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1.  Loss to follow-up before and after delivery among women testing HIV-positive during pregnancy in Johannesburg, South Africa 
Objective
HIV-positive pregnant women are at heightened risk of becoming lost to follow-up (LTFU) from HIV care. We examined LTFU before and after delivery among pregnant women newly-diagnosed with HIV.
Methods
Observational cohort study of all pregnant women ≥18 years (N=300) testing HIV-positive for the first time at their first ANC visit between January–June 2010, at a primary healthcare clinic in Johannesburg, South Africa. Women (n=27) whose delivery date could not be determined were excluded.
Results
Median (IQR) gestation at HIV testing was 26 weeks (21–30). 98.0% received AZT prophylaxis, usually started at the first ANC visit. Of 139 (51.3%) patients who were ART-eligible, 66.9% (95%CI 58.8–74.3%) initiated ART prior to delivery; median (IQR) ART duration pre-delivery was 9.5 weeks (5.1–14.2). Among ART-eligible patients, 40.5% (32.3–49.0%) were cumulatively retained through six months on ART. Of those ART-ineligible at HIV testing, only 22.6% (95%CI 15.9–30.6%) completed CD4 staging and returned for a repeat CD4 test after delivery. LTFU (≥1 month late for last scheduled visit) before delivery was 20.5% (95%CI 16.0–25.6%) and, among those still in care, 47.9% (95%CI 41.2–54.6%) within six months after delivery. Overall, 57.5% (95%CI 51.6–63.3%) were lost between HIV testing and six months post-delivery.
Conclusions
Our findings highlight the challenge of continuity of care among HIV-positive pregnant women attending antenatal services, particularly those ineligible for ART.
doi:10.1111/tmi.12072
PMCID: PMC3600093  PMID: 23374278
HIV/AIDS; pregnant; antenatal; loss to follow-up; retention; South Africa
2.  Cohort Profile: The Themba Lethu Clinical Cohort, Johannesburg, South Africa 
The Themba Lethu Clinical Cohort was established in 2004 to allow large patient-level analyses from a single HIV treatment site to evaluate National Treatment Guidelines, answer questions of national and international policy relevance and to combine an economic and epidemiologic focus on HIV research. The current objectives of the Themba Lethu Clinical Cohort analyses are to: (i) provide cohort-level information on the outcomes of HIV treatment; (ii) evaluate aspects of HIV care and treatment that have policy relevance; (iii) evaluate the cost and cost-effectiveness of different approaches to HIV care and treatment; and (iv) provide a platform for studies on improving HIV care and treatment. Since 2004, Themba Lethu Clinic has enrolled approximately 30 000 HIV-positive patients into its HIV care and treatment programme, over 21 000 of whom have received anti-retroviral therapy since being enrolled. Patients on treatment are typically seen at least every 3 months with laboratory monitoring every 6 months to 1 year. The data collected include demographics, clinical visit data, laboratory data, medication history and clinical diagnoses. Requests for collaborations on analyses can be submitted to our data centre.
doi:10.1093/ije/dys029
PMCID: PMC3619949  PMID: 22434860
3.  Poor CD4 recovery and risk of subsequent progression to AIDS or death despite viral suppression in a South African cohort 
Introduction
The prognostic role of CD4 response in the first six months of treatment in patients achieving early viral suppression during HIV treatment is unclear.
Methods
This was a cohort study of HIV-positive adults initiating antiretroviral therapy (ART) between April 2004 and August 2007 who achieved viral suppression (<400 copies/ml) by six months on treatment in South Africa. Immunological response at six months was defined as: (1) absolute CD4 reached (<200 vs. ≥200 cells/ml); (2) absolute CD4 reached (0–49, 50–200 and ≥200 cells/ml); and (3) CD4 increase from ART initiation (<0, 0–49, 50–199 and ≥200 cells/ml). We used Cox regression models to determine the relationship between each definition and both new AIDS-defining condition and death.
Results
A total of 4129 patients were eligible for analysis; 212 (5.1%) of those patients experienced a new AIDS-defining condition and 154 (3.7%) died. Smaller CD4 gains by six months were associated with higher hazards of progression to AIDS (CD4<50 vs. ≥200 cells/ml; adjusted hazard ratio (aHR): 2.6; 95% CI: 1.2–2.1) and death (aHR: 2.8; 95% CI: 1.4–5.7). A decrease in CD4 count since ART initiation through six months (aHR: 2.4; 95% CI: 1.2–4.9) and smaller CD4 count gains (0–49 cells/ml; aHR: 2.0; 95% CI: 1.2–3.4 and 50–199 cells/ml; aHR: 1.5; 95% CI: 0.9–2.2) were also associated with greater risk of progression to AIDS compared to an increase of ≥200 cells/ml. When we examined mortality differences by gender among this virally suppressed cohort, a higher proportion of males died compared to females, 4.7% versus 3.2%, p=0.01. However, in multivariable analysis, we did not observe any significant differences: aHR: 1.39; 95% CI: 0.98–1.95.
Conclusions
Patients on ART with poor CD4 recovery early in treatment are at greater risk of progression to new AIDS diagnosis or death despite viral suppression. Approaches to managing this sub-group of patients need further investigation.
doi:10.7448/IAS.17.1.18651
PMCID: PMC3942566  PMID: 24594114
discordance; immunologic response; CD4 cell count; viral suppression; AIDS; disease progression; antiretroviral therapy
4.  The Feasibility of Using Screening Criteria to Reduce Clinic Visits for Stable Patients on Antiretroviral Therapy in South Africa 
Objective
South African HIV care providers are exploring ways to reduce the intensity of patient visits while maintaining high quality of care. We used routinely collected data to model whether a simple screening tool could identify stable patients who would not need to see a doctor during a scheduled medical visit.
