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1.  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
2.  Public-Health and Individual Approaches to Antiretroviral Therapy: Township South Africa and Switzerland Compared 
PLoS Medicine  2008;5(7):e148.
Background
The provision of highly active antiretroviral therapy (HAART) in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. We compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting HAART in South Africa and Switzerland.
Methods and Findings
We analysed data from the Swiss HIV Cohort Study and two HAART programmes in townships of Cape Town, South Africa. We included treatment-naïve patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded intravenous drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4+ T cell counts were 80 cells/μl in South Africa and 204 cells/μl in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96% (95% confidence interval [CI] 95%–97%) in South Africa and 96% (94%–97%) in Switzerland, and 26% (22%–29%) and 27% (24%–31%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of HAART: adjusted hazard ratios were 5.90 (95% CI 1.81–19.2) during months 1–3 and 1.77 (0.90–3.50) during months 4–24.
Conclusions
Compared to the highly individualised approach in Switzerland, programmatic HAART in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to HAART and improve the prognosis of patients who start HAART with advanced disease.
Comparing HIV treatment in Switzerland, where drug selection is individualized, and South Africa, where a programmatic approach is used, Matthias Egger and colleagues find similar virologic outcomes over two years.
Editors' Summary
Background.
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since the first reported case in 1981, and more than 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of becoming infected. Then, in 1996, highly active antiretroviral therapy (HAART)—a combination of several antiretroviral drugs—was developed. Now, in resource-rich countries, clinicians provide individually tailored care for HIV-infected people by prescribing combinations of antiretroviral drugs chosen from more than 20 approved medicines. The approach to treatment of HIV in developed countries typically also includes frequent monitoring of the amount of virus in patients' blood (viral load), viral resistance testing (to see whether any viruses are resistant to specific antiretroviral drugs), and regular CD4 cell counts (an indication of immune-system health). Since the implementation of these interventions, the health and life expectancy of people with HIV has improved dramatically in these countries.
Why Was This Study Done?
The history of HIV care in resource-poor countries has been very different. Initially, these countries could not afford to provide HAART for their populations. In 2003, however, governments, international agencies, and funding bodies began to implement plans to increase HAART coverage in developing countries. By December 2006, more than a quarter of the HIV-infected people in low- and middle-income countries who urgently needed treatment were receiving HAART. However, instead of individualized treatment, HAART programs in developing countries follow a public-health approach developed by the World Health Organization. That is, drug regimens, clinical decision-making, and clinical and laboratory monitoring are all standardized. This public-health approach takes into account the realities of under-resourced health systems, but is it as effective as the individualized approach? The researchers addressed this question by comparing virologic responses (the effect of treatment on the viral load), changes to first-line (initial) therapy, and deaths in patients receiving HAART in South Africa (public-health approach) and in Switzerland (individualized approach).
What Did the Researchers Do and Find?
The researchers analyzed data collected since 2001 from more than 2,000 patients enrolled in HAART programs in two townships (Gugulethu and Khayelitsha) in Cape Town, South Africa, and from more than 1,000 patients enrolled in the Swiss HIV Cohort Study, a nationwide study of HIV-infected people. The patients in South Africa, who had a lower starting CD4 cell count and were more likely to have advanced AIDS than the patients in Switzerland, started their treatment for HIV infection with one of four first-line therapies, and about a quarter changed to a second-line therapy during the study. By contrast, 36 first-line regimens were used in Switzerland and half the patients changed to a different regimen. Despite these differences, the viral load was greatly reduced within a year in virtually all the patients and viral rebound (an increased viral load after a low measurement) developed within 2 years in a quarter of the patients in both countries. However, more patients died in South Africa than in Switzerland, particularly during the first 3 months of therapy.
What Do These Findings Mean?
These findings suggest that the public-health approach to HAART practiced in South Africa is as effective in terms of virologic outcomes as the individualized approach practiced in Switzerland. This is reassuring because it suggests that “antiretroviral anarchy” (the unregulated use of antiretroviral drugs, interruptions in drug supplies, and the lack of treatment monitoring), which is likely to lead to the emergence of viral resistance, is not happening in South Africa as some experts feared it might. Thus, these findings support the continued rollout of the public-health approach to HAART in resource-poor countries. Conversely, they also suggest that a more standardized approach to HAART could be taken in Switzerland (and in other industrialized countries) without compromising its effectiveness. Finally, the higher mortality in South Africa than in Switzerland, which partly reflects the many patients in South Africa in desperate need of HAART and their more advanced disease at the start of therapy, suggests that HIV-infected patients in South Africa and in other resource-limited countries would benefit from earlier initiation of therapy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050148.
The World Health Organization provides information about universal access to HIV treatment (in several languages) and on its recommendations for a public-health approach to antiretroviral therapy for HIV infection
More details on the Swiss HIV Cohort Study and on the studies in Gugulethu and Khayelitsha are available
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 detailed information about antiretroviral therapy and links to treatment guidelines for various countries
Information is available from Avert, an international AIDS charity, on HIV and AIDS around the world and on providing AIDS drug treatment for millions
doi:10.1371/journal.pmed.0050148
PMCID: PMC2443185  PMID: 18613745
3.  The Effect of Highly Active Antiretroviral Therapy on the Survival of HIV-Infected Children in a Resource-Deprived Setting: A Cohort Study 
PLoS Medicine  2011;8(6):e1001044.
This observational cohort study by Andrew Edmonds and colleagues reports that treatment with highly active antiretroviral therapy (HAART) markedly improves the survival of HIV-infected children in Kinshasa, DRC, a resource-deprived setting.
Background
The effect of highly active antiretroviral therapy (HAART) on the survival of HIV-infected children has not been well quantified. Because most pediatric HIV occurs in low- and middle-income countries, our objective was to provide a first estimate of this effect among children living in a resource-deprived setting.
Methods and Findings
Observational data from HAART-naïve children enrolled into an HIV care and treatment program in Kinshasa, Democratic Republic of the Congo, between December 2004 and May 2010 were analyzed. We used marginal structural models to estimate the effect of HAART on survival while accounting for time-dependent confounders affected by exposure. At the start of follow-up, the median age of the 790 children was 5.9 y, 528 (66.8%) had advanced or severe immunodeficiency, and 405 (51.3%) were in HIV clinical stage 3 or 4. The children were observed for a median of 31.2 mo and contributed a total of 2,089.8 person-years. Eighty children (10.1%) died, 619 (78.4%) initiated HAART, six (0.8%) transferred to a different care provider, and 76 (9.6%) were lost to follow-up. The mortality rate was 3.2 deaths per 100 person-years (95% confidence interval [CI] 2.4–4.2) during receipt of HAART and 6.0 deaths per 100 person-years (95% CI 4.1–8.6) during receipt of primary HIV care only. The mortality hazard ratio comparing HAART with no HAART from a marginal structural model was 0.25 (95% CI 0.06–0.95).
Conclusions
HAART reduced the hazard of mortality in HIV-infected children in Kinshasa by 75%, an estimate that is similar in magnitude but with lower precision than the reported effect of HAART on survival among children in the United States.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2009, an estimated 2.5 million children were living with HIV, the majority of whom (2.3 million) were in sub-Saharan Africa. Most (90%) of these children acquired HIV from their HIV-infected mothers during pregnancy, birth, or breastfeeding, highlighting the importance of giving effective drugs for the prevention of mother to child transmission. As such interventions are still not widely accessible or available in most resource-limited countries, where the burden of HIV is highest, every day an estimated 1,000 children were newly infected with HIV in 2009, but only 360,000 children were receiving highly active antiretroviral therapy (HAART).
Although HAART improves the survival of adults living with HIV, less is known about the degree to which HAART affects the survival of HIV-infected children—although response to antiretroviral treatment is known to differ across age groups. Furthermore, as the course of HIV disease in children is different from that in adults (partly because of the impact of the virus on the immature thymus, which can lead to high HIV RNA viremia and rapid death), it is inappropriate to extrapolate results from studies of adults to pediatric populations. Therefore, it is imperative that the effect of HAART on survival be quantified specifically in children.
