Vanquishing the Virus
Karen Lindsay finds new ways to treat people infected by hepatitis C with the ultimate goal of eradicating it.
When it comes to hepatitis, one of nature's quietest killers, Karen Lindsay, M.D., refuses to be silenced. In fact, she is downright deafening in her assault on the most chronic and devastating form of this mute microbe-hepatitis C. "I want to eradicate hepatitis C infection in as many patients as possible," the director of USC's Hepatitis Research Center proclaims loudly. "It can be done."
Some might say that predicting victory over the most common chronic bloodborne infection in the United States is unrealistic, even cocky. After all, 4 million Americans are thought to be infected with the virus, which can remain undetected for decades at a time. When it does make itself known, it is often in the form of cirrhosis-chronic inflammation of the liver-or primary liver cancer. Each year, some 12,000 hepatitis C patients will succumb to this virus' particular form of devastation.
Still, those who would doubt Karen Lindsay's proclamation obviously do not know Lindsay. They do not know that she has spent the last two decades tirelessly pursuing that precise goal-and scoring triumph after triumph. They do not know the role she has played in developing the first-and for a long time, the only-drug able to stop the hepatitis C virus in its tracks. They do not realize that she has also been a key investigator in the development and testing of ever-better, ever-safer treatments. And they do not know the hepatitis virus the way she does. Indeed, few do.
Lindsay has been hitting hepatitis hard for nearly 20 years-pretty much from the day she graduated medical school. "I came to USC in 1975 to do my internship and residency in medicine," she recalls. By the time she had completed her term as senior resident in internal medicine, she had developed an abiding interest in viral illnesses in general, and had met two of USC's pre-eminent hepatologists, Telfer Reynolds, M.D., and Alan Redeker, M.D. In 1979, she joined their research team to do a two-year fellowship in viral hepatitis. "And I've been working on the problem ever since," she says.
She has, of course, done more than just work on the problem-she has gone a long way towards solving it. In 1982, while at the University of California, Los Angeles-where Lindsay spent nine years-she and colleagues designed and conducted what she calls "the first big trial treating hepatitis B with alpha interferon." The overwhelmingly positive results of that trial led to the drug's approval by the U.S. Food and Drug Administration (FDA) for the treatment of chronic hepatitis B.
Three years later, after hearing results from a pilot study at the National Institutes of Health where patients with chronic hepatitis, then called "non A, non B," were treated with alpha interferon, she and her colleagues convinced the drug company Schering Plough to fund a larger study to see if these patients might benefit from interferon treatment. By the time the virus had been fully sequenced and analyzed-and named hepatitis C-the study was complete, and 93 percent of the non A, non B patients were shown to be positive for hepatitis C. On the basis of that study, says Lindsay, the FDA approved alpha interferon for the treatment of hepatitis C.
That was just the beginning: Over the years, Lindsay says, she has participated in the testing of every drug that has come through the FDA for viral hepatitis. And since 1992, when she returned to USC as an associate professor of clinical medicine, she has done so from the Keck School of Medicine.
The most recent-and perhaps the most promising-of these new drugs to pass through the USC Hepatitis Center are the pegylated interferons.
Standard alpha interferon, notes Lindsay, may pack a powerful punch, but it is not the perfect drug for hepatitis. For one thing, it has some nasty side effects-from flu-like symptoms to depression. According to the Centers for Disease Control and Prevention, up to 40 percent of patients taking standard interferon need to have their dosages dropped in order to cope with the side effects; 15 percent must discontinue it altogether.
In addition, standard interferon needs to be injected by the patient three to seven times a week-not a particularly friendly mode of delivery. Both of these limit the drug's usefulness to some degree, notes Lindsay: "If we could give it more often, it would be more effective."
Now, in a way, that is exactly what can happen. Pharmaceutical science has developed methods to attach molecules to already-developed pharmaceutical agents-molecules that help those agents to linger longer in the human body. In the case of alpha interferon, polyethylene glycol is attached, producing pegylated interferon, or peginterferon.
"Adding polyethylene glycol to alpha interferon reduces renal excretion of alpha interferon," says Lindsay, "which leads to higher levels of the drug in the blood for longer periods of time. It's more effective that way, and the side effects are lessened as well. And best of all, patients like it better, because they only have to inject it once a week versus three times a week or even daily."
