NEWS

Hepatitis C Vaccine Hampered by Viral Complexity, Many Technical Restraints

Judith Randal

Singly and together hepatitis B and C viruses are the leading cause of cirrhosis of the liver and hepatocellular carcinoma, the most common form of primary liver cancer by far. But while a vaccine against the widespread hepatitis B virus became available as early as 1982, one against hepatitis C — also bloodborne, equally commonplace, and frequently chronic — has proven far more elusive.

And the prospects for an HCV vaccine are not immediate. Despite being distantly related to the yellow fever virus for which there is a vaccine, says Robert Purcell, M.D., who heads viral hepatitis research at the National Institute of Allergy and Infectious Diseases, "it [HCV] shares with the Human Immunodeficiency Virus an extreme genetic heterogeneity, including hypervariable regions. Patients tend to harbor a mix of genomes and the mix typically varies from patient to patient and in the same patients over time."



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Dr. Robert Purcell

 
The long and short of it, according to Purcell, is that the propensity of this virus to mutate complicates the development of a vaccine. So, he said, does something else; that patients who clear the infection on their own — as about 15% do — can be reinfected if exposed to the virus again. While none of this, he believes, makes an HCV vaccine an impossibility, it may make one that confers durable protection difficult to achieve.

There are other obstacles both to vaccine development and to HCV research as a whole. Except for domestically-raised chimpanzees, which must be used sparingly because they are a threatened species and expensive, there is no animal model for this form of viral hepatitis. (Use of chimpanzees from the wild for biomedical research is forbidden.) Also, there is a dearth of suitable reagents for studying the virus, which although it has been cloned, cannot be grown in cell culture.

Scant Research

Such technical restraints have clearly put a damper on the study of HCV and the pace of research. Said the NIAID's Diana Berard, "HCV grant proposals have tended to fare poorly in the peer review process because they lack sufficient preliminary supportive data and the tools that would make it possible to get the data are largely missing."

On the other hand, to have heard Harold Margolis, M.D., of the Centers for Disease Control and Prevention, Atlanta, at a recent U.S. Public Health Service briefing on HCV, considerable progress in understanding HCV has been made in the last 20 years or so.



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Dr. Harold Margolis

 
It became apparent in the 1970s, Margolis recalled, that there must be an HCV because blood donors could be screened for A and B hepatitis viruses, but a lot of post-transfusion hepatitis was occurring anyway and 90% of it was clearly neither A nor B. In fact, the mystery "bug" was known as "non-A, non-B" hepatitis until 1988 when Michael Houghton, Ph.D., and his colleagues at the Chiron Corp. in Emeryville, Calif., successfully used molecular techniques to identify the virus, which had previously evaded detection because it is too small to be seen even with an electron microscope.

That discovery, Margolis and Jay Epstein, M.D., of the U.S. Food and Drug Administration told the briefing, has led to a succession of progressively more sensitive tests for the detection of antibodies to HCV in human blood. Together with the development of better confirmatory tests, these blood tests have dramatically improved the safety of the blood supply in those countries that use them. The risk of finding HCV per unit of transfused blood in the United States was once one in 200, said Epstein, but is now less than one in 100,000, resulting in about 200 new cases of HCV a year from blood and blood products.

There has also been incremental progress in treating chronic HCV infection, as was reported at the meeting by Jay Hoofnagle, M.D., of the National Institute of Diabetes and Digestive and Kidney Diseases. Alpha interferon, approved for the purpose in 1991, made it possible to eliminate the virus and reduce liver injury in 15% to 20% of those treated with it for a year. A combination regimen of interferon and ribavarin has since upped that response rate to as much as 40%.



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Dr. Jay Hoofnagle

 
That, of course, leaves ample room for improvement and there is movement in that direction. NIDDK, for example, has just awarded a 7-year multicenter contract which will bring researchers from nine institutions together first to decide (among other things) which new treatment strategies merit clinical trials and then — beginning in mid-2000 — to accrue the 600 to 800 patients needed to implement them.

Hoofnagle was careful to emphasize that the need is as much for therapies with fewer side-effects as for ones that are more effective for more patients. Current treatment, he said, induces malaise and extreme fatigue and some patients just are not up to the hair loss and sometimes profound depression that frequently result from these treatments.

What further worries him is the expense. The diagnostic workup is costly, at least $1,000 for the liver biopsy alone and the price of a course of treatment, already in the $11,000 to $12,000 range, will likely escalate.

"While it's not been possible to grow this virus in culture," he said, "its proteases — the enzymes that enable it to replicate and survive — have been isolated and well characterized. Very likely, new drugs that inhibit their activity will be coming along.

Treatment Barriers

"The trouble will be with access to treatment. It's largely limited to the well insured, even with current therapies. Still, we know that the prevalence of HCV is high in prisons and higher among African-Americans and in certain other groups, including present and former injection-drug and cocaine abusers, for example, than in the population at large. Yet, it is these very groups that are most likely not to have good insurance," Hoofnagle said.

As if all this wasn't sobering enough, NIAlD has reported that unless there are are better therapies, the number of deaths related to HCV — now about 8,000 to 10,000 a year in the United States and comparably low in most developed countries — can be expected to triple by 2015.

There is, in fact, already some evidence of where things could be heading. According to Hoofnagle, HCV is driving the rising incidence of primary liver cancer in the United States. Also, because of HCV, the demand for donor livers increasingly exceeds the supply. (Transplants do not cure HCV, as they readily become infected, too. They do, however, tend to slow the progress toward end-stage disease and so buy patients time.)

The irony here is that there has been a sharp fall in the number of new cases in many industrialized countries. In the United States, for instance, the number has dropped more than 80% since 1990. So why so much concern now?

One reason, obviously, is the lack of a vaccine, particularly because HCV is considerably more infectious than HIV. But the larger reason is the 85% chronicity of the infection whose symptoms are not ordinarily recognizable by either patients or physicians. In fact, HCV is typically silent clinically for at least 20 to 30 years.

Yet the virus can insidiously damage the liver. And the more of that injury there is, the greater the likelihood that significant cirrhosis will ensue, which, in turn, puts the patient at high risk of developing primary liver cancer, too.

Nor is that all. Because most people who contract HCV have no idea they are infected, they may, unknowingly, endanger themselves and others; themselves by failing to abstain from alcohol, and others by leaving personal items around, such as a razor, that might be tainted with traces of their blood.

With an estimated 4 million people in the United States and an estimated 170 million worldwide infected with HCV, many scientists view HCV as a viral time bomb. It is also a public health problem that almost surely will worsen before it gets better.



             
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