Hepatitis C Virus Infection in HIV-infected Patients Mark S. Sulkowski, MD

Address Division of Infectious Diseases, Johns Hopkins Medical Institutions, 1830 East Monument Street, Room 319, Baltimore, MD 21287-0003, USA. E-mail: [email protected] Current Infectious Disease Reports 2001, 3:469–476 Current Science Inc. ISSN 1523-3847 Copyright © 2001 by Current Science Inc.

The hepatitis C virus (HCV) is a spherical enveloped RNA virus of the Flaviviridae family, classified within the Hepacivirus genus. Since its discovery in 1989, HCV has been recognized as a major cause of chronic hepatitis and hepatic fibrosis that progresses in some patients to cirrhosis and hepatocellular carcinoma. In the United States, approximately 4 million people have been infected with HCV, and 10,000 HCVrelated deaths occur each year. Due to shared routes of transmission, HCV and HIV co-infection are common, affecting approximately one third of all HIV-infected persons in the United States. In addition, HIV co-infection is associated with higher HCV RNA viral load and a more rapid progression of HCV-related liver disease, leading to an increased risk of cirrhosis. HCV infection may also impact the course and management of HIV disease, particularly by increasing the risk of antiretroviral drug-induced hepatotoxicity. Thus, chronic HCV infection acts as an opportunistic disease in HIV-infected persons because the incidence of infection is increased and the natural history of HCV infection is accelerated in co-infected persons. Strategies to prevent primary HCV infection and to modify the progression of HCV-related liver disease are urgently needed among HIV/HCV co-infected individuals.

Introduction HIV-infected persons have an increased incidence of hepatitis C virus (HCV) infection and an accelerated course of chronic disease. Accordingly, the United States Public Health Service and Infectious Diseases Society of America consider management of HCV in their report on opportunistic infections in persons with HIV [1•].

Pathogen Hepatitis C virus is a spherical, enveloped RNA virus classified within the Hepacivirus genus of the Flaviviridae family.

The positive-sense, single stranded (approximately 9.6 kb), RNA genome contains a single large (approximately 3000 amino acid) open reading frame flanked by 3' and 5' untranslated regions [2]. HCV replication chiefly occurs within the cytoplasm of hepatocytes, although some studies have suggested replication may occur in some other cell types, such as B cells, T cells, and monocytes. In chronically infected humans, mathematical models of HCV kinetics suggest that up to 1.0 x 1012 virons are produced daily with a half life of approximately 2.5 hours [3]. This high level of virion turnover, coupled with the lack of proofreading by the RNA polymerase, results in the rapid accumulation of mutations, estimated at a rate of 0.9 to 1.92 x 10-3 base substitutions per year [4,5]. Consequently, within each infected person, HCV exists as a quasispecies, a group of closely related variants that typically share 91% to 99% sequence identity. HCV sequences from different individuals may have less than 60% RNA identity, and six major genotypes have been identified [6].

Epidemiology Hepatitis C virus is transmitted chiefly by percutaneous exposure to blood. Although transfusion of contaminated blood and blood products was once a major source of HCV transmission, incidence of post-transfusion HCV infection has dropped to less than 1:100,000 per unit transfused in the United States [7,8]. Injection drug use is the leading route of HCV transmission in the United States. Indeed, worldwide, 50% to 90% of injection drug users are HCV infected as a consequence of sharing contaminated needles and drug-use equipment [9–12]. Hepatitis C virus can also be transmitted between sexual partners, and from a mother to her infant [13]. A higher than expected HCV prevalence is frequently found in persons reporting high-risk sexual practices (eg, multiple sexual partners), and 15% to 20% of persons with acute hepatitis C have an anti–HCV-positive partner, or admit having multiple sexual partners in the 6 months before illness onset in the absence of other risk factors for infection [10]. In addition, in one study women attending a sexually transmitted disease clinic or were threefold more likely to have HCV infection if their sexual partner was HCV infected [14]. On the other hand, in at least five studies, the prevalence of HCV infection was less than 2% among long-term sexual partners of HCV-infected indivi-

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duals [15–19]. Thus, while there is evidence that HCV may be transmitted sexually, intercourse appears to be a relatively inefficient mode of transmission. Hepatitis C virus infection occurs in approximately 2% to 5% of infants born to HCV-positive mothers [13]. However, the incidence of mother-infant transmission increases approximately threefold if the mother is co-infected with HIV [20,21]. Because of shared routes of transmission, HCV and HIV co-infection is common. In the United States, there are thought to be 100,000 to 240,000 persons co-infected with HCV and HIV, representing 15% to 30% of the estimated 800,000 individuals with HIV infection. However, the prevalence of HCV/HIV co-infection varies depending on the route of HIV infection. Approximately 50% to 90% of persons who acquire HIV from injecting drugs are also HCV infected [22•]. Similarly, more than 50% of hemophiliacs who were exposed to nonscreened, non–heattreated blood products had HCV/HIV co-infection [23]. HCV infection is less common (< 10%) in men who acquired HIV infection from same-sex intercourse [14,24].

