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1.  The relation between efavirenz versus nevirapine and virologic failure in Johannesburg, South Africa 
Introduction
Previous research has raised concerns that patients given nevirapine (NVP)-based regimens experience more virologic failure than patients given efavirenz (EFV)-based regimens. We investigated this hypothesis in a cohort of HIV-positive patients at a large HIV treatment clinic in South Africa.
Methods
All antiretroviral therapy (ART)-naïve non-pregnant patients, ≥18 years old, without tuberculosis, who initiated treatment with either NVP or EFV from April 2004 to August 2011 at the Themba Lethu Clinic in Johannesburg, South Africa, were included. Log-binomial regression and modified Poisson regression were used to estimate risk ratios (RR) with 95% confidence intervals (CI) for predictors of virologic failure, virologic suppression, and loss to follow-up (LTF), whereas a Cox proportional hazards model was used to estimate the risk of death, all within one year.
Results
Of 12,840 included patients, 62.0% were female and the median baseline CD4 count was 98 cells/mm3 (36–169). Of these patients, 93.2% initiated an EFV-based regimen. After adjusting for baseline characteristics, no difference in death (adjusted Hazards Ratio (aHR): 0.92; 95% CI: 0.68–1.25), LTF (adjusted Risk Ratio (aRR): 1.00; 95% CI: 0.79–1.25), nor suppression (aRR: 0.98; 95% CI: 0.95–1.00) at one year was found between regimens. Among patients with ≥1 viral load ≥4 months after ART initiation, 4% (n=350) experienced virologic failure within 12 months of initiation. Patients initiating NVP-based regimens were 60% more likely to fail than patients initiating EFV-based regimens (aRR: 1.58; 95% CI: 1.13–2.22).
Conclusions
In this cohort, patients initiating NVP-based regimens experienced more virologic failure than patients initiating EFV-based regimens. Future guidelines should consider the implications of different efficacy profiles when making recommendations for which drugs to prioritize.
doi:10.7448/IAS.17.1.19065
PMCID: PMC4215701  PMID: 25361827
nevirapine; efavirenz; virologic failure; viral suppression; mortality; loss to follow-up; resource-limited settings
2.  Attrition through Multiple Stages of Pre-Treatment and ART HIV Care in South Africa 
PLoS ONE  2014;9(10):e110252.
Introduction
While momentum for increasing treatment thresholds is growing, if patients cannot be retained in HIV care from the time of testing positive through long-term adherence to antiretroviral therapy (ART), such strategies may fall short of expected gains. While estimates of retention on ART exist, few cohorts have data on retention from testing positive through long-term ART care.
Methods
We explored attrition (loss or death) at the Themba Lethu HIV clinic, Johannesburg, South Africa in 3 distinct cohorts enrolled at HIV testing, pre-ART initiation, and ART initiation.
Results
Between March 2010 and August 2012 we enrolled 380 patients testing HIV+, 206 initiating pre-ART care, and 185 initiating ART. Of the 380 patients enrolled at testing HIV-positive, 38.7% (95%CI: 33.9–43.7%) returned for eligibility staging within ≤3 months of testing. Of the 206 enrolled at pre-ART care, 84.5% (95%CI: 79.0–88.9%) were ART eligible at their first CD4 count. Of those, 87.9% (95%CI: 82.4–92.2%) initiated ART within 6 months. Among patients not ART eligible at their first CD4 count, 50.0% (95%CI: 33.1–66.9%) repeated their CD4 count within one year of the first ineligible CD4. Among the 185 patients in the ART cohort, 22 transferred out and were excluded from further analysis. Of the remaining 163, 81.0% (95%CI: 74.4–86.5%) were retained in care through two years on treatment.
