Treatment algorithm for the management of hepatitis C in HIV-coinfected persons

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1 Journal of Hepatology 44 (2006) S49 S55 Treatment algorithm for the management of hepatitis C in HIV-coinfected persons Mark S. Sulkowski* Johns Hopkins Medical Institutions, 1830 East Monument Street, Room 319, Baltimore, MD , USA In the era of highly effective antiretroviral therapy (ART), HCV-related liver disease has emerged as a significant cause of morbidity and mortality. Accordingly, expert panels have recommend that coinfected patients undergo medical evaluation for HCV-related liver disease, consideration for HCV treatment and, if indicated, orthotopic liver transplantation. While the treatment of such patients is complicated by medical, and psychiatric comorbidities, HIV disease, and concurrent antiretroviral therapy, randomized controlled trials support the safety, tolerability and efficacy of HCV treatment with peginterferon alfa (PEG-IFN) plus ribavirin (RBV) in HIV-infected persons. Although, the available data has led to consensus among experts regarding the need to medically manage HCV disease in HIVinfected persons, uncertainty remains regarding the best treatment algorithm for coinfected patients. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: HCV; HIV; Peginterferon; Ribavirin 1. Introduction In the era of highly effective antiretroviral therapy (ART), HCV-related liver disease has emerged as a significant cause of morbidity and mortality [1 3]. Accordingly, the International Consensus Panel, the Infectious Diseases Society of America (IDSA) and the American Association for the Study of Liver Disease (AASLD) have recommend that coinfected patients undergo medical evaluation for HCV-related liver disease, consideration for HCV treatment and, if indicated, orthotopic liver transplantation [4 7]. While the treatment of such patients is complicated by medical and psychiatric comorbidities, HIV disease, and concurrent antiretroviral therapy, randomized controlled trials support the safety, tolerability and efficacy of HCV treatment with peginterferon alfa (PEG-IFN) plus ribavirin (RBV) in HIV-infected persons [8 11]. Although, the available data has led to consensus among experts regarding the need to medically manage HCV disease in HIV-infected persons, uncertainty remains regarding the best treatment algorithm for coinfected patients. * Tel.: C ; fax: C address: msulkows@jhmi.edu (M.S. Sulkowski). 2. Management of HCV in the HIV co-infected patient 2.1. Diagnosis and pre-treatment evaluation Published guidelines recommend that HCV should be treated in persons with HIV, with efforts to deliver therapy to persons in whom the likelihood of serious liver disease and a treatment response are judged to outweigh the risk of treatment-related adverse effects (Table 1, Fig. 1) [4]. Accordingly, treatment decisions should be based on the systematic evaluation of each HIV-infected patient for the diagnosis of hepatitis C and its medical consequences. All HIV-infected persons should be screened for HCV infection because of the high prevalence of HCV infection in this group [4]. HCV screening should be done with enzyme immunoassays (EIA) licensed for the detection of anti-hcv [12]. Patients with positive anti-hcv results should have confirmatory testing performed using HCV RNA tests as the detection of HCV RNA indicates current infection. Since anti-hcv titers may be undetectable in persons with advanced AIDS and acute HCV infection, HCV RNA should be assessed in the blood when HCV infection is suspected in persons with negative anti-hcv results [12,13] /$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi: /j.jhep

2 S50 M.S. Sulkowski / Journal of Hepatology 44 (2006) S49 S55 Table 1 Recommendations for the management of HCV in HIV-infected patients from the AASLD Practice Guideline: diagnosis, management, and treatment of hepatitis C (adapted from Strader et al. [4]) 1 Anti-HCV testing should be performed in all HIV-infected persons (Grade, III) 2 HCV RNA testing should be performed to confirm HCV infection in HIV-infected persons who are positive for anti-hcv, as well as in those who are negative and have evidence of unexplained liver disease (Grade, III) 3 Hepatitis C should be treated in the HIV/HCV-coinfected person in whom the likelihood of serious liver disease and a treatment response are judged to outweigh the risk of morbidity from the adverse effects of therapy (Grade, III) 4 Initial treatment of hepatitis C in most HIV-infected persons is peginterferon alfa plus ribavirin for 48 weeks (Grade, III) 5 Given the high likelihood of adverse events, HIV/HCV-coinfected patients on HCV treatment should be monitored closely (Grade, III) 6 Ribavirin should be used with caution in persons with limited myeloid reserves and in those taking zidovudine and stavudine. When possible, patients receiving ddi should be switched to an equivalent antiretroviral before beginning therapy with ribavirin (Grade, III) 7 HIV-infected patients with decompensated liver disease may be candidates for orthotopic liver transplantation (Grade, III) Quality of evidence on which recommendation is based: I, randomized, controlled trials; II-1, controlled trials without randomization; II-2, cohort or casecontrol analytic studies; II-3, multiple time series, dramatic uncontrolled experiments; III, opinions of respected authorities, descriptive epidemiology. HIV/HCV co-infected individuals should be counseled to prevent liver damage and HCV transmission, and should be evaluated for the presence of chronic liver disease. Because alcohol ingestion accelerates the progression of liver disease, all HIV/HCV-infected patients should be advised to abstain from alcohol use [14]. Counseling regarding household and sexual practices to prevent HIV transmission also should be effective to prevent HCV transmission. Fig. 1. Treatment algorithm.