Design
We identified stable and non-stable visits from January 2007 to September 2011 at a large HIV clinic in Johannesburg, SA. Stable medical visits were defined as having all of the following: stable CD4 count, undetectable viral load, stable weight, not pregnant, no comorbidity, no regimen change within three months, and normal lab results for hemoglobin, ALT, and creatinine clearance.
Methods
We assessed the sensitivity and specificity of non-stable visits at predicting indicators of disease progression or needing additional care: a) ART regimen change; and b) follow-up visits in <2 and <4 weeks from previous visit.
Results
Stable visits had a sensitivity of 88.9% (95% CI 88.2–89.7) and a specificity of 44.8% (44.5–44.1) at predicting ART therapy changes, and a sensitivity of 72.6% (71.8–73.4) and specificity of 45.1% (44.8–45.4) for predicting a follow-up visit interval of <2 weeks and similar results for predicting a follow-up visit interval of <4 weeks.
Conclusions
Our retrospective analysis suggests an approach to potentially reduce the number of medical visits while missing few visits in which changes in regimen or additional care would be needed. Evaluation of our criteria in a primary care setting is needed to determine whether they could safely reduce visits.
doi:10.1097/QAI.0b013e318278e976
PMCID: PMC3619021  PMID: 23111577
6.  Patient retention from HIV diagnosis through one year on antiretroviral therapy at a primary healthcare clinic in Johannesburg, South Africa 
Objective
To compare patient retention at three stages of pre-antiretroviral (ART) care and two stages of post-ART care to identify when greatest attrition occurs.
Design
An observational cohort study.
Methods
We reviewed files of all adult, non-pregnant individuals testing HIV-positive January 1 – June 30, 2010, at a primary health clinic in Johannesburg, South Africa (N=842). We classified retention in pre-ART stage 1 (HIV diagnosis to CD4 results notification in ≤3 months), pre-ART stage 2 (initially ineligible for ART with repeat CD4 test ≤1 year of prior CD4), pre-ART stage 3 (initiating ART ≤3 months after first eligible CD4 result), as well as at 0–6 and 6–12 months post-ART.
Results
Retention among all patients during pre-ART stage 1 was 69.8% (95%CI 66.7–72.9%). For patients initially ART-ineligible (n=221), 57.4% (95%CI 49.5–65.0%) returned for a repeat CD4 during pre-ART stage 2. Among those ART-eligible (n=589), 73.5% (95%CI 69.0–77.6%) were retained during pre-ART stage 3. Retention increased with time on ART, from 80.2% (95%CI 75.3–84.5%) at 6 months to 95.3% (95%CI 91.7–97.6%) between 6–12 months. Cumulative retention from diagnosis to 12 months on ART was 36.9% (95%CI 33.0–41.1%) for those ART-eligible and 43.0% (95%CI 36.4–49.8%) from diagnosis to repeat CD4 testing within one year among those ART-ineligible.
Conclusions
Patient attrition in the first year following HIV diagnosis was greatest prior to ART initiation: over 25% at each of three pre-ART stages. As countries expand HIV testing and ART programs, success will depend on linkage to care, especially prior to ART eligibility and initiation.
doi:10.1097/QAI.0b013e318273ac48
PMCID: PMC3548953  PMID: 23011400
HIV/AIDS; antiretroviral therapy (ART); retention; attrition; linkage to care; South Africa
7.  Gender Differences in Mortality and CD4 Count Response Among Virally Suppressed HIV-Positive Patients 
Journal of Women's Health  2013;22(2):113-120.
Abstract
Background
Treatment outcomes for antiretroviral therapy (ART) patients may vary by gender, but estimates from current evidence may be confounded by disease stage and adherence. We investigated the gender differences in treatment response among HIV-positive patients virally suppressed within 6 months of treatment initiation.
Methods
We analyzed data from 7,354 patients initiating ART between April 2004 and April 2010 at Themba Lethu Clinic, a large urban public sector treatment facility in South Africa. We estimated the relations among gender, mortality, and mean CD4 response in HIV-infected adults virally suppressed within 6 months of treatment initiation and used inverse probability of treatment weights to correct estimates for loss to follow-up.
Results
Male patients had a 20% greater risk of death at both 24 months and 36 months of follow-up compared to females. Older patients and those with a low hemoglobin level or low body mass index (BMI) were at increased risk of mortality throughout follow-up. Men gained fewer CD4 cells after treatment initiation than did women. The mean differences in CD4 count gains made by women and men between baseline and 12, 24, and 36 months were 28.2 cells/mm3 (95% confidence interval [CI] 22.2–34.3), 60.8 cells/mm3 (95% CI 71.1-50.5 cells/mm3), and 83.0 cells/mm3 (95% CI 97.1-68.8 cells/mm3), respectively. Additionally, patients with a current detectable viral load (>400 copies/mL) and older patients had a lower mean CD4 increase at the same time points.
Conclusions
In this initially virally suppressed population, women showed consistently better immune response to treatment than did men. Promoting earlier uptake of HIV treatment among men may improve their immunologic outcomes.
doi:10.1089/jwh.2012.3585
PMCID: PMC3579326  PMID: 23350862
8.  Tenofovir use and pregnancy among women initiating HAART 
AIDS (London, England)  2012;26(18):2393-2397.
Objective
Recent studies have raised concerns about a change in rates of pregnancy among HIV-negative women exposed to tenofovir. Here, our objective was to determine among HIV-positive women whether use of tenofovir at HAART initiation or thereafter is associated with subsequent changes in incidence of pregnancy.
Design
Analysis of prospectively collected clinical data.
