Study Explores Sex-Based Differences in Safety, Efficacy of DAAs in Clinical Trials

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Despite reporting more adverse events than their male counterparts, female participants in phase 3 clinical trials evaluating combination direct-acting antiviral (DAA) regimens for chronic hepatitis C virus (HCV) infection completed the full treatment regimen and achieved high sustained virological response (SVR12) rates, according to findings from a recent study.

Published in Journal of Viral Hepatitis, results showed no clinically relevant sex-based differences in the safety or efficacy of FDA-approved combination DAA regimens, although numerically more female study participants experienced fatigue, headache, and gastrointestinal disorders compared to males.¹

“Publications on sex differences in efficacy and safety with DAAs for the treatment of HCV are limited and are mostly from the era of interferon/peginterferon and ribavirin-based regimens for GT1,” wrote investigators.¹

Although DAAs are estimated to be able to cure more than 95% of HCV cases, the World Health Organization estimates just 62% of those diagnosed with HCV received treatment in 2019. In addition to limited access to treatment among infected individuals, the safety and efficacy of DAAs may vary across certain demographics, including sex, highlighting the need for a more comprehensive understanding of potential differences in order to ensure the best treatment and clinical outcomes for affected patients.²

To assess potential sex-based differences in the efficacy and safety of combination DAA regimens for the treatment of HCV or HIV/HCV coinfection, Shuang Zhou, MS, PhD, ORISE fellow at the FDA, and a team of investigators examined data for adult patients treated at the approved DAA dosage and treatment duration from 40 phase 3 clinical trials submitted to the FDA to support an initial approval or major label change. For inclusion, patients were required to be > 18 years of age, mono-infected with HCV genotype (GT) 1–6 or co-infected with HCV GT 1 and HIV-1 virus at baseline, HCV treatment-naive or experienced, and either noncirrhotic or with compensated liver cirrhosis. Participants in treatment arms with doses or durations that were ultimately not FDA-approved were excluded.¹

The efficacy of DAA treatment was evaluated by SVR12, defined as an undetectable HCV RNA viral load 12 weeks after completion of the DAA regimen. Investigators separately evaluated participants mono-infected with HCV GT 1 or GT3 who received at least 1 dose of the DAA regimen. Investigators also conducted separate evaluations for participants who were coinfected with HCV GT1 and HIV-1 infection and treated for 12 weeks.¹

Investigators pooled all GTs for the safety analysis, which included all participants mono-infected with HCV GT 1–6 treated for 8, 12, or 24 weeks, and who received at least 1 dose of the DAA regimen. Mono-infected and co-infected participants were assessed separately using data collected up to 30 days after discontinuation of the DAA regimen. Investigators stratified participants based on treatment duration, with or without compensated cirrhosis, treatment-naïve, or experienced, and treated with ribavirin or not.¹

A total of 40 trials and 13,824 randomized participants were included in the study, of which 38% were female. Out of 40 trials, 6 had > 50% females enrolled. However, investigators pointed out several trials had low female enrollment, with participation rates ranging from 11% to 54%.

In the efficacy analyses, 3526 participants mono-infected with GT1, 1283 participants mono-infected with GT3, and 980 participants co-infected with GT1 and HIV-1 were included.¹

The unadjusted and adjusted odds ratios for achieving SVR12 in the overall GT1 mono-infected population were similar, (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.4-3.8; P = .002 and adjusted OR, 2.3; 95% CI, 1.4-3.9; P= .001, respectively). Among 17 subgroups assessed, the unadjusted OR for achieving SVR12 significantly favored White females (P = .001).¹

Investigators noted similar results for the GT3 mono-infected population, where the unadjusted and adjusted ORs for achieving SVR12 were similar (OR, 2.4; 95% CI, 1.5-3.8; P = .0001 and adjusted OR, 2.4; 95% CI, 1.5-3.8; P = .0004, respectively). In subgroup analyses, the unadjusted ORs for achieving SVR12 significantly favored females who were White (P < .0001), <60 years of age (P < .0001), non-cirrhotic (P = .001), and were treatment-experienced (P = .001).¹

A total of 6833 mono-infected and 1013 HIV-1/HCV co-infected participants were included in the safety analyses. Investigators noted numerically more female patients experienced fatigue, headache, and gastrointestinal disorders compared to males. They pointed out nearly all these adverse events were Grade 1 or 2 in severity and the difference between the proportion of females compared to males who developed these events was low.¹

“Despite some statistically significant findings, our analyses did not demonstrate clinically relevant sex differences in the parameters assessed. Females have a similar or numerically greater chance of achieving SVR12 compared to males,” investigators concluded.¹ “Even though no clinically relevant differences were observed, our work has important public health implications.”

References:

1. Zhou S, Qi K, Bersoff-Matcha SJ, et al. Sex-related difference analyses of efficacy and safety in clinical trials of direct-acting antivirals to treat chronic HCV genotype 1 and 3 infections. Journal of Viral Hepatitis. https://doi.org/10.1111/jvh.13901
2. World Health Organization. Hepatitis C. July 18, 2023. Accessed December 22, 2023. https://www.who.int/news-room/fact-sheets/detail/hepatitis-c