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What's New in Hepatitis B Treatment

(updated, November 2006)

Christine M. Kukka
HBV Project Manager;

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There are two types of drugs available to treat a chronic hepatitis B virus (HBV) infection:

• Interferons boost the immune system so it will aggressively wage war against the HBV infection.

• Antivirals or nucleoside analogues are designed to deliberately interfere with HBV's DNA so it can't reproduce itself.

These two treatments are usually used one at a time, but some doctors are experimenting to see if using them in combination to first knock down the amount of virus, and then boost the immune system to vanquish the remaining HBV, could be successful.

The U.S. Food and Drug Administration (FDA) has approved two types of interferon for hepatitis B treatment. The interferon available to adults and children is called conventional or interferon alpha-2b. Pegylated interferon, approved only for adults to date, is the newest interferon approved for hepatitis B. Fourantivirals - lamivudine (brand name Epivir-HBV), adefovir (Hepsera), entecavir (Baraclude), and telbivudine (Tyzeka), have been approved for hepatitis B in adults. Only lamivudine has been approved for treatment of children.

New hepatitis B drugs under development aim to improve on the antiviral and "immune boosting" qualities of these drugs. Because the current arsenal of drugs have had such limited success, the goals of treatment have been remarkably unambitious. Instead of aiming for a total cure, signaled by the immune system's production of surface antibodies, current treatment goals are simply to:

• Lower the volume of viruses (viral load), which is measured by HBV DNA in the bloodstream.

• Stop liver damage and achieve normal alanine aminotransferase or ALT levels. ALT is released by liver cells when they die, and above normal levels indicate liver damage.

• Spur the immune system to create the antibody to the hepatitis B "e" antigen (HBeAg). When HBeAg is present, it usually signals a high viral load and high risk of liver damage.

Doctors generally do not treat patients unless there is liver damage, including ALT levels that are more than twice normal, a liver biopsy that indicates inflammation and scarring, and a high viral load.

Interferons
Doctors usually prescribe interferon when ALT levels are elevated. Elevated ALTs indicate the immune system has noticed the infection and is attacking and killing the infected liver cells. To prescribe interferon when ALT levels are not elevated is tantamount to giving bullets to an army that is not at war. Conventional and pegylated interferon, administered by injection, works best when ALT is elevated and viral load is low - when the army is on the attack and there are few viruses to vanquish. Pegylated interferon, which is a time-release interferon requiring only one injection per week, is much more effective at spurring the immune system to target HBV than conventional interferon.

Pegylated interferon (Pegasys) has also shown promise in people who experience liver damage and high viral load even when they do not test positive for the “e” (HBeAg) antigen. This is called HBeAg-negative hepatitis B. About 43 percent of people with HBeAg-negative hepatitis B experienced lowered viral load with pegylated interferon and about 59 percent achieved normal ALT levels.

Also, pegylated interferon can be effective when both HBV DNA and ALT levels are elevated.

Antivirals
The four FDA-approved antiviral medications available to HBV-infected patients are lamivudine, approved for adults in 1998 and for children in 2000, adefovir, approved for adults in 2002, and currently in clinical trials for children, entecavir approved for adults in 2005, and telbivudine, approved for adults in October 2006. Antivirals are valuable because they can lower the rate of HBV replicating in the liver. Generally, when viral load drops, liver damage declines because there are fewer viruses invading liver cells and ALT levels also normalize.

Lamivudine (brand name Epivir-HBV): Administered as a daily pill or oral solution, lamivudine generally produces normal ALT levels and undetectable HBV DNA in about 65 percent of adults who take it.

While lamivudine is safe and rarely causes side effects, it is not a permanent or complete cure. It keeps the virus in check for only as long as it is taken. When treatment stops, HBV DNA and ALT levels usually rebound.

Lamivudine has one serious drawback. Some hepatitis B viruses develop resistance to lamivudine's antiviral punch. Over time, the non-resistant viruses decline, but the lamivudine-resistant HBV rebound until viral load and ALT levels start to climb once again. After four years of lamivudine treatment, more than 60 percent of patients develop lamivudine-resistant HBV.

Adefovir (brand name Hepsera): Adefovir appears to have all of lamivudine's antiviral clout, but none of its viral resistance. Today, doctors frequently switch patients who have developed viral resistance to lamivudine to adefovir.

Adefovir also appears effective against hepatitis B viruses that are able to replicate without secreting HBeAg. The immune system has a hard time identifying and zeroing in on this type of hepatitis B virus. When an HBV infection exists and lab tests can't find the "e" antigen, despite high viral loads and elevated ALT, it is called HBeAG-negative hepatitis.

If a patient is to be treated for the first time, which antiviral is best? To date, no medical organization has endorsed one antiviral over the other. It is important to discuss all the pros and cons of each antiviral with a doctor.

Entecavir (brand name Baraclude): is a potent inhibitor of HBV replication. In lab tests, this antiviral has shown the ability to reduce viral CCC DNA levels, which are believed to promote development of liver cancer. In studies that compared entecavir with lamivudine, entecavir was more effective in reducing HBV DNA levels, even when ALT levels were only slightly elevated. Early studies also suggest that entecavir-treated patients had a longer, sustained response to the drug, even after treatment ended, including those with HBeAg-negative hepatitis B. There have been a couple reports of viral resistance to entecavir developing, but nearly all occurred in patients who had already developed lamivudine-resistant viruses.

Telbivudine (brand name Tyzeka)stops HBV replication and normalizes ALT levels better than lamivudine and adefovir. Several trials compared the lamivudine and telbivudine and, after one year, telbivudine-treated patients had healthier ALT levels and lower viral load than those treated with lamivudine. One year-long study that compared telbivudine to adefovir in 135 patients with HBeAg-positive hepatitis B and elevated ALT found it produced more significant declines in HBV DNA than adefovir.

Telbivudine, to date, appears to cause no adverse side effects and there have been no reports of viral resistance to this drug.

New Antivirals:
There are several experimental antiviral medications that are currently in Phase III clinical trials.

Emtricitabine (FTC, Emtriva), already approved by FDA for treatment of HIV, has been found to be effective in lowering HBV DNA. Gilead Sciences reported treatment with emtricitabine reduced liver fibrosis in 62 percent of patients who received the drug, compared to 25 percent of patients who received placebo, and substantially lowered HBV DNA in 56 percent. However, researchers have found some instances of viral resistance to emtricitabine.

Clevudine (L-FMAU) has demonstrated potent antiviral activity and the ability to produce a sustained response, even months after treatment ended. In one study, 71 percent of patients who took clevudine maintained normal ALT levels six months after treatment ended, which is longer than with other antivirals. Clevudine, produced by Gilead, appeared to be well tolerated, and no HBV have developed resistance to clevudine to date.

Combination Treatment
Following the successes posted by doctors who use two or more drug combinations or "cocktails" to treat HIV and hepatitis C, many expect future HBV treatment will utilize a combination or sequential dosing of antivirals and interferons. However, to date they have not identified what drugs, and what treatment sequence, will be most effective in treating hepatitis B. Clinical trials are continuing to develop a successful combination treatment to stop liver damage from hepatitis B.

For more information about HBV Drugs please visit:

Hepatitis B Foundation Drug Watch at: www.hepb.org/02-0098.hepb

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