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Papers by Nonhlanhla Yende

Research paper thumbnail of Organizational contextual factors that predict success of a quality improvement collaborative approach to enhance integrated HIV-tuberculosis services: a sub-study of the Scaling up TB/HIV Integration trial

Implementation Science

Background A quality improvement (QI) collaborative approach to enhancing integrated HIV-Tubercul... more Background A quality improvement (QI) collaborative approach to enhancing integrated HIV-Tuberculosis (TB) services may be effective in scaling up and improving the quality of service delivery. Little is known of the role of organizational contextual factors (OCFs) in influencing the success of QI collaboratives. This study aims to determine which OCFs were associated with improvement in a QI collaborative intervention to enhance integrated HIV-TB services delivery. Methods This is a nested sub-study embedded in a cluster-randomized controlled trial. Sixteen nurse supervisors (clusters) overseeing 40 clinics were randomized (1:1) to receive QI training and mentorship, or standard of care support (SOC). In the QI arm, eight nurse supervisors and 20 clinics formed a “collaborative” which aimed to improve HIV-TB process indicators, namely HIV testing, TB screening, isoniazid preventive therapy (IPT) initiations, viral load testing, and antiretroviral therapy for TB patients. OCFs measu...

Research paper thumbnail of A cluster‐randomized controlled trial to improve the quality of integrated HIV‐tuberculosis services in primary healthcareclinics in South Africa

Journal of the International AIDS Society

Research paper thumbnail of High incidence and persistence of hepatitis B virus infection in individuals receiving HIV care in KwaZulu-Natal, South Africa

BMC Infectious Diseases

Background Hepatitis B virus (HBV), Human Immunodeficiency virus (HIV) and Tuberculosis (TB) are ... more Background Hepatitis B virus (HBV), Human Immunodeficiency virus (HIV) and Tuberculosis (TB) are common infections in South Africa. We utilized the opportunity of care provision for HIV-TB co-infected patients to better understand the relationship between these coinfections, determine the magnitude of the problem, and identify risk factors for HBV infection in HIV infected patients with and without TB in KwaZulu-Natal, South Africa. Methods This retrospective cohort analysis was undertaken in 2018. In-care HIV infected patients were included in the analysis. Results from clinical records were analysed to determine the prevalence, incidence, persistence and factors associated with HBsAg positivity in HIV-infected patients with or without TB co-infection. Results A total of 4292 HIV-infected patients with a mean age of 34.7 years (SD: 8.8) were included. Based on HBsAg positivity, the prevalence of HBV was 8.5% (363/4292) [95% confidence interval (CI): 7.7–9.3] at baseline and 9.4% (9...

Research paper thumbnail of Developing excellence in biostatistics leadership, training and science in Africa: How the Sub-Saharan Africa Consortium for Advanced Biostatistics (SSACAB) training unites expertise to deliver excellence

AAS Open Research

The increase in health research in sub-Saharan Africa (SSA) has generated large amounts of data a... more The increase in health research in sub-Saharan Africa (SSA) has generated large amounts of data and led to a high demand for biostatisticians to analyse these data locally and quickly. Donor-funded initiatives exist to address the dearth in statistical capacity, but few initiatives have been led by African institutions. The Sub-Saharan African Consortium for Advanced Biostatistics (SSACAB) aims to improve biostatistical capacity in Africa according to the needs identified by African institutions, through (collaborative) masters and doctoral training in biostatistics. We describe the SSACAB Consortium, which comprises 11 universities and four research institutions- supported by four European universities. SSACAB builds on existing resources to strengthen biostatistics for health research with a focus on supporting biostatisticians to become research leaders; building a critical mass of biostatisticians, and networking institutions and biostatisticians across SSA. In 2015 only four ...

Research paper thumbnail of HPV infection and the genital cytokine milieu in women at high risk of HIV acquisition

Nature Communications

Human papillomavirus (HPV) infection correlates with higher rates of HIV acquisition, but the und... more Human papillomavirus (HPV) infection correlates with higher rates of HIV acquisition, but the underlying biological mechanisms are unclear. Here we study associations between HPV and HIV acquisition and relate these to vaginal cytokine profiles in an observational cohort of women at high risk of HIV infection (CAPRISA 004, n = 779) and with 74% HPV prevalence. We report here that HPV infection associates with a 2.5-fold increase in HIV acquisition risk in this population (95% CI: 1.2–5.3). Among 48 vaginal cytokines profiled, cytokines associated with HPV infection overlap substantially with cytokines associated with HIV risk, but are distinct from those observed in HPV negative women. Although our data do not establish a causative link between HPV status and the risk of HIV, we suggest that increasing HPV vaccination coverage may carry an additional benefit of reducing the risk of contracting HIV infection, particularly in regions with high HPV prevalence.

Research paper thumbnail of Impact of pretreatment low-abundance HIV-1 drug-resistant variants on virological failure among HIV-1/TB-co-infected individuals

Journal of Antimicrobial Chemotherapy

Objectives To determine the impact of pretreatment low-abundance HIV-1 drug-resistant variants (L... more Objectives To determine the impact of pretreatment low-abundance HIV-1 drug-resistant variants (LA-DRVs) on virological failure (VF) among HIV-1/TB-co-infected individuals treated with NNRTI first-line ART. Methods We conducted a case–control study of 170 adults with HIV-1/TB co-infection. Cases had at least one viral load (VL) ≥1000 RNA copies/mL after ≥6 months on NNRTI-based ART, and controls had sustained VLs <1000 copies/mL. We sequenced plasma viruses by Sanger and MiSeq next-generation sequencing (NGS). We assessed drug resistance mutations (DRMs) using the Stanford drug resistance database, and analysed NGS data for DRMs at ≥20%, 10%, 5% and 2% thresholds. We assessed the effect of pretreatment drug resistance (PDR) on VF. Results We analysed sequences from 45 cases and 125 controls. Overall prevalence of PDR detected at a ≥20% threshold was 4.7% (8/170) and was higher in cases than in controls (8.9% versus 3.2%), P = 0.210. Participants with PDR at ≥20% had almost 4-fold...