Methods
We used Cox proportional hazards models and logistic regression to estimate hazard ratios and odds-ratios for the association of baseline tenofovir use and time to first incident pregnancy. We used marginal structural Cox models to estimate hazard ratios for the association of current tenofovir use and time to first incident pregnancy.
Results
We studied 7,275 women, of whom 1,199 were initiated on tenofovir-based HAART regimens, and who experienced a total of 894 pregnancies in 17,200 person-years of follow-up. Analyses showed slight reductions in hazards of pregnancy among women who used tenofovir, but without sufficient precision to draw strong conclusions. Sensitivity analyses confirmed main results.
Conclusions
Tenofovir may be associated with a lower hazard or rate of pregnancy in women receiving HAART. However, conclusions are limited by low precision, the observational nature of the data, and possible uncontrolled confounding by temporal trends in contraception use and other factors.
doi:10.1097/QAD.0b013e328359a95c
PMCID: PMC3725726  PMID: 22951630
9.  Increases in regimen durability associated with the introduction of tenofovir at a large public-sector clinic in Johannesburg, South Africa 
Introduction
In April 2010, tenofovir replaced stavudine in public-sector first-line antiretroviral therapy (ART) in South Africa. The association of tenofovir with fewer side effects and toxicities compared to stavudine could translate to increased durability of tenofovir-based regimens. We evaluated changes over time in regimen durability at the Themba Lethu Clinic, Johannesburg, South Africa.
Methods
This was a cohort analysis of treatment-naïve, non-pregnant adult patients initiated on ART between April 2004 and December 2011. First-line ART regimens before April 2010 consisted of stavudine or zidovudine with lamivudine and either efavirenz or nevirapine. Tenofovir was substituted for stavudine after April 2010. We evaluated the frequency and type of single-drug substitutions (excluding switches to second-line therapy). Cox models were used to evaluate the association of ART initiation year and antiretroviral drug type with single-drug substitutions in the first 12 months on treatment.
Results
One thousand nine hundred and sixty-four (10%) substitutions occurred amongst 19,699 patients. Excluding 2004 (year of treatment roll-out), before 2010 one-year single-drug substitutions ranged from 10.0 to 13.1%. In 2011, well after integration of tenofovir, substitutions decreased to 5.6%. Single-drug substitution was lowest amongst patients on tenofovir (5.1%) versus zidovudine (11.3%), 30 mg stavudine (10.5%) or 40 mg stavudine (14.4%). Adjusted Cox models showed that patients initiating treatment between 2005 and 2010 (vs. 2011) had a twofold increased hazard of single-drug substitution, while those on zidovudine or stavudine had a two to threefold increase in single-drug substitution versus tenofovir patients in the first 12 months on ART.
Conclusions
The decline in single-drug substitutions is associated with the introduction of tenofovir. Tenofovir use could improve regimen durability and treatment outcomes in resource-limited settings.
doi:10.7448/IAS.16.1.18794
PMCID: PMC3835788  PMID: 24256692
antiretroviral therapy; single-drug substitution; resource-limited setting; drug toxicities; drug side effects; regimen durability
10.  Antiretroviral Therapy Initiation during Tuberculosis Treatment and HIV-RNA and CD4-T Lymphocyte Responses 
Setting and Objective
We examined the effect of initiating ART on CD4 and viral response at different time periods during TB therapy (< 14 days; 15–60 days; or ≥60 days) using prospectively collected clinical data from a large HIV clinic in South Africa.
Methods
Cohort data analysis for 1499 TB/HIV co-infected patients classified according to timing of ART after the initiation of TB therapy.
Results
In adjusted modified Poisson regression models, CD4 and viral responses showed no significant differences according to timing of ART initiation (failure to increase CD4 by 6 months, <14 days vs. >60 days: RR 1.02 (95% CI 0.85–1.22), 15–60 days vs. >60 days: RR 1.00 (95% CI 0.86–1.15); failure to suppress virus by 6 months, <14 days vs. >60 days: RR 0.98 (95% CI 0.59–1.63), 15–60 days vs. >60 days: RR 0.96 (95% CI 0.66–1.41) and viral rebound at 12 months, 14 days vs. >60 days: RR 1.43 (95% CI 0.50–4.12), 15–60 days vs. >60 days: RR 1.14 (95% CI 0.39–3.34). Similar estimates were found in analysis restricted to patients with severe immunosuppression.
Conclusion
Concerns over the overlapping impact of TB treatment with ART on ART response should not be a reason to delay ART in patients with HIV-associated TB.
doi:10.5588/ijtld.11.0769
PMCID: PMC3727657  PMID: 22863288
Timing of ART; CD4 response; Viral response; TB–HIV co-infection
11.  Treatment Outcomes after Seven Years of Public-sector HIV treatment at the Themba Lethu Clinic in Johannesburg, South Africa 
AIDS (London, England)  2012;26(14):1823-1828.
Objectives
To assess outcomes over the first seven years of antiretroviral therapy at Themba Lethu Clinic, Johannesburg, South Africa.
Design
Observational cohort study.
Methods
Patients are managed according to South African National Treatment Guidelines. Mortality is ascertained through linkage with the national vital registration system. Loss to follow-up is defined as ≥3 months late for the last scheduled appointment.
Results
Between April 2004 and March 2010, 13,227 patients initiated ART, increasing from 1,794 in the year 2004/5 to 2,481 in 2009/10. Median CD4 at ART initiation increased 39% between 2004 and 2009 (82 vs. 114 cells/mm3). The proportion who died within one year on ART was below 11% at all calendar years, while the proportion lost by one year increased from 8.5% in 2004 to 12.1% in 2009 (RR: 1.42; 95%CI: 1.18-1.71).