Why Was This Study Done?
Most observational studies of the effects of treatment on child survival have been undertaken in high-income countries, such as Italy and the United States. As most children with HIV live in low-resource areas, where multiple factors, such as delayed presentation to care and a higher incidence of co-occurring conditions, might adversely affect treatment outcomes, there is a specific need for information on the effects of HAART in children with HIV living in low-income countries. Although some investigations have taken place in pediatric cohorts from such countries (for example, Côte d'Ivoire, Haiti, Lesotho, Thailand, and Zambia), the effect of HAART on mortality has not been accurately quantified among children in a resource-deprived setting. Therefore, in this observational clinical cohort study, the researchers investigated the effect of HAART on mortality in HIV-infected children in Kinshasa, in the Democratic Republic of the Congo (DRC).
What Did the Researchers Do and Find?
The researchers analyzed data from 790 children enrolled into an HIV program in Kinshasa, DRC, between December 2004 and May 2010 and used a statistical model (marginal structural models) to adjust for time-dependent confounding factors, such as the fact that HAART is typically initiated in sicker patients, for example, those with lower CD4 cell percentages. Assuming that all children starting HAART received it uninterruptedly throughout follow-up, using this statistical model, the researchers were able to compare the hazard ratio of death had all children initiated HAART to that had no children initiated HAART during follow-up.
In the study, 619 out of the 790 children (78.4%) initiated HAART during follow-up and were followed for a median of 31.2 months, with a median of 30 HIV care visits. Of those who started treatment, 110 (17.8%) switched to an alternative regimen because of an adverse event or treatment failure. During the 2,089.8 accrued person-years of follow-up, 80 children (10.1%) died, giving an overall mortality rate of 3.8 deaths per 100 person-years. The unadjusted mortality rate ratio comparing HAART to no HAART was 0.54. Using a marginal structural model, the researchers estimated that compared to no HAART, HAART reduced the hazard (rate) of mortality during follow-up by 75%.
What Do These Findings Mean?
These findings show that treatment with HAART markedly improved the survival of children infected with HIV in Kinshasa, DRC, and suggest that HAART is as effective in improving the survival of HIV-infected children in a severely resource-deprived country (still recovering from civil war) as in more resource-privileged settings—an important finding given that the vast majority of children receiving HAART live in resource-poor areas. This study provides additional evidence that accelerating rollout of antiretroviral therapy to children with HIV in resource-poor countries is lifesaving and effective. Future research needs to address how effective HAART is in understudied populations in resource-poor countries, such as undernourished children or those with co-infections such as tuberculosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001044.
The World Health Organization's Web site has more information about the treatment of children living with HIV
Médecins Sans Frontières's Campaign for Access to Essential Medicines Web site has more information on pediatric HAART
doi:10.1371/journal.pmed.1001044
PMCID: PMC3114869  PMID: 21695087
4.  Delayed-type hypersensitivity (DTH) test anergy does not impact CD4 reconstitution or normalization of DTH responses during antiretroviral therapy 
Introduction
Delayed-type hypersensitivity (DTH) testing is an in vivo assessment of cell-mediated immunity. Although highly active antiretroviral therapy (HAART) improves immunologic parameters, the relationship between DTH responsiveness and CD4 gains on HAART is not completely understood. We investigated CD4 reconstitution and the change in DTH responses from treatment baseline through 24 months of viral load (VL)-suppressive HAART in the U.S. Military HIV Natural History Study.
Methods
Treatment-naïve subjects with VL <400 copies/mL after ≥24 months on HAART were included (n=302). DTH testing consisted of ≥3 recall antigens, and responses were classified by the number of positive skin tests: anergic (0–1) or non-anergic (≥2). Pre-HAART DTH results were compared for the outcome of CD4 reconstitution at 24 months of HAART. Improvement in DTH responses was also analyzed for those anergic before HAART initiation.
Results
Non-anergic responses were observed in 216 (72%) participants, while 86 (28%) individuals were anergic prior to HAART initiation. Demographically there were similar distributions of age at HIV diagnosis and HAART initiation, as well as gender and race or ethnicity. There were no significant differences between non-anergic and anergic participants in pre-HAART CD4 count (409 cells/μL, interquartile range (IQR) 315–517 vs. 373 cells/μL, IQR 228–487; p=0.104) and VL (4.3 log10 copies/mL, IQR 3.4–4.9 vs. 4.4 log10 copies/mL, IQR 3.6–5.0; p=0.292). Median CD4 gains 24 months after HAART initiation were similar between the non-anergic (220 cells/μL, IQR 115–358) and anergic groups (246 cells/μL, IQR 136–358; p=0.498). For individuals anergic before HAART initiation, DTH normalization occurred at 24 months post-HAART in the majority of participants (51 of 86, 59%). Normalization of DTH responses was not associated with CD4 count at HAART initiation (OR 0.73, 95% CI 0.47, 1.09 per 100 cells; p=0.129) nor with AIDS diagnoses prior to HAART (OR 0.34, 95% CI 0.04, 2.51; p=0.283).
Conclusions
DTH responsiveness has been shown to predict HIV disease progression independent of CD4 count in untreated individuals. In the setting of HAART, pre-HAART anergy does not appear to impact CD4 gains or the ability to normalize DTH responses after 24 months of VL-suppressive HAART.
doi:10.7448/IAS.17.1.18799
PMCID: PMC3916671  PMID: 24499779
HIV; HAART; antiretroviral therapy; delayed-type hypersensitivity; DTH; CD4 cell count; anergy; anergic
5.  Factors associated with HIV RNA levels in pregnant women on non-suppressive HAART at conception 
Antiviral therapy  2010;15(1):41-49.
Background
Little is known about pregnancy patterns and levels of HIV RNA in HIV-infected women conceiving on highly-active antiretroviral therapy (HAART) with non-suppressed viral load (VL), nor their therapeutic management.
Methods
Linear mixed models were fitted to study changes in VL and potential associated factors including HAART type/duration and immune status among 127 women receiving HAART at conception with detectable VL enrolled in the prospective European Collaborative Study.
Results
Median duration of HAART at conception was 10 months. Seventy-eight (61%) women conceived on PI-based HAART. Seventy-two (57%) women remained on the same HAART regimen throughout pregnancy, 24 (19%) switched regimens and 31 (24%) interrupted HAART during early pregnancy. The intention-to-treat model indicated constant VL up to 10 gestational weeks; thereafter levels decreased significantly, by 0.06 log10 copies/ml weekly until delivery. At baseline, immune status was significantly associated with HIV RNA levels. Excluding treatment-interrupters, there was no significant difference in VL slope between women who did and did not modify their HAART regimens (p=0.14); women conceiving on NNRTI-based HAART had consistently lower VL throughout pregnancy than those on PI-based HAART (p=0.02). Most (64/103, 62%) women had detectable VL within four weeks of delivery (median 2.40 log10 copies/ml). The MTCT rate overall was 1.72% (95%CI 0.21-6.1%).
Conclusion
Practices regarding management of women conceiving on HAART with detectable VL vary in Western Europe. The existence of this group of pregnant women highlights the need for improved monitoring of and support for treated women before they become pregnant, as well as during pregnancy itself.
doi:10.3851/IMP1489
PMCID: PMC3428879  PMID: 20167990
HIV; pregnancy; HIV RNA; HAART
6.  A Randomized Controlled Trial Comparing the Effects of Counseling and Alarm Device on HAART Adherence and Virologic Outcomes 
PLoS Medicine  2011;8(3):e1000422.
Michael Chung and colleagues show that intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure, whereas use of an alarm device had no effect.
Background
Behavioral interventions that promote adherence to antiretroviral medications may decrease HIV treatment failure. Antiretroviral treatment programs in sub-Saharan Africa confront increasing financial constraints to provide comprehensive HIV care, which include adherence interventions. This study compared the impact of counseling and use of an alarm device on adherence and biological outcomes in a resource-limited setting.