Conclusions
Our findings from a well-resourced clinic demonstrate continual loss from all stages of HIV care and strategies to reduce attrition from all stages of care are urgently needed.
doi:10.1371/journal.pone.0110252
PMCID: PMC4203772  PMID: 25330087
3.  CD4 criteria improves the sensitivity of a clinical algorithm developed to identify viral failure in HIV-positive patients on antiretroviral therapy 
Introduction
Several studies from resource-limited settings have demonstrated that clinical and immunologic criteria are poor predictors of virologic failure, confirming the need for viral load monitoring or at least an algorithm to target viral load testing. We used data from an electronic patient management system to develop an algorithm to identify patients at risk of viral failure using a combination of accessible and inexpensive markers.
Methods
We analyzed data from HIV-positive adults initiated on antiretroviral therapy (ART) in Johannesburg, South Africa, between April 2004 and February 2010. Viral failure was defined as ≥2 consecutive HIV-RNA viral loads >400 copies/ml following suppression ≤400 copies/ml. We used Cox-proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI). Weights for each predictor associated with virologic failure were created as the sum of the natural logarithm of the adjusted HR and dichotomized with the optimal cut-off at the point with the highest sensitivity and specificity (i.e. ≤4 vs. >4). We assessed the diagnostic accuracy of predictor scores cut-offs, with and without CD4 criteria (CD4 <100 cells/mm3; CD4 < baseline; >30% drop in CD4), by calculating the proportion with the outcome and the observed sensitivity, specificity, positive and negative predictive value of the predictor score compared to the gold standard of virologic failure.
Results
We matched 919 patients with virologic failure (1:3) to 2756 patients without. Our predictor score included variables at ART initiation (i.e. gender, age, CD4 count <100 cells/mm3, WHO stage III/IV and albumin) and laboratory and clinical follow-up data (drop in haemoglobin, mean cell volume (MCV) <100 fl, CD4 count <200 cells/mm3, new or recurrent WHO stage III/IV condition, diagnosis of new condition or symptom and regimen change). Overall, 51.4% had a score 51.4% had a score ≥4 and 48.6% had a score <4. A predictor score including CD4 criteria performed better than a score without CD4 criteria and better than WHO clinico-immunological criteria or WHO clinical staging to predict virologic failure (sensitivity 57.1% vs. 40.9%, 25.2% and 20.9%, respectively).
Conclusions
Predictor scores or risk categories, with CD4 criteria, could be used to identify patients at risk of virologic failure in resource-limited settings so that these patients may be targeted for focused interventions to improve HIV treatment outcomes.
doi:10.7448/IAS.17.1.19139
PMCID: PMC4165719  PMID: 25227265
antiretroviral therapy; viral load; resource limited; monitoring; algorithm; HIV; CD4
4.  AZT Impairs Immunological Recovery on First-line ART: Collaborative analysis of cohort studies in Southern Africa 
AIDS (London, England)  2013;27(14):10.1097/QAD.0b013e328362d887.
Objectives
Zidovudine (AZT) is recommended for first-line antiretroviral therapy (ART) in resource limited settings. AZT may, however, lead to anemia and impaired immunological response. We compared CD4 counts over 5 years between patients starting ART with and without AZT in Southern Africa.
Design
Cohort study
Methods
Patients aged ≥16 years who started first-line ART in South Africa, Botswana, Zambia or Lesotho were included. We used linear mixed-effect models to compare CD4 cell count trajectories between patients on AZT-containing regimens and patients on other regimens, censoring follow-up at first treatment change. Impaired immunological recovery, defined as a CD4 count below 100 cells/μl at 1 year, was assessed in logistic regression. Analyses were adjusted for baseline CD4 count and haemoglobin level, age, gender, type of regimen, viral load monitoring and calendar year.
Results
72,597 patients starting ART, including 19,758 (27.2%) on AZT, were analysed. Patients on AZT had higher CD4 cell counts (150 vs.128 cells/μl) and haemoglobin level (12.0 vs. 11.0 g/dl) at baseline, and were less likely to be female than those on other regimens. Adjusted differences in CD4 counts between regimens containing and not containing AZT were −16 cells/μl (95% CI −18 to −14) at 1 year and −56 cells/μl (95% CI −59 to −52) at 5 years. Impaired immunological recovery was more likely with AZT compared to other regimens (odds ratio 1.40, 95% CI 1.22–1.61).
