Current Therapies for Chronic Hepatitis C

McKenzie C. Ferguson, Pharm.D.

Disclosures

Pharmacotherapy. 2011;31(1):92-111. 

In This Article

Special Considerations

Human Immunodeficiency Virus

Patients coinfected with HIV and HCV represent a unique challenge to the treatment of HCV. A large number of patients infected with HIV are also infected or become infected with HCV, leading to increased susceptibility to adverse treatment and disease effects, resulting in higher morbidity and mortality.[59] When patients with HIV are infected with HCV, they are less likely to spontaneously clear the virus, and the rate of liver disease progression may be accelerated.[59–62] Liver-related hospitalizations tripled for patients coinfected with HIV from 1994 to 2001.[6] Clinical judgment needs to be used regarding which coinfected patients to treat. Risk of serious liver disease should be weighed against the risk of morbidity from adverse events and anticipated treatment response.[7]

Peginterferon alfa plus ribavirin at standard dosages for 48 weeks is the recommended treatment for HIV-HCV–coinfected patients.[7,59,61,62] Two meta-analyses of six and seven, respectively, randomized controlled trials found that peginterferon in combination with ribavirin was shown to produce a higher probability of achieving SVR compared with treatment with interferon or peginterferon monotherapy.[59,62] Patients treated with peginterferon and ribavirin were less likely to withdraw from treatment and develop hepatic decompensation.[59] The SVR rate for patients with HIV and HCV genotypes 1 or 4 was 26%, versus 55% for genotypes 2 or 3.[62] A clinical outcome study of HIV-HCV–coinfected patients in Spain showed that patients who achieved SVR had a lower rate of all-cause mortality, liver-related death, and liver decompensation (p<0.05).[61]

Adverse effects and drug interactions with ribavirin are especially concerning in patients infected with both HIV and HCV. Anemia and neutropenia are of particular concern and require careful monitoring, dosage adjustment, and supplemental therapy as appropriate. Drug interactions with antiretroviral therapy also require careful evaluation. Ribavirin can increase the activity and toxicity of didanosine and other nucleoside reverse transcriptase inhibitors (NRTIs), with the potential to cause mitochondrial toxicity and lactic acidosis.[63] Other NRTIs that may interact through this mechanism include abacavir, lamivudine, stavudine, zalcitabine, and zidovudine. For this reason, concomitant administration of didanosine and ribavirin is contraindicated, and the other NRTIs should be used cautiously and only if the benefit of treatment outweighs the risk. Ribavirin can also reduce the effectiveness of stavudine and zidovudine.[18] Additive pharmacodynamic drug interactions may also result in increased adverse effects, including the risk of anemia with coadministration of ribavirin and zidovudine, and the risk of hepatotoxicity with the administration of ribavirin and lamivudine or zidovudine. Reduced adherence due to drug interactions, adverse effects, and poor tolerability should be assessed in every patient. In patients infected with both HIV and HCV, reducing and/or extending treatment durations and appropriately managing nonresponders (treatment algorithms) need to be more adequately studied before strong recommendations can be made in this population.[64]

End-Stage Renal Disease

The rate of infection with HCV is high among patients with end-stage renal disease (ESRD). The approach to treatment in patients with ESRD is different from that in patients with normal renal function. Altered pharmacokinetics and drug-related toxicities are concerns.[65] Both interferon and ribavirin are renally eliminated. Because ribavirin is not recommended for use in patients with moderate renal function impairment (creatinine clearance < 50 ml/min), most studies have evaluated the use of interferon monotherapy in patients with compromised renal function.[18,66] Ribavirin is not removed by hemodialysis. In renal dysfunction, the half-life of interferon and peginterferon is increased by as much as 40%, and the AUC is also increased by as much as 90% when compared with patients with normal renal function. For this reason, dosage reductions in patients with moderate-to-severe renal impairment are necessary. Important considerations for therapy in patients with ESRD include level of tolerance to adverse effects and the potential for increased toxicity, and reduced adherence.[65]

The AASLD guidelines do provide a class IIa recommendation for patients with severe kidney disease of careful monitoring and treatment at reduced dosages with peginterferon alfa-2a 135 μg/week or peginterferon alfa-2b 1 μg/kg/week, both with ribavirin 200–800 mg/day, and a class IIb recommendation for patients receiving dialysis that they be considered for treatment with conventional interferon or reduced-dose peginterferon. The recommendation also states that ribavirin can be added at a markedly reduced dosage with careful monitoring for adverse effects. The limited number of studies cited in support of using low-dose ribavirin in any setting of renal dysfunction (creatinine clearance < 50 ml/min) was associated with significant adverse effects, including hemolytic anemia, and often involved the use of growth factors.[7]

Few prospective clinical studies have evaluated the treatment of chronic HCV in patients with ESRD. Studies of treatment with conventional interferon monotherapy often included a very small number of patients and poor study design (observational studies). The SVR rates were found to be lower in treatment-naïve patients with normal renal function (13–19%) versus patients with renal impairment (33–37%), which indicate that interferon monotherapy may be more effective in patients with ESRD.[65] Studies of peginterferon monotherapy in patients with ESRD have shown reduced tolerability and SVR rates ranging from 12–75%.[65,66,67] Comparative studies are needed to determine which therapy is associated with better treatment response and better tolerability.[65,66] A meta-analysis of 20 prospective studies of interferon-based (nonpegylated) treatment in patients with ESRD and HCV revealed several characteristics associated with a higher likelihood of achieving SVR, including patients receiving a larger dose of interferon, a longer duration of treatment, full completion of treatment, female sex, lower HCV RNA, and virologic response.[67] More recent studies have begun focusing on the use of low-dose ribavirin in patients with ESRD, often based on serum ribavirin concentrations; however, once again, stronger evidence is needed before implementing this therapeutic strategy into routine practice.[65,66,68]

