Efficacy and completion rates of rifapentine and isoniazid (3HP) compared to other treatment regimens for latent tuberculosis infection: a systematic review with network meta-analyses

Abstract

Background: We conducted a systematic review and network meta-analysis (NMA) to examine the efficacy and completion rates of treatments for latent tuberculosis infection (LTBI). While a previous review found newer, short-duration regimens to be effective, several included studies did not confirm LTBI, and analyses did not account for variable follow-up or assess completion.

Methods: We searched MEDLINE, Embase, CENTRAL, PubMed, and additional sources to identify RCTs in patients with confirmed LTBI that involved a regimen of interest and reported on efficacy or completion. Regimens of interest included isoniazid (INH) with rifapentine once weekly for 12 weeks (INH/RPT-3), 6 and 9 months of daily INH (INH-6; INH-9), 3-4 months daily INH plus rifampicin (INH/RFMP 3-4), and 4 months daily rifampicin alone (RFMP-4). NMAs were performed to compare regimens for both endpoints.

Results: Sixteen RCTs (n = 44,149) and 14 RCTs (n = 44,128) were included in analyses of efficacy and completion. Studies were published between 1968 and 2015, and there was diversity in patient age and comorbidities. All regimens of interest except INH-9 showed significant benefits in preventing active TB compared to placebo. Comparisons between active regimens did not reveal significant differences. While definitions of regimen completion varied across studies, regimens of 3-4 months were associated with a greater likelihood of adequate completion.

Conclusions: Most of the active regimens showed an ability to reduce the risk of active TB relative to no treatment, however important differences between active regimens were not found. Shorter rifamycin-based regimens may offer comparable benefits to longer INH regimens. Regimens of 3-4 months duration are more likely to be completed than longer regimens.

Trial registration: ClinicalTrials.gov NCT02901288.

Keywords: Latent tuberculosis infection; Network meta-analysis; Systematic review.

Fig. 1

a and b: Network Diagrams, Available Evidence for Efficacy (Panel a) and Completion (Panel b). Totals of 16 RCTs (44,149 participants) and 14 RCTs (44,128 participants) were available for analyses of efficacy and completion, respectively. Treatment nodes are sized to reflect the proportion of patients studied on each intervention relative to the total number of patients studied. Edges joining different interventions are sized to reflect the proportion of studies informing each comparison (minimum 1 study). In comparisons where there is no line adjoining a pair of nodes, no eligible trials were identified. The online supplement provides a detailed summary of the numbers of studies in each connection as well as the total number of patients randomized to each intervention. Abbreviations. INH = isoniazid; RPT = rifapentine; RFMP = rifampin; PZA = pyrazinamide; trt = treatment; PL = placebo

Fig. 2

Efficacy, Pairwise Comparisons versus Placebo From Network Meta-Analysis. Pairwise comparisons from the RE informative analysis are shown as rate ratios and 95% CrIs, focusing on comparisons of active comparators versus control (placebo/no treatment) in the network. Values <1 suggest additional benefit with the comparator. A league table of all summary comparisons from the analysis is provided in Fig. 3

Fig. 3

Summary of Findings from RE Informative Prior Network Meta-Analysis, Efficacy (Rate Ratios with 95% CrI). A complete summary of estimates from the RE informative network meta-analysis for efficacy is shown. Statistically significant differences between regimens are shown in bold, underlined font. Treatments are ordered from upper left to lower right in order of decreasing SUCRA value. To draw interpretations from the results, the lower/right-most comparison for each comparison is the reference treatment. Abbreviations. INH = isoniazid; RPT = rifapentine; RFMP = rifampin; PZA = pyrazinamide

Fig. 4

Forest Plot, Comparisons versus Placebo-12 from Network Meta-Analysis, Completion. Pairwise comparisons from the RE informative anlaysis are shown as summary odds ratios and 95% CrIs, focusing on comparisons of active comparators versus the control group of Placebo-12 months in the network. Values >1 suggest greater likelihood of completion with the comparator, and regimens have been grouped according to duration. A league table of all summary comparisons from network meta-analysis is provided in Fig. 5

Fig. 5

Summary of Findings from RE Informative Prior Network Meta-Analysis (Odds Ratios with 95% CrI),. Completion of Treatment. A complete summary of estimates from the RE informative analysis for treatment completion is provided. Statistically significant differences between regimens are shown in bold, underlined font. Treatments are ordered from upper left to lower right in order of decreasing SUCRA value from the random effects analysis. To draw interpretations from the results, the lower/right-most comparison for each comparison is the reference treatment. Abbreviations. INH = isoniazid; RPT = rifapentine; RFMP = rifampin; PZA = pyrazinamide