3 M.S. Sulkowski / Journal of Hepatology 44 (2006) S49 S55 S51 Co-infected patients who are susceptible to hepatitis A virus or hepatitis B virus infections should be vaccinated [15]. All HIV/HCV-coinfected 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 albumin, prothrombin time, direct bilirubin and platelet count to determine hepatic function, and evaluation of liver histology by biopsy in most patients. Measurements of the serum ALT level and HCV RNA level are important to establish that the infection is ongoing but provide only limited information regarding HCV disease severity and rise of the disease progression for an individual patient [16]. HCV genotyping should be performed since the probability of virologic response to interferon-based therapies is strongly influenced by this parameter Liver biopsy Similar to the management of HIV disease, accurate assessment of the risk of disease progression is needed to weigh the potential risks and benefits of HCV treatment. The gold standard for evaluating the stage of HCV disease is the liver biopsy, which provides important information about HCV-related histologic activity and fibrosis stage, and may exclude alternative causes of liver disease [17]. Most studies indicate that liver biopsy can be safely performed in HIV-infected individuals [18]. However, histologic staging as a prognostic tool has several important limitations. First, the natural history of HCV disease progression among HIV-infected persons is poorly understood, and, some data indicate that HIV-infected patients with minimal liver disease may progress rapidly over a relatively short interval. Thus, the decision to defer HCV treatment in co-infected patients with little or no fibrosis is controversial. Indeed, some experts recommend the provision of HCV treatment to all eligible HIV-infected patients regardless of histologic disease [19]. Second, while biopsy is the best available method for determining the type and extent of liver injury, significant variability due to sampling and inter-observer variance has been described [20]. Third, complications such as serious bleeding and, rarely, death may occur [21]. Thus, there is a need for an alternative methods for staging liver disease among coinfected patients. There is substantial interest in developing non-invasive tests for the assessment of hepatic fibrosis [22]. The European MULTIVIRC group has studied a combination of six markers, alfa-2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A 1, GGT, and total bilirubin (FibroTest) in HIV-infected persons, demonstrating relatively high negative and positive predictive values [23]. However, confirmatory data is needed before these and other non-invasive measures of liver disease can be recommended for widespread use. Thus, for many patients, liver biopsy should be performed prior to HCV treatment to provide prognostic information and to guide treatment decisions. However, histologic staging is not a requirement for HCV treatment and should not be a barrier to care. Indeed, due to high rates of virologic response, some patients (e.g. those infected with HCV genotype 2 or 3 or 1 and low levels of hepatitis C viremia) may be best managed by the provision of HCV treatment in the absence of biopsy. Persons who choose to defer HCV treatment should be monitored for evidence of liver disease progression by follow-up liver biopsy at 2 3 year intervals HIV disease and antiretroviral therapy HIV disease and its treatment should be carefully evaluated prior to initiation of HCV treatment. The primary concern is the potential drug drug interactions between RBV, a guanosine nucleoside analog and anti-hiv nucleoside analogs. In vitro, ribavirin inhibits the anti-hiv activity of pyrimidine 2 0,3 0 -dideoxynucleosides, including zidovudine and stavudine, through the inhibition of their intracellular phosphorylation [24 26]. However, Gries and coworkers found that RBV did not alter the plasma pharmacokinetics or intracellular phosphorylation of lamivudine, stavudine and zidovudine in coinfected patients receiving PEG-IFN plus ribavirin [27]. On the other hand, a clinically important interaction between ribavirin and the purine nucleoside analogue, didanosine has been recognized. Through inhibition of inosine monophosphate dehydrogenase (IMPDH), ribavirin increases the intracellular conversion of didanosine to its active metabolite, which enhances its anti-hiv activity but also increase its in vivo toxicity, including mitochondrial effects [26,28,29]. Indeed, Fleischer and colleagues reported 29 cases of mitochondrial toxicity, including five deaths, associated with the concurrent use of didanosine and ribavirin [30]. Accordingly, didanosine should not be used with ribavirin. Polypharmacy also creates the potential for synergistic