Low haemoglobin predicts early mortality among adults starting antiretroviral therapy in an HIV care programme in South Africa: a cohort study.

BACKGROUND: Antiretroviral therapy (ART) has dramatically reduced morbidity and mortality among people with HIV infection; however, mortality after the start of ART is high in resource-limited settings. We investigated risk factors for mortality among adults starting ART in a multi-clinic community programme in South Africa. METHODS: Cohort of adults starting ART at 27 clinics between February 2005 and June 2006, followed to 31st March 2007. Kaplan-Meier survival estimates were used to describe overall mortality. Shared frailty Cox regression was used to identify baseline risk factors for early mortality. RESULTS: Among 1350 participants (median age 35.5 years, 60% female, median CD4 count 83/microL [interquartile range (27-147)], median follow-up 13.4 months), there were 185 deaths, overall mortality rate 13/100 pyrs; for 0-3, 3-9 and >9 months from ART start mortality rates were 24, 13 and 6/100 pyrs respectively. 43% of the deaths were in the first 3 months of treatment. Risk factors for mortality in univariable analysis were baseline CD4 count, viral load, haemoglobin and body mass index, in multivariable analysis adjusting for age and gender, only CD4 count and haemoglobin remained independently associated with proportional hazards not being satisfied for haemoglobin. Adjusted hazard ratios (aHR) for participants with haemoglobin <8, 8.1-9.9, >11.9(f)/12.9 (m) g/mL were 4.99, 3.05 and 0.12 respectively comparing to 10-11.9 (f)/12.9 (m)g/mL in the first 3 months of ART. aHRs for CD4 counts were 0.40, 0.38 and 0.34 for 50-99, 100-200 and >200/microL comparing to <50/microL. CONCLUSIONS: The high mortality rate in the first 3 months underlines the need for earlier HIV diagnosis so that ART can be initiated earlier. Low haemoglobin and low CD4 count are both strong predictors of mortality, and could be used to identify individuals at high risk who might benefit from intensive case management.

Effect of rifampicin-based antitubercular therapy and the cytochrome P450 2B6 516G>T polymorphism on efavirenz concentrations in adults in South Africa.

BACKGROUND: Rifampicin induces expression of the cytochrome P450 isoenzyme 2B6 (CYP2B6), which metabolizes efavirenz. The CYP2B6 516G>T polymorphism impairs efavirenz metabolism and occurs more commonly in Africans than in Caucasians. We explored the effect of rifampicin-based antitubercular therapy and the 516G>T polymorphism on efavirenz concentrations in HIV-infected patients in South Africa. METHODS: Between-patient and within-patient comparisons were made of mid-dosing interval efavirenz plasma concentrations in adults on antiretroviral therapy including efavirenz 600 mg daily, with and without antitubercular therapy. RESULTS: There were 142 participants (40 were on antitubercular therapy and 102 were controls), the mean weight was 66 kg. Median efavirenz concentration was 2.4 mg/l (interquartile range [IQR] 1.3-3.1) and 1.8 mg/l (IQR 1.4-4.4) in participants on antitubercular therapy and controls, respectively (P=0.734). Paired efavirenz concentrations during and after antitubercular therapy in 17 participants were also similar (P=0.113). Genotyping results were 60 (49%) G/G homozygotes, 46 (38%) G/T heterozygotes and 16 (13%) T/T homozygotes. In a multivariate logistic regression model adjusted for sex, weight and concomitant antitubercular therapy, the 516G>T polymorphism was strongly associated with high (>4 mg/l) efavirenz concentrations: odds ratio (OR) 4.4 (95% confidence interval [CI] 1.3-14.9) for G/T versus G/G and 31.1 (95% CI 6.6-146.6) for T/T versus G/G. High efavirenz concentrations were associated with severe sleep disturbance (P=0.048). Low (<1 mg/l) efavirenz concentrations were associated with virological failure (OR 12.5, 95% CI 2.7-57.3). CONCLUSIONS: Efavirenz can be used together with rifampicin-based antitubercular therapy without dose adjustment in this population. The 516G>T polymorphism occurred commonly and was associated with high efavirenz concentrations.

Risk factors for poor virological outcome at 12 months in a workplace-based antiretroviral therapy programme in South Africa: a cohort study.

BACKGROUND: Reasons for the variation in reported treatment outcomes from antiretroviral therapy (ART) programmes in developing countries are not clearly defined. METHODS: Among ART-naïve individuals in a workplace ART programme in South Africa we determined virological outcomes at 12 months, and risk factors for suboptimal virological outcome, defined as plasma HIV-1 viral load > or = 400 copies/ml. RESULTS: Among 1760 individuals starting ART before July 2004, 1172 were in follow-up at 12 months of whom 953 (81%) had a viral load measurement (median age 41 yrs, 96% male, median baseline CD4 count 156 x 10(6)/l). 71% (681/953) had viral load < 400 copies/ml at 12 months. In a multivariable analysis, independent predictors of suboptimal virological outcome at 12 months were <1 log decrease in viral load at six weeks (odds ratio [OR] 4.71, 95% confidence interval [CI] 2.56-8.68), viral load at baseline (OR 3.63 [95% CI 1.88-7.00] and OR 3.54 [95% CI 1.79-7.00] for 10,001-100,000 and >100,000 compared to < or = 10,000 copies/ml, respectively), adherence at six weeks (OR 3.50 [95% CI 1.92-6.35]), WHO stage (OR 2.08 [95% CI 1.28-3.34] and OR 2.03 [95% CI 1.14-3.62] for stage 3 and 4 compared to stage 1-2, respectively) and site of ART delivery. Site of delivery remained an independent risk factor even after adjustment for individual level factors. At 6 weeks, of 719 patients with self-reported adherence and viral load, 72 (10%) reported 100% adherence but had <1 log decrease in viral load; conversely, 60 (8%) reported <100% adherence but had > or = 1 log decrease in viral load. CONCLUSION: Virological response at six weeks after ART start was the strongest predictor of suboptimal virological outcome at 12 months, and may identify individuals who need interventions such as additional adherence support. Self reported adherence was less strongly associated but identified different patients compared with viral load at 6 weeks. Site of delivery had an important influence on virological outcomes; factors at the health system level which influence outcome need further investigation to guide development of effective ART programmes.

