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A New Day

Date: October 1, 2013

The new therapies are arriving at a crucial time, says Mark Sulkowski. “We’re just now getting into the peak of the impact of hepatitis C in the United States.”
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The new therapies are arriving at a crucial time, says Mark Sulkowski. “We’re just now getting into the peak of the impact of hepatitis C in the United States.”

One day in late 1995, David Frick began to suffer severe abdominal pain. A few months earlier, he had completed a PhD in biology at Johns Hopkins, and now he was doing a postdoctoral research fellowship on the Homewood campus, studying bacterial enzymes. When the pain hit, his first assumption was that it was appendicitis. He’d go under the knife, be away from his lab bench for a week or so, and then life would return to normal.

Or so he thought. A few days later, the diagnosis arrived: Frick had hepatitis C. He had probably acquired the virus from a contaminated blood product shortly after he was born, when he received transfusions to treat a rare disorder. After 20-odd years of silent destruction, the virus had caused extensive cirrhosis in his liver. He would need a transplant.

Two years later in Boston, where he was doing a postdoc at Harvard, Frick’s liver went into severe failure, and he received his transplant. It was a grueling experience, with long weeks in a hospital bed. “But the transplant year wasn’t the worst year of my life,” Frick says today. “The worst year of my life was the following year, when I went through the treatment for hepatitis C.”

After his transplant Frick needed to try to eradicate the virus from his body, so that hepatitis C wouldn’t ruin his second liver. That meant taking what was, in the late 1990s, the cutting-edge therapy for hepatitis C: 48 weeks of injections with interferon-alfa, a synthetic version of one of the body’s common antiviral proteins. Interferon-alfa carries brutal side effects: fevers, sweats, chills, depression, fatigue. “It felt like I had the flu for nearly an entire year,” Frick says. “I’m glad I did it—I’ve been perfectly fine ever since. But that was very, very tough.”

Frick, who now studies the hepatitis C virus (HCV) at the University of Wisconsin-Milwaukee, vowed to devote the rest of his career to hepatitis C until a more effective and tolerable cure was discovered. That moment appears finally to have arrived—thanks in part to decades of effort by Johns Hopkins researchers.

In the last three years, several new classes of drugs have emerged that directly target enzymes specific to the hepatitis C virus. As early as December 2013, the FDA might approve the first-ever interferon-free therapy for certain hepatitis C patients. Within a few years, says Mark Sulkowski, medical director of the Viral Hepatitis Clinic at Johns Hopkins, the standard treatment for hepatitis C might be just 12 weeks long—or even eight—and involve no interferon. Even better, the new medications appear to be effective for almost everyone, whereas roughly 50 percent of patients have failed to respond to interferon-alfa.

“These have truly been breakthroughs,” says Sulkowski. “The treatment stands to become dramatically simpler, more effective, and easier to tolerate.” Sulkowski has waited a long time to see these victories. For nearly two decades, he has directed clinical trials of hepatitis C medications at Hopkins. While most of those drugs have been brewed in pharmaceutical companies’ private labs, Hopkins researchers have played a central role in testing their safety and efficacy, especially among vulnerable populations such as people co-infected with HIV and HCV.

The new therapies are arriving at a crucial moment, Sulkowski adds. “We’re just now getting into the peak of the impact of hepatitis C in the United States,” he says. Millions of baby boomers are believed to have been exposed to the virus via intravenous drug use, tattooing, and contaminated blood transfusions between 1965 and 1990. (Blood products have been screened for the virus since 1992, so transfusion is no longer a danger.)  Because it takes decades for the virus to do its silent damage to the liver, the national rates of cirrhosis and liver cancer have only recently begun to spike upward. Each year since 2007, hepatitis C has been estimated to kill more Americans than HIV; liver cancer is one of the few types of cancer with a rising mortality rate.

“People say, [the virus] has a very slow progression rate,” Sulkowski says. “And that’s true. It takes decades to progress. But the peak infections in the U.S. occurred 30 or 40 years ago. So, now we’ve reached the time when many people are progressing. This is a major issue right now.”

When david frick received his blood transfusions as an infant in the late 1960s, hepatitis C was an unknown concept. The year 1974 saw the first scientific publication about transfusion-related liver infections that were not caused by the familiar hepatitis A or hepatitis B viruses. But it took another decade and a half until the viral pathogen behind what was then known as “non-A-non-B hepatitis” was finally found. In April 1989, a pair of papers in Science announced the discovery and basic structure of the hepatitis C virus.

