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.

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. FUNDING: WHO Global TB Programme. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to bedaquiline in patients treated for rifampicin-resistant tuberculosis: a cross-sectional and longitudinal study.

BACKGROUND: Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19). METHODS: Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes. FINDINGS: Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR. INTERPRETATION: Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential. FUNDING: National Institute for Communicable Diseases of South Africa.

High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen.

South African patients with rifampicin-resistant tuberculosis (TB) and resistance to fluoroquinolones and/or injectable drugs (extensively drug-resistant (XDR) and preXDR-TB) were granted access to bedaquiline through a clinical access programme with strict inclusion and exclusion criteria.PreXDR-TB and XDR-TB patients were treated with 24 weeks of bedaquiline within an optimised, individualised background regimen that could include levofloxacin, linezolid and clofazimine as needed. 200 patients were enrolled: 87 (43.9%) had XDR-TB, 99 (49.3%) were female and the median age was 34 years (interquartile range (IQR) 27-42). 134 (67.0%) were living with HIV; the median CD4+ count was 281 cells·µL-1 (IQR 130-467) and all were on antiretroviral therapy.16 out of 200 patients (8.0%) did not complete 6 months of bedaquiline: eight were lost to follow-up, six died, one stopped owing to side effects and one was diagnosed with drug-sensitive TB. 146 out of 200 patients (73.0%) had favourable outcomes: 139 (69.5%) were cured and seven (3.5%) completed treatment. 25 patients (12.5%) died, 20 (10.0%) were lost from treatment and nine (4.5%) had treatment failure. 22 adverse events were attributed to bedaquiline, including a QT interval corrected using the Fridericia formula (QTcF) >500 ms (n=5), QTcF increase >50 ms from baseline (n=11) and paroxysmal atrial flutter (n=1).Bedaquiline added to an optimised background regimen was associated with a high rate of successful treatment outcomes for this preXDR-TB and XDR-TB cohort.

Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study.

BACKGROUND: Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline. METHODS: In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment. FINDINGS: 24 014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to 743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28-0·46) and extensively drug-resistant tuberculosis (0·26, 0·18-0·38) compared with standard regimens. INTERPRETATION: Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen. FUNDING: None.

Treatment outcomes in multidrug resistant tuberculosis-human immunodeficiency virus Co-infected patients on anti-retroviral therapy at Sizwe Tropical Disease Hospital Johannesburg, South Africa.

BACKGROUND: Multidrug resistant-tuberculosis (MDR-TB) is a threat to global tuberculosis control which is worsened by human immune-deficiency virus (HIV) co-infection. There is however paucity of data on the effects of antiretroviral treatment (ART) before or after starting MDR-TB treatment. This study determined predictors of mortality and treatment failure among HIV co-infected MDR-TB patients on ART. METHODS: A retrospective medical record review of 1200 HIV co-infected MDR-TB patients admitted at Sizwe Tropical Disease Hospital, Johannesburg from 2007 to 2010 was performed. Chi-square test was used to determine treatment outcomes in HIV co-infected MDR-TB patients on ART. Multivariable logistic regression and Poisson models were used to determine predictors of mortality and treatment failure respectively. RESULTS: Mortality was higher (21.8% vs. 15.4%) among patients who started ART before initiating MDR-TB treatment compared with patients initiated on ART after commencing MDR-TB treatment (p = 0.013). Factors significantly associated with mortality included: the use of ART before starting MDR-TB treatment (OR 1.65, 95% CI 1.02-2.73), severely-underweight (OR 3.71, 95% CI 1.89-7.29) and underweight (OR 2.35, 95% CI 1.30-4.26), cavities on chest x-rays at baseline (OR 1.76, 95% CI 1.08-2.94), presence of other opportunistic infections (OR 1.80, 95% CI 1.10-2.94) and presence of other co-morbidities (OR 2.26, 95% CI 1.20-4.21). Factors predicting failure were severe anaemia (IRR (OR 4.72, 95% CI 1.47-15), other co-morbidities (OR 2.39, 95% CI 1.05-5.43) and modified individualised regimen at baseline (OR 2.15, 95% CI 0.98-4.71). CONCLUSIONS: High mortality among patients already on ART before initiating MDR-TB treatment is a worrisome development. Management of adverse-events, opportunistic infections and co-morbidities in these patients is important if the protective benefits of being on ART are to be maximized. There is the need to intensify intervention programmes targeted at early identification of MDR-TB, treatment initiation, drug monitoring and increasing adherence among HIV co-infected MDR-TB patients.

Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study.

BACKGROUND: Long-term treatment-related outcomes in patients with extensively drug-resistant (XDR) tuberculosis are unknown. We followed up a cohort of patients to address knowledge gaps. METHODS: Between March, 2008, and August, 2012, we prospectively followed up a cohort of 107 patients from three provinces in South Africa, who had been diagnosed with XDR tuberculosis between August 2002, and February, 2008. Available isolates from 56 patients were genotyped to establish strain type and used for extended susceptibility testing. FINDINGS: All patients were treated empirically as inpatients with a median of eight drugs (IQR six to ten). 44 patients (41%) had HIV. 36 (64%) of 56 isolates were resistant to at least eight drugs, and resistance to an increasing number of drugs was associated with the Beijing genotype (p=0·01). After 24 months of follow-up, 17 patients (16%) had a favourable outcome (ie, treatment cure or completion), 49 (46%) had died, seven (7%) had defaulted (interruption of treatment for at least 2 consecutive months), and 25 (23%) had failed treatment. At 60 months, 12 patients (11%) had a favourable outcome, 78 (73%) had died, four (4%) had defaulted, and 11 (10%) had failed treatment. 45 patients were discharged from hospital, of whom 26 (58%) had achieved sputum culture conversion and 19 (42%) had failed treatment. Median survival of patients who had failed treatment from time of discharge was 19·84 months (IQR 4·16-26·04). Clustering of cases and transmission within families containing a patient who had failed treatment and been discharged were shown with genotypic methods. Net sputum culture conversion occurred in 22 patients (21%) and median time to net culture conversion was 8·7 months (IQR 5·6-26·4). Independent predictors of probability of net culture conversion were no history of multidrug-resistant tuberculosis (p=0·0007) and use of clofazamine (p=0·0069). Independent overall predictors of survival were net culture conversion (p<0·0001) and treatment with clofazamine (p=0·021). Antiretroviral therapy was also a predictor of survival in patients with HIV (p=0·003). INTERPRETATION: In South Africa, long-term outcomes in patients with XDR tuberculosis are poor, irrespective of HIV status. Because appropriate long-stay or palliative care facilities are scarce, substantial numbers of patients with XDR tuberculosis who have failed treatment and have positive sputum cultures are being discharged from hospital and are likely to transmit disease into the wider community. Testing of new combined regimens is needed urgently and policy makers should implement interventions to minimise disease spread by patients who fail treatment. FUNDING: European and Developing Countries Clinical Trials Partnership, South African National Research Foundation (SARChI), and the South African Medical Research Council.

Factors influencing specialist care referral of multidrug- and extensively drug-resistant tuberculosis patients in Gauteng/South Africa: a descriptive questionnaire-based study.

BACKGROUND: Sizwe Tropical Diseases Hospital is the only specialized Hospital for the management of multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB cases in Gauteng Province. In South Africa, there is a mismatch between numbers of individuals with a laboratory diagnosis of drug-resistant tuberculosis (TB) and those being referred for the initiation of specialist treatment. We determined reasons for non-referral of MDR-TB and XDR-TB cases. METHODS: We conducted a descriptive questionnaire-based study amongst provincial primary health care facilities (PHC) and hospitals providing routine care for (drug-susceptible) TB, regarding specialist care referral of patients whose TB culture and susceptibility testing confirmed MDR-TB or XDR-TB diagnoses in the first half of 2008. RESULTS: In total 148 cases were analyzed; 144/148 (97%) had MDR-TB and 4/148 (3%) had XDR-TB. The main reason for non-referral to specialist care was loss to follow up, for patients diagnosed in-hospital (74/97; 76%) as well as in PHCs (11/21; 52%). Nineteen per cent (18/97) of patients diagnosed in hospital versus 33% (7/21) of patients diagnosed in PHCs deceased before referral. CONCLUSIONS: A significant problem in the fight to control DR-TB is follow-up after diagnosis with a delay in patient tracing. TB Focal Points in hospital need to be strengthened in order to improve on patient follow-up and care, and tracer teams should assist with community follow up.

