Nonhlanhla Yende-Zuma

The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial.

BACKGROUND Concerns about the immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during antituberculosis treatment in co-infected patients. OBJECTIVE To assess IRIS incidence, severity, and outcomes relative to the timing of ART initiation in patients with HIV-related tuberculosis. DESIGN Randomized, open-label clinical trial. (ClinicalTrials.gov registration number: NCT00398996) SETTING An outpatient clinic in Durban, South Africa. PATIENTS 642 patients co-infected with HIV and tuberculosis. MEASUREMENTS In a secondary analysis of the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial, IRIS was assessed in patients randomly assigned to initiate ART within 4 weeks of tuberculosis treatment initiation (early integrated treatment group), within 4 weeks of completion of the intensive phase of tuberculosis treatment (late integrated treatment group), or within 4 weeks after tuberculosis therapy completion (sequential treatment group). The syndrome was defined as new-onset or worsening symptoms, signs, or radiographic manifestations temporally related to treatment initiation, accompanied by a treatment response. Severity of IRIS, hospitalization, and time to resolution were monitored. RESULTS Incidence of IRIS was 19.5 (n = 43), 7.5 (n = 18), and 8.1 (n = 19) per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Among patients with a baseline CD4+ count less than 0.050 × 109 cells/L, IRIS incidence was 45.5, 9.7, and 19.7 per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Incidence of IRIS was higher in the early integrated treatment group than in the late integrated (incidence rate ratio, 2.6 [95% CI, 1.5 to 4.8]; P < 0.001) or sequential (incidence rate ratio, 2.4 [CI, 1.4 to 4.4]; P < 0.001) treatment groups. More severe IRIS cases occurred in the early integrated treatment group than in the other 2 groups (35% vs. 19%; P = 0.179), and patients in the early integrated treatment group had significantly higher hospitalization rates (42% vs. 14%; P = 0.007) and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) than patients in the other 2 groups. LIMITATIONS It was not possible to assess IRIS in more patients in the sequential treatment group (n = 74) than in the late integrated (n = 50) and early integrated (n = 32) treatment groups because of loss to follow-up, withdrawal, or death within 6 months of scheduled ART initiation. This study did not assess IRIS risk in nonambulatory patients or in those with extrapulmonary and smear-negative tuberculosis. CONCLUSION Initiation of ART in early stages of tuberculosis treatment resulted in significantly higher IRIS rates, longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings are particularly relevant to patients initiating ART with a CD4+ count less than 0.050 × 109 cells/L, given the increased survival benefit of early ART initiation in this group. PRIMARY FUNDING SOURCE Comprehensive International Program of Research on AIDS.

Implementation of Adolescent-Friendly Voluntary Medical Male Circumcision Using a School Based Recruitment Program in Rural KwaZulu-Natal, South Africa

Background Epidemiological data from South Africa demonstrate that risk of human immunodeficiency virus (HIV) infection in males increases dramatically after adolescence. Targeting adolescent HIV-negative males may be an efficient and cost-effective means of maximising the established HIV prevention benefits of voluntary medical male circumcision (VMMC) in high HIV prevalence–, low circumcision practice–settings. This study assessed the feasibility of recruiting male high school students for VMMC in such a setting in rural KwaZulu-Natal. Methods and Findings Following community and key stakeholder consultations on the acceptability of VMMC recruitment through schools, information and awareness raising sessions were held in 42 high schools in Vulindlela. A three-phase VMMC demand-creation strategy was implemented in partnership with a local non-governmental organization, ZimnadiZonke, that involved: (i) community consultation and engagement; (ii) in-school VMMC awareness sessions and centralized HIV counselling and testing (HCT) service access; and (iii) peer recruitment and decentralized HCT service access. Transport was provided for volunteers to the Centre for the AIDS Programme of Research in South Africa (CAPRISA) clinic where the forceps-guided VMMC procedure was performed on consenting HIV-negative males. HIV infected volunteers were referred to further care either at the CAPRISA clinic or at public sector clinics. Between March 2011 and February 2013, a total of 5165 circumcisions were performed, the majority (71%) in males aged between 15 and 19 years. Demand-creation strategies were associated with an over five-fold increase in VMMC uptake from an average of 58 procedures/month in initial community engagement phases, to an average of 308 procedures/month on initiation of the peer recruitment–decentralized service phase. Post-operative adverse events were rare (1.2%), mostly minor and self-resolving. Conclusions Optimizing a high volume, adolescent-targeted VMMC program was feasible, acceptable and safe in this setting. Adaptive demand-creation strategies are required to sustain high uptake.

