Hepatitis B
Multicenter trials of alpha interferon, 30-35 million units/week, given as 5 mu daily or 10 mu three times weekly for 16 weeks, demonstrated that 30-40% of treated patients developed nondetectable HBV DNA and HBeAg compared to a 5% response in untreated control patients. Currently, patients with chronic hepatitis with necroinflammatory activity on biopsy, detectable HBeAg, and elevated serum aminotransferases and HBV DNA levels seem best suited to receive therapy. Although early studies suggested that Asian patients had a lower response rate to treatment, re-analysis of the data demonstrated equivalent response rates in the subgroup with ALT elevation. Patients with cirrhosis, ascites, and portal hypertension should not receive treatment since the disease flare seen with interferon response may lead to decompensation (ascites, variceal bleeding) and in advanced cirrhosis may even precipitate liver failure and death.

The use of the nucleoside analog lamivudine (3-TC, Epivir) results in inhibition of viral replication and reduction in HBV DNA below the detectable limit for standard commercial assays. HBeAg seroconversion is seen in about 20% of both Asian and non-Asian patients. Prolonged therapy results in a YMDD-mutant HBV in 14-32% of patients with reversion to the wild type virus when the medication was stopped. The specific role of lamivudine in the long-term therapy of chronic hepatitis B is being evaluated. However, the effect of this drug in suppressing viral replication and the low side effect profile hold promise for the treatment of patients, including those awaiting liver transplantation. Clinical trials in progress with antivirals such as famciclovir and adefovir, immune stimulation drugs, and T cell vaccines either singly or in combination will elucidate the optimal therapy for chronic hepatitis B.

Chronic hepatitis B and D co-infection is rare in the United States and requires long-term interferon therapy for adequate viral suppression.

Hepatitis C
The treatment of chronic hepatitis C, now known to affect approximately 1.8% of the U.S. population, has evolved considerably during the past 13 years. Early studies using alpha-interferon (a IFN) demonstrated that a short course of treatment lowered serum ALT in approximately 40-50%.

All patients with chronic hepatitis C, elevated ALT, and compensated liver disease are potential candidates for therapy. Treatment of rare cases of acute hepatitis C is recommended. Although high HCV RNA levels and genotype 1 are associated with lower response rates, treatment should not be withheld in these patients. Currently three a-IFN products (Intron A, Roferon, and Infergen) are available to treat hepatitis C. Dosing is product-specific and management of therapy includes evaluation of response at treatment week 12, with continuation for 12 months in responders. Despite longer treatment courses, relapse occurs when treatment is discontinued. Virological response is defined as sustained (SVR) when HCV RNA remains nondetectable by PCR for at least six months after treatment discontinuation, and ALT normalization may or may not correlate with virological response.

In large studies in which all patients continued treatment regardless of week 12 response, SVR rates were 6-10% with a six-month course of a-IFN and 15-20% with a 12-month course. Therefore, continuation of therapy beyond 12 weeks is recommended only in responders. Although a-IFN therapy is difficult to tolerate in many patients, the clinical benefit of SVR is clear, in that significant histological improvement occurs.

Response to a-IFN occurs in two phases -- during the first 12 weeks, the induction phase, and beyond that point, the maintenance phase of therapy. Improving initial response rates is being addressed through the evaluation of higher, daily dosing regimens and longer-acting interferon products or combination therapy with Ribavirin. The optimal length of treatment once response is achieved is still unknown. However, treatment of relapse is effective in re-gaining a response, using both a-IFN monotherapy for 48 weeks or longer and the newly FDA-approved combination of interferon alfa-2b and oral ribavirin (Rebetron). Treatment of relapse using six months of combination therapy is associated with an SVR rate of 49% compared to only 4.9% in patients treated with monotherapy.

The use of interferon alfa-2b with oral ribavirin as initial therapy also has demonstrated marked improvement in response rates compared to a-IFN monotherapy. In recently completed international studies, combination therapy for 48 weeks was associated with a 41% SVR compared to a 16% SVR with 48 weeks of IFN monotherapy. Ribavirin-associated side effects include hemolytic anemia (which can be severe in 10% of patients, making it contraindicated in patients with vascular disease). It should not be used in patients who are or may become pregnant. The profile of psychiatric side effects are similar to monotherapy. All patients need careful psychiatric evaluation prior to treatment with interferon.

Since hepatitis C is a progressive disease associated with end-stage liver disease, liver failure, and hepatocellular carcinoma, and, since current therapies are more effective in earlier stage liver disease, it is prudent to review treatment options and consider therapy with all HCV patients. Management should also include advice to abstain from alcohol because of the known effect on the progression of the disease, vaccination against hepatitis A and B, and screening for hepatocellular carcinoma.