Drug products: Harvoni, Sovaldi
ATC code: J05AP08, J05AP51
No clear differences between men and women regarding effect and safety of sofosbuvir have been demonstrated. Several phase 3 studies, both randomized controlled trials and observational studies, does not show any differences in endpoints between men and women. Some analyses of hepatitis C patients treated with sofosbuvir showed that men were more likely to have a lack of efficacy and relapse. A per protocol analysis of a randomized controlled trial showed different effects in men and women of treatment with sofosbuvir and ledipasvir, which the original (intention-to-treat) analysis did not showed.
No studies with a clinically relevant sex analysis regarding pharmacokinetics or dosing of sofosbuvir have been found.
Several studies show no significant differences in effect between men and women [1, 3-10]. A few retrospective studies however, have indicated a difference in treatment effect between men and women [2,11,12]). The relevance of these findings remains unclear. No studies were designed specifically to detect sex differences with respect to treatment effect. However, in explorative analyses during drug development, male sex among other risk factors was associated with an increased risk of relapse when patients were treated with ledipasvir and sofosbuvir for 8 weeks rather than 12 weeks of therapy according to the EMA (European Medicines Agency) assessment report .In a retrospective analysis of HCV (hepatitis C virus) patients on treatment (216 men, 121 women) with regimens containing sofosbuvir the association between HCV RNA and sustained virologic response (SVR) was studied. SVR was 82.5 % and HCV RNA was detected in 27.4 % of the patients at week 4. An association was seen between detectable HCV RNA, on treatment at week 4, and virologic failure. 239 of 337 patients were included in the multivariate analysis of risk factors. Among other risk factors, male sex was found to be a predictor of failure to achieve SVR with an odds ratio (OR) for failure of 2.9 .In a retrospective analysis of 113 patients with HCV infection and older sofosbuvir-based treatment regimens that included ribavirin, SVR rates were slightly lower than in published clinical trials. Male sex was a statistically significant predictor for relapse with an OR of 9.48 . A reanalysis restricted to per-protocol data from 423 patients in the ION-3 trial, in which ledipasvir and sofosbuvir were given for 8 or 12 weeks for chronic HCV without cirrhosis, revealed a significant variation in sustained virologic response (SVR) by patient sex. The SVR rates were 98.9% in women and 92.6% in men at 8 weeks of treatment in this analysis. The original study revealed no subgroup differences  and it is important to note that per-protocol analysis is not what is normally used in randomized controlled trials. The authors of the reanalysis argue that since the therapy is highly effective and patients with missing outcome data are treated as treatment failure they will constitute a large part of the patients counted as treatment failures. This practice may, according to the authors, lead to impeded possibilities of detecting subgroup differences .A number of phase 3 trials evaluating sofosbuvir regimens in HCV patients did not show significant differences between men and women in treatment effect. These trials included between 151 and 865 patients and a mean of 65 % (range 54-89 %) of the patients were men. However, it is important to note that these studies were not specifically designed to detect differences based on patient's sex [1, 3-8].SVR was studied in a retrospective analysis of data from 1707 patients (1024 men, 683 women) treated with either a combination of paritaprevir, ritonavir, ombitasvir and dasabuvir (n=44) or sofosbuvir and ledipasvir (n=1663) for Hepatitis C infection. No significant difference was seen between the groups in SVR in the primary analysis. The sex of the patients did not have a significant impact in a multivariate analysis .In an observational analysis of 4026 HCV-infected patients (3863 men, 163 women), initiating sofosbuvir regimens with 12 weeks recommended treatment duration, patient sex was one of the cofactors in the analysis and did not have any effect on SVR. SVR rates were lower than in previously published clinical trials according to the authors .
No studies with a clinically relevant sex analysis regarding adverse effects of sofosbuvir have been found.
There is sparse data on the use of ledipasvir in pregnant women; consequentially pregnant women should not use sofosbuvir . Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Changes in the serum lipid and distal cholesterol biosynthesis metabolite profile were assessed in 127 HCV genotypes 2 and 3 patients treated with sofosbuvir and ribavirin. In multivariate analysis of the association between baseline lathosterol level (an established marker of whole-body cholesterol synthesis) and SVR (odds ratio 2.08 per lg/ml), the odds ratio for female vs. male sex was 3.57 .
Date of litterature search: 2016-04-04
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson