assays (for example, a commercially available test called the BED-EIA) that preferentially detect low-concentration, low-avidity antibodies. This type of test cannot, however, be used to determine whether an individual has an HIV infection, because it will miss a substantial fraction of infected people. Diagnosing HIV in an individual person requires more sensitive tests for antibody detection. In this study, the researchers have investigated whether a test called INNO-LIA, which is already being used in some countries to diagnose HIV infection, can also provide information about the recency (newness) of HIV infections.
What Did the Researchers Do and Find?
Between July 2005 and June 2006, 765 HIV infections were newly diagnosed in Switzerland. Using clinical and laboratory information collected at diagnosis, the researchers classified 195 of these infections as recent infections (occurring within the past year) and 161 as older infections. (The remaining infections could not be classified based on the available medical infomation.) The researchers then compared the ability of INNO-LIA (which measures antibodies to five HIV-1 antigens) and BED-EIA to distinguish recent from older HIV infections. BED-EIA correctly identified as recent 65% of the infections classified as recent based on the clinical information, and identified as older 80% of the infections classified as older based on the clinical information. In other words, this test was 65% sensitive (able to detect 65% of the truly recent infections as defined in this study) and was 80% specific (80% accurate in eliminating non-recent infections.) The two best algorithms (mathematical procedures) for converting INNO-LIA data into estimates of recent HV infections had sensitivities of 50% and 40% and specificities of 95% and 99%, respectively. Using actual test results and taking into account these sensitivities and specificities gave estimates of 35% and 33% for the proportion of the whole study population that had been recently infected. BED-EIA gave an estimate of 37%. Finally, a widely used window-based algorithm for recency estimation that uses the numbers of cases that are defined as recent by BED-EIA and the length of the window period for BED-EIA to calculate the annual number of new infections in populations indicated that 41% of the whole study population had been recently infected.
What Do These Findings Mean?
These findings indicate that numbers of recent HIV infections can be extracted from the INNO-LIA HIV diagnostic test and are comparable to those obtained using a window-based algorithm. The test could, therefore, provide a cost-effective means to improve HIV surveillance in countries like Switzerland that already use it for HIV diagnosis. However, because this approach relies on knowing the sensitivity and specificity of the INNO-LIA algorithms, which may vary between populations, the use of these algorithms to estimate numbers of recent HIV infections must be preceded by an assessment of their sensitivity and specificity in each new setting.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040343.
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including fact sheets on the symptoms of HIV infection, HIV testing, and a chapter on laboratory tests for HIV antibodies
NAM, a UK registered charity, provides information about all aspects of HIV and AIDS, including fact sheets on the stages of HIV infection and HIV testing
The US Centers for Disease Control and Prevention (CDC) provides information on HIV/AIDS, including information on HIV testing and on HIV surveillance by the CDC (in English and Spanish)
Information is available from Avert, an international AIDS charity, on the stages of HIV infection and on HIV testing
Details on the US Centers for Disease Control and Prevention and the World Health Organiztion HIV classification systems are available from the US Department of Veterans Affairs
doi:10.1371/journal.pmed.0040343
PMCID: PMC2100138  PMID: 18052604
21.  Antiretroviral Treatment and Prevention of Peripartum and Postnatal HIV Transmission in West Africa: Evaluation of a Two-Tiered Approach 
PLoS Medicine  2007;4(8):e257.
Background
Highly active antiretroviral treatment (HAART) has only been recently recommended for HIV-infected pregnant women requiring treatment for their own health in resource-limited settings. However, there are few documented experiences from African countries. We evaluated the short-term (4 wk) and long-term (12 mo) effectiveness of a two-tiered strategy of prevention of mother-to-child transmission of HIV (PMTCT) in Africa: women meeting the eligibility criteria of the World Health Organization (WHO) received HAART, and women with less advanced HIV disease received short-course antiretroviral (scARV) PMTCT regimens.