We followed the 1,794 patients initiated in April 2004-March 2005 through August, 2011 for 8,172 person-years. We estimated 25% of patients were lost and 16% died. The overall mortality rate was 3.59/100 PY (95%CI: 3.20-4.02). Of the 1,577 who completed ≥6 months of follow up, 213 (13.5%) failed first-line treatment in a median (IQR) of 25.9 (15.8-41.4) months on treatment. Of those who failed, 141 (66.2%) switched to second-line for a rate of 48.5/100 PY (95%CI: 41.1-57.2).
Conclusions
Despite some improvements over seven years, more intervention is needed in the first year on treatment to reduce overall attrition.
doi:10.1097/QAD.0b013e328357058a
PMCID: PMC3600649  PMID: 22739391
antiretroviral therapy; HIV; AIDS; mortality; resource-limited settings; sub-Saharan Africa
12.  Anemia among HIV-Infected Patients Initiating Antiretroviral Therapy in South Africa: Improvement in Hemoglobin regardless of Degree of Immunosuppression and the Initiating ART Regimen 
Journal of Tropical Medicine  2013;2013:162950.
Among those with HIV, anemia is a strong risk factor for disease progression and death independent of CD4 count and viral load. Understanding the role of anemia in HIV treatment is critical to developing strategies to reduce morbidity and mortality. We conducted a prospective analysis among 10,259 HIV-infected adults initiating first-line ART between April 2004 and August 2009 in Johannesburg, South Africa. The prevalence of anemia at ART initiation was 25.8%. Mean hemoglobin increased independent of baseline CD4. Females, lower BMI, WHO stage III/IV, lower CD4 count, and zidovudine use were associated with increased risk of developing anemia during follow-up. After initiation of ART, hemoglobin improved, regardless of regimen type and the degree of immunosuppression. Between 0 and 6 months on ART, the magnitude of hemoglobin increase was linearly related to CD4 count. However, between 6 and 24 months on ART, hemoglobin levels showed a sustained overall increase, the magnitude of which was similar regardless of baseline CD4 level. This increase in hemoglobin was seen even among patients on zidovudine containing regimens. Since low hemoglobin is an established adverse prognostic marker, prompt identification of anemia may result in improved morbidity and mortality of patients initiating ART.
doi:10.1155/2013/162950
PMCID: PMC3771419  PMID: 24069036
13.  Prevalent pregnancy, biological sex, and virologic response to antiretroviral therapy 
Objective
Pregnancy is a common indication for initiation of highly active antiretroviral therapy (HAART) in sub-Saharan Africa. Our objective was to evaluate how pregnancy at treatment initiation predicts virologic response to HAART.
Methods
We evaluated an open cohort of 9,173 patients who initiated HAART between April 2004 and September 2009 in the Themba Lethu Clinic in Johannesburg, South Africa. Risk ratios were estimated using log-binomial regression; hazard ratios were estimated using Cox proportional hazards models; time ratios were estimated using accelerated failure time models. We controlled for calendar date, age, ethnicity, employment status, history of smoking, tuberculosis, WHO stage, weight, body mass index, hemoglobin, CD4 count and CD4 percent, and whether clinical care was free. Extensive sensitivity and secondary analyses were performed.
Results
During follow-up, 822 non-pregnant women and 70 pregnant women experienced virologic failure. In adjusted analyses, pregnancy at baseline was associated with reduced risk of virologic failure by six months (risk ratio 0.66, 95% confidence limits [CL] 0.35, 1.22) and with reduced hazard of virologic failure over follow-up (hazard ratio 0.69, 95% CL 0.50, 0.95). The adjusted time ratio for failure was 1.44 (95% CL 1.13, 1.84), indicating 44% longer time to event among women pregnant at baseline. Sensitivity analyses generally confirmed main findings.
Conclusion
Pregnancy at HAART initiation is not associated with increased risk of virologic failure at six months or during longer follow-up.
doi:10.1097/QAI.0b013e318256b310
PMCID: PMC3404188  PMID: 22487586
Pregnancy; HIV; highly active antiretroviral therapy (HAART); South Africa
14.  The Impact of Choice of NNRTI on Short-Term Treatment Outcomes among HIV-Infected Patients Prescribed Tenofovir and Lamivudine in Johannesburg, South Africa 
PLoS ONE  2013;8(8):e71719.
Introduction
Recent WHO guidelines for resource-limited settings recommend tenofovir in first-line antiretroviral therapy (ART) yet there are suggestions that patients receiving nevirapine with tenofovir have worse outcomes than those receiving efavirenz. We sought to compare outcomes among those taking nevirapine vs. efavirenz with tenofovir and lamivudine.
Methods
We analyzed data on ART naïve, non-pregnant patients, ≥18 years old without tuberculosis co-infection, initiating tenofovir with lamivudine and either nevirapine or efavirenz between April 1, 2010 and July 31, 2011 (when South Africa’s public-sector use of tenofovir began) at Themba Lethu Clinic in South Africa. We measured virologic suppression (viral load <400 copies/ml), virologic failure (2 consecutive viral loads >1000 copies/ml), and attrition (death/loss to follow-up) all at 12 months after ART initiation. Modified Poisson regression with robust error estimation was used to estimate risk ratios (RR) and 95% confidence intervals (CI) for predictors of each outcome.
Results
2,254 patients were prescribed efavirenz, 131 nevirapine. Patients were followed a median (range) of 12.0 (0.1–12.0) person-months. 62.2% were female and median (IQR) age was 37.7 years (31.5–44.1). Patients prescribed efavirenz had similar initiating CD4 counts (median 132 for both regimens) but were somewhat more likely to be WHO Stage III or IV (39.6% vs. 33.6%) than those prescribed nevirapine. No difference in attrition was found (aRR: 0.83; 95% CI: 0.49–1.41). Among patients with ≥1 viral load within 1 year on ART, those prescribed nevirapine were as likely to reach virologic suppression (aRR: 0.97; 95% CI: 0.88–1.07) but more likely to experience virologic failure (aRR: 1.84; 95% CI: 1.02–3.31) than those prescribed efavirenz.
