Medicine Today Internal Medicine Webcast Series

Hepatitis C Management:

Management of Special Groups:
HCV-HIV Coinfection

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Key Points

  • HCV coinfection is prevalent in HIV-infected patients.

  • Concomitant HIV infection negatively affects the natural history of HCV infection by accelerating its course and blunting the response to antiviral therapy.

  • Treatment of HCV infection in HIV-positive patients is characterized by lower rates of sustained virologic response, particularly in patients with genotype 1 and high viral load.

  • Patients with compensated HIV infection and compensated liver disease should be considered for HCV treatment with standard doses of PEG-IFN and ribavirin.

  • Ribavirin and the nucleoside analog didanosine (ddI) should not be used together.

  • Administration of growth factors for hematologic support should be considered in lieu of dosage reductions, if possible.

Approximately 25% of HIV-infected patients in the United States are also infected ("coinfected") with HCV. The percentage of coinfection is greater in patients who acquired HIV through injection-drug abuse or blood/blood product transfusions than in those who acquired HIV through sexual exposure. In the 1980s, most coinfected patients had probably contracted HCV before they contracted HIV—in some cases 10 years before.94 Their outcomes may differ from those of patients who acquired both diseases at the same time.

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Natural History

Each disease affects the natural history of the other. HIV coinfection reduces the chance of recovery from acute hepatitis C; it increases the degree of HCV viremia, diminishes the antiviral response to IFN-based anti-HCV regimens, and accelerates the progression of HCV infection to cirrhosis, hepatocellular carcinoma, and liver failure.95 HCV coinfection increases the degree of hepatotoxicity from antiretroviral therapy and blunts immune recovery when HIV-infected patients receive antiretroviral therapy. HCV infection has become the leading cause of death in the HIV-infected population.96

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The steps in the diagnosis and general medical management of coinfected patients mirror those for HCV-monoinfected patients. One exception applies to patients who acquired HCV after they had already been rendered immunosuppressed from HIV infection; in these patients, a negative anti-HCV antibody test might represent a false-negative result. Therefore, these patients should have an HCV RNA assay regardless of the result of the anti-HCV antibody test. Also, some investigators have argued that a liver biopsy is less relevant in HIV-coinfected individuals because the more rapid progression of HCV infection warrants anti-HCV therapy in most of these patients.

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Candidates for Therapy

Despite the seriousness of these conditions, many patients are not being adequately treated. Those who are being treated are receiving their care, for the most part, from infectious disease specialists. Relatively few hepatologists feel comfortable managing both diseases. Therefore, any physician who is managing such a patient should consider doing so in collaboration with an infectious disease specialist who can initiate strategies other than basic antiretroviral treatment.

Martagon and Gordon suggested that coinfected patients with very low CD4 counts should not be treated with IFN-based therapy.97 As is discussed in more detail later, Soriano et al found that patients whose CD4 cell counts were greater than 500/mm3 experienced an increased hepatitis C virologic response to IFN.98 As a general rule, patients whose CD4 counts are higher than 250/mm3 are eligible for anti-HCV therapy. However, there is a paucity of data regarding the exact CD4 level that would qualify coinfected patients for treatment, and these patients should be managed in the context of a clinical trial whenever possible.

All coinfected patients are potential candidates for HIV therapy if they have no contraindications.

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As mentioned, treatment efficacy is diminished in coinfected patients, but the physician should follow established treatment recommendations as closely as possible. Such steps include encouraging a healthy lifestyle and vaccinating the patient against hepatitis A virus and HBV when appropriate.

Data indicate that anti-HCV therapy increases the risk of hepatotoxicity from antiretroviral therapy with nucleoside analogs (stavudine in particular), non-nucleoside reverse transcriptase inhibitors, and protease inhibitors (ritonavir in particular). Ribavirin and the nucleoside analog didanosine (ddI) should not be used together due to increased risk of various toxicities.

Soriano et al reported on the efficacy of IFN alfa-2b monotherapy for 12 months in 90 coinfected patients.98 They observed a sustained virologic response in 18 patients (20%), most of whom had baseline CD4 counts greater than 500/mm3.

Perez-Olmeda et al reported on the use of PEG-IFN alfa-2b plus low-dose ribavirin (800 mg/d) in 68 coinfected and HCV-treatment-naive patients (because this study was conducted in Spain, a significant proportion of patients [35%] had HCV genotype 3).99 Treatment was discontinued in 15% of patients due to adverse effects, a rate that was similar to those seen in large trials of monoinfected individuals. In an intention-to-treat analysis, a sustained virologic response was achieved by 19% of patients with genotype 1 and by 45.8% of patients with genotype 3. The relapse rate was greater than expected in these HIV-coinfected patients with genotype 3, and greater than that seen in monoinfected populations.

