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Hepatitis C Virus Infection as an Opportunistic Disease in Persons Infected with Human Immunodeficiency Virus

  1. Mark S. Sulkowski1,
  2. Eric E. Mast4,
  3. Leonard B. Seeff3, and
  4. David L. Thomas1,2
  1. 1Johns Hopkins University School of Medicine, Division of Infectious Diseases, Bethesda, Maryland
  2. 2Johns Hopkins University School of Public Health and Hygiene, Department of Epidemiology, Baltimore, Bethesda, Maryland
  3. 3National Institutes of Diabetes and Digestive and Kidney Diseases of the National Institute of Health, Bethesda, Maryland
  4. 4Hepatitis Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Disease, Centers for Disease Control and Prevention, Atlanta, Georgia
  1. Reprints or correspondence: Dr. Mark S. Sulkowski, Johns Hopkins University School of Medicine, 1830 East Monument St., Room 450C, Baltimore, MD 21287 (msulkows{at}jhmi.edu).
 
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Abstract

Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family and is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Owing to shared routes of transmission, HCV and human immunodeficiency virus (HIV) coinfection are common, affecting approximately one-third of all HIV-infected persons in the United States. In addition, HIV coinfection is associated with higher HCV RNA level and a more rapid progression of HCV-related liver disease, which leads 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 coinfected persons. Strategies to prevent primary HCV infection and to modify the progression of HCV-related liver disease are urgently needed for HIV-HCV-coinfected individuals.

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Background and Significance

The hepatitis C virus (HCV) is a spheric, 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 [1]. In the United States, ∼4 million people have been infected with HCV, and ∼10,000 HCV-related deaths occur each year [2].

Epidemiology. HCV is transmitted chiefly by percutaneous exposure to blood. Previously, transfusion of contaminated blood was a major source of HCV transmission. However, the risk of posttransfusion HCV infection decreased dramatically after routine screening of blood donations for antibody to HCV was initiated in the United States in May 1990 and after screening with multiantigen tests was implemented in July 1992. The incidence of posttransfusion HCV infection is now <1 per 100,000 units of blood transfused [3, 4]. Currently, injection drug use is the leading route of HCV transmission in the United States and many Western nations. Indeed, worldwide, 50%–90% of injection drug users are infected with HCV as a consequence of sharing contaminated needles and drug-use equipment [5–8].

HCV can also be transmitted between sex partners and from a mother to her infant [2]. A higher-than-expected HCV prevalence is frequently found among persons acknowledging high-risk sexual practices (e.g., multiple sex partners), and 15%–20% of persons with acute hepatitis C have a partner positive for HCV antibody or admit to having multiple sex partners in the 6 months before onset of illness, in the absence of other risk factors for infection [6]. In addition, 1 study found that women attending a clinic for sexually transmitted disease were 3-fold more likely to have HCV infection if their sex partner was HCV-infected [9]. On the other hand, in at least 5 studies, the prevalence of HCV infection was <2% among long-term sex partners of HCV-infected individuals [10–14].

Furthermore, a higher-than-expected prevalence of HCV infection has been found in only a few studies of men who have sex with men, and HIV coinfection has been associated with increased HCV transmission between sex partners in only 1 study [9, 14, 15]. Because of limitations in measurements of human behavior and lack of experimental models, it is unclear to what extent these disparate findings relate to unacknowledged percutaneous exposures or to the sexual transmission of HCV infection between same-sex or opposite-sex partners.

HCV infection occurs in ∼2%–5% of infants born to HCV-positive mothers [2]. The incidence of mother-infant transmission increases (7%–20%) if the mother is coinfected with HIV [16, 17]. In addition, 1 study found an increased rate of HIV transmission among infants born of mothers who were coinfected with HIV and HCV [18].

Because of shared routes of transmission, HCV and HIV coinfection is common in many settings. In the United States, there are thought to be 240,000 persons coinfected with HCV and HIV, which is ∼30% of the estimated 800,000 individuals with HIV infection. Similar data have been reported from outside the United States; 33% of >3000 patients with HIV infection followed in the EuroSIDA cohort study had evidence of HCV infection [19]. However, the prevalence of HCV-HIV coinfection varies, depending on the setting in which HIV infection occurs.