Natural History After acute infection, approximately 15% of individuals clear virus from the blood, and presumably have fully recovered from infection [25]. The remaining 70% to 85% of acutely infected persons have viremia that persists for life. Some persistently infected persons will develop hepatic fibrosis that progresses to cirrhosis, liver failure, and/or hepatocellular carcinoma [26]. The probability of cirrhosis after 20 years of infection is estimated to be between 5% and 25%, depending on the population studied [26–28]. After cirrhosis has developed, the rates of progression to liver failure and hepatocellular carcinoma are estimated to be approximately 2% to 4% and 1% to 7% per year, respectively [29].

HIV infection impact on hepatitis C progression HIV infection has been reported to exacerbate several steps in the natural history of hepatitis C. In one study, HIVinfected persons were less likely to have cleared viremia than those without HIV [30]. HIV infection has also been associated with higher HCV RNA viral load and a more rapid progression of HCV-related liver disease [31–39]. Eyster et al. [35,36] reported that HCV RNA levels were higher in hemophiliacs who became HIV infected compared with those who remained HIV negative, and liver failure occurred exclusively in HIV/HCV co-infected patients. Similarly, Darby et al. [37] studied mortality from liver disease and hepatocellular carcinoma among 4865 men with hemophilia who were exposed to HCV-contaminated blood products. At all ages, the cumulative risk of liver-related death was 1.4% (range, 0.7%–3.0%) for HIVuninfected men, and 6.5% (range, 4.5%–9.5%) for HIVinfected men [37]. Lesens et al. [38] found that the risk of

progressive liver disease was sevenfold higher in hemophiliacs with HCV/HIV co-infection than in those with HCV infection alone. As survival among HIV-infected patients increases due to the use of potent antiretroviral therapies and the prophylaxis of traditional opportunistic pathogens, hepatitis C-related morbidity and mortality among HIV-infected patients should increase. Indeed, HCV-related liver disease has been reported to be a major cause of hospital admissions and deaths among HIV-infected persons [40,41].

Hepatitis C virus infection impact on HIV disease progression There are conflicting reports on the effect of HCV infection on the natural history of HIV disease. In a prospective study of 416 HIV seroconverters, the 51.4% who were HCV co-infected had a similar HIV progression rate to those without HCV infection [42]. However, the reported followup averaged only 3 years. Among 1742 patients, Sulkowski et al. [43] found that HCV infection was not independently associated with progression to AIDS or death after adjusting for exposure to highly active antiretroviral therapy and HIV suppression. Conversely, Piroth et al. [44] reported that HCV co-infection was associated with a more rapid clinical and immunologic progression among HIV-infected patients with CD4 cell counts greater than 600 cells/mm. Similarly, Lesens et al. [38] found that co-infected individuals progressed rapidly to AIDS after the development of clinically significant liver disease. Among 3111 patients receiving potent antiretroviral therapy, Greub et al. [45••] reported that HCV-infected persons had a modestly increased risk of progression to a new AIDS-defining event or death, even among the subgroup with continuous suppression of HIV replication. Interestingly, Greub et al. [45••] also found that the magnitude of the CD4 cell increase following effective anti-HIV therapy was significantly less than that observed in HCV-uninfected persons, suggesting that HCV co-infection may blunt immune recovery following highly active antiretroviral therapy. Hepatitis C virus co-infection and highly active antiretroviral therapy-associated hepatotoxicity Antiretroviral drugs, such as zidovudine and HIV-1 protease inhibitors, have been associated with hepatotoxicity, which may interrupt HIV therapy and cause significant morbidity and mortality [46–50]. Some, but not all studies, suggest that drug-induced hepatotoxicity may be more common among patients with HIV/HCV coinfection, particularly with the use of HIV-1 protease inhibitors and antituberculosis drugs [49,51]. The mechanism of enhanced drug-induced hepatotoxicity among co-infected patients is unknown, but may be the result of underlying HCV-related liver disease or of immune reconstitution with enhanced cytolytic anti-HCV immune activity [52– 54]. However, while co-infected patients may be at increased risk for the development of hepatotoxicity, 88%

