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Pegasys+Lamivudine, Pegasys, or Lamivudine for HBV Therapy
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Reported by Jules Levin
In the treatment of HBV some treaters prefer to use interferon therapy before using oral drugs, while other treaters prefer oral drugs. Treatment strategies have yet to be well researched. A number of new drugs are available for HBV treatment or in early stages of development for including adefovir, tenofovir (only approved for HIV now), entecavir (phase III results presented at AASLD), lamivudine, and Pegylated interferon. The benefits of interferon are a short treatment of 4-12 months which may produce a high chance for HBeAg seroconversion 30-40%, a goal for HBV therapy. A study at AASLD showed a 50% seroconversion rate with adefovir after 144 weeks of treatment. A similar rate of seroconversion would be expected after 3 years of entecavir. So oral agents are easier to tolerate but it takes longer to achieve seroconversion. Researchers have yet to adequately explore various strategies for combining pegIFn with oral agents. At AASLD followup data was presented for one such strategy using Pegasys plus lamivudine. However, interferon in HBV/HIV+ individuals has not been well studied. Studies conducted prior to HAART found only hints of success. Studies in the HAART era with reconstituted immunity need to be conducted.
The authors found:
Pegasys showed significantly higher 24-week post-therapy response rates compared to lamivudine for: HBeAg seroconversion & HBV DNA response (<100,000 copies/ml). Combination Pegasys/lamivudine did not improve post-therapy response rates compared to Pegasys alone. There were 8 HBsAg seroconversions reported for patients taking Pegasys+placebo, 8 for patients tal=king Pegasys+lamivudine, compared to no patients taking lamivudine alone. No unexpected adverse events were reported & the addition of lamivudine to Pegasys did not alter the Pegasys safety profile. Roche has submitted an application to the FDA for approval to use Pegasys for HBV therapy for HBeAG+.
"Peginterferon alfa-2a (40KD) (PEGASYS®) Monotherapy and in Combination with Lamivudine is More Effective than Lamivudine Monotherapy in HBeAg-positive Chronic Hepatitis B: Results from a Large, Multinational Study"
814 patients were randomized to Pegasys 180 ug once weekly (qw) + oral placebo, or Pegasys 180 ug qw + lamivudine 100 mg qd, or lamivudine 100 mg qd for 48 weeks therapy with a 24 week followup period.
Patients were HBsAg+ for >6 months; HBeAg+, anti-HBs-negative; HBV DNA >500,000 copies/ml (COBAS AMPLICOR HBV MONITOR); serum ALT >1, but <=10 x ULN at screening (<20% with serum ALT 1-2 x ULN); liver biopsy proven chrnic HBV (maximum 30% with bridging fibrosis/cirrhosis). Persons were excluded for decompensated liver disease, coinfection with HAV, HCV, HDV, or HIV; anti-HBV therapy in 6 months prior to study.
Primary study endpoints:
HbEag seroconversion
HBV DNA <100,000 copies/ml (Cobas Amplicor HBV Monitor)
Secondary endpoints:
HBeAg loss
ALT normalization
HBsAg loss/seroconversion
BASELINE CHARACTERISTICS: 78% men; 87% Asian; mean age 32; mean weight 66 kg; mean baseline ALT 3.4-3.8 x ULN; mean baseline HBV DNA 9.7-10.1 log copies/ml; bridging fibrosis/cirrhosis 15-18%; prior lamivudine use 9-15%; prior conventional IFN 11-12%.
RESULTS
HBeAg SEROCONVERSION at END OF FOLLOW-up (Week 72)
Pegasys+placebo: 32% (n=271)
Pegasys + lamivudine: 27% (n=271)
Lamivudine: 19% (n=272)
Pegasys/placebo vs Pegasys/LAM p=0.232; Pegasys vs lamivudine p<0.001; Pegasys/placebo+lamivudine vs lamivudine p=0.023.
HBV DNA <100,000 cp/ml at END of FOLLOW-UP (Week 72)
Pegasys+placebo: 32%
Pegasys+lamivudine: 34%
Lamivudine: 22%
Pegasys+lamivudine & Pegasys+placebo were both significantly better than lamivudine alone. There was no difference between Pegasys/placebo & Pegasys/lamivudine.
HBV DNA LEVELS OVER TIME
At the end of 48 weeks treatment, HBV DNA reduction from baseline was -7.2, -5.8, and -4.5 log copies/ml for Pegasys/placebo, Pegasys/LAM, and lamivudine, respectively. But at week 72, HBV DNA reduction from baseline was -2.0 log for LAM, -2.6 log for Pegasys, & -2.4 log for Pegasys/LAM.
HBeAg SEROCONVERSION RATES OVER TIME
Pegasys/placebo: 27% at week 48 & 32% at week 72
Pegasys/lamivudine: 24% at week 48 & 27% at week 72
Lamivudine: 20% at week 48 7 19% at week 72
HBeAg SEROCONVERSION at END OF FOLLOW-UP ACCORDING TO BASELINE ALT
<=2 x ULN
29% for Pegasys/placebo
20% for Pegasys/LAM
20% for LAM
2-5 x ULN
30% for Pegasys/placebo
27% for Pegasys/LAM
16% for LAM
>5 x ULN
41% for Pegasys/placebo
37% for Pegasys/lamivudine
28% for LAM
HBsAg LOSS & SEROCONVERSION at END OF FOLLOW-UP Week 72
| Peg/pl | Peg/LAM | LAM | | HBsAg loss | 9 (3%) | 11 (4%) | 2 (<1%) | | HbsAg Seroconversion | 8 (3%) | 8 (3%) | 0 (0%) |
Differences between LAM & Pegasys arms are significant.
SAFETY
Reason for withdrawal of study medication
| Peg/pl | Peg/LAM | LAM | | Safety | 8 (3%) | 12 (4%) | 2 (<1%) | | Non-safety | 9 (3%) | 6 (2%) | 12 (4%) | | total | 17 (6%) | 18 (7%) | 14 (5%) |
Serious Adverse Events & Deaths
All Body Systems
| Peg/pl | Peg/Lam | LAM | | Total pts w/at least 1 SAE | 12 (4%) | 16 (6%) | 5 (2%) | | Total # of SAEs | 12 | 16 | 5 | | Deaths | 0 | 3* | 1** |
*3 deaths in combination group were unrelated to therapy (2 car accidents and 1 house fire (septic shock)).
**2 pts in LAM group had complete liver failure after cessation of therapy- 1 liver transplant & 1 death.
SAEs reported during treatment & up to 8 weeks post-therapy (including deaths).
ADVERSE EVENTS
Typical interferon side effects. In the Pegasys arms: pyrexia, fatigue, headache, myalgia, alopecia, decreased appetite, etc. There did not appear to be anything unusual on the list of adverse ebents.
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