New drugs Against Hepatitis: for hepatitis B--FTC, DAPD, 3TC, combination therapy, adefovir; hepatitis C- alpha thymosin, pegylated interferon, VX-497

Last year the outlook for humanity's struggle with hepatitis seemed grim. In March, U.S. Surgeon General David Satcher went before Congress to warn that hepatitis C posed "a grave threat to our society." By summer, magazine covers and newspaper headlines were decrying the "silent killer" as an insidious epidemic. The one treatment approved in the U.S. for chronic hepatitis B and C--alpha-interferon--cost $700 a month, caused sometimes intolerable side effects and beat back the virus in only 30 to 40 percent of sufferers. Meanwhile researchers were quietly fretting about a new hepatitis virus, called G, which appeared to be nearly as widespread as its cousin C, coursing through the blood of some four million people in the U.S. alone.

But now there are good reasons to think that science is gaining the upper hand, that millions of those already chronically infected with a hepatitis virus will be able to avoid the typical course of the disease: decades of slow liver damage often culminating in organ failure or cancer. Last December the U.S. Food and Drug Administration cleared two new hepatitis drugs for market. Several other compounds are moving briskly through clinical trials. Childhood immunization is sweeping the feet out from unde hepatitis B. Biologists have mapped a key vulnerability in the C virus and have started making drugs to attack it. And closer observations of people carrying the G virus have shown that it seems to do little if any damage to its hosts.

In truth, much of the media frenzy that followed Satcher's call to arms last spring probably exaggerated, or at least misplaced, the severity of the problem. According to the Centers for Disease Control and Prevention, the incidence of acute hepatitis B has fallen about 70 percent in the U.S. since its peak in 1985. The C virus is now spreading at less than one fifth the rate of a decade ago. Although chronic hepatitis C carriers outnumber those with hepatitis B by at least three to one in America, the CDC estimates that B still imposes the greater economic cost. Globally, the B virus is by far the most common cause of liver disease, infecting about 350 million people and killing more than a million a year. Because it spreads readily via sexual contact, unlike the C virus, half the world's population faces better than a 60 percent chance of contracting hepatitis B at some point in their lives.

Those odds should improve now that more than 80 countries have begun inoculating children against the disease. Saudi Arabia's immunization program, for example, cut the hepatitis B infection rate among young children from 7 to 0.5 percent in just eight years. But the vaccine is still so expensive that adding it to the shots donated to poor countries would require doubling or tripling the vaccine budgets of donor organizations.

To the millions already infected, a vaccine is of no use. Fortunately, a handful of new medicines, though no cheaper than interferon, do promise to help some of those whom it fails The first to go on sale is lamivudine, a drug discovered by BioChem Pharma in Laval, Quebec, and also known as 3TC, which has been used for several years in higher doses to treat HIV infection.

In a recent experiment, 16 percent of the subjects who swallowed one tablet a day for a year knocked the hepatitis B in their blood down to undetectable levels. But in reducing one problem, lamivudine creates another: drug-resistant strains of the virus that flourish in up to a third of the patients within months. "I'm worried that doctors are going to start using lamivudine too freely, and then we're going to have a mess on our hands," says Jay Hoofnagle, head of digestive diseases and nutrition research at the National Institutes of Health. "I recommend it only to my patients who have severe hepatitis."

E. Jenny Heathcote, a professor of medicine at the University of Toronto, goes further. "I'm not convinced that any patient with viral hepatitis should be treated with a single agent," she says. "It's like many years ago when we were trying to treat HIV with just AZT. In retrospect we realized that we should have been using cocktails [of several agents], because the virus becomes resistant so quickly to just one drug."

It is hoped that adefovir for HBV will make it to the market within the next few years. And Gilead Sciences in Foster City, Calif., began enrolling 500 patients this past January for a pivotal trial of adefovir. In smaller tests completed in November, just 12 weeks on adefovir pills depleted levels of the B virus in two thirds of patients by 99.99 percent--"from several billion copies to just a few hundred," Heathcote reports.

Equally important, observes Alison Murray, Gilead's director of clinical research, is that adefovir is effective against the lamivudine-resistant virus strains. That is a pleasant surprise, because all three antivirals work in roughly the same way. "The drug molecules resemble building blocks of DNA and RNA, except that they are missing a crucial side chain," Murray explains. As the drug seeps into all the cells of the liver, viruses pick it up and try to use it to construct copies of themselves. Without the critical link, however, the virus cannot attach other blocks onto the drug, and the viral assembly line shuts down.

If adefovir passes its final tests, medicine may at last turn the tables on hepatitis B. But researchers entertain little hope of finding a final cure. "The hepatitis B virus, like HIV, is made of DNA, so it is very stable once it gets into cells," Hoofnagle says. "The only way to get it out is to kill the infected cells--which would mean killing the liver," Murray adds. "So the best we can hope for is to control the disease and help the immune system suppress the virus."

FTC is similar to 3TC. DAPD and FTC are NRTIs in early stages of development by Triangle Pharmaceuticals and appear to be promising for treating HBV.

A third experimental drug may be handy for that purpose. In recent tests in Asia, alpha-thymosin, made by SciClone Pharmaceuticals in San Mateo, Calif., appeared to give a general boost to T cells, immune fighters that attack infected liver cells. It was reported that six months of twice-weekly injections reduced the virus to undetectable levels in 40 percent of the Taiwanese subjects who received it, an effect that lasted at least 18 months. If large-scale trials in Asia go well this year, thymosin might provide an additional ingredient for a potent cocktail against hepatitis B. Alpha-thymosin is also being looked at for hepatitis C. But some researchers are skeptical about alpha-thymosin.

Because hepatitis C is based on RNA, which is unstable, it should in theory be easier to cure. Spurred by the public anxiety about the disease, "almost every pharmaceutical company on the planet is looking for a new treatment for hepatitis C," Murray says. But the search is hampered by the fact that the C virus refuses to thrive in lab animals and human cell cultures. There is simply no fast way to tell whether a potential drug will work safely.

As a result, most of the advances against hepatitis C have been incremental improvements on interferon. In December the FDA granted Schering Plough permission to give its drug ribavirin, along with interferon, to anyone with hepatitis C. The two together seem to clear the virus from about 40 percent of patients, versus the 20 to 30 percent helped by interferon alone.

Roche Pharmaceuticals is reportedly testing interferon doped with polyethylene glycol. "At a conference recently, they claimed this raised the response rate to more than 60 percent," Hoofnagle remarks. The additional ingredient also allows patients to reduce weekly injections from three to one, he says, which may ease the flulike side effects considerably. As well, Schering Plough is testing their own version of a pegylated interferon.

With little hope of a vaccine--because people do not produce lasting immunity to hepatitis C even if they fight off the initial infection--

Hoofnagle wagers that the best way forward will be drugs that attack the C virus more directly. Some, such as VX-497 from Vertex Pharmaceuticals in Cambridge, Mass., will try to deny the virus access to the human enzymes it needs to reproduce. Vertex began human tests on VX-497 last September and expects to have results in by summer.

--W. Wayt Gibbs in San Francisco