Conclusions
Our results support the notion that, among patients prescribed tenofovir and lamivudine, virologic failure is more common among those taking nevirapine than among those taking efavirenz. Longer-term follow up and larger studies will be needed to confirm this finding.
doi:10.1371/journal.pone.0071719
PMCID: PMC3737125  PMID: 23940782
15.  Impact of nutritional supplementation on immune response, body mass index and bioelectrical impedance in HIV-positive patients starting antiretroviral therapy 
Nutrition Journal  2013;12:111.
Background
Challenges to HIV care in resource limited settings (RLS) include malnutrition. Limited evidence supports the benefit of nutritional supplementation when starting antiretroviral therapy (ART) in RLS.
Methods
Randomized controlled pilot study. HIV-positive ART-naive adults with self-reported weight loss were randomized to receive ART plus FutureLife porridge® nutritional supplement (NS) (388 kcal/day) or ART alone (Controls) for 6 months. Patients returned for monthly assessments and blood was drawn at enrolment and 6 months on ART. Differences in body composition, biochemical and laboratory parameters were estimated at 6 months on treatment.
Results
Of the 36 randomized patients, 26 completed the 6 month follow-up (11 NS vs 15 Controls). At enrolment, groups were similar in terms of age, gender, body mass index (BMI) and bioelectrical impedance. NS patients had a lower median CD4 count (60 cells/mm3 [IQR 12–105 vs 107 cells/mm3 [IQR 63–165]; p = 0.149) and hemoglobin (10.3 g/dL [IQR 9.0-11.3] vs 13.1 g/dL [IQR 11.1-14.7]; p = 0.001).
At 6 months, NS patients increased their median CD4 count by 151 cells/mm3 [IQR 120–174) vs 77 cells/mm3 [IQR 33–145] in the Controls. NS patients had higher mean percentage change in body weight (12.7% vs 4.9%; p = 0.047), BMI (7.8% vs 5.5%; p = 0.007), absolute CD4 count (83.0% vs 46.4%, p = 0.002) and hemoglobin (9.5% vs 1.0%; p = 0.026). Patients in the NS arm had a higher mean percentage fat-free mass (16.7% vs −3.5%, p = 0.036), total body water (13.0% vs −1.9%, p = 0.026), intracellular water (16.1% vs −4.1%, p = 0.010) and basal metabolic rate (5.3% vs −0.2%, p = 0.014) compared to Controls. Patients in the NS arm also showed an improvement in physical activity at 6 months post-ART initiation compared to Controls (p = 0.037).
Conclusion
Preliminary results are encouraging and suggest that NS taken concurrently with ART can promote weight gain, improve immune response and improve physical activity in HIV-positive patients that present at ART initiation with weight loss.
doi:10.1186/1475-2891-12-111
PMCID: PMC3750332  PMID: 23919622
Nutritional supplement; Antiretroviral therapy; Human immunodeficiency virus; Treatment outcomes
16.  Rates and Predictors of Failure of First-line Antiretroviral Therapy and Switch to Second-line ART in South Africa 
Objectives
To measure rates and predictors of virologic failure and switch to second-line ART in South Africa.
Design
Observational cohort study
Methods
We included ART-naïve adult patients initiated on public-sector ART (Jan 2000–July 2008) at five sites in South Africa who completed ≥6 months of follow-up. We estimated cumulative risk of virologic failure (viral load ≥400 copies/ml with confirmation above varying thresholds) and switching to second-line ART.
Results
19,645 patients (29,935 person-years) had a median of 1.3 years of study follow-up (1.8 years on ART) and a median CD4 count of 96 (IQR:40–159) cells/μl at ART initiation. 9.9% (4.5/100 person-years) failed ART in median 16 (IQR:12–23) months since ART initiation, with median 2.9 (IQR:1.8–5.0) months between first elevated and confirmatory viral loads. By survival analysis, using a confirmatory threshold of 400 copies/ml, 16.9% (95%CI:15.4–18.6%) failed by five years on ART, but only 7.8% (95%CI:6.6%-9.3%) using a threshold of 10,000. CD4 <25 vs. 100–199 (adjusted HR:1.57;95%CI 1.35–1.83), ART initiation viral load ≥1,000,000 vs. <10,000, (1.32;0.91–1.93) and 2+ gaps in care vs. 0 (95%CI:6.61; 4.52–9.68) were predictive of failure. Overall 10.1% (95%CI:9.0%-11.4%) switched to second-line by five years on ART. Lower CD4 at failure and higher rate of CD4 decline were predictive of switch (decline 100% to 51% vs. 25% to −25%, adjusted HR:1.96;95%CI:1.35–2.85).
Conclusions
In resource-limited settings with viral load monitoring, virologic failure rates are highly sensitive to thresholds for confirmation. Despite clear guidelines there is considerable variability in switching failing patients, partially in response to immunologic status and post-failure evolution.
doi:10.1097/QAI.0b013e3182557785
PMCID: PMC3392418  PMID: 22433846
HIV; AIDS; antiretroviral therapy; viral load; virologic treatment failure; second line
17.  Treatment Response and Mortality among Patients Starting Antiretroviral Therapy with and without Kaposi Sarcoma: A Cohort Study 
PLoS ONE  2013;8(6):e64392.
Background
Improved survival among HIV-infected individuals on antiretroviral therapy (ART) has focused attention on AIDS-related cancers including Kaposi sarcoma (KS). However, the effect of KS on response to ART is not well-described in Southern Africa. We assessed the effect of KS on survival and immunologic and virologic treatment responses at 6- and 12-months after initiation of ART.
