Identifying barriers to ART initiation and adherence: An exploratory qualitative study on PMTCT in Zambia.

BACKGROUND: Though antiretroviral therapy (ART) is widely available, HIV positive pregnant women in Zambia are less likely to start and remain on therapy throughout pregnancy and after delivery. This study sought to understand readiness to start ART among HIV pregnant women from the perspectives of both women and men in order to suggest more holistic programs to support women to continue life-long ART after delivery. METHODS: We conducted a qualitative study with HIV positive pregnant women before and after ART initiation, and men with female partners, to understand readiness to start lifelong ART. We conducted 28 in-depth interviews among women and 2 focus group discussions among male partners. Data were transcribed verbatim and analyzed in NVivo 12 using thematic analysis. Emerging themes from the data were organized using the social ecological framework. RESULTS: Men thought of their female partners as young and needing their supervision to initiate and stay on ART. Women agreed that disclosure and partner support were necessary preconditions to ART initiation and adherence and, expressed fear of divorce as a prominent barrier to disclosure. Maternal love and desire to look after one's children instilled a sense of responsibility among women which motivated them to overcome individual, interpersonal and health system level barriers to initiation and adherence. Women preferred adherence strategies that were discrete, the effectiveness of which, depended on women's intrinsic motivation. CONCLUSION: The results support current policies in Zambia to encourage male engagement in ART care. To appeal to male partners, messaging on ART should be centered on emphasizing the importance of male involvement to ensure women remain engaged in ART care. Programs aimed at supporting postpartum ART adherence should design messages that appeal to both men's role in couples' joint decision-making and women's maternal love as motivators for adherence.

Time to treatment disruption in children with HIV-1 randomized to initial antiretroviral therapy with protease inhibitors versus non-nucleoside reverse transcriptase inhibitors.

BACKGROUND: Choice of initial antiretroviral therapy regimen may help children with HIV maintain optimal, continuous therapy. We assessed treatment-naïve children for differences in time to treatment disruption across randomly-assigned protease inhibitor versus non-nucleoside reverse transcriptase inhibitor-based initial antiretroviral therapy. METHODS: We performed a secondary analysis of a multicenter phase 2/3, randomized, open-label trial in Europe, North and South America from 2002 to 2009. Children aged 31 days to <18 years, who were living with HIV-1 and treatment-naive, were randomized to antiretroviral therapy with two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Time to first documented treatment disruption to any component of antiretroviral therapy, derived from treatment records and adherence questionnaires, was analyzed using Kaplan-Meier estimators and Cox proportional hazards models. RESULTS: The modified intention-to-treat analysis included 263 participants. Seventy-two percent (n = 190) of participants experienced at least one treatment disruption during study. At 4 years, treatment disruption probabilities were 70% (protease inhibitor) vs. 63% (non-nucleoside reverse transcriptase inhibitor). The unadjusted hazard ratio (HR) for treatment disruptions comparing protease inhibitor vs. non-nucleoside reverse transcriptase inhibitor-based regimens was 1.19, 95% confidence interval [CI] 0.88-1.61 (adjusted HR 1.24, 95% CI 0.91-1.68). By study end, treatment disruption probabilities converged (protease inhibitor 81%, non-nucleoside reverse transcriptase inhibitor 84%) with unadjusted HR 1.11, 95% CI 0.84-1.48 (adjusted HR 1.13, 95% CI 0.84-1.50). Reported reasons for treatment disruptions suggested that participants on protease inhibitors experienced greater tolerability problems. CONCLUSIONS: Children had similar time to treatment disruption for initial protease inhibitor and non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy, despite greater reported tolerability problems with protease inhibitor regimens. Initial pediatric antiretroviral therapy with either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor may be acceptable for maintaining optimal, continuous therapy.

Test but not treat: Community members' experiences with barriers and facilitators to universal antiretroviral therapy uptake in rural KwaZulu-Natal, South Africa.

