Edward Linsmier for The New York Times
Arthur Rubens, 63, of Naples, Fla., was cured of hepatitis C after taking part in a clinical trial for a new drug.
Published: November 4, 2013
Determined to get rid of the hepatitis C infection that was slowly destroying his liver, Arthur Rubens tried one experimental treatment after another. None worked, and most brought side effects, like fever, insomnia, depression, anemia and a rash that “felt like your skin was on fire.”
But this year, Dr. Rubens, a professor of management at Florida Gulf Coast University, entered a clinical trial testing a new pill against hepatitis C. Taking it was “a piece of cake.” And after three months of treatment, the virus was cleared from his body at last.
“I had a birthday in September,” Dr. Rubens, 63, said. “I told my wife I don’t want anything. It would take away from the magnitude of this gift.”
Medicine may be on the brink of an enormous public health achievement: turning the tide against hepatitis C, a silent plague that kills more Americans annually than AIDS and is the leading cause of liver transplants. If the effort succeeds, it will be an unusual conquest of a viral epidemic without using a vaccine.
“There is no doubt we are on the verge of wiping out hepatitis C,” said Dr. Mitchell L. Shiffman, the director of the Bon Secours Liver Institute of Virginia and a consultant to many drug companies.
Over the next three years, starting within the next few weeks, new drugs are expected to come to market that will cure most patients with the virus, in some cases with a once-a-day pill taken for as little as eight weeks, and with only minimal side effects.
That would be a vast improvement over current therapies, which cure about 70 percent of newly treated patients but require six to 12 months of injections that can bring horrible side effects.
The latest data on the experimental drugs is being presented at The Liver Meeting in Washington, which ends Tuesday.
But the new drugs are expected to cost from $60,000 to more than $100,000 for a course of treatment. Access could be a problem, particularly for the uninsured and in developing countries. Even if discounts or generic drugs are offered to poor countries, there are no international agencies or charities that buy hepatitis C medications, as there are for H.I.V. and malaria drugs.
And some critics worry that the bill will be run up when huge numbers of people who would have done fine without them turn to the drugs. That is because many people infected with hepatitis C never suffer serious liver problems.
“The vast majority of patients who are infected with this virus never have any trouble,” said Dr. Ronald Koretz, emeritus professor of clinical medicine at the University of California, Los Angeles.
It is impossible to tell in advance whether an infected individual will go on to suffer serious consequences. For patients who can afford them, the temptation to take the new drugs before trouble arises will be powerful.
A Heavy Toll
An estimated three to four million Americans are infected with hepatitis C, and about 150 million worldwide — three to five times the number who have H.I.V. Most people who are infected do not know it, because it can take decades for the virus to damage the liver sufficiently to cause symptoms.
In the United States, the number of new infections has fallen to about 17,000 a year, from more than 200,000 per year in the 1980s, according to the Centers for Disease Control and Prevention. There has been a recent rise in cases among young people who inject pain medicines or heroin.
About 16,600 Americans had hepatitis C listed as a cause of death on death certificates in 2010, though that might vastly understate the mortality linked to the disease, according to the C.D.C. Although there are fewer new infections, the number of deaths is expected to keep rising as the infections incurred years ago increasingly take their toll.
Hepatitis C is spread mainly by the sharing of needles, though it can also be acquired during sex. The virus was transmitted through blood transfusions before testing of donated blood began in 1992. Dr. Rubens, the recently cured patient, believes he was infected when he worked as a paramedic long ago.
The main treatment has been interferon alfa, given in weekly injections for 24 or 48 weeks, combined with daily tablets of ribavirin. Neither drug was developed specifically to treat hepatitis C. The combination cures about half the patients, but the side effects — flulike symptoms, anemia and depression — can be brutal.
The new drugs, by contrast, are specifically designed to inhibit the enzymes the hepatitis C virus uses to replicate, the same approach used to control H.I.V. As with H.I.V., two or more hepatitis C drugs will be used together to prevent the virus from developing resistance.
One big difference is that H.I.V. forms a latent reservoir in the body, so H.I.V. drugs must be taken for life to prevent the virus from springing back. Hepatitis C does not form such a reservoir, so it can be eliminated permanently.
If no virus is detectable in the blood 12 weeks after treatment ends — a measure known as a sustained virologic response — there is almost no chance the virus will come back and the patient is considered essentially cured. The damaged liver can then heal itself somewhat, doctors say.
The new drugs now moving to market can achieve sustained viral responses in 80 to 100 percent of patients with treatment durations of 12 to 24 weeks, possibly shorter.
For Tom Espinosa, a building inspector in Oakland, Calif., the new treatments cannot arrive fast enough. Mr. Espinosa, 59, has advanced cirrhosis and some spots on his liver that might be cancer. He is so fatigued that he spends all weekend in bed. He has tried all available treatments and nothing worked, making him envious of other patients who were cured.
