Integrating human immunodeficiency virus and tuberculosis drug treatment.

Ph. D. University of KwaZulu-Natal, Durban 2014.The human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics are major global public health challenges. Worldwide, approximately 42% of TB patients are also co-infected with HIV, and sub-Saharan Africa (SSA) is home to the majority of the world’s infections of both HIV and TB. Dual infection has been shown to be associated with a higher risk of death. Integrating drug treatment for both diseases is therefore essential to improve survival. However, drug interactions between antiretroviral therapy (ART) and anti-TB medication remain a challenge to effective treatment integration. Although several drug interactions have been identified, only some are clinically relevant. The impact of significant interactions on public health outcomes is expected to be greatest when large numbers of patients are prescribed interacting drugs. Efavirenz (EFV) is the most commonly prescribed nucleoside reverse transcriptase inhibitor (NNRTI) component of first line ART in sub-Saharan Africa, particularly when rifampicin (RIF) based TB treatment is co-administered. RIF is known to up-regulate cytochrome P450 (CYP450) drug metabolizing enzymes resulting in decreased exposure to concomitantly administered drugs that utilize similar metabolic pathways. Therefore, the concomitant use of EFV with RIF would be expected to increase EFV clearance while absorption of TB drugs may also be compromised by advanced HIV disease. The efficacy of both TB and HIV treatment may thus be compromised by pharmacokinetic interactions, while more recent evidence also implicates genetic variation in drug metabolism as a predictor of drug exposure. To understand the significance of the EFV-RIF interaction better in a South African population, the pharmacokinetics of EFV during and after RIF-based TB treatment were investigated as an ancillary study of the ‘Starting Tuberculosis and Antiretroviral Therapy’ (START) trial (CAPRISA 001: NCT00091936). Participants were randomized to receive both ART and TB treatment simultaneously (integrated arm) or to initiate ART only on completion of TB treatment (sequential arm). In both arms, the ART regimen included once daily enteric-coated didanosine (400 mg for participants >60 kg; 250 mg for participants <60 kg), lamivudine 300mg and efavirenz. Based on the expected drug interactions, when EFV was administered in the presence of TB treatment, participants weighing less than 50kg received 600mg and those weighing 50kg or more received 800mg daily. After TB treatment was successfully completed, all patients received EFV 600mg. Blood samples for trough EFV plasma concentrations were obtained at the end of months 1, 2 and 3 during TB treatment and at the same time points after TB treatment was successfully completed. Additionally, approximated peak RIF concentrations were measured 2.5 hours post-dose at the end of months 1, 2 and 3 of TB treatment. The influence of single nucleotide polymorphisms, in CYP2B6, CYP2A6, and UGT2B7 on EFV concentrations, and in drug transporter genes (SLCO1B1) on RIF concentrations, was assessed post-trial from stored peripheral blood mononuclear cell (PBMC) samples. EFV concentration-time data were analyzed using a population pharmacokinetic nonlinear mixed effects model (NONMEM) to quantify the impact of RIF-based TB treatment on EFV clearance. Unexpectedly, there was an overall 29.5% reduction in EFV clearance during TB treatment. A bimodal distribution of EFV apparent clearance (CL/F) was evident and indicated that slow EFV metabolisers accounted for 21.9% of the population. EFV clearance after oral administration in fast metabolisers was 11.5 L/h/70kg off TB treatment and 7.6 L/h/70kg when on TB treatment. In slow metabolisers, however, the clearance estimates were 2.9 and 4.3 L/h/70kg in the presence and absence of TB treatment respectively. Building on the findings of the NONMEM analysis and in response to the US FDA prescribing change in 2012, that approved an EFV dose increase from 600mg to 800mg in patients weighing 50kg and more when on concomitant RIF, the presence and influence of pharmacogenetic polymorphisms of the CYP450 enzyme system on NNRTI plasma exposure during and after TB co-treatment and the effect of increasing the EFV dose was investigated. During TB treatment, median (IQR) EFV Cmin was 3.2 (2.6-6.3) μg/mL and 3.3 (2.4-9.5) μg/mL in the EFV 800mg and 600mg groups respectively, while off TB treatment Cmin was 2.0 (1.4 - 3.5) μg/mL. The frequency of the CYP2B6 *1, *6 and *18 haplotypes was 18.5%, 38.9% and 25.9% respectively. Polymorphisms in all three CYP2B6 genes studied (516T-785G-983C) were present in 11.1% of patients. Median (IQR) EFV concentrations in patients with the three mutations were 19.2 (9.5-20) μg/mL and 4.7 (3.5-5.6) μg/mL when on and off TB treatment. TB treatment, composite genotypes CYP2B6 516 GT/TT, CYP2B6 983 TC/CC or being a CYP2A6*9B carrier predicted median EFV Cmin > 4 μg/mL. Therefore, increasing the EFV dose to 800mg during TB treatment is unnecessary in African patients with these polymorphisms. As a critical component of first line TB treatment concerns about sub-optimal TB drug bioavailability were examined for RIF. The influence of drug transporter gene polymorphisms on RIF concentrations was also assessed. Median RIF (IQR) C2.5hr was found to be 3.6 (2.8-5.0) μg/mL while polymorphism frequency of the SLCO1B1 (rs4149032) drug transporter gene was high (0.76) and was associated with low RIF concentrations as was male gender and having a low haemoglobin. Increased RIF dosage warrants urgent consideration in African TB-HIV co-infected patients. In conclusion, concomitant RIF-containing TB treatment unexpectedly reduced EFV CL/F with a corresponding increase in EFV exposure. Polymorphisms of EFV metabolizing enzymes were frequent in this population and contribute to this outcome. While in South Africa where TB-HIV co-treatment is associated with elevated EFV concentrations, peak RIF concentrations were alarmingly low and well below the recommended target range of 8 to 24 μg/mL. Increased RIF dosage may be warranted in African TB-HIV co-infected patients whilst the need for EFV dose increase is not supported by these data. Recommendations for public health benefit, in this generalized epidemic in South Africa, include the consideration of an EFV dose reduction as a cost saving to improve life-long treatment sustainability, and a RIF dose increase to curb TB treatment failure and future development of multiple-drug resistant (MDR) TB