INTRODUCTION: Antiretroviral therapy (ART) has revolutionised the care of HIV-positive individuals resulting in marked decreases in morbidity and mortality, and markedly reduced transmission to sexual partners. However, these benefits can only be realised if individuals are aware of their HIV-positive status, initiated and retained on suppressive lifelong ART. Framed using the socio-ecological model, the present study explores factors contributing to poor ART uptake among community members despite high acceptance of HIV-testing within a Treatment as Prevention (TasP) trial. In this paper we identify barriers and facilitators to treatment across different levels of the socio-ecological framework covering individual, community and health system components. METHODS: This research was embedded within a cluster-randomised trial (ClinicalTrials.gov, number NCT01509508) of HIV treatment as Prevention in rural KwaZulu-Natal, South Africa. Data were collected between January 2013 and July 2014 from resident community members. Ten participants contributed to repeat in-depth interviews whilst 42 participants took part in repeat focus group discussions. Data from individual interviews and focus group discussions were triangulated using community walks to give insights into community members' perception of the barriers and facilitators of ART uptake. We used thematic analysis guided by a socio-ecological framework to analyse participants' narratives from both individual interviews and focus group discussions. RESULTS: Barriers and facilitators operating at the individual, community and health system levels influence ART uptake. Stigma was an over-arching barrier, across all three levels and expressed variably as fear of HIV disclosure, concerns about segregated HIV clinical services and negative community religious perceptions. Other barriers were individual (substance misuse, fear of ART side effects), community (alternative health beliefs). Facilitators cited by participants included individual (expectations of improved health and longer life expectancy following ART, single tablet regimens), community (availability of ART in the community through mobile trial facilities) and health system factors (fast and efficient service provided by friendly staff). DISCUSSION: We identified multiple barriers to achieving universal ART uptake. To enhance uptake in HIV care services, and achieve the full benefits of ART requires interventions that tackle persistent HIV stigma, and offer people with HIV respectful, convenient and efficient services. These interventions require evaluation in appropriately designed studies.

The Biology of the HIV-1 Latent Reservoir and Implications for Cure Strategies.

Antiretroviral therapy (ART) inhibits HIV replication but is not curative. During ART, the integrated HIV genome persists indefinitely within CD4+ T cells and perhaps other cells. Here, we describe the mechanisms thought to contribute to its persistence during treatment and highlight findings from numerous recent studies describing the importance of cell proliferation in that process. Continued progress elucidating the biology will enhance our ability to develop effective curative interventions.

Assessment of liver and renal functions in human immunodeficiency virus-infected persons on highly active antiretroviral therapy: A mixed cohort study.

BACKGROUND: Indian data on potential hepatorenal toxic effects of highly active antiretroviral therapy (HAART) in HIV/AIDS-affected persons is lacking. OBJECTIVES: To assess hepatorenal abnormalities in HIV-infected persons on HAART in a hospital-based mixed cohort study using concurrent and nonconcurrent data analysis. METHODS: Hepatorenal function tests, urinalysis and ultrasonogaphy for liver/kidneys (when applicable) were assessed in 400 (men 185; women 215) persons aged 2-84 (mean 47.8) years on HAART. Acute liver toxicity, acute kidney injury and chronic kidney disease were defined depending upon abnormal serum alanine aminotransferase, urea and creatinine levels/clearance as per standard guidelines. RESULTS: The duration of HAART was 1 month to 9 years (mean 3.7 years) with 284 (71%) individuals being on treatment for ≤5years. The major HAART regimens included zidovudine + lamivudine + nevirapine in 175 (43.8%), tenofovir + lamivudine + efavirenz in 174 (43.5%) and zidovudine + lamivudine + efavirenz in 20 (5%) individuals and were associated with grade-1 hepatic dysfunction in 57 (14.3%) individuals, with men aged between 31 and 45 years on antiretroviral therapy for >5 years being mainly affected. Forty two (17.1%) of 246 individuals with anemia and 15 (9.7%) of 154 individuals without anemia showed hepatic dysfunction. None had acute kidney injury, chronic kidney disease or abnormal urinalysis or ultrasonography. In contrast, the pretreatment elevated serum alanine amiotranerase in 99 (22.3%) and blood urea and/or creatinine levels in 16 (4%) individuals decreased significantly post highly active antiretroviral therapy. CONCLUSIONS: The study reflects the low frequency of regimen based highly active antiretroviral therapy-associated hepatic or nephrotoxicity despite prolonged use, especially in the absence of other risk factors. Preexisting anemia appears an important risk factor for highly active antiretroviral therapy-induced hepatotoxicity (OR 1.90, Cl 95% CI 1.02-3.57, P = 0.04). Highly active antiretroviral therapy-associated nephrotoxicity was not a significant problem. Study of viral load or other risk factors and potential of each drug for hepatorenal toxicity/dysfunction in HIV affected were not part of the study. A small number of subjects and retrospective analysis of biochemical parameters were other important limitations.