Methods and Findings
The MTCT-Plus Initiative is a multi-country, family-centred HIV care and treatment program for pregnant and postpartum women and their families. Pregnant women enrolled in Abidjan, Côte d'Ivoire received either HAART for their own health or short-course antiretroviral (scARV) PMTCT regimens according to their clinical and immunological status. Plasma HIV-RNA viral load (VL) was measured to diagnose peripartum infection when infants were 4 wk of age, and HIV final status was documented either by rapid antibody testing when infants were aged ≥ 12 mo or by plasma VL earlier. The Kaplan-Meier method was used to estimate the rate of HIV transmission and HIV-free survival. Between August 2003 and June 2005, 107 women began HAART at a median of 30 wk of gestation, 102 of them with zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) and they continued treatment postpartum; 143 other women received scARV for PMTCT, 103 of them with sc(ZDV+3TC) with single-dose NVP during labour. Most (75%) of the infants were breast-fed for a median of 5 mo. Overall, the rate of peripartum HIV transmission was 2.2% (95% confidence interval [CI] 0.3%–4.2%) and the cumulative rate at 12 mo was 5.7% (95% CI 2.5%–9.0%). The overall probability of infant death or infection with HIV was 4.3% (95% CI 1.7%–7.0%) at age week 4 wk and 11.7% (95% CI 7.5%–15.9%) at 12 mo.
Conclusions
This two-tiered strategy appears to be safe and highly effective for short- and long-term PMTCT in resource-constrained settings. These results indicate a further benefit of access to HAART for pregnant women who need treatment for their own health.
In an observational cohort study from Côte d'Ivoire, François Dabis and colleagues report on prevention of mother-to-child HIV transmission among women receiving antiretroviral therapy according to World Health Organization recommendations.
Editors' Summary
Background
Effective treatments are available to prevent AIDS in people who are infected with HIV, but not everyone with HIV needs to take medication. Usually, anti-HIV medication is recommended only for those whose immune systems have been significantly affected by the virus, as evidenced by symptoms or by the results of a blood test, the CD4 lymphocyte (“T cell”) count. Treating HIV usually requires a combination of three or more medications. These combinations (called HAART) must be taken every day, can cause complications, and can be expensive.
Worldwide, more than half a million children became infected with HIV each year. Most of these children acquire HIV from their mothers during pregnancy or around the time of birth. If a pregnant woman with HIV takes HAART, her chances of passing HIV to the baby are greatly reduced, but the possible side effects of HAART on the baby are not known. Also, most transmission of HIV from mothers to babies occurs in poor countries where supplies of HAART are limited. For these reasons, World Health Organization (WHO) does not recommend that every pregnant woman receive HAART to prevent HIV transmission to the baby, unless the woman needs HAART for her own health (for example if her T cells are low or she has severe symptoms of HIV infection). For pregnant women with HIV who do not need to take HAART for their own health, less complicated treatments, involving a short course of one or two HIV drugs, can be used to reduce the risk of passing HIV to the baby.
Why Was This Study Done?
The WHO recommendations for HAART in pregnancy are based on the best available evidence, but it is important to know how well they work in actual practice. The authors of this study were providing HIV treatment to pregnant women with HIV in West Africa through an established clinic program in Abidjan, Côte d'Ivoire, and wanted to see how well the WHO recommendations for HAART or short-course treatments, depending on the mother's condition, were working to protect babies from HIV infection.
What Did the Researchers Do and Find?
The researchers studied 250 HIV-infected pregnant women who received HIV medications in the Abidjan program between mid-2003 and mid-2005. In accordance with WHO guidelines, 107 women began HAART for their own health during pregnancy, and 143 women did not qualify for HAART but received other short course treatments (scARV) to prevent HIV transmission to their babies. The authors monitored mothers and babies for treatment side effects and tested the babies for HIV infection up to age 1 y.
They found that HAART was relatively safe during pregnancy, although babies born to women on HAART were more likely (26.3%) to have low birth weight than babies born to women who received scARV (12.4%). Also, 7.5% of women on HAART developed side effects requiring a change in their medications. Combining the results from HAART and scART groups, the chance of HIV transmission around the time of birth was 2.2%, increasing to 5.7% at age 1 y. (Three-quarters of the infants were breast-fed; safe water for mixing formula was not reliably available.) The study found no difference in risk of HIV infection between babies whose mothers received HAART and those whose mothers received scARV according to guidelines.
What Do These Findings Mean?
These results support the safety and effectiveness of the WHO two-tiered approach for preventing mother-to-child transmission. This study was not designed to compare HAART to scART directly, because the women who received HAART were the ones with more advanced HIV infection, which might have affected their babies in many ways.
Compared to earlier pregnancy studies of HAART in rich countries, this study of the WHO approach in West Africa showed similar success in protecting infants from HIV infection around the time of birth. Unfortunately, because formula feeding was not generally available in resource-limited settings, protection declined over the first year of life with breast-feeding, but some protection remained.
This study confirms that close monitoring of pregnant women on HAART is necessary, so that drugs can be changed if side effects develop. The study does not tell us whether using scARV in pregnancy might change the virus in ways that would make it more difficult to treat the same women with HAART later if they needed it. The reason for low birth weight in some babies born to mothers on HAART is unclear. It may be because the women who needed HAART had more severe health problems from their HIV, or it may be a result of the HAART itself.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040257.
