A research team investigates the causes of liver injury in those on HAART
by Chael Needle
LifeGuide
Treatment Horizons
If a patient on HAART who is HIV/hepatitis C-coinfected starts to show abnormal liver function, then a physician more than likely will strongly consider taking that patient off antiretrovirals. But what if HAART, which has often been theorized as a cause of liver injury, is not to blame? Without this answer, patients might miss out on the benefits of a treatment that had been working well for them and risk HIV viral load rebounds.
Researchers at the University of Cincinnati (UC) Academic Health Center have been awarded a $3.4 million, five-year NIAID grant to work toward this answer by evaluating the causes of liver injury following use of antiretroviral drugs for HIV/HCV-coinfected patients.
“Liver disease has emerged as a major disease of morbidity and mortality in patients with HIV in Western countries, at least where antiretroviral therapies are available,” notes Dr. Kenneth Sherman, MD, PhD, director of the UC College of Medicine’s Digestive Disease Division and principal investigator of the trial.
Dr. Sherman’s grant proposal evolved out of an earlier study, where he and Boston-based Dr. Ray Chung looked at the relationships between HIV, HAART, and hepatitis within an AIDS Clinical Trials Group (ACTG) patient cohort. They found that, among patients who were initiating HAART, many had a “bump” in HCV viral loads. The “bump” occurred regardless of which antiretroviral agents had been used. This observation went against expectations: With HAART helping to restore immune functions, one would think that all other infections would be better controlled, says Sherman. He noted that “among patients treated with effective HAART, previously common opportunistic infections like Kaposi’s sarcoma and pneumocystis have become rare.”
What might explain this paradoxical increase in HCV viral load? To answer this question, Sherman needed a better defined population than the ACTG cohort study had permitted. When Abbott Laboratories accepted his proposal to access its Phase III Kaletra approval trials, he found that population: treatment-naive patients randomized to receive either lopinavir/ritonavir or nelfinavir, each “with the same stable nucleoside backbone.” Dr. Sherman and his team were able to study those with HVC, and see what happened through the treatment trial.
They found that in both treatment regimen arms HCV viral load increased. In both the nelfinavir arm and the lopinavir/ritonavir arm, these increases were “associated with the development of ALT flares, in most cases, at the time when HCV was increasing.” Levels of ALT, an enzyme produced in liver cells, often increase because of liver inflammation or damage. For the purposes of this protocol, a flare was defined as a doubling of ALT levels.
As a hepatologist who works closely with a large HIV group at UC, Dr. Sherman has frequently heard from physicians who, after noting flares in patients at twelve to fifteen weeks after initializing HAART, want to stop HAART for fear of drug toxicity. Many of these flares, at least in patients with HCV, however, might not be a result of drug toxicity but rather this paradoxical ALT flare associated with initiation of HAART and subsequent immune response. The present five-year study will test hypotheses about the cause of these ALT flares. Finding out what happens in this context is important, says Dr. Sherman, to determine treatment approaches for HIV/HCV coinfected patients.
The study is a small clinical trial of thirty coinfected patients, at both UC and NYU, who will be treated with standard therapies. Dr. Sherman reminds us that the type or class of drug does not seem to matter in terms of ALT flares associated with initiating HAART, only that flares seem to occur when effective therapy is used. “Although there may be some drug differences, that drug difference may be more due to efficacy in terms of actually restoring immune status rather than simply a direct drug effect.”
Through very frequent sampling of patients, the researchers will develop mathematical kinetic models similar to those used in the early days of ART. But while those models were used to analyze HIV viral decline, these models will focus on what happens during HCV viral increase, and specifically in relation to HIV viral decline. The researchers will investigate the possible emergence of a “more fit, more replicative or active strain [of HCV] during the early stages of immune reconstitution;” study CTL responses “to see how an emerging regenerated immune system is associated with this injury process;” obtain liver biopsies from patients whose ALT flares reach certain levels; and study intrahepatic hepatitis C viral replication and the associated immune response and try to evaluate the specific HCV immune responses in those patients, among other concerns of liver injury.
Though the results of the study are still a long way off, Dr. Sherman stresses the importance of finding out the causes of liver injury. Citing several U.S.-based studies and a major French study, Dr. Sherman offers that in “those with underlying HBV and HCV, more patients die of liver disease in recent years than die of typical AIDS-related complications.”
Chael Needle wrote about protease inhibitor-resistant HIV for the April issue.
May 2006
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