Infectious Disease · Medical Literature
Preserved Spermatogenesis and Hormonal Function in Men Receiving a Pretomanid Regimen (BPaMZ) for Pulmonary Drug-Resistant Tuberculosis.
Abstract
Pretomanid is a component of the World Health Organization-recommended treatment regimen for drug-resistant tuberculosis in patients aged ≥ 14 years. While preclinical rodent studies identified testicular toxicity as a potential clinical liability at elevated doses, no corresponding effects were observed in nonhuman primates nor clinical hormone assessments. This phase 2 clinical trial assessed testicular safety of therapy with bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in 26 adult males with drug-resistant tuberculosis recruited from South Africa and Georgia. The study included 26 weeks of treatment followed by 52 weeks of safety monitoring until study week 78. The primary endpoint measured change in total sperm count from baseline at week 26, with secondary endpoints evaluating sperm concentration, semen volume, and reproductive hormone concentrations. Results demonstrated favorable testicular safety outcomes. Mean total sperm count increased from 48.8 to 68.8 × 106 per ejaculate by week 26. Fifteen participants (68%) showed increased sperm counts, while 17 (77%) exhibited higher sperm concentrations from baseline to week-26 Thirteen participants (59%) experienced ≥ 50% improvement in both parameters. Two participants demonstrated > 50% decreases in total sperm count; however, sperm concentration reductions were < 50%, suggesting low semen volume as a factor. Testosterone levels increased from baseline, peaking at week 44, while inhibin B demonstrated steady increases, peaking at week 78. Follicle-stimulating hormone and luteinizing hormone remained stable throughout the study period. All assessable participants achieved sputum culture conversion by week 12. Pharmacokinetic analysis revealed no correlation between pretomanid plasma concentrations and sperm count changes. These findings provide reassurance that pretomanid does not impair human spermatogenesis nor disrupt reproductive hormone homeostasis.
Clinical relevance
Does a 26-week course of the BPaMZ regimen (bedaquiline, pretomanid, moxifloxacin, pyrazinamide) cause clinically significant testicular toxicity, as measured by changes in sperm parameters and reproductive hormones, in adult males with drug-resistant tuberculosis? __SNAPSHOT__ {"studyDesign":"Open-label, single-arm Phase 2 clinical trial (BPaMZ/SEM study)","setting":"Four clinical sites in South Africa and Georgia","sampleSize":"n=26 enrolled; 22 completed treatment and assessed for study endpoints","population":"Adult males (≥18 years) with drug-resistant pulmonary tuberculosis (rifampicin- and/or isoniazid-resistant, fluoroquinolone-susceptible); excluded were men with prior male infertility, vasectomy, azoospermia at screening, known erectile dysfunction, active reproductive tract disease, or HIV with CD4 <100 cells/µL","intervention":"BPaMZ regimen: pretomanid 200 mg once daily + bedaquiline 200 mg once daily (weeks 1–8) then 100 mg once daily (weeks 9–26) + moxifloxacin 400 mg once daily + pyrazinamide 1,500 mg once daily for 26 weeks","comparator":"Not applicable (single-arm study); baseline values served as within-subject reference","primaryOutcome":"Change in total sperm count from baseline at week 26","followUp":"78 weeks total (26 weeks of treatment + 52 weeks of safety monitoring)","fundingSource":"Not reported in abstract; study fulfills an FDA post-marketing requirement for pretomanid — industry involvement likely but not confirmed in available abstract"}
Key findings
Primary outcome (total sperm count at week 26): mean total sperm count increased from 48.8 × 10⁶ to 68.8 × 10⁶ per ejaculate, an absolute increase of +20.0 × 10⁶ per ejaculate (calculated). Fifteen of 26 participants (68%) demonstrated increased total sperm counts from baseline, and 17 of 26 (77%) showed higher sperm concentrations from baseline. Mean semen volume was unchanged at both week 12 and week 26. Reproductive hormone changes were directionally consistent with improved gonadal function, not toxicity: testosterone and inhibin B generally increased from baseline, while FSH and LH were variable but generally at or below baseline levels by follow-up — a pattern opposite to what would be expected with testicular toxicity. An external safety monitoring committee reviewed semen and safety parameters continuously throughout dosing and identified no signal of reproductive toxicity requiring protocol modification or early termination. All 26 participants achieved sputum culture negativity from week 8 onward, indicating microbiologic efficacy. Safety signals identified: 2 participants discontinued treatment due to elevated liver enzymes (hepatotoxicity, consistent with known pyrazinamide and bedaquiline risks), 1 withdrew due to pyrazinamide resistance, and 1 withdrew consent. Two participants experienced serious adverse events (infectious exacerbation of bronchiectasis; elevated liver enzymes). No p-values, confidence intervals, or formal statistical comparisons are reported in the available abstract.
