Update on HIV and Hepatitis C Virus Co-Infection

Hepatitis C Treatment

Who Should Be Treated?

All patients with chronic HCV infection should be considered for antiviral therapy.8 Multiple factors must be considered in deciding whom to treat. These include genotype, degree of fibrosis, symptoms, need for or currently on HAART, age, severity of other underlying conditions, and patient motivation.8 Patients with a detectable plasma HCV RNA on qualitative assay, histologic evidence of portal or bridging fibrosis with moderate to severe degrees of inflammation and necrosis, persistently elevated serum aminotransferase (ALT) levels (>2 times the upper limit of normal), and without contraindications are good candidates for antiviral therapy.^8,23

Contraindications to Treatment

The following patients have contraindications to treatment: Patients with clinically decompensated cirrhosis secondary to HCV (ascites, persistent jaundice, wasting, variceal hemorrhage, or hepatic encephalopathy), kidney/liver/heart/or other solid-organ transplant, and severe depression.²³ Contraindications to ribavirin include patients with unstable cardiopulmonary disease, erythropoietin-resistant anemia, and hemoglobinopathies. These patients, however, can take pegylated interferon-based monotherapy in absence of other contraindications.⁸ Treatment of HCV with interferon (IFN) and/or ribavirin is contraindicated during pregnancy.8 Women of childbearing age should agree to use contraception during treatment and for 6 months after its completion prior to the initiation of HCV treatment .⁸

Counseling and Prevention

Counseling all patients with chronic hepatitis C to avoid alcohol consumption is necessary due to the increased risk of fibrotic progression.^8,10,32 Co-infected patients are at increased risk of fulminant hepatic failure with the hepatitis A virus (HAV) and should be advised to take 2 doses of the HAV vaccine before the CD4+ count becomes <200 cells/μL as well as the hepatitis B (HBV) vaccine series.^8,32

Treatment Recommendations and Outcomes

Treatment recommendations for HCV/HIV co-infected patients remain complicated. The goal of antiviral therapy in co-infected patients is a sustained virologic response (SVR), which is defined as the absence of detectable HCV-RNA six months after the completion of treatment.²⁹ Approved antiviral therapies for patients with HCV mono-infection include monotherapy with standard interferons (alfa-2a, alfa-2b or IFN alfacon-1) or pegylated (PEG) interferons (alfa-2a or alfa-2b) and combination therapy with standard or PEG IFN plus ribavirin. In HCV mono-infected patients, sustained viral response has been observed in approximately 40% of patients with HCV genotype 1 and as high as 70% to 80% in patients with genotypes 2 or 3 with the pegylated interferon plus ribavirin combination, which is actually 7% to 12% higher than the standard IFN/ribavirin combination.¹⁶

Because data on the optimal duration of therapy for coinfected individuals is lacking, most clinicians utilize treatment recommendations for HCV mono-infected patients. For patients with HCV genotype 1 (estimated at 75% by the CDC) who have an EVR at 12 weeks of treatment, the CDC recommends a 48 week treatment duration with PEG IFN plus ribavirin. Patients who do not demonstrate an EVR at 12 weeks will not likely achieve an SVR regardless of treatment duration, and in such patients, it is recommended that treatment be stopped.^8,36 For patients with HCV genotypes 2 or 3, the recommended treatment duration is 24 weeks for co-infected individuals.^8,25 However, some specialists still recommend that the duration should extend to 48 weeks for co-infected patients.^8,29,36

Four pivotal studies, the French Ribavic (ANRS HCO2) study, the Laguno et al. study (also known as the Laguno study), the AIDS Clinical Trials Group A5071 study (ACTG 5071), and the AIDS Pegasys Ribavirin International Co-infection Trial (APRICOT), have validated the effi cacy of PEG IFN plus ribavirin combination therapy in HIV/HCV co-infected individuals.^33-36 The summary in Table 2 demonstrates that the SVR in co-infected patients on PEG IFN plus ribavirin have ranged from 27% to 44%.^33-36 These results may not be as high as the SVR in mono-infected individuals, but they do represent an improvement in SVR compared to the standard IFN/ribavirin combination in co-infected individuals. Response to treatment is more favorable in genotypes 2 or 3 as compared to genotype 1, and therefore, genotype remains a strong predictor of SVR. Other predictors of SVR in these studies included low HCV viral load for genotypes 1 and 4 (<800,000 IU/ml), younger age, absence of cirrhosis, and ALT levels three times the upper limits of normal.^10,29

The RIBAVIC, ACTG 5071, and APRICOT studies demonstrated that early virologic response (EVR), which is defined as an undetectable HCV RNA level (<50 IU per ml) or a decrease of 2 log10 or more in the HCV viral load by week 12 of treatment, had a negative predictive value.^25,29-30 In this case, the studies found that patients who did not have an EVR at week 12 of treatment failed to achieve an SVR at week 72.^35-36 Chung et al. also found that in subjects who did not have virologic response to treatment, more than one-third did have histologic evidence of improvement based on liver biopsy.³⁵ Thus, the treatment combination appears to be beneficial for more than just the virologic response, and more studies are therefore needed to evaluate the treatment as maintenance therapy. It was also found that PEG IFN alfa-2a monotherapy was more effective than IFN alfa-2a plus ribavirin (SVR 20% vs. 12%, P=0.008), a finding that makes PEG IFN alone a better alternative for patients with ribavirin contraindications.³⁶

