HIV and Hepatitis Co-Infections Challenging

BOSTON, April 6 -- Co-infection with HIV and either hepatitis B or C remains a clinical challenge, but new therapies appear to have increased the opportunities for effective treatment.

The risk of death from hepatitis is inversely related to the degree of immune system compromise as measured by the CD4 cell count, said Margaret James Koziel, M.D., of Harvard and Marion Peters, M.D., of the University of California San Francisco, in a review in the April 5 issue of the New England Journal of Medicine.

Liver disease among co-infected patients is "becoming a leading cause of death" worldwide, they pointed out.

The prevalence of HCV and HBV infection among HIV-positive people varies depending on risk factors for transmission, the researchers noted. HCV spreads most easily through exposure to contaminated blood or blood products, so that it is linked to patients with hemophilia or a history of intravenous drug use. Among these patients, rates of co-infection approach 70% to 95%, compared with 1% to 12% among men who have sex with men.

On the other hand, HBV is typically acquired during sexual activity in adolescence or young adulthood. Chronic infection develops in 20% of adults with HIV infection after exposure to HBV. The overall prevalence of chronic HBV infection among HIV-positive persons in the U.S. and western Europe is less than 10%, and it is highest among men who have sex with men and among intravenous drug users.

The main effect of HIV on HCV infection is to accelerate the natural history of the disease, Drs. Koziel and Peters said, although immune restoration with antiretroviral therapy lowers the death rate from liver disease.

The effect of HCV infection on the progress of HIV is less clear. Some reports indicate that HCV slows immune reconstitution, but the effect is modest. At the same time, hepatotoxic effects of HIV therapy are more likely to develop in patients with HCV and HBV.

There is no non-invasive test to predict the degree of injury in HCV-HIV co-infected patients, so many specialists recommend a liver biopsy, to aid in the choice of treatment options.

The goal in HCV therapy is to reach an undetectable level of serum HCV RNA six months after the end of therapy, and the standard of care is pegylated interferon alfa (Pegasys) plus ribivarin (Copegus, Rebetol).

In mono-infected patients sustained responses are seen in up to 55% of patients with HCV genotypes 1 or 4 and up to 80% in those with genotypes 2 and 3.

In co-infected patients, clinical trials have shown response rates that are slightly lower -- between 14% and 44% for genotypes 1 and 4 and between 44% and 73% for the other genotypes.

A key factor is early virological response, defined as no detectable serum HCV RNA or at least a reduction by a factor of 100 after 12 weeks of therapy, Drs. Koziel and Peters said.

"If a patient has not had an early virologic response, the likelihood of a sustained virologic response is negligible," they said.

It's also important to note that ribivarin can interact with some antiretroviral medications, so that modifying HIV therapy may be necessary before starting HCV treatment, they said.

Future directions include:

• The long-term administration of interferon, in the hope of preventing the progression of fibrosis, even without a cure.
• New agents targeting the serine protease and RNA-dependent RNA polymerase proteins.
• The possible benefits of liver transplants in co-infected patients.

The risks in cases of HBV-HIV co-infection are similar -- cirrhosis, end-stage liver disease, and death -- and treatment goals are the suppression of viral replication and improvement in liver disease, Drs. Koziel and Peters said.

"Patients with HIV infection, if nonimmune, should be vaccinated against both hepatitis A virus (HAV) and HBV because of the increased severity of hepatitis in patients with preexisting liver disease. Failure to induce immunity to HAV and HBV is a function of both missed opportunities for vaccination and the immunocompromised state," they wrote.

"In HIV-infected persons, antibody titers after vaccination are lower and less durable than they are in those who do not have HIV infection, and fewer HIV-infected persons have protective levels of antibodies against hepatitis B surface antigen (HbsAg). The rates of response to HAV or HBV vaccines decrease with lower CD4 cell counts and higher levels of HIV RNA."

Long-term therapy of HBV infection is the rule, with nucleoside and nucleotide reverse transcriptase inhibitors, such as lamivudine (3TC) and telbivudine (Tyzeka). Pegylated interferon alfa is effective in mono-infection, but hasn't been tested in patients with both HBV and HIV.

Lamivudine shouldn't be used alone, because of high levels of resistance, approaching 20% to 25% in a year and 90% after four years of therapy, the researchers said.

In patients who need treatment for HBV but not HIV, it's important to choose medications without activity against HIV in order to avoid generating drug-resistant HIV strains.

(Researchers reported at this year's Conference on Retroviruses and Opportunistic Infections that entecavir (Baraclude) may cause HIV resistance when used in patients not being treated for HIV. CROI: HIV Resistance Linked to Hepatitis Drug)

One important area for future research is the long-term efficacy of combination regimens, the authors said, both in patients with HIV alone and HIV and HBV together.