The safety and tolerability of linezolid in novel short-course regimens containing bedaquiline, pretomanid and linezolid to treat rifampicin-resistant tuberculosis: an individual patient data meta-analysis

Background: Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials. Methods: A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid. Results: Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200 mg linezolid, 68 of 195 (35%) experienced a grade 3–4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600 mg linezolid. Conclusions: Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600 mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB

Biological determinants of immune reconstitution in HIV-infected patients receiving antiretroviral therapy: The role of interleukin 7 and interleukin 7 receptor alpha and microbial translocation

Background. Multiple host factors may influence CD4(+) T cell reconstitution in human immunodeficiency virus (HIV)-infected patients after suppressive antiretroviral therapy (ART). We hypothesized that residual immune activation and polymorphisms in the interleukin 7 (IL-7) receptor alpha (IL-7R alpha) gene were important for immune recovery. Methods. We examined HIV-infected patients receiving suppressive ART (n = 96) for their IL-7R alpha haplotypes and measured levels of lipopolysaccharide (LPS), soluble CD14, and IL-7 in plasma samples collected before and after ART initiation. Levels of soluble IL-7R alpha were measured in HIV-infected patients with IL-7R alpha haplotype 2 (n = 11) and those without IL-7R alpha haplotype 2 (n = 22). Multivariate analysis was used to identify variables associated with faster recovery to CD4(+) T cell counts of > 500 and > 200 cells/mu L. Results. Both LPS and soluble CD14 levels were significantly decreased with ART (P 500 cells/mu L was significantly associated with higher baseline CD4(+) T cell count, younger age, lower pre-ART LPS level, higher pre-ART soluble CD14 level, lower pre-ART IL-7 level, and IL-7R alpha haplotype 2 (hazard ratio, 1.50; 95% confidence interval, 1.03-2.19; P = .034). HIV-infected patients with haplotype 2 had significantly lower soluble IL-7R alpha levels compared with those of patients without haplotype 2 (P 500 cells/mu L