Modulation of HCV replication after combination antiretroviral therapy in HCV/HIV co-infected patients

Abstract

The hepatitis C virus (HCV) is an important contributor to morbidity and mortality in patients co-infected with HIV. Co-infection results in increased HCV replication and more rapid rates of liver disease progression. The effect of HIV combination antiretroviral therapy (cART) on HCV replication has not been studied in depth. To address this issue, we enrolled a small cohort of HCV/HIV co-infected patients into a cART initiation trial and used dynamic modeling combined with evaluation of immune responses and microarray profiles to determine how effective treatment of HIV affects HCV. Treatment with cART resulted in increased HCV replication and increased alanine aminotransferase (ALT) in a subset of patients. Subjects with evidence of hepatic injury (increased ALT) were more likely to have HCV-specific immune responses directed against HCV epitopes. Over time, HCV viral loads declined. Reproducible and biologically important gene expression changes occurred in co-infected patients who underwent successful cART. The effective suppression of HIV by cART initiated a cascade of early and late events in treated patients. Early events involving down-regulation of interferon-stimulated genes may have led to transiently increased viral replication and hepatic injury. At later time points, HCV viral load declined to levels comparable to those seen in the setting of HCV monoinfection. These findings support early antiretroviral therapy in those with HCV/HIV co-infection.

Figure 1

ALT levels (U/L, units per liter) for all subjects from baseline through week 24 of cART treatment. ALT is a marker of hepatocyte injury. Points show mean values for weeks 0, 4, 12, 16, 20 and 24. Bars show S.E.M.

Figure 2

The necroinflammatory component score represents a composite measure of inflammation and injury as described by Ishak et al (J Hepatology, 1995). Paired scores show baseline activity at pretreatment screening and following biopsy after subject met protocol-specified criteria for increased HCV RNA or serum ALT.

Figure 3

Heat map of gene expression changes that occurred following cART treatment in HIV/HCV co-infected patients. Gene expression changes are depicted as the ratio of gene expression at 24 weeks following cART compared to baseline gene expression prior to treatment. Genes that decrease from their baseline values are blue, and those that increase are red. Four clusters are indicated corresponding to genes that (i) increased or (ii) decreased following cART treatment in the patients whose HCV titers rose, (iii) that increased in response to cART for nearly all patients, and (iv) that decreased in response to cART. A change in expression pattern can be seen between the first 6 patients on the left who had a drop in HCV titer, as compared to the 2 patients on the right who had a rise in titer.