Research paper thumbnail of HIV treatment outcomes among people with initiation CD4 counts >500 cells/µL after implementation of Treat All in South African public clinics: a retrospective cohort study

Journal of the International AIDS Society

Introduction: The World Health Organisation recommends to Treat All people with HIV, irrespective... more Introduction: The World Health Organisation recommends to Treat All people with HIV, irrespective of CD4 count. However, people with CD4 counts >500 cells/µL may be asymptomatic and therefore less motivated to adhere to antiretroviral therapy (ART). We aimed to assess whether people initiated with CD4 counts >500 cells/µL had worse treatment outcomes compared to those initiated at lower CD4 counts. Methods: We performed a retrospective cohort study among non-pregnant adults initiating ART at eight public clinics in South Africa between September 2016, when Treat All was implemented, and August 2017. We assessed whether initiation CD4 count >500 cells/µL was associated with the outcomes of attrition (death, lost to follow-up or treatment interruption >180 days), and viraemia >1000 copies/mL, by twelve months using Cox proportional hazards and Poisson regression models. Results and discussion: Among 4952 patients initiating ART, the median age was 32.4 years (interquartile range (IQR) 27.2 to 39.7), 58.9% were women and 30.3% had an initiation CD4 count >500 cells/µL. After twelve months, 3382 (68.3%) were retained in care, 303 (6.1%) had transferred to another clinic, 1010 (20.4%) were lost to follow-up, 232 (4.7%) had a treatment interruption >180 days and 25 (0.5%) were known to have died. Overall, 1267 experienced attrition at a median time of 91 days (IQR 23 to 213), with 302 of these (23.8%) experiencing attrition immediately after their ART initiation visit. Among those in care at twelve months with viral load results, 4.6% had viraemia. In multivariable analysis, the hazard of attrition was similar between patients newly eligible for ART with CD4 counts >500 cells/µL compared to those with CD4 ≤500 cells/µL (adjusted hazard ratio 1.03, 95% confidence interval (CI) 0.90 to 1.17). The risk of viraemia was lower among patients with CD4 counts >500 cells/µL compared to those with CD4 ≤500 cells/µL (adjusted risk ratio 0.58, 95% CI 0.37 to 0.92). Conclusions: After implementation of Treat All in South African public clinics, we found that patients newly eligible for ART with initiation CD4 counts >500 cells/µL had comparable or better outcomes compared to those with lower CD4 counts. These finding support ongoing implementation of Treat All in our setting.

Research paper thumbnail of Trends in HIV Prevention, Treatment, and Incidence in a Hyperendemic Area of KwaZulu-Natal, South Africa

JAMA Network Open

IMPORTANCE In Africa, the persistently high HIV incidence rate among young women is the major obs... more IMPORTANCE In Africa, the persistently high HIV incidence rate among young women is the major obstacle to achieving the goal of epidemic control. OBJECTIVE To determine trends in coverage of HIV prevention and treatment programs and HIV incidence. DESIGN, SETTING, AND PARTICIPANTS This cohort study consisted of 2 sequential, communitybased longitudinal studies performed in the Vulindlela and Greater Edendale area in KwaZulu-Natal,

Research paper thumbnail of Factors associated with unsuppressed viremia in women living with HIV on lifelong ART in the multi-country US-PEPFAR PROMOTE study: A cross-sectional analysis

PLOS ONE

Background Despite recent efforts to scale-up lifelong combination antiretroviral therapy (cART) ... more Background Despite recent efforts to scale-up lifelong combination antiretroviral therapy (cART) in sub-Saharan Africa, high rates of unsuppressed viremia persist among cART users, and many countries in the region fall short of the UNAIDS 2020 target to have 90% virally suppressed. We sought to determine the factors associated with unsuppressed viremia (defined for the purpose of this study as >200 copies/ml) among sub-Saharan African women on lifelong cART. Methods This cross-sectional analysis was based on baseline data of the PROMOTE longitudinal cohort study at 8 sites in Uganda, Malawi, Zimbabwe and South Africa. The study enrolled 1987 women living with HIV who initiated lifelong cART at least 1-5 years ago. Socio-demographic, clinical, and cART adherence data were collected. We used multivariable Poisson regression with robust variance to identify factors associated with unsuppressed viremia. Results At enrolment, 1947/1987 (98%) women reported taking cART. Of these, HIV-1 remained detectable in 293/1934 (15%), while 216/1934 (11.2%) were considered unsuppressed (>200 copies/ml). The following factors were associated with an increased risk of

Research paper thumbnail of Risk of Nephrotoxicity in Patients With Drug-Resistant Tuberculosis Treated With Kanamycin/Capreomycin With or Without Concomitant Use of Tenofovir-Containing Antiretroviral Therapy

JAIDS Journal of Acquired Immune Deficiency Syndromes

Research paper thumbnail of Integrated provision of topical pre‐exposure prophylaxis in routine family planning services in South Africa: a non‐inferiority randomized controlled trial