Drug-associated adverse events and their relationship with outcomes in patients receiving treatment for extensively drug-resistant tuberculosis in South Africa.

BACKGROUND: Treatment-related outcomes in patients with extensively drug-resistant tuberculosis (XDR-TB) are poor. However, data about the type, frequency and severity of presumed drug-associated adverse events (AEs) and their association with treatment-related outcomes in patients with XDR-TB are scarce. METHODS: Case records of 115 South-African XDR-TB patients were retrospectively reviewed by a trained researcher. AEs were estimated and graded according to severity [grade 0 = none; grade 1-2 = mild to moderate; and grade 3-5 = severe (drug stopped, life-threatening or death)]. FINDINGS: 161 AEs were experienced by 67/115(58%) patients: 23/67(34%) required modification of treatment, the offending drug was discontinued in 19/67(28%), reactions were life-threatening in 2/67(3.0%), and 6/67(9.0%) died. ∼50% of the patients were still on treatment at the time of data capture. Sputum culture-conversion was less likely in those with severe (grade 3-5) vs. grade 0-2 AEs [2/27(7%) vs. 24/88(27%); p = 0.02]. The type, frequency and severity of AEs was similar in HIV-infected and uninfected patients. Capreomycin, which was empirically administered in most cases, was withdrawn in 14/104(14%) patients, implicated in (14/34) 41% of the total drug withdrawals, and was associated with all 6 deaths in the severe AE group (renal failure in five patients and hypokalemia in one patient). CONCLUSION: Drug-associated AEs occur commonly with XDR-TB treatment, are often severe, frequently interrupt therapy, and negatively impact on culture conversion outcomes. These preliminary data inform on the need for standardised strategies (including pre-treatment counselling, early detection, monitoring, and follow-up) and less toxic drugs to optimally manage patients with XDR-TB.

How many sputum culture results do we need to monitor multidrug-resistant-tuberculosis (MDR-TB) patients during treatment?

Discharge of a hospital patient after a single negative sputum culture may save money when treating multidrug-resistant tuberculosis. However, after initial sputum conversion in 336 South Africans, 11.6% and 5.4% reconverted after 1 and 2 months, respectively. These findings endorse the WHO definitions of 2 negative cultures taken ≥ 30 days apart after sputum culture conversion.

Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study.

BACKGROUND: Data from Kwazulu Natal, South Africa, suggest that almost all patients with extensively drug-resistant (XDR) tuberculosis are HIV-positive, with a fatal outcome. Since, there are few data for the treatment-related outcomes of XDR tuberculosis in settings with a high HIV prevalence, we investigated the associations of these diseases in such settings to formulate recommendations for control programmes. METHODS: In a retrospective cohort study, we analysed the case records of patients (>16 years old) with XDR tuberculosis (culture-proven at diagnosis) between August, 2002, and February, 2008, at four designated provincial treatment facilities in South Africa. We used Cox proportional hazards regression models to assess risk factors associated with the outcomes-mortality and culture conversion. FINDINGS: 195 of 227 patients were analysed. 21 died before initiation of any treatment, and 174 patients (82 with HIV infection) were treated. 62 (36%) of these patients died during follow-up. The number of deaths was not significantly different in patients with or without HIV infection: 34 (41%) of 82 versus 28 (30%) of 92 (p=0.13). Treatment with moxifloxacin (hazard ratio 0.11, 95% CI 0.01-0.82; p=0.03), previous culture-proven multidrug-resistant tuberculosis (5.21, 1.93-14.1; p=0.001), and number of drugs used in a regimen (0.59, 0.45-0.78, p<0.0001) were independent predictors of death. Fewer deaths occurred in patients with HIV infection given highly active antiretroviral therapy than in those who were not (0.38, 0.18-0.80; p=0.01). 33 (19%) of 174 patients showed culture conversion, of which 23 (70%) converted within 6 months of initiation of treatment. INTERPRETATION: In South Africa, patients with XDR tuberculosis, a substantial proportion of whom are not infected with HIV, have poor management outcomes. Nevertheless, survival in patients with HIV infection is better than previously reported. The priorities for the country are still prevention of XDR tuberculosis, and early detection and management of multidrug-resistant and XDR tuberculosis through strengthened programmes and laboratory capacity. FUNDING: South African Medical Research Council, European Union Framework 7 program, and European Developing Countries Clinical Trials Partnership.