Use of anti-retroviral therapy in tuberculosis patients on second-line anti-TB regimens: a systematic review

Abstract

Introduction: Use of antiretroviral therapy (ART) during treatment of drug susceptible tuberculosis (TB) improves survival. However, data from HIV infected individuals with drug resistant TB are lacking. Second line TB drugs when combined with ART may increase drug interactions and lead to higher rates of toxicity and greater noncompliance. This systematic review sought to determine the benefit of ART in the setting of second line drug therapy for drug resistant TB.

Methods: We included individual patient data from studies that evaluated treatment of drug-resistant tuberculosis in HIV-1 infected individuals published between January 1980 and December of 2009. We evaluated the effect of ART on treatment outcomes, time to smear and culture conversion, and adverse events.

Results: Ten observational studies, including data from 217 subjects, were analyzed. Patients using ART during TB treatment had increased likelihood of cure (hazard ratio (HR) 3.4, 95% CI 1.6-7.4) and decreased likelihood of death (HR 0.4, 95% CI 0.3-0.6) during treatment for drug resistant TB. These associations remained significant in patients with a CD4 less than 200 cells/mm(3) and less than 50 cells/mm(3), and when correcting for drug resistance pattern.

Limitations: We identified only observational studies from which individual patient data could be drawn. Limitations in study design, and heterogeneity in a number of the outcomes of interest had the potential to introduce bias.

Discussion: While there are insufficient data to determine if ART use increases adverse drug interactions when used with second line TB drugs, ART use during treatment of drug resistant TB appears to improve cure rates and decrease risk of death. All individuals with HIV appear to benefit from ART use during treatment for TB.

Figure 1. Flow diagram for study inclusion.

Two authors each sent data that was represented by two included studies, therefore 12 references actually included. ¹ Lew W, Pai M, Oxlade O, Martin D and Menzies D. Initial drug resistance and tuberculosis treatment outcomes: systematic review and meta-analysis. Ann Intern Med 2008;149:123–34. ² Menzies D, Benedetti A, Paydar A, et al. Standardized treatment of active tuberculosis in patients with previous treatment and/or with mono-resistance to isoniazid: a systematic review and meta-analysis. PLoS Med 2009; 6:e1000150. Reasons for Exclusion II. Inappropriate study design (n = 34); Outcomes of interest are not measured (n = 22); Not deemed research/no data collected (n = 18); No TB drug resistance or drug resistance testing (n = 21); No HIV+ patients or HIV-testing (n = 37); No TB-infected patients or TB treatment (n = 4); No 2^nd line drug TB therapy used (n = 16); No ART data collected (n = 3); Author contacted for another study/same patients (n = 12). Other Reasons for Exclusion III (other n = 11): Not interested (n = 1); Inappropriate study design (n = 1); No HIV (n = 3); In process of publication (n = 1); Already contacted (n = 5).

Figure 2. Kaplan Meier Curve for survival comparing ART vs. no ART among all-patients (N = 216).

Note: 1 additional death occurred at month 37.

Figure 3. Kaplan Meier Curve for cure comparing ART vs. no ART among all-patients (N = 216).

Note: 1 additional cure event occurred at month 60.