A year later, a young physician named David L. Thomas began a fellowship in infectious diseases at Johns Hopkins. Early in his fellowship, he was asked to lead a journal club discussion of the 1989 Science papers. He has been hooked on hepatitis C ever since. “It was a cutting-edge topic,” says Thomas, who is now director of the Division of Infectious Diseases at Hopkins. “But it wasn’t immediately clear what a significant public health challenge hepatitis C would turn out to be.”

Thomas, perhaps more than any other single scientist, helped alert the world to the severity of the hepatitis C problem. “We knew that it was a transfusion issue,” he says. “So it was natural to ask whether the virus could also be transmitted through other blood vectors.”

Sadly, the answer turned out to be yes. Throughout the 1990s, Thomas worked with Hopkins colleagues at the schools of Medicine and Public Health to document the alarmingly high rates of hepatitis C infection among IV drug users in Baltimore and other sites around the world. The team also studied sexual transmission (which turned out not to be a major vector), transmission during childbirth, and needle stick injuries among Johns Hopkins Hospital employees.

Those early needle stick studies became a vital source of information about the virus’s life cycle: Because Thomas and his colleagues knew almost the exact time of transmission, they could draw blood samples from the employees daily to learn how the virus evaded the human immune system during the acute phase of infection.

The studies also allowed Hopkins researchers to examine the mechanisms that allow a lucky minority of people—roughly 20 to 30 percent—to clear the virus from their systems without developing chronic infections. That line of research, which was led by Chloe Thio, an associate professor of medicine, and Priya Duggal, a geneticist at the Bloomberg School of Public Health, has helped lay the groundwork for potential vaccines.

 After several years of study, a basic epidemiological portrait emerged. After exposure to the virus, between 70 and 80 percent of patients develop chronic infections. (More than 150 million people internationally, including 3.2 million in the United States, are now estimated to have chronic hepatitis C.) Of those chronic infections, between 15 and 30 percent will eventually cause liver cirrhosis, though that process can take as long as 30 years. And among hepatitis C patients who progress to cirrhosis, between 1 and 3 percent each year will develop liver cancer.

“The most alarming thing is that roughly half of the people with chronic hepatitis C in the United States have not been diagnosed,” says Scott Holmberg, chief of the epidemiology and surveillance branch of the viral hepatitis center at the Centers for Disease Control, which recently recommended that all Americans born between 1945 and 1965 be screened for the virus. “And among those who have been diagnosed, only a relatively small proportion have been treated, in part because the treatments have been so difficult to take.”

That will soon change. While his Hopkins colleagues have analyzed the virus and traced the vectors of public infection, Sulkowski has spent years leading clinical trials of potential new treatments. He has seen firsthand the side effects that made David Frick’s year of treatment so miserable. But in the last two years, Sulkowski’s team has led trials of drugs that appear to radically change the nature of treatment for hepatitis C.

“The cornerstone of hepatitis C treatment since the late 1990s has been interferon-alfa and ribavirin, a regimen that carries severe side effects,” Sulkowski says. “So what we have had, in effect, is a treatment that’s effective for many people, but toxic. And the special challenge is that hepatitis C is an asymptomatic disease, right up to the time your liver has already sustained severe damage.”

“It can be hard for people to wrap their heads around the idea that they have a potentially fatal illness,” Sulkowski continues. “They feel fine, and now you’re asking them to take medications that will make them feel sick for a year.”

In the last five years, however, several new drugs have emerged that promise radical improvements on the traditional regimen. In 2011, the FDA approved two medications—boceprevir and telaprevir—that target one of the virus’s protease enzymes, much as the cornerstone medications for HIV target that virus’s protease. Taken in combination with interferon and ribavirin, those medications have dramatically improved the proportion of patients who can completely clear the virus from their systems, from roughly 40 percent to roughly 75 percent, according to Sulkowski. But they have only added to the traditional therapy’s burden of side effects.

It is the next generation of medications that most excites Sulkowski, because they promise to do away entirely with interferon injections and ribavirin. These medications target the virus’s polymerase enzyme, which helps to assemble new strands of RNA when the virus replicates, as well as a viral protein known as NS5A. In recent clinical trials, a pair of these new agents—sofosbuvir, a polymerase inhibitor, and declatasvir, an NS5A inhibitor—have demonstrated the ability to clear the virus in almost 100 percent of patients, and they appear to be far better tolerated than the traditional therapies. Sofosbuvir was submitted to the FDA for approval this summer, with a decision expected in December.