Methods and Findings
A randomized controlled, factorial designed trial was conducted in Nairobi, Kenya. Antiretroviral-naïve individuals initiating free highly active antiretroviral therapy (HAART) in the form of fixed-dose combination pills (d4T, 3TC, and nevirapine) were randomized to one of four arms: counseling (three counseling sessions around HAART initiation), alarm (pocket electronic pill reminder carried for 6 months), counseling plus alarm, and neither counseling nor alarm. Participants were followed for 18 months after HAART initiation. Primary study endpoints included plasma HIV-1 RNA and CD4 count every 6 months, mortality, and adherence measured by monthly pill count. Between May 2006 and September 2008, 400 individuals were enrolled, 362 initiated HAART, and 310 completed follow-up. Participants who received counseling were 29% less likely to have monthly adherence <80% (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.49–1.01; p = 0.055) and 59% less likely to experience viral failure (HIV-1 RNA ≥5,000 copies/ml) (HR 0.41; 95% CI 0.21–0.81; p = 0.01) compared to those who received no counseling. There was no significant impact of using an alarm on poor adherence (HR 0.93; 95% CI 0.65–1.32; p = 0.7) or viral failure (HR 0.99; 95% CI 0.53–1.84; p = 1.0) compared to those who did not use an alarm. Neither counseling nor alarm was significantly associated with mortality or rate of immune reconstitution.
Conclusions
Intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure during 18-month follow-up, while use of an alarm device had no effect. As antiretroviral treatment clinics expand to meet an increasing demand for HIV care in sub-Saharan Africa, adherence counseling should be implemented to decrease the development of treatment failure and spread of resistant HIV.
Trial registration
ClinicalTrials gov NCT00273780
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Adherence to HIV treatment programs in poor countries has long been cited as an important public health concern, especially as poor adherence can lead to drug resistance and inadequate treatment of HIV. However, two factors have recently cast doubt on the poor adherence problem: (1) recent studies have shown that adherence is high in African HIV treatment programs and often better than in Western HIV clinics. For example, in a meta-analysis of 27 cohorts from 12 African countries, adequate adherence was noted in 77% of subjects compared to only 55% among 31 North America cohorts; (2) choice of antiretroviral regimens may impact on the development of antiretroviral resistance. In poor countries, most antiretroviral regimens contain non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine or efavirenz, which remain in the patient's circulation for weeks after single-dose administration. This situation means that such patients may not experience antiretroviral resistance unless they drop below 80% adherence—contrary to the more stringent 95% plus adherence levels needed to prevent resistance in regimens based on unboosted protease inhibitors—ultimately, off-setting some treatment lapses in resource-limited settings where NNRTI-based regimens are widely used.
Why Was This Study Done?
Given that adherence may not be as crucial an issue as previously thought, antiretroviral treatment programs in sub-Saharan Africa may be spending scarce resources to promote adherence to the detriment of some potentially more effective elements of HIV treatment and management programs. Although many treatment programs currently include adherence interventions, there is limited quality evidence that any of these methods improve long-term adherence to HIV treatment. Therefore, it is necessary to identify adherence interventions that are inexpensive and proven to be effective in resource-limited settings. As adherence counseling is already widely implemented in African HIV treatment programs and inexpensive alarm devices are thought to also improve compliance, the researchers compared the impact of adherence counseling and the use of an alarm device on adherence and biological outcomes in patients enrolled in HIV programs in rural Kenya.
What Did the Researchers Do and Find?
The researchers enrolled 400 eligible patients (newly diagnosed with HIV, never before taken antiretroviral therapy, aged over 18 years) to four arms: (1) adherence counseling alone; (2) alarm device alone; (3) both adherence counseling and alarm device together; and (4) a control group that received neither adherence counseling nor alarm device. The patients had blood taken to record baseline CD4 count and HIV-1 RNA and after starting HIV treatment, returned to the study clinic every month with their pill bottles for the study pharmacist to count and recorded the number of pills remaining in the bottle, and to receive another prescription. Patients were followed up for 18 months and had their CD4 count and HIV-1 RNA measured at 6, 12, and 18 months.
Patients receiving adherence counseling were 29% less likely to experience poor adherence compared to those who received no counseling. Furthermore, those receiving intensive early adherence counseling were 59% less likely to experience viral failure. However, there was no significant difference in mortality or significant differences in CD4 counts at 18 months follow-up between those who received counseling and those who did not. There were no significant differences in adherence, time to viral failure, mortality, or CD4 counts in patients who received alarm devices compared to those who did not.
What Do These Findings Mean?
The results of this study suggest that intensive adherence counseling around the time of HIV treatment initiation significantly reduces poor adherence and virologic treatment failure, while using an alarm device has no effect. Therefore, investment in careful counseling based on individual needs at the onset of HIV treatment initiation, appears to have sustained benefit, possibly through strengthening the relationship between the health care provider and patient through communication, education, and trust. Interactive adherence counseling supports the bond between the clinic and the patient and may result in fewer patients needing to switch to expensive second-line medications and, possibly, may help to decrease the spread of resistant HIV. These findings define an adherence counseling protocol that is effective and are highly relevant to other HIV clinics caring for large numbers of patients in sub-Saharan Africa.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000422.
UNAIDS provides information about HIV treatment strategies
The American Public Health Association has information about adherence to HIV treatment regimens
The US Department of Health and Human Services has information for patients about adherence to HIV treatment
The World Health Organization provides information about HIV treatment pharmacovigilance
doi:10.1371/journal.pmed.1000422
PMCID: PMC3046986  PMID: 21390262
7.  Factors Impacting Early Mortality in Tuberculosis/HIV Patients: Differences between Subjects Naïve to and Previously Started on HAART 
PLoS ONE  2012;7(9):e45704.
Background
Mortality among patients with tuberculosis (TB)/HIV is highest during the first few months of antituberculous therapy. The objective of this study was to assess the factors associated with early mortality among TB/HIV patients and whether these factors are similar for HAART naïve and those with prior HAART initiation.
Methods
Prospective cohort study including HIV patients with tuberculosis confirmed by culture, cared for at a referral center in Rio de Janeiro, Brazil. Multivariable Cox analysis was used to assess predictors of mortality within 3 months of antituberculous therapy.
Results
Among 227 patients included, 90 (40%) started HAART before TB diagnosis. The median time to TB diagnosis after ARV initiation was 5.9 months (interquartile range [IQR] 3.0–8.9 months). Fourteen patients (6%) died within the first 3 months. Mortality was not different between patients previously started on HAART and those who were naïve to it. In the overall adjusted analysis, HAART use during TB treatment (hazard ratio [HR] = 0.21, 95% confidential interval [CI] = 0.06–0.72) and CD4 lymphocyte count >100 cells/mm3 (HR = 0.21, 95% CI = 0.04–0.99) were associated with lower mortality, while subjects with unknown baseline CD4 lymphocyte count (HR = 9.39, 95% CI = 2.56–34.5) had higher mortality. In subgroup analysis, among HAART naïve subjects, disseminated TB (HR = 5.32, 95% CI = 1.09–25.8) and unknown baseline CD4 lymphocyte count (HR = 13.2, 95% CI = 2.71–64.5) were associated with significantly higher mortality, while HAART (HR = 0.14, 95% CI = 0.03–0.69) predicted a better outcome. Among subjects previously started on HAART, mortality was significantly associated with duration of TB symptoms >120 days (HR = 6.15, 95% CI = 1.15–32.9).
Conclusions
Predictors of early mortality among TB/HIV patients may vary according to the timing of HAART initiation. Among HAART naïve patients, mortality was influenced by baseline clinical severity, HAART use and, possibly, the quality of care preceding TB diagnosis. For patients with prior HAART initiation, longer delays in TB diagnosis predicted a significantly higher mortality.
doi:10.1371/journal.pone.0045704
PMCID: PMC3458068  PMID: 23049842
8.  Treatment and disease progression in a birth cohort of vertically HIV-1 infected children in Ukraine 
BMC Pediatrics  2010;10:85.
Background
Ukraine has the highest HIV prevalence (1.6%) and is facing the fastest growing epidemic in Europe. Our objective was to describe the clinical, immunological and virological characteristics, treatment and response in vertically HIV-infected children living in Ukraine and followed from birth.
