Reply to Antonucci et al.

    Los Angeles Biomedical Research Institute at HarborUniversity of California, Los Angeles, Medical Center, Division of HIV Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles
    Rho, Chapel Hill, North Carolina
    The Chinese University of Hong Kong, School of Public Health, Hong Kong, China

    We read with great interest the letter by Antonucci et al. [1] responding to our article describing the relationship between hepatitis C virus (HCV) genotype and HCV RNA load, CD4+ T cell count, and HIV-1 disease progression [2]. Our study, which was conducted in HIV-1/HCVcoinfected children and adolescents with hemophilia enrolled in the Hemophilia Growth and Development Study (HGDS), made the novel observation that, compared with those with HCV nongenotype 1 infection, those with HCV genotype 1 infection had lower absolute and percentage CD4+ T cell measurements. As with any new finding, confirmation in other cohorts and further study to determine whether the results can be extrapolated to other populations are vital. Antonucci et al. performed a related analysis in a cohort of 302 patients followed longitudinally in the Italian Cohort Naive for Antiretrovirals (I.Co.N.A.). This cohort was considerably different from the HGDS cohort, being an adult cohort of whom 24% were women and 84% had injection drug use as the primary risk factor for HIV-1 infection. In addition, the study population included a larger percentage of patients with nongenotype 1 infection than did the HGDS cohort (49% vs. 22%). Despite these differences, Antonucci et al. found the same relationship between HCV genotype and CD4+ T cell count that we reported in our study. Although follow-up of the I.Co.N.A. was limited to a mean of 4.6 months, compared with up to 7 years for the HGDS cohort, Antonucci et al. also failed to see a difference in change over time in CD4+ T cell count by HCV genotype.

    In the editorial commentary by Núez and Soriano that accompanied our article [3], it was proposed that the difference in CD4+ T cell count may have been related to the higher HCV RNA loads seen in those infected with HCV genotype 1, an observation made in the HIV-1/HCVcoinfected (P = .038) and the HIV-1uninfected (P = .008) HGDS participants [2] as well as by others [48]. Antonucci et al. reported that they did not observe a difference in HCV RNA load by HCV genotype in the I.Co.N.A. Furthermore, they showed that the difference in CD4+ T cell count by HCV genotype remained unchanged even when adjusted for HCV RNA load. Because we had previously shown in the HGDS cohort an independent relationship between HCV RNA load and HIV-1 disease progression [9]an observation subsequently confirmed by Herrero-Martinez et al. [5]we also considered this possibility. In our article, we described how the addition of HCV RNA load to the Cox proportional hazards model minimally influenced the relationship between HCV genotype 1 and AIDS-related mortality [2]. Moreover, we have since reanalyzed the data and have found that adjusting for HCV RNA load does not alter the significant association between HCV genotype 1 and decreased absolute (P = .035) and percentage (P = .03) CD4+ T cell measurements.

    We agree with Núez and Soriano and with Antonucci et al. that the observed relationship between HCV genotype and CD4+ T cell count in HIV-1infected individuals requires further exploration. In their editorial commentary, Núez and Soriano suggested several mechanisms that might explain these findings, including the possibility that HCV has a direct effect on CD4+ T cells [10], as we had proposed in our original study [2]. Although this possibility cannot be excluded, our data suggest that the relationship between HCV genotype and CD4+ T cell count is specific to those coinfected with HIV-1 and HCV, because no relationship between HCV genotype and either absolute or percentage CD4+ T cell measurements was identified in the HIV-1uninfected participants in the HGDS cohort [2]. Further investigation is needed, to better define both the interactions between HIV-1 and HCV infection and how HCV RNA load and genotype influence the natural history of HIV-1 disease.

    References

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    2.  Yoo TW, Donfield S, Lail A, Lynn HS, Daar ES. Effect of hepatitis C virus (HCV) genotype on HCV and HIV-1 disease. Hemophilia Growth and Development Study. J Infect Dis 2005; 191:410. First citation in article

    3.  Núez M, Soriano V. Hepatitis C virus (HCV) genotypes and disease progression in HIV/HCVcoinfected patients. J Infect Dis 2005; 191:13. First citation in article

    4.  Hofmann H. Genotypes and virus load in patients with hepatitis C infection. Infection 1995; 23:1338. First citation in article

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    7.  Berger A, Prondzinski MVD, Doerr HW, Rabenau H, Weber B. Hepatitis C plasma viral load is associated with HCV genotype but not with HIV coinfection. J Med Virol 1996; 48:33943. First citation in article

    8.  Garcia F, Roldan C, Hernandez-Quero J, et al. Relationship between viral genotype and viral load in patients with chronic hepatitis C. Eur J Clin Microbiol Infect Dis 1996; 15:8847. First citation in article

    9.  Daar ES, Lynn H, Donfield S, et al. Hepatitis C virus load is associated with human immunodeficiency virus type 1 disease progression in hemophiliacs. J Infect Dis 2001; 183:58995. First citation in article

    10.  Laskus T, Radkowski M, Piasek A, et al. Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: evidence of active replication in monocyte/macrophages and lymphocytes. J Infect Dis 2000; 181:4428. First citation in article