Dose-related adverse events in South African patients prescribed clofazimine for drug-resistant tuberculosis

Background. Optimal drug levels and minimal toxicity are critical factors in improving treatment outcomes for patients prescribed new and repurposed medicine for drug-resistant (DR) tuberculosis (TB). The optimal dose and dose-related safety of clofazimine (CFZ), a repurposed medicine for DR TB, in the South African (SA) population are unknown.Objectives. To report on dose-related adverse events in patients receiving CFZ plus a background regimen for DR TB.Methods. In a retrospective review of patient folders from 2012 to 2014, adverse events documented for patients receiving high- (≥200 mg) and low-dose (100 mg) CFZ in a centralised DR TB hospital in KwaZulu-Natal Province, SA, were investigated for an association between dose-weight interactions and adverse events.Results. Of 600 patients included, 78.7% (n=472) weighed ≥50 kg. Of these, 17.4% (n=82) received 100 mg CFZ and 82.6% (n=390) received >200 mg. Of 128 patients (21.3%) who weighed <50 kg, 68.0% (n=87) received 100 mg CFZ and 32.0% (n=41) received ≥200 mg. Of 463 patients (77.2%) who were HIV-positive, 94.0% were on antiretrovirals. There was no difference between the dose-weight cohorts in the background regimen given in addition to high- or low-dose CFZ. The frequency and types of adverse events observed were similar to the published literature. When analysed per dose-weight cohort, patients weighing <50 kg and receiving high-dose CFZ (≥200 mg) had a 2.6 times higher risk of any adverse event (adjusted odds ratio (aOR) 2.57; 95% confidence interval (CI) 1.02 - 6.05; p=0.05: reference category <50 kg and 100 mg). Patients weighing <50 kg and receiving high-dose CFZ had a 3.3 times higher risk of gastrointestinal adverse events than patients weighing <50 kg and receiving 100 mg CFZ (aOR 3.30; 95% CI 1.51 - 7.19; p=0.003). A high risk of chest pain was observed in patients receiving high- and low-dose CFZ, irrespective of weight. Patients weighing <50 kg receiving high-dose CFZ had a slightly higher risk of adverse events related to the skin (aOR 1.2; 95% CI 0.55 - 2.62; p=0.7) There were no documented reports of the CFZ dose being reduced or the drug being stopped due to adverse events in the sample population.Conclusions. There is an association between dose-weight interaction and adverse events. The odds of any adverse event occurring were higher when low-weight patients (<50 kg) received high-dose CFZ (≥200 mg). Gastrointestinal and skin-related adverse events were more common when high-dose CFZ was used in patients weighing <50 kg. Chest pain was reported in patients receiving high- and low-dose CFZ, irrespective of weight, and may be a symptom of cardiac toxicity. Plasma concentrations of CFZ may be affected by drug-drug interactions, so active drug safety monitoring including electrocardiograms is recommended routinely when CFZ is part of the regimen

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

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

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

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 measured at baseline were physical infrastructure, key staff, flexibility of clinic hours, monitoring data for improvement (MDI), and leadership support. Surveys were administered to clinic staff at baseline and month 12 to assess perceptions of supportiveness of contexts for change, and clinic organization for delivering integrated HIV-TB services. Linear mixed modelling was used to test for associations between OCFs and HIV-TB process indicators. Results: A total of 209 clinic staff participated in the study; 97 (46.4%) and 112 (53.6%) from QI and SOC arms, respectively. There were no differences between the QI and SOC arms scores achieved for physical infrastructure (78.9% vs 64.7%; p = 0.058), key staff (95.8 vs 92; p = 0.270), clinic hours (66.9 vs 65.5; p = 0.900), MDI (63.3 vs 65; p = 0.875, leadership support (46.0 vs 57.4; p = 0.265), and perceptions of supportiveness of contexts for change (76.2 vs 79.7; p = 0.128 and clinic organization for delivering integrated HIV-TB services (74.1 vs 80.1; p = 0.916). IPT initiation was the only indicator that was significantly improved in the parent study. MDI was a significantly associated with increasing IPT initiation rates [beta coefficient (β) = 0.004; p = 0.004]. Discussion: MDI is a practice that should be fostered in public health facilities to increase the likelihood of success of future QI collaboratives to improve HIV-TB service delivery. Trial registration: Clinicaltrials.gov, NCT02654613. Registered 01 June 2015