Trends in HIV Prevalence in Pregnant Women in Rural South Africa.

Background:Despite substantial progress in the delivery of HIV prevention programs, some communities continue to experience high rates of HIV infection. We report on temporal trends in HIV prevalence in pregnant women in a community in rural KwaZulu-Natal in South Africa. Methods:Annual, anonymous cross-sectional HIV sero-prevalence surveys were conducted between 2001 and 2013 among first visit prenatal clinic attendees. The time periods 2001 to 2003 were defined as pre-antiretroviral therapy (ART), 2004 to 2008 as early ART, and 2009 to 2013 as contemporary ART roll-out, to correspond with the substantial scale-up of ART program. Results:Overall, HIV prevalence rose from 35.3% [95% confidence interval (CI): 32.3 to 38.3] pre-ART (2001–2003) to 39.0% (95% CI: 36.8 to 41.1) in the early ART (2004–2008) to 39.3% (95% CI: 37.2 to 41.4) in the contemporary ART (2009–2013) roll-out periods. In teenage women (<20 years), HIV prevalence declined from 22.5% (95% CI: 17.5 to 27.5) to 20.7% (95% CI: 17.5 to 23.8) and to 17.2% (95% CI: 14.3 to 20.2) over the similar ART roll-out periods (P = 0.046). Prevalence increased significantly in women 30 years and older (P < 0.001) over the same time period largely because of survival after ART scale up. Teenage girls with male partners of age 20–24 and ≥ 25 years had a 1.7-fold (95% CI: 1.3–2.4; P = 0.001) and 3-fold (95% CI: 2.1 to 4.3; P < 0.001) higher HIV prevalence respectively. Conclusions:Notwithstanding the encouraging decline in teenagers, the ongoing high HIV prevalence in pregnant women in this rural community, despite prevention and treatment programs, is deeply concerning. Targeted interventions for teenagers, especially for those in age-disparate relationships, are needed to impact this HIV epidemic trajectory.

Women with pregnancies had lower adherence to 1% tenofovir vaginal gel as HIV preexposure prophylaxis in CAPRISA 004, a phase IIB randomized-controlled trial.

Background Antiretroviral prophylaxis may be a critical strategy to reduce periconception HIV transmission. Maximizing the benefit of periconception pharmacologic HIV risk-reduction requires an understanding of the links between pregnancy and adherence to this prevention strategy. Methods We assessed study gel adherence among women with pregnancies compared to women without pregnancies enrolled in the CAPRISA 004 phase IIB trial of 1% vaginal tenofovir gel. Pregnancy was assessed with monthly urine tests. Adherence was measured monthly and defined as proportion of sex acts covered by two returned, used applicators based on pre- and post-coital dosing. High adherence was defined as a median adherence score of >80%, that is, more than 80% of sex acts were covered by two applications of study gel. A multivariate generalized estimating equations (GEE) model with a binomial distribution was used to assess covariates associated with high adherence (>80%) over time. Median adherence before and after pregnancy was compared using Wilcoxon signed rank test. Results Among 868 women, 53 had at least 1 pregnancy (4.06 per 100 woman years, 95% CI: 3.04, 5.31). Women with pregnancies had lower median adherence compared to women without pregnancies (50% [IQR: 45–83] vs. 60% [IQR: 50–100], p = 0.02). Women with pregnancies also had a 48% lower odds of high adherence compared to women without pregnancies when adjusting for confounders (aOR 0.52, 95%CI: 0.41–0.66, p<0.0001). Among women with pregnancies, adherence before and after pregnancy was not different (50% [IQR: 46–83] vs. 55% [IQR: 20–100], p = 0.68). Conclusions Women with pregnancies were less likely to have high adherence to study gel compared to women without pregnancies. Understanding these differences may inform findings from HIV prevention trials and future implementation of antiretroviral prophylaxis for at-risk women who choose to conceive. The protocol for the parent trial is registered on ClinicalTrials.gov, NCT00441298, http://www.clinicaltrials.gov/ct2/show/NCT00441298.

Integrin α4β7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes.