Journal of the International AIDS Society

Introduction: Tenofovir-containing oral pre-exposure prophylaxis (PrEP) is recommended for those ... more Introduction: Tenofovir-containing oral pre-exposure prophylaxis (PrEP) is recommended for those at substantial risk as part of combination HIV prevention. However, there are limited data, beyond clinical trial settings, to guide the introduction of PrEP in healthcare services with adequate levels of adherence. Since young women in Africa are at high risk of HIV and likely to utilize family planning (FP) services, the feasibility, acceptability and effectiveness of integrating topical PrEP provision into routine FP services was assessed. Methods: This two-arm, randomized controlled, non-inferiority, open-label extension trial was undertaken in urban and rural KwaZulu-Natal, South Africa. HIV-negative eligible women (n = 372) from the parent trial (Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004) were randomized to receive tenofovir gel either through intervention (FP clinics, n = 189) or control clinics (CAPRISA research clinics, n = 183). Non-inferiority was predefined as gel use in the intervention clinics would be no more than 20% lower than in the control clinics. Adherence, retention and HIV incidence rates were assessed. Results: Women were enrolled between November 2012 and October 2014, and followed up for 682.3 women-years (mean = 22 months). Baseline characteristics of women in intervention and control clinics were comparable and retention rates were 92.1% and 92.3% respectively. Women in intervention clinics and control clinics returned on average 5.2 (95% confidence interval (CI): 4.7 to 5.7) and 5.7 (CI: 5.2 to 6.2) used gel applicators per month respectively, with a mean difference of À0.47 (CI: À1.16 to 0.21). Per-protocol estimates were on average 5.5 (CI: 5.0 to 6.1) and 5.8 (CI: 5.3 to 6.3) respectively, with a mean difference of À0.25 (CI: À0.98 to 0.48), meeting the non-inferiority criteria. Adherence, based on proportion of reported sex acts covered by two gel doses, was 79.9%

Research paper thumbnail of Assessing the safety and pharmacokinetics of the monoclonal antibodies, VRC07-523LS and PGT121 in HIV negative women in South Africa: study protocol for the CAPRISA 012A randomised controlled phase I trial

BMJ Open

IntroductionDespite extensive prevention campaigns and scale-up of antiretroviral therapy, HIV in... more IntroductionDespite extensive prevention campaigns and scale-up of antiretroviral therapy, HIV incidence among young women in southern Africa remains high. While the development of an efficacious vaccine remains a challenge, the discovery of broadly neutralising monoclonal antibodies (mAbs) has created the opportunity to explore passive immunisation as a long-acting injectable HIV prevention strategy. The purpose of this trial is to provide safety, pharmacokinetic (PK) and functional activity data of VRC07-523LS and PGT121 when administered subcutaneously (SC) to young South African women. Going forward, the aim is to select the ideal dose and/or monoclonal antibody for co-formulation and testing with CAP256-VRC26.25LS, a potent monoclonal antibody against subtype C virus, in an efficacy trial.Methods and analysisCAPRISA 012A is a randomised, double blinded, placebo-controlled phase I trial to assess the safety and PK profile of two mAbs, VRC07-523LS and PGT121 administered SC to 35...

Research paper thumbnail of Factors associated with unsuppressed viremia in women living with HIV on lifelong ART in a multi-country cohort study: US-PEPFAR PROMOTE study

Background: Despite recent efforts to scale-up lifelong combination antiretroviral therapy (cART)... more Background: Despite recent efforts to scale-up lifelong combination antiretroviral therapy (cART) in sub-Saharan Africa, high rates of unsuppressed viremia persist among cART users, and many countries in the region fall short of the UNAIDS 2020 target to have 90% virally suppressed. We sought to determine the factors associated with unsuppressed viremia (defined for the purpose of this study as >200 copies/ml) among African women on lifelong cART. Methods: This analysis was based on baseline data of the PROMOTE longitudinal cohort study at 8 sites in Uganda, Malawi, Zimbabwe and South Africa. The study enrolled 1987 women living with HIV who initiated lifelong cART at least 1 year previously to assesses long-term safety and effectiveness of cART. Socio-demographic, clinical, and cART adherence data were collected. We used multivariable Poisson regression with robust variance to identify factors associated with unsuppressed viremia. Results: At enrolment, 1947/1987 (98%) women reported taking cART. Of these, HIV-1 remained detectable in 293/1934 (15%), while 216/1934 (11.2%) were considered unsuppressed (>200 copies/ml). The following factors were associated with an increased risk of unsuppressed viremia: not having household electricity (adjusted prevalence rate ratio (aPRR) 1.74, 95% confidence interval (CI) 1.28-2.36, p<0.001); self-reported missed cART doses (aPRR 1.63, 95% CI 1.24-2.13, p<0.001); recent hospitalization (aPRR 2.48, 95% CI 1.28-4.80, p=0.007) and experiencing abnormal vaginal discharge in the last three months (aPRR 1.88; 95% CI 1.16-3.04, p=0.010). Longer time on cART (aPRR 0.75, 95% CI 0.64-0.88, p<0.001) and being older (aPRR 0.77, 95% CI 0.76-0.88, p<0.001) were associated with reduced risk of unsuppressed viremia. made available for use under a CC0 license.

Research paper thumbnail of Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy

Frontiers in Microbiology

Darboe et al. Transcriptomic TB Signature for HIV-Infected excellent diagnostic discrimination be... more Darboe et al. Transcriptomic TB Signature for HIV-Infected excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95%CI 0.94-1). Performance was lower in HIV-infected individuals (AUC 0.83; 95%CI 0.81-0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads.