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Figure 1. Clinical management of antiretroviral-associated hepatotoxicity in the hepatitis C virus (HCV)-coinfected patient. Clinical management of antiretroviral-associated hepatotoxicity has not been defined, and strategies must be individualized. In addition, the long-term impact of mild to moderate elevations in liver enzyme on HCV-related fibrosis progression is unknown, and the effectiveness of anti-HCV therapy for the suppression of drug-related liver toxicity has not been evaluated. *Consider acute hepatitis A virus and hepatitis B virus infection; other infectious causes of hepatitis (cytomegalovirus, Epstein Barr virus, Mycobacterium avium complex); acute cholecystitis; ethanol and other illicit drugs; other hepatotoxic medications (fluconazole, trimethoprim-sulfamethoxazole); and mitochondrial toxicity (lactate level). ARV—antiretroviral.

of a large cohort of HCV-co-infected patients prospectively studied did not experience significant hepatotoxicity following highly active antiretroviral therapy [49]. Thus, the available evidence suggests that antiretroviral therapies can be safely administered to HIV-infected patients with chronic hepatitis C; however, serum liver enzymes should be closely monitored in these patients (Fig. 1) [1•].

Diagnosis All HIV-infected persons should be screened for HCV infection because of the high prevalence of HCV infection in this group [1•]. HCV screening should be done with enzyme immunoassays licensed for the detection of antibody to HCV in blood [55]. Patients with positive anti-HCV results by enzyme immunoassay should have confirmatory testing performed using HCV RNA tests. The detection of HCV RNA in a person with a positive anti-HCV result indicates current infection. Anti-HCV titers may decline to undetectable levels in persons with advanced immunodeficiency (CD4 cell count < 100/mm 3) [55,56]. Thus, HCV RNA should be assessed in the blood when HCV infection is suspected in persons with negative anti-HCV results. The clinical significance of quantitative HCV RNA levels (ie, viral load) in HIVinfected patients is not known, and should not be interpreted based on the well-described relationship of HIV viral load and HIV disease progression [57].

alcohol ingestion accelerates the progression of liver disease and significantly increases the risk of cirrhosis, all HIV/HCV-infected patients should be advised to abstain from alcohol use [13]. Counseling regarding household and sexual practices to prevent HIV transmission should also be effective in preventing HCV transmission. HIV-infected patients with chronic HCV infection should be vaccinated for hepatitis A virus and hepatitis B virus, because most of these patients have risk factors for acquiring these infections [58]. In addition, HCV-infected patients with chronic liver disease who become infected with hepatitis A virus are at increased risk for fulminant hepatitis [59]. HIV/HCV-co-infected patients should be evaluated for the presence of chronic liver disease. Assessments of disease severity should include a history and physical examination for signs and symptoms of chronic liver disease, measurement of blood albumen, prothrombin time, direct bilirubin and platelet count to determine hepatic function, and evaluation of liver histology by biopsy in many patients. Measurements of serum alanine aminotransferase levels and HCV RNA levels are important to establish that the infection is ongoing, but provide only limited information regarding HCV disease severity and disease progression for an individual patient [60]. The best tool for evaluating the stage of infection is liver biopsy, which provides important information about HCV-related disease activity and fibrosis stage, and may exclude alternative causes of liver disease. Most studies indicate that liver biopsy can be safely performed in HIV-infected individuals [61,62].

Management HIV-infected individuals with chronic HCV infection should be counseled to prevent liver damage and HCV transmission, and should be evaluated for chronic liver disease and consideration of anti-HCV treatment. Because

Treatment As of June 2001, there were no published guidelines for treatment of HCV infection in HIV-infected persons. None-

