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Researchers explore the most effective management of patients with chronic hepatitis C

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, which progresses in some patients to cirrhosis of the liver—when critical liver functions such as drug detoxification and vitamin absorption markedly deteriorate—and hepatocellular carcinoma (a type of cancer affecting the liver). Between 3 and 4 million people in the United States have chronic hepatitis C, and 10,000 HCV-related deaths occur each year. Without effective treatments, HCV-related problems and death are expected to increase nearly three-fold by the year 2015.

Researchers at the Johns Hopkins University Evidence-based Practice Center recently published the results of three studies on management of chronic hepatitis C, which followed an exhaustive and systematic review of the scientific literature published between January 1996 and March 2002. Their work was supported by the Agency for Healthcare Research and Quality (contract 290-97-0006). The three studies are summarized here.

Chander, G., Sulkowski, M.S., Jenckes, M.W., and others (2002, November). "Treatment of chronic hepatitis C: A systematic review." Hepatology 36, pp. S135-S144.

The researchers examined studies on the efficacy and safety of current treatments for chronic hepatitis C in previously untreated patients and patients in selected subgroups, as well as treatment impact on long-term clinical outcomes, such as hepatocellular carcinoma and death from liver failure. Results consistently showed that combination therapy with high-dose, once-weekly peginterferon and daily ribavirin was more effective than standard three-times-a-week interferon and daily ribavirin in treatment of chronic hepatitis C among previously untreated people infected with HCV genotype 1 (sustained virologic response, SVR, 42 vs. 33 percent) and had similar profiles for safety and tolerance. Studies also consistently showed that ranges of SVR rates were higher with peginterferon than standard interferon monotherapy in previously untreated patients (10 to 39 percent vs. 3 to 19 percent).

Studies also consistently showed that treatment with interferon and ribavirin was more efficacious than interferon alone in previously untreated patients and previous nonresponders to interferon and relapsers. Although more efficacious than retreatment with interferon monotherapy, standard interferon and ribavirin was still relatively ineffective (SVR, 13 to 14 percent) for the treatment of chronic hepatitis C in patients who failed prior interferon-based therapy. Studies were moderately consistent in showing that interferon-based treatment decreased the risk for liver cancer.

Unfortunately, the vast majority of trials either failed to include or specifically excluded patients with relatively higher prevalence of HCV infection (for example, hemodialysis patients, hemophiliacs, those co-infected with HIV, black patients, and patients with psychiatric disorders) and those at increased risk for HCV-related liver disease progression (for example, people coinfected with HIV or hepatitis B virus). Future trials should address the optimal doses of peginterferon and ribavirin and the optimal duration of therapy, particularly among those infected with HCV genotypes 2 and 3. Understudied populations (for example, blacks, those with psychiatric disorders, drug addicts, those with end-stage renal disease, and people with HIV infection) should be included in future trials.

Gebo, K.A., Herlong, H.F., Torbenson, M.S., and others (2002, November). "Role of liver biopsy in management of chronic hepatitis C: A systematic review." Hepatology 36, pp. S161-S172.

Some experts have questioned the role of liver biopsy in management of hepatitis C, since its value in predicting treatment response is incompletely defined, and it can be associated with serious complications and significant expense. The researchers reviewed the literature to find out how well the results of pretreatment liver biopsy predicted outcomes of treatment in patients with chronic hepatis C and how well biochemical blood tests and serologic markers of fibrosis predicted the degree of fibrosis (replacement of smooth muscle with fibrous connective tissue) on liver biopsy.

The evidence suggested that advanced fibrosis or cirrhosis of the liver (lobes of the liver are covered with fibrous tissue, the lobules are infiltrated with fat, and blood flow through the liver is obstructed) on initial liver biopsy was associated with a modestly decreased likelihood of a sustained virologic response (SVR) to treatment. Studies also showed relatively consistently that serum aminotransferases (a class of enzymes) have modest value in predicting fibrosis on biopsy; hyaluronic acid and laminin, which are markers of extracellular matrix degeneration, may have value in predicting fibrosis; and panels of tests may have the greatest value in predicting fibrosis or cirrhosis.

Biochemical and serologic tests were best at predicting no or minimal fibrosis or at predicting advanced fibrosis/ cirrhosis, and they were poor at predicting intermediate levels of fibrosis. Studies on the relation of pretreatment liver biopsy findings to treatment outcomes had important limitations, and few studies discussed the complications of biopsy. Given these limitations, the studies were relatively consistent in suggesting that the presence of advanced fibrosis or cirrhosis on biopsy may predict a modest decrease in the likelihood of having an SVR.

Despite the important limitations of available blood tests, they could have a role in management of patients who are concerned about the risk or cost of a liver biopsy or in a clinical setting in which liver biopsy cannot be readily obtained, according to the researchers. They suggest that future studies focus more on the potential value of a panel of tests for predicting fibrosis than on liver biopsy.

Gebo, K.A., Chander, G., Jenckes, M.W., and others (2002, November). "Screening tests for hepatocellular carcinoma in patients with chronic hepatitis C: A systematic review." Hepatology 36, pp. S84-S92.

The incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C ranges from 0 to 1.6 percent per year, and rises to between 1 and 6 percent for patients with cirrhosis of the liver. Screening patients with chronic hepatitis C with serum alpha-fetoprotein (AFP) and liver ultrasound may improve detection of HCC, according to this systematic review of studies on screening tests to detect HCC in patients with hepatitis C.

One nonrandomized prospective cohort study suggested that HCC was detected earlier and was more often amenable to surgical resection in patients who had twice yearly screening with serum AFP and hepatic ultrasound than in patients who had usual care. Twenty-four studies, which included patients with chronic hepatitis C or B or both, addressed the sensitivities and specificities of screening tests. They were relatively consistent in showing that the sensitivity of serum AFP for detecting HCC usually was moderately high at 45 to 100 percent, with a specificity of 70 to 95 percent, for a threshold of between 10 and 19 ng/mL.

Many clinicians use ultrasound to screen for HCC. The few studies that evaluated ultrasound screening for HCC reported high specificity but variable sensitivity, depending on the population being screened. However, these studies varied in the screening frequency, experience of the ultrasonographer, and the extent of liver disease in the screened patients. Studies evaluating AFP varied widely in study design and patient eligibility criteria.

The researchers caution that it is not clear whether screening for HCC in patients with chronic hepatitis C will identify enough tumors at an early enough (treatable) stage to offset the risk of invasive tests on patients with false-positive screening tests (test shows cancer when there is none). They call for more studies to determine whether routine screening and surveillance for HCC actually improves outcomes in these patients.

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