All-cause mortality after antiretroviral therapy initiation in HIV-positive women from Europe, Sub-Saharan Africa and the Americas.

BACKGROUND: Women account for over half of persons living with HIV/AIDS globally. We examined geographic variation in all-cause mortality after antiretroviral therapy (ART) for women living with HIV (WLWH) worldwide. METHODS: We pooled data from WLWH at least 18 years initiating ART 2000-2014 within COHERE (Europe) and IeDEA regions (East Africa, West Africa, South Africa, North America, Latin America/Caribbean). Mortality rates were calculated at 0-3, 3-6, 6-12, 12-24 and 24-48 months after ART, and mortality rate ratios were compared with European rates with piecewise exponential parametric survival models based on Poisson regression. FINDINGS: One hundred ninety thousand, one hundred and seventy-five WLWH (16% Europe, 47% East Africa, 13% West Africa, 19% South Africa, 1% South America, 3% North America and 2% Central America/Caribbean) were included. The highest death rates occurred 0-3 months after ART [1.51 (95% CI 1.25-1.82) per 100 person-years in Europe, 12.45 (11.30-13.73), 14.03 (13.12-15.02) and 9.44 (8.80-10.11) in East, West and South Africa, and 1.53 (0.97-2.43), 7.83 (5.44-11.27) and 17.02 (14.62-19.81) in North, South America and Central America/Caribbean, respectively] and declined thereafter. Mortality in Europe was the lowest, with regional differences greatest in the first 3 months and smaller at longer ART durations [adjusted rate ratios 24-48 months after ART: 3.63 (95% CI 3.04-4.33), 5.61 (4.84-6.51) and 3.47 (2.97-4.06) for East, West and South Africa; 2.86 (2.26-3.62), 2.42 (1.65-3.55) and 2.50 (1.92-3.26) for North, South America and Central America/Caribbean, respectively]. CONCLUSION: Global variations in short-term and long-term mortality among WLWH initiating ART may inform context-specific interventions.

Stigma against patients with HIV/AIDS in the rapid expansion of antiretroviral treatment in large drug injection-driven HIV epidemics of Vietnam.

BACKGROUND: Despite existing efforts to provide antiretroviral treatment (ART) for all HIV-diagnosed people, stigma deprives them of the highest attainable health status and challenges the effectiveness of ART program in Vietnam. This study aimed to assess five dimensions of HIV-related stigma and explore its associated factors among ART patients in a multisite survey. Implications of this study support the development of HIV policies to improve patients' access, utilization, and outcomes of ART program toward the 90-90-90 goal in Vietnam. METHODS: A total of 1133 ART patients who were recruited by convenience sampling method from 8 ART clinics in Hanoi and Nam Dinh in a cross-sectional study from January to August 2013. Multivariate logistic regression was employed to identify factors associated with stigmatization. RESULTS: The majority of participants reported experiencing stigmatization due to shame (36.9%), blame/judge (21.6%), and discrimination (23.4%). Further, 91.5% of participants disclosed their HIV status with others. The likelihood of experiencing stigmatization did not only associate with the patients' socioeconomic status (e.g., age, occupation, education) and HIV status disclosure, but also their health problems. Those with anxiety or depression and perceived lower quality of life were more likely to experience stigma. CONCLUSIONS: To maximize the efficiency of the ART program, it is essential to develop interventions that reduce stigma involving individuals, families, and communities, and recognize and address complex health problems especially those patients showing depressive symptoms. Increasing quality of life of HIV-positive patients by providing vocational training, financial, family, and peer support will reduce the likelihood of experiencing stigma.

Modern Human Immunodeficiency Virus Therapy: Progress and Prospects.

Safe and effective lifelong treatment to control human immunodeficiency virus (HIV) infection is one of the greatest scientific and public health achievements of the past century. The majority of infected individuals able to maintain a daily oral regimen now have a normal or near-normal life expectancy. More than 30 approved drugs and dozens of formulations have produced thousands of possible drug combinations used clinically in the past, but today most patients receive only a handful of high priority and rigorously tested regimens. Unique features of antiretroviral therapy include the need for lifelong treatment to control virus replication and the possibility of rapid emergence of permanent drug resistance if these agents are not properly used. Although three-drug combination oral regimens have radically altered the course of this epidemic, the future will include long-acting injectable and implantable drugs and devices to treat and prevent infection.

