Infection with multiple HCV genotypes linked to faster HIV disease progression

Concurrent infection with more than one genotype of hepatitis C virus (HCV) is associated with more rapid HIV disease progression, according to a European study published in the November 19^th, 2004 edition of AIDS.

HIV/HCV coinfection has been linked to more rapid liver disease progression, but its effect on the course of HIV disease progression remains controversial and recent studies have yielded conflicting data. One possible reason for these disparate results is that the effect of hepatitis C on HIV disease progression may vary by HCV genotype.

Researchers with the European Seroconverter Study and the Italian Seroconverter Study analyzed data from 126 HIV/HCV-coinfected injecting drug users from seven European countries (Austria, France, Italy, the Netherlands, Scotland, Spain, and Switzerland) with known dates of HIV infection. About two-thirds (68%) were male, and the average age at HIV seroconversion was 27 years.

Participants’ HCV genotypes were determined early in the course of HIV infection. Genotype 1 was most common (48%), followed by genotype 3 (34%), genotype 4 (13%), and genotype 2 (1%); 5% were infected with more than one HCV genotype (one subject with 1b and 3a; four with 1b and 4; and one with 3a and 4). None of the participants were receiving treatment for hepatitis C.

The researchers analysed the effect of highly active antiretroviral therapy (HAART), which became available between March 1996 and September 1966 (depending on study site). By July 1997, 60% of subjects had started HAART, and by January 1999, the proportion was 75%.

Participants with missing CD4 cell measurements or whose CD4 counts were less than 200 cells/mm³ at baseline were excluded from the analysis of immunological progression, leaving data from 108 subjects. After a median follow-up period of 7.3 years, subjects with HCV genotype 1 and those with multiple HCV genotypes experienced more rapid immunological progression to a CD4 cell count of 200 cells/mm³ or fewer, compared with genotype 3 patients (adjusted hazard ratio 2.02, 95% CI 1.04-3.92 for genotype 1; HR 2.74, 95% CI 0.95-7.90 for multiple genotypes). When the analysis was limited to pre-HAART data, the differences were even greater (HR 3.92, 95% CI 1.51-10.20 for genotype 1; HR 4.38, 95% CI 1.04-18.40 for multiple genotypes).

Further breaking down the data from the whole study period, the researchers determined that the increased risk of immunological decline was linked to infection with HCV genotype 1a, but not 1b. Moreover, subjects with only genotype 4 - which the researchers identified as being “on the rise among injecting drug users” - experienced significantly slower immunological progression than those with only genotype 1.

Overall, patients with multiple HCV genotypes also experienced faster clinical progression to AIDS or pre-AIDS death (excluding non-natural causes such as overdose, suicide, or accidents), but this did not reach statistical significance (HR 3.36, 95% CI 0.82-13.79). Looking only at data from the pre-HAART era, however, subjects infected with more than one genotype had a significantly higher risk of clinical progression than those with only genotype 3 (HR 6.54, 95% CI 1.39-30.76). Unlike immunological decline, infection with genotype 1 alone was not associated with more rapid clinical progression, and no significant differences in clinical progression were observed when comparing subjects with only genotype 1, 3, or 4.

The authors concluded that HIV disease progression differs by HCV genotype, “being especially enhanced in those harbouring HCV infection involving more than one HCV genotype.” Given that the difference was much greater before the advent of HAART, they suggested that efficacious combination antiretroviral therapy “may diminish the effect of HCV genotype on HIV disease progression.”

In their discussion, the authors noted that it is not yet known how multiple HCV genotypes might cause faster HIV disease progression, although other researchers have suggested that different genotypes many interact differently with the HIV virus, or may have differing effects on CD4 cell proliferation within the liver. Since HCV may be cleared naturally by the immune system or eradicated with treatment, and since prior infection with one HCV strain does not prevent subsequent reinfection, the authors recommended that “HCV genotype should ideally be measured prior to HIV infection and longitudinally at different time-points within HIV-infected individuals to gain a better understanding of the effect of HCV genotype on HIV progression.”