Drug products: Pegasys®
ATC code: L03AB11
Substances: peginterferon alfa-2a
Studies have shown conflicting results regarding sex-based differences in virological response of peginterferon alfa-2a, both for hepatitis C and hepatitis B. Most studies include peginterferon alfa-2a as a combination treatment and rarely as a monotherapy, which complicates the interpretation of the individual effect of peginterferon alfa-2a.
Women are, in a higher extent than men, affected by adverse effects (e.g. anemia, thyroid dysfunction, infection and neutropenia) of peginterferon alfa-2a treatment for hepatitis C. However, studies have shown conflicting results regarding sex-based differences in safety-related dose reductions or discontinuations of peginterferon alfa-2a combination treatment with ribavirin for hepatitis C.
Approximately 30% of chronic hepatitis C patients are estimated to have persistently normal ALT (at least three normal ALT values during 6 months) and this is more common in women than men. The long-term prognosis is unknown and compared to patients with increased ALT, the viral load and genotype appears to be similar .
As peginterferon alfa-2a for treatment of hepatitis C is often given as combination therapy with ribavirin it is difficult to know which of the studied medicines that cause changes in effect and/or adverse events.
No differences in peginterferon alfa-2a pharmacokinetics have been seen between men and women and no sex differentiation in dosing has been recommended by the manufacturer [1, 2]. In a one-compartment pharmacokinetic model constructed in a study, clearance of peginterferon alfa-2a is expected to be higher in men than in women (187 men, 105 women with hepatitis C, treated with peginterferon alfa-2a and ribavirin) .
According to the Committee for Medicinal Products for Human Use (CHMP), “sex is a significant baseline prognostic factor for sustained virological response in patients treated with PEG-IFN alfa-2a monotherapy but not with PEG-IFN alfa-2a plus ribavirin” .
There are conflicting results regarding sex-based efficacy differences of peginterferon alfa-2a treatment of hepatitis C. Based on univariate and/or multivariate logistic regression analyses, female sex is in some studies associated with a sustained or rapid virological response (SVR or RVR) for hepatitis C with combination treatment of peginterferon alfa-2a and ribavirin [4-12], whereas the same is said for male sex in other studies [13-16] (in some studies non-pegylated interferon and/or peginterferon alfa-2b were also included, and in one study also amantadine). Furthermore, other studies have shown that the patient’s sex isn’t associated with an SVR/RVR [17-25].
In some studies, the sustained virological respone (SVR) for hepatitis C is higher in premenopausal women than men, among those who received ≥80% of the prescribed antiviral doses of combined treatment with peginterferon alfa and ribavirin. When menopausal/postmenopausal women are included in the analyses, there is no longer any distinct sex differences in SVR, according to these studies . In one study in hepatitis C patients treated with peginterferon alfa-2a and ribavirin, male sex was shown to be associated with SVR, but only for patients ≥ 65 years (250 men, 167 women) . Furthermore, in another study (431 men, 315 women), the SVR rate of menopausal women, treated with peginterferon alfa-2a (or alfa-2b) and ribavirin for hepatitis C (genotype 1), was similar to that of men, but significantly lower than that of premenopausal women. On the other hand, for hepatitis C genotype 2, the SVR rates were significantly higher in men than in women .
In a pivotal study with patients co-infected with both chronic hepatitis C and HIV, the patient’s sex was shown to have no effect on SVR for hepatitis C in those treated with peginterferon alfa-2a in combination with ribavirin . However, the SVR for hepatitis C was lower in women than in men among those co-infected with chronic hepatitis C and HIV who received monotherapy with peginterferon alfa-2a in this study . The European medicines agency (EMA) advises caution with the interpretation of these data, since there was a much smaller proportion of women, compared with men, in this study (697 men, 163 women in total, divided into three treatment groups) .
There are also conflicting results regarding sex-based efficacy differences of peginterferon alfa-2a treatment of hepatitis B. The patient’s sex wasn’t identified as a significant predictor of treatment response of peginterferon alfa-2a in patients with hepatitis B, in one study . However, in another study, male sex was shown to be an independent predictor of treatment response of peginterferon alfa-2a (with or without lamivudine), based on data from three randomized studies, but only in HBeAg-positive Asian patients and not in HBeAg-negative Asian patients or caucasians . Contrary to these studies, female sex was shown to be a predictor of treatment response of peginterferon alfa-2a (or peginterferon alfa-2b) in patients with hepatitis B, in one study (based on data from two other studies) . Furthermore, female sex was shown to be a predictor of treatment response after 24 weeks of peginterferon alfa-2a treatment, with or without lamivudine, in another study with hepatitis B patients. However, the patient’s sex wasn’t a significant predictor of treatment response one year post-treatment in that study .