Methods
The European Collaborative Study (ECS) is an ongoing cohort study, in which HIV-1 infected pregnant women are enrolled and followed in pregnancy, and their children prospectively followed from birth. ECS enrolment in Ukraine started in 2000 initially with three sites, increasing to seven sites by 2009.
Results
A total of 245 infected children were included in the cohort by April 2009, with a median age of 23 months at most recent follow-up; 33% (n = 77) had injecting drug using mothers and 85% (n = 209) were infected despite some use of antiretroviral prophylaxis for prevention of mother-to-child transmission. Fifty-five (22%) children had developed AIDS, at a median age of 10 months (IQR = 6-19). The most prevalent AIDS indicator disease was Pneumocystis jiroveci pneumonia (PCP). Twenty-seven (11%) children had died (median age, 6.2 months). Overall, 108 (44%) children had started highly active antiretroviral treatment (HAART), at a median 18 months of age; median HAART duration was 6.6 months to date. No child discontinued HAART and 92% (100/108) remained on their first-line HAART regimen to date. Among children with moderate/severe immunosuppression, 36% had not yet started HAART. Among children on HAART, 71% (69/97) had no evidence of immunosuppression at their most recent visit; the median reduction in HIV RNA was 4.69 log10 copies/mL over a median of 10 months treatment. From survival analysis, an estimated 94%, 84% and 81% of children will be alive and AIDS-free at 6, 12 and 18 months of age, respectively. However, survival increased significantly over time: estimated survival rates to 12 months of age were 87% for children born in 2000/03 versus 96% for those born in 2004/08.
Conclusion
One in five children had AIDS and one in ten had died. The half of children who received HAART has responded well and survival has significantly improved over time. Earlier diagnosis and prompt initiation of HAART remain key challenges.
doi:10.1186/1471-2431-10-85
PMCID: PMC2997768  PMID: 21092301
9.  HIV DNA and cognition in a Thai longitudinal HAART initiation cohort 
Neurology  2009;72(11):992-998.
Objectives:
The extent to which highly active antiretroviral therapy (HAART) era cognitive disorders are due to active processes, incomplete clearance of reservoirs, or comorbidities is controversial. This study aimed to determine if immunologic and virologic factors influence cognition after first-time HAART in Thai individuals with HIV-associated dementia (HAD) and Thai individuals without HAD (non-HAD).
Methods:
Variables were captured longitudinally to determine factors predictive of degree of cognitive recovery after first-time HAART. Neuropsychological data were compared to those of 230 HIV-negative Thai controls.
Results:
HIV RNA and CD4 lymphocyte counts were not predictive of HAD cross-sectionally or degree of cognitive improvement longitudinally. In contrast, baseline and longitudinal HIV DNA isolated from monocytes correlated to cognitive performance irrespective of plasma HIV RNA and CD4 lymphocyte counts pre-HAART (p < 0.001) and at 48 weeks post HAART (p < 0.001). Levels exceeding 3.5 log10 copies HIV DNA/106 monocyte at baseline distinguished all HAD and non-HAD cases (p < 0.001). At 48 weeks, monocyte HIV DNA was below the level of detection of our assay (10 copies/106 cells) in 15/15 non-HAD compared to only 4/12 HAD cases, despite undetectable plasma HIV RNA in 26/27 cases. Baseline monocyte HIV DNA predicted 48-week cognitive performance on a composite score, independently of concurrent monocyte HIV DNA and CD4 count (p < 0.001).
Conclusions:
Monocyte HIV DNA level correlates to cognitive performance before highly active antiretroviral therapy (HAART) and 48 weeks after HAART in this cohort and baseline monocyte HIV DNA may predict 48-week cognitive performance. These findings raise the possibility that short-term incomplete cognitive recovery with HAART may represent an active process related to this peripheral reservoir.
GLOSSARY
= antiretroviral;
= confidence interval;
= circulating recombinant form;
= global deficit score;
= highly active antiretroviral therapy;
= HIV-associated dementia;
= International HIV Dementia Scale;
= interquartile range;
= neurocognitive impairment;
= peripheral blood mononuclear cell;
= Thai Depression Inventory score.
doi:10.1212/01.wnl.0000344404.12759.83
PMCID: PMC2677463  PMID: 19289739
10.  Bimodal virological response to antiretroviral therapy for HIV infection: an application using a mixture model with left censoring 
Study objective
To assess whether HIV RNA levels (log10 scale) in highly active antiretroviral therapy (HAART) treated population have a bimodal distribution, suggesting optimal or suboptimal response to HAART.
Methods
The study population from two ongoing cohort studies comprised 564 men (4785 person visits) and 1173 women (8675 person visits) with known dates of HAART initiation and with HIV RNA measurements before and after initiation. Values below detection limit of assays were treated in the analysis as left censored. Maximum likelihood methods were used to estimate parameters and to determine possible bimodality of HIV RNA distributions.
Results
A two component mixture model fitted HIV RNA levels significantly better than did a single component distribution at different years from HAART initiation in both therapy experienced and therapy naive patients. In the fifth year after HAART initiation, 32% of men and 44% of women had HIV RNA in the higher component with medians of 5247 and 9253 copies/ml, respectively, suggesting suboptimal virological response to HAART, which was associated with poor adherence and lower frequency of CCR5 heterozygous genotype.
Conclusion
The bimodal distribution of HIV RNA persisted during the years after HAART initiation. The high occurrence of suboptimal virological response at the fifth year after HAART initiation underscore the needs for careful monitoring and patient education about the importance of treatment adherence. This data analysis overcomes limitations of measurement techniques of observations having values below detection limits and serves to characterise the dynamics of the virological response to therapies.
doi:10.1136/jech.2005.044644
PMCID: PMC2566033  PMID: 16905728
mixture model; left censoring; HIV RNA; HAART
11.  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
12.  HIV DNA and cognition in a Thai longitudinal HAART initiation cohort 
Neurology  2009;72(11):992-998.
Objectives
The extent to which highly active antiretroviral therapy (HAART) era cognitive disorders are due to active processes, incomplete clearance of reservoirs, or comorbidities is controversial. This study aimed to determine if immunologic and virologic factors influence cognition after first-time HAART in Thai individuals with HIV-associated dementia (HAD) and Thai individuals without HAD (non-HAD).
Methods
Variables were captured longitudinally to determine factors predictive of degree of cognitive recovery after first-time HAART. Neuropsychological data were compared to those of 230 HIV-negative Thai controls.
Results
HIV RNA and CD4 lymphocyte counts were not predictive of HAD cross-sectionally or degree of cognitive improvement longitudinally. In contrast, baseline and longitudinal HIV DNA isolated from monocytes correlated to cognitive performance irrespective of plasma HIV RNA and CD4 lymphocyte counts pre-HAART (p < 0.001) and at 48 weeks post HAART (p < 0.001). Levels exceeding 3.5 log10 copies HIV DNA/106 monocyte at baseline distinguished all HAD and non-HAD cases (p < 0.001). At 48 weeks, monocyte HIV DNA was below the level of detection of our assay (10 copies/106 cells) in 15/15 non-HAD compared to only 4/12 HAD cases, despite undetectable plasma HIV RNA in 26/27 cases. Baseline monocyte HIV DNA predicted 48-week cognitive performance on a composite score, independently of concurrent monocyte HIV DNA and CD4 count (p < 0.001).
Conclusions
Monocyte HIV DNA level correlates to cognitive performance before highly active antiretroviral therapy (HAART) and 48 weeks after HAART in this cohort and baseline monocyte HIV DNA may predict 48-week cognitive performance. These findings raise the possibility that short-term incomplete cognitive recovery with HAART may represent an active process related to this peripheral reservoir.
doi:10.1212/01.wnl.0000344404.12759.83
PMCID: PMC2677463  PMID: 19289739
13.  Predictors of suboptimal CD4 response among women achieving virologic suppression in a randomized antiretroviral treatment trial, Africa 
BMC Infectious Diseases  2014;14:331.
