Almost 2 years ago I reviewed the topic of hepatitis C virus (HCV) infection in the setting of HIV.1 Given the advances-and some setbacks-in our understanding of HCV pathogenesis and treatment in the coinfected population, it's time for an update. First, some good news: the prevalence of HCV coinfection in men who have sex with men (MSM) at risk for HIV disease remains low, at least in the United States.2 Sexual transmission of HCV does occur, but it is very inefficient, and HCV serologies should not be used routinely for HIV-negative MSM who lack other risk factors for hepatitis C.2 This recommendation was supported by a recently published survey conducted from 1999 through 2003 of public health sexually transmitted disease clinics and HIV testing programs in New York City, Seattle, and San Diego, in which all clients were offered hepatitis C counseling and testing.2 Among 1699 clients who were not injection drug users (IDUs) and who were MSM, only 1.5% tested positive for HCV, and 3.6% of 3455 "non-IDU, non-MSMs" were HCV-positive. In contrast, the prevalence of HCV seropositivity in male and female IDUs ranged from 47% to 57% (mean, 51%) in this survey.2 But implementation of prevention activities appears to be having an impact. In 1987, HCV seroprevalence among San Francisco IDUs was 75.9% for those injecting less than 2 years and 91.1% for those injecting for 6 to 9 years.3 By 2000, these figures fell to 46.8% for those injecting less than 2 years, and 71.3% for those injecting 6 to 9 years (P < .0001).3 However, all IDUs should still clearly be evaluated for hepatitis C. In addition, cognizant of the serious consequences of potential interactions between HCV and HIV, all HIV-positive persons, including MSM, should be tested for hepatitis C regardless of reported risk factors. Liver-related disease continues to increase in the HIV-infected population. In a EuroSIDA observational longitudinal study of 10,937 persons, there was a 13% annual increase of death due to liver disease (P < .0001) and a 12% annual increase of death for those receiving antiretroviral therapy (P < .02).4 The strongest correlate of liver-related mortality was HCV seropositivity at study recruitment (45.7% vs 16.7%), and only 4% of the cohort had received treatment for hepatitis C.4 Neither sex, age, race, geographic region, nor antiretroviral use was implicated in the development of liver-related disease.4 Antiretroviral treatment may, indeed, afford some protection in this setting. In another study, HIV/HCV-coinfected patients who received highly effective antiretroviral therapy as their initial treatment for a mean of 3.3 years had liver histological results comparable to those in patients with HCV monoinfection for necroinflammatory score, rate of fibrosis progression, prevalence of cirrhosis, and mean time to development of cirrhosis.5 A survey of 1011 coinfected persons followed for a mean of 5.3 years confirmed that end-stage liver disease is the main cause of death for those receiving antiretroviral therapy.6 However, a significant increase in CD4 counts after HIV treatment initiation and the proportion of time with undetectable HIV viral load were independent markers of good hepatic outcomes in this study. There are several means by which HIV could accelerate liver-related disease in HIV/HCV-coinfected persons. Apart from steatohepatitis and cirrhosis, hepatitis C is associated with 47% of cases of liver cancer, compared with a 15% association with hepatitis B virus (HBV) infection and 5% occurring in the setting of HBV/HCV coinfection.7 Hepatitis C also confers a 20% to 30% increased risk of non-Hodgkin lymphoma, a 3-fold higher risk of Waldenstrom macroglobulinemia, and a 4-fold increase in risk of cryoglobulinemia.8 Untreated HIV infection could magnify the incidence and severity of all of these complications. HIV-associated cytokine dysregulation, particularly of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), may also limit efficient clearance from the liver and promote hepatic inflammation and fibrogenesis. Early suppression of HIV slows progression of HCV-related liver fibrosis in coinfected patients.9 Management of hepatitis C in the setting of HIV infection, however, typically results in fewer sustained virological responses (SVRs) than in those with HCV monoinfection. The annual incidence of clinical decompensation in one coinfected cohort was 7%,6 considerably higher than in HCV-monoinfected patients.10 In addition, the criteria for diagnosis and treatment of hepatitis C, which were established in the monoinfected population, may be inadequate in the setting of HIV infection. Severe HIV-related immunosuppression can lead to false-negative results on HCV serological tests. In addition, relying on liver enzyme abnormalities to predict the need for hepatitis C therapy is problematic. About 30% of HIV-negative persons with chronic hepatitis C have persistently normal alanine aminotransferase (PNALT) levels, defined on the basis of 3 or more normal ALT values.11 Although formerly defined as healthy HCV carriers, a minority have histological liver damage despite their normal liver biochemistry findings. This subset is particularly problematic in the HIV/HCV-coinfected population. In a study of 326 HCV/HIV-coinfected patients, only 7.4% had PNALT levels, but analysis of liver