 |
|
|
| |
EASL Hepatitis B Report 2: Pegasys Study in Hepatitis B
|
| |
| |
After this introductory section about hepatitis B is my report on the study of Pegasys for hepatitis B which was presented at EASL several days ago (EASL April 14-18, 2004, Berlin). This study is a registration study for Roche to gain approval for Pegasys in the treatment of HBV.
INTRODUCTION
Hepatitis B can be transmitted by blood or bodily fluids and sources for transmission include childbirth (perinatal transmission), sharing needles for intravenous drug use, high risk sexual behavior, and transfusion. HBV is more easily transmitted than HIV. HBV can be prevented by getting vaccinated against hepatitis B. Many people don't know there is a vaccination to prevent HBV and you should ask your doctor about this.
Most people spontaneously clear HBV, about 85%, after infection. Between a third and a quarter of people infected chronically with HBV are expected to develop progressive liver disease (including cirrhosis and primary liver cancer). HBV can cause cirrhosis, digestive haemorrage, liver failure, and liver disease. It's estimated that 10% of HIV-infected people have HBV.
According to the World Health Organization almost half of the world's population lives in an area with high HBV prevalence. 300-400 million people have chronic HBV.
There are a number of serum markers for HBV including HBeAg, HBsAg, and antibody for HBV. Hepatitis B is more complex than HIV or HCV and it is important to understand these serum markers and the role they play in testing or screening, and management of the disease.
Occult HBV: HBV DNA can be detected in the liver of patients without hepatitis b "surface" antigen (HBsAg) in the serum. Clearance of serum HBsAg may occur without clearance of HBV DNA in the liver. One study of HBV progression in HIV-infection in the MACS group showed HBV can progress 5 times more quickly in HIV infected than HBV monoinfected individuals, but clearly this subject of progression rate in coinfected patients has not been adequately studied.
The clinical goal of therapy is to prevent or reverse cirrhosis, hepatic decompensation, and liver cancer. With current drug therapy cure or eradication of HBV does not appear to occur. With the development of new HBV drugs, and there are a number in developmental stages, the advent of combination therapy will be studied. The results of these studies may yield new information about HBV management and treatment. Interferon is one of several treatments for HBV including lamivudine, adefovir and tenofovir (not FDA approved yet for HBV, approved for HIV). The role of each of these drugs in treating HBV and strategies for treatment is not well understood. The role of combination therapy is not understood yet. Although some thought leaders believe combination therapy may be more effective and some early research suggests this may be true, the added effectiveness of combination therapy has not yet been established. The role of combining oral antivirals such as adefovir with interferon has not yet been adequately explored.
Drug resistance appears to be a consideration in HBV treatment. Lamivudine resistance has been shown to develop after 1 year of therapy in 24% of patients, after two years of therapy in 38% of patients, 56% after 3 yrs therapy, and 70% after 4 years. The risk for developing resistance may be higher in HIV-infected patients. Resistance to adefovir does not occur as easily. From an overview of adefovir studies, resistance to adefovir occurs at these rates: 0% after 1 year, 2% after 2 years, and 3.9% after 3 years. Data on resistance after 4 years treatment will be presented soon.
Reduction in HBV DNA (viral load) is associated with normalization of ALT, improvement in liver histology (disease in the liver), and HBsAg loss and serocnversion—goals of therapy. The degree of viral load reduction needed is not yet clear. I will report a summary and review of the several important studies presented at EASL with use of adefovir, but the current report covers an important oral presentation in the last session at EASL on Pegasys for treating HBV. Roche is submitting data from Pegasys studies to the FDA and other regulatory agencies around the world for approval of Pegasys to treat HBV, and this study below is one of those registration studies.
"Peginterferon alfa-2a (40KD) (PEGASYS) Monotherapy is More Effective Than Lamivudine Monotherapy in the Treatment of HBeAg-Negative Chronic Hepatitis B"
72-week results from a Phase III, partially double-blind study
Patrick Marcellin (Service D'Hepatologie, INSERM Unite 481 and Centre De Recherches Claude Bernard Sur Les Hepatitis Virales, Hopital Beaujon, Clichy, France) and others reported on this study at EASL.
