Adjusting the effect of integrating antiretroviral therapy and tuberculosis treatment on mortality for non-compliance : an instrumental variables analysis using a time-varying exposure.

Doctoral Degree. University of KwaZulu-Natal, Pietermaritzburg.In South Africa and elsewhere, research has shown that the integration of antiretroviral therapy (ART) and tuberculosis (TB) treatment saves lives. The randomised controlled trials (RCTs) which provided this compelling evidence used intent-to-treat (ITT) strategy as part of their primary analysis. As much as ITT is protected against selection bias caused by both measured and unmeasured confounders, but it is capable of drawing results towards the null and underestimate the e ectiveness of treatment if there is too much non-compliance. To adjust for non-compliance, \as-treated"and \per-protocol"comparisons are commonly made. These contrast study participants according to their received treatment, regardless of the treatment arm to which they were assigned, or limit the analysis to participants who followed the protocol. Such analyses are generally biased because the subgroups which they compare often lack comparability. In view of the shortcomings of the \as-treated"and \per-protocol"analyses, our objective was to account for non-compliance by using instrumental variables (IV) analysis to estimate the e ect of ART initiation during TB treatment on mortality. Furthermore, to capture the full complexity of compliance behaviour outside the TB treatment duration, we developed a novel IV-methodology for a time-varying measure of compliance to ART. This is an important contribution to the IV literature since IV-methodology for the e ect of a time-varying exposure on a time-to-event endpoint is currently lacking. In RCTs, IV analysis enable us to make use of the comparability o ered by randomisation and thereby have the capability of adjusting for unmeasured and measured confounders; they have the further advantage of yielding results that are less sensitive to random measurement error in the exposure. In order to carry out IV analysis, one needs to identify a variable called an instrument, which needs to satisfy three important assumptions. To apply the IV methodology, we used data from Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial which was conducted by the Centre for the AIDS Programme of Research in South Africa. This trial enrolled HIV and TB co-infected patients who were assigned to start ART either early or late during TB treatment or after TB treatment completion. The results from IV analysis demonstrate that survival bene t of fully integrating TB treatment and ART is even higher than what has been reported in the ITT analysis since non-compliance has been accounted for

A retrospective cohort study of body mass index and survival in HIV infected patients with and without TB co-infection.

CAPRISA, 2018.Abstract available in pdf

Adjusting the effect of integrating antiretroviral therapy and tuberculosis treatment on mortality for non-compliance: a time-varying instrumental variables analysis.

CAPRISA, 2019.Abstract available in PDF

Using joint models to study the association between CD4 count and the risk of death in TB/HIV data

BACKGROUND: The association structure linking the longitudinal and survival sub-models is of fundamental importance in the joint modeling framework and the choice of this structure should be made based on the clinical background of the study. However, this information may not always be accessible and rationale for selecting this association structure has received relatively little attention in the literature. To this end, we aim to explore four alternative functional forms of the association structure between the CD4 count and the risk of death and provide rationale for selecting the optimal association structure for our data. We also aim to compare the results obtained from the joint model to those obtained from the time-varying Cox model. METHODS: We used data from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) AIDS Treatment programme, the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) study, an open-label, three armed randomised, controlled trial between June 2005 and July 2010 (N=642). In our analysis, we combined the early and late integrated arms and compared results to the sequential arm. We utilized the Deviance Information Criterion (DIC) to select the final model with the best structure, with smaller values indicating better model adjustments to the data. RESULTS: Patient characteristics were similar across the study arms. Combined integrated therapy arms had a reduction of 55% in mortality (HR:0.45, 95% CI:0.28-0.72) compared to the sequential therapy arm. The joint model with a cumulative effects functional form was chosen as the best association structure. In particular, our joint model found that the area under the longitudinal profile of CD4 count was strongly associated with a 21% reduction in mortality (HR:0.79, 95% CI:0.72-0.86). Where as results from the time-varying Cox model showed a 19% reduction in mortality (HR:0.81, 95% CI:0.77-0.84). CONCLUSIONS: In this paper we have shown that the “current value” association structure is not always the best structure that expresses the correct relationship between the outcomes in all settings, which is why it is crucial to explore alternative clinically meaningful association structures that links the longitudinal and survival processes

Assessing adherence to antiretroviral therapy in a rural paediatric cohort in KwaZulu-Natal, South Africa.

CAPRISA, 2016.Abstract available in pdf

Community-based intervention is necessary for the control of HIV in North-Central Nigeria.

Objectives: To determine factors associated with the observed high prevalence of HIV in North-Central Nigeria. Methods: In a cross-sectional multisite study conducted in 2007, behavioral, medical, and demographic data were obtained from pregnant women (N = 1011) who were tested for the presence of antibody against HIV-1 and HIV-2. Results: The overall prevalence of HIV-1 in the 1011 women included in the study was 10.3% (95% confidence interval (CI) 8.4–12.2). In the multivariate analysis, HIV-1 seropositivity was significantly associated with women from the Makurdi (odds ratio (OR) 31.3, 95% CI 3.8–255.7) and Minna (OR 15.4, 95% CI 1.7–135.1) sites in comparison with Panyam site. The presence of tuberculosis (OR 10.7, 95% CI 2.4–48.3) was also significantly associated with HIV-1 seropositive status. Factors associated with HIV-1 also differed between sites. The presence of antibody against HIV-2 was not observed. Conclusions: The high HIV-1 prevalence observed in this study corroborates previous observations in North-Central Nigeria. Disparity in the prevalence across communities was also seen. This is the only detailed socio-epidemiological and behavioral study that has explored potential factors associated with HIV-1 in North-Central Nigeria, and it revealed that differences in risk factors explain the disparity in prevalence across communities

