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

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

CAPRISA, 2016.Abstract available in pdf

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.

CAPRISA, 2017.Abstract available in pdf

Recurrent tuberculosis among HIV-coinfected patients: a case series from KwaZulu-Natal.

CAPRISA, 2018.Abstract available in pdf

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 human immunodeficiency virus (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 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 > 1000 copies/ml on two occasions, taken at least 4 weeks apart) were assessed in these patients. Results—A total of 501 TB-HIV co-infected patients were followed for a mean of 16.0 (95% confidence interval (CI): 15.5 to 16.6) months after antiretroviral therapy (ART) initiation. The standard first-line ARVs 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 to 3.5), and complete regimen changes due to virological failure in 25 patients (incidence rate: 3.7 per 100 person-years; CI: 2.4 to 5.5). The most common treatment limiting toxicities were neuropsychiatric effects (n=4; 0.8%), elevated transaminase levels and hyperlactatemia (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+ cell count <50cells/mm3 (p<0.001) at ART initiation and body mass index greater than 25 kg/m2 (p=0.01) at entry into the study. Conclusion—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

Ex vivo HIV entry into blood CD4+ T cells does not predict heterosexual HIV acquisition in women.

CAPRISA, 2018.Abstract available in pdf

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

CAPRISA, 2017.Abstract available in pdf

The multi-country PROMOTE HIV antiretroviral treatment observational cohort in Sub-Saharan Africa: objectives, design, and baseline findings.

CAPRISA, 2018.Abstract available in pdf