Results of amfAR Hepatitis Co-Infection Study Could Help Improve Treatment
April 15, 2004—New study results from amfAR's clinical research program showed modest results for treating hepatitis C infection in patients with HIV, but may provide a useful guide for further study and for developing treatment guidelines for this population. The study appears in the April 2004 issue of Hepatology.
Hepatitis C infection (HCV) is commonly seen in people with HIV, particularly those who were infected by intravenous drug use or transfusion of tainted blood products. Though once a sideline to the ravages of HIV disease, now that people are living longer, healthier lives with the help of highly active antiretroviral therapy, the liver diseases caused by HCV have become a significant health concern. Although it is not known exactly how many people with HIV also have HCV, one study found a co-infection prevalence rate of 16 percent. Among people who were infected with HIV in the 1980s through blood transfusions or shared needles, some experts estimate as many as 50 to 70 percent are co-infected. Rates of HAART-associated liver toxicity and other liver disease have caused significant increases in death rates and hospitalizations among people who are co-infected—so much so that the U.S. Public Health Service now recommends routine HCV screening and treatment.
"We conducted this study since no one was seriously addressing the safety and effectiveness of HCV treatment in HIV co-infected persons" said Jeffery Smith, amfAR's Director of Clinical Research and project manager for the trial. "There was anecdotal data to suggest that HCV treatments were less effective in persons with HIV, but we had to determine through a randomized, controlled trial whether that was in fact the case."
While the management of HCV in HIV-negative people has evolved and improved significantly, even basic questions about the risk of HCV therapy and the possible interactions between drugs for HCV and antiretrovirals have not been well explored. To shed more light on this issue, the amfAR DCRI 010 research group, led by Drs. Jay Kostman of the Presbyterian Medical Center in Philadelphia and Norbert Bräu of the Bronx Veterans Affairs Medical Center, conducted a randomized, placebo-controlled, multicenter trial to compare the safety and efficacy of treating HCV with interferon alfa-2b (IFN) with the booster drug ribavirin or a placebo. In HIV-negative patients, this combination has been shown to suppress the viral load of HCV in about 42 to 46 percent.
The team enrolled 110 patients with HIV and untreated HCV. All participants received interferon therapy and half also took ribavirin, which has been shown to boost the effectiveness of interferon. Interferon alfa augments cells' ability to defend against invading viruses and stimulates the immune system. Ribavirin, a drug once tested to treat HIV, is an antiviral drug that plays a role in blocking HCV replication, although the mechanism for doing so is not understood. Participants were tested for HCV load after 12 weeks, and those who showed HCV still present in the blood—in this case, all but three patients—began taking ribavirin as well at the 16-week mark. At the end of the 18-month follow-up, 11 percent of the people in the intervention group and 6 percent of the people who received delayed ribavirin therapy showed a sustained viral response, with undetectable HCV in their blood.
A laboratory study done in the mid-1980s showed that ribavirin may interfere with the action of AZT to stop HIV replication. However, treatment with the drug combination did not seem to interfere with the control of HIV; no additional opportunistic infections were observed and, indeed, CD4+ percentages actually rose in some participants who were taking ribavirin.
However, 55 patients (51%) stopped treatment, mostly because of intolerable side effects, including fatigue, anemia, depression, and anxiety. A significant proportion (22%) also had their dosages lowered to correct neutropenia and anemia, which may have contributed to the low percentage that achieved a sustained viral response. Also, patients who were taking AZT (zidovudine) did experience higher rates of anemia compared with other study participants, which may indicate a cumulative effect of the three drugs.
Although the overall findings were disappointing, the study "is an important first step on a steep learning curve to defining the standard of care" for people who are co-infected with HIV and HCV, Dr. Mark S. Sulkowski of Johns Hopkins wrote in the accompanying editorial. The analysis of reasons people dropped out of the study may be particularly helpful, he writes, because it can provide "a roadmap to improved treatment outcomes." Health care providers can directly address such concerns as anemia, psychological address, poor adherence and relapse into substance abuse through concomitant therapies and directly observed therapy, for instance.
During the first 16 weeks of the study, it became clear that boosting IFN with ribavirin is "essential to achieve a viral response," wrote Sulkowski. In the study, only one of the three patients who did not begin ribavirin therapy showed a reduction in HCV load. The other two participants dropped out.
"This study laid the groundwork for understanding the treatment of HCV in HIV-infected persons" said Dr. Norbert Bräu, lead author of the report. "We learned that treatment is possible, but maintaining patients on therapy can be difficult due to the rigorous treatment schedule, side effects of the drugs, and behavioral issues, such as substance abuse, that are common in the co-infected group. In addition, we have a better understanding of side effects, specifically hemolytic anemia, due to ribavirin, and potential ways to prevent it." As clinicians gain experience in treating HCV infection in people with HIV, he added, they will be better able to manage the drug-related side effects, leading to fewer discontinuations of therapy and better outcomes.