Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial.

BACKGROUND: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. METHODS: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631. FINDINGS: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss. INTERPRETATION: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss. FUNDING: USAID and Janssen Research & Development.

A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis.

BACKGROUND: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011. METHODS: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority. RESULTS: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively. CONCLUSIONS: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.).

Achieving high treatment success for multidrug-resistant TB in Africa: initiation and scale-up of MDR TB care in Ethiopia--an observational cohort study.

BACKGROUND: In Africa, fewer than half of patients receiving therapy for multidrug-resistant TB (MDR TB) are successfully treated, with poor outcomes reported for HIV-coinfected patients. METHODS: A standardised second-line drug (SLD) regimen was used in a non-governmental organisation-Ministry of Health (NGO-MOH) collaborative community and hospital-based programme in Ethiopia that included intensive side effect monitoring, adherence strategies and nutritional supplementation. Clinical outcomes for patients with at least 24 months of follow-up were reviewed and predictors of treatment failure or death were evaluated by Cox proportional hazards models. RESULTS: From February 2009 to December 2014, 1044 patients were initiated on SLD. 612 patients with confirmed or presumed MDR TB had ≥ 24 months of follow-up, 551 (90.0%) were confirmed and 61 (10.0%) were suspected MDR TB cases. 603 (98.5%) had prior TB treatment, 133 (21.7%) were HIV coinfected and median body mass index (BMI) was 16.6. Composite treatment success was 78.6% with 396 (64.7%) cured, 85 (13.9%) who completed treatment, 10 (1.6%) who failed, 85 (13.9%) who died and 36 (5.9%) who were lost to follow-up. HIV coinfection (adjusted HR (AHR): 2.60, p<0.001), BMI (AHR 0.88/kg/m(2), p=0.006) and cor pulmonale (AHR 3.61, p=0.003) and confirmed MDR TB (AHR 0.50, p=0.026) were predictive of treatment failure or death. CONCLUSIONS: We report from Ethiopia the highest MDR TB treatment success outcomes so far achieved in Africa, in a setting with severe resource constraints and patients with advanced disease. Intensive treatment of adverse effects, nutritional supplementation, adherence interventions and NGO-MOH collaboration were key strategies contributing to success. We argue these approaches should be routinely incorporated into programmes.

Economic evaluation of shortened, bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis (STREAM stage 2): a within-trial analysis of a randomised controlled trial.

BACKGROUND: The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens. METHODS: STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631. FINDINGS: 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia, $1900 in India, $3950 in Moldova, and $7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia, $3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from $1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India. INTERPRETATION: At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable. FUNDING: USAID and Janssen Research & Development.

Treatment of drug-resistant tuberculosis among people living with HIV.

PURPOSE OF REVIEW: This review aims to describe the key principles in treatment of drug-resistant tuberculosis (TB) in people living with HIV, including early access to timely diagnostics, linkage into care, TB treatment strategies including the use of new and repurposed drugs, co-management of HIV disease, and treatment complications and programmatic support to optimize treatment outcomes. These are necessary strategies to decrease the likelihood of poor treatment outcomes including lower treatment completion rates and higher mortality. RECENT FINDINGS: Diagnosis of drug-resistant TB is the gateway into care; yet understanding the utility and the limitations of genotypic methods in this population is necessary. The principles of TB treatment in HIV-infected individuals are similar to those without HIV co-infection, with few exceptions. However, adverse effects with potential significant morbidity may emerge during treatment, and timely antiretroviral therapy is essential to improve mortality in this patient population. Emerging data on the use of new and repurposed drugs and short course multidrug-resistant TB regimens and adherence strategies benefiting this population are reviewed. SUMMARY: The clinical complexity of co-managing drug-resistant TB and HIV, and the higher rate of poor treatment outcomes in this population demand careful clinical management strategies, and multidisciplinary and comprehensive programmatic interventions to optimize treatment success in this vulnerable group.