Ritonavir/saquinavir safety concerns curtail antiretroviral therapy options for tuberculosis–HIV-co-infected patients in resource-constrained settings.

CorrespondenceNo abstract available

A qualitative study of patient motivation to adhere to combination antiretroviral therapy in South Africa.

CAPRISA, 2015.Abstract available in pdf

COVID-19 vaccine hesitancy in KwaZulu-Natal, South Africa: A survey of unvaccinated adults

Background: Concerns and misconceptions surrounding coronavirus disease 2019 (COVID-19) vaccines may account for vaccine hesitancy and low uptake. Aim: To determine prevalence of COVID-19 vaccine hesitancy, vaccine-related misconceptions, and predictors of vaccine hesitancy among South Africans. Setting: Community setting in five districts in KwaZulu- Natal province. Methods: Between August 20, 2021, and September 27, 2021, we conducted a cross-sectional survey, interviewing 300 unvaccinated adults amid the national vaccination campaign. Predictors of hesitancy were identified through multivariable logistic regression analysis. Results: Participants had a median age of 29 years (IQR: 23–39), 86.7% were Black African, 63.2% were male, 53.3% resided in rural communities, and 59.3% (95% CI: 53.8% – 64.9%) were classified as vaccine hesitant. The primary reason for not vaccinating was a lack of trust in the vaccine (62.1%). Factors associated with reduced vaccine hesitancy included age (participants aged 35–49 years: OR: 0.28, 95% CI: 0.18–0.64, p = 0.003; participants over 50 years: OR: 0.18, 95% CI: 0.07–0.47, p = 0.0004), previous COVID-19 infection (OR: 0.31, 95% CI: 0.11–0.87, p = 0.03), and receiving vaccine information from healthcare workers (OR: 0.32, 95% CI: 0.10–1.0, p = 0.05). Unemployed (OR: 2.14, 95% CI: 1.1–4.2, p = 0.03) and self-employed individuals (OR: 2.98, 95% CI: 1.27–7.02, p = 0.01) were more likely to be vaccine hesitant. Conclusion: COVID-19 vaccine hesitancy rates are high in KwaZulu-Natal. Uptake could be enhanced by healthcare workers leading information campaigns with messages targeting younger individuals, the unemployed, and the self-employed. Contribution: This survey provides evidence to improve COVID-19 vaccination uptake in South Africa