Methods
We analyzed prospectively collected data from a cohort of HIV-infected adults initiating ART in South Africa. Differences in mortality between those with and without KS at ART initiation were estimated with Cox proportional hazard models. Log-binomial models were used to assess differences in CD4 count response and HIV virologic suppression within a year of initiating treatment.
Results
Between January 2001–January 2008, 13,847 HIV-infected adults initiated ART at the study clinics. Those with KS at ART initiation (n = 247, 2%) were similar to those without KS (n = 13600,98%) with respect to age (35 vs. 35yrs), presenting CD4 count (74 vs. 85cells/mm3) and proportion on TB treatment (37% vs. 30%). In models adjusted for sex, baseline CD4 count, age, treatment site, tuberculosis and year of ART initiation, KS patients were over three times more likely to have died at any time after ART initiation (hazard ratio[HR]: 3.62; 95% CI: 2.71–4.84) than those without KS. The increased risk was highest within the first year on ART (HR: 4.05; 95% CI: 2.95–5.55) and attenuated thereafter (HR: 2.30; 95% CI: 1.08–4.89). Those with KS also gained, on average, 29 fewer CD4 cells (95% CI: 7–52cells/mm3) and were less likely to increase their CD4 count by 50 cells from baseline (RR: 1.43; 95% CI: 0.99–2.06) within the first 6-months of treatment.
Conclusions
HIV-infected adults presenting with KS have increased risk of mortality even after initiation of ART with the greatest risk in the first year. Among those who survive the first year on therapy, subjects with KS demonstrated a poorer immunologic response to ART than those without KS.
doi:10.1371/journal.pone.0064392
PMCID: PMC3673971  PMID: 23755122
18.  Outcomes of stable HIV-positive patients down-referred from doctor-managed ART clinics to nurse-managed primary health clinics for monitoring and treatment 
AIDS (London, England)  2011;25(16):10.1097/QAD.0b013e32834b6480.
Objective
Compare clinical, immunologic and virologic outcomes amongst stable HIV-positive patients down-referred (DR) to nurse-managed primary health care clinic (PHC) for treatment maintenance to those who remained at the doctor-managed treatment-initiation site (TI).
Design
We conducted a matched cohort analysis amongst stable HIV patients at the Themba Lethu Clinic, in Johannesburg, South Africa. Eligible patients met the criteria for down-referral (undetectable viral load <10-months, ART >11-months, CD4 ≥200cells/mm3, stable weight and no opportunistic infections) regardless of whether they were down-referred to a PHC for treatment maintenance between February 2008-January 2009. Patients were matched 1:3 (DR:TI) using propensity scores.
Methods
We calculated rates and hazard ratios for the effect of down-referral on loss to follow-up (LTFU) and mortality and the relative risk of down-referral on viral rebound by 12-months of follow-up.
Results
693 DR patients were matched to 2079 TI patients. Two (0.3%) DR and 32 (1.5%) TI patients died, 10 (1.4%) DR and 87 (4.2%) TI were lost, while 22 (3.3%) DR and 100 (5.6%) TI experience viral rebound by 12-months of follow-up. After adjustment, patients down-referred were less likely to die (HR 0.2; 95%CI: 0.04-0.8), become LTFU (HR 0.3; 95%CI: 0.2-0.6) or experience viral rebound (RR 0.6; 95%CI 0.4-0.9) than TI patients during follow-up.
Conclusions
The utilization of nurse-managed PHCs for treatment maintenance of stable patients could decrease the burden on specialized doctor-managed ART clinics. Patient outcomes for DR patients at PHCs appear equal, if not better, than those achieved at ART clinics amongst stable patients.
doi:10.1097/QAD.0b013e32834b6480
PMCID: PMC3669640  PMID: 21997488
antiretroviral therapy; task-shifting; nurse-managed vs. doctor-managed care; mortality; loss to follow-up; resource-limited setting; scaling-up
19.  Prevalent tuberculosis and mortality among HAART initiators 
AIDS (London, England)  2012;26(6):770-773.
The effect of tuberculosis on mortality in people initiating highly active antiretroviral treatment (HAART) remains unclear; here, we strengthened a previous cohort analysis. Multivariate Cox proportional hazards models were used to assess the association of baseline tuberculosis and time to all-cause mortality among HAART initiators. In reanalysis, treatment for tuberculosis at time of HAART initiation remained unassociated with increased risks of all-cause mortality, with adjusted hazard ratios ranging from 1.00 to 1.09.
doi:10.1097/QAD.0b013e328351f6b8
PMCID: PMC3348652  PMID: 22313956
20.  Outcomes of Antiretroviral Treatment in Programmes with and without Routine Viral Load Monitoring in Southern Africa 
AIDS (London, England)  2011;25(14):1761-1769.
Objectives
To compare outcomes of antiretroviral therapy (ART) in South Africa, where viral load monitoring is routine, with Malawi and Zambia, where monitoring is based on CD4 cell counts.
Methods
We included 18,706 adult patients starting ART in South Africa and 80,937 patients starting in Zambia or Malawi. We examined CD4 responses in models for repeated measures, and the probability of switching to second-line regimens, mortality and loss to follow-up in multi-state models, measuring time from six months.