World Health Organization has a page on prevention of mother-to-child transmission of HIV
“Women, Children, and HIV” is a resource site from the François Xavier Bagnoud Center and UCSF
The MTCT-Plus initiative at Columbia University supports the programs in Abidjan
doi:10.1371/journal.pmed.0040257
PMCID: PMC1949842  PMID: 17713983
22.  Routine HIV Testing in Botswana: A Population-Based Study on Attitudes, Practices, and Human Rights Concerns 
PLoS Medicine  2006;3(7):e261.
Background
The Botswana government recently implemented a policy of routine or “opt-out” HIV testing in response to the high prevalence of HIV infection, estimated at 37% of adults.
Methods and Findings
We conducted a cross-sectional, population-based study of 1,268 adults from five districts in Botswana to assess knowledge of and attitudes toward routine testing, correlates of HIV testing, and barriers and facilitators to testing, 11 months after the introduction of this policy. Most participants (81%) reported being extremely or very much in favor of routine testing. The majority believed that this policy would decrease barriers to testing (89%), HIV-related stigma (60%), and violence toward women (55%), and would increase access to antiretroviral treatment (93%). At the same time, 43% of participants believed that routine testing would lead people to avoid going to the doctor for fear of testing, and 14% believed that this policy could increase gender-based violence related to testing. The prevalence of self-reported HIV testing was 48%. Adjusted correlates of testing included female gender (AOR = 1.5, 95% CI = 1.1–1.9), higher education (AOR = 2.0, 95% CI = 1.5–2.7), more frequent healthcare visits (AOR = 1.9, 95% CI = 1.3–2.7), perceived access to HIV testing (AOR = 1.6, 95% CI = 1.1–2.5), and inconsistent condom use (AOR = 1.6, 95% CI = 1.2–2.1). Individuals with stigmatizing attitudes toward people living with HIV and AIDS were less likely to have been tested for HIV/AIDS (AOR = 0.7, 95% CI = 0.5–0.9) or to have heard of routine testing (AOR = 0.59, 95% CI = 0.45–0.76). While experiences with voluntary and routine testing overall were positive, 68% felt that they could not refuse the HIV test. Key barriers to testing included fear of learning one's status (49%), lack of perceived HIV risk (43%), and fear of having to change sexual practices with a positive HIV test (33%).
Conclusions
Routine testing appears to be widely supported and may reduce barriers to testing in Botswana. As routine testing is adopted elsewhere, measures should be implemented to assure true informed consent and human rights safeguards, including protection from HIV-related discrimination and protection of women against partner violence related to testing.
Editors' Summary
Background.
In 2005, there were 5 million new infections with the human immunodeficiency virus (HIV), and the disease it causes—acquired immunodeficiency syndrome (AIDS)—killed three million people. Despite the increased availability of drugs that can fight HIV (antiretrovirals), the AIDS epidemic continues to grow, particularly in sub-Saharan Africa. To halt it, more needs to be done to prevent the spread of HIV. Education about safe sex can help—HIV is most commonly spread through unprotected sex with an infected partner—but increasing HIV testing is of paramount importance. Unfortunately, the uptake of voluntary counseling and testing in sub-Saharan Africa is worryingly low. Fear of being stigmatized—socially disgraced—and discriminated against, fears about the positive result itself, and worries about access to antiretroviral drugs are all putting people off being tested.
Why Was This Study Done?
In Botswana, one in three adults is infected with HIV. Since 2002, antiretroviral drugs have been freely available but enrollment in the Botswana National Treatment Program during its first two years was slow, in part due to inadequate uptake of voluntary HIV testing. Consequently, in early 2004, the government introduced a policy of routine HIV testing in which all patients are tested for HIV when they visit their doctor unless they opt out. A major aim of this approach to HIV testing, which was formally recommended in June 2004 by UNAIDS and the World Health Organization, is to increase uptake of HIV testing and treatment, and to reduce HIV-related stigma by treating the HIV test like any other routine medical procedure. However, there are fears that the policy could back-fire—people might not visit their doctors, for example, because they are afraid of being tested and think that they will not be able to refuse the test. In this study, the researchers investigated knowledge of and attitudes to routine testing in Botswana to understand better the consequences of a routine testing policy.
What Did the Researchers Do and Find?
