Lerato Mohapi

Timing of Antiretroviral Therapy for HIV-1 Infection and Tuberculosis

BACKGROUND Antiretroviral therapy (ART) is indicated during tuberculosis treatment in patients infected with human immunodeficiency virus type 1 (HIV-1), but the timing for the initiation of ART when tuberculosis is diagnosed in patients with various levels of immune compromise is not known. METHODS We conducted an open-label, randomized study comparing earlier ART (within 2 weeks after the initiation of treatment for tuberculosis) with later ART (between 8 and 12 weeks after the initiation of treatment for tuberculosis) in HIV-1 infected patients with CD4+ T-cell counts of less than 250 per cubic millimeter and suspected tuberculosis. The primary end point was the proportion of patients who survived and did not have a new (previously undiagnosed) acquired immunodeficiency syndrome (AIDS)-defining illness at 48 weeks. RESULTS A total of 809 patients with a median baseline CD4+ T-cell count of 77 per cubic millimeter and an HIV-1 RNA level of 5.43 log(10) copies per milliliter were enrolled. In the earlier-ART group, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks, as compared with 16.1% in the later-ART group (95% confidence interval [CI], -1.8 to 8.1; P=0.45). Among patients with screening CD4+ T-cell counts of less than 50 per cubic millimeter, 15.5% of patients in the earlier-ART group versus 26.6% in the later-ART group had a new AIDS-defining illness or died (95% CI, 1.5 to 20.5; P=0.02). Tuberculosis-associated immune reconstitution inflammatory syndrome was more common with earlier ART than with later ART (11% vs. 5%, P=0.002). The rate of viral suppression at 48 weeks was 74% and did not differ between the groups (P=0.38). CONCLUSIONS Overall, earlier ART did not reduce the rate of new AIDS-defining illness and death, as compared with later ART. In persons with CD4+ T-cell counts of less than 50 per cubic millimeter, earlier ART was associated with a lower rate of new AIDS-defining illnesses and death. (Funded by the National Institutes of Health and others; ACTG A5221 ClinicalTrials.gov number, NCT00108862.).

Maraviroc versus Efavirenz, Both in Combination with Zidovudine-Lamivudine, for the Treatment of Antiretroviral-Naive Subjects with CCR5-tropic HIV-1 Infection

BACKGROUND The MERIT (Maraviroc versus Efavirenz in Treatment-Naive Patients) study compared maraviroc and efavirenz, both with zidovudine-lamivudine, in antiretroviral-naive patients with R5 human immunodeficiency virus type 1 (HIV-1) infection. METHODS Patients screened for R5 HIV-1 were randomized to receive efavirenz (600 mg once daily) or maraviroc (300 mg once or twice daily) with zidovudine-lamivudine. Coprimary end points were proportions of patients with a viral load <400 and <50 copies/mL at week 48; the noninferiority of maraviroc was assessed. RESULTS The once-daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria. In the primary 48-week analysis (n = 721), maraviroc was noninferior for <400 copies/mL (70.6% for maraviroc vs 73.1% for efavirenz) but not for <50 copies/mL (65.3% vs 69.3%) at a threshold of -10%. More maraviroc patients discontinued for lack of efficacy (11.9% vs 4.2%), but fewer discontinued for adverse events (4.2% vs 13.6%). In a post hoc reanalysis excluding 107 patients (15%) with non-R5 screening virus by the current, more sensitive tropism assay, the lower bound of the 1-sided 97.5% confidence interval for the difference between treatment groups was above -10% for each end point. CONCLUSIONS Twice-daily maraviroc was not noninferior to efavirenz at <50 copies/mL in the primary analysis. However, 15% of patients would have been ineligible for inclusion by a more sensitive screening assay. Their retrospective exclusion resulted in similar response rates in both arms Trial registration. ClinicalTrials.gov identifier: (NCT00098293) .

Temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across South Africa, 2002-2007

Objective:Little is known about the temporal impact of the rapid scale-up of large antiretroviral therapy (ART) services on programme outcomes. We describe patient outcomes [mortality, loss-to-follow-up (LTFU) and retention] over time in a network of South African ART cohorts. Design:Cohort analysis utilizing routinely collected patient data. Methods:Analysis included adults initiating ART in eight public sector programmes across South Africa, 2002–2007. Follow-up was censored at the end of 2008. Kaplan–Meier methods were used to estimate time to outcomes, and proportional hazards models to examine independent predictors of outcomes. Results:Enrolment (n = 44 177, mean age 35 years; 68% women) increased 12-fold over 5 years, with 63% of patients enrolled in the past 2 years. Twelve-month mortality decreased from 9% to 6% over 5 years. Twelve-month LTFU increased annually from 1% (2002/2003) to 13% (2006). Cumulative LTFU increased with follow-up from 14% at 12 months to 29% at 36 months. With each additional year on ART, failure to retain participants was increasingly attributable to LTFU compared with recorded mortality. At 12 and 36 months, respectively, 80 and 64% of patients were retained. Conclusion:Numbers on ART have increased rapidly in South Africa, but the programme has experienced deteriorating patient retention over time, particularly due to apparent LTFU. This may represent true loss to care, but may also reflect administrative error and lack of capacity to monitor movements in and out of care. New strategies are needed for South Africa and other low-income and middle-income countries to improve monitoring of outcomes and maximize retention in care with increasing programme size.

Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort

Background:The World Health Organization recommends isoniazid preventive therapy (IPT) for preventing tuberculosis in HIV-infected adults, although few countries have instituted this policy. Both IPT and highly active antiretroviral therapy (HAART) used separately result in reductions in tuberculosis risk. There is less information on the combined effect of IPT and HAART. We assessed the effect of IPT, HAART or both IPT and HAART on tuberculosis incidence in HIV-infected adults in South Africa. Methods:Two clinical cohorts of HIV-infected patients were studied. Primary exposures were receipt of IPT and/or HAART and the primary outcome was incident tuberculosis. Crude incident rates and incident rate ratios were calculated and Cox proportional hazards models investigated associations with tuberculosis risk. Results:Among 2778 HIV-infected patients followed for 4287 person-years, 267 incident tuberculosis cases were diagnosed [incidence rate ratio (IRR) = 6.2/100 person-years; 95% CI 5.5–7.0]. For person-time without IPT or HAART, the IRR was 7.1/100 person-years (95% CI 6.2–8.2); for person-time receiving HAART but without IPT, the IRR was 4.6/100 person-years (95% CI 3.4–6.2); for person-time after IPT but prior to HAART, the IRR was 5.2/100 person-years (95% CI 3.4–7.8); during follow-up in patients treated with HAART after receiving IPT the IRR was 1.1/100 person-years (95% CI 0.02–7.6). Compared to treatment-naive patients, HAART-only patients had a 64% decreased hazard for tuberculosis [adjusted hazard ratio (aHR) = 0.36; 95% CI 0.25–0.51], and patients receiving HAART after IPT had a 89% reduced hazard (aHR = 0.11; 95% CI 0.02–0.78). Conclusion:Tuberculosis risk is significantly reduced by IPT in HAART-treated adults in a high-incidence operational setting in South Africa. IPT is an inexpensive and cost-effective strategy and our data strengthen calls for the implementation of IPT in conjunction with the roll-out of HAART.

Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study.

Methods We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confi rmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of fi rst-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modifi ed intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with ClinicalTrials.gov, number NCT00931463.BACKGROUND Uncertainty exists about the best treatment for people with HIV-1 who have virological failure with first-line combination antiretroviral therapy of a non-nucleoside analogue (NNRTI) plus two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NtRTI). We compared a second-line regimen combining two new classes of drug with a WHO-recommended regimen. METHODS We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confirmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of first-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modified intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with ClinicalTrials.gov, number NCT00931463. FINDINGS We enrolled 558 patients, of whom 541 (271 in the control group, 270 in the raltegravir group) were included in the primary analysis. At 48 weeks, 219 (81%) patients in the control group compared with 223 (83%) in the raltegravir group met the primary endpoint (difference 1·8%, 95% CI -4·7 to 8·3), fulfilling the criterion for non-inferiority. 993 adverse events occurred in 271 participants in the control group versus 895 in 270 participants in the raltegravir group, the most common being gastrointestinal. INTERPRETATION The raltegravir regimen was no less efficacious than the standard of care and was safe and well tolerated. This simple NtRTI-free treatment strategy might extend the successful public health approach to management of HIV by providing simple, easy to administer, effective, safe, and tolerable second-line combination antiretroviral therapy. FUNDING University of New South Wales, Merck, AbbVie, the Foundation for AIDS Research.