Findings
In South Africa 9.8% (9.1–10.5%) had switched at 3 years, 1.3% (95% CI 0.9–1.6%) remained on failing first-line regimens, 9.2% (8.5–9.8%) were lost to follow-up and 4.3% (3.9–4.8%) had died. In Malawi and Zambia more patients were on a failing first-line regimen (3.7%, 3.6–3.9%), fewer patients had switched (2.1%, 2.0–2.3%) and more patients were lost (15.3%, 15.0–15.6%) or had died (6.3%, 6.0–6.5%). Median CD4 cell counts were lower in South Africa at start of ART (93 vs. 132 cells/µL, p<0.001) but higher after 3 years (425 vs. 383 cells/µL, p<0.001). The hazard ratio comparing South Africa with Malawi and Zambia, adjusted for age, sex, first-line regimen and CD4 cell count, was 0.58 (95% CI 0.50–0.66) for death and 0.53 (0.48–0.58) for loss to follow-up.
Conclusions
Over 3 years of ART mortality was lower in South Africa than in Malawi or Zambia. The more favourable outcome in South Africa might be explained by viral load monitoring leading to earlier detection of treatment failure, adherence counselling and timelier switching to second-line ART.
doi:10.1097/QAD.0b013e328349822f
PMCID: PMC3605707  PMID: 21681057
21.  Incident Pregnancy and Time to Death or AIDS among HIV-Positive Women Receiving Antiretroviral Therapy 
PLoS ONE  2013;8(3):e58117.
Background
Little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in sub-Saharan Africa. We examined the effect of incident pregnancy after HAART initiation on clinical response to HAART.
Methods
We evaluated a prospective clinical cohort of adult women initiating HAART in Johannesburg, South Africa between 1 April 2004 and 31 March 2011, and followed up until an event, transfer, drop-out, or administrative end of follow-up on 30 September 2011. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study. Main exposure was having experienced pregnancy after HAART initiation; main outcome was death and (separately) death or new AIDS event. We calculated adjusted hazard ratios (HRs) and 95% confidence limits (CL) using marginal structural Cox proportional hazards models.
Results
The study included 7,534 women, and 20,813 person-years of follow-up; 918 women had at least one recognized pregnancy during follow-up. For death alone, the weighted (adjusted) HR was 0.84 (95% CL 0.44, 1.60). Sensitivity analyses confirmed main results, and results were similar for analysis of death or new AIDS event. Incident pregnancy was associated with a substantially reduced hazard of drop-out (HR = 0.62, 95% CL 0.51, 0.75).
Conclusions
Recognized incident pregnancy after HAART initiation was not associated with increases in hazard of clinical events, but was associated with a decreased hazard of drop-out. High rates of pregnancy after initiation of HAART may point to a need to better integrate family planning services into clinical care for HIV-infected women.
doi:10.1371/journal.pone.0058117
PMCID: PMC3592862  PMID: 23520489
22.  Relationship between Renal Dysfunction, Nephrotoxicity and Death among HIV Adults on Tenofovir 
AIDS (London, England)  2011;25(13):1603-1609.
Objective
In April 2010 the South African government added Tenofovir disoproxil fumarate to its first-line antiretroviral therapy (ART) for HIV patients. We analyzed the relationship between renal dysfunction at tenofovir initiation, nephrotoxicity and mortality.
Design
Retrospective cohort analysis of HIV-infected adults who received tenofovir and had a creatinine clearance done at initiation at the Themba Lethu Clinic, Johannesburg, South Africa between April 2004-September 2009.
Methods
We estimated the relationship between renal dysfunction, nephrotoxicity [any decline in kidney function from baseline (acute or chronic) that is secondary to a toxin (including drugs)] and mortality for patients initiated on tenofovir-containing regimens using marginal structural models and inverse probability of treatment weights to correct estimates for lost to follow-up and confounding.
Results
Of 890 patients initiated on tenofovir, 573 (64.4%) had normal renal function (>90ml/min), 271 (30.4%) had mild renal dysfunction (60-89ml/min) and 46 (5.2%) had moderate renal dysfunction (30-59ml/min). 2.4% experienced nephrotoxicity, 7.8% died and 9.7% were lost during 48-months of follow-up. Patients with mild (HR 4.8; 95%CI: 1.5-15.2) or moderate (HR 15.0; 95%CI: 3.4-66.5) renal dysfunction were at greatest risk of nephrotoxicty, while those with mild (HR 1.2; 95%CI: 0.7-2.3) or moderate (HR 3.2; 95%CI: 1.3-7.8) renal dysfunction vs. normal renal function were at highest risk of death by 48-months.
Conclusion
Much of the incident renal dysfunction in tenofovir patients is likely related to pre-existing renal pathology, which may be exacerbated by tenofovir. With expanded use of tenofovir, screening for renal dysfunction prior to initiation and dose adjustment is necessary to help improve ART outcomes.
doi:10.1097/QAD.0b013e32834957da
PMCID: PMC3586413  PMID: 21646902
nephrotoxicity; mortality; lost to follow-up; tenofovir; creatinine clearance; resource-limited setting
23.  Increased risk of mortality and loss to follow-up among HIV-positive patients with oropharyngeal candidiasis and malnutrition prior to ART initiation – A retrospective analysis from a large urban cohort in Johannesburg, South Africa 
Objective
We investigated the effect of oropharyngeal candidiasis (OC) and body mass index (BMI) prior to ART initiation on treatment outcomes of HIV-positive patients.
Methods
Treatment outcomes included failure to increase CD4 count by ≥50 or ≥100cells/mm3 or failure to suppress viral load (<400copies/ml) at 6- or 12-months in addition to loss to follow-up (LTFU) and mortality by 12-months. Risk and hazard ratios were estimated using log-binomial regression and Cox proportional hazards models, respectively.
Results
Baseline CD4 <100cells/mm3, low BMI (<18.5 kg/m2), low hemoglobin and elevated aspartate transaminase were associated with OC at ART initiation. Patients with low BMI with/without OC were at risk of mortality (Hazard Ratio (HR)2.42 95%CI 1.88–3.12; HR1.87 95% CI 1.54-2.28) and LTFU (HR1.36 95%CI 1.02–1.82; HR1.55 95% CI 1.30-1.85).
