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Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection.

ABSTRACT: Bedaquiline, a potent new therapy for drug-resistant tuberculosis, results in improved survival including in HIV patients with multidrug and extensively drug-resistant tuberculosis. In line with WHO recommendations, in South Africa and other low-income and middle-income settings, antiretroviral therapy is switched from generic fixed-dose combination efavirenz-containing regimens to twice-daily nevirapine with separate companion pills because of interactions between efavirenz and bedaquiline. Early data suggest a signal for low antiretroviral therapy adherence after this antiretroviral therapy switch. Mortality and other tuberculosis-specific benefits noted with bedaquiline treatment in multidrug and extensively drug-resistant tuberculosis HIV might be compromised by HIV viral failure, and emergent antiretroviral resistance. Programmatic responses, such as adherence support and dual pharmacovigilance, should be instituted; antiretroviral therapy initiation with fixed-dose combinations without bedaquiline drug interactions should be strongly considered.

SUBMITTER: O'Donnell MR

PROVIDER: S-EPMC7155388 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection.

O'Donnell Max R MR Padayatchi Nesri N Daftary Amrita A Orrell Catherine C Dooley Kelly E KE Rivet Amico K K Friedland Gerald G

The lancet. HIV 20190301 3

Bedaquiline, a potent new therapy for drug-resistant tuberculosis, results in improved survival including in HIV patients with multidrug and extensively drug-resistant tuberculosis. In line with WHO recommendations, in South Africa and other low-income and middle-income settings, antiretroviral therapy is switched from generic fixed-dose combination efavirenz-containing regimens to twice-daily nevirapine with separate companion pills because of interactions between efavirenz and bedaquiline. Ear ...[more]

PMID: 30846058

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Project description:BackgroundEvidence on the efficacy of antiretroviral therapy (ART) regimen switches on the mortality of patients with HIV drug resistance (HIVDR) is limited.ObjectiveWe aim to provide policy guidance for ART regimen selection and evaluate the effectiveness of ART regime switches for people living with HIV and HIV-1 drug resistance.MethodsThis retrospective observational cohort study included 179 people living with HIV and HIV-1 drug resistance from 2011 to 2020. The time that participants switched treatment regimens either to protease inhibitor (PI)-based ART regimens (PIs) or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART regimens (NNRTIs) was taken as an observation starting point and followed up every 12 months. The parametric g-formula was used to estimate the 5-year risk of mortality under the situations of (1) natural course, (2) immediate switch to NNRTIs, (3) immediate switch to PIs, and (4) if CD4(+) T cells<200 switched to PIs.ResultsThe follow-up time of the 179 patients ranged from 30 to 119 months. The median follow-up time was 90 months. During a follow-up of 15,606 person-months, 27 individuals died in the cohort. The estimated 5-year risk of mortality under natural course, immediate switch to NNRTIs, immediate switch to PIs, and if CD4(+), and switch to PIs if T cells<200 were 11.62% (95% CI 7.82-17.11), 31.88% (95% CI 20.79-44.94), 2.87% (95% CI 0.32-7.07), and 5.30% (95% CI 2.07-10.21), respectively. The risk ratios (RRs) of immediate switch to NNRTIs, immediate switch to PIs, and switch to PIs if CD4(+) T cells<200, compared with natural course mortality rate, were 2.74 (95% CI 2.01-3.47), 0.25 (95% CI: 0.04-0.54), and 0.46 (95% CI 0.22-0.71), respectively. The risk differences were 20.26% (95% CI 10.96-28.61), -8.76% (95% CI -13.34 to -5.09) and -6.32% (95% CI -9.75 to -3.11), respectively.ConclusionsOur study found that a PI-based ART regimen was beneficial for reducing mortality in people living with HIV and HIV-1 drug resistance. More effort should be given to find HIV-1 drug resistance earlier to ensure a timely adjustment to PI-based ART, thereby maximizing the benefit of early switch treatment for people living with HIV and HIV-1 drug resistance.

Project description:Bedaquiline (BDQ), which is recommended for the treatment of drug-resistant tuberculosis (DR-TB), was introduced in Taiwan in 2014. Due to the alarming emergence of BDQ resistance, we conducted BDQ resistance analyses to strengthen our DR-TB management program. This retrospective population-based study included initial Mycobacterium tuberculosis isolates from 898 rifampicin-resistant (RR) or multidrug-resistant (MDR) TB cases never exposed to BDQ during 2008–2019. We randomly selected 65 isolates and identified 28 isolates with BDQ MIC<0.25μg/ml and MIC≥0.25μg/ml as the control and study groups, respectively. BDQ drug susceptibility testing (DST) using the MGIT960 system and Sanger sequencing of the atpE, Rv0678, and pepQ genes was conducted. Notably, 18 isolates with BDQ MIC=0.25μg/ml, 38.9% (7/18), and 61.1% (11/18) isolates were MGIT-BDQ resistant and susceptible, respectively. Consequently, we recommended redefining MIC=0.25μg/ml as an intermediate-susceptible category to resolve discordance between different DST methods. Of the 93 isolates, 22 isolates were MGIT-BDQ-resistant and 77.3% (17/22) of MGIT-BDQ-resistant isolates harbored Rv0678 mutations. After excluding 2 MGIT-BDQ-resistant isolates with borderline resistance (GU400growth control-GU100BDQ≤1day), 100% (15/15) harbored Rv0678 gene mutations, including seven novel mutations [g-14a, Ile80Ser (N=2), Phe100Tyr, Ala102Val, Ins g 181–182 frameshift mutation (N=2), Del 11–63 frameshift mutation, and whole gene deletion (N=2)]. Since the other 22.7% (5/22) MGIT-BDQ-resistant isolates with borderline resistance (GU400growth control-GU100BDQ≤1day) had no mutation in three analyzed genes. For isolates with phenotypic MGIT-BDQ borderline resistance, checking for GU differences or conducting genotypic analyses are suggested for ruling out BDQ resistance. In addition, we observed favorable outcomes among patients with BDQ-resistant isolates who received BDQ-containing regimens regardless of Rv0678 mutations. We concluded that based on MIC≥0.25μg/ml, 3.1% (28/898) of drug-resistant TB cases without BDQ exposure showed BDQ resistance, Rv0678 was not a robust marker of BDQ resistance, and its mutations were not associated with treatment outcomes.

Dataset Information

Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection.

Publications

Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection.

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