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

HIV prevalence among high school learners - opportunities for schools-based HIV testing programmes and sexual reproductive health services

Young girls in sub Saharan Africa are reported to have higher rates of human immunodeficiency virus (HIV) infection compared to boys in the same age group. Knowledge of HIV status amongst high schools learners provides an important gateway to prevention and treatment services. This study aimed at determining the HIV prevalence and explored the feasibility of HIV testing among high school learners. Between September 2010 and February 2011, a linked, anonymous cross-sectional survey was conducted in two public sector high schools in the rural KwaZulu-Natal midlands. Following written informed consent, dried blood spot samples (DBS) were collected and tested for HIV. The overall and age-specific HIV prevalence were compared with select demographic variables. The HIV prevalence in learners aged 12 to 25 in school A was 4.7% (95% CI 2.8-6.5) compared to 2.5% (95% CI 1.6-3.5) in school B, (p = 0.04). Whilst the HIV prevalence was similar for boys at 1.3% (95% CI 0-2.8) in school A and 1.7% (95% CI 0.5-2.8) in school B, the prevalence in girls was consistently higher and was 7.7% (95% CI 4.5-10.9) in school A and 3.2% (95% CI 1.8-4.6) in school B. The age-specific HIV prevalence in girls increased 1.5 to 2 fold for each two year age category, while for boys the prevalence was stable across all age groups. The high HIV prevalence in female learners underscores the importance of sexual reproductive health and schools-based HIV testing programs as an important gateway to prevention and treatment services

Mortality in HIV and tuberculosis patients following implementation of integrated HIV-TB treatment: Results from an open-label cluster-randomized trial

Background: HIV-TB treatment integration reduces mortality. Operational implementation of integrated services is challenging. This study assessed the impact of quality improvement (QI) for HIV-TB integration on mortality within primary healthcare (PHC) clinics in South Africa. // Methods: An open-label cluster randomized controlled study was conducted between 2016 and 2018 in 40 rural clinics in South Africa. The study statistician randomized PHC nurse-supervisors 1:1 into 16 clusters (eight nurse-supervisors supporting 20 clinics per arm) to receive QI, supported HIV-TB integration intervention or standard of care (control). Nurse supervisors and clinics under their supervision, based in the study health districts were eligible for inclusion in this study. Nurse supervisors were excluded if their clinics were managed by municipal health (different resource allocation), did not offer co-located antiretroviral therapy (ART) and TB services, services were performed by a single nurse, did not receive non-governmental organisation (NGO) support, patient data was not available for > 50% of attendees. The analysis population consists of all patients newly diagnosed with (i) both TB and HIV (ii) HIV only (among patients previously treated for TB or those who never had TB before) and (iii) TB only (among patients already diagnosed with HIV or those who were never diagnosed with HIV) after QI implementation in the intervention arm, or enrolment in the control arm. Mortality rates was assessed 12 months post enrolment, using unpaired t-tests and cox-proportional hazards model. (Clinicaltrials.gov, NCT02654613, registered 01 June 2015, trial closed). // Findings: Overall, 21 379 participants were enrolled between December 2016 and December 2018 in intervention and control arm clinics: 1329 and 841 HIV-TB co-infected (10·2%); 10 799 and 6 611 people living with Human Immunodeficiency Virus (HIV)/ acquired immunodeficiency syndrome (AIDS) (PLWHA) only (81·4%); 1 131 and 668 patients with TB only (8·4%), respectively. Average cluster sizes were 1657 (range 170–5782) and 1015 (range 33–2027) in intervention and control arms. By 12 months, 6529 (68·7%) and 4074 (70·4%) were alive and in care, 568 (6·0%) and 321 (5·6%) had completed TB treatment, 1078 (11·3%) and 694 (12·0%) were lost to follow-up, with 245 and 156 deaths occurring in intervention and control arms, respectively. Mortality rates overall [95% confidence interval (CI)] was 4·5 (3·4–5·9) in intervention arm, and 3·8 (2·6–5·4) per 100 person-years in control arm clusters [mortality rate ratio (MRR): 1·19 (95% CI 0·79–1·80)]. Mortality rates among HIV-TB co-infected patients was 10·1 (6·7–15·3) and 9·8 (5·0–18·9) per 100 person-years, [MRR: 1·04 (95% CI 0·51–2·10)], in intervention and control arm clusters, respectively. // Interpretation: HIV-TB integration supported by a QI intervention did not reduce mortality in HIV-TB co-infected patients. Demonstrating mortality benefit from health systems process improvements in real-world operational settings remains challenging. Despite the study being potentially underpowered to demonstrate the effect size, integration interventions were implemented using existing facility staff and infrastructure reflecting the real-world context where most patients in similar settings access care, thereby improving generalizability and scalability of study findings

Correction to: Addressing challenges in scaling up TB and HIV treatment integration in rural primary healthcare clinics in South Africa (SUTHI): a cluster randomized controlled trial protocol

Following publication of the original article [1], the authors reported an error in the wording of the study hypothesis. The error occurs in the Aims and Objectives sub-section of the Methods section and is highlighted in bold below