Preserved Spermatogenesis and Hormonal Function in Men Receiving a Pretomanid Regimen ( BPaMZ ) for Pulmonary Drug‐Resistant Tuberculosis

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 × 10 6 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.