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Hepatitis B Report: adefovir; Pegasys
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Friday was Hepatitis B day at the EASL conference. Adefovir for HBV received much attention in the 2pm oral session. There was a presentation on Pegasys used for HBV, which I believe was the first of Pegasys for HBV. HBV looks as though it's turning into a very manageable disease. A study combining adefovir with Pegasys for HBV should be considered. Results from a pilot study reported here discuss the development of a new test that may evaluate whether or not HBV could be eradicated. It appears as though treatment for HBV will become combination therapy, which may offer the best prospects for achieving optimal results. Researchers reported that cirrhosis may regress in some patients who respond to adefovir. The same finding was reported at 2001 AASLD for HCV. It appears that viral response in HBV and HCV is associated with the possibility for regression of cirrhosis.
Adefovir
Marion Peters reported a preliminary 16 week analysis of adefovir alone and in combination with 3TC in HBV monoinfected patients who had 3TC resistance and were on 3TC therapy. In study GS-00-461 adefovir 10 mg once daily (n=19) was compared to adefovir + 3TC 100 mg (n=20) and 3TC 100 mg (n=19) in patients with YMDD 3TC mutations. Patients will receive 48 weeks therapy. Patients had >1 million HBV DNA copies while on 3TC therapy. The baseline HBV DNA was about 8 log copies/ml and ALT was 70-100. Patients had 24 to 37 months prior 3TC use. Patients receiving adefovir or adefovir + 3TC had the same reduction in serum HBV DNA (-2.46 log). Patients staying on 3TC alone had no reduction in viral load. ALT normalized in 6-8 of 20 patients on either regimen including adefovir. 1 patient had an ALT flare and they were receiving adefovir+3TC. There were no study withdrawals and no one interrupted study therapy. Peters reported all study regimens were well tolerated. And the study is ongoing.
Gilead Sciences reported on an evaluation of liver histology in HbeAg positive chronic patients treated with adefovir (10 or 30 mg) or placebo 515 patients were randomized and 441 had before and after liver biopsies. Treatment was for 48 weeks. Liver histology was scored by 1 histopathologist who was blinded to which treatment patients were receiving. They used the Knodell and Ishak scoring systems. Improvement was defined as 2 or more reduction in the Knodell necroinflammatory score with no worsening of fibrosis. Baseline patient characteristics were comparable in the placebo, adefovir 10 mg, and adefovir 30 mg arms. 76% were men. 60% were Asian. 35% were white. Median HBV DNA was 8.4 log. 25% of patients had previously received interferon therapy and 2% had received 3TC. ALT was about 95. Total Knodell scores were 9-9.7. Fibrosis was 1.5 to 1.8. 4-7% had cirrhosis. Necroinflammation was 7.4 to 7.8.
RESULTS: Patients received either dose of adefovir had much better chance of improved histology (53% vs 25%); patients receiving adefovir also had less risk of no improvement (43% vs 75%). Patients receiving adefovir achieved 2-3 times better improvements in necroinflammatory scores. The authors said histologic improvements were consistent regardless of age, gender, ethnicity, serum HBV DNA, serum ALT, total Knodell score, or prior interferon therapy. Patients receiving adefovir were less likely to experience no improvement (15% vs 26) or worsening in necroinflammatory score (13% vs 34%). The same was found for fibrosis improvement: 41% receiving adefovir improved vs 26% receiving placebo; 45% receiving adefovir stayed the same vs 50% receiving placebo; 15% receiving adefovir worsened vs 26% receiving placebo.
Patients receiving placebo did not experience improvement as evaluated by total Knodell score, by necroinflammation score, or fibrosis scores (Ishak and Knodell). Patients receiving adefovir experienced 2.6 point reductions in total Knodell and necroinflammation scores, and 0.2 to 0.3 for fibrosis. Improvements were significant. Cirrhosis progression reversed from F4 to F3 in 45% (5/11) of patients receiving adefovir 10 mg vs 0% (0/12) of patients receiving placebo. 39% (18/46) of patients receiving adefovir 10 mg experienced cirrhosis regression from F3/F4 to F0/F1 compared to 22% (13/58) in the placebo group. 71% of patients receiving adefovir 10 mg experienced HbeAg loss and histologic improvement compared to 29% receiving placebo. 72% of patients receiving adefovir had HBV DNA <400 and histologic improvement compared to 0% receiving placebo. Patients with HBV DNA between 400 to 100,000 (59% vs 41) as well as patients with >100,000 (40% vs 24%) were more likely to also see benefit if they were receiving adefovir.