Background
A subset of HIV-1 infected patients starting highly active antiretroviral treatment (HAART) experience suboptimal CD4 response (SCR) despite virologic suppression. We studied the rate of and risk factors for SCR among women starting HAART in the ACTG A5208 study conducted in 7 African countries. 741 HAART-naive women with screening CD4 count <200 cells/μL were randomized to start HAART with Tenofovir/Emtricitabine plus either Nevirapine or Lopinavir/Ritonavir.
Methods
This analysis includes the 625 women who remained on-study through 48 weeks without experiencing protocol-defined virologic failure. We defined SCR as < 100 CD4 cells/μL increase from baseline and absolute CD4 cell count < 350 cells/μL, both at 48 weeks after HAART initiation.
Results
The baseline characteristics for the 625 women prior to HAART initiation were: median age 33 years, screening CD4 count 134 cells/μL, and HIV-1 RNA 5.1 log10 copies/mL; 184 (29%) were WHO Stage 3 or 4.
Seventy one (11%) of these 625 women experienced SCR. Baseline factors independently associated with increased odds of SCR included older age, lower HIV-1 RNA, positive Hepatitis B surface antigen, and site location. At 96 weeks, only 6% of the SCR group had CD4 ≥ 350 cells/μL compared with 67% in the non SCR group.
Conclusion
After starting HAART, 11% of women with virologic suppression through 48 weeks experienced SCR. These patients were also less likely to achieve CD4 ≥ 350 cells/μL by 96 weeks. The underlying causes and long term clinical implications of SCR deserve further investigation.
Trial registration
Clinicaltrials.gov Identifier: NCT00089505
doi:10.1186/1471-2334-14-331
PMCID: PMC4083139  PMID: 24938526
HIV; Antiretroviral therapy; HAART; Immune response; CD4
14.  Clinical, demographic and laboratory parameters at HAART initiation associated with decreased post-HAART survival in a U.S. military prospective HIV cohort 
Background
Although highly active antiretroviral therapy (HAART) has improved HIV survival, some patients receiving therapy are still dying. This analysis was conducted to identify factors associated with increased risk of post-HAART mortality.
Methods
We evaluated baseline (prior to HAART initiation) clinical, demographic and laboratory factors (including CD4+ count and HIV RNA level) for associations with subsequent mortality in 1,600 patients who began HAART in a prospective observational cohort of HIV-infected U.S. military personnel.
Results
Cumulative mortality was 5%, 10% and 18% at 4, 8 and 12 years post-HAART. Mortality was highest (6.23 deaths/100 person-years [PY]) in those with ≤ 50 CD4+ cells/mm3 before HAART initiation, and became progressively lower as CD4+ counts increased (0.70/100 PY with ≥ 500 CD4+ cells/mm3). In multivariate analysis, factors significantly (p < 0.05) associated with post-HAART mortality included: increasing age among those ≥ 40 years (Hazard ratio [HR] = 1.32 per 5 year increase), clinical AIDS events before HAART (HR = 1.93), ≤ 50 CD4+ cells/mm3 (vs. CD4+ ≥ 500, HR = 2.97), greater HIV RNA level (HR = 1.36 per one log10 increase), hepatitis C antibody or chronic hepatitis B (HR = 1.96), and HIV diagnosis before 1996 (HR = 2.44). Baseline CD4+ = 51-200 cells (HR = 1.74, p = 0.06), and hemoglobin < 12 gm/dL for women or < 13.5 for men (HR = 1.36, p = 0.07) were borderline significant.
Conclusions
Although treatment has improved HIV survival, defining those at greatest risk for death after HAART initiation, including demographic, clinical and laboratory correlates of poorer prognoses, can help identify a subset of patients for whom more intensive monitoring, counseling, and care interventions may improve clinical outcomes and post-HAART survival.
doi:10.1186/1742-6405-9-4
PMCID: PMC3320559  PMID: 22339893
Highly active antiretroviral therapy; mortality; CD4+ lymphocyte count
15.  Reduction of Maternal Mortality with Highly Active Antiretroviral Therapy in a Large Cohort of HIV-Infected Pregnant Women in Malawi and Mozambique 
PLoS ONE  2013;8(8):e71653.
Background
HIV infection is a major contributor to maternal mortality in resource-limited settings. The Drug Resource Enhancement Against AIDS and Malnutrition Programme has been promoting HAART use during pregnancy and postpartum for Prevention-of-mother-to-child-HIV transmission (PMTCT) irrespective of maternal CD4 cell counts since 2002.
Methods
Records for all HIV+ pregnancies followed in Mozambique and Malawi from 6/2002 to 6/2010 were reviewed. The cohort was comprised by pregnancies where women were referred for PMTCT and started HAART during prenatal care (n = 8172, group 1) and pregnancies where women were referred on established HAART (n = 1978, group 2).
Results
10,150 pregnancies were followed. Median (IQR) baseline values were age 26 years (IQR:23–30), CD4 count 392 cells/mm3 (IQR:258–563), Viral Load log10 3.9 (IQR:3.2–4.4), BMI 23.4 (IQR:21.5–25.7), Hemoglobin 10.0 (IQR: 9.0–11.0). 101 maternal deaths (0.99%) occurred during pregnancy to 6 weeks postpartum: 87 (1.1%) in group 1 and 14 (0.7%) in group 2. Mortality was 1.3% in women with
Conclusions
Antiretrovirals for PMTCT purposes have significant impact on maternal mortality as do CD4 counts and nutritional status. In resource-limited settings, PMTCT programs should provide universal HAART to all HIV+ pregnant women given its impact in prevention of maternal death.
doi:10.1371/journal.pone.0071653
PMCID: PMC3747183  PMID: 23990966
HIV medicine  2009;11(5):289-298.
Objectives
While highly active antiretroviral therapy (HAART) decreases long-term morbidity and mortality, its short-term effect on hospitalization rates is unknown. The primary objective of this study was to determine hospitalization rates over time in the year after HAART initiation for virological responders and nonresponders.
Methods
Hospitalizations among 1327 HAART-naïve subjects in an urban HIV clinic in 1997–2007 were examined before and after HAART initiation. Hospitalization rates were stratified by virological responders (≥ 1 log10 decrease in HIV-1 RNA within 6 months after HAART initiation) and nonresponders. Causes were determined through International Classification of Diseases, 9th Revision (ICD-9) codes and chart review. Multivariate negative binomial regression was used to assess factors associated with hospitalization.
Results
During the first 45 days after HAART initiation, the hospitalization rate of responders was similar to their pre-HAART baseline rate [75.1 vs. 78.8/100 person-years (PY)] and to the hospitalization rate of nonresponders during the first 45 days (79.4/100 PY). The hospitalization rate of responders fell significantly between 45 and 90 days after HAART initiation and reached a plateau at approximately 45/100 PY from 91 to 365 days after HAART initiation. Significant decreases were seen in hospitalizations for opportunistic and nonopportunistic infections.
Conclusions
The first substantial clinical benefit from HAART may be realized by 90 days after HAART initiation; providers should keep close vigilance at least until this time.
doi:10.1111/j.1468-1293.2009.00776.x
PMCID: PMC3077939  PMID: 20002778
AIDS-defining illness; antiretroviral therapy; healthcare utilization; hospitalization; immune reconstitution
Background
Among HIV-infected persons initiating highly active antiretroviral therapy (HAART), early CD4+ lymphocyte count increases are well described. However, whether CD4+ levels continue to increase or plateau after 4-6 years is controversial.
Methods
To address this question and identify other determinants of CD4+ response, we analyzed data for 1,846 persons from a prospective HIV military cohort study who initiated HAART, who had post-HAART CD4+ measurements, and for whom HIV seroconversion (SC) date was estimated.
Results
CD4+ count at HAART initiation was ≤ 200 cells/mm3 for 23%, 201-349 for 31%, 350-499 for 27%, and ≥500 for 19%. The first 6 months post-HAART, the greatest CD4+ increases (93-151 cells) occurred, with lesser increases (22-36 cells/year) through the first four years. Although CD4+ changes for the entire cohort were relatively flat thereafter, HIV viral load (VL) suppressors showed continued increases of 12-16 cells/year. In multivariate analysis adjusting for baseline CD4+ and post-HAART time interval, CD4+ responses were poorer in those with: longer time from HIV SC to HAART start, lower pre-HAART CD4+ nadir, higher pre-HAART VL, and clinical AIDS before HAART (P < 0.05).
