Pegasys as first-line treatment for hepa B
Higher response rates than lamivudine seen in studies
The diseases caused by hepatitis B and C impose a huge health and economic burden on society because of their long-term sequelae: liver cirrhosis and hepatocellular carcinoma. Present in up to 20 percent of individuals worldwide, the hepatitis B (HBV) virus kills 250,000 people every year. The hepatitis C virus (HCV) is catching up--it has infected about 170 million people, and prevalence rates of as high as 22 percent have been reported in some areas of the world. Up to 80 percent of those infected progress to chronic hepatitis and liver decompensation.
Advances in molecular biology and medical science promise to change the landscape. Powerful new drugs are currently undergoing phase-II and phase-III clinical trials, and time-tested therapies are drawing closer scrutiny. Dr. Stuart Keith Roberts of the Gastroenterology Society of Australia shared several research findings suggesting definitive cures for these diseases.
"Hepatitis B ... is a progressive disease, and therefore, treatment should be considered in all ... [to] arrest progression and prevent long-term complications," Roberts said in a symposium organized by Roche Philippines during the recent joint annual convention of the Philippine Society of Gastroenterology and the Philippine Society of Digestive Endoscopy.
New agents
Several antiviral agents for hepatitis B have been developed, and are nearing market release. Entecavir, telbivudine, clevudine, emtricitabine, and tenofovir are all currently undergoing large phase-III trials, all leading to marked improvements over the previous generation of nucleoside analogues.
Studies show entecavir produced superior results in terms of undetectable HBV DNA compared with lamivudine, and telbivudine-treated patients were DNA-negative at the end of treatment, also compared with lamivudine. Tenofovir, a drug approved for the treatment of HIV infection, seems to possess in vivo and in vitro activity against the wild-type strains of hepatitis B, as well as those determined to be lamivudine-resistant.
Said Roberts: "I think the nucleoside analogues are certainly evolving and it's exciting to see [them]. But they have their disadvantages... and that is the need for long-term or continuous therapy and the ongoing problem of resistance."
A modified version of the drug, pegylated interferon alpha-2a 40 kDa (Pegasys), has been shown to overcome some of the limitations of interferon without sacrificing efficacy. Polyethylene glycol (PEG) was added ("pegylated") to interferon, allowing prolonged concentration peaks (considerably lowering the frequency of administration), sustained absorption, restricted distribution, and reduced clearance.
Piratvisuth et al. (2004) showed pegylated interferon alpha-2a, with or without lamivudine, led to statistically better results in terms of ALT normalization, a decrease of serum HBV concentration, HBsAg loss, and HBsAg seroconversion than those receiving lamivudine alone.
Roberts presented results of large phase-III studies involving Pegasys in patients with chronic hepatitis B and who are HBeAg positive. Hepatitis B envelope antigen is a good marker of active viral multiplication, and a positive HBeAg may indicate a chronic active disease.
One of the studies, presented by Liao before the American Association for the Study of Liver Diseases in 2004, showed 32 percent of patients receiving Pegasys had HBeAg seroconversions compared with only 19 percent in patients who received lamivudine. The pegylated interferon, either alone or in combination with lamivudine, also showed superior virologic responses compared with lamivudine alone.
In another study involving 500 patients without the envelope antigen, Pegasys alone or with lamivudine normalized the ALT levels in 60 percent of the patients, while only 44 percent exhibited similar biochemical parameters in patients treated with lamivudine. HBV DNA levels below 20,000 copies/mL were seen in 43 percent of patients given Pegasys alone or in combination with lamivudine, compared with 29 percent of patients given lamivudine alone. "Pegasys certainly has higher response rates than lamivudine in this difficult treatment group," said Roberts.
No unexpected side effects with Pegasys were seen other than fever, fatigue, headache, and myalgia. Withdrawals from study medication also proved to be low in the three treatment groups--six percent in the Pegasys-monotherapy arm, seven percent in the combination-therapy arm, and five percent in the lamivudine monotherapy arm, "once again indicating that Pegasys was well tolerated," Roberts said.
In light of these findings, and the disadvantages shown with the use of nucleoside analogues, Roberts suggested considering Pegasys as initial treatment for chronic hepatitis B. "We really should be looking at interferon-based therapy as first-line treatment and reserving our nucleoside analogues for second-line in treatment-naïve patients excluding those with cirrhosis," he argued.
|
