STATEMENT OF
LEONARD B. SEEFF, M.D.
SENIOR SCIENTIST FOR HEPATITIS C RESEARCH
NATIONAL INSTITUTES OF DIABETES, DIGESTIVE, AND KIDNEY DISEASES
NATIONAL INSTITUTES OF HEALTH
AND
FORMER CHIEF, GASTROENTEROLOGY & HEPATOLOGY
VETERANS AFFAIRS MEDICAL CENTER, WASHINGTON, D.C.
FOR HOUSE COMMITTEE ON VETERANS' AFFAIRS
SUBCOMMITTEE ON BENEFITS

July 16, 1998

Mr. Chairman and Members of the Subcommittee,

I am honored to be invited to appear before this committee to comment on the issue of hepatitis C as it affects veterans who are cared for in Veterans Affairs Medical Centers. I regret deeply that I was unable to appear in person, and I proffer my sincerest apologies. As you may be aware, the Centers for Disease Control and Prevention (CDC) is holding a meeting in Atlanta, Georgia on July 15-18,1988, to discuss the issue of hepatitis C virus infection. The aim of this meeting is to develop updated guidelines and recommendations for the identification, counseling, testing, and referral of persons at risk for hepatitis C virus infection. I have been asked to attend the meeting as one of the consultants and to address the issue for the panel of the natural history of the infection. I believe that the information that derives from the CDC meeting will have much relevance to the future deliberations of this Subcommittee.

The request to me from this Subcommittee, I believe, was to address the issue of hepatitis C in general terms and, in particular, to review the problem as it affects veterans attending VA facilities. Let me begin then with a very short and general overview of the topic.

As you are aware, hepatitis C virus infection has been recognized recently as a common and potentially serious medical problem that is responsible for a major proportion of liver disease-related morbidity and mortality in the United States. Although identified as early as 1974 as transfusion-associated non-A, non-B hepatitis, it was only after discovery of the actual hepatitis C virus in late 1989, permitting the development of specific diagnostic tests which reached a high level of sensitivity by 1992, that the true extent of the problem began to emerge. In fact, these tests were essential to the recognition of the true magnitude of the infection because the vast majority of acutely infected persons - as many as 85% to 90% - are unaware that they have been infected. Indeed, both acute and chronic hepatitis C are characterized by a paucity of symptoms and hence infected persons are most commonly identified for the first time only when they are tested at the time that they donate blood for transfusion purposes, when they undergo a routine physical examination for insurance or employment purposes, or when they are being evaluated for other medical conditions.

The major concern regarding hepatitis C, as you are aware, is that almost all persons who develop the infection remain infected (the current evidence is that chronic infection evolves in about 80-85% of those who develop acute hepatitis), that the infection persists for life in almost all such persons, and that the persisting virus infection sets the stage for progression to cirrhosis and, occasionally, to liver cancer. The currently held view is that cirrhosis will develop in about 20% of chronically-infected individuals, and liver cancer in about 1%. Since liver cancer related to hepatitis C virus infection almost never occurs in the absence of cirrhosis, outcomes have been examined specifically in persons who have compensated or stable hepatitis C-related cirrhosis. Such studies suggest that the risk of development of liver cancer in this subgroup is about 1-5% per year. If one now adds to these statistics the emerging evidence that hepatitis C virus infection appears to be a very common problem (4 million people in this country are believed to be infected), that many formerly undefinable causes for cirrhosis and liver cancer can now be attributed to hepatitis C virus infection, and that this infection is currently the most common basis for liver transplantation, it is easy to see why there is presently such great distress regarding this infection. Indeed, it is these issues that have been, and continue to be, blazoned in the popular press, not always appropriately, in my opinion, and that has helped to raise the level of anxiety about hepatitis C.