Research paper thumbnail of Adjusting the Effect of Integrating Antiretroviral Therapy and Tuberculosis Treatment on Mortality for Noncompliance

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

Infectious Diseases of Poverty

Background: High early morbidity and mortality following antiretroviral therapy (ART) initiation ... more Background: High early morbidity and mortality following antiretroviral therapy (ART) initiation has been a distinguishing feature of ART programmes in resource limited settings (RLS) compared to high-income countries. This study assessed how well body mass index (BMI: kg/m 2) correlated with survival among HIV infected patients with and without TB co-infection. Methods: We retrospectively evaluated clinical data from 1000 HIV infected patients, among whom 389 were also co-infected with TB, between January 2008 and December 2010, in KwaZulu-Natal, South Africa. Results: Among 948 patients eligible for analysis, 15.7% (149/948) were underweight (< 18.50), 55.9% (530/948) had normal BMI (≥18.50-24.90), 18.7% (177/948) were overweight (25.00-29.00) and 9.7% (92/948) were obese (≥30.00). Irrespective of TB status, underweight patients, had significantly higher risk of death compared to those with normal BMI at baseline (aHR = 2.9; 95% CI: 1.5-5.7; P = 0.002). Conclusions: Irrespective of TB co-infection, low BMI correlated with mortality in HIV infected patients. Trial registration: UKZN Biomedical Research Ethics Committee Reference number E 248/05,

Research paper thumbnail of Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis

Pharmacogenomics

Aim: We report the prevalence and effect of genetic variability on pharmacokinetic parameters of ... more Aim: We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin. Materials & methods: Genotypes for SLCO1B1, NAT2, PXR, ABCB1 and UGT1A genes were determined using a TaqMan® Genotyping OpenArray™. Nonlinear mixed-effects models were used to describe drug pharmacokinetics. Results: Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively. Of the 58 patients contributing drug concentrations, rapid and intermediate acetylators had 2.3- and 1.6-times faster isoniazid clearance than slow acetylators. No association was observed between rifampicin pharmacokinetics and SLCO1B1, ABCB1, UGT1A or PXR genotypes. Conclusion: Clinical relevance of the effects of genetic variation on isoniazid concentrations and low first-line tuberculosis drug exposures observed require further investigation.

Research paper thumbnail of An Evaluation to Determine the Strongest CD4 Count Covariates during HIV Disease Progression in Women in South Africa

Infectious Diseases and Therapy

Introduction: Past endeavours to deal with the obstacle of expensive Cluster of Difference 4 (CD4... more Introduction: Past endeavours to deal with the obstacle of expensive Cluster of Difference 4 (CD4 ?) count diagnostics in resource-limited settings have left a long trail of suggested continuous CD4 ? count clinical covariates that turned out to be a potentially important integral part of the human immunodeficiency virus (HIV) treatment process during disease progression. However, an evaluation to determine the strongest candidates among these CD4 ? count covariates has not been well documented. Methods: The Centre for the AIDS Programme of Research in South Africa (CAPRISA) initially enrolled HIV-negative (phase 1) patients into different study cohorts. The patients who seroconverted (237) during follow-up care were enrolled again into a post-HIV infection cohort where they were further followed up with weekly to fortnightly visits up to 3 months (phase 2: acute infection), monthly visits from 3-12 months (phase 3: early infection) and quarterly visits thereafter (phase 4: established infection) until antiretroviral therapy (ART) initiation (phase 5). The CD4 ? count and 46 covariates were repeatedly measured at each phase of the HIV disease progression. A multilevel partial least squares approach was applied as a variable reduction technique to determine the strongest CD4 ? count covariates. Results: Only 18 of the 46 investigated clinical attributes were the strongest CD4 ? count covariates and the top 8 were positively and independently associated with the CD4 ? count. Besides the confirmatory lymphocytes, these were basophils, albumin, haematocrit, alkaline phosphatase (ALP), mean corpuscular volume (MCV), platelets, potassium and monocytes. Overall, electrolytes, proteins and red blood cells were the dominant categories for the strongest covariates. Conclusion: Only a few of the many previously suggested continuous CD4 ? count clinical covariates showed the potential to become an important integral part of the treatment process. Prolonging the pre-treatment period of the HIV disease progression by effectively Enhanced digital features To view enhanced digital features for this article go to

Research paper thumbnail of Recurrent tuberculosis among HIV-coinfected patients: a case series from KwaZulu-Natal

Infection and Drug Resistance

Background: Recurrent tuberculosis (TB) following TB treatment completion in HIV-infected individ... more Background: Recurrent tuberculosis (TB) following TB treatment completion in HIV-infected individuals remains a major public health burden. We assessed the role of various risk factors in mediating the development of recurrent TB and subsequent resistance to antiretroviral therapy and anti-TB drugs. Patients and methods: We analyzed secondary demographic, clinical, and laboratory data from medical records of five HIV-infected TB patients enrolled between 2009 and 2014 in a prospective observational study investigating TB recurrence. Paired clinical isolates of Mycobacterium tuberculosis were typed by IS6110 restriction fragment length polymorphism analysis to determine the mechanism of TB recurrence. Plasma samples were genotyped to determine acquisition of HIV drug resistance mutations on antiretroviral treatment (ART). Results: All five patients were HIV-coinfected, with a previous history of TB infection and prior exposure to anti-TB treatment, and residual lung damage, and demonstrated poor treatment adherence-significant risk factors linked to the development of recurrent TB disease. Furthermore, three of the five patients had multiple episodes of drug-susceptible TB infection with subsequent drug-resistant TB infection. Genotyping of the initial and recurrent M. tuberculosis isolates demonstrated three cases of recurrent TB because of relapse and two because of reinfection. All five patients had no mutations at ART initiation; however, by the end of the study follow-up, all patients developed dual class resistance. Conclusion: This series demonstrates the complexity of recurrent TB in HIV coinfection. We highlight the challenges of managing coinfected patients and the increased propensity for the development of drug resistance. We report on the role of various risk factors mediating the development of resistance and subsequent clinical impact. This report underscores the need for structural clinical and adherence interventions for the management of complex treatment and dosing.

Research paper thumbnail of Ex vivo HIV entry into blood CD4+ T cells does not predict heterosexual HIV acquisition in women

PLOS ONE

IIb trial to assess the safety and effectiveness of the vaginal microbicide 1% tenofovir gel for ... more IIb trial to assess the safety and effectiveness of the vaginal microbicide 1% tenofovir gel for the prevention of HIV infection in women in South Africa TABLE OF CONTENTS PROTOCOL TEAM ROSTER .