Antiretroviral Therapies in Women after Single-Dose Nevirapine Exposure

BACKGROUND Peripartum administration of single-dose nevirapine reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but selects for nevirapine-resistant virus. METHODS In seven African countries, women infected with HIV-1 whose CD4+ T-cell counts were below 200 per cubic millimeter and who either had or had not taken single-dose nevirapine at least 6 months before enrollment were randomly assigned to receive antiretroviral therapy with tenofovir–emtricitabine plus nevirapine or tenofovir-emtricitabine plus lopinavir boosted by a low dose of ritonavir. The primary end point was the time to confirmed virologic failure or death. RESULTS A total of 241 women who had been exposed to single-dose nevirapine began the study treatments (121 received nevirapine and 120 received ritonavir-boosted lopinavir). Significantly more women in the nevirapine group reached the primary end point than in the ritonavir-boosted lopinavir group (26% vs. 8%) (adjusted P=0.001). Virologic failure occurred in 37 (28 in the nevirapine group and 9 in the ritonavir-boosted lopinavir group), and 5 died without prior virologic failure (4 in the nevirapine group and 1 in the ritonavir-boosted lopinavir group). The group differences appeared to decrease as the interval between single-dose nevirapine exposure and the start of antiretroviral therapy increased. Retrospective bulk sequencing of baseline plasma samples showed nevirapine resistance in 33 of 239 women tested (14%). Among 500 women without prior exposure to single-dose nevirapine, 34 of 249 in the nevirapine group (14%) and 36 of 251 in the ritonavir-boosted lopinavir group (14%) had virologic failure or died. CONCLUSIONS In women with prior exposure to peripartum single-dose nevirapine (but not in those without prior exposure), ritonavir-boosted lopinavir plus tenofovir–emtricitabine was superior to nevirapine plus tenofovir–emtricitabine for initial antiretroviral therapy. (Funded by the National Institute of Allergy and Infectious Diseases and the National Research Center; ClinicalTrials.gov number, NCT00089505.).

Viremia and drug resistance among HIV-1 patients on antiretroviral treatment: a cross-sectional study in Soweto, South Africa

Background:We assessed risk factors for viremia and drug resistance among long-term recipients of antiretroviral therapy (ART) in South Africa. Methods:In 2008, we conducted a cross-sectional study among patients receiving ART for 12 months or more. Genotypic resistance testing was performed on individuals with a viral load higher than 400 RNA copies/ml. Multiple logistic regression analysis was used to assess associations. Results:Of 998 participants, 75% were women with a median age of 41 years. Most (64%) had been on treatment for more than 3 years. The prevalence of viremia was 14% (n = 139): 12% (102/883) on first-line [i.e. nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen] and 33% (37/115) on second-line (i.e. protease inhibitor (PI)-based regimen) ART. Of viremic patients, 78% had drug resistance mutations. For NRTIs, NNRTIs and PIs, the prevalence of mutations was 64, 81 and 2%, respectively, among first-line failures and 29, 54 and 6%, respectively, among second-line failures. M184V/I, K103N and V106A/M were the most common mutations. Significant risk factors associated with viremia on first-line regimen included concurrent tuberculosis treatment [odds ratio (OR) 6.4, 95% confidence interval (CI) 2.2–18.8, P < 0.01] and a recent history of poor adherence (OR 2.7, 1.3–5.6, P = 0.01). Among second-line failures, attending a public clinic (OR 4.6, 95% CI 1.8–11.3, P < 0.01) and not having a refrigerator at home (OR 6.7, 95% CI 1.2–37.5, P = 0.03) were risk factors for virological failure. Conclusion:Risk factors for viral failure were line regimen dependent. Second-line ART recipients had a higher rate of viremia, albeit with infrequent PI drug resistance mutations. Measures to maintain effective virologic suppression should include increased adherence counseling, attention to concomitant tuberculosis treatment and heat-stable formulations of second-line ART regimens.

Body mass index and risk of tuberculosis and death.

