It has been established that hepatitis C virus (HCV) genotype and HCV viral load are the strongest predictors of sustained virological response (SVR) in HIV positive patients treated with pegylated interferon plus ribavirin.

Several studies conducted since the introduction of effective combination antiretroviral therapy, or HAART, have evaluated the impact of antiretroviral therapy on HCV RNA levels in coinfected patients. Most showed that HCV viral load did not decrease during the first months of antiretroviral treatment, and might even increase significantly (by at least 0.5 log10) in some patients.

Furthermore, the lower rate of virological response to anti-HCV therapy observed in studies of coinfected patients might be due to a high level of HCV replication in individuals with suppressed immunity.

Some researchers have suggested that HAART might produce a significant decrease in HCV RNA load after 12 months of successful antiretroviral treatment, and might lead to HCV clearance in some cases. However, studies of this hypothesis have been limited by their small sample size or short follow-up period (no longer than 1 year).

In the June 1, 2008 Journal of Acquired Immune Deficiency Syndromes, French researchers reported on changes in plasma HCV RNA viral load during the first 24 months after initiation of protease inhibitor (PI)-containing HAART among HCV-HIV coinfected participants enrolled in the Agence Nationale de Recherches sur le SIDA (ANRS) CO8 APROCO-COPILOTE cohort study.

The APROCO-COPILOTE cohort is a prospective observational cohort in France looking at the effects of PI-based regimens in the context of routine clinical care. A total of 1281 HIV positive, antiretroviral-naive patients infected were enrolled between May 1997 and June 1999 at the time they initiated a PI-containing HAART regimen.

Patients were eligible for inclusion in the current study if they were HCV-infected and had detectable plasma HCV RNA using a sensitive polymerase chain reaction (PCR) assay. Both individuals who had never been treated for hepatitis C and those who had received previous anti-HCV treatment at least 6 months before without documented virological response were eligible; those receiving anti-HCV treatment during the follow-up period, however, were excluded.

At baseline, plasma HCV viral load did not differ significantly according to age, sex, duration of HIV infection, CD4 cell count, plasma HIV RNA level, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values, or HCV genotype.

Plasma samples were evaluated at baseline and after 4, 12, and 24 months of PI-based therapy, using a single laboratory. The following potential determinants of plasma HCV load were considered for statistical analysis: patient age, sex, HIV transmission risk group, AIDS stage at baseline, HCV genotype, type of PI initially prescribed, and duration of PI therapy.

Results

In this study, researchers were able to evaluate HCV viral load changes in a large population of coinfected patients during a longer follow-up period than those of previous studies. Plasma HCV RNA levels did not change significantly in a majority of patients receiving HAART regimens containing a PI over a 24 month-period, but individual responses were variable, with increases and decreases tending to cancel each other out. HCV clearance was obtained in 4% of patients.

"It is highly plausible that the observed results are linked to the effect of regression to the mean rather than representing a true biologic variation," the study authors noted. "There was no association between HCV load variation and viro-immunologic parameters linked to HIV disease."

With regard to the observed HCV clearance in 4% of patients, the study authors wrote, "Whether this represents spontaneous clearance or is linked to antiretroviral therapy cannot be solved.

"A CD4 cell response against HCV antigens (primarily core antigens) can be observed in peripheral blood mononuclear cells (PBMCs) in HCV-HIV-coinfected patients receiving [combination antiretroviral therapy]," they continued. "This response may be restored by [combination antiretroviral therapy], explaining the suppression of HCV RNA." But they also observed that, conversely, HCV viral load strongly increased in 3 patients who had an undetectable HCV load before initiation of [combination antiretroviral therapy].

"To our knowledge, such a phenomenon has never been described, although an increase in HCV load has been reported. The increased number of cytotoxic T lymphocytes might cause immune-mediated lysis [destruction] of HCV-infected cells, resulting in intracellular virus release," they suggested. "Alternatively, decreased HIV RNA levels could be associated with reduction in endogenous alfa-interferon, favoring an elevated HCV load."

In summary, the authors concluded that PI-containing HAART is most often not associated with biologically significant changes in HCV viral load in the first 24 months after its initiation. However, they noted, "Strong individual variations can be observed, ranging from a high increase in HCV load to HCV clearance."

Based on these findings, they recommended that, "HCV-HIV coinfected patients should receive specific treatment of their hepatitis C, preferably before starting [combination antiretroviral therapy]."

Centre Hospitalier Universitaire de Bordeaux, Hôpital Pellegrin, Fédération des Maladies Infectieuses et Tropicales, Bordeaux, France; Université Victor Segalen Bordeaux 2, Laboratoire de Virologie EA 2968, Bordeaux, France; INSERM, U593, Université Victor Segalen, ISPED, Bordeaux, France; Laboratoire de Pathologie Infectieuse, Faculté Xavier Bichat, Paris, France; Université Nantes, JE2437, Nantes, France.

7/04/08

Reference

D Neau, P Trimoulet, E Pereira, and others (ANRS CO8 APROCO-COPILOTE Study Group). Evolution of plasma hepatitis C virus load in patients coinfected by HIV and hepatitis C virus started on a protease inhibitor-containing antiretroviral regimen, Agence Nationale de Recherches sur le SIDA CO8 APROCO-COPILOTE Cohort [Letters to the Editor]. Journal of Acquired Immune Deficiency Syndromes 48(2): 227-229. June 1, 2008.

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