HCV is ∼10-fold more likely than HIV to be transmitted by an accidental needle-stick exposure and is acquired more readily by injection drug users than is HIV [7, 20]. Thus, 50%–90% of persons who acquire HIV from injecting drugs are also HCV-infected. Similarly, >50% of hemophiliacs who were exposed to nonscreened, non-heat-treated blood products had HCV-HIV coinfection [21]. Conversely, HCV infection is much less common among men who acquire HIV infection from same-sex intercourse (<10%) [9, 22].

Natural history of HCV infection. The natural history of HCV infection is incompletely understood. In ∼15% of individuals, the virus clears from the blood after acute infection, and liver enzyme levels become and remain normal [23, 24]. The remaining 85% of acutely infected persons develop chronic, persistent viremia and, often intermittently, elevated alanine aminotransferase (ALT) levels. Although at any time more than one-half of chronically infected persons can have normal ALT levels, some persons with chronic HCV infection will have progressive hepatic fibrosis and may develop life-threatening complications, such as cirrhosis and/or hepatocellular carcinoma [25, 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 2%–4% and 1%–7% per year, respectively [29–31].

Unfortunately, the rate of disease progression cannot be predicted for an individual patient because reliable markers of disease outcomes are not available. Currently available laboratory tests are imperfect indicators of disease progression. The magnitude of ALT elevation does not correlate well with disease outcome or the histologic stage of disease, although in persons with persistently normal ALT levels, disease usually progresses slowly [31]. Unlike the HIV RNA level, which is highly correlated with HIV disease progression, the HCV RNA level does not appear to be closely associated with the outcome of hepatitis C and thus has little role in predicting the prognosis for an individual patient [32–34].

The best tool for evaluating the stage of infection is liver biopsy, but for several reasons, liver histology is an imperfect indicator of the ultimate disease course [35].

Impact of HIV infection on HCV disease progression. HIV coinfection is an important cofactor in HCV disease progression. HIV infection is associated with higher HCV RNA level and a more rapid progression of HCV-related liver disease [36–40]. Eyster et al. reported that HCV RNA levels increased 8-fold faster in hemophiliacs who became HIV-infected than in those who remained HIV-negative, and liver failure occurred exclusively in HIV-HCV-coinfected patients [39, 40]. Similarly, Darby et al. studied mortality associated with 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 after the presumed exposure to HCV was 1.4% (range, 0.7%–3%) for HIV-uninfected men and 6.5% (range, 4.5%–9.5%) for HIV-infected men [41].

Furthermore, Lesens et al. found that an increased risk of progressive liver disease emerged after 17 years of HCV infection, and the risk was 7-fold higher for hemophiliacs with HCV-HIV coinfection than for those with HCV infection [42]. Among HCV-infected persons without hemophilia, Pol et al. found that HIV coinfection was an independent risk factor for the development of cirrhosis [43].

In addition to increasing the risk of HCV-related cirrhosis, HIV coinfection appears to accelerate the rate of disease progression. In the study by Darby et al., the occurrence of liver failure frequently was within 10 years of the first exposure to HCV [41]. Before the mid-1990s, when highly active antiretroviral therapy (HAART) became available, HIV infection was generally fatal within 12 years [34]. Thus, in many cases there could have been no more than 12 years of coinfection before liver failure, which suggests that HIV infection abbreviates the typical 15- to 20-year natural history of hepatitis C. An accelerated disease course has also been associated with other forms of immunosuppression, such as agammaglobulinemia [44].

Taken together, these data suggest that chronic HCV infection acts as an opportunistic pathogen in HIV-infected persons, since both the incidence and the severity of the disease are increased in HIV-infected persons. Furthermore, these seminal studies may underestimate the effect of HIV infection on the course of chronic hepatitis C because of competing mortality due to AIDS and other OIs. As survival among HIV-infected patients increases as a result of the use of HAART and prophylaxis against traditional opportunistic pathogens, hepatitis C-related morbidity and mortality among HIV-infected patients should increase. Indeed, HCV-related liver disease has already been reported to be a major cause of hospital admissions and deaths among HIV-infected persons [45].

Like HIV coinfection, alcohol use is an important cofactor in HCV disease progression. Among HCV-infected individuals, alcohol ingestion, particularly in quantities >50 g/d, accelerates the progression of liver disease and significantly increases the risk of cirrhosis [46–48].