Minimal change nephrotic syndrome in patients infected with human immunodeficiency virus: a retrospective study of 8 cases.

BACKGROUND: Human immunodeficiency virus (HIV) is associated with diverse glomerular diseases. Characteristics of minimal change nephrotic syndrome (MCNS) in this setting have been little studied, and the specific features of this uncommon association remain to be determined. METHODS: We conduct a retrospective study. Clinical, biological and pathological characteristics of patients with MCNS and HIV infection were assessed. We evaluated HIV infection by in situ hybridization and CMIP expression by immunochemistry on kidney biopsies and compared it to HIV-associated nephropathy (HIVAN) and idiopathic MCNS. RESULTS: Eight patients were identifies. In all but one of these cases, MCNS occurred after HIV diagnosis (mean of 9.5 years). Acute kidney injury was detected in three cases. Mean CD4+ lymphocyte count was 733/mm3 and three patients had a detectable HIV viral load. In situ hybridization for HIV-1 RNA detection yielded a positive signal in a few tubular cells in the renal parenchyma in two of four patients with HIV infection associated with MCNS. Podocytes of these patients presented strong positive immunostaining for CMIP (4/4). Three patients suffered steroid-dependent nephrotic syndrome, and another two patients had at least one relapse. Rituximab treatment was initiated in four cases. After a median follow-up of 20 months, all patients were in remission (complete in 5 cases). CONCLUSIONS: In patients with MCNS occurring in a context of HIV infection, podocyte injury seems to be associated with CMIP induction rather than renal HIV infection but further studies are needed to determine the molecular link between these two conditions.

Protease Inhibitors and Cardiovascular Outcomes in Patients With HIV and Heart Failure.

BACKGROUND: Incident heart failure (HF) is increased in persons with human immunodeficiency virus (PHIV). Protease inhibitors (PIs) are associated with adverse cardiac remodeling and vascular events; however, there are no data on the use of PIs in PHIV with HF. OBJECTIVES: This study sought to compare characteristics, cardiac structure, and outcomes in PHIV with HF who were receiving PI-based versus non-PI (NPI) therapy. METHODS: This was a retrospective single-center study of all 394 antiretroviral therapy-treated PHIV who were hospitalized with HF in 2011, stratified by PI and NPI. The primary outcome was cardiovascular (CV) mortality, and the secondary outcome was 30-day HF readmission rate. RESULTS: Of the 394 PHIV with HF (47% female, mean age 60 ± 9.5 years, CD4 count 292 ± 206 cells/mm3), 145 (37%) were prescribed a PI, whereas 249 (63%) were prescribed NPI regimens. All PI-based antiretroviral therapy contained boosted-dose ritonavir. PHIV who were receiving a PI had higher rates of hyperlipidemia, diabetes mellitus, and coronary artery disease (CAD); higher pulmonary artery systolic pressure (PASP); and lower left ventricular ejection fraction. In follow-up, PI use was associated with increased CV mortality (35% vs. 17%; p < 0.001) and 30-day HF readmission (68% vs. 34%; p < 0.001), effects seen in all HF types. Predictors of CV mortality included PI use, CAD, PASP, and immunosuppression. Overall, PIs were associated with a 2-fold increased risk of CV mortality. CONCLUSIONS: PI-based regimens in PHIV with HF are associated with dyslipidemia, diabetes, CAD, a lower left ventricular ejection fraction, and a higher PASP. In follow-up, PHIV with HF who are receiving a PI have increased CV mortality and 30-day HF readmission.

National characteristics and trends in antiretroviral treatment in Australia can be accurately estimated using a large clinical cohort.

OBJECTIVES: Cohort studies are often used as a national surveillance tool to monitor trends in HIV treatment and morbidity outcomes. However, there are limited studies validating the accuracy of using cohorts as a representation of the overall HIV-positive population. We compared data from a large Australian HIV-positive cohort study (Australian HIV Observational Database [AHOD]) and a 10% longitudinal sample from Australia's subsidized prescription medication scheme (Pharmaceutical Benefits Scheme [PBS]) to assess the use of cohorts for providing representative data for surveillance and monitoring purposes. STUDY DESIGN AND SETTING: Basic demographics and treatment information from July 1, 2013, to March 31, 2016, were divided into half-yearly periods to compare HIV trends between AHOD (n = 2,488) and PBS (n = 18,409) patients. RESULTS: In both data sets, most patients were men, aged above 50 years, and primarily resided in New South Wales. Both data sets revealed a significant shift toward the increased use of integrase strand transfer inhibitors and a gradual decline in the use of protease inhibitors and nonnucleoside reverse-transcriptase inhibitors among the treated population in Australia. Similarly, a substantial increase in the use of once daily, single-tablet, fixed-dose combination regimens was also observed. CONCLUSION: Our results show that observational cohort studies can serve as useful surrogate surveillance tools for monitoring patient characteristics and HIV treatment trends.