There is no question that chronic infection with the hepatitis C virus is a potentially serious, uncomfortable, and life-threatening problem. But the news about the disease is not necessarily all bad. One of the most difficult issues facing researchers is how to determine the frequency of progressive liver disease among those infected. This is not a simple task. The problems are that disease onset remains undefined in most instances because of lack of symptoms, that symptoms are generally absent also during most of the course of the chronic infection, and that serious end-stage liver disease, should it occur, usually emerges 20 to 30 years after the initial infection. Therefore, much of the information derives from studying persons with already clearly-established chronic liver disease, which tends to bias interpretation since infected persons without symptoms may not be identified and included in such analyses. Only through long-term studies that begin at the time of onset or early in the course of the infection is it possible to accurately determine the frequency and rate of progression to severe liver disease. I can state that in a couple of such studies that I have conducted together with a large number of colleagues, as well as in studies reported by others, it would appear that progressive disease is far from inevitable. Indeed, results of these studies indicate that close to 80% of persons initially infected have a relatively benign course, at least over a period of 25 years, with minimal liver disease-related morbidity and mortality. The remaining approximately 20%, predominantly those with clear-cut cirrhosis, do have a potentially serious medical problem. The total number who fall into this last category will depend, of course, on the total size of the infected population – the larger the number of infected persons, the larger the number of persons with serious liver-related illness. Based on the current CDC data that 4 million persons in this country are infected, one can anticipate that three-quarter to one million persons are at risk of developing serious chronic liver disease because of hepatitis C virus infection. More research is needed to confirm these data, to define why only a limited number of infected persons have progressive disease, and to establish means of accurately determining early in the course of the infection who is destined to develop serious disease. One item that is believed to play an important role in enhancing progressive liver disease is chronic alcoholism, but other factors that could have an additive or permissive effect also need to be sought.

Another positive note is the fact that treatment of the chronic infection which, until now, has been only modestly successful, at best, is beginning to show real improvement. Unfortunately, treatment outcomes are still far from ideal, and much more research in this area is needed and, indeed, is in progress.

Now, with that somewhat abbreviated preliminary overview, what is known about the issue among veterans who attend Veterans Affairs Medical Centers? Based on the knowledge of risk factors for acquisition and progression of hepatitis C virus infection, it might be anticipated that the problem should be relatively common among such individuals. Certainly, previous studies have identified large outbreaks of hepatitis B virus infection among military personnel, attributable to parenteral drug abuse. The most important risk factors for HCV transmission include blood transfusions prior to 1992, parenteral drug abuse, the recently recognized item of snorting of cocaine and, perhaps, but far from proven, tattooing and body piercing. Such risk factors would seem to be more common among veteran than non-veteran groups, a higher rate of transfusions being anticipated particularly among those who go into combat. Other risk factors, such as the controversial one of sexual transmission, also are relevant although it is unclear, at least to me, whether promiscuity (believed to be the salient feature), is any greater among veterans than among non-veterans. A surrogate item identified by CDC investigators is the fact of belonging to lower socioeconomic groups, currently the bulk of veterans attending VA facilities. Added to the potentially greater likelihood of acquisition of the virus is the fact that chronic alcoholism remains an important and common concern among veteran patients and hence, there may also be a greater likelihood of progressive chronic liver disease among veteran patients. Clearly, the issue of chronic liver disease in the VA is one that will continue to require careful surveillance and appropriate attention.

Now what about the frequency of HCV infection among VA medical center patients? Routine screening for HCV has not, to my knowledge, been undertaken in VA Medical Centers, no more than it has among non-VA medical institutions. That HCV infection is common in the VA setting seems unquestioned. In my liver clinic, as seems to be the case in virtually all other liver clinics, both VA and non-VA located, patients with hepatitis C represent by far the bulk of patients seen. I would estimate that fully 80% of persons that attend the Liver Clinic at the VA Medical Center in Washington DC are there for evaluation because of the problem of hepatitis C. I am not aware of any large-scale, multicenter studies that have been undertaken in VA Medical Centers. Dr. Gary Roselle and others, from the VA Medical Center in Cincinnati, conducted a four-year survey between 1991 and 1994 of all VA Medical Center laboratories that do HCV screening to determine the rates of positive results over these time periods. A dramatic increase was noted each year, the increase being more than 285% over the entire 4-year period, occurring in all geographic regions, while the increase in the total number of patients seen was just 4.9%. Impressive though these data are, they cannot inform accurately as to whether the actual number of infected cases increased. The likelihood is that over this time period, there was greater awareness of the problem, prompting increasing requests by house staff for hepatitis serologic testing. Furthermore, test procedures were changing during this period and the data did not take into account the important issue, at that time, of false-positive results.

