Promising Results in Phase II Study of Treatment with Pegasys in HBEAG Positiv

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Epivir HBV Effective and Well-Tolerated in Children with Chronic Hepatitis B Virus (HBV) Infection



Results of a 6-month interim analysis of a 2 year follow-on study examining the safety and efficacy of Epivir HBV (lamivudine) in children, and the durability of response to therapy, were presented at the 52nd annual meeting of the American Association for the Study of Liver Diseases (52nd AASLD) conference in Dallas, Texas.



The study is a 2-year, open-label continuation of a 1-year placebo controlled study in 286 pediatric patients with compensated chronic hepatitis B. This is the largest trial to date of hepatitis B therapy in pediatric patients.



The 1-year study found that patients who received Epivir-HBV had a higher rate of complete virologic response (CVR) [undetectable serum HBV DNA and loss of hepatitis B "e" antigen (HBeAg)] at the conclusion of the study (23%) than those who received placebo (13%). This 6-month interim analysis of the follow-on study showed further responses were gained during the additional treatment period, and CVR was shown to be as durable as natural seroconversion.



Epivir-HBV is the only oral therapy available for pediatric patients and was approved for use in children aged 2-17 years by the Food and Drug Administration on August 16, 2001, for the treatment of compensated chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation. Epivir-HBV was initially approved in December 1998 for treatment of chronic hepatitis B in adults.



"With these new data, we learn more about the efficacy of lamivudine in children with chronic hepatitis B," said Dr. Maureen Jonas, Clinical Director, Hepatology, Children's Hospital, Boston, Massachusetts, and lead researcher of both the 1-year pediatric trial and the 2-year follow-on study. "This orally administered, well-tolerated drug is an important addition to our therapeutic options for chronic hepatitis B in children."



The pediatric indication is based on 1-year histologic and serologic responses in adult patients as well as the 1-year study in pediatric patients. The recommended dosage of Epivir-HBV in children aged 2 to 17 years is 3 mg/kg, up to a maximum of 100 mg once daily. Epivir-HBV is approved for 1 year of treatment.



New Pediatric Clinical Data



This study is an extension of the initial placebo-controlled trial that formed the basis for the approval of Epivir-HBV for use in children. Children who completed the initial 52-week placebo-controlled trial were stratified based on HBeAg status after 48 weeks of treatment to either open-label lamivudine treatment (Stratum A for HBeAg+ve) or observation (Stratum B for HBeAg-ve). Of the 276 children who continued, 213 HBeAg +ve patients were in Stratum A (79 previous placebo, 134 lamivudine), and 63 HBeAg-ve patients were included in Stratum B (14 previous placebo, 49 lamivudine).



In Stratum A, 10% of patients who did not gain CVR after 12 months of lamivudine treatment in the previous study, experienced CVR after the additional 6 months of treatment. In this group, 35% of patients were HBV DNA negative and 47% were ALT normal after 18 months. For patients who did not achieve CVR by 6 months, ALT and HBV DNA levels were maintained below baseline in the majority (76% and 92%, respectively).



In Stratum B, CVR was durable at month 18 (83%, 33/40) in children treated with lamivudine who had this response in the previous study, and was comparable between lamivudine treated and spontaneous seroconverters.



The cumulative incidence of YMDD variant HBV in patients treated with up to 18 months of lamivudine was 54/163 (33%) as compared to 31/166 (19%) at 12 months. For the subgroup of patients receiving 18 months continuous treatment the rate the rate of YMDD variant HBV was 53/118 (45%).



1-Year Study



In the previous 1-year study, children with chronic hepatitis B were randomly assigned to receive either lamivudine (3 mg/kg up to a maximum of 100 mg/day) or placebo once daily for 52 weeks: 191 received lamivudine and 97 received placebo. The primary endpoint for therapeutic efficacy was complete virologic response (CVR) (loss of serum hepatitis B e antigen [HBeAg] and undetectable serum hepatitis B virus [HBV] DNA) at week 52 of treatment. The study was conducted between September 1998 and July 2000 at 40 centers in North America, South America, and Europe.



Complete virologic response occurred by week 52 in 23% of children treated with lamivudine compared with 13% of placebo-treated patients (P=0.037). Children treated with lamivudine also experienced a greater frequency of sustained ALT normalization, HBeAg loss, and reduction of HBV DNA to undetectable levels at 52 weeks, which were all significant improvements compared to placebo.



The safety and effectiveness of treatment beyond 1 year have not been established. In this study adolescents (aged 13 to 17 years) showed less treatment effect than younger children.



The optimal duration of treatment, durability of treatment response, and relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known. Epivir HBV has not been shown to reduce the transmission of HBV to others.



Safety Information



In controlled clinical trials in adults, the most commonly observed adverse events with Epivir-HBV (and placebo) were ear, nose, and throat infections, 25% (21%); malaise and fatigue, 24% (28%); and headache, 21% (24%). The most commonly observed adverse events in the 1-year pediatric trial and the 6-month follow-on were similar; in addition, respiratory symptoms (cough, bronchitis, and viral respiratory infections) were reported in both lamivudine and placebo recipients.



In controlled clinical trials among adults, the incidence of YMDD variant HBV was 16% to 32% at 52 weeks. In the pediatric trial, 1-year occurrence was 19% and the occurrence in the follow-on study 45%.



Lamivudine-treated patients (adult and pediatric) with YMDD-variant HBV at 12 months and 18 months showed diminished treatment responses in comparison to patients treated with Epivir-HBV without evidence of YMDD variants. The long-term clinical significance of YMDD-variant HBV is not known.



Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals.



Human immunodeficiency virus (HIV) counseling and testing should be offered to all patients before beginning Epivir HBV and periodically during treatment, because EPIVIR?HBV Tablets and Oral Solution contain a lower dose of the same active ingredient (lamivudine) as EPIVIR® Tablets and Oral Solution used to treat HIV infection. If treatment with EPIVIR?HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely because of subtherapeutic dose and inappropriate monotherapy.



Pancreatitis has been reported, particularly in HIV-infected pediatric patients with prior nucleoside exposure.



Disease Overview



Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV). It is one of the more common serious infectious diseases in the world. Chronic hepatitis B causes at least 1 million premature deaths every year from cirrhosis or cancer of the liver.



In the U.S., approximately 30% of chronic hepatitis B infections are acquired perinatally or during early childhood. The risk of developing chronic hepatitis B infection varies inversely with age at the time of infection, with chronic infection occurring in 90% of infants infected at birth. In the U.S., early childhood infection with HBV is concentrated in certain ethnic minority populations, including Alaskan Eskimos, Pacific Islanders, and infants born to immigrant women from countries where HBV infection is endemic, especially Asia. Although the CDC has recommended universal vaccination for all infants in the U.S., not all children are receiving the vaccination for hepatitis B.



Epivir HBV is manufactured by GlaxoSmithKline under agreement from Shire Pharmaceuticals Group plc.



11/19/01



Reference

M Jonas and others. A follow-on study in children with chronic hepatitis B (CHB) who completed a placebo controlled lamivudine study-a 6-month interim analysis. Abstract 707.