Impact of HCV infection on HIV disease progression. Although HIV disease clearly accelerates the progression of HCV disease, the reverse impact, namely, the effect of HCV infection on the natural history of HIV disease, is less certain. Dorrucci et al. conducted a prospective study of 416 acute HIV seroconverters, of whom 51.4% were HCV-coinfected, and found that HCV coinfection did not influence the rate of clinical or immunologic progression of HIV disease over a period of ∼3 years [49]. Conversely, Sabin et al. found that, among HIV-HCV-coinfected hemophiliacs, patients with HCV genotype 1 had a more rapid progression to AIDS and death than did those infected with other genotypes [50]. Piroth et al. reported that HCV coinfection was associated with a more rapid clinical and immunologic progression among HIV-infected patients with CD cell counts >600/mm3 [51]. Similarly, Lesens et al. found that coinfected individuals progressed rapidly to AIDS after the development of clinically significant liver disease [42]. Thus, while the effect of HCV coinfection is controversial, the most reliable data with regard to HIV seroconverters indicate no effect on the natural history of HIV disease over a relatively short period of time [49, 51].

HIV-HCV coinfection and HAART-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 [52–56]. Furthermore, 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 anti-tuberculosis drugs [57, 58]. The mechanism that causes enhanced drug-induced hepatotoxicity among coinfected patients is unknown, but this effect may be the result of underlying HCV-related liver disease or of immune reconstitution with enhanced cytolytic HCV antibody immune activity [59–61].

However, although coinfected patients may be at increased risk for the development of hepatotoxicity, 88% of a large cohort of HCV-coinfected patients prospectively studied did not have significant hepatotoxicity after HAART, and no irreversible outcomes were observed among those patients experiencing toxic effects [61]. Thus, the available evidence suggests that antiretroviral therapies can be safely administered to HIV-infected patients with chronic hepatitis C; however, these patients' serum liver enzyme levels should be closely monitored.

HCV is an opportunistic infection. In summary, HCV infection acts as an opportunistic disease among HIV-infected persons, because the incidence of infection is increased and the natural history of HCV infection is accelerated in HIV-infected persons. In addition, HCV infection may impact the course and management of HIV infection. Thus, strategies to prevent primary HCV infection and modify HCV disease progression are urgently needed for HIV-infected individuals.

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Primary Prevention of Infection

Health care professionals in all patient care settings should routinely ask HIV-infected persons about risk factors for acquiring HCV infection, including occupational exposure to blood, use of illegal drugs (injection and noninjection), and high-risk sexual practices (e.g., multiple sex partners or a history of sexually transmitted diseases) [2]. Patients who have these risk factors should be provided information regarding how to reduce their risk for acquiring blood-borne and sexually transmitted infections.

Primary prevention of injection drug use would eliminate the chief route of HCV transmission in the United States. Patients should be counseled to stop using injection drugs, which may be facilitated through substance-abuse treatment and relapse prevention programs. Patients who continue to use injection drugs should be counseled to use safer injection practices as a means of harm reduction. Specifically, patients should never reuse or share syringes, needles, water, or drug-preparation equipment [2]. Although participation in syringe-exchange programs has been associated with increased once-only use of syringes, there is conflicting evidence regarding its impact on the incidence of HCV infection. An earlier case-control study suggested that participating in a syringe exchange program led to a reduction in hepatitis C; however, a subsequent, prospective cohort study by Hagan et al. found participating in a needle exchange program did not appear to protect against HCV seroconversion [62, 63]. Clearly, more investigation is needed to develop and implement strategies for the prevention of HCV transmission by injection drug users.

HCV infection has also been associated with intranasal cocaine use in 1 study [10]. However, among patients with acute hepatitis C identified in the Centers for Disease Control and Prevention's Sentinel Counties study of viral hepatitis since 1991, intranasal cocaine use in the absence of injection drug use was uncommon [2464]. Thus, at least in the recent past, intranasal cocaine use has rarely appeared to contribute to transmission. Nonetheless, it is prudent to advise HIV-infected individuals who continue to use drugs intranasally that they should not share equipment.

Although there are no published data from the United States that indicate that persons with exposure to tattooing and body piercing alone are at increased risk for HCV infection, patients should be informed of the potential risk of HCV infection through these exposures if proper infection-control practices are not followed. Patients should also be advised not to share toothbrushes, razors, and other personal care items that might be contaminated with blood. In addition, although the risk of sexual transmission of HCV appears to be low, HIV-infected patients should be encouraged to use precautionary barriers (e.g., latex condoms) to reduce the risk of acquiring sexually transmitted pathogens [2].