The researchers interviewed adults throughout Botswana about their knowledge of and attitudes to routine HIV testing 11 months after introduction of the policy. Only half of the participants had heard of routine testing before being interviewed but nearly all were in favor of routine testing. More than half thought it would reduce HIV-related stigma and the violence toward women that is associated with an HIV-positive status. However, almost half believed that routine testing might prevent people from going to the doctor because of fear of testing and a few thought the policy would increase violence against women. Nearly half of the interviewees had had an HIV test and the researchers found, for example, that women were more likely to have been tested than men and that people with stigmatizing attitudes toward people living with HIV and AIDS were less likely to be tested. Fear of learning one's HIV status, lack of perceived risk, and fear of having to change sexual practices if positive all stopped people taking the test. Finally, although experiences with testing were generally positive, approximately two-thirds of interviewees who had been tested felt that it would have been difficult to refuse the test.
What Do These Findings Mean?
These results show that there is widespread support for routine HIV testing in Botswana, a finding supported by recent increases in treatment uptake. Routine testing, write the researchers, holds significant promise for the prevention and treatment of HIV/AIDS in Botswana and elsewhere. In particular, increasing the number of people tested for HIV may reduce HIV-related stigma, which should further increase testing and hopefully slow the spread of HIV. But the results of this study also highlight some areas of concern. Whenever HIV testing policies are implemented, human rights must be protected by ensuring that patients have all the information necessary to make an informed and free decision about being tested, by providing protection for women against violence related to HIV status, and by ensuring total confidentiality. Careful monitoring of Botswana's program and similar programs will be needed to ensure that these human rights are fully met, conclude the researchers.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030261
• US National Institute of Allergy and Infectious Diseases factsheet on HIV infection and AIDS
• US Department of Health and Human Services information on AIDS
• US Centers for Disease Control and Prevention information on HIV/AIDS
• UNAIDS and World Health Organization 2004 policy statement on HIV testing
• AVERT, a UK-based charity, provides information about HIV and AIDS in Botswana
A cross-sectional, population-based study of 1,268 adults from five districts in Botswana showed that routine HIV testing appears to be widely supported and may reduce barriers to HIV testing.
doi:10.1371/journal.pmed.0030261
PMCID: PMC1502152  PMID: 16834458
23.  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
24.  Reciprocal prediction of medication adherence and neurocognition in HIV/AIDS(e–Pub ahead of print) 
Neurology  2010;74(15):1217-1222.
Background:
Antiretroviral medications have been shown to benefit neurocognition in HIV/AIDS, and neurocognitive deficits are a risk factor for poor adherence to these medications. However, little is known about the predictive pathways linking medication adherence with cognitive ability.
Methods:
In the current 6-month cohort study, antiretroviral medication adherence was tracked prospectively among 91 HIV-positive adults using electronic monitoring. Comprehensive neuropsychological evaluations were performed at baseline and 6 months.
Results:
Multivariate path analyses provided evidence that antiretroviral adherence and cognitive ability are reciprocally related, although the neurocognitive pathways of this relationship appear to vary by predictive direction. Executive function and learning/memory were most strongly predictive of levels of medication adherence achieved, whereas higher levels of adherence were predictive of relative improvements in a wide range of frontostriatal brain functions including processing speed, attention, executive functions, and motor functioning.
Conclusions:
These data provide evidence that cognition and adherence are reciprocally related in HIV/AIDS. In particular, executive dysfunction may play a key role in this relationship. Interventions aimed at improving or preserving executive functions could hold promise for interrupting progressive declines in adherence and neurocognitive ability in HIV/AIDS.
GLOSSARY
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= highly active antiretroviral therapy;
= Medication Event Monitoring System;
= protease inhibitor.
doi:10.1212/WNL.0b013e3181d8c1ca
PMCID: PMC2865732  PMID: 20220123
25.  The Value of Various Assessment Techniques in Detecting the Effects of Concussion on Cognition, Symptoms, and Postural Control 
Journal of Athletic Training  2009;44(6):663-665.
Abstract
Reference/Citation:
Broglio SP, Puetz TW. The effect of sport concussion on neurocognitive function, self-report symptoms, and postural control: a meta-analysis. Sports Med. 2008;38(1):53–67.
Clinical Question:
How effective are various concussion assessment techniques in detecting the effects of concussion on cognition, balance, and symptoms in athletes?
Data Sources:
Studies published between January 1970 and June 2006 were identified from the PubMed and PsycINFO databases. Search terms included concussion, mild traumatic brain injury, sport, athlete, football, soccer, hockey, boxing, cognition, cognitive impairment, symptoms, balance, and postural control. The authors also handsearched the reference list of retrieved articles and sought the opinions of experts in the field for additional studies.