Brief summary: Pegasys monotherapy showed significantly higher rate of ALT normalization than Lamivudine at week 72 (after 24 weeks of followup: 24 weeks after stopping 48 weeks of therapy) (59% vs 44%, p=0.004); significantly higher percentage of patients achieving HBV DNA <20,000 copies/ml than Lamivudine (43% vs 29%, p=0.003). At the end of 48 weeks of treatment HBV DNA declined by --5.9 log copies/ml for patients talking Pegasys/Lamivudine, -4.2 for patients taking Lamivudine; and --4.1 for patients taking Pegasys monotherapy. 24 weeks after stopping therapy HBV DNA increased some; HBV DNA decline from baseline was --2.3 log copies/ml for Pegasys, -1.6 for Lamivudine, and --2.4 for Pegasys/Lamivudine. 70-80% of patients in study had paired biopsies. Necroinflammatory activity at the end of 72 weeks followup was improved in half the patients. HBsAg loss was reported in 7 patients taking Pegasys (4%), 3% taking Pegasys/Lamivudine, and 0% taking Lamivudine, and the differences between the two Pegasys arms and the Lamivudine arm was significant. Seroconversion was reported in 5 (3%) of patients taking Pegasys, 2% of patients taking Pegasys/lamivudine, and 0% taking Lamivudine; only the difference between Pegasys and Lamivudine was significant. Response rates for each of 4 genotypes are detailed below (A, B, C, D). Adverse events listed below, authors report no unexpected adverse events. Interferon has more side effects than Lamivudine. But depression does not appear to occur as much in treating HBV as in HCV. In this study depression rate was 3-4% for patients taking Pegasys. Withdrawal rates were 4-8% for the two Pegasys arms and 0-2% for the Lamivudine arms.
Conventional interferons and lamivudine are first-line treatments for chronic hepatitis B (CHB). Recent data have shown that peginterferon alfa-2a (40KD) (PEGASYS) is superior to conventional IFNa in HBeAg-positive CHB (Cooksley et al, J Viral Hepat 2003).
The objective of this study is to compare PEGASYS with and without lamivudine to lamivudine alone in the treatment of HBeAg-negative CHB. Adults (ITT population, n=537) with HBeAg-negative CHB received PEGASYS 180 mg once-weekly plus placebo, PEGASYS 180 mg once-weekly plus lamivudine 100 mg daily, or lamivudine 100 mg daily, for 48 weeks, with 24-weeks follow-up.
Key Inclusion Criteria for Patients
HBsAg positive
HBeAg negative, anti-HBe positive for at least 6 months
HBV DNA >100,000 copies/ml (Cobas Amplicor HBV Monitor)
Serum ALT >1 but 10 or less times the ULN at screening (less than 20% with serum ALT 1-2 x ULN)
Liver biopsy proven CHB
Key Exclusion Criteria
Decompensated liver disease
Coinfection with HCV, HDV (delta virus), HIV
Anti-HBV therapy in 6 months prior to study
STUDY ENDPOINTS
Co-primary Endpoints
--normal ALT (<=1 x ULN) at end of followup
--HBV DNA <20,000 copies/ml at end of followup (Cobas Amplicor HBV Monitor)
Secondary Endpoints
--HBV DNA over time
--histology at end of followup (Ishak)
--HBsAg loss/seroconversion at end of followup
BASELINE CHARACTERISTICS
Pegasys/placebo, n=177
Pegasys/Lamivudine, n=178
Lamivudine, n=181
Baseline characteristics were comparable in all treatment groups.
Male: 82-86%
Race: 36-38% Caucasian; 60-62% Asian
Mean age: 40-41 yrs
Mean weight: 70-71 kg
Mean baseline ALT: 3-3.5 x ULN
Mean Baseline HBV DNA (log copies/ml): 7.14 (Pegasys/placebo); 7.35 (Pegasys/Lamivudine); 7.24 (Lamivudine)
Bridging Fibrosis/Cirrhosis: 31% Pegasys/placebo; 22% Pegasys/Lamivudine; 29% Lamivudine
Prior use of Lamivudine: 4%, 8%, 5%, respectively
Prior use of IFNs: 6%, 10%, 8%, respectively
RESULTS
WEEK 72 PRIMARY ENDPOINTS
|
|
Pegasys
|
Pegasys/Lam
|
Lam
|
|
ALT Normalization
|
59%
|
60%
|
44%
|
|
Both Pegasys monotherapy (p=0.004) & Pegasys/Lamivudine (p=0.003) were significantly better than lamivudine.