or additive drug-related toxicity. For example, zidovudine (ZDV) use may be associated with anemia due to bone marrow suppression. Brau and colleagues reported that, compared to other antiretroviral agents, ZDV was associated with significantly more anemia in persons receiving HCV treatment [31]. However, in another study, epoetin alfa (40,000 IU weekly) effectively increased hemoglobin levels in anemic patients receiving RBV and ZDV [32]. Thus, patients receiving ZDV-containing ART should be closely monitored for anemia after the initiation of PEG/ RBV and, if anemia develops, treated with epoetin alfa. Alternatively, consideration may be given to stop ZDV before starting HCV treatment. In light of this complex polypharmacy, some experts advocate HCV treatment in HIV-infected persons with relatively high CD4 cell counts (O350 cells/mm 3 ) for whom ART is typically not recommended. However, other

4 S52 M.S. Sulkowski / Journal of Hepatology 44 (2006) S49 S55 experts hypothesize that HIV treatment improves anti- HCV-specific immunity and will lead to better HCV outcomes. Interestingly, in clinical trials in co-infected patients, pre-treatment CD4 cell count and HIV RNA level was not significantly associated with achieving a sustained viral response. Indeed, among patients receiving PEG-IFN alfa-2a/rbv in the study by Torriani et al., the SVR rate was similar across baseline CD4 cell count categories:! 200/mm 3, 47%; 200!350/mm 3, 36%; andr350/mm 3, 42%. Furthermore, the use of ART or type of ART did not significantly impact the SVR rate [9]. Thus, HIV treatment in coinfected patients under consideration for HCV treatment with PEG-IFN/RBV should be based on published guidelines for the management of HIV disease [33] Strategies for the delivery of HCV treatment Once HCV treatment is decided, multidisciplinary programs are needed to effectively deliver HCV therapy to patients who need treatment and have no contraindications to PEG-IFN/RBV. Additionally, coinfected patients for whom the potential risk of treatment outweighs the potential benefits also have important medical needs. For coinfected patients with minimal liver disease and extensive medical or psychiatric comorbidities, efforts should focus on prevention of liver disease progression, including programs to promote alcohol abstinence, and vaccination of susceptible persons to prevent hepatitis A and B infection. In contrast, coinfected patients for whom the potential risk of HCV disease and potential benefit of HCV treatment outweigh any potential treatment risks, medical and psychosocial interventions should focus on the removal of modifiable barriers to HCV treatment. For example, while active drug and/or alcohol use is not a contraindication to HCV treatment, there is convincing evidence that active substance use severely limits the effectiveness of medical care [34]. Accordingly, interventions that lead to reduction or cessation of substance abuse, such as methadone maintenance therapy, will undoubtedly improve effectiveness of HCV treatment [35]. Finally, health care providers with expertise in the management of both HIV and HCV infections are needed to maximize HCV treatment outcomes in coinfected patients HCV treatment Based on the findings of four randomized, controlled trials, initial treatment of HCV should be peginterferon alfa plus ribavirin for 48 weeks (Table 2) [8 11]. In all four studies, HCV genotype and HCV RNA level ( viral load ) were the strongest pre-treatment predictors of sustained virologic response (SVR). Among patients receiving PEG- IFN alfa-2a plus RBV in the trial by Torriani et al., the SVR rate was 29 and 62% in patients co-infected with HCV genotype 1 and 2 or 3, respectively, and, among patients coinfected with genotype 1, the SVR rate was 18 and 61% Table 2 Comparison of four randomized controlled trials for peginterferon plus ribavirin Torriani et al. Chung et al. Carrat et al. Laguno et al. Number of subjects Country Multinational United States France Spain Regimen Peginterferon Peginterferon alfa-2a 180 mcg/week Peginterferon alfa-2a 180 mcg/week Ribavirin 800 mg/day Dose escalation, mg/day at 4 week intervals Peginterferon alfa-2b 1. 5 mcg/kg/week Peginterferon alfa-2b 100 mcg or 150 mcg/week (weight-based) 800 mg/day 600, 800, 1000, 1200 mg/ day (weight-based) Duration 48 weeks 48 weeks 48 weeks 48 weeks except 24 weeks for HCV genotype 2 or 3 and HCV RNA!800, 000 IU/mL Baseline characteristics a White race CD4 cell count, mean 530 cells 474 cells 482 cells 570 cells Undetectable HIV RNA ART Bridging fibrosis or cirrhosis (cirrhosis) Genotype HCV RNAO800,000 IU/mL (O1,000,000 IU/mL) 47 Sustained virologic response a Genotype Genotypes 1 and Genotypes 2 and a Peginterferon/RBV group of each protocol; values shown are percentage (%).

