Safety and Effectiveness of an All-Oral, Bedaquiline-Based, Shorter Treatment Regimen for Rifampicin-Resistant Tuberculosis in High Human Immunodeficiency Virus (HIV) Burden Rural South Africa: A Retrospective Cohort Analysis

Abstract

Background: At the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and 2 months of linezolid (LZD) for all patients initiating the shorter 9-12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions.

Methods: We conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between 1 July 2018 and 30 April 2019 in 3 facilities in King Cetshwayo District. An electronic register (EDR web) and facility-based clinical charts were used to collect variables, which were entered into an Epi-Info database.

Results: Our cohort included 117 patients; 68.4% (95% confidence interval [CI]: 59.3-76.3) tested positive for human immunodeficiency virus (HIV). The median time to culture conversion was 56 days (95% CI: 50-57). Treatment success was achieved in 75.2% (95% CI: 66.5-82.3) of patients. Mortality within the cohort was 12.8% (95% CI: 7.8-20.3). Anemia was the most frequent severe adverse event (AE). The median time to develop severe anemia was 7.1 weeks (interquartile range [IQR] 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2% (95% CI: 17.8-34.5) of participants.

Conclusions: An all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. AEs are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to train staff in the monitoring, management, and reporting of AEs.

Keywords: adverse event management; all-oral short regimen; bedaquiline; linezolid; multidrug resistant.

Figure 2.

Diagrammatic overview of the short standardized Bedaquiline-based regimen, indicating recommended duration of each drug as of November 2018 in South Africa (National Department of Health Interim Guidance for the Implementation of Injectable Free Regimens for Rifampicin-Resistant Tuberculosis).

Figure 1.

Flow diagram of selection of study participants from patients notified with RR-TB in King Cetshwayo district, Kwa-Zulu Natal, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: DR-TB, drug-resistant tuberculosis; INH, isoniazid; RR-TB, rifampicin-resistant tuberculosis.

Figure 3.

Kaplan-Meier survival estimates for smear/culture positive RR-TB patients at baseline in King Cetshwayo district, 1 July 2018 to 30 April 2019. A, Time to culture conversion (n = 67). B, Time to smear conversion (n = 52). C, Time to culture conversion by HIV status (n = 67); log-rank test within 6 months of follow-up: P = .104. D, Time to culture conversion by CD4 count (n = 45); log-rank test within 3 months of follow-up: P = .826. Abbreviations: HIV, human immunodeficiency virus; RR-TB, rifampicin-resistant tuberculosis.

Figure 4.

Frequency of severe AEs experienced in RR-TB patients during first 24 weeks after treatment initiation (N = 62), receiving a short standardized BDQ-based regimen in King Cetshwayo district between 1 July 2018 and 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; RR-TB, rifampicin-resistant tuberculosis.

Figure 5.

Graphic illustration of episodes of treatment interruption (N = 94) per individual drug (drug name; n) following an AE in patients during the first 24 weeks of the short standardized BDQ-based regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; CLF, clofazimine; E, ethambutol; ETH, ethionamide; INH hd, high dose isoniazid; LFX, levofloxacin; LZD, linezolid; PZA, pyrazinamide.