The hepatitis C virus (HCV) was first identified by molecular cloning in 1988. It was subsequently determined that this agent caused the majority of cases of transfusion-related hepatitis (formerly known as non-A, non-B hepatitis). Identification of the virus spawned the development of several diagnostic tests leading to the currently available enzyme-linked immunosorbent assay (ELISA), a confirmatory radioimmunoblot assay and, most recently, qualitative and quantitative assays that can identify specific HCV RNA. Mass screening of blood donors as well as at-risk individuals has identified approximately 4 million persons in the United States who are infected with HCV.¹

Population-based studies have found that about 40 percent of patients with chronic liver disease are infected with HCV, resulting in 8,000 to 10,000 deaths per year.¹ Moreover, HCV-related liver disease is the leading reason for liver transplantation in this country. Data such as these led the National Institutes of Health (NIH) to publish a consensus statement on HCV in 1997 and, most recently, the Centers for Disease Control and Prevention (CDC) to issue updated guidelines for the prevention and control of HCV.^1,2 Part 2 of an overview of the guidelines is presented by Moyer and colleagues in this issue. Part 2 covers prevention counseling and treatment.³ Part 1, which covers serologic testing and diagnosis, is in the January 1, 1999, issue of AFP.⁴

The fact that 4 million Americans are infected with HCV indicates a major public health problem. However, beyond this absolute number, the clinical significance of the epidemiologic data is less certain. Although it is believed that chronic infection will develop in about 85 percent of persons infected with HCV, many of these individuals will have a latent period lasting 20 to 30 years before any serious sequelae of liver disease develop.⁵ Among persons who have persistent infection, chronic active hepatitis may develop in 25 to 50 percent, cirrhosis may develop in 8 to 40 percent, and hepatocellular carcinoma may develop in 1 to 4 percent.²

The difficulty for clinicians is identifying patients whose HCV infection will progress to more severe liver disease. Unfortunately, no clinical features, risk factors or laboratory parameters (including alanine aminotransferase [ALT] levels and HCV RNA levels) are known to help identify the subset of patients at risk for progressive disease. This paucity of current clinical information, especially as it relates to the natural history of HCV, makes it difficult for physicians and patients to decide what to do when a test result for HCV is found to be positive.

For patients between the ages of 18 and 60 years, current guidelines advocate further medical evaluation, including a liver biopsy.² If the histopathologic findings reveal portal or bridging fibrosis with inflammatory changes, a 12-month course of injected interferon given three times weekly is an option. However, interferon therapy has shown only about a 20 percent overall response rate.⁶ In most trials, a “response” is usually defined only by normalization of ALT levels, sometimes a negative HIV RNA quantitative assay at one year after therapy and, rarely, by histopathology. Interferon therapy is additionally fraught with significant side effects, including fatigue, depression, thyroid dysfunction, anemia and thrombocytopenia.^2,5 A one-year course of interferon costs about $5,000.

Unfortunately, many patients infected with HCV also have problems with substance abuse, co-infection with human immunodeficiency virus (HIV), and a history of depression—making them either poor candidates or non-candidates for the currently available therapies. In my own practice, approximately 40 percent of HIV-infected patients are HCV-positive and, for the reasons mentioned, the majority are not good candidates for interferon therapy.

Interestingly, HCV infection is similar to HIV infection and may be a cofactor for its transmission.⁵ This certainly appears to be the case among HIV-infected women, who vertically transmit HCV to their newborns at a rate three times higher than noninfected mothers.⁷ While tremendous progress has been made in the past three years in the development of more than a dozen highly effective antiviral medications to treat HIV infection, we still have only interferon and the recently approved nucleoside analog ribavirin to treat patients infected with HCV. The similarity to HIV may go even further, because it may not be possible to eradicate these RNA viruses from their human hosts.⁸ Thus, the available therapies of interferon and ribavirin may be even less effective than the currently reported 20 to 50 percent short-term success rates.^2,5

Despite published guidelines and the growing use of interferon outside of clinical trials, the critical question in 1999 is which patients should be referred for liver biopsy and possible treatment? Despite the large number of published studies that have looked at the treatment of HCV infection with interferon as well as other experimental therapies, no long-term prospective data are available that show interferon actually prevents the development of end-stage liver disease.⁹ Better data should be available in five to 10 years, but for now we really do not know if treating the majority of patients with HCV will have any effect on morbidity or mortality from cirrhosis or hepatocellular cancer.^6,9

I believe if one identifies a patient with HCV infection who could be a treatment candidate based on the NIH or CDC guidelines, it is the obligation of the testing physician, or perhaps a consulting physician, to appropriately explain the course of therapy. One must discuss the significant commitment on the part of the patient to the medication. The patient should be informed that interferon therapy may be life-altering, depending on side effects, and that even under ideal circumstances the drug(s) may not work in at least 50 percent and perhaps even 80 percent of patients. If the patient is willing to proceed and has no contraindications to interferon, performing a liver biopsy to define the degree of hepatic disease is appropriate. If a patient elects not to be treated, periodic follow-up with monitoring of hepatic function every six to 12 months is acceptable.

Until we have better long-term data on both treated and untreated patients, the hepatitis C epidemic will continue to be an uncertainty for family physicians, as well as other physicians dealing with this disease. Hopefully, ongoing research will result in the development of oral antiviral therapies such as HCV-specific protease inhibitors that will be easy to administer and be better tolerated by patients. Returning to the model of HIV treatment, combination antiviral therapy may be needed for better management of HCV infections.

The current CDC recommendations regarding counseling and screening for HCV infection are quite sound and are based on the best available data. The family physician can play a key role by identifying patients infected with HCV and advising them to avoid hepatotoxic substances, especially alcohol, which definitely will worsen their prognosis.¹⁰ Vaccination against hepatitis A and, if appropriate, hepatitis B, should be offered. Close monitoring of hepatic transaminase levels may be prudent for patients receiving hepatically metabolized medications, such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or hypoglycemic agents, such as metformin or troglitazone.

Risk reduction in regard to transmission of HCV is another key role for the family physician. Beyond these interventions, many patients currently found to be HCV-antibody positive may be best served by watchful waiting. The recommendations may change when we have more effective therapies and more data are available on the natural history of HCV infections.