Research paper thumbnail of Organizational contextual factors that predict success of a quality improvement collaborative approach to enhance integrated HIV-tuberculosis services: a sub-study of the Scaling up TB/HIV Integration trial

Implementation Science

Background A quality improvement (QI) collaborative approach to enhancing integrated HIV-Tubercul... more Background A quality improvement (QI) collaborative approach to enhancing integrated HIV-Tuberculosis (TB) services may be effective in scaling up and improving the quality of service delivery. Little is known of the role of organizational contextual factors (OCFs) in influencing the success of QI collaboratives. This study aims to determine which OCFs were associated with improvement in a QI collaborative intervention to enhance integrated HIV-TB services delivery. Methods This is a nested sub-study embedded in a cluster-randomized controlled trial. Sixteen nurse supervisors (clusters) overseeing 40 clinics were randomized (1:1) to receive QI training and mentorship, or standard of care support (SOC). In the QI arm, eight nurse supervisors and 20 clinics formed a “collaborative” which aimed to improve HIV-TB process indicators, namely HIV testing, TB screening, isoniazid preventive therapy (IPT) initiations, viral load testing, and antiretroviral therapy for TB patients. OCFs measu...

Research paper thumbnail of A cluster‐randomized controlled trial to improve the quality of integrated HIV‐tuberculosis services in primary healthcareclinics in South Africa

Journal of the International AIDS Society

Research paper thumbnail of High incidence and persistence of hepatitis B virus infection in individuals receiving HIV care in KwaZulu-Natal, South Africa

BMC Infectious Diseases

Background Hepatitis B virus (HBV), Human Immunodeficiency virus (HIV) and Tuberculosis (TB) are ... more Background Hepatitis B virus (HBV), Human Immunodeficiency virus (HIV) and Tuberculosis (TB) are common infections in South Africa. We utilized the opportunity of care provision for HIV-TB co-infected patients to better understand the relationship between these coinfections, determine the magnitude of the problem, and identify risk factors for HBV infection in HIV infected patients with and without TB in KwaZulu-Natal, South Africa. Methods This retrospective cohort analysis was undertaken in 2018. In-care HIV infected patients were included in the analysis. Results from clinical records were analysed to determine the prevalence, incidence, persistence and factors associated with HBsAg positivity in HIV-infected patients with or without TB co-infection. Results A total of 4292 HIV-infected patients with a mean age of 34.7 years (SD: 8.8) were included. Based on HBsAg positivity, the prevalence of HBV was 8.5% (363/4292) [95% confidence interval (CI): 7.7–9.3] at baseline and 9.4% (9...

Research paper thumbnail of Developing excellence in biostatistics leadership, training and science in Africa: How the Sub-Saharan Africa Consortium for Advanced Biostatistics (SSACAB) training unites expertise to deliver excellence

AAS Open Research

The increase in health research in sub-Saharan Africa (SSA) has generated large amounts of data a... more The increase in health research in sub-Saharan Africa (SSA) has generated large amounts of data and led to a high demand for biostatisticians to analyse these data locally and quickly. Donor-funded initiatives exist to address the dearth in statistical capacity, but few initiatives have been led by African institutions. The Sub-Saharan African Consortium for Advanced Biostatistics (SSACAB) aims to improve biostatistical capacity in Africa according to the needs identified by African institutions, through (collaborative) masters and doctoral training in biostatistics. We describe the SSACAB Consortium, which comprises 11 universities and four research institutions- supported by four European universities. SSACAB builds on existing resources to strengthen biostatistics for health research with a focus on supporting biostatisticians to become research leaders; building a critical mass of biostatisticians, and networking institutions and biostatisticians across SSA. In 2015 only four ...

Research paper thumbnail of HPV infection and the genital cytokine milieu in women at high risk of HIV acquisition

Nature Communications

Human papillomavirus (HPV) infection correlates with higher rates of HIV acquisition, but the und... more Human papillomavirus (HPV) infection correlates with higher rates of HIV acquisition, but the underlying biological mechanisms are unclear. Here we study associations between HPV and HIV acquisition and relate these to vaginal cytokine profiles in an observational cohort of women at high risk of HIV infection (CAPRISA 004, n = 779) and with 74% HPV prevalence. We report here that HPV infection associates with a 2.5-fold increase in HIV acquisition risk in this population (95% CI: 1.2–5.3). Among 48 vaginal cytokines profiled, cytokines associated with HPV infection overlap substantially with cytokines associated with HIV risk, but are distinct from those observed in HPV negative women. Although our data do not establish a causative link between HPV status and the risk of HIV, we suggest that increasing HPV vaccination coverage may carry an additional benefit of reducing the risk of contracting HIV infection, particularly in regions with high HPV prevalence.

Research paper thumbnail of Impact of pretreatment low-abundance HIV-1 drug-resistant variants on virological failure among HIV-1/TB-co-infected individuals

Journal of Antimicrobial Chemotherapy

Objectives To determine the impact of pretreatment low-abundance HIV-1 drug-resistant variants (L... more Objectives To determine the impact of pretreatment low-abundance HIV-1 drug-resistant variants (LA-DRVs) on virological failure (VF) among HIV-1/TB-co-infected individuals treated with NNRTI first-line ART. Methods We conducted a case–control study of 170 adults with HIV-1/TB co-infection. Cases had at least one viral load (VL) ≥1000 RNA copies/mL after ≥6 months on NNRTI-based ART, and controls had sustained VLs <1000 copies/mL. We sequenced plasma viruses by Sanger and MiSeq next-generation sequencing (NGS). We assessed drug resistance mutations (DRMs) using the Stanford drug resistance database, and analysed NGS data for DRMs at ≥20%, 10%, 5% and 2% thresholds. We assessed the effect of pretreatment drug resistance (PDR) on VF. Results We analysed sequences from 45 cases and 125 controls. Overall prevalence of PDR detected at a ≥20% threshold was 4.7% (8/170) and was higher in cases than in controls (8.9% versus 3.2%), P = 0.210. Participants with PDR at ≥20% had almost 4-fold...

