Hepatitis C: Identifying the Sustained Responder

David R. Gretch, MD, Assistant Professor of laboratory Medicine, Viral Hepatitis Laboratory, University of Washington, Seattle, Washington

David R. Gretch, MD, PhD
A native of Great Falls, Montana, Dr. Gretch earned his BS degree in Biology from the College of Great Falls in 1981, received graduate-level training in Biochemistry at the University of Montana (1981 ­ 1983), and earned his MD and PhD (Microbiology) degrees from the University of Iowa in 1990. Dr. Gretch completed his residency training in Laboratory Medicine and Pathology at the University of Washington in 1993. His current positions at the University of Washington include Assistant Professor of laboratory Medicine and Adjunct Assistant Professor of Medicine, Director of Phlebotomy and Specimen Processing, Assistant Director of the Virology Division, and Director of the Viral Hepatitis Laboratory.

Dr. Gretchs’ major research focus is the virological basis of chronic hepatitis C in humans, encompassing diagnosis, molecular epidemiology, pathogenesis, treatment, and development of research models. Additional research interests include the clinical virology of chronic hepatitis B, and pathogenesis of viral hepatitis in HIV-positive individuals.

Dr. Gretch is active in the training of postdoctoral fellows, and has over 100 publications, book chapters, abstracts and editorials to his credit.

Determining the clinical stage and prognosis of chronic hepatitis C and identifying patients with hepatitis C virus (HCV) infection who are likely to respond to therapy are two challenges for physicians. A number of factors complicate the diagnosis and management of hepatitis C, including the following: (1) symptoms are not predictive of disease activity (<20% of patients develop symptoms); (2) histological liver disease may be present without physical signs; and (3) elevated alanine aminotransferase (ALT) levels can indicate liver damage and inflammatory changes, but fluctuate widely in many patients during the course of the disease.

Enzyme immunoassays are suitable for screening and as an initial test for patients with chronic liver disease. These tests indicate past or present infection but do not differentiate acute, chronic or resolved infection. Because false positive results have been reported in up to 40% of healthy blood donors, positive enzyme immunoassay results should be verified with a supplemental assay. Recombinant immunoblot assays may resolve false positive results from enzyme immunoassays but they do not distinguish active HCV infection. Determination of serum ALT levels is relatively inexpensive and noninvasive; however, these levels fluctuate widely in most patients (may rise with interferon treatment) and may spontaneously normalize in 30 to 40% of patients. A single ALT level cannot be used to exclude ongoing hepatic injury. Thus, this test is less effective for assessing therapeutic response than molecular assays for HCV RNA.

Quantitative HCV RNA tests measure the amount of circulating viral genomes. These tests may be useful for identifying patients who are likely to respond to treatment, for selecting optimal treatment regimens and for monitoring the early treatment response. However, quantitative tests are generally not as sensitive as qualitative tests such as reverse transcription polymerase chain reaction (RT-PCR), and should therefore not be used to exclude diagnosis of HCV infection or to determine treatment endpoint.

Qualitative tests directly detect the presence of circulating HCV RNA genomes in patient serum as early as 1 to 2 weeks after exposure. They are the most sensitive test for HCV, detecting <100 HCV RNA copies/ml, and have high specificity (97 to 99%). These tests are more useful for evaluating the diagnosis of active HCV viremia, and for determining virological treatment endpoints (i.e. clearance of viremia) than quantitative tests. Finally, determination of HCV genotype may also be useful for predicting response to treatment and for tailoring therapeutic regimens.

A number of studies have shown that early loss of HCV RNA (early viral clearance) during therapy is predictive of sustained virological response. A Japanese study of 114 patients who received interferon for 24 weeks reported a significantly (p<0.05) higher rate of sustained response in patients with loss of HCV RNA during the first week compared with those with loss of HCV RNA during weeks 2 or 4 (76% vs. 36 and 13%, respectively). No sustained responses were reported in 55 patients who retained HCV RNA after 4 weeks of interferon treatment. Similarly, data from 2 large studies conducted by the Consensus Interferon Study Group (one in treatment-naïve patients and the other in nonresponders and relapsers), showed that early viral clearance predicted sustained response. Of the 28 patients who were sustained responders to standard interferon treatment, nearly half had already cleared HCV RNA (<100 copies/ml) by week 2 (figure) and patients with early clearance were more likely to be sustained responders than those with later clearance.

In summary, ALT is an unreliable measure of HCV infection or response to therapy. Qualitative tests are useful for diagnosing active HCV viremia and for determining virological treatment endpoints. Quantitative tests are useful for pretreatment evaluation of viral load, and for assessing viral load changes during the early treatment period. Virological predictors of sustained response to therapy include HCV genotype and HCV viral load (pretreatment), early disappearance of HCV RNA (during treatment) and negative HCV RNA results by RT-PCR 6 months after treatment.

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