Torriani et al randomized 868 coinfected, HCV-treatment-naive patients to one of three regimens: PEG-IFN alfa-2a (180 µg/week) plus ribavirin (800 mg/d), PEG-IFN alfa-2a plus placebo, or IFN alfa-2a plus ribavirin, each for 48 weeks.100 The primary end point was sustained virologic response, defined as serum HCV RNA <50 IU/mL after 24 weeks of follow-up (week 72). Patients were excluded if they had decompensated liver or HIV disease, as well as for other standard criteria. The patients were predominantly entered into the study outside of the United States and were predominantly Caucasian, male, young (<40 years old), and thin. Sixty percent of patients were infected with HCV genotype 1 and 26% with genotype 3. A total of 72% had a serum HCV RNA level >800,000 IU/mL and 16% had bridging fibrosis or cirrhosis on liver biopsy.

PEG-IFN plus ribavirin was the most effective treatment regimen, yielding a sustained virologic response in 40% of patients, compared with 20% with PEG-IFN plus placebo (p < 0.001) and 12% with IFN plus ribavirin (p < 0.001). Genotype 1 and high viral load were independently and significantly associated with lower sustained virologic response rates (odds ratios of 3.37 and 3.56, respectively; p < 0.001 for each) (Figure 12). The negative predictive power of an early virologic response was 98%, and thus similar to that in a monoinfected population. These results underscore the need for continued improvement in therapeutic options for these patients, especially for those coinfected with HCV genotype 1 who have high baseline viral loads.

Chung and colleagues reported results from the AIDS Clinical Trials Group (ACTG) A5071 study, in which coinfected subjects were randomized to 48 weeks of therapy with either PEG-IFN alfa-2a (180 µg/week) (n = 66) or IFN alfa-2a (n = 67).101 All patients also received 600 mg/d of ribavirin for 4 weeks, 800 mg/d for 4 weeks, and 1,000 mg/d for the remainder of the 48 weeks. The sustained virologic response rate was significantly higher in the PEG-IFN arm (27% vs. 12%, p = 0.03). As in the studies by Soriano et al98 and Torriani et al,100 patients with HCV genotype 1 had a lower sustained virologic response rate (14% in the PEG-IFN arm) and had a relapse rate of more than 50% after end-of-treatment response. The predictive value of an early virologic response held true in this study, as the absence of such a response had a negative predictive value of 100%. Histologic data also were reported from this study. Notably, histologic improvement was observed in 35% of patients without a viral response who underwent liver biopsy and in 52% of patients with a viral response who underwent biopsy.

No data are available as to the indications or benefits of maintenance therapy for HCV/HIV-coinfected individuals, but the histologic data from the ACTG study suggest that such an approach would be beneficial.

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In the study by Perez-Olmeda et al,99 the tolerability of PEG-IFN alfa-2b plus low-dose ribavirin was good, and weight loss was the only factor that was more significant and more prevalent in coinfected patients than it was in mono-infected patients treated with the same agents. However, IFN-based therapies caused a small and reversible drop in CD4 cell counts during treatment. Anemia was also worse in these patients, probably as a result of comorbid disease or drug toxicity. Finally, severe hepatotoxicity caused by antiretrovirals—defined as transaminase levels greater than 10 times the upper limit of normal in patients with normal baseline ALTs and greater than five times the upper limit of normal in those with abnormal baseline ALTs—appeared to be slightly more common in patients who also received IFN-based therapies.

No new significant adverse events were seen in the studies by the ACTG investigators, but more patients in the PEG-IFN alfa-2a groups experienced serious adverse events, including neutropenia <500 cells/mm3, thrombocytopenia <20,000 cells/mm3, and anemia (hemoglobin <6.5 g/dL). In the study by Torriani et al,100 25% of patients randomized to PEG-IFN alfa-2a plus ribavirin were withdrawn from therapy. Absolute mean CD4 counts decreased during treatment, and 10 AIDS-defining events occurred during the study. Hepatic decompensation occurred in 14 cirrhotic patients who received at least one dose of medication, and 10 patients died during the study. These sobering findings underscore the risks of treating HCV infection in patients with serious medical conditions.

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