5 M.S. Sulkowski / Journal of Hepatology 44 (2006) S49 S55 S53 among with those with high (O800,000 IU/mL) or low (%800,000 IU/mL) hepatitis C viral loads, respectively [9]. In each study, the lowest SVR rates were observed in patients with genotype 1 and high levels of hepatitis C viremia. Interestingly, among HIV seronegative patients with genotype 1 infection, Hadziyannis and coworkers found that higher doses of RBV ( mg/day) were significantly more effective than the lower RBV dose (800 mg/day). Due to concern about anemia, low dose RBV (800 mg/day) was selected for the treatment of hepatitis C in coinfected patients in the studies by Torriani et al. and Carrat et al., leading to speculation that higher RBV doses may be more effective in coinfected patients with HCV genotype. However, to date, randomized controlled trials of higher doses of RBV have not been conducted in HIV/HCV coinfected patients. In an uncontrolled study, Laguno and colleagues found that higher RBV doses ( mg/day) according to body weight in combination with PEG-IFN alfa-2b were not associated with higher rates of anemia and may be associated with higher SVR rates [10]. While further research is needed, published guidelines recommend that patients coinfected with HCV genotype 1 be treated with PEG-IFN plus weight-based RBV (!75 kg, 1000 mg/day; R75 kg 1200 mg/day) [4 7] Management of patients non-responsive to peginterferon/ribavirin therapy Among HIV-infected patients treated with PEG- IFN/RBV, the pattern of early virologic response is highly predicative of virology failure; indeed, SVR was observed only 1% of subjects who had less than a 2Klog 10 reduction in HCV RNA from baseline or an undetectable HCV RNA after 12 weeks of treatment [8 11]. Accordingly, coinfected patients who fail to achieve a virologic response after 12 weeks of therapy are persons for whom continued therapy is unlikely to lead to SVR. Unfortunately, no data are available to guide the management of hepatitis C in HIV-infected patients for whom PEG-IFN/RBV is ineffective. Among HIV seronegative patients, multiple strategies are under investigation including the use of daily injections of interferon alfacon-1, high dose PEG-IFN induction therapy, and the use of PEG- IFN in combination with specific HCV polymerase or serine protease inhibitors. In addition, among persons with advanced fibrosis, an alternative strategy under investigation is the use of low-dose peginterferon alfa (PEG-IFN alfa 2b 0.5 mcg/kg weekly or PEG-IFN alfa-2a 90 mcg weekly) over long periods of time (3 5 years) as a means to delay fibrosis progression and forestall the development of hepatic decompensation and/or hepatoma. While there are no data to support the use of long-term or maintenance PEG- IFN therapy in co-infected persons, Chung and colleagues observed less hepatic necroinflammatory activity on paired liver biopsy in 35% of subject who failed to respond virologically after 24 weeks of PEG-IFN/RBV therapy, suggesting that continued HCV treatment may provide histologic benefit [8]. While clinical trials are underway to address the safety and efficacy of long-term PEG-IFN in coinfected patients, some experts advocate for such treatment in patients with advanced fibrosis (e.g. bridging fibrosis or cirrhosis) Management of patients with decompensated liver disease The medical care of coinfected patients with cirrhosis is complex, particularly for those with decompensation. In conjunction with hepatologists, cirrhotic patients should be evaluated for the management of liver-related complications such as portal hypertension, coagulopathy, encephalopathy, ascites, and hepatocellular carcinoma. Importantly, persons with hepatic decompensation are not candidates for interferon-based therapy. Mauss and coworkers reported that 10.4% of cirrhotic patients (14 of 133) enrolled in the study by Torriani et al. experienced hepatic decompensation, leading to death in six subjects [36]. Importantly, one-half of these cases occurred in persons with evidence of hepatic insufficiency (Child-Turcotte- Pugh scorer7) prior to starting HCV therapy. Thus, coinfected patients with end-stage liver disease should be referred for liver transplant evaluation. Although HIV infection is no longer considered a contraindication to liver transplantation and an increasing number of coinfected patients have been successfully transplanted, it is important to treat coinfected persons before severe liver disease occurs [37]. 3. Conclusions Infection with HCV is common in HIV-infected persons and represents an increasingly important public health problem. The medical management of hepatitis C in HIVinfected persons is complicated by immune suppression, potential drug interactions and toxicities, and the relative paucity of health care providers with expertise in the management of both hepatitis C and HIV. Nonetheless, four recently published randomized controlled trials support the safety, tolerability and efficacy of HCV treatment with PEG-IFN/RBV in HIV-infected persons; accordingly, the impetus to treat hepatitis C in HIV-infected persons is strong and the standard of care for the management of hepatitis C in the HIV-infected person has been defined. However, uncertainty remains with respect to important clinical issues such as the role of liver biopsy and management of absence of non-responders to current therapies. In addition, the delivery of HCV care is inconsistent, and formidable barriers to treatment exist in many settings. Accordingly, the development and implementation of on-site multidisciplinary programs combining the expertise of HIV specialists, hepatologists,

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