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Secondary Prevention of Disease

Testing for HCV infection. All HIV-infected persons should be screened for HCV infection because of its high prevalence in this group and because of the opportunity to prevent liver disease. Testing for HCV infection should be done with EIAs licensed for the detection of antibody to HCV in blood [65]. Patients who are EIA-positive for HCV antibody should undergo confirmatory testing to verify infection, by means of either supplemental antibody testing (RIBA) or reverse transcriptase-PCR for HCV RNA. The detection of HCV RNA in a person with HCV antibody indicates current infection. However, since some persons with chronic HCV infection have intermittent viremia, a single finding of undetectable HCV RNA must be interpreted cautiously [23].

HIV-infected patients with advanced immunodeficiency may lose HCV antibody reactivity, and HCV antibody in patients with acute infection may remain undetectable in EIAs for weeks after HCV acquisition [66]. Thus, the presence of HCV RNA in the blood should be assessed when acute or chronic HCV infection is suspected clinically in persons with negative HCV antibody results. The clinical significance of quantitative HCV RNA levels (i.e., HCV viral load) in HIV-infected patients is not known and should not be interpreted on the basis of the well-described relationship of HIV viral load and HIV disease progression [34].

Prevention of HCV disease progression. HIV-infected individuals with evidence of chronic HCV infection should be provided with information regarding the prevention of liver damage, undergo medical evaluation for chronic liver disease, and, if indicated, then be considered for treatment. Alcohol use should be evaluated for all patients; those who use it more than occasionally (>20 g/w) should be counseled to stop and, when necessary, should be counseled to enter alcohol treatment and relapse-prevention programs. In addition, because the effect of occasional, moderate alcohol use (<20 g/w) on the rate of disease progression is not known, it may be prudent to advise all HIV-HCV-coinfected patients to abstain from alcohol use, except when necessary to administer medications for the management of HIV infection (e.g., ritonavir liquid formulation) [2].

HIV-infected patients with chronic HCV infection who are susceptible to hepatitis A virus (HAV) or hepatitis B virus (HBV) infections should be vaccinated, because most of these patients have risk factors for acquiring HAV and HBV infection [67]. In addition, HCV-infected patients with chronic liver disease who become infected with HAV are at increased risk for fulminant hepatitis [68]. Because of the high prevalence of HAV infection and HBV infection in this population, prevaccination screening for antibodies to hepatitis A virus (HAV IgG) and to hepatitis B surface antigen is generally cost-effective and should be performed [69, 70].

There is no evidence that vaccination for either HAV or HBV exacerbates the long-term progression of HIV infection [71]. Although vaccine immunogenicity is reduced in persons with advanced immunodeficiency, more than two-thirds develop protective antibody responses to both hepatitis A and hepatitis B vaccines [72, 73].

HIV-HCV-coinfected persons should be advised not to start any new medications—including over-the-counter, herbal, or alternative medicines—without consulting with their health care providers [2]. In addition, HIV-HCV-coinfected patients may be at increased risk for HAART-associated hepatotoxicity and should have their serum liver enzyme levels closely monitored during antiretroviral therapy. However, the majority of coinfected patients do not appear to develop significant and/or symptomatic hepatitis after the initiation of antiretroviral drug therapy [61].

HIV-HCV-coinfected patients should be evaluated for the presence of chronic liver disease. Disease severity should be assessed on the basis of medical history; physical examination findings (signs and symptoms of chronic liver disease); and serum albumin concentration, prothrombin time, and platelet count (measured to determine hepatic function). Determinations of the serum ALT level and HCV RNA level are important to establish that the infection is ongoing and to evaluate for treatment, but these levels provide only limited information regarding HCV disease severity [33]. Evaluation of liver histology by means of biopsy should be considered.

The liver biopsy may provide important information about HCV-related disease activity and the stage of fibrosis and may exclude alternative causes of liver disease [34313335]. Most studies indicate that liver biopsy can be safely performed for HIV-infected individuals and should be done according to current practice guidelines by a specialist knowledgeable in this area [74].

HCV therapy outcomes. HIV-HCV-coinfected patients should be considered for treatment for hepatitis C [75]. 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 ALT levels, detectable HCV RNA, and histologic findings of portal or bridging fibrosis, or at least moderate degrees of inflammation or necrosis [75]. Among HCV-infected patients without HIV coinfection, interferon (IFN)-α monotherapy or combination therapy with IFN-α plus ribavirin may yield a sustained virological response (defined as an undetectable HCV RNA level >6 months after the completion of antiviral therapy) and may modify the natural history of HCV disease.