In two pivotal studies, the response rates of peginterferon alfa-2a (with or without lamivudine) were higher in women than in men in subgroup analyses in patients with chronic hepatitis B patients (data not shown) .
The risk of anemia during combination treatment with peginterferon alfa-2a and ribavirin in hepatitis C patients is higher in women than in men .
Premenopausal women also experience more adverse reactions than men (for example anemia, weight loss, nausea, vision impairment, reduced thyroid function and infections) during combination treatment with peginterferon alfa and ribavirin for hepatitis C .
Biphasic thyroiditis and thyrotoxicosis was also shown to be associated with female sex in a study which included postmenopausal women (515 men, 354 women, mean age was 44.3 years) . The hepatitis C treatment were peginterferon alfa-2a or albumin-interferon alfa-2b .
Furthermore, female sex was shown to be associated with serious adverse events in a study with hepatitis C patients who received peginterferon alfa-2a/alfa-2b + ribavirin and boceprevir/telaprevir (401 men, 314 women with mean age 54,1 years) .
Female sex was also shown to be a significant factor associated with an increase in total bilirubin levels ≥ 1.0 mg/dL in another study among hepatitis C patients treated with peginterferon alfa-2a or alfa-2b, with ribavirin and simeprevir (92 men, 100 women with mean age 61,9 years) .
In another study, female sex was shown to be a predictor of anemia and multiple adverse effects (i.e. all possible combinations of anemia, bilirubin, neutropenia and pruritus), but the patient’s sex was not shown to be a predictor of bilirubin, neutropenia, pruritus or rash as independent adverse effects (433 men, 276 women). The active hepatitis C treatment was either peginterferon alfa (unknown if 2a and/or 2b), ribavirin and simeprevir or peginterferon alfa, ribavirin and telaprevir .
A higher frequency of neutropenia in women, than in men, was however shown in another study with hepatitis C treatment of peginterferon alfa-2a and ribavirin, along with a higher frequency in women of both anemia and adverse effects in general (6056 men, 2797 women) .
A numerically higher proportion of women, compared to men, experienced abdominal pain, oral candidiasis and sinusitis during monotherapy with peginterferon alfa-2a in a pivotal study with patients co-infected with both chronic hepatitis C and HIV (no statistically analysis presented). The proportion of women with anemia was similar to the proportion of men with anemia during monotherapy with peginterferon alfa-2a in this study .
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
In some studies, the doses of antiviral drugs (peginterferon alfa + ribavirin) to hepatitis C patients were shown to be modified to a higher extent in premenopausal women than in men. Premenopausal women was also shown to interrupt or suspend the hepatitis C antiviral treatment in a higher extent than men . Female sex was shown to be a prognostic factor for safety-related dose reductions or discontinuations of combination treatment with peginterferon alfa-2a and ribavirin in a study among Caucasian hepatitis C patients without cirrhosis, where the patient’s mean age were 46 years . In concordance, another study where the patient’s mean age was approximately 43-45 years, showed that female sex was associated with dose reductions of both peginterferon alfa-2a and ribavirin (6056 men, 2797 women) . However, in a study, where the patient’s mean age were 48 years, no statistically significant association between the patient’s sex and treatment discontinuation within 4-12 months (combination treatment of peginterferon alfa-2a or alfa-2b, with ribavirin, for hepatitis C) were shown (65 men, 60 women) . Contrary to these studies, male sex was shown to be a significant independent predictor of safety-related discontinuation of hepatitis C treatment with peginterferon alfa-2a and ribavirin within the first 12 weeks (2027 men,913 women) .
In a systematic review and meta-analysis, female sex was shown to be a weak predictive variable of major depression during hepatitis C treatment with peginterferon alfa (or interferon alfa) and ribavirin (OR=1.40; 95% CI= 1.02-1.91) .
Date of litterature search: 2021-05-26
Reviewed by: Diana Rydberg
Approved by: Karin Schenck-Gustafsson