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theless, principles for the treatment of HIV-uninfected persons are useful. Treatment is currently recommended for patients with chronic hepatitis C who are at the greatest risk for progression to cirrhosis as characterized by persistently elevated alanine aminotransferase levels, detectable HCV RNA, and histologic findings of portal or bridging fibrosis, or at least moderate degrees of inflammation or necrosis [63]. Two distinct benefits have been attributed to HCV treatment. First, it is possible to eradicate the infection, referred to as a sustained virologic response (undetectable HCV RNA at the end of treatment and 6 months later). Soriano et al. [64,65] have reported that sustained virologic response can be achieved in persons with HIV/HCV co-infection. A second potential benefit of HCV treatment is a reduction in the risk of liver failure and liver cancer [66–68]. It is important to note that this benefit does not appear to be restricted to patients with sustained virologic response. These preliminary data form the basis for treating patients at the greatest risk for end-stage liver disease (eg, those with advanced hepatic fibrosis) to prevent hepatic decompensation without regard to virologic response. This approach may be especially pertinent to HIV/HCV-co-infected patients who generally have more liver disease, lower sustained virologic response, and limited access to orthotopic liver transplantation compared with HCVinfected adults without HIV [22•]. These following medical regimens have been approved by the US Food and Drug Administration for the treatment of chronic HCV infection: monotherapy with interferon alfa-2b, interferon alfa-2a, interferon alfacon-1, pegylated interferon alfa-2b, and combination therapy with interferon alfa-2b plus ribavirin. Few studies have been published examining the use of interferon alfa for treatment of chronic HCV infection in HIV-infected patients. Boyer et al. [69] reported a sustained biochemical response in only one of 12 HIV-infected patients receiving interferon alfa. Similarly, Marriott et al. [70] found that only three of 14 HIV-infected patients treated with interferon alfa for 1 year achieved a sustained virologic response. On the other hand, in the largest published study, Soriano et al. and the Spanish Hepatitis Study Group [64] treated 90 co-infected patients (CD4 cell counts > 200 cells/mm3) with interferon alfa for 12 months. In an intention-to-treat analysis, 18 (20%) of 90 HIV-infected patients achieved a sustained virologic response to therapy, determined 12 months after the end of therapy; as expected, sustained response was associated with a pretreatment CD4 cell count of greater than 500 cells/mm3. Thus, based on limited data, interferon alfa therapy appears to be reasonably well tolerated, and may be effective for the treatment of HCV infection in HIV-infected patients. Among HIV-uninfected patients, randomized, placebocontrolled clinical trails have clearly demonstrated that interferon alfa plus ribavirin combination therapy is more effective than interferon alone for the treatment of chronic

HCV infection [71,72]. While studies are currently underway in the United States and Europe, there are few published data addressing the safety and efficacy of interferon alfa-2b and ribavirin therapy in HIV-infected persons. However, recently several retrospective treatment series have suggested that interferon alfa-2b plus ribavirin is reasonably well tolerated and may led to the eradication of HCV infection in some HIV-infected patients [73–75]. More recently, the addition of the inert polyethylene glycol (PEG) moiety to the interferon alfa molecule has allowed for once weekly subcutaneous injection that provides continuous exposure to the active interferon molecule. In HIV-uninfected persons, randomized clinical trials have demonstrated that both pegylated interferon alfa-2a (branched, 40-kD PEG) and interferon alfa-2b (linear, 12-kD PEG) are more effective than standard interferon alfa monotherapy with a similar adverse effect profile [76,77]. Pegylated interferon alfa has also been studied in combination with ribavirin. Among 1730 HIV-uninfected patients with chronic HCV infection, Manns et al. [78] demonstrated higher sustained virologic response rates among HCV genotype 1-infected persons receiving pegylated interferon alfa-2b once weekly plus ribavirin (42%) compared with those receiving standard interferon alfa-2b thrice weekly plus ribavirin (33%). Thus, based on the ease of administration (once weekly injection) and the superior efficacy of PEG-interferon alfa plus ribavirin in patients infected with HCV genotype 1, it is anticipated combination therapy with PEG-interferon alfa will largely replace the use of standard interferon alfa in combination with ribavirin for the treatment of chronic HCV infection. Although studies of pegylated interferon alfa with and without ribavirin are currently underway, there are no published data on its safety and effectiveness for the treatment of HIV/HCV-coinfected persons. Interferon alfa therapy is associated with many adverse effects [79]. The majority of side effects are relatively minor, treatable with adjunctive therapies, and in most cases reversible with discontinuation of therapy. With the first several does of interferon alfa, the majority (60%– 90%) of patients experience influenza-like symptoms (eg, fever, malaise, tachycardia, chills, headache, arthalgia, and myalgia), which may be ameliorated by acetaminophen or nonsteroidal anti-inflammatory drugs. Fatigue, malaise, anorexia, weight loss, skin rash, and reversible alopecia can occur months into therapy. Additionally, neuropsychiatric side effects (irritability, insomnia, mood and cognitive changes) are observed in 25% to 60% of patients, but generally can be managed effectively with pharmacologic agents. Rarely, depression can be severe and suicides have been reported in persons taking interferon alfa. Interferon-associated thyroid dysfunction occurs in approximately 4% of patients and may take the form of thyroiditis, hypothyroidism, or hyperthyroidism [80]. Interferon may also causes neutropenia, mild anemia, and thrombocytopenia, adverse

