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Report 1 on Hepatitis B at the Liver Conference AASLD
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Reported by Jules Levin
I am in Boston at the 55th Annual Meeting of the American association for the Study of Liver Diseases
October 29-November 2, 2004
Boston, MA. There were 5 million people here celebrating a parade today in honor of the Red Sox Nation's success in winning the Baseball World Series. The town is mobbed. I don't think AASLD organizers knew the red Sox would acquire Curt Schilling when the selected Boston. I love the cod fillet, however. I bought 2 Red Sox caps, I'm not sure they'll let me reenter NYC now.
On the NATAP website you can visit our HIV, HCV & HBV sections where you'll find the latest comprehensive reporting of data and information from medical journals & worldwide conferences.
This year's meeting is a major hepatitis B meeting. For several years there has been much anticipation of the availability of numerous drugs for HBV. Study data for several new HBV drugs are being presented at this meeting. Adding this to the already available adefovir, lamivudine, and interferon presses the issue of strategizing therapy. Up until now studies of combination therapy for HBV treatment have not yielded much benefit but studies have been very limited. In HBV monoinfection the use of peginterferon can be effective. But, the utility of Peginterferon in HBV/HIV coinfection has not yet been adequately explored. Studies of standard interferon in coinfection have yielded only hints of benefit but studies were in the pre-HAART era. Studies need to be conducted in patients with reconstituted immune systems, high CD4s & low viral loads. As well, HBV & diagnostic blood tests are complex in HBV. A good understanding of how to use diagnostic blood tests is crucial in strategizing for therapy & understanding a patient's disease.
More than two billion people worldwide have been infected with hepatitis B virus and approximately 350-400 million of these people are chronically infected. According to the World Health Organization, more than half a million people worldwide die each year from primary liver cancer, and up to 80 percent of liver cancers are due to hepatitis B. There are 530,000 hepatocellular carcinoma cases per year: 59% HBV-related & 22% HCV-related.
AIMS OF THERAPY
Virologic
--durable suppression of HBV DNA (<100,000 copies/ml)
--loss of HBeAg in serum; seroconversion to anti-HBe
--loss of HBsAg; seroconversion to anti-HBs
Biochemical: normalize ALT
Histologic improvement--inflammation & fibrosis
--for HBeAg negative/anti-HBeAg positive/HBV-DNA positive (precore mutant): HBeAg seroconversion not an endpoint; long-term therapy the rule; more risk for serious liver disease with cirrhosis
HBV DRUGS IN DEVELOPMENT
peginterferon
entecavir
telbivudine
tenofovir
therapeutic vaccines
remofovir
FTC (Emtricitabine)
clevudine
with all these drugs becoming available its important to develop treatment guidelines so drugs are not used as serial monotherapy where resistance develops. Combination studies must be quickly conducted and we need studies of PegIFN in HIV+ individuals with reconsituted immunity.
At the meeting, a new drug entecavir will have presented 48-week results from 3 large phase III studies in 1600 patients with chronic HBV & HBeAg negative, and positive patients, and in 3TC resistant HBeAg negative patients. The studies compare entecavir to lamivudine. At the Bristol Myers Squibb symposium tonite previews of data were presented for entecavir & other drugs being presented at AASLD. For entecavir, median HBV DNA reductions (viral load) ranging from 5 to 7 logs across the 3 studies, statistically significant histologic improvements & greater magnitude of histologic improvements than lamivudine, and ALT normalizations. Safety, adverse events, and discontinuations were similar between lamivudine & entecavir. Administration and a marketing authorization application for entecavir with the European Medicines Evaluation Agency (EMEA). I will report more details after viewing the presentations. entecavir 0.5 mg once daily vs 3TC (lamivudine) 100 mg once daily treatment for HBeAg positive disease, week 48, 715 patients: 72% histologic improvement (entecavir) vs 62%; HBV DNA <400 copies/ml: 69% (entecavir) vs 36% (3TC); HBV DNA mean change: -6.98 log vs -5.46; normalization of ALT: 78% entecavir vs 70% 3TC. Safety profile comparable between two drugs. Entecavir 0.5 mg QD vs lamivudine 100 mg QD in patients with HBeAg negative HBV, 650 patients, 48 weeks; 70% histologic improvement vs 61% 3TC; HBV DNA <400 copies/ml 91% vs 73% 3TC; HBV DNA -5.2 log for ETV vs -4.66 for 3TC. ETV 1.0 mg QD vs 3TC in lamivudine-refractory patients with HBeAg-positive disease, 286 pts, 48 weeks: histologic improvement: 55% vs 28%, composite endpoint: 56% vs 4%; HBV DNA -5.14 vs .048 log; HBV DNA <0.7 MEg/ml 74% vs 10%; ALT normalization: 71% vs 7%; HBV DNA -4.30 log vs -0.15 log.
FTC is active against HIV & HBV and is similar to 3TC. 48-week results are reported by Gilead at this meeting. 248 patients had chronic HBV and were HBsAg positive, HBeAg positive or negative, and HBV DNA positive, and had elevated ALT. Details will be reported after the presentation.
LdC and LdT (telbivudine) are sister drugs. 28 days results from a phase I/II dose ranging study are being presented at AASLD. Early LdT data has previously been reported: -5.99 log after 52 weeks telbivudine vs -4.67 log for 3TC. There is an abstract here on viral kinetics.
At this meeting: remofovir, new HBV drug--3 log reduction in HBV DNA at week 4.
Clevudine is a new HBV drug being developed by Gilead & 12 weeks results are reported here from a dose ranging study.
Pegasys phase III study results for HBV have been submitted to the FDA. Results are reported here from a study comparing Pegasys+lamivudine to pegasys, and lamivudine. PegIFN 2-ab+3TC, 52 weeks vs 3TC: 36% SVR vs 14%; 3.91 log reduction vs 2.83; 21% 3TC resistance vs 40%. Pegasys, Pegasys+3TC vs 3TC alone, 1 year: HBV DNA <100,000 c/ml- 32%, 34% vs 22%; ALT normalization: 41%, 39% vs 28%; HBeAg seroconversion: 32%, 27%, vs 19%.
A three year update is reported here for adefovir. And of course there are a number of studies of adefovir and lamivudine at this meeting. Of note. results are reported here on a conbination study of adefovir plus FTC versus adefovir alone, week 48. This is a small, single center study of asian HBeAg+ patients. The arms were not balanced. There was a log difference in HBV DNA at baseline. The investigator used the Digene assay which is a relatively insensitive assay. The study was re-run with a PCR assay. Using PCR, the median reduction at week 48 was 3.4 log for ADV & 5.44 logs for ADV+FTC. These are similar results seen in the ADV+lamivudine study by Sung which showed a 5.4 log reduction at week 52 for ADV+LAM in HBeAG+ patients. I will report resistance data & more details after the presentation of the study at AASLD. In the ADV+LAM study no one developed ADV resistance and 1/50 (<2%) developed YMDD LAM resistance compared to 20% in the LAM alone arm.
LB80380/ANA380 is being developed by Anadys Pharmaceuticals and phase I/II study results in multiple, ascending doses in a 28-day study are reported at AASLD.
Of note, there is a study here evaluating whether lamivudine in late pregnancy, in addition to HBV vaccination plus HBIg in infants can reduce mother-to-child transmission of HBV.
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