An estimated 150–300 thousand persons are infected with both hepatitis C virus (HCV) and HIV in the United States. Although the management of hepatitis C in HIV infected persons in 2002 is largely predicated on data from persons without HIV, it is important to appreciate the extent to which HIV infection may modify the transmission, natural history, diagnosis, and treatment of hepatitis C. ⁽¹⁾

Transmission

In more than 60 percent of published studies, the rate of HCV transmission from an HIV/HCV co-infected mother to her infant is greater than from HIV uninfected mothers. Increased heterosexual HCV transmission from HIV/HCV co-infected persons also has been reported, but in fewer than half of studies. Nonetheless, these data do not substantially modify existing United States Public Health Service recommendations for recognition and prevention of HIV and HCV transmission. ^(2,3)

Natural History

In the majority of published studies, progression of hepatitis C to cirrhosis and end-stage liver disease occurs more rapidly and in a greater proportion of HIV/HCV co-infected persons, and in several hemophilia cohorts and HIV treatment clinics, end-stage liver disease is a or the leading cause of death among HIV infected persons. Although the risk of cirrhosis associated with HIV infection varies substantially in different settings, in a meta-analysis, Graham and coworkers estimated that the average risk of progressive liver disease is 2.9-fold (95 percent CI, 1.7–5.0) higher in HIV/HCV co-infected persons. ⁽⁴⁾ Large prospective studies are needed in unbiased HIV/HCV co-infected populations to characterize the risk of cirrhosis more precisely. In the meantime, decisions regarding the timing of medical treatment and the frequency of monitoring HIV/HCV co-infected persons (e.g., by liver biopsy or with fibrosis markers, if available) should be commensurate with the observed increased risk and rate of progression to end-stage liver disease.

Diagnosis and Screening

Because the prevalence of hepatitis C is increased in HIV infected persons and HIV/HCV co-infected persons have an increased risk of cirrhosis and HAART-related liver toxicity, the United States Public Health Service and Infectious Diseases Society of America recommend that all HIV infected persons be screened for hepatitis C by using an enzyme immunoassay for detection of antibodies to HCV^{. (3)} HCV antibodies can be detected in the majority of HIV/HCV co-infected persons. However, in some studies HCV antibodies were not be detected in up to  10 percent of HIV/HCV co-infected persons, especially in those with advanced HIV-related immune suppression (CD4+ lymphocytes < 100/mm 3 ). Thus, it is reasonable to test for HCVRNA in HCV antibody negative, HIV infected persons with unexplained liver enzyme elevations.

Treatment

No medications are approved by the United States Food and Drug Administration for the treatment of HCV infection in HIV infected persons, reflecting the absence of completed, randomized controlled trials investigating the treatment of more than 100 HIV/HCV co-infected persons. Therefore, the timing and choice of medical treatment for HIV/HCV co-infected persons are largely driven by their increased rate of progression of liver disease and the results of treatment of HIV uninfected persons.

Nonetheless, a number of important issues in the treatment of hepatitis C in HIV infected persons can be addressed by accumulating published and formally presented data. 1. Sustained virologic responses can be achieved in HIV infected persons. Soriano et al. have demonstrated loss of HCV RNA from serum for >3 years after a course of interferon alpha in HIV infected persons. ⁽⁵⁾

2. The addition of ribavirin to interferon alpha improves the likelihood of on-treatment (and presumably sustained) virologic responses in HIV/HCV co-infected persons. In an interim analysis of data from 110 HIV/HCV co-infected persons randomized to interferon alfa-2b with ribavirin or placebo, HCV RNA was undetectable after 12 weeks of therapy among 23 percent of persons receiving combination therapy compared to 5 percent of those receiving interferon alone. ⁽⁶⁾

3. On-treatment virologic responses to pegylated interferon and ribavirin are better than responses to unpegylated interferon alpha and ribavirin. In ACTG a5071, in which 134 persons were randomized to pegylated interferon alpha plus ribavirin or unpegylated interferon alpha plus ribavirin, week 24 virologic responses were noted in 15 percent of those in the unpegylated arm vs. 44 percent of those randomized to pegylated interferon alpha, an effect that was also observed among persons with genotype 1 infection (7 percent vs. 33 percent, respectively). ⁽⁷⁾

4. Although in vitro studies suggest ribavirin may diminish the efficacy of AZT, d4T, and 3TC, and increase levels of ddI, in several small published and presented case series, HIV RNA levels do not increase more in HIV/HCV co-infected persons taking ribavirin than in controls. Given apparent benefits and the burden of disease, many experts currently recommend its use in the treatment of hepatitis C in HIV/HCV co-infected persons, with careful monitoring.

5. As with HIV uninfected persons, the likelihood of a sustained virologic response in HIV/HCV co-infected persons varies by HCV genotype, pretreatment immune status, and other factors like HCV RNA level, stage of liver disease, gender, possibly race, and duration of treatment, which may need to be longer when virologic responses are delayed and in immunosuppressed persons.

6. Some HIV/HCV co-infected persons will not be able to take existing medical therapies, and liver transplant is rarely available for HIV/HCV co-infected persons.

Conclusion

Given the mounting morbidity and mortality associated with hepatitis C in HIV infected persons, the management tools (e.g., HCV RNA testing and liver biopsy) and therapies (e.g., pegylated interferon alpha and ribavirin) recommended for management of hepatitis C in persons without HIV should be made available for HIV/HCV co-infected persons while research is vigorously conducted to demonstrate their optimal use.

References

1. Sulkowski MS, Thomas DL. Hepatitis C in the HIV infected Patient. Ann Intern Med 2002(in press).

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2. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47 (No. RR-19):1–39.

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3. CDC. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: disease-specific recommendations. MMWR 1999;48:1–82.

4. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, Koziel MJ. Influence of human immunodeficiency virus infection on the course of hepatitis c virus infection: a meta-analysis. Clin Infect Dis 2001;33:562–9.

5. Soriano V, Bravo R, García-Samaniego J, Castilla J, González J, Castro A, Llibre JM. Relapses of chronic hepatitis C in HIV-infected patients who responded to interferon therapy. AIDS 1997;11:400–1.

6. Kostman JR et al. Results of a multicenter, randomized, double-blind, controlled trial of interferon alfa-2b/ribavirin combination therapy in HCV/HIV co-infected persons. Program and abstracts of The 1st IAS Conference on HIV Pathogenesis and Treatment; July 8–11, 2001; Buenos Aires, Argentina. Abstract 555.

7. Cheung R, Andersen J, Alston MV, Robbins G, Nevin T, Colquhoun D, Sherman K, Peters M, Harb G, Volderding P, van der Horst, C. A randomized controlled trial of pegylated interferon alpha-2a with ribavirin versus interferon alpha-2a with ribavirin for the treatment of chronic HCV in HIV co-infection. ATG A5071. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, 2002. Abstract LB15.