Background:
Testicular toxicity was observed in rodents exposed to high doses of pretomanid. Pretomanid is approved for use in treatment regimens for drug-resistant tuberculosis (DR-TB). This study evaluated the testicular safety of 26 weeks of pretomanid in adult males with DR-TB as part of a BPaMZ (bedaquiline, pretomanid, moxifloxacin, pyrazinamide) regimen.
Methods:
Twenty-six men with DR-TB were enrolled at 4 sites in South Africa and Georgia. They received BPaMZ at recommended doses for 26 weeks, with a 52-week safety follow-up. The primary outcome was the change from baseline in total sperm count at Week 26. Secondary outcomes included change from baseline in total sperm count at Week 12 and 44; change from baseline over time in sperm concentration, sperm volume, and male reproductive hormones (testosterone, inhibin B, FSH, LH).
Results:
Of 26 men enrolled, 22 completed treatment and were assessed for study endpoints. Among completers, mean age was 36 years, 68% were Black and 36% living with HIV. At the Week 26 timepoint (primary outcome), mean total sperm count increased from baseline by 20.0×106 sperm/ejaculate. Mean sperm concentration increased from baseline at Week 26 by 25.8×106 sperm/mL. For both total sperm count and sperm concentration, 13/22 (59%) participants had a >50% increase by Week 26. At Week 26, 2 participants had a >50% decrease in total sperm count, maybe due to low semen volume, while none had a >50% decrease in sperm concentration. There was large variability in sperm parameters among participants. Mean semen volume was unchanged at both Week 12 and 26. Reproductive hormone changes showed improved gonadal status, consistent with improved spermatogenesis. Body weight increased, indicating improved health status. Sputum cultures were negative in all participants from Week 8 onwards. Of 26 enrolled participants, 2 discontinued treatment due to elevated liver enzymes, one due to pyrazinamide resistance and one withdrew consent. Two participants experienced serious adverse events (infectious exacerbation of bronchiectasis and increased liver enzymes).
Conclusions:
This is the first study designed to investigate severe testicular toxicity in adult males with DR-TB. Results show that pretomanid, as part of the BPaMZ regimen, does not appear to have negative effects on reproductive function in adult males with DR-TB.