Research paper thumbnail of HIV treatment outcomes among people with initiation CD4 counts >500 cells/µL after implementation of Treat All in South African public clinics: a retrospective cohort study

Journal of the International AIDS Society

Introduction: The World Health Organisation recommends to Treat All people with HIV, irrespective... more Introduction: The World Health Organisation recommends to Treat All people with HIV, irrespective of CD4 count. However, people with CD4 counts >500 cells/µL may be asymptomatic and therefore less motivated to adhere to antiretroviral therapy (ART). We aimed to assess whether people initiated with CD4 counts >500 cells/µL had worse treatment outcomes compared to those initiated at lower CD4 counts. Methods: We performed a retrospective cohort study among non-pregnant adults initiating ART at eight public clinics in South Africa between September 2016, when Treat All was implemented, and August 2017. We assessed whether initiation CD4 count >500 cells/µL was associated with the outcomes of attrition (death, lost to follow-up or treatment interruption >180 days), and viraemia >1000 copies/mL, by twelve months using Cox proportional hazards and Poisson regression models. Results and discussion: Among 4952 patients initiating ART, the median age was 32.4 years (interquartile range (IQR) 27.2 to 39.7), 58.9% were women and 30.3% had an initiation CD4 count >500 cells/µL. After twelve months, 3382 (68.3%) were retained in care, 303 (6.1%) had transferred to another clinic, 1010 (20.4%) were lost to follow-up, 232 (4.7%) had a treatment interruption >180 days and 25 (0.5%) were known to have died. Overall, 1267 experienced attrition at a median time of 91 days (IQR 23 to 213), with 302 of these (23.8%) experiencing attrition immediately after their ART initiation visit. Among those in care at twelve months with viral load results, 4.6% had viraemia. In multivariable analysis, the hazard of attrition was similar between patients newly eligible for ART with CD4 counts >500 cells/µL compared to those with CD4 ≤500 cells/µL (adjusted hazard ratio 1.03, 95% confidence interval (CI) 0.90 to 1.17). The risk of viraemia was lower among patients with CD4 counts >500 cells/µL compared to those with CD4 ≤500 cells/µL (adjusted risk ratio 0.58, 95% CI 0.37 to 0.92). Conclusions: After implementation of Treat All in South African public clinics, we found that patients newly eligible for ART with initiation CD4 counts >500 cells/µL had comparable or better outcomes compared to those with lower CD4 counts. These finding support ongoing implementation of Treat All in our setting.

Research paper thumbnail of Trends in HIV Prevention, Treatment, and Incidence in a Hyperendemic Area of KwaZulu-Natal, South Africa

JAMA Network Open

IMPORTANCE In Africa, the persistently high HIV incidence rate among young women is the major obs... more IMPORTANCE In Africa, the persistently high HIV incidence rate among young women is the major obstacle to achieving the goal of epidemic control. OBJECTIVE To determine trends in coverage of HIV prevention and treatment programs and HIV incidence. DESIGN, SETTING, AND PARTICIPANTS This cohort study consisted of 2 sequential, communitybased longitudinal studies performed in the Vulindlela and Greater Edendale area in KwaZulu-Natal,

Research paper thumbnail of Factors associated with unsuppressed viremia in women living with HIV on lifelong ART in the multi-country US-PEPFAR PROMOTE study: A cross-sectional analysis

PLOS ONE

Background Despite recent efforts to scale-up lifelong combination antiretroviral therapy (cART) ... more Background Despite recent efforts to scale-up lifelong combination antiretroviral therapy (cART) in sub-Saharan Africa, high rates of unsuppressed viremia persist among cART users, and many countries in the region fall short of the UNAIDS 2020 target to have 90% virally suppressed. We sought to determine the factors associated with unsuppressed viremia (defined for the purpose of this study as >200 copies/ml) among sub-Saharan African women on lifelong cART. Methods This cross-sectional analysis was based on baseline data of the PROMOTE longitudinal cohort study at 8 sites in Uganda, Malawi, Zimbabwe and South Africa. The study enrolled 1987 women living with HIV who initiated lifelong cART at least 1-5 years ago. Socio-demographic, clinical, and cART adherence data were collected. We used multivariable Poisson regression with robust variance to identify factors associated with unsuppressed viremia. Results At enrolment, 1947/1987 (98%) women reported taking cART. Of these, HIV-1 remained detectable in 293/1934 (15%), while 216/1934 (11.2%) were considered unsuppressed (>200 copies/ml). The following factors were associated with an increased risk of

Research paper thumbnail of Risk of Nephrotoxicity in Patients With Drug-Resistant Tuberculosis Treated With Kanamycin/Capreomycin With or Without Concomitant Use of Tenofovir-Containing Antiretroviral Therapy

JAIDS Journal of Acquired Immune Deficiency Syndromes

Research paper thumbnail of Integrated provision of topical pre‐exposure prophylaxis in routine family planning services in South Africa: a non‐inferiority randomized controlled trial