The authors concluded that treatment with adefovir resulted in significant improvement in histology in patients with HBeAg chronic HBV; improvement in necroinflammation in all components (Knodell); improvement in fibrosis (Ishak and ranked assessment). Improvement was greater in patients with HBeAg loss.
This is an analysis from the study just above. Gilead Sciences reported on the loss of 3TC resistance mutations after patients switched to adefovir. 100% of patients in this analysis had 3TC resistance (n=59). 6/19 (32%) receiving adefovir reverted to wild-type virus by week 32, while only 1/12 receiving adefovir+3TC reverted. HBV DNA suppression was maintained in all patients who lost YMDD 3TC mutations.
In a separate oral presentation, it was reported that inhibition of HBV replication was associated with enhanced virus-specific T-cell reactivity in a proportion of patients receiving adefovir. The different patterns of this immune response was associated with the magnitude of the viral response.
Researchers from France, Germany, Australia, and Gilead reported on the development of a quantitative assay for hepatitis B cccDNA levels in patients with chronic HBV. Werle reported HBV covalently closed circular DNA (cccDNA) is a key intermediate in HBV replication; cccDNA is the transcriptional template for viral pre-gonomic RNA and messenger RNAs. In other words, cccDNA is used to make copies of HBV. Viral persistence is due to amplification and maintenance of a pool of cccDNA in the nuclei of infected cells. Werle said little is known about the amount of cccDNA in patients chronically infected with HBV, and cccDNA levels are likely to vary during different disease states: acute infection, progression to chronic infection, resolution of acute or chronic infection, and during antiviral therapy. The objective of this work was to develop a rapid method for cccDNA detection using real time PCR using a biopsy; to monitor cccDNA levels during the natural history of chronic HBV infection; and to evaluate the intracellular clearance of HBV during adefovir therapy.
In the natural history study there were 58 patients: 37 with chronic active hepatitis, HBeAg+; 15 with chronic active hepatitis, HBeAg- (presumed pre-core mutants; 3 inactive carriers, HBeAg-, 3 with HBsAg clearance (HBsAg-, anti-HBc+, anti-HBs+). In the adefovir therapy study there were 20 patients (16 received adefovir and 4 placebo for 48 weeks) from the phase III Gilead GS-437 study (HBeAG+, HBV DNA+). Werle went on to describe the methods and strategy used to develop the new assay for quantitative detection of cccDNA by real time PCR. Three labs were used in Lyon, Melbourne, and Hamburg and average interlab variability was less than 2-fold of the mean ccc values. Werele reported there was no correlation between cccDNA copy number and interlab vriability.
RESULTS: In monitoring of cccDNA levels during the natural history study, the measured baseline and week 48 mean cccDNA copies/cell in HbeAG+ and HbeAg- (pre-core mutant) patients, as well as baseline and week 48 mean HBV DNA copies/cell. They found that pre-core mutant patients have <0.1 cccDNA copies/cell and this was 47-fold less compared to HBeAg+ patients. HBeAg+ patients also had a higher mean level of total HBV DNA copies/cell. Adefovir therapy resulted in a mean 9-fold reduction (90%) of cccDNA copies/cell (p<0.05), while there was no reduction inpatients receiving placebo. Seroconverters had significantly less cccDNA copies/cell (<0.7 copies/cell vs 3.7 cccDNA copies/cell); they also had lower levels of HBV DNA copies/cell at baseline than non-seroconverters.
The authors concluded that a rapid, selective and reproducible method for quantifying cccDNA from liver biopsies has been developed. The data indicate that methodpreliminary data indicate that 48 weeks adefovir therapy results in significant decrease in hepatic cccDNA; the kinetics of cccDNA loss appear slower than those for serum HBV DNA and total intracellular HBV DNA. Additional studies are warranted to demonstrate that monitoring cccDNA may provide an indicator of the efficacy of antiviral therapy and could be an independent predictor of outcome.
