Bedaquiline and clofazimine : successes and challenges

Bedaquiline, a novel therapeutic drug, and clofazimine, a re-purposed drug, are front-line therapies recommended by WHO to treat rifampicin-resistant or multidrugresistant tuberculosis. Both drugs have been in use in South Africa at least 10 years: bedaquiline since 2007 and clofazimine since 2010. The use of bedaquiline in programmatic settings in South Africa has reduced the risk of all-cause mortality threefold (hazard ratio 0·35, 95% CI 0·28–0·46)1 and achieved treatment success in at least 70% of patients.2 The inclusion of clofazimine in combination therapy has reduced treatment duration from 18–24 months to 9–12 months. South Africa has adopted both drugs extensively in the modified short and long regimens for rifampicin-resistant or multidrug-resistant tuberculosis. According to the electronic drug-resistant tuberculosis register, as of June 1, 2020, 29 193 individuals in South Africa have received bedaquiline, and 30 599 have received clofazimine. Emerging resistance and cross-resistance have been reported.http://www.thelancet.com/microbeam2021Medical Microbiolog

Bedaquiline and clofazimine : successes and challenges

Bedaquiline, a novel therapeutic drug, and clofazimine, a re-purposed drug, are front-line therapies recommended by WHO to treat rifampicin-resistant or multidrugresistant tuberculosis. Both drugs have been in use in South Africa at least 10 years: bedaquiline since 2007 and clofazimine since 2010. The use of bedaquiline in programmatic settings in South Africa has reduced the risk of all-cause mortality threefold (hazard ratio 0·35, 95% CI 0·28–0·46)1 and achieved treatment success in at least 70% of patients.2 The inclusion of clofazimine in combination therapy has reduced treatment duration from 18–24 months to 9–12 months. South Africa has adopted both drugs extensively in the modified short and long regimens for rifampicin-resistant or multidrug-resistant tuberculosis. According to the electronic drug-resistant tuberculosis register, as of June 1, 2020, 29 193 individuals in South Africa have received bedaquiline, and 30 599 have received clofazimine. Emerging resistance and cross-resistance have been reported.https://www.thelancet.com/microbeam2022Medical Microbiolog

Delays and loss to follow-up before treatment of drug-resistant tuberculosis following implementation of Xpert MTB/RIF in South Africa: A retrospective cohort study.

