Efficacy and safety of shorter multidrug-resistant or rifampicin-resistant tuberculosis regimens: a network meta-analysis

Abstract

Background: Drug-resistant tuberculosis (DR-TB) remains a threat to public health. Shorter regimens have been proposed as potentially valuable treatments for multidrug or rifampicin resistant tuberculosis (MDR/RR-TB). We undertook a systematic review and network meta-analysis to evaluate the efficacy and safety of shorter MDR/RR-TB regimens.

Methods: We searched PubMed/MEDLINE, Cochrane Center for Clinical Trials (CENTRAL), Scopus, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, US Food and Drug Administration, and Chinese Clinical Trial Registry for primary articles published from 2013 to July 2023. Favorable (cured and treatment completed) and unfavorable (treatment failure, death, loss to follow-up, and culture conversion) outcomes were assessed as the main efficacy outcomes, while adverse events were assessed as the safety outcomes. The network meta-analysis was performed using R Studio version 4.3.1 and the Netmeta package. The study protocol adhered to the PRISMA-NMA guidelines and was registered in PROSPERO (CRD42023434050).

Result: We included 11 eligible studies (4 randomized control trials and 7 cohorts) that enrolled 3,548 patients with MDR/RR-TB. Treatment with a 6-month combination of BdqLzdLfxZTrd/Eto/H had two times more favorable outcomes [RR 2.2 (95% CI 1.22, 4.13), P = 0.0094], followed by a 9-11 month combination of km/CmMfx/LfxPtoCfzZEHh [RR1.67 (95% CI 1.45, 1.92), P < 0.001] and a 6-month BdqPaLzdMfx [RR 1.64 (95% CI 1.24, 2.16), P < 0.0005] compared to the standard longer regimens. Treatment with 6 months of BdqPaLzdMfx [RR 0.33 (95% CI 0.2, 0.55), P < 0.0001] had a low risk of severe adverse events, followed by 6 months of BdqPaLzd [RR 0.36 (95% CI 0.22, 0.59), P ≤ 0.001] and BdqPaLzdCfz [RR 0.54 (95% CI 0.37, 0.80), P < 0.0001] than standard of care.

Conclusion: Treatment of patients with RR/MDR-TB using shorter regimens of 6 months BdqLzdLfxZTrd/Eto/H, 9-11 months km/CmMfx/LfxPtoCfzZEHh, and 6 months BdqPaLzdMfx provides significantly higher cure and treatment completion rates compared to the standard longer MDR/RR-TB. However, 6BdqPaLzdMfx, 6BdqPaLzd, and 6BdqPaLzdCfz short regimens are significantly associated with decreased severity of adverse events. The findings are in support of the current WHO-recommended 6-month shorter regimens.

Keywords: Multidrug-resistant tuberculosis (MDR-TB); Network meta-analysis; Rifampicin-resistant tuberculosis (RR-TB); Short- term regimens; Systematic review.

Fig. 1

PRISMA-NMA flow chart of study selection for inclusion in the systematic review and network meta-analysis

Fig. 2

Risk of bias summary: review authors’ judgments about each risk of bias item for each included study using the Cochrane Collaboration’s tool for assessing the ‘Risk of bias’

Fig. 3

Risk of bias summary: review authors’ judgments about each risk of bias item for each included study using ROBIN’s tool

Fig. 4

Network diagram for a favorable outcome among MDR-TB patients treated with short regimens

Fig. 5

Forest plot for favorable outcomes among MDR-TB patients treated with shorter regimens

Fig. 6

Net rank plot for a favorable outcome among MDR-TB patients treated with short regimens

Fig. 7

Network diagram for loss to follow-up among MDR-TB patients treated with short regimens

Fig. 8

Forest plot for loss to follow-up among MDR-TB patients treated with short regimens

Fig. 9

Forest plot for treatment failure among MDR-TB patients treated with short regimens

Fig. 10

Forest plot for culture conversion among MDR-TB patients treated with short regimens after 2 months

Fig. 11

Network diagram for severe adverse events among MDR-TB patients treated with short regimens

Fig. 12

Forest plot for severe adverse events among MDR-TB patients treated with short regimens

Fig. 13

Forest plot for renal adverse events among MDR-TB patients treated with short regimens

Fig. 14

Forest plot for hepatic adverse events among MDR-TB patients treated with short regimens

Fig. 15

Forest plot for cardiac conduction (QTc prolongation) adverse events among MDR-TB patients treated with short regimens

Fig. 16

Forest plot for gastrointestinal adverse events among MDR-TB patients treated with short regimens

Fig. 17

Forest plot for ear and labyrinth adverse events among MDR-TB patients treated with short regimens

Fig. 18

Forest plot for peripheral neuropathy adverse events among MDR-TB patients treated with short regimens

Fig. 19

Forest plot for serious adverse events among MDR-TB patients treated with short regimens

Fig. 20

Network diagram for TB-related death among MDR-TB patients treated with short regimens

Fig. 21

Net rank plot for TB-related death among MDR-TB patients treated with short regimens

Fig. 22

Forest plot for TB-related death among MDR-TB patients treated with short regimens