Do not wait to manage hepatitis C virus in HIV-positive patients

SAN DIEGO — Clinicians should not be deterred from treating hepatitis C virus (HCV) in patients infected with HIV because of insufficient data and lack of consensus for the best management approach, said David L. Thomas, MD.

Increasing numbers of individuals with HCV and HIV are dying from HCV-related liver failure rather than from the complications of HIV disease. This trend is largely attributed to the use of highly active antiretroviral therapy (HAART) for HIV. At one New England medical center, 50% of deaths among patients infected with HIV in 1998 were related to liver failure caused by HCV, compared with 10% in 1991.

By understanding the natural history of HCV infection and the benefits and adverse effects of available therapies, clinicians can make reasonable judgments about treatment in most instances, said Thomas, an associate professor of medicine at Johns Hopkins University School of Medicine in Baltimore.

In deciding to treat the coinfected patient, Thomas said, clinicians have several issues to consider: the likelihood that a patient will die or experience morbidity from liver disease; that treatment will result in a virologic response or an attenuation of histologic progression of disease; that an adverse event might occur while trying to achieve these outcomes; and that another medical problem will cause morbidity and mortality before hepatitis C.

“In the pre-HAART era, there was little enthusiasm for treating HCV in individuals infected with HIV, principally because there was so much competing mortality [from HIV disease],” Thomas said at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. “Individuals infected with HIV were dying of opportunistic infections, not liver disease. In addition, there was little evidence that treatment could be successful. Now this is no longer a serious consideration for most individuals infected with HIV and we have increasing data that it is possible to provide [effective] treatment.”

Available data suggest that sustained virologic responses from anti-HCV therapy, even interferon monotherapy, are possible in patients with HCV and HIV, even though a treatment response is 30% to 50% less likely to occur in these patients than in patients infected with HIV alone. Emerging data show that ribavirin improves response to interferon, said Thomas, who also observed that no drug has an FDA-approved indication for treating HCV in patients with HIV.

Although guidelines are loose with respect to treating HCV in patients with HIV, “there’s a pretty good consensus that you need to optimize the HIV care first,” Thomas said.

Evidence to date suggests that the best available treatment for HCV in patients infected with HIV is a regimen of peginterferon alfa-2a (Pegasys, Roche) and ribavirin, Thomas said. He cited a study by Ray Chung, MD, and colleagues in which 134 coinfected patients were randomized to receive peginterferon alfa-2a at a dose of 180 mg a week or standard interferon alfa-2a at an initial dose of 6 million units three times a week, which was later reduced to 3 million units three times a week. In each test arm, ribavirin was given at an escalating dose beginning with 600 mg and increasing to a 1 g in both arms. The researchers stratified subjects according to HCV genotype (1, 2 or 3).

At week 24, 44% of patients who received peginterferon plus ribavirin had a virologic response (no virus detected) compared with 15% of patients who received standard interferon plus ribavirin. The difference in treatment effect was greater among patients with HCV genotype 1 – about 33% of patients in the peginterferon arm had a virologic response compared with only 7% in the standard interferon arm. Among patients with the other HCV genotypes, 80% of patients responded to peginterferon plus ribavirin compared with 40% of those who received standard interferon plus ribavirin.

Moreover, a significant proportion of virologic nonresponders in both arms had a histologic response — 15 (40%) of 37 patients who received peginterferon alfa-2a plus ribavirin versus 6 (26%) of 23 patients with standard treatment.

U.S. Public Health Service guidelines recommend that all individuals infected with HIV be screened for HCV using at least a second-generation assay that detects antibodies. The principal screening test for HCV antibodies is the enzyme immunoassay (EIA). A small subset of patients has seronegative HCV infections (HCV RNA detected in the absence of HCV antibodies). Still, guidelines recommend that clinicians start with an antibody-screening test. If the test detects no antibodies, but a patient has evidence of liver disease, primarily unexplained elevations in liver enzymes, an HCV RNA test should be performed, Thomas said.

The RIBA test has little value in the HIV/HCV coinfected individual, he said. The qualitative RNA test, although providing important information about presence or absence of infection, “is really not as useful as moving right on to a quantitative test to confirm a positive EIA,” he said. With the results of the EIA and quantitative RNA tests, as well as a determination of HCV genotype, clinicians are ready to engage a patient in hepatitis C management, Thomas said.

One-fourth of individuals infected with HIV in the United States are coinfected with HCV — a total of approximately 200,000 people, Thomas said. The rate of coinfection, however, varies with how individuals become infected with HIV. For example, coinfection rates of 60% to 90% have been reported among injection drug users.

Studies show that HIV adversely affects each stage in the natural history of hepatitis C, Thomas said. HIV increases the proportion of individuals who will progress to persistent HCV infection and cirrhosis. HIV also decreases the time required for cirrhosis to develop and for cirrhosis to progress to end-stage liver disease or hepatocellular carcinoma.

“As a rule of thumb,” Thomas explained, “the coinfected person has twice the likelihood of having cirrhosis compared with somebody with hepatitis C alone.”

Thomas said he does not believe HCV has a major effect on progression of HIV disease, although some studies suggest that it increases the risk of HIV disease progression. For example, a Swiss study of individuals with HIV — some of whom had concurrent HCV infection — found that progression to a new AIDS-defining clinical event or death was 1.7 times as likely to occur in coinfected persons than in individuals infected with HIV alone. The study also found that coinfected individuals receiving potent antiretroviral therapy experienced a smaller CD4-cell recovery than those without HCV infection.

Potential drug interactions

The adverse effects of anti-HCV treatment are the “dominant consideration” in some coinfected patients, he said. Interferon alfa can cause suppression of CD4 counts, and ribavirin may decrease phosphorylation of zidovudine (AZT, Retrovir, GlaxoSmith- Kline) and stavudine (d4T, Zerit, Bristol-Myers Squibb), perhaps, leading to decreases in the levels of these drugs and loss of control of HIV infection. Furthermore, data suggest that adding ribavirin to didanosine (ddI, Videx, Bristol-Myers Squibb) increases didanosine-related toxicities, including pancreatitis. Recently, the FDA added a black box warning against the use of ribavirin in patients taking ddI due to fatal complications.

For more information:

·         Thomas, DL. Hepatitis C in the HIV Infected Patient. Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. Sept. 27-30, 2002. San Diego.

·         Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet. 2000. 25;356:1800-1805.

·         Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562-569.