Injection Drug Abuse

Special considerations are necessary before initiating treatment for chronic HCV in patients with a history of injection drug abuse. These considerations include evaluating the benefits of treatment, the risk of reinfection, comorbid psychiatric illness, and adherence to therapy and monitoring.[7,69] Although some data indicate a lower rate of SVR is achieved in patients with injection drug abuse, the data are conflicting.[69,70] A recent retrospective study showed no significant differences in efficacy in adherent patients with active injection drug abuse.[70] The pharmacokinetics of methadone are not significantly altered by peginterferon.[71] A study evaluating treatment of acute HCV in injection drug users has shown promising results on SVR and greater compliance with a short treatment regimen.[72] This was a prospective, open-label, nonrandomized study in 23 patients with injection drug abuse and acute HCV who received peginterferon alfa-2b for 12 weeks. Results showed an overall SVR in 17 patients (74%).

Pregnancy

Routine screening of all pregnant women for HCV infection is not recommended by AASLD or the American College of Obstetricians and Gynecologists.[7,73] No evidence suggests that HCV infection will adversely affect pregnancy outcomes in terms of fetal or obstetric complications.[74] In addition, no specific agencies have guidelines for treatment or monitoring of HCV during pregnancy. Given that ribavirin is absolutely contraindicated in pregnant women, and strict precautions must be undertaken to prevent pregnancy in women of child-bearing age, treatment must occur well before conception or after delivery. Because ribavirin has a multiple-dose half-life of 12 days, it can persist for up to 6 months in nonplasma compartments. For this reason, pregnancy must be avoided both during treatment with ribavirin and for 6 months after treatment in female patients and female partners of male patients.[18]

From 2003–2009, 351 pregnancies have been tracked in the Ribavirin Pregnancy Registry, six of which described birth outcomes with defects. Three of these exposures were direct exposure, and three were as a result of indirect ribavirin exposure. Specific defects included one cardiac defect, two cases of torticollis, one case of glucose-6-phosphate dehydrogenase deficiency, one case of hypospadias, and one case of polydactyly. A larger sample of patients from the registry is planned in order to assess the relative risk of birth defects associated with ribavirin.[75] Interferon monotherapy has not been well studied in pregnant women, and interferons are classified as pregnancy category C. Peginterferon alfa-2a contains benzyl alcohol. Interferons should be considered to have abortifacient potential.[19,20]

Pediatrics

In children with HCV, the focus is on promoting awareness, diagnosis, and initiating early treatment. Since the implementation of routine blood screening, vertical transmission has replaced transfusion-associated HCV as the most common mode of HCV transmission in the pediatric population in the United States.[7] Maternal viral load is the most important factor associated with vertical transmission.[76] Most children with HCV are asymptomatic, as in adults, and the standard therapy is peginterferon in combination with ribavirin. Peginterferon alfa-2b is FDA approved for patients aged 3 years or older and is dosed at 60 μg/m2/week subcutaneously in combination with ribavirin 15 mg/kg/day. A treatment duration of 48 weeks is recommended as a class I recommendation by AASLD regardless of genotype.[7] Treatment should be considered in the same manner as in adults, with additional consideration given to patient age and stress.

Most children who undergo treatment tolerate therapy well, but adverse effects are commonly reported such as flu-like symptoms, pyrexia, headache, vomiting, fatigue, and neutropenia.[18,77–79] Studies have shown that pediatric patients, especially adolescents, who received ribavirin experienced suicidal ideation or attempted suicide more frequently than adults (2.4% vs 1%). This occurred both during treatment and follow-up. In addition, weight loss (mean percentile decrease of 13%) and decreased linear growth (mean percentile decrease of 9%) occurred in pediatric patients treated for 48 weeks, which was mostly reversible during the 6 months after treatment.[18]

One of the earliest pediatric studies on the use of peginterferon alfa for treatment of HCV was an open-label, noncontrolled study in 62 children, aged 2–17 years.[78] The children were administered peginterferon alfa-2b 1.5 μg/kg/week subcutaneously in combination with ribavirin 15 mg/kg/day in two divided doses for 48 weeks. Most patients (75.8%) had genotype 1. Overall rate of SVR was 59%, including 47.8% of patients with genotype 1 HCV and 100% of those with genotype 2 or 3 (p=0.0003). Adverse events frequently reported included leucopenia (75.4%), neutropenia (55.7%), flu-like symptoms (82%), and fever (51%). Other events included weight loss (19.7%) and temporary mood swings (14.8%).

A more recent open-label study was conducted in 30 children, aged 3–16 years, to evaluate peginterferon alfa-2b 1 μg/kg/week subcutaneously in combination with ribavirin 15 mg/kg/day.[79] In this study, children with genotype 1 were treated for 48 weeks and those with genotype 2 or 3 were treated for 24 weeks. Most patients had genotype 1, were treatment naïve, and acquired HCV through vertical transmission. Overall, SVR was attained in 50% of patients. Adverse effects included flu-like symptoms, fever, fatigue, headache, decreased appetite, and weight loss. Body weight decreased in 20% of children (> 5% weight loss occurred in 7%) but returned to baseline by week 48. Growth was reduced by 1.6 cm in 22 of 26 children compared with the growth velocity 50th percentile for age and sex but was entirely normal in the 6 months after treatment. Neutropenia (absolute neutrophil count < 1000 cells/mm3) occurred in nine patients necessitating reductions in dosing. Further studies in children are needed to clarify treatment duration in those with genotype 2 or 3 and long-term clinical outcomes.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....