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

CAPRISA, 2016.Abstract available in pdf

Low rifampicin concentrations in tuberculosis patients with HIV infection.

CAPRISA, 2014Abstract available in pdf

Co-enrollment in multiple HIV prevention trials — Experiences from the CAPRISA 004 Tenofovir gel trial

Background: In settings where multiple HIV prevention trials are conducted in close proximity, trial participants may attempt to enroll in more than one trial simultaneously. Co-enrollment impacts on participant's safety and validity of trial results. We describe our experience, remedial action taken, inter-organizational collaboration and lessons learnt following the identification of co-enrolled participants. Experiences: Between February and April 2008, we identified 185 of the 398 enrolled participants as ineligible. In violation of the study protocol exclusion criteria, there was simultaneous enrollment in another HIV prevention trial (ineligible co-enrolled, n = 135), and enrollment of women who had participated in a microbicide trial within the past 12 months (ineligible not co-enrolled, n = 50). Following a complete audit of all enrolled participants, ineligible participants were discontinued via study exit visits from trial follow-up. Custom-designed education program on co-enrollment impacting on participants' safety and validity of the trial results was implemented. Shared electronic database between research units was established to enable verification of each volunteer's trial participation and to prevent future co-enrollments. Lessons learnt: Interviews with ineligible enrolled women revealed that high-quality care, financial incentives, altruistic motives, preference for sex with gel, wanting to increase their likelihood of receiving active gel, perceived low risk of discovery and peer pressure are the reasons for their enrollment in the CAPRISA 004 trial. Conclusion: Instituting education programs based on the reasons reported by women for seeking enrollment in more than one trial and using a shared central database system to identify co-enrollments have effectively prevented further co-enrollments

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

Integration of antiretroviral therapy with tuberculosis treatment.

Background. We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved. Methods. We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier- ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here. Results. At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P = 0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P = 0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P = 0.006). Conclusions. Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death

Recruitment of high risk women for HIV prevention trials: baseline HIV prevalence and sexual behavior in the CAPRISA 004 tenofovir gel trial

<p>Abstract</p> <p>Background</p> <p>Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection compared to men but have limited options to reduce their HIV risk. Microbicides could fill an important HIV prevention gap for sexually active women who are unable to successfully negotiate mutual monogamy or condom use.</p> <p>Purpose</p> <p>This paper describes the baseline sample characteristics in the CAPRISA 004 trial which assessed the safety and effectiveness of the vaginal microbicide, 1% tenofovir gel for HIV prevention in South Africa.</p> <p>Methods</p> <p>This analysis assessed the baseline demographic, clinical and sexual behavior data of women screened and enrolled into the trial. The characteristics were summarized using descriptive summary measures; expressed as means and percent for categorical variables.</p> <p>Results</p> <p>HIV prevalence at screening was 25.8% [95% Confidence Interval (CI):23.9-27.7). Of the 889 eligibly enrolled women who contributed follow-up data, rural participants recruited from a family planning (FP) clinic were younger, more likely to be living apart from their regular partner, reported lower coital frequency, had lower condom use (p < 0.001). In contrast, urban participants recruited from a sexually transmitted disease (STD) clinic reported higher numbers of lifetime sexual partners, new partners in the last 30 days and receiving money in exchange for sex (p < 0.001).</p> <p>Conclusion</p> <p>The populations selected provide suitable diverse target groups for HIV prevention intervention studies.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00441298">NCT 00441298</a></p