Antiviral therapy

antiviral therapy

Michelle M. Lipman, MD and Scott J. Cotler, MD

Rush University Medical Center, 1725 West Harrison Street, Suite 206, Chicago, IL 60612, USA.

Introduction

Treatment

Diet and lifestyle

Pharmacologic treatment

• Treatment in special situations

Other treatments

Emerging therapies

References and Recommended Reading

Opinion Statement

Current treatment for hepatitis C virus infection consists of pegylated interferon and ribavirin. The most important predictors of response to antiviral therapy for HCV include genotype 2 or 3 infection, baseline viral load less than 2 million copies/mL, and the absence of cirrhosis. Hepatitis C genotype and viral load should be obtained prior to initiating therapy. Liver biopsy can be used to stage the liver disease, to provide prognostic information, and to evaluate for coexisting causes of liver injury. Patients with genotype 1 infection require 48 weeks of therapy and a ribavirin dosage of 1000 to 1200 mg/d to achieve an optimal response. Patients with genotype 2 or 3 infection require only 24 weeks of treatment and a ribavirin dose of 800 mg/d. Treatment may be discontinued in patients who do not have a 100-fold reduction in hepatitis C virus RNA level from baseline at week 12 because they are unlikely to achieve a sustained response with further therapy. Patients with cirrhosis and hepatic decompensation or a small hepatocellular carcinoma should be evaluated for liver transplantation.

Introduction

Hepatitis C virus (HCV) is estimated to have reached the United States around 1910, based on molecular analysis of long-term serial samples obtained from infected patients [1]. The projected emergence of HCV in the United States coincides with the return of soldiers from the Spanish-American war and the introduction of blood typing to allow for blood transfusion. Currently, HCV is the most common, chronic blood-borne infection in the United States. At least 3.9 million persons are anti-HCV seropositive and 2.7 million have chronic viremia [2].

The rate of chronicity of acute HCV is quite high, with estimates ranging from 54% to 85% [3]. Cross-sectional studies suggest that cirrhosis develops in 20% to 25% of persons with HCV within 20 years, whereas progression to cirrhosis may require 50 or more years in another 25% to 30% of infected individuals. The remaining 50% of persons with HCV appear to have an intermediate rate of development of cirrhosis. More rapid progression of liver disease is associated with alcohol abuse, male gender, older age at the time of infection, and coinfection with HIV [4, 5]. Other factors that may accelerate hepatic fibrosis include advancing age, hepatic steatosis, and increased hepatic iron stores. Persons with HCV and cirrhosis develop hepatocellular carcinoma at a rate of 1% to 4% per year [6].

Complications and financial costs due to HCV are projected to increase substantially in the coming years based on the large reservoir of infection and the concentration of HCV in young people. Hepatitis C is the leading indication for liver transplantation, accounting for 40% to 50% of cases. Need for liver transplantation due to HCV is expected to continue to rise until 2015, and the demand for repeat transplantation for HCV recurrence is increasing. Direct medical expenditures for HCV are projected to reach $10.7 billion between 2010 and 2019, excluding the cost of liver biopsies, hepatocellular carcinoma screening, and antiviral therapy [7].

Hepatitis C virus replication is rapid and error prone, leading to the generation of genetic heterogeneity. Hepatitis C is categorized into six major genotypes that differ in their amino acid sequence by approximately 30%. Genotype 1 is most prevalent in the United States (75%), followed by genotype 2 (15%), and genotype 3 (7%) [8]. Viral mutations produce closely related strains within an individual, which are referred to as quasi-species. Genetic heterogeneity contributes to the high rate of chronicity observed with acute HCV infection and poses a barrier to vaccine development.

Antibody testing using an enzyme-linked immunosorbent assay (ELISA) is the first step in establishing the diagnosis of hepatitis C. Molecular testing is used for early detection of acute infection, to establish the presence of viremia in chronically infected anti-HCV seropositive persons, and to monitor the response to therapy. Both qualitative and quantitative polymerase chain reaction (PCR) assays are available, and the quantitative tests were recently standardized to international units. Genotype testing should be performed on HCV-treatment candidates. Genotype is the strongest predictor of response to antiviral therapy and guides the duration of treatment. Liver biopsy is the most accurate way to stage HCV-related liver disease, and histologic findings provide prognostic information. Liver biopsy is also important when laboratory tests suggest a coexisting process such as autoimmune hepatitis, iron overload, nonalcoholic steatohepatitis (NASH), or the possibility of cirrhosis. There is a trend toward deferring a pretreatment liver biopsy in patients who are motivated to take treatment and have factors predicting a high sustained virologic response (SVR) rate.

