Bruce R. Bacon, MD

NIH Consensus Development Conference
Management of Hepatitis C: 2002 

Bethesda, Maryland
June 10-12, 2002

At the 1997 NIH Consensus Development Conference on Management of Hepatitis C, it was concluded that “….treatment of patients with persistently normal ALT is not beneficial and may actually induce liver enzyme abnormalities.” ⁽¹⁾ Since that time, this issue has been controversial with some investigators supportive of treatment and others suggesting that no work-up or therapy is necessary for these patients. Approximately 30 percent of patients with chronic hepatitis C have normal ALT levels, and another 40 percent have ALT levels that are less than two times the upper limit of normal. ⁽²⁾ Most patients with normal ALT levels have mild degrees of inflammation with mild or no fibrosis and their rate of disease progression is reduced compared to those with elevated ALT levels. (^3,4) However, some patients with persistently normal ALT levels can progress to advanced fibrosis and cirrhosis. ^(3–6)

The issue regarding treatment of these patients has often focused on how to proceed in patients with mild disease, recognizing that ALT levels may actually be just a proxy for mild histology. The best treatment trials that have been performed are the registration trials for FDA approval, and those have all required that patients have elevated ALT levels to be included in the study. Therefore, there are no large treatment trials of normal ALT patients. When interferon monotherapy was used for HCV patients with normal ALT levels, sustained response (SR) rates generally ranged from 15 percent to 20 percent. These SR rates are similar to the results of studies obtained when interferon monotherapy was used to treat patients with elevated ALT levels.

Since the NIH Consensus Conference recommendations were issued in 1997, treatment of chronic hepatitis C has progressed from interferon monotherapy to combination therapy using interferon and ribavirin, and more recently to pegylated interferon and ribavirin. A few studies of interferon plus ribavirin in chronic hepatitis C patients with normal or near normal ALT levels have been reported. Gordon and colleagues studied patients from one of the large registration trials in which a total of 1,744 patients with hepatitis C received either interferon and placebo or interferon and ribavirin for 24 or 48 weeks. ⁽⁷⁾ Of these, 105 individuals (6 percent) had minimally elevated ALT levels, defined as ¡Ü1.3 times the upper limit of normal (ULN), at their entry visit. Histologic activity index and fibrosis scores were lower amongst these patients with baseline ALT levels ¡Ü1.3 times the ULN. There was no difference in SR between patients with ALT levels ¡Ü1.3 times the ULN (24.8 percent) compared to those with ALT levels > 1.3 times the ULN (26.8 percent) for all treatment groups. Lee and Sherman studied 19 patients with ALT levels that were either normal or < 1.5 times the ULN. ⁽⁸⁾ Nine of the 19 patients (47 percent) had an SR. In studies from our group at Saint Louis University, Di Bisceglie, et al. reported on a group of interferon monotherapy nonresponders who were re-treated with the combination of interferon and ribavirin. ⁽⁹⁾ In total, of 124 patients were studied; 24 had normal ALT levels and 100 had elevated ALT levels. There was no difference in SR between the two groups (26 percent vs. 34 percent). Further, we have coordinated an investigator-initiated multicenter study evaluating the use of interferon and ribavirin in treatment of naïve patients with chronic hepatitis C who have persistently normal ALT levels. One hundred seventeen patients have been enrolled in this study and are currently in treatment or followup phases of the study. Thus, all reported studies have shown that SR rates for normal or near normal ALT patients are equivalent to those of elevated ALT patients when the combination of interferon and ribavirin is used.

Currently, the standard of care for most patients with chronic hepatitis C is to use the combination of pegylated interferon and ribavirin. Overall SR rates of about 55 percent can be achieved. There are no studies of normal ALT patients being treated with pegylated interferon and ribavirin, although a large investigator-initiated multicenter study is currently under way. When evaluating the effect of pegylated interferon and ribavirin, Manns and colleagues compared patients with minimal or no fibrosis to those with bridging fibrosis or cirrhosis. ⁽¹⁰⁾ When pegylated interferon and ribavirin were used as therapy, the SR rates for those with mild histologic changes were better (57 percent) than those with more advanced histology (44 percent).

In summary, approximately 30 percent of patients with chronic hepatitis C have normal ALT levels and another 40 percent have ALT levels < 2 times the ULN. The majority of these patients have disease that is histologically mild, but these patients can have progressive liver disease with the development of advanced fibrosis and cirrhosis. It no longer seems reasonable to conclude that SR rates for patients with normal ALT levels are any different than those for patients with elevated ALT levels. The issue at hand is whether or not patients with mild liver disease should be treated. There are numerous other factors which impact on this decision, including genotype, histology, patient motivation, symptoms, co-morbid illness, and the age of the patient. ALT levels may have less importance in deciding who should be treated.

References

1. Marcellin P, Levy S, Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels. Hepatology 1997;26:133S–136S.

2. Conry-Cantilena C, VanRaden M, Gibble J, Melpolder J, Shakil AO, Viladomiu L, Cheung L, Di Bisceglie AM, Hoofnagle J, Shih JW, Kaslow R, Ness P, Alter HJ. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med 1996;334:1691–6.

3. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology 1997;26:15S–20S.

4. Gholson CF, Morgan K, Catinis G, Favrot D, Taylor B, Gonzalez E, Balart L. Chronic hepatitis C with normal aminotransferase levels: a clinical histologic study. American Journal of Gastroenterology 1997;92:1788–92.

5. Persico M, Persico E, Suozzo R, Conte S, De Seta M, Coppola L, Palmentieri B, Sasso FC, Torella R. Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels. Gastroenterology 2000;118:760–4.

6. Puoti C, Magrini A, Stati T, Rigato P, Montagnese F, Rossi P, Aldegheri L, Resta S. Clinical, histological, and virological features of hepatitis C virus carriers with persistently normal or abnormal alanine transaminase levels. Hepatology 1997;26:1393–8.

 7. Gordon SC, Fang JWS, Silverman AL, McHutchison JG, Albrecht JK. The significance of baseline serum alanine aminotransferase on pretreatment disease characteristics and response to antiviral therapy in chronic hepatitis C. Hepatology 2000;32:400–4.

8. Lee SS, Sherman M. Pilot study of interferon-á and ribavirin treatment in patients with chronic hepatitis C and normal transaminase values. J Virol Hepatitis 2001;8:202–5.

9. Di Bisceglie AM, Thompson J, Smith-Wilkaitis NS, Brunt EM, Bacon BR. Combination of interferon and ribavirin in chronic hepatitis C: Re-treatment of nonresponders to interferon. Hepatology 2001;33:704–7.

10. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M-H, Albrecht JK, and the International Hepatitis Interventional Therapy Group. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–63.