BACKGROUND: South Africa has a large burden of rifampicin-resistant tuberculosis (RR-TB), with 18,734 patients diagnosed in 2014. The number of diagnosed patients has increased substantially with the introduction of the Xpert MTB/RIF test, used for tuberculosis (TB) diagnosis for all patients with presumptive TB. Routine aggregate data suggest a large treatment gap (pre-treatment loss to follow-up) between the numbers of patients with laboratory-confirmed RR-TB and those reported to have started second-line treatment. We aimed to assess the impact of Xpert MTB/RIF implementation on the delay to treatment initiation and loss to follow-up before second-line treatment for RR-TB across South Africa. METHODS AND FINDINGS: A nationwide retrospective cohort study was conducted to assess second-line treatment initiation and treatment delay among laboratory-diagnosed RR-TB patients. Cohorts, including approximately 300 sequentially diagnosed RR-TB patients per South African province, were drawn from the years 2011 and 2013, i.e., before and after Xpert implementation. Patients with prior laboratory RR-TB diagnoses within 6 mo and currently treated patients were excluded. Treatment initiation was determined through data linkage with national and local treatment registers, medical record review, interviews with health care staff, and direct contact with patients or household members. Additional laboratory data were used to track cases. National estimates of the percentage of patients who initiated treatment and time to treatment were weighted to account for the sampling design. There were 2,508 and 2,528 eligible patients in the 2011 and 2013 cohorts, respectively; 92% were newly diagnosed with RR-TB (no prior RR-TB diagnoses). Nationally, among the 2,340 and 2,311 new RR-TB patients in the 2011 and 2013 cohorts, 55% (95% CI 53%-57%) and 63% (95% CI 61%-65%), respectively, started treatment within 6 mo of laboratory receipt of their diagnostic specimen (p < 0.001). However, in 2013, there was no difference in the percentage of patients who initiated treatment at 6 mo between the 1,368 new RR-TB patients diagnosed by Xpert (62%, 95% CI 59%-65%) and the 943 diagnosed by other methods (64%, 95% CI 61%-67%) (p = 0.39). The median time to treatment decreased from 44 d (interquartile range [IQR] 20-69) in 2011 to 22 d (IQR 2-43) in 2013 (p < 0.001). In 2013, across the nine provinces, there were substantial variations in both treatment initiation (range 51%-73% by 6 mo) and median time to treatment (range 15-36 d, n = 1,450), and only 53% of the 1,448 new RR-TB patients who received treatment were recorded in the national RR-TB register. This retrospective study is limited by the lack of information to assess reasons for non-initiation of treatment, particularly pre-treatment mortality data. Other limitations include the use of names and dates of birth to locate patient-level data, potentially resulting in missed treatment initiation among some patients. CONCLUSIONS: In 2013, there was a large treatment gap for RR-TB in South Africa that varied significantly across provinces. Xpert implementation, while reducing treatment delay, had not contributed substantially to reducing the treatment gap in 2013. However, given improved case detection with Xpert, a larger proportion of RR-TB patients overall have received treatment, with reduced delays. Nonetheless, strategies to further improve linkage to treatment for all diagnosed RR-TB patients are urgently required

Prevalence of drug-resistant mutations in newly diagnosed drug-naïve HIV-1-infected individuals in a treatment site in the Waterberg District, Limpopo province

Aim. We studied the prevalence of resistance mutations in drug-naïve HIV-infected individuals at the Bela-Bela treatment site to gather information on the presence of antiretroviral (ARV) drug-resistant viruses in drug-naïve populations, so as to improve treatment guidance. Subjects and methods. Drug-naive HIV-1-infected individuals were sequentially recruited between February 2008 and December 2008 from individuals visiting the voluntary counseling and testing (VCT) services of the Bela-Bela HIV/AIDS Wellness Clinic. Viral subtyping was done by phylogenetic analysis; drug-resistant mutations were determined according to the Stanford HIV Drug Resistance Interpretation and the International AIDS society-USA guidelines. Results. A drug-resistant mutation prevalence of 3.5% (95% confidence interval 0.019796 - 0.119077) comprising Y181C and L33F was observed; 98% of the viruses were HIV-1 subtype C on the protease (PR) and reverse transcriptase (RT) gene regions. Conclusion. The prevalence of drug-resistant mutations in drug-naïve persons may be low in Bela-Bela after 8 years of access to antiretroviral treatment (ART), and resistance testing before initiating treatment may not be needed

A call to action: Addressing the reproductive health needs of women with drug-resistant tuberculosis

Although there is substantial risk to maternal and neonatal health in the situation of pregnancy during treatment for rifampicin-resistant tuberculosis (RR-TB), there is little evidence to guide clinicians as to how to manage this complexity. Of the 49 680 patients initiated on RR-TB treatment from 2009 to 2014 in South Africa, 47% were women and 80% of them were in their reproductive years (15 - 44). There is an urgent need for increased evidence of the safety of RR-TB treatment during pregnancy, increased access to contraception during RR-TB treatment, and inclusion of reproductive health in research on the prevention and treatment of TB.

Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF

Background In South Africa, sputum smear microscopy has been replaced with Xpert MTB/RIF as the initial diagnostic test for tuberculosis. In a pragmatic parallel cluster-randomised trial, we evaluated the eff ect on patient and programme outcomes. Methods We randomly allocated 20 laboratories (clusters) in medium-burden districts of South Africa to either an Xpert (immediate Xpert) or microscopy (Xpert deferred) group (1:1), stratifi ed by province. At two primary care clinics per laboratory, a systematic sample of adults giving sputum for tuberculosis investigation was assessed for eligibility. The primary outcome was mortality at 6 months from enrolment. Masking of participants’ group allocation was not possible because of the pragmatic trial design. The trial is registered with the ISRCTN registry (ISRCTN68905568) and the South African Clinical Trial Register (DOH-27-1011-3849). Findings Between June and November, 2012, 4972 people were screened, and 4656 (93·6%) enrolled (median age 36 years; 2891 [62%] female; 2212 [62%] reported being HIV-positive). There was no diff erence between the Xpert and microscopy groups with respect to mortality at 6 months (91/2324 [3·9%] vs 116/2332 [5·0%], respectively; adjusted risk ratio [aRR] 1·10, 95% CI 0·75–1·62]). Interpretation Xpert did not reduce mortality at 6 months compared with sputum microscopy. Improving outcomes in drug-sensitive tuberculosis programmes might require not only better diagnostic tests but also better linkage to care

Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF.

BACKGROUND: In South Africa, sputum smear microscopy has been replaced with Xpert MTB/RIF as the initial diagnostic test for tuberculosis. In a pragmatic parallel cluster-randomised trial, we evaluated the effect on patient and programme outcomes. METHODS: We randomly allocated 20 laboratories (clusters) in medium-burden districts of South Africa to either an Xpert (immediate Xpert) or microscopy (Xpert deferred) group (1:1), stratified by province. At two primary care clinics per laboratory, a systematic sample of adults giving sputum for tuberculosis investigation was assessed for eligibility. The primary outcome was mortality at 6 months from enrolment. Masking of participants' group allocation was not possible because of the pragmatic trial design. The trial is registered with the ISRCTN registry (ISRCTN68905568) and the South African Clinical Trial Register (DOH-27-1011-3849). FINDINGS: Between June and November, 2012, 4972 people were screened, and 4656 (93·6%) enrolled (median age 36 years; 2891 [62%] female; 2212 [62%] reported being HIV-positive). There was no difference between the Xpert and microscopy groups with respect to mortality at 6 months (91/2324 [3·9%] vs 116/2332 [5·0%], respectively; adjusted risk ratio [aRR] 1·10, 95% CI 0·75-1·62]). INTERPRETATION: Xpert did not reduce mortality at 6 months compared with sputum microscopy. Improving outcomes in drug-sensitive tuberculosis programmes might require not only better diagnostic tests but also better linkage to care. FUNDING: Bill & Melinda Gates Foundation

Organisation of care for people receiving drug-resistant tuberculosis treatment in South Africa: a mixed methods study

From BMJ via Jisc Publications RouterHistory: received 2023-03-03, accepted 2023-10-09, ppub 2023-11, epub 2023-11-18Peer reviewed: TrueAcknowledgements: The authors wish to thank the Departments of Health of the Western Cape, Eastern Cape, KwaZulu-Natal, and acknowledge the staff at the NHLS for their tremendous input and assistance. We give special mention to the late Dr Iqbal Masters and Mrs Anna Maria Evans for their contributions to the study. We also appreciate the support of Staff Nurse Cheryl Liedeman and Dr Widaad Zemanay.Publication status: PublishedFunder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/N015924/1Funder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100010269; Grant(s): MR/N015924/1Funder: Australian National Health and Medical Research Council; Grant(s): APP1174455Karina Kielmann - ORCID: 0000-0001-5519-1658 https://orcid.org/0000-0001-5519-1658Objectives: Treatment for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) is increasingly transitioning from hospital-centred to community-based care. A national policy for decentralised programmatic MDR/RR-TB care was adopted in South Africa in 2011. We explored variations in the implementation of care models in response to this change in policy, and the implications of these variations for people affected by MDR/RR-TB. Design: A mixed methods study was done of patient movements between healthcare facilities, reconstructed from laboratory records. Facility visits and staff interviews were used to determine reasons for movements. Participants and setting: People identified with MDR/RR-TB from 13 high-burden districts within South Africa. Outcome measures: Geospatial movement patterns were used to identify organisational models. Reasons for patient movement and implications of different organisational models for people affected by MDR/RR-TB and the health system were determined. Results: Among 191 participants, six dominant geospatial movement patterns were identified, which varied in average hospital stay (0–281 days), average patient distance travelled (12–198 km) and number of health facilities involved in care (1–5 facilities). More centralised models were associated with longer delays to treatment initiation and lengthy hospitalisation. Decentralised models facilitated family-centred care and were associated with reduced time to treatment and hospitalisation duration. Responsiveness to the needs of people affected by MDR/RR-TB and health system constraints was achieved through implementation of flexible models, or the implementation of multiple models in a district. Conclusions: Understanding how models for organising care have evolved may assist policy implementers to tailor implementation to promote particular patterns of care organisation or encourage flexibility, based on patient needs and local health system resources. Our approach can contribute towards the development of a health systems typology for understanding how policy-driven models of service delivery are implemented in the context of variable resources.pubpu