biopsies from this retrospective study showed that 70% of such patients had some degree of liver fibrosis, and 1 in 4 required treatment.11 Older age and CD4+ cell counts less than 500/µL were independently associated with a stage of liver fibrosis that fulfilled histological criteria for hepatitis C treatment despite PNALT levels. Apart from HIV infection, other factors associated with hepatitis C progression, which characterize many HIV-infected groups, include heavy alcohol consumption (more than 50 g/d), disease acquisition at age 40 years or older, HBV coinfection, fatty liver disease, and type 2 diabetes mellitus.7 Treatment of hepatitis C in persons with HIV disease is important, with HCV eradication being the ultimate goal. In HIV-negative persons, short-course therapies involving pegylated interferon (IFN) alfa 2b and ribavirin are possible, and 99% of those who become negative for HCV RNA at 6 months are likely to have an indefinite SVR.7 In fact, if patients fail to have more than a 2-log decrease in their viral load at 12 weeks, further therapy with an IFN/ribavirin regimen usually proves futile.7 There is also little evidence for extrahepatic HCV reservoirs-early data implicating lymphocytes and glial cells have been questioned7-further supporting the goal of a cure. Clearly, HCV/HIV coinfection presents treatment challenges. Genotype 1 HCV infection does not respond as well as genotypes 2 and 3 to IFN-based therapies, and African Americans, overrepresented in the HIV population, are more commonly infected with genotype 1 and less responsive to IFN-based therapy.12 The latter observation appears unrelated to medication adherence and may stem from racial differences in CD4+ T-cell responses to HCV core antigens.13 Insulin resistance, a feature of HIV disease exacerbated by certain antiretroviral drugs, also reduces the chances of responding to current hepatitis C therapies.7 So what might be done? In terms of identifying those coinfected patients who require therapy, there are promising approaches apart from liver biopsy.10 Transient elastography, a measure of liver stiffness, may identify significant hepatic fibrosis, cirrhosis, and portal hypertension.10 Portal hypertension is an excellent predictor of clinical decompensation in persons with chronic liver disease.14 Finally, there are new therapies on the horizon. The most advanced in clinical trials is telaprevir (VX-950), a specific inhibitor of the HCV genotype 1 serine protease.15 Telaprevir given orally has been used alone, in combination with peginterferon, and most recently, with interferon and ribavirin with highly promising results.15 Other small-molecule inhibitors of HCV are also in clinical trials or under development.15 Therapy for hepatitis C, like the most promising HIV therapies, will definitely involve combinations of several drugs however, and the need for inclusion of IFN alfa, the agent responsible for most medication adherence concerns, is unlikely to disappear with any of them.7 References: References1. Laurence J. HCV infection in the setting of HIV: prevalence, disease, treatment. AIDS Reader. 2006;16:115-116. 2. Buffington J, Murray PJ, Schlanger K, et al. Low prevalence of hepatitis C antibody in men who have sex with men who do not inject drugs. Public Health Rep. 2007;122(suppl 2):63-67. 3. Tseng FC, O’Brien TR, Zhang M, et al. Seroprevalence of hepatitis C virus and hepatitis B virus among San Francisco injection drug users, 1998 to 2000. Hepatology. 2007;46:666-671. 4. Mocroft A, Soriano V, Rockstroh J, et al. Is there evidence for an increase in the death rate from liver-related disease in patients with HIV? AIDS. 2005;19:2117-2125. 5. Verma S, Wang CH, Govindarajan S, et al. Do type and duration of antiretroviral therapy attenuate liver fibrosis in HIV-hepatitis C virus-coinfected patients? Clin Infect Dis. 2006;42:262-270. 6. Pineda JA, Garcia-Garcia JA, Aguilar-Guisado M, et al. Clinical progression of hepatitis C virus-related chronic liver disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy. Hepatology. 2007;46:622-630. 7. Jacobson IA. Refinement to revolution in hepatitis C therapy. Medicine Grand Rounds, New York Presbyterian Hospital, September 6, 2007. 8. Giordano TP, Henderson L, Landgren O, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA. 2007;297:2010-2017. 9. Marine-Barjoan E, Saint-Paul MC, Pradier C, et al. Impact of antiretroviral treatment on progression of hepatic fibrosis in HIV/hepatitis C virus co-infected patients. AIDS. 2004;18:2163-2170. 10. Garcia-Samaniego J, Forns X. Hepatitis C virus and human immunodeficiency virus: the un-won battle. Hepatology. 2007;46:611-614. 11. Uberti-Foppa C, De Bona A, Galli L, et al. Liver fibrosis in HIV-positive patients with hepatitis C virus. Role of persistently normal alanine aminotransferase levels. J Acquir Immune Defic Syndr. 2006;41:63-67. 12. Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131:470-477. 13. Rosen HR, Weston SJ, Im K, et al. Selective decrease in hepatitis C virus-specific immunity among African Americans and outcome of antiviral therapy. Hepatology. 2007;46:350-358. 14. Blasco A, Forns X, Carrion JA, et al. Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation. Hepatology. 2006;43:492-499. 15. Modi AA, Hoofnagle JH. New therapies for hepatitis C. Hepatology. 2007;46:615-617.