Introduction to HIV infection and HIV neurology.

In this introductory chapter the impact of combination antiretriviral therapy is discussed. Three different "types" of HIV infection are described according to medication adherence and efficacy. Next, general principles of HIV related neurologic complications are defined. Last, a clinical approach to the HIV infected patient with a neurologic complication is then detailed.

Global developments in HIV neurology.

Neurologic conditions associated with HIV remain major contributors to morbidity and mortality, and are increasingly recognized in the aging population on long-standing combination antiretroviral therapy (cART). Importantly, growing evidence suggests that the central nervous system (CNS) serves as a reservoir for viral replication with major implications for human immunodeficiency virus (HIV) eradication strategies. Though there has been major progress in the last decade in our understanding of the pathogenesis, burden, and impact of HIV-associated neurologic conditions, significant scientific gaps remain. In many low-income settings, second- and third-line cART regimens that carry substantial neurotoxicity remain treatment mainstays. Further, patients continue to present severely immunosuppressed with CNS opportunistic infections. Public health efforts should emphasize improvements in access and optimizing treatment of HIV-positive patients, specifically in resource-limited settings, to reduce the risk of neurologic sequelae.

Neuropharmacology.

With virologically suppressive antiretroviral therapy, immune system recovery is now achievable for persons living with HIV (PLWH). This immune recovery is associated with dramatic reductions in acquired immune deficiency syndrome (AIDS) defining illnesses including HIV dementia. However, milder form of cognitive disturbances are widely reported in PLWH despite effective antiretroviral therapy. The underlying pathogenic mechanisms of these cognitive disturbances remain elusive, with many potential pathogenic mechanisms including residual brain damage prior to the initiation of antiretroviral therapy and neuroinflammation and ongoing immune system disturbances despite antiretroviral therapy. Lifestyle factors and concomitant infections and medical problems are also likely to be major contributing factors. The penetration of antiretroviral agents into the central nervous system compartment resulting in a lack of suppression of HIV viremia in the brain has generated much interest as well as potential neuro-toxicities from antiretroviral agents themselves. This chapter reviews the clinical pharmacology, both the pharmacokinetic and pharmacodynamic effects, of antiretroviral therapy in the central nervous system compartment.

HAART in HIV/AIDS Treatments: Future Trends.

AIDS (acquired immune deficient syndrome) is a deadly human viral infectious disease caused by HIV (human immune-deficient virus) infection. Almost every AIDS patient losses his/her life before mid 1990s. AIDS was once the 1st disease killer in US (1993). After one decade hard work, antiviral drug cocktails-high active anti-retroviral therapy (HAART) have been invented for almost all HIV infection treatments. Due to the invention of HAART, 80-90% HIV/AIDS patients still effectively response to HAART for deadly AIDS episode controls and life saving. Yet, this type of HIV therapeutics is incurable. HIV/AIDS patients need to take HAART medications regularly and even life-long. To counteract this therapeutic drawback, more revolutionary efforts (different angles of therapeutic modes/attempts) are urgently needed. In this article, the major progresses and drawbacks of HIV/AIDS chemotherapy (HAART) to HIV/AIDS patients have been discussed. Future trends (updating pathogenesis study, next generations of drug developments, new drug target discovery, different scientific disciplinary and so on) are highlighted.

Routine CD4 monitoring in HIV patients with viral suppression: Is it really necessary? A Portuguese cohort.