Study Selection:
Studies were included if they were published in English; described a sample of athletes concussed during athletic participation; reported outcome measures of neurocognitive function, postural stability, or self-report symptoms; compared the postconcussion assessments with preseason (healthy) baseline scores or a control group; completed at least 1 postinjury assessment within the first 14 days after the concussion (to reflect neurometabolic recovery); and provided enough information for the authors to calculate effect sizes (means and SDs at baseline and postinjury time points). Selected studies were grouped according to their outcome measure (neurocognitive function, symptoms, or postural control) at initial and follow-up (if applicable) time points. Excluded articles included review articles, abstracts, case studies, editorials, articles without baseline data, and articles with data extending beyond the 14-day postinjury time frame.
Data Extraction:
From each study, the following information was extracted by one author and checked by the second author: participant demographics (sport, injury severity, incidence of loss of consciousness, and postconcussion assessment times), sample sizes, and baseline and postconcussion means and SDs for all groups. All effect sizes (the Hedge g) were computed so that decreases in neurocognitive function and postural control or increases in symptom reports resulted in negative effect sizes, demonstrating deficits in these domains after concussion. The authors also extracted the following moderators: study design (with or without control group), type of neurocognitive technique (Standardized Assessment of Concussion, computerized test, or pencil-and-paper test), postconcussion assessment time, and number of postconcussion assessments.
Main Results:
The search identified 3364 possible abstracts, which were then screened by the authors, with 89 articles being further reviewed for relevancy. Fifty articles were excluded because of insufficient data to calculate effect sizes, lack of a baseline assessment or control group, or because the data had been published in more than one study. The remaining 39 studies met all of the inclusion criteria and were used in the meta-analysis; 34 reported neurocognitive outcome measures, 14 provided self-report symptom outcomes, and 6 presented postural control as the dependent variable. The analyzed studies included 4145 total participants (concussed and control) with a mean age of 19.0 ± 0.4 years. The quality of each included study was also evaluated by each of the 2 authors independently using a previously published 15-item scale; the results demonstrated excellent agreement between the raters (intraclass correlation coefficient  =  0.91, 95% confidence interval [CI]  =  0.83, 0.95). The quality appraisal addressed randomization, sample selection, outcome measures, and statistical analysis, among other methodologic considerations. Quality scores of the included studies ranged from 5.25 to 9.00 (scored from 0–15).
The initial assessment demonstrated a deficit in neurocognitive function (Z  =  7.73, P < .001, g  =  −0.81 [95% CI  =  −1.01, −0.60]), increase in self-report symptoms (Z  =  2.13, P  =  .03, g  =  −3.31 [95% CI  =  −6.35, −0.27]), and a nonsignificant decrease in postural control (Z  =  1.29, P  =  .19, g  =  −2.56 [95% CI  =  −6.44, 1.32]).
For the follow-up assessment analyses, a decrease in cognitive function (Z  =  2.59, P  =  .001, g  =  −26 [95% CI  =  −0.46, −0.06]), an increase in self-report symptoms (Z  =  2.17, P  =  .03, g  =  −1.09 [95% CI  =  −2.07, −0.11]), and a nonsignificant decrease in postural control (Z  =  1.59, P  =  0.11, g  =  −1.16 [95% CI  =  −2.59, 0.27]) were found.
Neurocognitive and symptom outcomes variables were reported in 10 studies, and the authors were able to compare changes from baseline in these measures during the initial assessment time point. A difference in effect sizes was noted (QB(1)  =  5.28, P  =  .02), with the increases in self-report symptoms being greater than the associated deficits in neurocognitive function.
Conclusions:
Sport-related concussion had a large negative effect on cognitive function during the initial assessment and a small negative effect during the first 14 days postinjury. The largest neurocognitive effects were found with the Standardized Assessment of Concussion during the immediate assessment and with pencil-and-paper neurocognitive tests at the follow-up assessment. Large negative effects were noted at both assessment points for postural control measures. Self-report symptoms demonstrated the greatest changes of all outcomes variables, with large negative effects noted both immediately after concussion and during the follow-up assessment. These findings reiterate the recommendations made to include neurocognitive measures, postural control tests, and symptom reports into a multifaceted concussion battery to best assess these injuries.
doi:10.4085/1062-6050-44.6.663
PMCID: PMC2775369  PMID: 19911094
patient-oriented evidence; POEM; clinical outcomes; children

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