Interferon alfa is the mainstay of treatment for HCV. It has direct antiviral and immune modulating effects, as well as anti-inflammatory and antiproliferative activity. Viral kinetic modeling has helped to characterize the response of HCV to interferon therapy. HCV levels decrease exponentially 24 to 48 hours after initiation of antiviral therapy. The rapid "first phase" decline

in viremia is followed by a more gradual "second phase" response with continued treatment [9]. Based on mathematical modeling, Neumann et al. [9] suggested that the first phase decline in viremia is related to interferon blocking HCV production or release. The second phase reduction in virus levels was hypothesized to reflect immune-mediated clearance of infected hepatocytes and inhibition of viral production. Both phases of the viral response are associated with SVR.

Ribavirin is now part of the standard treatment regimen for HCV and is given in combination with interferon. It is a synthetic guanosine nucleoside analogue that reduces aminotransferase levels in patients with HCV, but has a minimal effect on viremia. However, combining ribavirin with interferon improves the antiviral efficacy over interferon alone [10, 11]. The mechanism of ribavirin in the treatment of HCV remains under investigation. Ribavirin may act in part as an immune modulator and may function as a viral RNA mutagen [12]. Ribavirin inhibits inosine monophosphate dehydrogenase and may reduce viral protein synthesis by decreasing the intracellular concentration of guanosine triphosphate (GTP).

Treatment

Diet and lifestyle

• Excess alcohol consumption is associated with an increased rate of progression to cirrhosis. The question is how much alcohol is too much in persons with HCV? A study of 233 HCV patients, 80% of whom reported consuming less than 140 g/wk of alcohol, showed that even relatively low alcohol intake is associated with increased levels of viremia and hepatic fibrosis [13]. Ongoing alcohol use decreases the efficacy of treatment for HCV. Abstinence from alcohol is generally recommended for persons with HCV.

• Nonalcoholic steatohepatitis is the most common cause of liver disease in the United States and may contribute to the progression of hepatic fibrosis in persons with HCV. Factors linked to NASH, including obesity (body mass index >30 kg/m2), steatosis, and diabetes, have been associated with increased hepatic fibrosis in chronic HCV. Type 2 diabetes mellitus and steatohepatitis were recently identified as independent risk factors for advanced liver disease in HCV infection. Response rates to pegylated interferon and ribavirin are reduced in patients with body weights in excess of 75 to 85 kg. Treatment of NASH through weight loss and careful management of diabetes and hyperlipidemia may be beneficial in patients with HCV.

• The relationship between tobacco use and the severity of hepatic fibrosis in HCV was evaluated in a cross-sectional study of 310 patients [14]. Smokers were more often young, male, had consumed alcohol, and had a history of intravenous drug use. However, both age-adjusted and multivariate analysis showed a relationship between tobacco use and increased hepatic fibrosis. Patients should be informed of the potential deleterious effect of tobacco use on the natural history of HCV, and smoking cessation should be strongly encouraged.

• Increased hepatic iron stores have been linked to more rapid progression of fibrosis. A recent study demonstrated a higher incidence of cirrhosis in patients with HCV who were heterozygous for hereditary hemochromatosis [15]. Persons with HCV should be cautioned against self-medicating with iron and should avoid taking high doses of vitamin C, which can increase iron absorption.

Pharmacologic (drug) treatment

• The primary goal of pharmacologic treatment is to achieve viral eradication. An SVR is defined as HCV RNA undetectable in blood 6 months after completion of antiviral therapy. Over 95% of patients who achieve an SVR remain free of detectable viremia during 4 to 10 years of follow-up [16, 17].

• The secondary goal of pharmacologic treatment is to stabilize or improve liver histology and to reduce the risk of hepatic decompensation and hepatocellular carcinoma. Sustained responders and even some relapsers and nonresponders may attain these secondary benefits from interferon therapy.

Interferon alfa

Standard dosage: Monotherapy (now rarely used): 3 million IU of interferon alfa 2a or 2b or 9 mg of interferon alfacon-1, three times per week, administered subcutaneously (SC) for 48 weeks. Combination with ribavirin: unmodified interferon is given according to the same dosing schedule when combined with ribavirin. The duration of treatment is based on the HCV genotype and the interim response. Patients with genotype 2 or 3 infection are treated for 24 weeks and those with genotype 1 infection require 48 weeks of therapy.

Contraindications: Hypersensitivity to interferon alfa or any component of the product, decompensated liver disease, and autoimmune hepatitis. Use with caution in patients with thrombocytopenia or leukopenia, history of severe depression or other psychiatric illness, severe renal disease, symptomatic heart disease, seizure disorders, or compromised central nervous system (CNS) function.

Main drug interactions: Interferon interacts with drugs metabolized by the cytochrome P-450 (CYP) 1A2. Theophylline and phenobarbital levels may increase with interferon administration. Giving interferon with zidovudine increases bone marrow suppression. Interferon may potentiate the neurotoxicty of vidarabine. Vinblastine may increase the toxicity of interferon.

Main side effects

Table 1: Common side effects of interferon, pegylated interferon alfa-2a, and pegylated interferon alfa-2b

Flu-like symptoms

  • Headache
  • Fatigue
  • Myalgia
  • Arthralgia
  • Musculoskeletal pain

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