Conclusions
In Southern Africa AZT is associated with inferior immunological recovery compared to other backbones. Replacing AZT with another NRTI could avoid unnecessary switches to second-line ART.
doi:10.1097/QAD.0b013e328362d887
PMCID: PMC3815688  PMID: 23660577
zidovudine; immunological recovery; southern Africa; Cohort study; first-line ART
5.  Kaposi sarcoma-associated herpesvirus and response to antiretroviral therapy: A prospective study of HIV-infected adults 
Background
The possible impact of co-infection with Kaposi’s sarcoma associated herpes virus on the response to antiretroviral therapy (ART) is unknown. Prospective studies are rare, particularly in Africa.
Methods
We enrolled a prospective cohort of HIV-infected adults initiating ART in Johannesburg, South Africa. Subjects were defined as seropositive to KSHV if reactive to either KSHV lytic K8.1 or latent Orf73 antigen or both. Subjects were followed from ART initiation until 18-months on treatment. HIV viral load and CD4 counts were tested 6 monthly. Linear generalized estimating and log-binomial regression models were used to estimate the effect of KSHV infection on immunologic recovery and response as well as HIV viral load suppression within 18-months after ART initiation.
Results
385 subjects initiating ART from November 2008-March 2009 were eligible including 184 (48%) KSHV+. The KSHV+ group was similar to the KSHV− in terms of age, gender, initiating CD4 count, body mass index, tuberculosis and haemoglobin levels. The KSHV+ group gained a similar number of cells at 6- (difference of 10 cells/mm3, 95% CI: −11–31), 12- (3 cells/mm3, 95% CI: −19–25) and 18-months (24 cells/mm3, 95% CI: −13–61) compared to the KSHV− group. Adjusted relative risk of failure to suppress viral load to <400 copies/mL (1.03; 95% CI: 0.90–1.17) were similar for KSHV+ and KSHV− by 6-months on treatment.
Conclusions
In a population with a high KSHV prevalence, HIV-positive adults co-infected with KSHV achieved similar immunologic and virologic responses to ART early after treatment initiation compared to those KSHV−.
doi:10.1097/QAI.0b013e3182969cc1
PMCID: PMC3712196  PMID: 23614996
Kaposi sarcoma herpesvirus; antiretroviral therapy; resource-poor setting; virologic suppression
6.  Treatment Outcomes of HIV-Infected Adolescents Attending Public-Sector HIV Clinics Across Gauteng and Mpumalanga, South Africa 
Abstract
There is little evidence comparing treatment outcomes between adolescents and other age groups, particularly in resource-limited settings. A retrospective analysis of data from seven HIV clinics across urban Gauteng (n=5) and rural Mpumalanga (n=2), South Africa was conducted. The analysis compared HIV-positive antiretroviral treatment (ART)-naive young adolescents (10–14 years), older adolescents (15–19), and young adults (20–24 years) to adults (≥25 years) initiated onto standard first-line ART between April 2004 and August 2010. Log-binomial regression was used to estimate relative risk (RR) of failure to suppress viral load (≥400 copies/ml) or failure to achieve an adequate CD4 response at 6 or 12 months. The effect of age group on virological failure, mortality, and loss to follow-up (LTFU; ≥90 days since scheduled visit date) was estimated using Cox proportional hazards models. Of 42,427 patients initiating ART, 310 (0.7%) were young adolescents, 342 (0.8%) were older adolescents, and 1599 (3.8%) were young adults. Adolescents were similar to adults in terms of proportion male, baseline CD4 count, hemoglobin, and TB. Compared to adults, both older adolescents (6 months RR 1.75 95% CI 1.25–2.47) and young adults (6 months RR 1.33 95% CI 1.10–1.60 and 12 months RR 1.64 95% CI 1.23–2.19) were more likely to have an unsuppressed viral load and were more likely to fail virologically (HR 2.90 95% CI 1.74–4.86; HR 2.94 95% CI 1.63–5.31). Among those that died or were LTFU, the median time from ART initiation until death or LTFU was 4.7 months (IQR 1.5–13.2) and 10.9 months (IQR 5.0–22.7), respectively. There was no difference in risk of mortality by age category, compared to adults. Young adolescents were less likely to be LTFU at any time period after ART initiation (HR 0.43 95% CI 0.26–0.69) whereas older adolescents and young adults were more likely to be LTFU after ART initiation (HR 1.78 95% CI 1.34–2.36; HR 1.63 95% CI 1.41–1.89) compared to adults. HIV-infected adolescents and young adults between 15 and 24 years have poorer ART treatment outcomes in terms of virological response, LTFU, and virological failure than adults receiving ART. Interventions are needed to help improve outcomes and retention in care in this unique population.