“I became resentful for a little while, but I got over it,” he said. With time possibly running out, he plans to try the first new drug to hit the market.
To be sure, many of the new drug combinations have not been extensively tested yet. Side effects might still show up. And the drugs are not expected to work as well for patients with severe cirrhosis or those co-infected with H.I.V.
“I just don’t think we know the answer until we get more widespread clinical experience,” said Charles M. Rice, a hepatitis C expert at Rockefeller University. “We may be in for some surprises still.”
Researchers and patients have been disappointed before, when the first two direct-acting antiviral pills, telaprevir and boceprevir, reached the market in 2011. The drugs, which inhibited the virus’s protease enzyme, still required interferon and ribavirin, but they raised the cure rate to about 70 percent.
There was a huge rush to treatment. But doctors now say that side effects were worse than expected, in part because the sickest patients had been excluded from the clinical trials of the drugs.
“A lot of that didn’t come to light until after the drugs were approved,” said Dr. Brian R. Edlin, an associate professor of public health and medicine at Weill Cornell Medical College. “Then it turns out they were just horrible.”
Among the new drugs, the one garnering the most excitement is sofosbuvir, from Gilead Sciences, which is expected to be approved by the Food and Drug Administration by Dec. 8. It inhibits the virus’s polymerase enzyme, which builds new genomes out of RNA so the virus can replicate.
Sofosbuvir is an evil decoy of sorts. It looks like a building block of RNA. But once it is mistakenly incorporated into the RNA chain, the chain cannot grow and the virus cannot reproduce.
The effectiveness of the new drugs can vary depending on which strain of hepatitis C, known as genotypes, the patient has.
People infected with hepatitis C genotypes 2 and 3 — which account for 20 to 25 percent of cases in the United States — will take sofosbuvir with ribavirin but without interferon, making this the first all-oral treatment for hepatitis C. Treatment for genotype 2 will be 12 weeks, but for genotype 3 it will probably be 24 weeks.
Genotype 1, which accounts for more than 70 percent of patients in the United States, will still require interferon and ribavirin along with sofosbuvir, but only for 12 weeks. In a clinical trial, about 90 percent of previously untreated patients taking this combination achieved a sustained virologic response. The combination is expected to be somewhat less effective in those for whom previous treatments did not work.
Gilead hopes to have an all-oral treatment for genotype 1 approved by the end of 2014. It would be a once-a-day pill containing both sofosbuvir and another experimental Gilead drug, ledipasvir. This combination, used along with ribavirin, is what cured Dr. Rubens.
Other companies, including AbbVie, Merck and Bristol-Myers Squibb, are in a heated race to also bring all-oral combinations to market in the next two years or so.
Liver specialists will be able to put together an all-oral regimen for genotype 1 very soon, however, by prescribing both sofosbuvir and simeprevir, a Johnson & Johnson protease inhibitor that is expected to win approval soon. One study has shown this combination to be extremely effective, though insurers may balk at paying for two expensive drugs.
Awaiting Better Options
These new drugs are likely to alter the calculus about who gets treated and when.
Many doctors are now “warehousing” their hepatitis C patients — urging them to forgo treatment until the new drugs are approved.
“There’s no way I’m going to put them on an interferon regimen when we’re a year away from having interferon-free regimens,” said Dr. Scott Friedman, the chief of liver diseases at the Icahn School of Medicine at Mount Sinai. “It’s rare you have to pull the trigger and get them on treatment in that period of time.”
Gilead estimates that only 58,000 Americans with hepatitis C are now undergoing treatment, a small fraction even of those who know they are infected. Wanting to avoid interferon’s side effects, some patients without symptoms try to monitor their liver and start treatment only if it shows signs of deterioration.
But with the new more tolerable treatments, some experts say, it makes sense to treat early-stage disease to prevent cirrhosis and the accompanying risk of liver cancer.
And it is likely that more pre-symptomatic patients will be found through wider screening. Both the United States Preventive Services Task Force and the C.D.C. have recently begun to recommend that all baby boomers — people born from 1946 to 1964 — be tested for infection with hepatitis C, since they represent about three quarters of all cases.
“It will be test and treat,” said Dr. Eugene Schiff, the director of the liver diseases center at the University of Miami, who is a consultant to drug companies.
Pharmaceutical companies, of course, have a financial interest in seeing that more people get screened and treated, and they have been providing support for hepatitis C awareness campaigns and sponsoring studies on the benefits of screening and treatment.
The all-oral regimens also may make it more feasible to treat the people who are most likely to spread the virus — intravenous drug users, the homeless and prison inmates, many of whom also have mental health problems.
“I can’t treat an unstable patient safely with interferon,” said Dr. Diana Sylvestre, who runs a clinic in Oakland, Calif. that treats illicit drug users and former users. “But I can sure as hell give them a few pills.”