Marcellin et al. reported that in 96% of patients with no detectable HCV RNA 6 months after therapy, the virological response and histologic improvement were sustained during long-term follow-up [76]. Similarly, Lau et al. reported that 5 patients in whom a virological response was evident at 6 months posttreatment still had a favorable clinical and histologic status 6–13 years after therapy, as well as no detectable HCV RNA in the serum and liver tissue [77]. Furthermore, even in the absence of a sustained virological response, IFN-α therapy may lower the risk of progression to hepatocellular carcinoma in HCV-infected patients with established cirrhosis [78, 79].

IFN-α in HIV-HCV coinfection. Treatment of HCV infection is clearly beneficial for some patients; however, few study reports have described the use of IFN-α for treatment of chronic HCV infection in HIV-infected patients. Boyer et al. reported a sustained biochemical response in only 1 of 12 HIV-infected patients receiving IFN-α [80]. Similarly, Marriott et al. found that only 3 of 14 HIV-infected patients treated with IFN-α for 1 year achieved a sustained virological response [81].

On the other hand, in the largest published study to date, Soriano and the HIV/Hepatitis Spanish Study Group treated 90 coinfected patients (CD4 cell counts >200/mm3) with IFN-α for 12 months. In an intention-to-treat analysis, 18 (20%) of the 90 HIV-infected patients achieved a sustained virological response to therapy, determined 12 months after the end of therapy; as expected, sustained response was associated with a pretreatment CD4 cell count >500/mm3 (OR, 2.92). In this study IFN-α appeared to be well-tolerated, although 10 patients experienced a >50% reduction in CD4 cell count, which was irreversible for 3 patients [82, 83]. Thus, on the basis of limited data, IFN-α therapy appears to be reasonably well-tolerated and may be effective for the treatment of HCV infection in HIV-infected patients.

IFN-α and ribavirin. Randomized, placebo-controlled clinical trials have clearly demonstrated the safety and enhanced antiviral efficacy of IFN-α plus ribavirin, compared with IFN-α alone, for the treatment of chronic HCV infection [84, 85]. Although studies are currently under way in the United States and Europe, there are no published data that address the safety and efficacy of therapy with IFN-α-2b and ribavirin for HIV-infected persons.

The major toxic effect of oral ribavirin appears to be dose-dependent hemolytic anemia, which is reversible after withdrawal of the drug. Ribavirin-induced anemia may be of increased importance for HIV-coinfected patients because of the high prevalence of anemia and the potential for limited myeloid reserves, as a result of comorbid diseases or concurrent drug toxicity [86].

Moreover, 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 [87–89]. 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 toxicity in vivo [89, 90]. Thus, although the enhanced efficacy of IFN-α-2b plus ribavirin in HIV-uninfected persons is compelling, more data demonstrating the safety and effectiveness of this combination are needed before its use can be recommended for the treatment of HCV-HIV-coinfected patients.

In addition to concerns about the use of ribavirin, however, many HIV-infected patients may have comorbid conditions, such as major depressive illness, cytopenia, and active illicit drug or alcohol use, which may prevent or complicate IFN-α therapy. Therefore, treatment for hepatitis C in coinfected patients should occur in a clinical trial or be coordinated by health care providers with experience in treating both HIV and HCV disease.

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Prevention of Recurrence

In HIV-HCV-coinfected patients, the durability of virological treatment response and whether maintenance therapy is necessary for virological responders are unknown. Patients whose virological response is sustained after treatment should be counseled regarding the prevention of reinfection with HCV, and patients with significant pretreatment liver disease should be advised to continue to avoid alcohol use.

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Research Priorities

Areas of special concern include the prevention of HCV infection among injection drug users, delineation of the mechanism of the impact of HIV infection on the natural history of hepatitis C, and treatment of HCV infection in HIV-infected patients. Additional studies are needed to define the impact of HIV on the natural history of hepatitis C in patients receiving HAART and the impact of antiretroviral therapy and immune reconstitution on HCV disease.

In addition, the safety and efficacy of antiviral therapy with IFN-α and/or IFN-α plus ribavirin for HIV-HCV-coinfected patients must be urgently evaluated through scientifically rigorous clinical trials. New antiviral drugs must be developed for the treatment of HCV infection, and these agents should be evaluated early in the course of their development in HCV-HIV-coinfected patients. Finally, appropriate strategies for the management of end-stage liver disease in HIV-HCV-coinfected persons should be investigated, such as the role of liver transplantation.

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