Conclusions
Small but positive long-term increases in CD4+ count in virally suppressed patients were observed. CD4+ response to HAART is influenced by multiple factors including duration of preceding HIV infection, and optimized if treatment is started with virally suppressive therapy as early as possible.
doi:10.1186/1742-6405-8-2
PMCID: PMC3037838  PMID: 21244701
PLoS ONE  2013;8(10):e76986.
Background
The contribution of HIV-infection to periodontal disease (PD) is poorly understood.  We proposed that immunological markers would be associated with improved clinical measures of PD.
Methods
We performed a longitudinal cohort study of HIV-infected adults who had started highly active antiretroviral therapy (HAART) <2 years. PD was characterized clinically as the percent of teeth with ≥1 site with periodontal probing depth (PPD) ≥5.0mm, recession (REC) >0mm, clinical attachment level (CAL) ≥4.0mm, and bleeding on probing (BOP) at ≥4 sites/tooth and microbiologically as specific periodontopathogen concentration. Linear mixed-effects models were used to assess the associations between immune function and PD.
Results
Forty (40) subjects with median 2.7 months on HAART and median nadir CD4+ T-cell count of 212 cells/μl completed a median 3 visits. Over 24 months, CD4+ T-cell count increased by a mean 173 cells/µl (p<0.001) and HIV RNA decreased by 0.5 log10 copies/ml (p<0.001); concurrently, PPD, CAL and BOP decreased by a mean 11.7%, 12.1%, and 14.7% respectively (all p<0.001). Lower nadir CD4+ T-cell count was associated with worse baseline REC (-6.72%; p=0.04) and CAL (9.06%; p<0.001). Further, lower nadir CD4+ T-cell count was associated with a greater relative longitudinal improvement in PPD in subjects with higher baseline levels of Porphyromonas gingivalis (p=0.027), and BOP in subjects with higher baseline levels of Porphyromonas gingivalis or Treponema denticola (p=0.001 and p=0.006 respectively). Longitudinal changes from baseline in CD4+ T-cell count and level of HIV RNA were not independently associated with longitudinal changes in any clinical markers of PD.
Conclusion
Degree of immunosuppression was associated with baseline gingival recession. After HAART initiation, measures of active PD improved most in those with lower nadir CD4+ T-cell counts and higher baseline levels of specific periodontopathogens. Nadir CD4+ T-cell count differentially influences periodontal disease both before and after HAART in HIV-infected adults.
doi:10.1371/journal.pone.0076986
PMCID: PMC3795634  PMID: 24146949
PLoS Medicine  2013;10(8):e1001494.
Using a randomized controlled trial, Marc Lallemant and colleagues ask if a CD4-based monitoring and treatment switching strategy provides a similar clinical outcome compared to the standard viral load-based strategy for adults with HIV in Thailand.
Please see later in the article for the Editors' Summary
Background
Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand.
Methods and Findings
The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50–250/mm3) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm3. The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6–11.4) in VL versus 7.4% (5.1–10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2–8.4) in VL versus 7.5% (5.0–11.1) in CD4 (p = 0.097). Median time from treatment initiation to switch was 11.7 months (7.7–19.4) in VL and 24.7 months (15.9–35.0) in CD4 (p = 0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8–8.0) in VL versus 15.8 months (8.5–20.4) in CD4 (p = 0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported.
Conclusions
The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings.
Trial registration
ClinicalTrials.gov NCT00162682
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (most of them living in low-and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV infection leads to the destruction of immune system cells (including CD4 cells, a type of white blood cell), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (HAART)—combined drugs regimens that suppress viral replication and allow restoration of the immune system—became available. For people living in affluent countries, HIV/AIDS became a chronic condition but, because HAART was expensive, HIV/AIDS remained a fatal illness for people living in resource-limited countries. In 2003, the international community declared HIV/AIDS a global health emergency and, in 2006, it set the target of achieving universal global access to HAART by 2010. By the end of 2011, 8 million of the estimated 14.8 million people in need of HAART in low- and middle-income countries were receiving treatment.
Why Was This Study Done?
At the time this trial was conceived, national and international recommendations were that HIV-positive individuals should start HAART when their CD4 count fell below 200 cells/mm3 and should have their CD4 count regularly monitored to optimize HAART. In 2013, the World Health Organization (WHO) recommendations were updated to promote expanded eligibility for HAART with a CD4 of 500 cells/mm3 or less for adults, adolescents, and older children although priority is given to individuals with CD4 count of 350 cells/mm3 or less. Because HIV often becomes resistant to first-line antiretroviral drugs, WHO also recommends that viral load—the amount of virus in the blood—should be monitored so that suspected treatment failures can be confirmed and patients switched to second-line drugs in a timely manner. This monitoring and switching strategy is widely used in resource-rich settings, but is still very difficult to implement for low- and middle-income countries where resources for monitoring are limited and access to costly second-line drugs is restricted. In this randomized non-inferiority trial, the researchers compare the performance of a CD4-based treatment monitoring and switching strategy with the standard viral load-based strategy among HIV-positive adults in Thailand. In a randomized trial, individuals are assigned different interventions by the play of chance and followed up to compare the effects of these interventions; a non-inferiority trial investigates whether one treatment is not worse than another.
What Did the Researchers Do and Find?
The researchers assigned about 700 HIV-positive adults who were beginning HAART for the first time to have their CD4 count (CD4 arm) or their CD4 count and viral load (VL arm) determined every 3 months. Participants were switched to a second-line therapy if their CD4 count declined by more than 30% from their peak CD4 count (CD4 arm) or if a viral load of more than 400 copies/ml was recorded (VL arm). The 3-year cumulative risk of clinical failure (defined as death, a new AIDS-defining event, or a CD4 count of less than 50 cells/mm3) was 8% in the VL arm and 7.4% in the CD4 arm. This difference in clinical failure risk met the researchers' predefined criterion for non-inferiority. The probability of a treatment switch was similar in the two arms, but the average time from treatment initiation to treatment switch and the average duration of a high viral load after treatment switch were both longer in the CD4 arm than in the VL arm. Finally, the future-drug-option score, a measure of viral drug resistance profiles, was similar in the two arms at the time of treatment switch.
What Do These Findings Mean?
These findings suggest that, in Thailand, a CD4 switching strategy is non-inferior in terms of clinical outcomes among HIV-positive adults 3 years after beginning HAART when compared to the recommended viral load-based switching strategy and that there is no difference between the strategies in terms of viral suppression and immune restoration after 3-years follow-up. Importantly, however, even though patients in the CD4 arm spent longer with a high viral load than patients in the VL arm, the emergence of HIV mutants resistant to antiretroviral drugs was similar in the two arms. Although these findings provide no information about the long-term outcomes of the two monitoring strategies and may not be generalizable to routine care settings, they nevertheless provide reassurance that using CD4 counts alone to monitor HAART in HIV treatment programs in resource-limited settings is an appropriate strategy to use as viral load measurement becomes more affordable and feasible in these settings.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001494.
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); its 2010 recommendations for antiretroviral therapy for HIV infection in adults and adolescents are available as well as the June 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the global HIV/AIDS epidemic, on HIV and AIDS in Thailand, on universal access to AIDS treatment, and on starting, monitoring and switching HIV treatment (in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about HIV and AIDS
More information about this trial (the PHPT-3 trial) is available
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about HIV treatment
doi:10.1371/journal.pmed.1001494
PMCID: PMC3735458  PMID: 23940461
PLoS Medicine  2006;3(12):e484.
Background
During acute and early HIV-1 infection (AEI), up to 60% of CD4+ T cells in the lamina propria of the lower gastrointestinal (GI) tract are lost as early as 2–4 wk after infection. Reconstitution in the peripheral blood during therapy with highly active antiretroviral therapy (HAART) is well established. However, the extent of immune reconstitution in the GI tract is unknown.
