Background We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, optimal time to initiate ART during tuberculosis treatment remains contentious. Methods To address this, we conducted a 3-arm, open-label randomized controlled trial in South Africa in acid-fast bacilli smear positive patients (n=642) with HIV and CD4+ counts <500 cells/mm3. Findings on the early therapy group (ART initiated within 4 weeks of tuberculosis treatment initiation, n=214) and late therapy group (ART initiated within the first 4 weeks of the continuation phase of tuberculosis treatment, n=215) are presented here. Results Median CD4+ count and viral load at baseline was 150 cells/mm3 and 161000 copies/ml, being similar in both groups. Incidence rate of AIDS or death was 6.9 (18/259.4) and 7.8 (19/244.2) per 100 person-years in the early and late therapy groups respectively (Incidence Rate Ratio (IRR)=0.89; 95%Confidence Interval (95%CI): 0.44,1.79; P=0.73). However, in patients with CD4+ counts <50 cells/mm3, the incidence rates of AIDS or death were 8.5 (early) and 26.3 (late) per 100 person-years (IRR=0.32; 95%CI: 0.07,1.13; P=0.06). Immune reconstitution inflammatory syndrome (IRIS) incidence rates were 20.2 (early) and 7.7 (late) per 100 person-years (IRR=2.62; 95%CI: 1.48,4.82; P<0.001). Adverse events requiring antiretroviral drug switches occurred in 10 (early) and 1 (late) patients (P=0.006). Conclusions The benefits of AIDS-free survival balanced against the risks of IRIS and ART-related adverse events, support early ART initiation in patients with CD4+ counts <50 cells/mm3 and deferred ART initiation to the continuation phase of tuberculosis treatment when CD4+ counts are higher.

Background Concerns about immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during anti-tuberculosis treatment in co-infected patients. Objective We assessed IRIS incidence, severity, and outcomes relative to timing of ART initiation in patients with HIV-related tuberculosis (HIV-TB). Setting An outpatient clinic in Durban, South Africa Patients 642 HIV-TB co-infected patients Design In a secondary analysis of the SAPiT trial, IRIS was assessed in patients randomized to initiate ART either within four weeks of tuberculosis treatment initiation (early integrated-treatment arm), within four weeks of completion of the intensive phase of tuberculosis treatment (late integrated-treatment arm) or within four weeks after tuberculosis therapy completion (sequential-treatment arm). IRIS was defined as new onset or worsening symptoms, signs or radiographic manifestations temporally related to treatment initiation accompanied by a treatment response. IRIS severity, hospitalization and time to resolution were monitored. Results IRIS incidence 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 arms, respectively; P < 0.001, and 45.5, 9.7 and 19.7 per 100 person-years in patients with baseline CD4+ counts <50 cells/mm3, P = 0.004. IRIS incidence was higher in the early integrated- compared to the late integrated- (incidence rate ratio (IRR) = 2.6, 95%confidence interval (CI): 1.5 to 4.8; P < 0.001) or sequential-treatment arm (IRR=2.4, 95%CI: 1.4 to 4.4; P < 0.001). IRIS cases in the early integrated-treatment arm were more severe (34.9% vs. 18.9%, P = 0.18); had significantly higher hospitalization rates (18/43 vs. 5/37; P = 0.01), and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) compared to IRIS cases in the other two arms. Limitation IRIS could not be assessed, due to LTFU, withdrawal or death within 6 months of scheduled ART initiation, in more patients from the sequential treatment arm (n=74) than in the late integrated treatment arm (n=50) and in the early integrated treatment arm (n=32). This study did not assess IRIS risk in non-ambulant patients and in patients with extra-pulmonary and smear negative pulmonary tuberculosis. Conclusion Initiation of ART early during tuberculosis treatment resulted in significantly higher IRIS rates, with longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings, particularly relevant to patients initiating ART with CD4+ counts < 50 cells/mm3, need to be considered together with the increased survival benefit of early ART initiation in this group. Clintrials.gov: NCT00398996

BackgroundA large and compelling clinical evidence base has shown that integrated TB and HIV services leads to reduction in human immunodeficiency virus (HIV)- and tuberculosis (TB)-associated mortality and morbidity. Despite official policies and guidelines recommending TB and HIV care integration, its poor implementation has resulted in TB and HIV remaining the commonest causes of death in several countries in sub-Saharan Africa, including South Africa. This study aims to reduce mortality due to TB-HIV co-infection through a quality improvement strategy for scaling up of TB and HIV treatment integration in rural primary healthcare clinics in South Africa.MethodsThe study is designed as an open-label cluster randomized controlled trial. Sixteen clinic supervisors who oversee 40 primary health care (PHC) clinics in two rural districts of KwaZulu-Natal, South Africa will be randomized to either the control group (provision of standard government guidance for TB-HIV integration) or the intervention group (provision of standard government guidance with active enhancement of TB-HIV care integration through a quality improvement approach). The primary outcome is all-cause mortality among TB-HIV patients. Secondary outcomes include time to antiretroviral therapy (ART) initiation among TB-HIV co-infected patients, as well as TB and HIV treatment outcomes at 12 months. In addition, factors that may affect the intervention, such as conditions in the clinic and staff availability, will be closely monitored and documented.DiscussionThis study has the potential to address the gap between the establishment of TB-HIV care integration policies and guidelines and their implementation in the provision of integrated care in PHC clinics. If successful, an evidence-based intervention comprising change ideas, tools, and approaches for quality improvement could inform the future rapid scale up, implementation, and sustainability of improved TB-HIV integration across sub-Sahara Africa and other resource-constrained settings.Trial registrationClinicaltrials.gov, NCT02654613. Registered 01 June 2015.

Taken as prescribed, that is, with high adherence, combination antiretroviral therapy (ART) has changed HIV infection and disease from being a sure predictor of death to a manageable chronic illness. Adherence, however, is difficult to achieve and maintain. The CAPRISA 058 study was conducted between 2007 and 2009 to test the efficacy of individualized motivational counselling to enhance ART adherence in South Africa. As part of the overall trial, a qualitative sub-study was conducted, including 30 individual interviews and four focus group discussions with patients in the first 9 months of ART initiation. Data were inductively analyzed, using thematic analysis, to identify themes central to ART adherence in this context. Four themes emerged that characterize the participants' experiences and high motivation to adhere to ART. Participants in this study were highly motivated to adhere, as they acknowledged that ART was 'life-giving', in the face of a large amount of morbidity and mortality. They were further supported by techniques of routine remembering, and highlighted the importance of good social support and access to supportive healthcare workers, to their continued success in negotiating their treatment. Participants in the current study told us that their adherence motivation is enhanced by free accessible care, approachable and supportive healthcare workers, broad social acceptance of ART, and past first-hand experiences with AIDS-related co-morbidity and mortality. Programs that include specific attention to these aspects of care will likely be successful in the long term.