Background:High BMI has been shown to be protective against tuberculosis (TB) among HIV-uninfected individuals, as well as against disease progression and mortality among those with HIV. We examined the effect of BMI on all-cause mortality and TB incidence among a cohort of HIV-infected adults in Soweto, South Africa. Methods:A clinical cohort of 3456 HIV-infected adults from South Africa was prospectively followed from 2003 to 2008 with regular monitoring. The primary exposure was BMI and the outcomes of interest were all-cause mortality and a newly diagnosed episode of TB. Cox proportional hazard models assessed associations with risk of mortality or incident TB. Results:Incidence rates of mortality were 10.4/100 person-years for baseline BMI of 18.5 or less, 3.6/100 person-years for baseline BMI 18.6–25, 1.7/100 person-years for baseline BMI 25.1–30, and 1.6/100 person-years for baseline BMI more than 30. Compared to those with normal BMI, overweight and obese participants had a significantly reduced risk of mortality [adjusted hazard ratio 0.59 (95% confidence interval, CI 0.40–0.87) and 0.48 (95% CI 0.29–0.80), respectively]. Incidence rates of TB by baseline BMI were 7.3/100 person-years for underweight, 6.0/100 person-years for normal, 3.2/100 person-years for overweight, and 1.9/100 person-years for obese. Compared to those with normal BMI, those with overweight and obese BMI were at a significantly reduced risk of developing TB [adjusted hazard ratio 0.56 (95% CI 0.38–0.83) and 0.33 (95% CI 0.19–0.55), respectively]. Conclusion:HIV-infected individuals with obese and overweight BMI have a significantly reduced risk of both mortality and TB, after adjusting for HAART use and CD4 cell count.

A Qualitative Assessment of Decisions Affecting Contraceptive Utilization and Fertility Intentions among HIV-Positive Women in Soweto, South Africa

The HIV epidemic in sub-Saharan Africa disproportionately affects women of reproductive age. The increasing provision of Highly Active Anti-Retroviral Therapy (HAART) with improved prognosis and maternal-fetal outcomes calls for an understanding of fertility planning for HIV-positive women. We describe the effect of HIV and HAART on pregnancy desires and contraceptive use among HIV-positive women in Soweto, South Africa. Focus group discussions and in-depth interviews were conducted with 42 HIV-positive women of reproductive age. Analysis was performed using ATLAS-ti (ATLAS-ti Center, Berlin). Emergent themes were impact of HIV diagnosis on pregnancy intentions; factors affecting contraceptive uptake including real and normative side effects, body image, and perceived vaginal wetness; and the mitigating influence of partnership on both pregnancy intentions and contraceptive use. Routine counseling about pregnancy desires and contraception should be offered to HIV-positive women.

Adherence to Drug-Refill Is a Useful Early Warning Indicator of Virologic and Immunologic Failure among HIV Patients on First-Line ART in South Africa

Background Affordable strategies to prevent treatment failure on first-line regimens among HIV patients are essential for the long-term success of antiretroviral therapy (ART) in sub-Saharan Africa. WHO recommends using routinely collected data such as adherence to drug-refill visits as early warning indicators. We examined the association between adherence to drug-refill visits and long-term virologic and immunologic failure among non-nucleoside reverse transcriptase inhibitor (NNRTI) recipients in South Africa. Methods In 2008, 456 patients on NNRTI-based ART for a median of 44 months (range 12–99 months; 1,510 person-years) were enrolled in a retrospective cohort study in Soweto. Charts were reviewed for clinical characteristics before and during ART. Multivariable logistic regression and Kaplan-Meier survival analysis assessed associations with virologic (two repeated VL>50 copies/ml) and immunologic failure (as defined by WHO). Results After a median of 15 months on ART, 19% (n = 88) and 19% (n = 87) had failed virologically and immunologically respectively. A cumulative adherence of <95% to drug-refill visits was significantly associated with both virologic and immunologic failure (p<0.01). In the final multivariable model, risk factors for virologic failure were incomplete adherence (OR 2.8, 95%CI 1.2–6.7), and previous exposure to single-dose nevirapine or any other antiretrovirals (adj. OR 2.1, 95%CI 1.2–3.9), adjusted for age and sex. In Kaplan-Meier analysis, the virologic failure rate by month 48 was 19% vs. 37% among adherent and non-adherent patients respectively (logrank p value = 0.02). Conclusion One in five failed virologically after a median of 15 months on ART. Adherence to drug-refill visits works as an early warning indicator for both virologic and immunologic failure.