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Peginterferon alfa-2a

Klassificering: A

Preparat: Pegasys®

ATC kod: L03AB11

Substanser: peginterferon alfa-2a

Sammanfattning

Studier har visat motsägande resultat huruvida det finns könsskillnader i virologisk respons av peginterferon alfa-2a, både för hepatit C och hepatit B. De flesta studier har studerat peginterferon alfa-2a i kombinationsbehandling och sällan som monoterapi, vilket försvårar tolkningen av effekten av enbart peginterferon alfa-2a.

Kvinnor drabbas i större utsträckning av biverkningar (såsom anemi, tyroideadysfunktion, infektion och neutropeni) av behandling med peginterferon alfa-2a mot hepatit C. Det finns motsägande resultat vad gäller eventuella könsskillnader i biverkningsrelaterade dosreduceringar eller utsättningar av kombinationsbehandling av peginterferon alfa-2a med ribavirin mot hepatit C.

Additional information

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 [1].

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.

Pharmacokinetics and dosing

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) [3].

Effects

Hepatitis C

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” [1].

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 [26]. 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) [27]. 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 [28].

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 [1]. 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 [1]. 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) [1].

Hepatitis B

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 [29]. 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 [30]. 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) [31]. 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 [32].

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) [1].

Adverse effects

The risk of anemia during combination treatment with peginterferon alfa-2a and ribavirin in hepatitis C patients is higher in women than in men [2].

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 [26].

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) [33]. The hepatitis C treatment were peginterferon alfa-2a or albumin-interferon alfa-2b [33].

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) [34].

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) [35].

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 [36].

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) [37].  

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 [1].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

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 [26]. 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 [38]. 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) [37]. 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) [17]. 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) [39].

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) [40].

Försäljning på recept

Något fler män än kvinnor hämtade ut läkemedel innehållande peginterferon alfa-2b (ATC-kod L03AB10) på recept i Sverige år 2020, totalt 46 män och 43 kvinnor.Fler män än kvinnor hämtade ut läkemedel innehållande peginterferon alfa-2a (ATC_kod L03AB11) på recept i Sverige år 2020, totalt 434 män och 369 kvinnor [41].