Treatment outcomes 24 months after initiating short, all-oral bedaquiline-containing or injectable-containing rifampicin-resistant tuberculosis treatment regimens in South Africa : a retrospective cohort study

DATA SHARING : The data used for this analysis in the form of deidentified participant data and a data dictionary will be made available after publication. Investigators wishing to access these data will need to have an approved research proposal and complete a data access agreement. All inquiries should be sent to the corresponding author ([email protected] or [email protected]).SUPPLEMENTARY MATERIAL 1 : French translation of the abstract. SUPPLEMENTARY MATERIAL 2 : Appendices.BACKGROUND : There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group). METHODS : Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9–12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes. FINDINGS : Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8–20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1–8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0–5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4–11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment. INTERPRETATION : Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.WHO Global TB Programme.http://www.thelancet.com/infectionhj2023Medical Microbiolog

Cost-effectiveness of bedaquiline, pretomanid and linezolid for treatment of extensively drug-resistant tuberculosis in South Africa, Georgia and the Philippines

Objectives Patients with highly resistant tuberculosis have few treatment options. Bedaquiline, pretomanid and linezolid regimen (BPaL) is a new regimen shown to have favourable outcomes after six months. We present an economic evaluation of introducing BPaL against the extensively drug-resistant tuberculosis (XDR-TB) standard of care in three epidemiological settings. Design Cost-effectiveness analysis using Markov cohort model. Setting South Africa, Georgia and the Philippines. Participants XDR-TB and multidrug-resistant tuberculosis (MDR-TB) failure and treatment intolerant patients.InterventionsBPaL regimen. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Incremental cost per disability-adjusted life years averted by using BPaL against standard of care at the Global Drug Facility list price. (2) The potential maximum price at which the BPaL regimen could become cost neutral. Results BPaL for XDR-TB is likely to be cost saving in all study settings when pretomanid is priced at the Global Drug Facility list price. The magnitude of these savings depends on the prevalence of XDR-TB in the country and can amount, over 5 years, to approximately US$3 million in South Africa, US$ 200 000 and US$60 000 in Georgia and the Philippines, respectively. In South Africa, related future costs of antiretroviral treatment (ART) due to survival of more patients following treatment with BPaL reduced the magnitude of expected savings to approximately US$ 1 million. Overall, when BPaL is introduced to a wider population, including MDR-TB treatment failure and treatment intolerant, we observe increased savings and clinical benefits. The potential threshold price at which the probability of the introduction of BPaL becoming cost neutral begins to increase is higher in Georgia and the Philippines (US$3650 and US$ 3800, respectively) compared with South Africa (US$ 500) including ART costs. Conclusions Our results estimate that BPaL can be a cost-saving addition to the local TB programmes in varied programmatic settings