“The flu-like symptoms of interferon are gone,” Sulkowski says. “The severe fatigue is gone. Anemia, which has been a consequence of the first protease inhibitors, is no longer a major issue. And the treatment duration has been reduced to, in some cases, 12 weeks, down from 24.”

Because the medications in the pipeline appear so promising, many physicians are urging their patients to defer treatment unless they already show signs of significant liver fibrosis. “I’m encouraging my patients to wait until the new medications come on line,” Thomas says.

“I wouldn’t take any of the old stuff,” says Lynda Dee, a Baltimore attorney who tested positive for hepatitis C several years ago. From firsthand observation of friends and acquaintances, she drew her own conclusion: “Interferon-alfa and ribavirin are a nightmare.” 

Since early tests showed that her liver had not been severely damaged, Dee decided to wait for better treatments to emerge. When she learned last year about the opportunity to participate in a clinical trial of the new antiviral drugs, she chose to sign on. “There’s always a lot of angst associated with something like that,” she says. “But it seems to have worked beautifully.”

Andrew Cameron, who directs the liver transplant program at Hopkins, also sees great promise in the new medications. Among hepatitis C patients whose livers have already deteriorated so badly that they require transplantation, the traditional therapies have usually done poorly, both before and after transplant, Cameron says. People with end-stage liver disease are especially intolerant of interferon’s side effects.

“If we can use easy-to-tolerate drugs to clear the virus or reduce the viral load before surgery, that will make a huge difference,” Cameron says. Among other things, it will broaden the range of livers available to hepatitis C patients. Traditionally, these patients have been restricted to livers from donors younger than 50 or 55, because (for reasons not well understood) the hepatitis C virus tends to roar back and quickly destroy livers from older donors. Since roughly half the transplant pool is from donors older than 55, this has been a major burden for hepatitis C patients. “We might soon be able to open up the entire range of donors to hepatitis C cases,” Cameron says. “That’s very, very exciting.”

Alongside their excitement, hepatitis researchers like Sulkowski also raise four notes of caution about the new wave of medications. One is that the drugs have not been thoroughly tested so far on some of the most medically vulnerable populations, including people who carry both HIV and HCV and those with advanced liver disease. (Clinical trials in that group are presently under way, and Sulkowski says that the early findings are promising.)

A second concern: It’s not known yet whether viral resistance will emerge as these drugs are used in real-world settings. “That’s a question that I don’t think we have much data for yet,” says Susanna Naggie, a Duke University scientist who earned her MD at Hopkins in 2002. “But the early signs are that it probably will matter. Some recent data suggested that of the people who have failed treatment on [the protease inhibitors approved in 2011], half of them have protease-related mutations in the virus.” The solution, Naggie says, will probably be to use combinations of drugs from different classes, as is done in HIV therapy.

Third, scientists hope that the apparent success of the new drugs will not slow down funding of vaccine development for hepatitis C. Andrea Cox, an associate professor at Hopkins, is currently conducting a clinical trial of a potential vaccine [see sidebar].

Finally, researchers foresee difficult conflicts ahead about how many people should be offered the new medications, which are expected to carry a price tag of tens of thousands of dollars, at least initially. Should the drugs be given to the millions of people who are HCV-positive, or only to those who have already suffered actual liver damage? Should some patients be asked to wait until the drugs get cheaper? “I don’t know of any precedent for this kind of thing in the history of medicine,” says Hopkins virologist Stuart Ray. “This won’t be an easy ethical decision.” Recall that only 15 to 30 percent of chronic hepatitis C infections are estimated to result in full-blown liver cirrhosis. If you’re an HCV-positive individual, you might understandably feel that it’s worth $70,000 to reduce that risk to zero. But will private insurance companies and Medicare agree?

Even with all of those cautions in mind, these scientists seem palpably joyous about the imminent transformation of hepatitis C therapy.  “It was completely unimaginable a decade ago, or even two years ago, that we would have these kinds of treatment advances,” Sulkowski says. “Soon we’ll be able to tell patients that they’ll only have to take one pill, once or twice a day, for 12 weeks.”