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Table 1. Guide to treatment of the HIV/HCV-co-infected patient Before starting therapy Review HIV disease status including CD4 count, HIV RNA level, use of antiretroviral therapy, and active opportunistic diseases Examine comorbid conditions such as depression, drug and alcohol use, and cardiopulmonary disease Consider a liver biopsy to confirm the diagnosis of HCV, assess the grade and stage of disease, and rule out other diagnoses; in situations where a liver biopsy is contraindicated or patient declines, therapy can be given without a pretreatment liver biopsy Measure serum HCV RNA by PCR to document that viremia is present Test for HCV genotype to help determine the probability of virologic response Measure blood counts and aminotransferases to establish a baseline for these values Counsel the patient about the relative risks and benefits of treatment; side effects should be thoroughly discussed During therapy Measure blood counts and aminotransferases at weeks 2 and 4, and at 4- to 8-week intervals thereafter; consider the concurrent administration of filgrastim in the management of interferon-associated neutropenia Measure HIV RNA, absolute CD4 cell count and percentage CD4 at 12-week intervals Adjust the dose of ribavirin downward (by 200 mg at a time) if significant anemia occurs (hemoglobin less than 10 g/dL or hematocrit < 30% ) and stop ribavirin if severe anemia occurs (hemoglobin < 8.5 g/dL or hematocrit < 26%); consider the concurrent administration of epoetin alfa (40,000 IU by subcutaneous injection weekly) in the management of treatment-related anemia Evaluate for neuropsychiatric complications monthly (depression screen); consider use of anti-depressants (eg, selective serotonin reuptake inhibitors) and/or consultation with a mental health provider Measure thyroid-stimulating hormone levels every 3 to 6 months during therapy Measure HCV RNA by PCR at 24 weeks: if HCV RNA is still present, stop therapy; if HCV RNA is negative, continue therapy for at least an additional 24 weeks Reinforce the need to practice strict birth control during therapy and for 6 months thereafter At the end of therapy, test HCV RNA by PCR to assess whether there is an end-of-treatment response After therapy Measure aminotransferases every 2 months for 6 months Six months after stopping therapy, test for HCV RNA by PCR; if HCV RNA is still negative, the chance for a long-term virologic response is very high; relapses have rarely been reported after this point Adapted from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Chronic hepatitis C: current disease management. Accessible at http//www.niddk.nih.gov. HCV—hepatitis C virus; PCR—polymerase chain reaction.

events that are often minor and may respond to dose reduction and/or the administration of filgrastim (granulocyte-colony stimulating factor). Ribavirin also causes side effects. During the first 4 weeks of therapy, approximately 80% of patients develop a doserelated hemolytic anemia. With interferon alfa-2b and ribavirin combination therapy, the hemoglobin level usually decreases by 2 to 3 g/dL. In rare circumstances, anemia occurs more rapidly and has caused angina and myocardial infarction. Thus, ribavirin should be used cautiously in persons with pre-existing cardiac disease, and older patients or those with significant cardiac risk factors should undergo pretreatment cardiac testing. There is preliminary evidence suggesting that epoetin alfa can effectively increase the hemoglobin level in some patients experiencing ribavirin-associated anemia [81]. Ribavirin may also be associated with rash, pruritus, nasal congestion, cough, and gout. Importantly, ribavirin causes birth defects and must not be administered to either pregnant women or men intending to conceive. An additional concern regarding the use of ribavirin in HIV-infected persons is the potential for drug-drug interactions between ribavirin, a guanosine nucleoside analogue,

and anti-HIV nucleoside analogues. In vitro, ribavirin appears to inhibit the anti-HIV activity of pyrimidine 2',3'dideoxynucleosides, including zidovudine, zalcitabine, and stavudine through the inhibition of their intracellular phosphorylation [82–84]. Conversely, ribavirin may increase the intracellular conversion of didanosine to its active metabolite, which appears to enhance its anti-HIV activity in vitro, but may also increase its in vivo toxicity, including mitochondrial effects [84–86]. Although in vivo studies of potential drug-drug interactions have not been completed, several small case series published to data have failed to detect clinically significant interaction between ribavirin and nucleoside analogues [74,87].

Conclusions Despite the uncertainties and limitations of currently available HCV treatment strategies, HCV treatment may be beneficial for some HCV/HIV-coinfected persons. HCV treatment in coinfected patients should be coordinated by health care providers with experience in treating both HIV and HCV disease (Table 1).

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