PURPOSE: CD4 cell-count has been regarded as the key surrogate marker for prognostic staging and therapeutic monitoring of HIV-infected individuals. Our purpose was to assess the probability of maintaining a CD4 count >200 cells/µL in patients with continuous viral suppression and CD4 cell counts >200 cells/µL. METHODS: Retrospective cohort study of HIV-infected patients, treatment naïve, who started antiretroviral therapy between 2007 and 2011. We estimated the probability of maintaining CD4 counts >200 cells/µL during continuous viral suppression using the Kaplan-Meier method. The hazard ratios of a CD4 count <200 cells/µL were estimated and compared using Cox proportional hazards regression. RESULTS: 401 patients were included: 70.1% men; median age 37 years; 98.8% HIV-1 infected. The median duration of continuous viral suppression with CD4 counts >200 cells/µL was 40.5 months. Ninety-three percent of patients maintained CD4 counts ≥200 cells/µL during the period of continuous viral suppression. Compared with those with an initial CD4 count ≥350 cells/µL, patients with initial CD4 count <300 cells/µL had a significantly higher risk of a CD4 count <200 cells/µL. Patients with viral suppression and CD4 counts ≥350 cells/µL had a 97.1% probability of maintaining CD4 cell counts ≥200 cells/µL for 48 months. CONCLUSIONS: The probability of a CD4 count <200 cells/µL in an HIV-infected patient with viral suppression and CD4 ≥350 cells/µL was very low. These data suggests less frequent monitoring of CD4 counts in these patients.

Treatment guidelines and early loss from care for people living with HIV in Cape Town, South Africa: A retrospective cohort study.

BACKGROUND: South Africa has undergone multiple expansions in antiretroviral therapy (ART) eligibility from an initial CD4+ threshold of ≤200 cells/µl to providing ART for all people living with HIV (PLWH) as of September 2016. We evaluated the association of programmatic changes in ART eligibility with loss from care, both prior to ART initiation and within the first 16 weeks of starting treatment, during a period of programmatic expansion to ART treatment at CD4+ ≤ 350 cells/µl. METHODS AND FINDINGS: We performed a retrospective cohort study of 4,025 treatment-eligible, non-pregnant PLWH accessing care in a community health center in Gugulethu Township affiliated with the Desmond Tutu HIV Centre in Cape Town. The median age of participants was 34 years (IQR 28-41 years), almost 62% were female, and the median CD4+ count was 173 cells/µl (IQR 92-254 cells/µl). Participants were stratified into 2 cohorts: an early cohort, enrolled into care at the health center from 1 January 2009 to 31 August 2011, when guidelines mandated that ART initiation required CD4+ ≤ 200 cells/µl, pregnancy, advanced clinical symptoms (World Health Organization [WHO] stage 4), or comorbidity (active tuberculosis); and a later cohort, enrolled into care from 1 September 2011 to 31 December 2013, when the treatment threshold had been expanded to CD4+ ≤ 350 cells/µl. Demographic and clinical factors were compared before and after the policy change using chi-squared tests to identify potentially confounding covariates, and logistic regression models were used to estimate the risk of pre-treatment (pre-ART) loss from care and early loss within the first 16 weeks on treatment, adjusting for age, baseline CD4+, and WHO stage. Compared with participants in the later cohort, participants in the earlier cohort had significantly more advanced disease: median CD4+ 146 cells/µl versus 214 cells/µl (p < 0.001), 61.1% WHO stage 3/4 disease versus 42.8% (p < 0.001), and pre-ART mortality of 34.2% versus 16.7% (p < 0.001). In total, 385 ART-eligible PLWH (9.6%) failed to initiate ART, of whom 25.7% died before ever starting treatment. Of the 3,640 people who started treatment, 58 (1.6%) died within the first 16 weeks in care, and an additional 644 (17.7%) were lost from care within 16 weeks of starting ART. PLWH who did start treatment in the later cohort were significantly more likely to discontinue care in <16 weeks (19.8% versus 15.8%, p = 0.002). After controlling for baseline CD4+, WHO stage, and age, this effect remained significant (adjusted odds ratio [aOR] = 1.30, 95% CI 1.09-1.55). As such, it remains unclear if early attrition from care was due to a "healthy cohort" effect or to overcrowding as programs expanded to accommodate the broader guidelines for treatment. Our findings were limited by a lack of generalizability (given that these data were from a single high-volume site where testing and treatment were available) and an inability to formally investigate the effect of crowding on the main outcome. CONCLUSIONS: Over one-quarter of this ART-eligible cohort did not achieve the long-term benefits of treatment due to early mortality, ART non-initiation, or early ART discontinuation. Those who started treatment in the later cohort appeared to be more likely to discontinue care early, and this outcome appeared to be independent of CD4+ count or WHO stage. Future interventions should focus on those most at risk for early loss from care as programs continue to expand in South Africa.