Journal of the International AIDS Society

Introduction: Tenofovir-containing oral pre-exposure prophylaxis (PrEP) is recommended for those ... more Introduction: Tenofovir-containing oral pre-exposure prophylaxis (PrEP) is recommended for those at substantial risk as part of combination HIV prevention. However, there are limited data, beyond clinical trial settings, to guide the introduction of PrEP in healthcare services with adequate levels of adherence. Since young women in Africa are at high risk of HIV and likely to utilize family planning (FP) services, the feasibility, acceptability and effectiveness of integrating topical PrEP provision into routine FP services was assessed. Methods: This two-arm, randomized controlled, non-inferiority, open-label extension trial was undertaken in urban and rural KwaZulu-Natal, South Africa. HIV-negative eligible women (n = 372) from the parent trial (Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004) were randomized to receive tenofovir gel either through intervention (FP clinics, n = 189) or control clinics (CAPRISA research clinics, n = 183). Non-inferiority was predefined as gel use in the intervention clinics would be no more than 20% lower than in the control clinics. Adherence, retention and HIV incidence rates were assessed. Results: Women were enrolled between November 2012 and October 2014, and followed up for 682.3 women-years (mean = 22 months). Baseline characteristics of women in intervention and control clinics were comparable and retention rates were 92.1% and 92.3% respectively. Women in intervention clinics and control clinics returned on average 5.2 (95% confidence interval (CI): 4.7 to 5.7) and 5.7 (CI: 5.2 to 6.2) used gel applicators per month respectively, with a mean difference of À0.47 (CI: À1.16 to 0.21). Per-protocol estimates were on average 5.5 (CI: 5.0 to 6.1) and 5.8 (CI: 5.3 to 6.3) respectively, with a mean difference of À0.25 (CI: À0.98 to 0.48), meeting the non-inferiority criteria. Adherence, based on proportion of reported sex acts covered by two gel doses, was 79.9%

Research paper thumbnail of Assessing the safety and pharmacokinetics of the monoclonal antibodies, VRC07-523LS and PGT121 in HIV negative women in South Africa: study protocol for the CAPRISA 012A randomised controlled phase I trial

BMJ Open

IntroductionDespite extensive prevention campaigns and scale-up of antiretroviral therapy, HIV in... more IntroductionDespite extensive prevention campaigns and scale-up of antiretroviral therapy, HIV incidence among young women in southern Africa remains high. While the development of an efficacious vaccine remains a challenge, the discovery of broadly neutralising monoclonal antibodies (mAbs) has created the opportunity to explore passive immunisation as a long-acting injectable HIV prevention strategy. The purpose of this trial is to provide safety, pharmacokinetic (PK) and functional activity data of VRC07-523LS and PGT121 when administered subcutaneously (SC) to young South African women. Going forward, the aim is to select the ideal dose and/or monoclonal antibody for co-formulation and testing with CAP256-VRC26.25LS, a potent monoclonal antibody against subtype C virus, in an efficacy trial.Methods and analysisCAPRISA 012A is a randomised, double blinded, placebo-controlled phase I trial to assess the safety and PK profile of two mAbs, VRC07-523LS and PGT121 administered SC to 35...

Research paper thumbnail of Factors associated with unsuppressed viremia in women living with HIV on lifelong ART in a multi-country cohort study: US-PEPFAR PROMOTE study

Background: Despite recent efforts to scale-up lifelong combination antiretroviral therapy (cART)... more Background: Despite recent efforts to scale-up lifelong combination antiretroviral therapy (cART) in sub-Saharan Africa, high rates of unsuppressed viremia persist among cART users, and many countries in the region fall short of the UNAIDS 2020 target to have 90% virally suppressed. We sought to determine the factors associated with unsuppressed viremia (defined for the purpose of this study as >200 copies/ml) among African women on lifelong cART. Methods: This analysis was based on baseline data of the PROMOTE longitudinal cohort study at 8 sites in Uganda, Malawi, Zimbabwe and South Africa. The study enrolled 1987 women living with HIV who initiated lifelong cART at least 1 year previously to assesses long-term safety and effectiveness of cART. Socio-demographic, clinical, and cART adherence data were collected. We used multivariable Poisson regression with robust variance to identify factors associated with unsuppressed viremia. Results: At enrolment, 1947/1987 (98%) women reported taking cART. Of these, HIV-1 remained detectable in 293/1934 (15%), while 216/1934 (11.2%) were considered unsuppressed (>200 copies/ml). The following factors were associated with an increased risk of unsuppressed viremia: not having household electricity (adjusted prevalence rate ratio (aPRR) 1.74, 95% confidence interval (CI) 1.28-2.36, p<0.001); self-reported missed cART doses (aPRR 1.63, 95% CI 1.24-2.13, p<0.001); recent hospitalization (aPRR 2.48, 95% CI 1.28-4.80, p=0.007) and experiencing abnormal vaginal discharge in the last three months (aPRR 1.88; 95% CI 1.16-3.04, p=0.010). Longer time on cART (aPRR 0.75, 95% CI 0.64-0.88, p<0.001) and being older (aPRR 0.77, 95% CI 0.76-0.88, p<0.001) were associated with reduced risk of unsuppressed viremia. made available for use under a CC0 license.

Research paper thumbnail of Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy

Frontiers in Microbiology

Darboe et al. Transcriptomic TB Signature for HIV-Infected excellent diagnostic discrimination be... more Darboe et al. Transcriptomic TB Signature for HIV-Infected excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95%CI 0.94-1). Performance was lower in HIV-infected individuals (AUC 0.83; 95%CI 0.81-0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads.