Uppdaterat: 2021-06-29

Litteratursökningsdatum: 2021-05-26

Referenser

  1. Pegasys (peginterferon alfa-2a). EPAR - Scientific discussion European Medicines Agency (EMA). [updated 2005-04-01, cited 2021-05-26]. länk
  2. Pegasys (peginterferon alfa-2a). Summary of Product Characteristics. European Medicines Agency (EMA) [updated 2007-06-20, cited 2021-05-26].
  3. Saleh MI. A Bayesian Approach for Population Pharmacokinetic Modeling of Pegylated Interferon α-2a in Hepatitis C Patients. Clin Pharmacokinet. 2017;56(11):1369-1379. PubMed
  4. Wu CK, Chang KC, Tseng PL, Lu SN, Chen CH, Wang JH et al. Comparison of Therapeutic Response and Clinical Outcome between HCV Patients with Normal and Abnormal Alanine Transaminase Levels. PLoS One. 2016;11(3):e0142378. PubMed
  5. Livingston SE, Townshend-Bulson LJ, Bruden DJ, Homan CE, Gove JE, Plotnik JN, Simons BC, Spradling PR, McMahon BJ. Results of interferon-based treatments in Alaska Native and American Indian population with chronic hepatitis C. Int J Circumpolar Health. 2016;75:30696. länk
  6. Andriulli A, Morisco F, Ippolito AM, Di Marco V, Valvano MR, Angelico M et al. HCV genotype 1 subtypes (1a and 1b): similarities and differences in clinical features and therapeutic outcome. Hepatol Int. 2015;9(1):52-7. PubMed
  7. Beinhardt S, Rutter K, Stättermayer AF, Ferenci P. Revisiting the predictors of a sustained virologic response in the era of direct-acting antiviral therapy for hepatitis C virus. Clin Infect Dis. 2013;56(1):118-22. PubMed
  8. Tsubota A, Shimada N, Yoshizawa K, Furihata T, Agata R, Yumoto Y et al. Contribution of ribavirin transporter gene polymorphism to treatment response in peginterferon plus ribavirin therapy for HCV genotype 1b patients. Liver Int. 2012;32(5):826-36. PubMed
  9. Floreani A, Cazzagon N, Boemo DG, Baldovin T, Baldo V, Egoue J, Antoniazzi S, Minola E. Female patients in fertile age with chronic hepatitis C, easy genotype, and persistently normal transaminases have a 100% chance to reach a sustained virological response. Eur J Gastroenterol Hepatol. 2011;23(11):997-1003. PubMed
  10. Roberts SK, Weltman MD, Crawford DH, McCaughan GW, Sievert W, Cheng WS, Rawlinson W, Desmond PV, Marks PS, Yoshihara M, Rizkalla B, Depamphilis JK, Dore GJ; Chariot Study Group. Impact of high-dose peginterferon alfa-2A on virological response rates in patients with hepatitis C genotype 1: a randomized controlled trial. Hepatology. 2009;50(4):1045-55. länk
  11. Conjeevaram HS, Fried MW, Jeffers LJ, Terrault NA, Wiley-Lucas TE, Afdhal N, Brown RS, Belle SH, Hoofnagle JH, Kleiner DE, Howell CD; Virahep-C Study Group. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131(2):470-7. länk
  12. Mangia A, Ricci GL, Persico M, Minerva N, Carretta V, Bacca D et al. A randomized controlled trial of pegylated interferon alpha-2a (40 KD) or interferon alpha-2a plus ribavirin and amantadine vs interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C. J Viral Hepat. 2005;12(3):292-9. PubMed
  13. Gürbüz Y, Tülek NE, Tütüncü EE, Koruk ST, Aygen B, Demirtürk N et al. Evaluation of Dual Therapy in Real Life Setting in Treatment-Naïve Turkish Patients with HCV Infection: A Multicenter, Retrospective Study. Balkan Med J. 2016;33(1):18-26. PubMed
  14. Sadeghi S, Davari M, Asli E, Gharibzadeh S, Vaziri F, Jamnani FR, Fateh A, Siadat SD. Effect of IL15 rs10833 and SCARB1 rs10846744 on virologic responses in chronic hepatitis C patients treated with pegylated interferon-α and ribavirin. Gene. 2017;630:28-34. länk
  15. El Raziky M, Fathalah WF, Zakaria Z, Eldeen HG, Abul-Fotouh A, Salama A, Awad A, Esmat G, Mabrouk M. Predictors of Virological Response in 3,235 Chronic HCV Egyptian Patients Treated with Peginterferon Alpha-2a Compared with Peginterferon Alpha-2b Using Statistical Methods and Data Mining Techniques. J Interferon Cytokine Res,. 2016;36(5):338-46. länk
  16. Huang CF, Yu ML, Kao JH, Tseng TC, Yeh ML, Huang JF, Dai CY, Lin ZY, Chen SC, Wang LY, Juo SH, Chuang WL, Liu CH. Profound week 4 interferon responsiveness is mandatory for hepatitis C genotype 1 patients with unfavorable IL-28B genotype. J Clin Virol. 2013;56(4):293-8. länk
  17. Nordstrom EM, Keniston A, Baouchi F, Martinez-Camacho A. Interferon-based hepatitis C therapy in a safety net hospital: access, efficacy, and safety. Eur J Gastroenterol Hepatol. 2017;29(1):10-16. PubMed
  18. Grebely J, Alavi M, Micallef M, Dunlop AJ, Balcomb AC, Phung N, Weltman MD, Day CA, Treloar C, Bath N, Haber PS, Dore GJ; ETHOS Study Group. Treatment for hepatitis C virus infection among people who inject drugs attending opioid substitution treatment and community health clinics: the ETHOS Study. Addiction. 2016;111(2):311-9. länk
  19. Esmat GE, Al Akel W, Abdel Aziz RA, Al Sayed Taha A, Sabry D, Rashed LA et al. Hepatitis C Viral Kinetic Changes in a Retrospective Cohort Study of Chronic Hepatitis C Virus Egyptian Patients on Pegylated Interferon and Ribavirin Therapy. J Interferon Cytokine Res. 2016;36(3):149-58. PubMed
  20. Sandoval-Ramirez JL, Mata-Marín JA, Huerta García G, Gaytán-Martínez JE. Responses to peginterferon alfa-2a vs alfa-2b plus ribavirin in a Mexican population with chronic hepatitis C. J Infect Dev Ctries. 2015;9(3):267-73. PubMed
  21. Isaksen K, Aabakken L, Grimstad T, Karlsen L, Sandvei PK, Dalgard O. Hepatitis C treatment at three Norwegian hospitals 2000-2011. Tidsskr Nor Laegeforen. 2015;135(22):2052-8. PubMed
  22. Jabłonowska E, Piekarska A, Koślińska-Berkan E, Omulecka A, Szymańska B, Wójcik K. Sustained virologic response and IL28B single-nucleotide polymorphisms in patients with chronic hepatitis C treated with pegylated interferon alfa and ribavirin. Acta Biochim Pol. 2012;59(3):333-7. PubMed
  23. Lee S, Varano J, Flexman JP, Cheng W, Watson MW, Rossi E et al. Decreased IP-10 and elevated TGFbeta1 levels are associated with viral clearance following therapy in patients with hepatitis C virus. Dis Markers. 2010;28(5):273-80. PubMed
  24. Schott E, Witt H, Hinrichsen H, Neumann K, Weich V, Bergk A et al. Gender-dependent association of CTLA4 polymorphisms with resolution of hepatitis C virus infection. J Hepatol. 2007;46(3):372-80. PubMed
  25. Schaefer M, Hinzpeter A, Mohmand A, Janssen G, Pich M, Schwaiger M et al. Hepatitis C treatment in "difficult-to-treat" psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects. Hepatology. 2007;46(4):991-8. PubMed
  26. Vera Regitz-Zagrosek. Sex and Gender Differences in Pharmacology. Springer-Verlag Berlin Heidelberg; 2012.
  27. Yu JW, Sun LJ, Kang P, Yan BZ, Zhao YH. Efficacy and factors influencing treatment with peginterferon alpha-2a and ribavirin in elderly patients with chronic hepatitis C. Hepatobiliary Pancreat Dis Int. 2012;11(2):185-92. länk
  28. Villa E, Cammà C, Di Leo A, Karampatou A, Enea M, Gitto S et al. Peginterferon-Α_2B plus ribavirin is more effective than peginterferon-Α_2A plus ribavirin in menopausal women with chronic hepatitis C. J Viral Hepat. 2012;19(9):640-9. PubMed
  29. Charatcharoenwitthaya P, Sukeepaisarnjaroen W, Piratvisuth T, Thongsawat S, Sanpajit T, Chonprasertsuk S, Jeamsripong W, Sripariwuth E, Komolmit P, Patcharatrakul T, Boonsirichan R, Bunchorntavakul C, Tuntipanichteerakul S, Tanwandee T; Thai Association for the Study of the Liver on Chronic Hepatitis B. Treatment outcomes and validation of the stopping rule for response to peginterferon in chronic hepatitis B: A Thai nationwide cohort study. Gastroenterol Hepatol. 2016;31(11):1874-1881. länk
  30. Wei L, Wedemeyer H, Liaw YF, Chan HL, Piratvisuth T, Marcellin P, Jia J, Tan D, Chow WC, Brunetto MR, Diago M, Gurel S, Morozov V, He H, Zhu Y, Wat C, Surujbally B, Thompson AJ. No association between IFNL3 (IL28B) genotype and response to peginterferon alfa-2a in HBeAg-positive or -negative chronic hepatitis B. PLoS One. 2018;137(7):e0199198. länk
  31. Buster EH, Hansen BE, Lau GK, Piratvisuth T, Zeuzem S, Steyerberg EW, Janssen HL. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology. 2009;137(6):2002-9. länk
  32. Bonino F, Marcellin P, Lau GK, Hadziyannis S, Jin R, Piratvisuth T, Germanidis G, Yurdaydin C, Diago M, Gurel S, Lai MY, Brunetto MR, Farci P, Popescu M, McCloud P; Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007;56(5):699-705. länk
  33. Mammen JS, Ghazarian SR, Rosen A, Ladenson PW. Patterns of interferon-alpha-induced thyroid dysfunction vary with ethnicity, sex, smoking status, and pretreatment thyrotropin in an international cohort of patients treated for hepatitis C. Thyroid. 2013;23(9):1151-8. PubMed
  34. Callefi LA, Villela-Nogueira CA, de Barros Tenore S, Carnaúba-Júnior D, Coelho HSM, Pinto PTA, Nabuco LC, Pessoa MG, Ferraz MLCG, Ferreira PRA, de Lourdes Candolo Martinelli A, Chachá SGF, de Souza Paiva Ferreira A, de Macedo Bisio AP, Brandão-Mello CE, Álvares-Da-Silva MR, Reuter T, Ivantes CAP, de Mello Perez R, Mendes-Correa MCJ. Effectiveness and safety of first-generation protease inhibitors in real-world patients with hepatitis C virus genotype 1 infection in Brazil: a multicenter study. Clinics (Sao Paulo). 2017;72(6):378-385. länk
  35. Tahata Y, Hiramatsu N, Oze T, Morishita N, Harada N, Yamada R et al. The impact of an inosine triphosphate pyrophosphatase genotype on bilirubin increase in chronic hepatitis C patients treated with simeprevir, pegylated interferon plus ribavirin. J Gastroenterol. 2016;51(3):252-9. PubMed
  36. Akpo EI, Sbarigia U, Wan G, Kleintjens J. Determinant Factors of the Direct Medical Costs Associated with Genotype 1 Hepatitis C Infection in Treatment-Experienced Patients. Drugs R D. 2015;15(4):335-49. PubMed
  37. Lee SS, Roberts SK, Berak H, Dusheiko GM, Harley HA, Gane EJ et al. Safety of peginterferon alfa-2a plus ribavirin in a large multinational cohort of chronic hepatitis C patients. Liver Int. 2012;32(8):1270-7. PubMed
  38. Foster GR, Coppola C, Derbala M, Ferenci P, Orlandini A, Reddy KR, Tallarico L, Shiffman ML, Ahlers S, Bakalos G, Hassanein T; GUARD-C Study Group. Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort. PLoS One. 2016;11(3):e0151703. länk
  39. Marcellin P, Roberts SK, Reddy KR, Harrison SA, Jensen DM, Hadziyannis S, Diago M, Weltman M, Messinger D, Tatsch F, Rizzetto M. Safety profile of standard- vs high-dose peginterferon alfa-2a plus standard-dose ribavirin in HCV genotype 1/4 patients: pooled analysis from 5 randomized studies. Expert Opin Drug Saf. 2012;11(6):901-9. länk
  40. Udina M, Castellví P, Moreno-España J, Navinés R, Valdés M, Forns X et al. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2012;73(8):1128-38. PubMed
  41. Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2020 [cited 2021-03-10.] länk

Författare: Therese Wennersten

Faktagranskat av: Diana Rydberg

Godkänt av: Karin Schenck-Gustafsson

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