CD4+ T cells expressing α4β7 play an important role in HIV pathogenesis. Indicative integrins in HIV The gut is thought to be a major viral reservoir in HIV infection, and studies in nonhuman primates suggest that targeting the α4β7 integrin on T cells may be a viable therapy. Sivro et al. now extend these findings to humans by examining HIV acquisition in multiple African cohorts. Higher frequencies of α4β7+ circulating CD4+ T cells before infection were associated with increased HIV acquisition, viral load at set point, and more rapid CD4+ T cell decline. These exciting data confirm that integrin targeting could help reduce the spread of HIV. The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α4β7 promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that α4β7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α4β7+ peripheral blood CD4+ T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for α4β7 binding. In addition, pre-HIV α4β7+ CD4+ T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4+ T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV α4β7+ CD4+ T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4+ T cells expressing α4β7 were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between α4β7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α4β7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α4β7 integrin as a clinical intervention during HIV infection.

Changes to antiretroviral drug regimens during integrated TB-HIV treatment: results of the SAPiT trial.

BACKGROUND Frequency of drug changes in combination antiretroviral therapy among patients starting both tuberculosis (TB) and HIV therapy, as a result of treatment-limiting toxicity or virological failure, is not well established. METHODS Patients in the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial were randomized to initiate antiretroviral therapy (ART) either early or late during TB treatment or after completion of TB treatment. Drug changes due to toxicity (defined as due to grade 3 or 4 adverse events) or virological failure (defined as viral load >1,000 copies/ml on two occasions, taken ≥4 weeks apart) were assessed in these patients. RESULTS A total of 501 TB-HIV-coinfected patients were followed for a mean of 16.0 months (95% CI 15.5, 16.6) after ART initiation. The standard first-line antiretrovirals used were efavirenz, lamivudine and didanosine. Individual drug switches for toxicity occurred in 14 patients (incidence rate 2.1 per 100 person-years, 95% CI 1.1, 3.5), and complete regimen changes due to virological failure in 25 patients (incidence rate 3.7 per 100 person-years, 95% CI 2.4, 5.5). The most common treatment limiting toxicities were neuropsychiatric effects (n=4, 0.8%), elevated transaminase levels and hyperlactataemia (n=3, 0.6%), and peripheral neuropathy (n=2, 0.4%). Complete regimen change due to treatment failure was more common in patients with CD4(+) T-cell count <50 cells/mm(3) (P<0.001) at ART initiation and body mass index >25 kg/m(2) (P=0.01) at entry into the study. CONCLUSIONS Both drug switches and complete regimen change were uncommon in patients cotreated for TB-HIV with the chosen regimen. Patients with severe immunosuppression need to be monitored carefully, as they were most at risk for treatment failure requiring regimen change.

High rates of tuberculosis in patients accessing HAART in rural South Africa.

Background:The challenge of early tuberculosis (TB) infection among rural patients accessing highly active antiretroviral therapy (HAART) in a resource-limited setting with high HIV and TB burden has not been fully quantified. Methods:This is a retrospective study nested within a prospective study of 969 patients consecutively initiated onto HAART at the CAPRISA AIDS Treatment programme in rural KwaZulu-Natal between January 2007 and December 2010. Patients were screened for clinical symptoms consistent with TB using a standardized checklist, and routine clinical investigations that included sputum microscopy and chest x-ray diagnosis. Results:Of 969 HIV-infected patients initiated on HAART, 173 [17.9%; 95% confidence interval (CI): 15.5 to 20.4] had active TB at HAART initiation. TB incidence rates were 3-fold higher in the first 3 months (early incident TB) after HAART initiation [11.5/100 person-years (py); 95% CI: 7.1 to 17.5] compared with 4–24 months (late incident TB) post-HAART initiation (3.2/100 py; 95% CI: 2.2 to 4.5; incidence rate ratio: 3.6; 95% CI: 2.0 to 6.4; P < 0.001). Immune status of patients at HAART initiation did not impact TB incidence rates in patients with CD4+ counts of <50 (5.3/100) and >200 (4.9/100 py; P = 0.81) cells per cubic millimeter. CD4+ count gains achieved 12 months post-HAART initiation were significantly different in patients with early incident TB versus late incident TB; P = 0.03. Conclusions:Rural HIV treatment programmes in TB-endemic settings experience high rates of TB irrespective of immunologic status of patients at HAART initiation, or duration on HAART.

Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women

Several clinical trials have demonstrated that antiretroviral (ARV) drugs taken as pre-exposure prophylaxis (PrEP) can prevent HIV infection, with the magnitude of protection ranging from −49 to 86% (refs. ). Although these divergent outcomes are thought to be due primarily to differences in product adherence, biological factors likely contribute. Despite selective recruitment of higher-risk participants for prevention trials, HIV risk is heterogeneous even within higher-risk groups. To determine whether this heterogeneity could influence patient outcomes following PrEP, we undertook a post hoc prospective analysis of results from the CAPRISA 004 trial for 1% tenofovir gel (n = 774 patients), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine proinflammatory cytokines were measured in cervicovaginal lavages at >2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% confidence interval (CI): 7–80%) but was 3% protective (95% CI: −104–54%) if genital inflammation was present. Among women who highly adhered to the gel, tenofovir protection was 75% (95% CI: 25–92%) in women without inflammation compared to −10% (95% CI: −184–57%) in women with inflammation. Immunological predictors of HIV risk may modify the effectiveness of tools for HIV prevention; reducing genital inflammation in women may augment HIV prevention efforts.

Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB

Objectives We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB. Methods Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400 mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and again 4 weeks after treatment completion, when given alone as a single dose. Moxifloxacin concentration-time data were analysed using non-linear mixed-effects models. Results We included 58 patients; 42 (72.4%) were HIV co-infected and 40 (95%) of these were on efavirenz-based ART. Moxifloxacin pharmacokinetics was best described using a two-compartment disposition model with first-order lagged absorption and elimination using a semi-mechanistic model describing hepatic extraction. Oral clearance (CL/F) of moxifloxacin during rifampicin-based TB treatment was 24.3 L/h for a typical patient (fat-free mass of 47 kg), resulting in an AUC of 16.5 mg·h/L. This exposure was 7.8% lower than the AUC following the single dose of moxifloxacin given alone after TB treatment completion. In HIV-co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4%, resulting in a further 30% reduction in moxifloxacin AUC. Conclusions Moxifloxacin clearance was high and plasma concentrations low in our patients overall. Moxifloxacin AUC was further decreased by co-administration of efavirenz-based ART and, to a lesser extent, rifampicin. The clinical relevance of the low moxifloxacin concentrations for TB treatment outcomes and the need for moxifloxacin dose adjustment in the presence of rifampicin and efavirenz co-treatment need further investigation.

The Effect of Timing of Initiation of Antiretroviral Therapy on Loss to Follow-up in HIV-Tuberculosis Coinfected Patients in South Africa: An Open-Label, Randomized, Controlled Trial.

Objective:To evaluate the effect of early integrated, late-integrated, and delayed antiretroviral therapy (ART) initiation during tuberculosis (TB) treatment on the incidence rates of loss to follow-up (LTFU) and to evaluate the effect of ART initiation on LTFU rates within trial arms in patients coinfected with TB and HIV. Methods:A substudy within a 3-armed, open label, randomized, controlled trial. Patients were randomized to initiate ART either early or late during TB treatment or after the TB treatment completion. We reported the incidence and predictors of LTFU from TB treatment initiation during the 24 months of follow-up. LTFU was defined as having missed 4 consecutive monthly visits with the inability to make contact. Results:Of the 642 patients randomized, a total of 96 (15.0%) were LTFU at a median of 6.0 [interquartile range (IQR), 1.1–11.3] months after TB treatment initiation. Incidence rates of LTFU were 7.5 per 100 person-years (PY) [95% confidence interval (CI): 4.9 to 11], 10.9 per 100 PY (95% CI: 7.6 to 15.1), and 11.0 per 100 PY (95% CI: 7.6 to 15.4) in the early integrated, late-integrated, and delayed treatment arms (P = 0.313). Incidence rate of LTFU before and after ART initiation was 31.7 per 100 PY (95% CI: 11.6 to 69.0) vs. 6.1 per 100 PY (95% CI: 3.7 to 9.4); incidence rate ratio (IRR) was 5.2 (95% CI: 2.1 to 13.0; P < 0.001) in the early integrated arm; 31.9 per 100 PY (95% CI: 20.4 to 47.5) vs. 4.7 per 10 PY (95% CI: 2.4 to 8.2) and IRR was 6.8 (95% CI: 3.4 to 13.6; P < 0.0001) in the late-integrated arm; and 21.9 per 100 PY (95% CI: 14.6 to 31.5) vs. 2.8 per 100 PY (95% CI: 0.9 to 6.6) and IRR was 7.7 (95% CI: 3.0 to 19.9; P < 0.0001) in the sequential arm. Conclusion:LTFU rates were not significantly different between the 3 trials arms. However, ART initiation within each trial arm resulted in a significant reduction in LTFU rates among TB patients.