Pharmaceutical Services Division requested an updated systematic review of peginterferon alfa-2a (Pegasys) for the treatment of chronic hepatitis B, previously reviewed by the Therapeutics Initiative in November 2006.
Peginterferon alfa-2a injection (Pegasys) is categorized as an anti-viral compound and as a biological response modifier. The recommended dose is 180μg once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh.
The prevalence of hepatitis B infection in Canada is estimated to be 0.7-0.9%. The incidence of developing chronic infection (defined as hepatitis B surface antigen positivity 6 months post exposure) after the acute infection is not known. However, it appears to be dependent on age and immune status. The major risk factors for infection in Canadian-born individuals without HBV seroprotection include unprotected sex and injection drug use. However, the risk factors for infection in Canadian immigrant patients include vertical transmission during childbirth and the use of contaminated needles for vaccination and other medical procedures in developing countries. Individuals with chronic hepatitis B infections are at an increased risk of developing liver-related complications such as cirrhosis, hepatic decompensation and hepatocellular carcinoma. The presence of HBeAg in an individual with chronic hepatitis B has been associated with more long-term liver-related complications as compared with its absence.
Chronic hepatitis B treatment involves two classes of drugs: nucleoside or nucleotide analogues (such as lamivudine, telbivudine, entecavir, adefovir) and immuno modulatory agents (such as interferon alfa-2b, pegylated interferon alfa-2a).
- In DBRCTs does peginterferon alpha-2a (Pegasys) provide a therapeutic advantage in terms of mortality and/or morbidity compared to interferon alfa-2b, lamivudine, adfovir, entacavir, telbivudine, or placebo in patients with chronic hepatitis B?
- Are there any risks or potential harms associated with the use of peginterferon alpha-2a (Pegasys) for the treatment of chronic hepatitis B?
Double blind randomized controlled trials in adult patients with HBeAg positive or HbeAg negative chronic hepatitis B comparing peginterferon alfa-2a to interferon alfa-2b, lamivudine, adfovir, entacavir, telbivudine, or placebo will be included.
Health outcomes will be assessed according to the following hierarchy: total serious adverse events; all cause mortality including liver-related mortality; non-fatal SAEs; liver morbidity including hepatocellular carcinoma and cirrhosis of the liver; quality of life; drug tolerability (including withdrawal due to adverse events and dose modification due to adverse events); other adverse effects (total and specific events including flu-like, psychiatric, infectious and gastrointestinal); and surrogate outcome measures such as improvement of liver fibrosis (diagnosed by histology); loss of viral DNA; loss of HBeAg, loss of HBsAg and normalization of liver enzymes (ALT). Trials reporting on clinically relevant health outcomes are critically appraised. Trials reporting surrogate markers are summarized. The relationship between surrogate markers (such as reduction of HBV-DNA levels, loss of HBeAg, etc) and clinically relevant health outcomes has not been established
Search strategy and findings
Databases searched: Medline (1966-March 2009), EMBASE (1966-March 2009), CENTRAL (issue 1, 2009), the Cochrane Database of Systematic Reviews (issue 1, 2009) and bibliographies of all identified articles.
In the previous (November 2006) report three randomized controlled trials met the inclusion criteria, one of them compared peginterferon alfa-2a with interferon alfa-2a (Cooksley et al 2003) and the other 2 trials compared peginterferon alfa-2a with lamivudine (Lau et al 2005 study included HbeAg positive patients and Marcellin et al 2004 study included HbeAg negative patients). There was no RCT identified comparing peginterferon alfa-2a with placebo or no treatment control group.
No new randomized controlled trials were identified since the last review in November 2006. Three additional publications from previously included RCTs were found. Two systematic review publications were identified. (Piratvisuth et al 2008, Bonino 2007 and Marcellin et al 2008)
Cooksley et al 2003 is an open-label trial, which assessed the efficacy and safety of different doses of peginterferon alfa-2a vs. interferon alfa-2a 4.5 MIU for 24 weeks of therapy followed by 24 weeks of treatment-free follow up in 194 interferon-naïve patients with chronic hepatitis B. There was a non-significant higher incidence of serious adverse events in the peginterferon alfa-2a 180μg/week group (8.6%) as compared with interferon 4.5 MIU /three times a week group (4%). The most common causes of SAEs were gastrointestinal disorders and infections. There was no difference in virologic or immunologic outcomes (such as loss of DNA or seroconversion) between peginterferon alfa-2a 180μg/wk and interferon alfa-2a 4.5 MIU group. The basis of choosing 180μg/week dose as the recommended dose is not clear since the efficacy in terms of surrogate outcome measures did not differ among the different peginterferon regimens (90, 180 and 270μg/week) and the number of patients who required dose modification due to lab abnormalities was significantly higher in the peginterferon alfa-2a groups (22 to 30%) as compared to interferon 4.5 MIU (10%), particularly the higher incidence of neutropenia or thrombocytopenia in the peginterferon 180 and 270μg/wk groups.
No randomized controlled trial was identified that compared peginterferon alfa-2a with interferon alfa-2b.
Lau et al 2005 trial (blinded for lamivudine) assessed the efficacy and safety of peginterferon alfa-2a 180μg/week vs. lamivudine 100mg/day versus combination of the two drugs in HbeAg positive patients with chronic hepatitis B for a period of 48 weeks of therapy followed by 24 weeks of treatment-free follow up. One patient died in the lamivudine group from decompensation of the liver, during the treatment-free follow-up. The incidence of hepatocellular carcinoma or cirrhosis or quality of life was not reported. There was no difference between peginterferon alfa-2a 180μg group and lamivudine 100 mg/d monotherapy groups in the incidence of serious adverse events (4% vs. 2%), improved biopsies (49% vs. 51%) or withdrawals due to adverse events (3% vs. 1%). Significantly higher number of patients required dose modification in the peginterferon 180μg monotherapy group as compared to lamivudine 100mg monotherapy group [due to adverse events (ARI=7%, NNH=14) and due to abnormal laboratory parameters neutropenia, thrombocytopenia or elevated liver enzymes (ARI=37%, NNH=3)]. The number of patients with more than 1 adverse event was also higher in the peginterferon 180μg monotherapy group as compared with the lamivudine 100 mg monotherapy group (ARI=33%, NNH=4). There were significant increases in several adverse events in the pegylated interferon group compared to lamivudine group: pyrexia (NNH=3), myalgia (NNH=5) and fatigue (NNH=4), headache (NNH=6), alopecia (NNH=6), anorexia (NNH=8), rash (NNH=17) and pruritus (NNH=13). At the end of follow-up, there was significantly higher rate of seroconversion and loss of DNA in the peginterferon group, 87 (32%) and 86 (32%), as compared to lamivudine group 52 (19%) and 60 (22%), respectively. However, the higher rate of patients who did not complete the trial (dropouts) in the lamivudine group 42 (15%) as compared with those in peginterferon group 28 (10%) could bias the effect size in favour of peginterferon. The significant increase in dose reduction due to adverse events as well as lab abnormalities with peg interferon 180μg dose favours the argument for using lower dose of peg interferon.
Marcellin et al 2004 is a randomized partially double blind trial that assessed the efficacy and safety of pegylated interferon alfa-2a 180μg/wk vs. lamivudine 100 mg/day versus combination of the two study drugs in 552 patient with HBeAg negative chronic hepatitis B for a period of 48 weeks of treatment and 24 weeks of treatment-free follow-up period. Since combination therapy is not an approved indication of peginterferon alfa-2a, the following summary focuses on the monotherapy arms of the trial. One patient died in the peginterferon alfa-2a 180μg/wk monotherapy group due to thrombotic thrombocytopenic purpura. The incidence of hepatocellular carcinoma or cirrhosis or quality of life was not reported. There was no statistically significant difference between peginterferon alfa-2a 180μg monotherapy group and lamivudine 100mg/d monotherapy group in the incidence of serious adverse events [9 (5%) vs. 5 (3%)] or in improvement of fibrosis by histological index activity [21/143 (15%) vs. 22/125 (18%)]. Significant higher number of patients in peginterferon alfa-2a 180μg monotherapy group as compared with lamivudine 100mg/d monotherapy group had more than 1 adverse event (ARI=37,NNH=3) and significant increases were observed in several adverse events: pyrexia (NNH=2), myalgia (NNH=5), fatigue (NNH=5), headache (NNH=7), alopecia (NNH=9), anorexia (NNH=7), arthralgia (NNH=9) and diarrhea (NNH=13)]. Withdrawals due to adverse events were also significantly higher in the peginterferon alfa-2a 180μg/wk group (ARI=7, NNH=15) and the number of patients who required dose modification due to neutropenia, thrombocytopenia or elevation of liver enzymes was also significantly higher (ARI=37, NNH=3). The significant increase in dose reduction due to adverse events as well as lab abnormalities with peginterferon 180μg dose favour the argument for using lower dose of peginterferon. At the end of follow-up, there were significantly higher rates for normalization of ALT and loss of DNA (for both <20,000 and <400 copies/ml) in the peginterferon group (59%, 43% and 19%, respectively) as compared to lamivudine group (44%, 29% and 7%, respectively). However, the statistically significantly higher rate of patients not completing the trial (dropouts) in the lamivudine group can bias the effect size in favour of the peginterferon group.
The pooled data analysis of the two trials (Lau et al 2005 and Marcellin et al 2004) showed a statistically significant higher incidence of serious adverse events with peginterferon alfa-2a 180μg/wk as compared with lamivudine 100mg/d (ARI=2.5%, NNH=40) and of withdrawals due to adverse events (ARI=4.24%, NNH=24).
Due to a significant increase in dose reduction due to adverse events as well as the laboratory parameter abnormalities associated with the peginterferon 180μg dose, the basis of using the 180μg dose of peginterferon alfa-2a seems questionable.
Summary of additional publications
Piratvisuth et al 2008 is a subgroup analysis of the Lau and Marcellin trials reporting that Asian patients (87% of total randomized patients in Lau et al and 61% in Marcellin et al) have similar outcomes to the total trial populations (in terms of HBeAg seroconversion, normalization of ALT, DNA copies/mL).
A second study (Bonino 2007) did not report clinical findings, but analysed the full RCT cohort to determine which baseline characteristics predicted serological and virologic outcome.
Marcellin et al 2008 was a safety and quality of life analysis comparing treatment with Pegasys in chronic hepatitis B patients vs. chronic hepatitis C patients. Since there were no placebo or appropriate comparators included in the analysis, this publication is referenced for information only.
The systematic reviews by Shamliyan et al 2009 concluded that “evidence was insufficient to assess treatment effect on clinical outcomes or determine whether inconsistent improvements in selected intermediate measures are reliable surrogates. Future research is needed to provide evidence-based recommendations about optimal antiviral therapy in adults with chronic hepatitis B infection”. The systematic review by Rudin et al 2007 suggested that “pegylated interferon monotherapy and its combination with lamivudine were comparable, the use of this combination is not justified”.
Overall summary of harm data
Pegasys® harm includes a black box warning as well as a recent (October 2008) FDA warning about cerebrovascular complications due to stroke in patients not at risk for stroke; and a recent (March 2008) Health Canada warning that patients given Pegasys combined with telbivudine developed serious peripheral neuropathy.
Peginterferon vs. Interferon
- No studies were identified comparing peg-interferon alfa-2a to interferon alfa-2b.
- There is insufficient evidence that peginterferon alfa-2a 180μg/week provides a therapeutic advantage, in terms of mortality and serious morbidity, compared with interferon alfa-2a for 24 weeks of therapy followed by 24 weeks of treatment-free follow-up period in patients with chronic hepatitis B.
- There was no statistically significant difference in surrogate outcomes (such as loss of DNA or seroconversion) between peginterferon alfa-2a 180μg and interferon alfa-2a 4.5 MIU groups. The basis of choosing the 180μg is unclear (due to non-significant difference in efficacy or dose modification rates but higher incidence of neutropenia and thrombocytopenia in peginterferon 180μg and 270μg groups).
Peginterferon vs. Lamivudine
- There is sufficient evidence that peginterferon alfa-2a 180μg/week provides a therapeutic disadvantage in terms of serious morbidity compared with lamivudine 100mg/d for 48 weeks of therapy followed by 24 weeks of follow-up period in patients with chronic hepatitis B. The absolute increase in serious adverse events was 2.5% and the number needed to harm (NNH) was 40.
- Peginterferon yielded a significantly higher response rate in terms of surrogate markers at the end of 72 weeks.
- Bloodborne Pathogens Section Report. Health Canada- Notifiable Disease Online. 2003. Accessed online in July 31,2006. Bonino, F. Marcellin, G, Lau, K, et.al. Predicting response to peginterferon ά-2a, lamivudine and the two combined for HbeAg-negative chronic hepatitis B. Gut 2007; 56:699-705.
- Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295(1):65-73, 2006. Chu CM, Hung SJ, Lin J, Tai DI, Liaw YF. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. American Journal of Medicine 116(12):829-34, 2004.
- Cooksley WGE, Piratvisuth T, Lee S-D, Mahachai V, Chao Y-C, Tanwandee T et al. Peginterferon a-2a (40 kDa): An advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. Journal of Viral Hepatitis 2003; 10(4): 298-305.
- Drugs@FDA [Website]. Pegasys Label and Approval History. Letter 10/31/2008. Last accessed March 26, 2009.
- Health Canada [Website]. Drugs & Health Prodects. Advisories, Warnngs & Recalls. Last accessed on March 26, 2009.
- Lau GKK, Piratvisuth T, Kang XL, Marcellin P, Thongsawat S, Cooksley G et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. New England Journal of Medicine 2005; 352(26):2682-2695.
- Marcellin P, Lau GKK, Bonino F, Farci P, Hadziyannis S, Jin R et al. Peginterferon Alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. New England Journal of Medicine 2004; 351(12):1206-1217.
- Marcellin, P. Lau, G., Zeuzem, S., et.al. Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs. chronic hepatitis C treated with peginterferon alpha-2a. Liver International : 477-485, 2008.
- McMahon BJ, Holck P, Bulkow L, Snowball M. Serologic and clinical outcomes of 1536 Alaska natives chronically infected with hepatitis B virus. Annals of Internal Medicine 2001; 135(9):759-768. Medication Guide Pegasys (peginterferon alfa-2a). New Jersey: Hoffmann-La Roche Inc. 15 p. 2003-2008.
- Piratvisuth, T, Lau, G., Chao, Y., et.al. Sustained response to peginterferon alfa-2a (40 kD) with or without lamivudine in Asian patients with HbeAg-positive and HbeAg-negative chronic hepatitis B. Hepatology International 2:102-10, 2008.
- Rudin D. Lamivudine and interferon versus lamivudine monotherapy for HBeAg-positive hepatitis B treatment: A meta-analysis of randomized, controlled trials. Advances in Therapy 24(4): (pp 784-795), 2007 Date of Publication: Jul 2007 2007; (4): 784-795.
- Shamliyan TA, MacDonald R, Shaukat A, Taylor BC, Yuan J-M, Johnson JR et al. Antiviral therapy for adults with chronic hepatitis B: A systematic review for a National Institutes of Health Consensus Development Conference. Annals of Internal Medicine 150(2)()(pp 111-124), 2009 Date of Publication: 20 Jan 2009 2009;(2):111-124.
- Sherman M., Shafran S., Burak, K., et.al. Management of chronic hepatitis B: Consensus guidelines. Canadian Journal of Gastroenterology, Vol. 21, Suppl C, June 2007.
- Tepper M. “Acute Hepatitis B” Incidence in Canada; Canada Comunicable Disease Report. 23-07. 1997. National Notifiable Diseases Registry System.
- Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma.[see comment]. New England Journal of Medicine 347(3):168-74, 2002.