|
|
HBV DNA <20,000 c/ml
|
43%
|
44%
|
29%
|
|
Both Pegasys monotherapy (p=0.007) and Pegasys/Lamivudine (p=0.003) performed significantly better than Lamivudine.
|
HBV DNA REDUCTION. On treatment after at week 48 HBV DNA declined by mean --5.9 log copies/ml in the Pegasys/Lamivudine patient group, -4.2 log copies/ml in the Lamivudine group, and --4.1 in the Pegasys group. After 24 weeks followup HBV DNA was --1.6 log below baseline in the Lamivudine group, -2.4 log in the Pegasys/Lamivudine group, ans --2.3 log in the Pegasys group.
HISTOLOGICAL RESPONSE. All paired biopsies were analyzed by an independent histopathologist who was unaware of the timing of biopsy and treatment received.
Patients with paired biopsies:
Pegasys- 80%; Pegasys/Lamivudine- 78%; Lamivudine- 68%.
NECROINFLAMMATORY ACTIVITY at End of Followup (week 72): patients with paired biopsies.
Improvement= >=2 point reduction in score.
Pegasys: 56%
Pegasys/Lamivudine: 46%
Lamivudine: 46%
Worsening= >=2 point increase in score.
Pegasys: 11%
Pegasys/Lamivudine: 16%
Lamivudine: 17%
FIBROSIS at End of Followup (Week 72): patients with paired biopsies.
Improvement= >=2 point reduction in score.
Pegasys: 15%
Pegasys/Lamivudine: 12%
Lamivudine: 17%
Worsening= >=2 point increase in score.
Pegasys: 8%
Pegasys/Lamivudine: 11%
Lamivudine: 5%
|
HBsAg Loss and Seroconversion at End of Followup (Week 72)
|
|
|
Pegasys
|
Pegasys/LAM
|
LAM
|
|
HBsAg loss
|
4%
|
3%
|
0%
|
|
Pegasys vs LAM p=0.007' Pegasys/LAM vs LAM
p=0.030
|
|
's' seroconversion
|
3%
|
2%
|
0%
|
Pegasys vs LAM, p=0.029
GENOTYPE DISTRIBUTION
|
|
Pegasys
|
Pegasys/LAM
|
LAM
|
|
A
|
6%
|
6%
|
4%
|
|
B
|
24%
|
23%
|
27%
|
|
C
|
36%
|
39%
|
31%
|
|
D
|
31%
|
30%
|
35%
|
HBV DNA <20,000 copies/ml -- End of Followup (Week 72) by Genotype | Pegasys | Pegasys/LAM | LAM | | A: 45% | 20% | 12% | | B: 53% | 32% | 51% | | C: 56% | 59% | 30% | | D: 20% | 39% | 16% |
PREDICTORS OF RESPONSE
Multivariate analysis
Treatment group 0.005
Gender 0.010
Log baseline ALT 0.019
Log baseline HBV DNA 0.043
Geographical region 0.052
Weight 0.136
Age 0.330
Genotype 0.665
ADVERSE EVENTS
|
|
Pegasys
|
Pegasys/LAM
|
LAM
|
|
Patients w/>= AE
|
88%
|
87%
|
48%
|
|
Pyrexia
|
69%
|
55%
|
4%
|
|
Fatigue
|
42%
|
42%
|
18%
|
|
Myalgia
|
27%
|
27%
|
6%
|
|
Headache
|
24%
|
19%
|
8%
|
|
Decreased appetite
|
18%
|
15%
|
3%
|
|
Arthralgia
|
15%
|
15%
|
3%
|
|
Alopecia
|
14%
|
11%
|
<1%
|
|
Diarrhea
|
11%
|
6%
|
3%
|
|
Injection site reaction
|
6%
|
12%
|
0%
|
WITHDRAWALS | Pegasys | Peg/LAM | LAM | | All reasons | 8% | 6% | 2% | | safety | 7% | 4% | 0% |
DEPRESSION
Pegasys: 3%
Pegasys/LAM: 4%
LAM: 1%
Depression rates are much higher previously reported in patients with chronic HCV (16-20%).
|
| |
|
|
|
|
|