Methods and Findings
Fifty-four AEI patients and 18 uninfected control participants underwent colonic biopsy. Forty of the 54 AEI patients were followed after initiation of antiretroviral therapy (18 were studied longitudinally with sequential biopsies over a 3-y period after beginning HAART, and 22 were studied cross sectionally after 1–7 y of uninterrupted therapy). Lymphocyte subsets, markers of immune activation and memory in the peripheral blood and GI tract were determined by flow cytometry and immunohistochemistry. In situ hybridization was performed in order to identify persistent HIV-1 RNA expression. Of the patients studied, 70% maintained, on average, a 50%–60% depletion of lamina propria lymphocytes despite 1–7 y of HAART. Lymphocytes expressing CCR5 and both CCR5 and CXCR4 were persistently and preferentially depleted. Levels of immune activation in the memory cell population, CD45RO+ HLA-DR+, returned to levels seen in the uninfected control participants in the peripheral blood, but were elevated in the GI tract of patients with persistent CD4+ T cell depletion despite therapy. Rare HIV-1 RNA–expressing cells were detected by in situ hybridization.
Conclusions
Apparently suppressive treatment with HAART during acute and early infection does not lead to complete immune reconstitution in the GI mucosa in the majority of patients studied, despite immune reconstitution in the peripheral blood. Though the mechanism remains obscure, the data suggest that there is either viral or immune-mediated accelerated T cell destruction or, possibly, alterations in T cell homing to the GI tract. Although clinically silent over the short term, the long-term consequences of the persistence of this lesion may emerge as the HIV-1–infected population survives longer owing to the benefits of HAART.
Despite early initiation of anti-HIV therapy, loss of T cells in the gastrointestinal mucosa persisted for years in most members of a clinical cohort identified early after HIV-1 infection.
Editors' Summary
Background.
AIDS causes disease by inactivating the body's immune response against infection. The AIDS virus (HIV) is most active against the white blood cells called T lymphocytes, particularly the CD4 T lymphocytes, which recognize infection and activate other cells of the immune system to fight it. In what was formerly believed to be a gradual process, HIV infection is now known to deplete a subset of the body's CD4 lymphocytes, called memory cells, quite rapidly—over only a few days—within a few weeks after a person becomes infected with the AIDS virus. This was not known until recently because researchers were counting CD4 cells only in blood, while a majority of the memory lymphocytes are located in and around the digestive system. It is these intestinal memory lymphocytes that are rapidly wiped out, while those in the blood fall much more gradually, usually over several years. Few studies of mucosal lymphocytes have been done in humans because such studies require biopsies of the intestinal lining (mucosa).
Why Was This Study Done?
Although CD4 cells in the blood can return and remain at normal levels when HIV infection is treated with antiviral drugs, it has been unclear as to whether the mucosal CD4 cells return as well. People who begin treatment as soon as possible after becoming infected with HIV might seem to have the best chance of regaining their mucosal immunity, compared to those who wait until the CD4 cells in their blood have fallen, which is a generally accepted reason to start medication for HIV. Therefore, the researchers wanted to see whether people who start treatment early after becoming infected with HIV might experience restoration of their mucosal immunity over time and, if so, what kinds of lymphocytes would return.
What Did the Researchers Do and Find?
The researchers studied people who started treatment for HIV within a few weeks to months of becoming infected and who then remained on treatment. Some volunteers underwent biopsies of the intestinal mucosa before starting treatment and then at various points from 1 y until as long as 3 y after infection. Others volunteered for biopsy only one time, anywhere from less than 1 y to 7 y following treatment. The biopsy specimens were examined under the microscope and with a technique called flow cytometry using specific staining methods to assess their structure and functional characteristics. Results were compared to biopsies from a group of HIV-uninfected volunteers.
The researchers found that the percentage of CD4 lymphocytes dropped much lower in the intestinal mucosa than in blood during early infection and then, unlike in blood, remained low even after several years of treatment for HIV. In the microscope images, they found that mucosal CD4 cells were lost mostly from regions of active battle against invading germs, rather than from “training sites” for new CD4 cells. Over time, only 30% of the volunteers showed return of CD4 cells to normal levels in these active sites.
Unlike T lymphocytes in the blood, which tend to return to a resting state after HIV is treated, the T lymphocytes in the intestinal mucosa tended to persist in an activated state despite HIV treatment, even though only a tiny fraction of these cells were found to be infected with HIV. A high level of activation of mucosal lymphocytes soon after infection was found to predict poor restoration of mucosal CD4 cells over time.
What Do These Findings Mean?
These experiments confirm that studying easily obtained blood lymphocytes provides only a limited view of how HIV affects the immune system as a whole. The finding that immune cells of the intestinal mucosa remain depleted and over-activated for years despite antiretroviral treatment raises the concern that over time this will result in clinical problems. Fortunately, this does not appear to be the case in most people currently being treated for HIV, some for as long as 10 y, but the results of this study suggest that we should remain vigilant for gastrointestinal problems resulting from impaired immunity over time. The finding that mucosal lymphocytes do appear to return to normal levels in a minority of volunteers is of interest, and suggests that early interventions to reduce activation of intestinal T cells (such as antimicrobial or immunomodulatory treatment) might be worth investigating in those recently infected with HIV. Finally, these results suggest that a vaccine to prevent HIV may need to stimulate immune responses that can act very quickly following infection, before the bulk of lymphocytes capable of countering the infection are lost, perhaps irreversibly.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030484.
UCSF HIV InSite includes resources on HIV immunology and vaccine development
AIDS fact sheets and brochures from the US National Institute of Allergy and Infectious Diseases
Medline Plus article on acute HIV infection from the US National Library of Medicine
doi:10.1371/journal.pmed.0030484
PMCID: PMC1762085  PMID: 17147468
Background
The heterogeneity of CD4+ T-cell counts and HIV-1 RNA at 5-12 years after the initiation of highly active antiretroviral therapy (HAART) remains largely uncharacterized.
Methods
In the Multicenter AIDS Cohort Study, 614 men who initiated HAART contributed data 5-12 years subsequently. Multivariate regression was used to evaluate the predictors of CD4+ counts and HIV-1 RNA levels.
Results
At 5-12 years post-HAART, the median CD4+ T-cell count was 586 (inter quartile range (IQR): 421-791) cells/μl and 78% of the HIV-1 RNA measurements were undetectable. Higher CD4+ T-cell counts 5-12 years post-HAART were predicted by higher CD4+ T-cell counts and higher total lymphocyte count pre-HAART, lack of hepatitis B or C virus co-infections, and greater CD4+ T-cell change as well as suppressed HIV-1 RNA in the first 5 years after starting HAART. Older men (≥50 years) with 351-500 CD4+ cells/μl at HAART initiation had adjusted mean CD4+ T-cell count of 643 cells/μl at 10-12 years post-HAART, which was similar to the adjusted mean CD4+ T-cell count (670 cells/μl, p=0.45) in this period for younger men starting HAART with lower CD4+ T-cell counts. HIV-1 RNA suppression in the first 5 years post-HAART predicted subsequent viral suppression.
Conclusion
Immunological and virological responses in the first five years post-HAART predicted subsequent CD4+ T-cell counts and HIV-1 RNA levels. The association between age and subsequent CD4+ T-cell count supports incorporating age in guidelines for use of HAART.
doi:10.1097/QAI.0b013e31821e9f21
PMCID: PMC3293185  PMID: 21602699
CD4+ T-cells; HIV-1 RNA; HAART; response; age effects
PLoS ONE  2012;7(1):e29777.
Background
The incidence and correlates of breast milk HIV-1 RNA detection were determined in intensively sampled women receiving highly active antiretroviral therapy (HAART) for the prevention of mother-to-child HIV-1 transmission.
Methods
Women initiated HAART at 34 weeks of pregnancy. Breast milk was collected every 2–5 days during 1 month postpartum for measurements of cell-associated HIV DNA and cell-free HIV RNA. Plasma and breast milk were also collected at 2 weeks, 1, 3 and 6 months for concurrent HIV-1 RNA and DNA measurements. Regression was used to identify cofactors for breast milk HIV-1 RNA detection.