The only large, population-based screening study in the VA of which I am aware is one that was conducted at my VA Medical Center here in Washington, DC over a 6-week period at the beginning of 1994. The intent of our study was to screen 1,000 consecutive patients who were admitted to the facility, regardless of which section they entered, for the presence of hepatitis B and hepatitis C markers. We accomplished our aim in 839 patients and were astonished to find that, whereas 3% were infected with hepatitis B, 21% had markers of hepatitis C virus infection. Half of these individuals had normal liver function. The frequency was significantly higher in African-American than white patients, and risk factors that correlated with a positive result include illicit drug use (injection and snorting), multiple sexual partners, and a history of sexually-transmitted disease. Strikingly, over 90% were not aware of their positive status and about the same percentage had never had a known bout of acute hepatitis. When we later studied the positive group for the viral genotypes in order to determine whether those who belonged to the Vietnam era had the genotype characteristic for that country, we found that, in fact, they all bore the genotype seen in the American-based infection.

Although we were surprised by these results, we noted that they were similar to those of a screening study that had been performed a little earlier among persons seen in the emergency room at Johns Hopkins University, in which a prevalence figure of 18.5% was noted. The populations studied in these two screening surveys both derived from the "inner city" and both identified parenteral drug abuse as the apparently most common risk factor. Similar data, I believe, have been noted at the VA Medical Center in San Francisco as may be mentioned to you by Dr. Theresa Wright in her testimony before you. Obviously, these results cannot be applied to other VA Medical Centers that have not conducted similar surveys, particularly facilities located in more rural areas. Aditional surveys are therefore needed, and indeed are in process or are being planned. Dr. Wright has received funds, I believe, to conduct a large survey at her institution. She will probably inform you of this. In collaboration with investigators from the Department of Defense, I am planning to conduct a survey, with approval, of patients attending several geographically diverse VA facilities in order to obtain broader-based information. Finally, the recently submitted letter by Dr. Kizer to all VA institutions requiring that all attending veterans who fit specifically-defined risk categories be screened for hepatitis C will provide vast and critically-needed information on the VA-wide prevalence of HCV infection, and will permit categorization according to the period of military service.

I am not aware of any specific data relating HCV prevalence according to time of service, in particular, among Vietnam era veterans. Using age as a surrogate for time of service, there appears to be a higher frequency of hepatitis C positivity in the age group that would coincide with the Vietnam era veteran in some studies, including the one conducted at our Medical Center. However, in comparing these data with those of the general population, as described in the NHANES III survey by CDC investigators, there appears to be little difference between veterans and non-veterans in this regard. These data can possibly be interpreted as indicating that parenteral drug use flourished in the 1960’s and 1970’s among all segments of society.

I sincerely hope that I have responded appropriately and informatively to the questions posed by the staff of the Subcommittee. Hepatitis C infection is clearly a problem for the Nation as well as for veterans at Veterans Affairs Medical Centers. I am most pleased that the issue is being considered of importance and that efforts to respond to the problem are underway. It is clear that more research is needed both to identify the true scope of the problem, to devise ways to prevent the infection and to curb progression once infection has occurred, to learn about factors that promote disease progression, to understand the mechanisms involved in viral retention and disease production, and to improve markedly the treatment armamenterium. Equally important is the need to educate both patients and physicians about this viral infection, and to embark on a campaign to limit the intense anxiety that is presently being engendered about this infection without denying or underplaying its potentially serious manifestations and consequences.