Pegasys for HBV
The effectiveness of Pegasys at 3 different doses was compared to the efficacy of standard interferon (IFN a-2a) in HBV given 3 times per week. 194 patients were randomized to one of 3 doses of once weekly Pegasys (90 ug, 180 ug, or 270 ug) or 4.5 MIU IFN a-2a 3 times per week. Patients received 24 weeks of treatment and there was a 24-week follow-up period. End of follow-up results were reported at week 48. Measures of response were HbeAg loss, quantitative HBeAg, ALT normalization, and HBV DNA <500,000 copies/ml. Patients had comparable baseline characteristics. Baseline HBV DNA levels appeared from a graph to be a little over 9 log for all patients in the study. Most patients were male Asians and about 9% had cirrhosis. Cirrhosis or transition to cirrhosis was present in 8-10%. The Cobas Amplicor HBV Monitor test was used, sensitivity of 200 copies/ml. ALT at baseline was 2 to <10 times the upper limit of normal (ULN); on average ALT was 3.2 to 4.5 times the ULN. Age was about 32, weight 64 kg.
At week 24 of treatment, patients on all of the 3 Pegasys dose regimens exerienced equal reductions in median on-treatment quantitative HbeAg. From the graph presented it appeared that baseline HbeAg levels were lower in the Pegasys groups than in the patients receiving the standard interferon regimen, and that Pegasys reductions had greater initial slope of decline. After 48 weeks (end of follow-up) 25% in the IFN group (n=51) had HbeAg loss and seroconversion compared to about 35% in the Pegasys groups (about 47 in each of the Pegasys dose groups). Looking at a "combined response" (HbeAg loss, HBV-DNA <500,000 copies, ALT normalization) at the end of follow-up, 12% (n=51) in the IFN group had a response, 27% (n=49) achieved this in the 90 ug dose group, 28% in the 180 ug group (n=46), and only 19% in the 270 ug group (n=48).
When looking at mean log reduction in HBV DNA at week 24 of treatment (achieving what appeared to be a 1 log greater reduction), it appeared from the graph as though the 3 Pegasys doses performed better than the standard interferon. The 2 higher Pegasys doses appeared to perform slightly better than the 90 ug dose. The 180 ug Pegasys dose appeared to reduce HBV DNA greater and more rapidly than the 90 ug dose. Withdrawals were about the same across all study arms (2-4% due mostly to lab abnormality or adverse event).
The presenter said that patients with low ALT (2 or less x the upper limit of normal) and high viral load (>8 log) are more difficult to treat. These types of patients appeared to respond better to Pegasys in this study than the standard interferon regimen. The Pegasys group was better at reducing HBV DNA (25% vs 17%) and loss of HbeAg (44% vs 17%) in patients with >8 log HBV DNA and <2 x ULN ALT, although the numbers of patients in this analysis were small. Researchers looked at patients with either low ALT or high HBV DNA, and the numbers of patients in these analyses were greater (9-77). Patients with ALT 0 to <2 x the upper limit of normal or 2 to <5 ULN had better combined response with Pegasys (27% vs 11% and 22% vs 7%, respectively), Patients with ALT >5 x ULN responded about the same to interferon or Pegasys (25% vs 29%, respectively). Patients with high baseline viral load (>11 log) responded better to Pegasys than the standard interferon regimen (20%, n=15 vs 0%, n=3). Patients with baseline HBV DNA of 5 to 8.5 log had a better response to Pegasys: 56% (n=27) vs 38% (n=13). Patients with 8.5 to 11 log: Pegasys 36% (n=97) vs interferon 24% (n=34). None of the cirrhotic patients responded to the standard interferon regimen, but 38% to 54% responded to Pegasys (combined response).
The study authors concluded that Pegasys shows promise in treating HbeAg+ patients with chronic HBV. The 180 ug dose had more rapid and greater drop in HBeAg (although as I said baseline HBeAg was lower in the Pegasys patients), and a larger reduction in HBV DNA levels compared with the conventional interferon. In patients with difficult to treat disease Pegasys appeared to have greater efficacy. Tolerability did not appear to be different between Pegasys and standard interferon regimen. Larger studies are needed to confirm these findings.
Finally, a poster was presented for LdT, which is a new drug in early development for HBV. The drug looks potent in early human study results.
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