Lindsay was the lead investigator of a recent multi-center, international study of peginterferon, in which 1,200 patients were given either peginterferon or alpha interferon, with no other antiviral treatment. (Standard treatment today calls for alpha interferon paired with an antiviral drug called ribavirin.) Lindsay is still analyzing the data from the trial, but initial results have indicated that twice as many of the patients taking peginterferon were found to completely clear the virus, compared to patients taking alpha interferon. "When combined with ribavirin, peginterferon should raise the sustained virologic response rate even higher," notes Lindsay. "I expect this combination therapy to become the optimal treatment for hepatitis C in the near future."
That would not only mean fewer hepatitis patients but also a reduction in the demand for liver transplants (hepatitis C's destruction of that organ is the top reason such transplants are done in this country) and in the number of liver cancer cases (both hepatitis B and C are top causes of liver cancer). That is one of the reasons Lindsay is so excited about getting these treatments to work for as many people as possible-the potential benefit, after all, is so immense.
"With antiviral therapy for herpes, HIV, etc., you don't eradicate the virus; you suppress it," she explains. "With hepatitis C we can eradicate it-and by that I mean we can't find it for years after treatment is completed, during which time the liver heals and liver scar tissue goes away." And once the infection is no longer detectable, the likelihood that it will kick-start a cancerous cascade is drastically reduced.
There is another important effect as well-the patients really start to feel better. "The majority of individuals with hepatitis C infection are infected for years to decades with no obvious clinical evidence of the infection," says Lindsay. "They compensate for the disease for all the years they have it, without even knowing it. When you get rid of the virus, they begin to feel better, and realize for the first time that they had felt poorly during the period of chronic infection."
But interferon-pegylated or not-does not work for everyone. Throughout all the trials that have been conducted, there have always been a varying percentage of patients whose hepatitis C infection simply does not respond to the drug's biological barrage. And yet, ever since physicians began using interferon on hepatitis C, they have noticed a curious phenomenon: The non-responders-those patients in which the drug reduces the virus level only a little or not at all-often seem to improve in other ways. For one thing, biopsies taken of their livers while on the drug often show a lessening of inflammation and, in some, a reduction in scar tissue. And their risk of developing cancer diminishes.
"And so," says Lindsay, "we've developed a hypothesis that if you treat someone with interferon over the long term, even if they don't respond, they may see benefits in reduction of cancer, liver disease, inflammation and scar tissue formation." And that, she says, is something worth looking into.
The National Institute of Diabetes and Digestive and Kidney Diseases obviously agrees. In May of 1999, they launched a study called the HALT-C (the Hepatitis C Anti-viral Long-term Treatment Against Cirrhosis) trial-and the Keck School of Medicine was chosen as one of 10 clinical centers. Between 1,100 and 1,300 of these so-called "non-responders"-who will already have been unsuccessfully treated with alpha interferon-will be treated with peginterferon plus ribavirin for 24 weeks. If they do not have a virological response, they will be arbitrarily put into one of two groups: they will either be treated with peginterferon or given no treatment for another three-and-a-half years, during which time they will be carefully followed to monitor the course of their disease.
Lindsay notes that a number of ancillary studies have been planned around HALT-C, including several that were designed-at least in part-here at USC.
One such study will look at the neuropsychiatric effects not only of the disease, but also of its treatment. Indeed, interferon treatment has been associated with depression, irritability and difficulty concentrating-some patients have even developed a full-fledged psychosis while on the drug. "It's a fascinating but horrible phenomenon," notes Lindsay, "and this will be the first time we've really been able to examine these side effects closely."
Lindsay is excited by the chance to find new ways to delve deeper into this disease's mysteries. But she never takes her eye off the ultimate prize: vanquishing the hepatitis C virus, whatever it takes.
"Five years ago, if you told hepatologists you could eradicate hepatitis C, or markedly reduce liver scar tissue by treating the virus, they would have laughed at you," notes Lindsay. "But the truth is, you can. And by doing so, you can completely prevent the liver failure, transplantation and even death that used to be a given with this disease."
In other words, you can silence the silent killer. Or, at least, Karen Lindsay-dedicated to the cause and unwilling to back down from its challenge-believes you can. And that's something to shout about.
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