The increasing burden of tuberculosis in pregnant women, newborns and infants under 6 months of age in Durban, KwaZulu Natal

Objectives. In spite of the global epidemic of tuberculosis (TB) which has been exacerbated by HIV, the impact of these coinfections on maternal and perinatal health has been limited. We document new evidence from Durban, KwaZulu- Natal, on the increasing effects of TB in pregnant women, neonates and infants.Method. Women with TB were prospectively tudied at the antenatal clinics and obstetric and labour wards at King Edward VIII Hospital, Durban, between 1996 and 1998. The incidence of TB was calculated, and the population attributable fraction of TB due to HIV infection in pregnancy was estimated. Concurrently, culture-confirmed cases of Mycobacterium tubaculosis in neonates and infants under 6 months of age at the hospital were documented.Results. One hundred and forty-six cases of maternal TB were detected. TB occurred in 0.1% and 0.6% of maternities in 1996 and 1998 respectively. Overall, TB rate for HIV non-infected maternities was 72.9/ 105, and for HIV-infected maternities , 774.5/ 105. The attributable fraction of TB related to HIV in pregnancy was 71.7%; 10.3% of these mothers died. There was a 2.2-fold increase in the caseload of culture-confirmed TB in neonates and young infants at the hospital.Conclusion. In regions where TB and HIV preval nee is high, efforts to improve maternal and perinatal health must include the detection of TB in pregnancy

Open Access A Quality Improvement Intervention to Inform Scale-Up of Integrated HIV-TB Services: Lessons Learned From KwaZulu-Natal, South Africa

In South Africa, mortality rates among HIV-TB coinfected patients are among the highest in the world. The key to reducing mortality is integrating HIV-TB services, however, a generalizable implementation method and package of tested change ideas to guide the scale-up of integrated HIV-TB services are unavailable. We describe the implementation of a quality improvement (QI) intervention, health systems’ weaknesses, change ideas, and lessons learned in improving integrated HIV-TB services. / Methods: Between December 1, 2016, and December 31, 2018, 8 nurse supervisors overseeing 20 primary health care (PHC) clinics formed a learning collaborative to improve a set of HIV-TB process indicators. HIV-TB process indicators comprised: HIV testing services (HTS), TB screening among PHC clinic attendees, isoniazid preventive therapy (IPT) for eligible HIV patients, antiretroviral therapy (ART) for HIV-TB coinfected patients, and viral load (VL) testing at month 12. Routine HIV-TB process data were collected and analyzed. / Results: Key change interventions, generated by health care workers, included: patient-flow redesign, daily data quality checks; prior identification of patients eligible for IPT and VL testing. Between baseline and post-QI intervention, IPT initiation rates increased from 15.9% to 76.4% (P=.019), HTS increased from 84.8% to 94.5% (P=.110), TB screening increased from 76.2% to 85.2% (P=.040), and VL testing increased from 61.4% to 74.0% (P=.045). ART initiation decreased from 95.8% to 94.1% (P=.481). / Discussion: Although integrating HIV-TB services is standard guidance, existing process gaps to achieve integration can be closed using QI methods. QI interventions can rapidly improve the performance of processes, particularly if baseline performance is low. Improving data quality enhances the success of QI initiatives

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

Introduction: Tuberculosis (TB) remains the most common cause of death among people living with HIV. Integrating HIV and TB services reduces mortality but is sub-optimally implemented. Quality improvement (QI) methods offer a low-cost and easily implementable approach to strengthening healthcare delivery systems. This trial assessed a QI intervention on key process indicators for delivering integrated HIV-TB care in rural South African primary healthcare (PHC) clinics. Methods: Sixteen nurse supervisors, (each with a cluster of clinics) overseeing 40 PHC clinics, were randomized 1:1 to the intervention or the standard of care (SOC) groups. The QI intervention comprised three key components: clinical and QI skills training, on-site mentorship of nurse supervisors and clinic staff, and data quality improvement activities to enhance accuracy and completeness of routine clinic data. The SOC comprised monthly supervision and data feedback meetings. From 01 December 2016 to 31 December 2018, data were collected monthly by a team of study-appointed data capturers from all study clinics. This study's outcomes were HIV testing services (HTS), TB screening, antiretroviral therapy (ART) initiation, isoniazid preventive therapy (IPT) initiation and viral load (VL) testing. Results: The QI group (eight clusters) comprised 244 clinic staff who attended to 13,347 patients during the trial compared to the SOC group (eight clusters) with 217 clinic staff who attended to 8141 patients. QI mentors completed 85% (510/600) of expected QI mentorship visits to QI clinics. HTS was 19% higher [94.5% vs. 79.6%; relative risk (RR)=1.19; 95% CI: 1.02–1.38; p=0.029] and IPT initiation was 66% higher (61.2 vs. 36.8; RR=1.66; 95% CI: 1.02–2.72; p=0·044), in the QI group compared to SOC group. The percentage of patients screened for TB (83.4% vs. 79.3%; RR=1.05; p=0.448), initiated on ART (91.7 vs. 95.5; RR=0.96; p=0.172) and VL testing (72.2% vs. 72.8%; RR=0.99; p=0.879) was similar in both groups. Conclusions: QI improved HIV testing and IPT initiation compared to SOC. TB screening, ART initiation and VL testing remained similar. Incorporating QI methods into routine supervision and support activities may strengthen integrated HIV-TB service delivery and increase the success of future QI scale-up activities

Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis

Background: Bedaquiline and clofazimine are important drugs in the treatment of drug-resistant tuberculosis and are commonly used across southern Africa, although drug susceptibility testing is not routinely performed. In this study, we did a genotypic and phenotypic analysis of drug-resistant Mycobacterium tuberculosis isolates from cohort studies in hospitals in KwaZulu-Natal, South Africa, to identify resistance-associated variants (RAVs) and assess the extent of clofazimine and bedaquiline cross-resistance. We also used a comprehensive dataset of whole-genome sequences to investigate the phylogenetic and geographical distribution of bedaquiline and clofazimine RAVs in southern Africa. Methods: In this study, we included M tuberculosis isolates reported from the PRAXIS study of patients with drug-resistant tuberculosis treated with bedaquiline (King Dinuzulu Hospital, Durban) and three other cohort studies of drug-resistant tuberculosis in other KwaZulu-Natal hospitals, and sequential isolates from six persistently culture-positive patients with extensively drug-resistant tuberculosis at the KwaZulu-Natal provincial referral laboratory. Samples were collected between 2013 and 2019. Microbiological cultures were done as part of all parent studies. We sequenced whole genomes of included isolates and measured bedaquiline and clofazimine minimum inhibitory concentrations (MICs) for isolates identified as carrying any Rv0678 variant or previously published atpE, pepQ, and Rv1979c RAVs, which were the subject of the phenotypic study. We combined all whole-genome sequences of M tuberculosis obtained in this study with publicly available sequence data from other tuberculosis studies in southern Africa (defined as the countries of the Southern African Development Community), including isolates with Rv0678 variants identified by screening public genomic databases. We used this extended dataset to reconstruct phylogenetic relationships across lineage 2 and 4 M tuberculosis isolates. Findings: We sequenced the whole genome of 648 isolates from 385 patients with drug-resistant tuberculosis recruited into cohort studies in KwaZulu-Natal, and 28 isolates from six patients from the KwaZulu-Natal referral laboratory. We identified 30 isolates with Rv0678 RAVs from 16 (4%) of 391 patients. We did not identify any atpE, pepQ, or Rv1979c RAVs. MICs were measured for 21 isolates with Rv0678 RAVs. MICs were above the critical concentration for bedaquiline resistance in nine (43%) of 21 isolates, in the intermediate category in nine (43%) isolates, and within the wild-type range in three (14%) isolates. Clofazimine MICs in genetically wild-type isolates ranged from 0·12-0·5 μg/mL, and in isolates with RAVs from 0·25-4·0 μg/mL. Phylogenetic analysis of the extended dataset including M tuberculosis isolates from southern Africa resolved multiple emergences of Rv0678 variants in lineages 2 and 4, documented two likely nosocomial transmission events, and identified the spread of a possibly bedaquiline and clofazimine cross-resistant clone in eSwatini. We also identified four patients with pepQ frameshift mutations that may confer resistance. Interpretation: Bedaquiline and clofazimine cross-resistance in southern Africa is emerging repeatedly, with evidence of onward transmission largely due to Rv0678 mutations in M tuberculosis. Roll-out of bedaquiline and clofazimine treatment in the setting of limited drug susceptibility testing could allow further spread of resistance. Designing strong regimens would help reduce the emergence of resistance. Drug susceptibility testing is required to identify where resistance does emerge. Funding: Wellcome Trust, National Institute of Allergy and Infectious Diseases and National Center for Advancing Translational Sciences of the National Institutes of Health