Practice implications
This study is the first prospectively designed clinical trial evaluating testicular toxicity of pretomanid in humans as a regulatory post-marketing commitment. It provides reassurance that 26 weeks of pretomanid at the WHO-recommended dose (200 mg daily) within the BPaMZ regimen does not appear to impair spermatogenesis or male reproductive hormonal function in adult males with DR-TB. Notably, the observed increases in sperm parameters and testosterone/inhibin B likely reflect recovery from TB-associated illness (hypogonadism is common in untreated TB) rather than a drug benefit per se — a critical confound inherent to the single-arm design. The study did not establish whether BPaMZ is causally safe for testicular function; it ruled out a severe adverse effect analogous to that seen in rodents, but the absence of a control arm precludes attribution of sperm improvements to treatment. The findings are most applicable to adult males (≥18 years, ≥45 kg) with rifampicin- and/or isoniazid-resistant, fluoroquinolone-susceptible pulmonary TB. Adolescent males (ages 14–17 years), who are eligible for pretomanid per WHO guidelines, were not enrolled. Men with pre-existing azoospermia, severe reproductive tract disease, or advanced immunosuppression (HIV with CD4 <100) were excluded. The BPaMZ regimen — rather than the more commonly deployed BPaL (bedaquiline, pretomanid, linezolid) regimen — was deliberately chosen to avoid linezolid as a confound, so these reproductive safety data cannot be directly extrapolated to BPaL. The study authors note these findings support planned pediatric studies including boys, with appropriate monitoring. Only the abstract is available for this review; full data including confidence intervals, subgroup analyses, and complete hormone kinetics have not been independently verified. __LIMITATIONS__ Single-arm design with no concurrent control group; within-subject comparisons cannot distinguish drug effects from spontaneous improvement driven by TB disease recovery and improved nutritional status (body weight increased during treatment).,Very small sample size (n=26 enrolled, n=22 completers) provides limited statistical power to detect modest or delayed reproductive toxicity signals.,Attrition: 4 of 26 participants (15%) did not complete treatment, including 2 due to hepatotoxicity, reducing the evaluable population.,Study population restricted to adult males ≥18 years; adolescent males (14–17 years), who are a WHO-eligible population for pretomanid, were not studied.,BPaMZ was used rather than BPaL; reproductive safety data cannot be generalized to the BPaL regimen.,Inability to isolate pretomanid's individual contribution from the other three agents (bedaquiline, moxifloxacin, pyrazinamide), each of which may independently affect testicular or hormonal function.,Large inter-individual variability in sperm parameters is reported; without confidence intervals or p-values in the abstract, the precision and statistical significance of the primary endpoint change cannot be assessed.,Follow-up of 52 weeks post-treatment may be insufficient to detect delayed spermatogenic recovery curves or long-term hormonal perturbations.,Recruitment from only two countries (South Africa and Georgia) limits geographic and ethnic generalizability.,Only the abstract is available for this review; complete statistical analyses, subgroup data, and full adverse event tables were not independently verifiable. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ This first-in-human, prospectively designed testicular safety trial found no evidence of spermatogenic or hormonal toxicity attributable to 26 weeks of the BPaMZ regimen in adult males with DR-TB, with mean total sperm count increasing from 48.8 to 68.8 × 10⁶ per ejaculate. The single-arm design, small sample, and probable confounding from TB-related hypogonadism resolution preclude a definitive causal safety claim, but the findings are sufficient to provide practical clinical reassurance at the WHO-recommended pretomanid dose. These results meaningfully address a longstanding regulatory concern and support continued use of pretomanid-containing regimens in adult males without additional reproductive monitoring beyond standard care, while reinforcing the need for dedicated safety data in adolescent males.