First Specific Drugs Raise Hopes for Hepatitis C

[Finally, it looks like an alternative to Interferon is coming. I took it back in 2003 and it worked without severe side effects. Others I know had hellacious experiences. YMMV]

Science 8 April 2011:
Vol. 332 no. 6026 pp. 159-160
DOI: 10.1126/science.332.6026.159
NEWS & ANALYSIS

INFECTIOUS DISEASES
First Specific Drugs Raise Hopes for Hepatitis C

Martin Enserink

BERLIN—A virus that chronically infects 170 million people around the world is about to meet some new and formidable foes. Regulatory agencies in both the United States and Europe are soon expected to green-light the first two antiviral drugs specifically developed to treat chronic hepatitis C, a treacherous infection that can cause cirrhosis of the liver and liver cancer, often decades after infection occurs.

The drugs, both of which target a viral enzyme called the NS3-4A protease, promise to rid 70% to 80% of patients of their infection—a significant step up from the current, nonspecific therapy, which cures barely half of those treated. And they are just the first to emerge from a pipeline bursting with other candidates, which has galvanized the field and made hepatitis C the most prominent topic at the International Liver Congress held here last week. “This is a disease we should be able to lick,” says Charles Rice of the Center for the Study of Hepatitis C at Rockefeller University in New York City.

Yet Rice and others caution that there is a lot of work ahead and that the two new protease inhibitors have significant problems—including side effects, high costs of perhaps as much as $20,000 per patient, and resistance in the ever-changing hepatitis C virus (HCV). Their introduction later this year could create “a hangover after the party,” noted Heiner Wedemeyer, secretary general of the European Association for the Study of the Liver in Geneva, Switzerland.

Many drug companies have entered the hepatitis C field because of the large number of infected people. But they have to hurry. Most patients were infected through blood transfusions before the virus was discovered in 1989. Since then, screening has made transmission through donated blood rare, and although other modes of transmission exist—such as needle sharing by injecting drug users and some sexual practices—infection rates in Western countries have dropped sharply. As more patients are treated or die, the market in rich countries will start shriveling. “The companies are all racing against each other, and against time,” says Kenny Simmen, the vice president for virology research at Janssen, the Belgian company that has developed one of the new protease inhibitors, telaprevir, together with Vertex in Cambridge, Massachusetts. (The other one is Merck's boceprevir.)

The current standard therapy is a combination of pegylated interferon α, a compound that has a wide range of virus-fighting effects on the immune system, and ribavirin, an antiviral that does little against HCV by itself but boosts interferon α's effects. That combination can cause flulike symptoms and depression and needs to be taken for at least 24 and often 48 weeks; yet it completely eliminates the virus in just 40% to 50% of patients.

In phase III studies that added the new protease inhibitors to the standard mix, the cure rate shot up to 70% to 80%, even for genotype 1, the most difficult-to-treat type of HCV and the most common in the United States, Europe, and Japan. But the new drugs also add their share of side effects: Telaprevir can cause anal itching and rash, and boceprevir can cause a bad taste in the mouth; both cause anemia.

Indeed, the current strategy is so “scary” that doctors may have trouble persuading some patients who have tried it in vain to give it another try with a protease inhibitor added in, Rice says. Other questions remain as well. Hepatologists would like to see much more data on safety and efficacy in patients who are already suffering from cirrhosis, for instance.

The ultimate goal for the field is to ditch ribavirin and interferon α through a combination of two, three, or four HCV-specific antiviral drugs, says Johan Neyts of the Rega Institute for Medical Research in Leuven, Belgium. A triple or quadruple whammy might prevent the emergence of resistance seen in patients treated with one or two specific antivirals, he says.

Plenty of antiviral candidates are in phase II and III trials, aimed at a variety of targets. More protease inhibitors are coming, but so are drugs targeting other viral proteins, such as an enzyme called polymerase. Promising preliminary results from a combination of two polymerase inhibitors, both produced by a company called Pharmasset, made its stock price soar in early March.

Other companies are targeting human proteins, such as Cyclophilin A, which is essential in HCV's replication; promising phase II results presented here showed that one of these drugs, Novartis's alisporivir, is much harder for the virus to elude than most other candidates. Eventually, a series of clinical trials will likely establish one or more combinations with a high cure rate, a short duration, and few side effects, says Neyts—but it may take the best part of the decade.

Meanwhile, the advent of better treatments has helped propel hepatitis C onto countries' political agendas and triggered a push for awareness. Even in Western countries, many infected people—about a third in the United States—don't know their status. “There is no other disease in which the gap between the scale of the problem and the level of awareness is so wide,” says Charles Gore, president of the World Hepatitis Alliance, a patient group. Many countries plan to expand screening among risk groups and encourage patients to get treatment; the U.S. Health and Human Services Department, for instance, will unveil a new action plan next month.

The challenges are greatest in the developing world, where most patients reside. In Egypt, more than 10% of the population is infected with hepatitis C, the result of 1970s and '80s treatment campaigns against schistosomiasis, a parasitic disease, in which needles were often reused. Transmission through unsafe medical practices continues even today, says Arnaud Fontanet, an epidemiologist at the Pasteur Institute.

The astronomical price of treatment is a huge obstacle. In Egypt, negotiations have brought the price of interferon α and ribavirin down by about 90%, to some $3000 per patient, but that is still far too high, Fontanet says. The new wave of drugs will make treatment more expensive. China, which has 40 million patients—more than any other country—and a burgeoning biotech and pharmaceutical industry, might be better off developing its own cheap antiviral drugs, says Ralf Altmeyer, director of the Pasteur Institute in Shanghai.

Yet, “we have more immediate issues than price,” says Steven Wiersma, who has set up a new unit for viral hepatitis at the World Health Organization in Geneva. The first order of business, he says, is to raise the profile of the disease, gather data on prevalence, and halt transmission. “We don't have basic awareness of what the disease is among the governments and the health professionals.… We're several steps away from even discussing prices.”