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Hepatitis B Therapy at AASLD
Written for NATAP by Douglas T. Dieterich, MD
Cabrini Hospital and NYU Medical Center, NYC
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The therapy of hepatitis B is becoming almost as complicated as the disease itself. It is suffering from the success of all the new therapies coming as well as some information on the older therapies. I will attempt to keep this as uncomplicated as possible and have been debating how to organize this, alphabetical order or order of likely approval and I think it would be better to put this in historical perspective to build on the base and educate those still confused by the field.
The first treatment approved by the FDA for HBV was alfa interferon 2b at a disabling dose of 10 MIU thrice weekly or 5 MIU daily for 4 months. This resulted in about a 25% HbeAg to HbeAb seroconversion rate and a histological benefit on liver biopsy. In late 1998 3TC or lamivudine was approved at a dose of 100 mg per day, considerably less than the HIV dose of 300 mg per day. One years' treatment resulted in a seroconversion rate of about 25%, like interferon and a histological benefit on biopsy similar to interferon's. The difference in this therapy was that HBV resistance developed in nearly as many patients who seroconverted per year. The good news was that the resistant virus was seen as more benign than the wild type virus and even though the virus was still replicating, the seroconversion rate was significantly higher if the patients continued taking 3TC. News from this meeting however suggested that the early biopsy benefit is lost after 4 years on 3TC and the biopsies start to worsen again. This is beginning to sound like the HIV story where sequential nucleoside analogue therapy resulted in sequential nucleoside resistance and I believe that is clearly the case.
Why not combine the two therapies? Well there were several combination trials presented here in Dallas. They, unlike the first study performed a few years ago, showed that combination 3TC and interferon is better than either alone and that interferon prevents the development of 3TC resistance mutations. There was even a combination trial of famciclovir and interferon, which showed some benefit. Famciclovir is approved for the treatment of herpes virus infections but not for hepatitis B. It does however have some activity against hepatitis B albeit slightly less than 3TC. Famciclovir and 3TC share some resistance mutations as well, but not all and there is one paper from 2000 at least that demonstrates synergy between the two. In my practice, for patients not on clinical trials, I always use the combination of famciclovir and 3TC.
The advances in interferon technology to pegylate it and lengthen the half life so that it can be administered weekly, have spread to hepatitis B treatment as well. One study showed that pegylated interferon alfa 2 a is clearly superior to plain alfa 2a interferon thrice weekly in the treatment of hepatitis B. Clearly the next step is to combine pegylated interferon and 3TC in a trial. That trial is now in progress, but has no results to date.
The next drug likely to be approved in the US for HBV is adefovir. It is a nuceotide analogue similar to tenofovir which just arrived on pharmacy shelves in early November for the treatment of HIV. Adefovir was studied in HIV patients and had little activity and quite a bit of kidney toxicity at 120 mg and 60 mg per day. The HBV dose is fortunately only 10 mg and so far has demonstrated very little toxicity and a great deal of efficacy. Long-term data were presented up to 136 weeks for adefovir, which showed a seroconversion rate of 21% and only 3/39 patients discontinued drug for toxicity. Also encouraging was the loss of e Ag in 39% and the HBV DNA < 400 copies of 61% at week 48 and 70% at week 100 demonstrating a 3.75 log drop in HBV DNA. One of the biggest advantages of adefovir was that over 2 years no resistance developed! There were some mutations found in the HBV genome, but they did not confer resistance to adefovir. That is very promising and encouraging. HIV HBV infection is becoming a bigger problem each year because after 4 years of 3TC treatment over 90% of HIV HBV infected patients demonstrate 3TC resistant HBV. An abstract from Paris clearly showed in 35 HIV HBV co-infected patients with 3TC resistant HBV that adefovir reduced HBV DNA by 4.74 logs. This was accompanied by 3/33 patients seroconverting from e Ag to e Ab. This demonstrates the efficacy of adefovir in 3TC resistant virus even in HIV patients. There was no change in HIV RNA or CD4 count in these patients. Combinations of adefovir and 3TC were studied for drug-drug interactions and there appear to be none, paving the way for a combination adefovir 3TC trial, which is ongoing now. There is every reason to believe that this drug will be licensed in the US by this time next year for the treatment of hepatitis B and 3TC resistant hepatitis B
Next in the arena is FTC, a close cousin of 3TC. There was originally no real reason to suspect that this would be any better than 3TC. However in a large multiple dose trial presented here the highest dose 200 mg resulted in 61% of patients with <4700 copies of HBV DNA, but even more impressive was the e Ag loss of 50% and the eAb seroconversion rate of 23%. Only 2 patients developed the classic 550 and 526 mutations, which are the same as the 3TC resistant ones. There were no serious side effects noted in this trial. From the same company, Triangle, another drug clevudine or L-FMAU was studied first in an animal toxicology study and shown to be safe in animals. Then it was studied in a 28 day trial in man . The results were somewhat surprisingly good. All three doses showed as much as a 3 log drop in HBV DNA in the 28 days, but what was surprising was that HBV DNA stayed down by as much as 2 logs even 5 months after stopping clevudine!. The highest dose resulted in some ALT elevations, but that just may mean that it is working well. The obvious next step is to combine these two agents and the results of that trial will be really interesting.
editorial notes: Entecavir is a new hepatitis B drug. A study was presented on entecavir vs 3TC resistance-
New Hepatitis B Drugs at AASLD (LDT, adefovir, entecavir)
http://www.natap.org/2001/aasld2/day13.htm
One study of entecavir in transplant patients clearly showed activity of about a 1.5 log drop in HBV DNA in heavily pre treated patients suggesting that entecavir may indeed be active in 3TC resistant patients.
LDT is another nucleoside made by Novirio which has good activity against HBV and HIV and the phase I dose escalation results were presented here which showed linear pharmacokinetics, a good thing to have. A large combination trial with 3TC is due to get started in the US any day now and it should be exciting. The trial design is very intriguing and adventurous and should look immediately for synergies between the two drugs.
D4C is the Achillion addition to the hepatitis B nucleoside pool. A phase I trial in healthy volunteers was presented which revealed good absorption and good half-life. In vitro this drug shows activity against both wild type and 3TC resistant hepatitis B. This is also a promising new agent for which trials are presently underway.
There is much progress in the world of hepatitis B now and much of it is proceeding in the direction of combination therapy based on the building blocks of 3 TC and perhaps pegylated interferon. Nucleoside only combinations, of course have fewer side effects and appear to be the wave of the future.
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