Research paper thumbnail of Adjusting the Effect of Integrating Antiretroviral Therapy and Tuberculosis Treatment on Mortality for Noncompliance

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

Infectious Diseases of Poverty

Background: High early morbidity and mortality following antiretroviral therapy (ART) initiation ... more Background: High early morbidity and mortality following antiretroviral therapy (ART) initiation has been a distinguishing feature of ART programmes in resource limited settings (RLS) compared to high-income countries. This study assessed how well body mass index (BMI: kg/m 2) correlated with survival among HIV infected patients with and without TB co-infection. Methods: We retrospectively evaluated clinical data from 1000 HIV infected patients, among whom 389 were also co-infected with TB, between January 2008 and December 2010, in KwaZulu-Natal, South Africa. Results: Among 948 patients eligible for analysis, 15.7% (149/948) were underweight (< 18.50), 55.9% (530/948) had normal BMI (≥18.50-24.90), 18.7% (177/948) were overweight (25.00-29.00) and 9.7% (92/948) were obese (≥30.00). Irrespective of TB status, underweight patients, had significantly higher risk of death compared to those with normal BMI at baseline (aHR = 2.9; 95% CI: 1.5-5.7; P = 0.002). Conclusions: Irrespective of TB co-infection, low BMI correlated with mortality in HIV infected patients. Trial registration: UKZN Biomedical Research Ethics Committee Reference number E 248/05,

Research paper thumbnail of Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis

Pharmacogenomics

Aim: We report the prevalence and effect of genetic variability on pharmacokinetic parameters of ... more Aim: We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin. Materials & methods: Genotypes for SLCO1B1, NAT2, PXR, ABCB1 and UGT1A genes were determined using a TaqMan® Genotyping OpenArray™. Nonlinear mixed-effects models were used to describe drug pharmacokinetics. Results: Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively. Of the 58 patients contributing drug concentrations, rapid and intermediate acetylators had 2.3- and 1.6-times faster isoniazid clearance than slow acetylators. No association was observed between rifampicin pharmacokinetics and SLCO1B1, ABCB1, UGT1A or PXR genotypes. Conclusion: Clinical relevance of the effects of genetic variation on isoniazid concentrations and low first-line tuberculosis drug exposures observed require further investigation.

Research paper thumbnail of An Evaluation to Determine the Strongest CD4 Count Covariates during HIV Disease Progression in Women in South Africa

Infectious Diseases and Therapy

Introduction: Past endeavours to deal with the obstacle of expensive Cluster of Difference 4 (CD4... more Introduction: Past endeavours to deal with the obstacle of expensive Cluster of Difference 4 (CD4 ?) count diagnostics in resource-limited settings have left a long trail of suggested continuous CD4 ? count clinical covariates that turned out to be a potentially important integral part of the human immunodeficiency virus (HIV) treatment process during disease progression. However, an evaluation to determine the strongest candidates among these CD4 ? count covariates has not been well documented. Methods: The Centre for the AIDS Programme of Research in South Africa (CAPRISA) initially enrolled HIV-negative (phase 1) patients into different study cohorts. The patients who seroconverted (237) during follow-up care were enrolled again into a post-HIV infection cohort where they were further followed up with weekly to fortnightly visits up to 3 months (phase 2: acute infection), monthly visits from 3-12 months (phase 3: early infection) and quarterly visits thereafter (phase 4: established infection) until antiretroviral therapy (ART) initiation (phase 5). The CD4 ? count and 46 covariates were repeatedly measured at each phase of the HIV disease progression. A multilevel partial least squares approach was applied as a variable reduction technique to determine the strongest CD4 ? count covariates. Results: Only 18 of the 46 investigated clinical attributes were the strongest CD4 ? count covariates and the top 8 were positively and independently associated with the CD4 ? count. Besides the confirmatory lymphocytes, these were basophils, albumin, haematocrit, alkaline phosphatase (ALP), mean corpuscular volume (MCV), platelets, potassium and monocytes. Overall, electrolytes, proteins and red blood cells were the dominant categories for the strongest covariates. Conclusion: Only a few of the many previously suggested continuous CD4 ? count clinical covariates showed the potential to become an important integral part of the treatment process. Prolonging the pre-treatment period of the HIV disease progression by effectively Enhanced digital features To view enhanced digital features for this article go to

Research paper thumbnail of Recurrent tuberculosis among HIV-coinfected patients: a case series from KwaZulu-Natal

Infection and Drug Resistance

Background: Recurrent tuberculosis (TB) following TB treatment completion in HIV-infected individ... more Background: Recurrent tuberculosis (TB) following TB treatment completion in HIV-infected individuals remains a major public health burden. We assessed the role of various risk factors in mediating the development of recurrent TB and subsequent resistance to antiretroviral therapy and anti-TB drugs. Patients and methods: We analyzed secondary demographic, clinical, and laboratory data from medical records of five HIV-infected TB patients enrolled between 2009 and 2014 in a prospective observational study investigating TB recurrence. Paired clinical isolates of Mycobacterium tuberculosis were typed by IS6110 restriction fragment length polymorphism analysis to determine the mechanism of TB recurrence. Plasma samples were genotyped to determine acquisition of HIV drug resistance mutations on antiretroviral treatment (ART). Results: All five patients were HIV-coinfected, with a previous history of TB infection and prior exposure to anti-TB treatment, and residual lung damage, and demonstrated poor treatment adherence-significant risk factors linked to the development of recurrent TB disease. Furthermore, three of the five patients had multiple episodes of drug-susceptible TB infection with subsequent drug-resistant TB infection. Genotyping of the initial and recurrent M. tuberculosis isolates demonstrated three cases of recurrent TB because of relapse and two because of reinfection. All five patients had no mutations at ART initiation; however, by the end of the study follow-up, all patients developed dual class resistance. Conclusion: This series demonstrates the complexity of recurrent TB in HIV coinfection. We highlight the challenges of managing coinfected patients and the increased propensity for the development of drug resistance. We report on the role of various risk factors mediating the development of resistance and subsequent clinical impact. This report underscores the need for structural clinical and adherence interventions for the management of complex treatment and dosing.

Research paper thumbnail of Ex vivo HIV entry into blood CD4+ T cells does not predict heterosexual HIV acquisition in women

PLOS ONE

IIb trial to assess the safety and effectiveness of the vaginal microbicide 1% tenofovir gel for ... more IIb trial to assess the safety and effectiveness of the vaginal microbicide 1% tenofovir gel for the prevention of HIV infection in women in South Africa TABLE OF CONTENTS PROTOCOL TEAM ROSTER .