December 18, 2006

Early Therapy for HIV/HCV Coinfected
(AIDSmeds.com)

(AIDSmeds.com)—A new study suggests that people living with both HIV and hepatitis C virus (HCV) infection shouldn't wait until their CD4 (T4 cell) counts fall below 300 before starting antiretroviral therapy. The results were published in the December issue of the online medical journal PLoS Medicine by researchers from the Partners AIDS Research Center (PARC) at Massachusetts General Hospital (MGH) in Boston.

Because HIV and HCV have overlapping transmission routes – such as contaminated blood products, sharing drug injection needles, and unprotected sex – between 25% and 33% of people living with HIV are coinfected with HCV.

Most people who are infected with HCV experience chronic disease, leading to life-threatening liver damage (hepatitis). While it usually takes decades for HCV infection to causes liver failure, people infected with HIV and HCV can experience more rapid disease progression. What's more, as the health of liver becomes compromised due to HCV infection, antiretroviral therapy can be less effective and tolerable.

Over the years, researchers have found that a sizable minority of people who are infected with HCV manage to control the virus and never get liver disease. Studies involving these people suggest that their immune systems mount a strong immune response to HCV.

Researchers at PARC have been studying similar immune responses in long-term nonprogressors (LTNPs), a small group of HIV-positive people who maintain very low viral loads and higher CD4 cell counts for many years without antiretroviral therapy.

Many of these patients, PARC investigators and other groups suggest, have particularly robust HIV-specific CD4 and "killer" CD8 cell responses that maintain control of HIV replication very early on in the course of infection. Similar CD4 and CD8 cell responses have been shown to play a role in the control of HCV infection.

Building upon this knowledge, the PARC researchers set out to understand how infection with HIV compromises CD4 and CD8 responses to HCV and, ultimately, the control of HCV disease progression.

The PARC research team recruited 94 patients, all of whom were infected with HCV, and divided them into four groups. Once group was made up of patients with HIV and HCV coinfection, all of whom had high HCV viral loads. A second group consisted of coinfected patients with undetectable HCV viral loads. The two other groups included patients infected with HCV but not HIV, either with high or undetectable levels of HCV.

The researchers focused on the individuals who, despite coinfection with HIV, were able to control their HCV infection. They found that those individuals managed to maintain relatively high levels of CD4 and CD8 cells that specifically recognize HCV.

However, a quarter of these patients failed to maintain undetectable HCV viral loads over an observation period of 2.5 years. This HCV viral load rebound was associated with a drop in the HCV-specific CD4 cell response. Following HCV viral load rebounds in these patients, HCV did not return to undetectable levels during the study. During the same period, none of the 16 HIV-uninfected people with controlled HCV infection experienced a recurrence of detectable HCV.

Of interest, the researchers discovered a common feature among the coinfected patients who were able to maintain low HCV viral loads. Maintaining higher CD4 cell counts, either through long-term nonprogression of HIV or the use of antiretroviral therapy, was the most important shared characteristic of these individuals. In other words, coinfected patients who did not let their CD4 cell count fall below 300 were more likely keep their HCV infection in check, compared to those who saw their CD4 counts fall below this threshold.

These results, the authors suggest, may have significant implications for people infected with both HIV and HCV. A primary finding of this study is that HCV control is lost in HIV-positive people with depleted CD4 counts, notably counts below 300. In turn, early antiretroviral treatment may be of significant benefit to coinfected patients.

"T-cell responses against HCV are preserved by avoiding CD4+ cell depletion due to progressive HIV infection," the researchers write," indicating a potential immunologic benefit of treatment of HIV in coinfected individuals before the CD4 cell counts fall below 300 cells per microliter, a threshold at the higher end of the current range where initiation of treatment is typically recommend."

"Currently a nationwide trial is recruiting people for a study examining whether earlier treatment of HIV will improve hepatitis C treatment outcomes," says Arthur Kim, MD, of PARC and a lead investigator of the study. "Part of this study will investigate how earlier treatment may affect immune responses. It also will be important to follow the impact of loss of HCV control on liver disease, since this will probably have important consequences for patients with HIV."

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