Results
Of 259 breast milk specimens from 25 women receiving HAART, 34 had detectable HIV-1 RNA (13%, incidence 1.4 episodes/100 person-days 95% CI = 0.97–1.9). Fourteen of 25 (56%) women had detectable breast milk HIV-1 RNA [mean 2.5 log10 copies/ml (range 2.0–3.9)] at least once. HIV-1 DNA was consistently detected in breast milk cells despite HAART, and increased slowly over time, at a rate of approximately 1 copy/106 cells per day (p = 0.02). Baseline CD4, plasma viral load, HAART duration, and frequency of breast problems were similar in women with and without detectable breast milk HIV-1 RNA. Women with detectable breast milk HIV-1 RNA were more likely to be primiparous than women without (36% vs 0%, p = 0.05). Plasma HIV-1 RNA detection (OR = 9.0, 95%CI = 1.8–44) and plasma HIV-1 RNA levels (OR = 12, 95% CI = 2.5–56) were strongly associated with concurrent detection of breast milk HIV-1 RNA. However, no association was found between breast milk HIV-1 DNA level and concurrent breast milk HIV-1 RNA detection (OR = 0.96, 95%CI = 0.54–1.7).
Conclusions
The majority of women on HAART had episodic detection of breast milk HIV-1 RNA. Breast milk HIV-1 RNA detection was associated with systemic viral burden rather than breast milk HIV-1 DNA.
doi:10.1371/journal.pone.0029777
PMCID: PMC3256181  PMID: 22253778
We studied the time course of immunological and virological markers after highly active antiretroviral therapy (HAART) interruption in chronically human immunodeficiency virus type 1 (HIV-1)-infected patients immunized with an HIV lipopeptide preparation. In a prospective open pilot study, 24 HIV-1-infected HAART-treated patients with undetectable plasma viral loads (pVLs) and CD4+ T-cell counts above 350/mm3 were immunized at weeks 0, 3, and 6 with a candidate vaccine consisting of six HIV lipopeptides. At week 24, patients with pVLs of <1.7 log10 copies/ml were invited to stop taking HAART. Antiretroviral therapy was resumed if the pVL rose above 4.47 log10 copies/ml and/or if the CD4+ cell count fell below 250/mm3. Immunological and virologic parameters were studied before and after HAART interruption. The median baseline and nadir CD4+ cell counts were 482 (interquartile range [IQR], 195 to 826) and 313 (IQR, 1 to 481)/mm3, respectively. New specific CD8+ cell responses to HIV-1 epitopes were detected after immunization in 13 (57%) of 23 assessable patients. Twenty-one patients were evaluated 96 weeks after HAART interruption. The median time to pVL rebound was 4 weeks (IQR, 2 to 6), and the median peak pVL was 4.26 (IQR, 3 to 5) log10 copies/ml. Thirteen of these 21 patients resumed HAART a median of 60 weeks after immunization (IQR, 9.2 to 68.4 weeks), when the median pVL was 4.8 (IQR, 2.9 to 5.7) log10 copies/ml and the median CD4+ cell count was 551 (IQR, 156 to 778)/mm3. Eight patients were still off therapy at 96 weeks, with a median pVL of 4 (IQR, 1.7 to 4.6) log10 copies/ml and a median CD4+ cell count of 412 (IQR, 299 to 832)/mm3. No clinical disease progression had occurred. Despite the lack of a control arm, these findings warrant a randomized study of therapeutic vaccination with HIV lipopeptides followed by long-term HAART interruption in AIDS-free chronically infected patients.
doi:10.1128/CVI.00165-07
PMCID: PMC2268255  PMID: 18184824
Background
The aim of this study was to explore the effects of HCV co-infection on virological effectiveness and on CD4+ T-cell recovery in patients with an early and sustained virological response after HAART.
Methods
We performed a longitudinal analysis of 3,262 patients from the MASTER cohort, who started HAART from 2000 to 2008. Patients were stratified into 6 groups by HCV status and type of anchor class. The early virological outcome was the achievement of HIV RNA <500 copies/ml 4–8 months after HAART initiation. Time to virological response was also evaluated by Kaplan-Meier analysis. The main outcome measure of early immunological response was the achievement of CD4+ T-cell increase by ≥100/mm3 from baseline to month 4–8 in virological responder patients. Late immunological outcome was absolute variation of CD4+ T-cell count with respect to baseline up to month 24. Multivariable analysis (ANCOVA) investigated predictors for this outcome.
Results
The early virological response was higher in HCV Ab-negative than HCV Ab-positive patients prescribed PI/r (92.2% versus 88%; p = 0.01) or NNRTI (88.5% versus 84.7%; p = 0.06). HCV Ab-positive serostatus was a significant predictor of a delayed virological suppression independently from other variables, including types of anchor class. Reactivity for HCV antibodies was associated with a lower probability of obtaining ≥100/mm3 CD4+ increase within 8 months from HAART initiation in patients treated with PI/r (62.2% among HCV Ab-positive patients versus 70.9% among HCV Ab-negative patients; p = 0.003) and NNRTI (63.7% versus 74.7%; p < 0.001). Regarding late CD4+ increase, positive HCV Ab appeared to impair immune reconstitution in terms of absolute CD4+ T-cell count increase both in patients treated with PI/r (p = 0.013) and in those treated with NNRTI (p = 0.002). This was confirmed at a multivariable analysis up to 12 months of follow-up.
Conclusions
In this large cohort, HCV Ab reactivity was associated with an inferior virological outcome and an independent association between HCV Ab-positivity and smaller CD4+ increase was evident up to 12 months of follow-up. Although the difference in CD4+ T-cell count was modest, a stricter follow-up and optimization of HAART strategy appear to be important in HIV patients co-infected by HCV. Moreover, our data support anti-HCV treatment leading to HCV eradication as a means to facilitate the achievement of the viro-immunological goals of HAART.
doi:10.1186/1742-6405-9-18
PMCID: PMC3409064  PMID: 22703595
HIV; HCV; HAART
Background
Risk factors associated with preeclampsia in HIV-infected women remain largely unknown. Systemic angiogenic imbalance contributes to preeclampsia in HIV-uninfected women, but changes in angiogenic markers after HAART initiation have not been studied.
Methods
The Mma Bana study randomized 560 HIV-infected, HAART-naive pregnant women with CD4 counts ≥ 200 cells/mm3 between 26–34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine or abacavir/zidovudine/lamivudine. Another 170 participants with CD4 counts < 200 cells/mm3 initiated nevirapine/zidovudine/lamivudine between 18–34 weeks gestation. Characteristics of 11 women who developed preeclampsia were compared with the remaining722 Mma Bana participants who delivered, using logistic regression. Plasma samples drawn at HAART initiation and one month later from 60 women without preeclampsia and at HAART initiation for all11 preeclamptic women were assayed for placental growth factor (PlGF) and soluble FMS toll-like tyrosine kinase-1 (sFlt-1),
Results
Pre-HAART viral load > 100,000 copies/ml was associated with preeclampsia (OR 5.8; 95% CI 1.8, 19.4; p = 0.004). Median pre-HAART PlGF level was lower and sFLT-1 was higher in women who developed preeclampsia versus those who did not (130 vs 992 pg/ml, p=0.001; 17.5 vs 9.4 pg/ml, p=0.03, respectively). In multivariate analysis, PlGF and viral load remained significantly associated with preeclampsia. No significant changes in angiogenic factors were noted after 1 month of HAART treatment among non-preeclamptic women.
Conclusions
Pre-HAART viral load > 100,000 copies/ml and PlGF predicted preeclampsia among women starting HAART in pregnancy. Among non-preeclamptic women, HAART treatment did not significantly alter levels of PlGF or sFlt-1 one month into treatment.
doi:10.1097/QAI.0b013e318286d77e
PMCID: PMC3683097  PMID: 23344545
HIV-1; viral load; pregnancy; preeclampsia; HAART

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