doi:10.1089/aid.2012.0215
PMCID: PMC3653371  PMID: 23373540
7.  The interplay between CD4 cell count, viral load suppression and duration of ART on mortality in a resource-limited setting 
Objective
To examine the interaction between CD4 cell count, viral load suppression and duration of ART on mortality.
Methods
Cohort analysis of HIV-infected patients initiating ART between April 2004 and June 2011 at a large public-sector clinic in Johannesburg, South Africa. A log-linear model with Poisson distribution was used to estimate risk of death as a function of the interaction between current CD4 count, current viral load suppression and duration on ART in 12-month intervals. We calculated predicted mortality using estimated coefficients within combinations of predictors.
Results
Among 14,932 ART patients, 1,985 (13.3%) died. Current CD4 was the strongest predictor of death (<50 vs. ≥550 cells/mm3 - RR: 46.3; 95%CI: 26.8–80), while unsuppressed current viral load vs. suppressed (RR: 1.8; 95%CI: 1.5–2.1) and short duration of ART (0–11.9 vs. 66–71.9 months RR: 1.7; 95%CI: 1.2–2.3) also predicted death. Our interaction model showed that mortality was highest in the first 12-months on treatment across all CD4 and viral load strata. As current CD4 and duration on ART increased and viral load suppression occurred, mortality dropped. CD4 count was the strongest predictor of death. The relative effect of current CD4 count varied strongly by viral load and duration of ART (from 1.3 to 55). Lack of suppression increased the risk of mortality upwards of 6-fold depending on time on ART and current CD4.
Conclusions
Our findings show that while CD4 count is the strongest predictor of death, the effect is modified by viral load and the duration of ART. Assessment of risk should take into account all three factors.
doi:10.1111/tmi.12079
PMCID: PMC3625450  PMID: 23419157
current CD4 count; current viral load; antiretroviral therapy; mortality; resource limited setting
8.  Immune recovery after starting ART in HIV-infected patients presenting and not presenting with tuberculosis in South Africa 
We studied the immune response after starting antiretroviral treatment (ART) in 15,646 HIV-infected patients with or without tuberculosis (TB) at presentation in three ART programs in South Africa between 2003–2010. Patients presenting with TB had similar increases in CD4 cells compared to all other patients (adjusted difference 4.9 cells/µl per six months, 95% CI 0.2–9.7). Younger age, advanced clinical stage, female sex, and lower CD4 cell count at ART start were all associated with steeper CD4 slopes. In South Africa HIV-infected patients presenting with TB experience immune recovery after starting ART that is no worse than in other patients.
doi:10.1097/QAI.0b013e318288b39d
PMCID: PMC3671097  PMID: 23364513
tuberculosis; HIV; antiretroviral treatment; immune response; CD4 cell count; linear mixed model
9.  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
10.  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
11.  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
12.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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