Conclusion
Low BMI (with/without OC) at ART initiation was associated with poor treatment outcomes. Conversely, normal BMI with OC was associated with adequate CD4 response and reduced LTFU compared to without OC.
doi:10.1016/j.oooo.2011.09.004
PMCID: PMC3370659  PMID: 22669142
antiretroviral therapy; body mass index; Candida; mortality; oral thrush; resource-limited setting (RLS)
24.  Poorer ART Outcomes with Increasing Age at a Large Public Sector HIV Clinic in Johannesburg, South Africa 
Background
As the current HIV-positive population ages, the absolute number of patients >50 years on treatment is increasing.
Methods
We analyse differences in treatment outcomes by age category (18-29, 30-39, 40-49, 50-59 and ≥60) among 9139 HIV-positive adults initiating ART in South Africa.
Results
The adjusted hazard ratios for all-cause mortality increased with increasing age, with the strongest association in the first 12-months of follow-up amongst 50-59 (HR 1.67; 95% CI: 1.24-2.23) vs. those <30. However, patients 50-59 years were less likely to be lost during 24-months on ART (HR 0.75; 95% CI: 0.59-0.94) vs. <30. By 6- and 12-months on treatment, older patients were less likely to increase their CD4 count by ≥50 cells/mm3.
Conclusion
While older patients are at higher risk of mortality and have poorer immunological responses than their younger counterparts, they are more likely to adhere to care and treatment in the first 24-months on ART.
doi:10.1177/1545109711421641
PMCID: PMC3272319  PMID: 21951728
HIV; age; antiretroviral; mortality; treatment response; loss to follow-up
25.  Gender Differences in Survival among Adult Patients Starting Antiretroviral Therapy in South Africa: A Multicentre Cohort Study 
PLoS Medicine  2012;9(9):e1001304.
Morna Cornell and colleagues investigate differences in mortality for HIV-positive men and women on antiretroviral therapy in South Africa.
Background
Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART.
Methods and Findings
Analyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population.
Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22–1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12–1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86–1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located.
Conclusions
HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
About 34 million people (most living in low- and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of becoming infected. Then, in 1996, antiretroviral therapy (ART)—cocktails of drugs that keep HIV in check—became available. For people living in affluent countries, HIV/AIDS became a chronic condition. However, ART was expensive and, for people living in poorer countries, HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global emergency, and governments and international agencies began to implement plans to increase ART coverage in resource-limited countries. Since then, ART programs in these countries have grown rapidly. In South Africa, for example, about 52% of the 3.14 million adults in need of ART were receiving an ART regimen recommended by the World Health Organization by the end of 2010.
Why Was This Study Done?
The outcomes of ART programs in resource-limited countries need to be evaluated thoroughly so that these programs can be optimized. One area of concern to ART providers is that of gender differences in survival among patients receiving treatment. In sub-Saharan Africa, for example, men are more likely to die than women while receiving ART. This gender difference in mortality may arise because men initiating ART in many African ART programs have more advanced HIV disease than women (early ART initiation is associated with better outcomes than late initiation) or because men are more likely to be lost to follow-up than women (failure to continue treatment is associated with death). Other possible explanations for gender differentials in mortality on ART include gender differences in immunologic and virologic responses to treatment (increased numbers of immune system cells and reduced amounts of virus in the blood, respectively). In this multicenter cohort study, the researchers examine the size of, and risk factors for, gender differences in mortality on ART in South Africa by examining data collected from adults starting ART at International Epidemiologic Databases to Evaluate AIDS South Africa (IeDEA-SA) collaboration sites.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 46,201 ART-naïve adults who started ART between 2002 and 2009 in eight IeDEA-SA ART programs. At ART initiation, men had a lower CD4 count on average and were more likely to have advanced HIV disease than women. During the study, after allowing for factors likely to affect mortality such as HIV disease stage at initiation, men on ART had a 31% higher risk of dying than women. Men were more likely to be lost to follow-up than women, but men and women who were lost to follow-up were equally likely to die. Women had a slightly better immunological response to ART than men but virologic suppression was similar in both genders. Importantly, in analyses of mortality limited to individuals who were virologically suppressed at 12 months and to patients who had a good immunological response to ART, men still had a higher risk of death than women. However, the gender differences in mortality on ART were smaller than the gender differences in age-standardized mortality in the HIV-negative South African population.
What Do These Findings Mean?
These analyses show that among South African patients initiating ART between 2002 and 2009, men were more likely to die than women but that this gender difference in mortality on ART cannot be completely explained by gender differences in baseline characteristics, loss to follow-up, or virologic and/or immunologic responses. Instead, the observed gender differences in mortality can best be explained by background gender differences in mortality in the whole South African population. Because substantial amounts of data were missing in this study (for example, HIV disease stage was not available for all the patients), these findings need to be interpreted cautiously. Moreover, similar studies need to be done in other settings to investigate whether they are generalizable to the South African national ART program and to other countries. If confirmed, however, these findings suggest that the root causes of gender differences in mortality on ART may be unrelated to HIV/AIDS or to the characteristics of ART programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001304.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information on the treatment of HIV/AIDS in South Africa is available from the Southern African HIV Clinicians Society
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care, and on HIV/AIDS in South Africa (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in several languages); its 2010 ART guidelines can be downloaded
Information about the IeDEA-SA collaboration is available
The Treatment Action Campaign provides information on antiretroviral therapy and South African HIV statistics
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs
doi:10.1371/journal.pmed.1001304
PMCID: PMC3433409  PMID: 22973181

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