Evaluation of a workplace HIV treatment programme in South Africa.

OBJECTIVE: To review the experience of implementing a workplace HIV care programme in South Africa and describe treatment outcomes in sequential cohorts of individuals starting antiretroviral therapy (ART). DESIGN: A review of an industrial HIV care and treatment programme. Between October 2002 and December 2005, 2262 patients enrolled in the HIV care programme. RESULTS: CD4 cell counts increased by a median of 90, 113 and 164 cells/microl by 6, 12 and 24 months on treatment, respectively. The viral load was suppressed below 400 copies/ml in 75, 72 and 72% of patients at 6, 12 and 24 months, respectively, at an average cost of US$1654, 3567 and 7883 per patient virally suppressed, respectively. Treatment outcomes in sequential cohorts of patients were consistent over time. A total of 93.6% of patients at 14,752 clinic visits reported missing no tablets over the previous 3 days. Almost half the patients (46.8%) experienced one or more adverse events, although most were mild (78.7%). By the end of December 2005, 30% of patients were no longer on ART, mostly because of defaulted or stopped treatment (12.8%), termination of employment (8.2%), or death (4.9%). CONCLUSION: This large workplace programme achieved virological results among individuals retained in the programme comparable to those reported for developed countries; more work is needed to improve retention. Monitoring treatment outcomes in sequential cohorts is a useful way of monitoring programme performance. As the programme has matured, the costs of programme implementation have reduced. Counselling is a central component of an ART programme. Challenges in implementing a workplace ART programme are similar to the challenges of public-sector programmes.

Hepatotoxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B.

OBJECTIVE: Hepatotoxicity is a significant complication of antiretroviral therapy (ART). We assessed the incidence of and risk factors for hepatotoxicity among HIV-infected individuals on ART in South Africa. DESIGN: We conducted a retrospective cohort study in a workplace HIV care program in South Africa which uses a first-line regimen of efavirenz, zidovudine, and lamivudine and provides routine clinical and laboratory monitoring. METHODS: We included subjects with baseline and follow-up alanine transaminase and aspartate aminotransferase tests. Severe hepatotoxicity cases were identified during the first 12 months of ART. Potential risk factors, including concomitant medication use, tuberculosis, and hepatitis B and C, were determined from clinical records, database queries, and serological testing. Associations with hepatotoxicity were investigated using Cox proportional hazards modeling. RESULTS: Of the 868 subjects (94% male, median age 41 years), the median nadir CD4 cell count was 136/microl, 25% received concomitant tuberculosis treatment during ART, and 17% of a randomly selected subset were positive for hepatitis B surface antigen (HBsAg). We identified 7.7 episodes of severe hepatotoxicity per 100 person-years. Tuberculosis treatment increased risk 8.5 fold, positive HBsAg 3.0 fold, and nadir CD4 cells count < 100/microl 1.9 fold. Importantly, the fraction of patients with severe hepatotoxicity on ART (4.6%) was similar to the fraction with liver enzyme elevations > 5 times the upper limit of normal before starting ART (4%). CONCLUSIONS: In this African ART cohort, we found a low incidence of and minimal morbidity due to hepatotoxicity. HBsAg and concomitant tuberculosis therapy significantly increased the risk of hepatotoxicity.

Use of traditional medicine by HIV-infected individuals in South Africa in the era of antiretroviral therapy.

As antiretroviral therapy (ART) becomes more available in African countries, the potential for interaction with traditional medicines becomes more important. We carried out a cross-sectional survey among individuals with moderate or advanced HIV disease attending a workplace clinic providing ART in South Africa to determine prevalence of traditional medicine use, source, recommended products and costs. Among 44 clinic attendees (100% male, median age 42 years, 30 taking ART), 37 (84%) reported ever using traditional medicines, 25 obtained from a healer or herbalist, eight from their own fields and four from a pharmacy. Fourteen of the 44 (32%) were currently using traditional medicines, most frequently African potato (9/14) and Aloe vera (3/14). Seven out of 30 persons taking ART (23%) reported currently using traditional medicines. Participants spent 4 - 27 pounds per month on traditional medicines. Traditional medicine use is common among individuals with moderate and advanced HIV disease. Concomitant use with ART has the potential for drug interactions and should be discussed routinely in ART counselling. Further work is warranted to investigate whether commonly used traditional medicines interact with ART in vivo.