Based on the results of these randomized, controlled trials, the CDC, NIH, and the HIV Medicine Association/IDSA recommend the use of PEG IFN alfa-2a 180 μg administered weekly by subcutaneous injection (or PEG IFN alfa-2b 1.5 μg/kg) plus oral ribavirin in a dose of 600-1,400mg/kg daily for chronic hepatitis C in patients co-infected with HIV (See Table 3).⁸

Response to HCV therapy may correlate to CD4+ T lymphocyte count. Patients with higher CD4+ cell counts (>500 cells/μL) have demonstrated more favorable response to treatment.³⁷ Furthermore, HAART appears to favorably affect the course of HCV by lowering liver-related morbidity and mortality in co-infected patients.¹² Thus, the CDC recommends that HCV treatment should be considered before the CD4+ T lymphocyte count falls below 500 cells/μL.8,14 However, for HIV-infected patients who already have a CD4+ T lymphocyte count below 500, the recommendation is to initiate antiretroviral treatment prior to treating HCV.

Monitoring and Adverse Effects

The best monitor for treatment response at this time is the quantitative HCV RNA assay. The CDC’s recommendations⁸ for treatment monitoring of HCV in HIV-infected patients are the following:

• Quantitative HCV RNA assay should be done at the end of weeks 12 and 24 of treatment.
• Patients with undetectable HCV RNA levels should have a repeat HCV RNA assay at 24 weeks after treatment completion.
• Patients who do achieve a SVR should have HCV RNA levels repeated at 6 month intervals for 1-2 years to exclude late virologic relapse or re-infection (for patients with continued exposure risk).

Figure 1. Laboratory Testing for HCV in HIV-infected Patients

Relapse is defined as the absence of detectable HCV RNA at the end of treatment (ETR) that is not sustained over time, and nonresponse is the absence of ETR or SVR.⁸ For non–responders with minimal disease, it is better to wait before restarting therapy, but for non-responders with more advanced disease, re-treatment is the option of choice.²⁹

Re-treatment decisions should be based on type of previous treatment, type of response or non-response, tolerability to previous therapy, extent of liver damage, and HCV genotype.^8,10 Strategies for re-treatment include high-dose induction of PEG IFN/ribavirin combination and long-term maintenance therapy with PEG IFN to delay or prevent liver disease progression.²⁹ Relapse rates in all of the co-infection treatment trials were significant (approximately 20%).^29,36 For treatment relapsers, studies are being conducted to examine increasing duration of treatment, higher ribavirin dosing, and newer therapies.²⁹

Toxicities to interferon alfa commonly include influenza-like symptoms (fever, myalgia, HA, and fatigue) and problems with depression.⁸ These symptoms occurred in 20%-45% of patients in all four PEG IFN studies.²⁹ Depression may be severe enough to lead to suicide and peaks around the 4th month of treatment.^8,29 Cytopenias (thrombocytopenia, neutropenia, decrease in CD4+ cell count) are also common complications of IFN therapy. Neutropenia has been documented in 50% patients receiving the PEG IFN/ribavirin combination.²⁹ Other complications include retinopathy, neuropathy, exacerbation of autoimmune disease, and weight loss.

Ribavirin toxicities include a dose dependent hemolytic anemia, cough, and dyspepsia. The occurrence of drug-drug interactions between ribavirin and anti-HIV pyrimidine nucleoside analogues (ZDV, stavudine, zalcitabine, and lamivudine) have been concerning and warrant closer monitoring of patients who are on these antiretroviral therapies.⁸ Furthermore, interactions between ribavirin and didanosine have led to the inhibition of mitochondrial DNA and have been significant enough to cause severe pancreatitis and lactic acidosis.^33-34 Therefore, the combination of ribavirin and didanosine is contraindicated currently.8 Furthermore, the APRICOT study found a reduction in the total number of CD4+ cells but an increase in the percentage; however, during the study follow-up, the cell counts returned to pretreatment levels.^29,36

Some of these complications of therapy may be treated with agents such as NSAIDS (flu-like symptoms), antidepressants, filgrastin (neutropenia), and erythropoietin (anemia).^8,29,34 Although G-CSF has been utilized for the treatment of neutropenia, there have been no randomized trials to confirm the efficacy of this treatment in co-infected patients.²⁹ Because of the multitude of adverse effects that may occur with HCV treatment, the CDC recommends that ongoing monitoring and laboratory evaluation occur. Baseline CBC, HCV RNA viral load, CD4+ T lymphocyte count, and mental health evaluations should be checked before initiation of and during treatment.