Coping with Hepatitis C: The Practical Aspects of Managing Antiviral Therapy with Pegylated Interferon

The World Health Organization (WHO) estimates that 3% of the global population is infected with hepatitis C virus (HCV). In the United States, the Third National Health and Nutrition Exam-ination Survey (NHANES-III) estimated that at least 1.8% of adults (3.9 million individuals) have detectable HCV antibody and 2.7 million people are truly viremic with detectable HCV ribonucleic acid (RNA) in the blood. These patients are at risk for chronic viral hepatitis and potentially for hepato-cellular carcinoma in a period of 20 to 30 years after original infection. HCV is the most common blood-borne infection nationwide. It is the leading cause of liver transplantation and a major cause of primary hepatic cancer. Evidence suggests that prognosis is worsened by the presence of comorbid liver disorders.

Recent advances in pharmacologic options including interferon (IFN) and pegylated interferon (PEG-IFN) alone or in combination with antiviral agents have shown promising evidence of slowing disease progression and, in some cases, of eradicating viral infection and restoring normal hepatic function. These advances and the management of their adverse effects were the subjects of an adjunct symposium conducted in conjunction with the 37th Annual Conference of the American Academy of Physician Assistants held in New Orleans in May 2003.

This program was supported by an unrestricted educational grant from Roche Laboratories, Inc.

Challenges in Providing Optimal Antiviral Therapy in Hepatitis C

Hepatitis C is now recognized as the most common cause of chronic liver disease and cirrhosis in the United States and is currently estimated to cause between 8,000 and 12,000 deaths per year. Mortality is expected to triple or quadruple over the next few decades as past exposures evolve to full pathology. At present, approximately 35,000 new HCV infections occur annually, but the prevalence is expected to quadruple in the near future. The need for liver transplantation due to HCV is expected to increase by 528% in the next 5 years due to the fact that the majority of individuals are infected in their 20s and 30s and are now approaching the 20- and 30-year anniversaries of infection, the points at which severe complications of benign disease and potential malignant disease occur.

Kenneth D. Ingram, PA-C of the Oregon Health and Science University, explained that HCV has little in common with the genetic structure of the other hepatitis viruses. HCV is a member of the flavivirdae family, which includes such viruses as those responsible for yellow fever and dengue. The viral particle consists of an envelope derived from hepatocyte host membranes into which virally encoded glycoproteins are inserted, surrounding a nucleocapsid and a double-stranded RNA genome of about 9,500 nucleotides. Six major genotypes and approximately 100 subtypes have been identified. Genotype 1 is the most common in North America, accounting for about 75% of infections, followed in frequency by genotypes 2 and 3. Geno-type does not seem to be correlated with alanine transaminase (ALT) abnormality or disease severity.

The incubation period for HCV ranges from 2 to 20 weeks. At presentation, only about 23% of cases have evidence of acute hepatitis, as a result of which the majority of patients, if untreated, progress to chronic infection. During the incubation period, the ALT level typically rises sharply in the first 4 to 6 weeks, then tapers off gradually until leveling at a point up to three times higher than normal. Both symptomatic and non-symptomatic patients eventually develop an HCV antibody response, thus making it difficult to determine other than by polymerase chain reaction (PCR) testing for HCV RNA or by liver biopsy if the individual has resolved the infection or is chronically infected.

Approximately 15% of individuals exposed to HCV clear the virus spontaneously for reasons that have thus far eluded investigators. Virtually all others, if untreated, progress to chronic hepatitis defined as HCV infection with liver inflammation. Approximately 15% of patients with chronic hepatitis develop hepatic cirrhosis, which places them at risk for decompensation or progression to hepatocellular carcinoma. Factors mediating increased progression are alcohol consumption, male gender, HIV co-infection, hepatitis B co-infection, and age greater than 40 years at the time of infection.

The principal risk factors for exposure to HCV are intravenous drug use, transfusion prior to 1992 (after which blood was screened for HCV), hemophilia, and blood contact during surgical or emergency procedures. Sexual transmission is more controversial, as even evidence that having multiple sexual partners is not compelling. Risk does appear to rise in instances of traumatic intercourse with vaginal tears and in anal intercourse. Passage from mother to child during delivery occurs in less than 5% of live births with infected mothers. Individuals at risk for HCV should be screened for HCV antibody. Because of the potential for false positive results, individuals testing positive should then be tested with PCR techniques for detection of viral DNA in their blood. These tests can determine the actual viral load and the genotype of the infectious agent. The viral genotype is highly predictive of response to treatment, but it is not a predictor of disease progression.

Charles D. Howell, MD, of the University of Maryland, opened his presentation by saying that the primary therapeutic objective in HCV is the long-term eradication of the virus after treatment is completed in order to prevent progression to end-stage hepatic disease. A sustained virologic response is defined as an undetectable serum HCV-RNA at least 6 months after the end of treatment. Other objectives are to improve the patient’s quality of life and to improve liver biopsy features. It has been established that for periods of as long as 10 years, patients who meet the criteria for sustained virologic response show continuous histologic improvement and lack of progression to end-stage cirrhosis, especially if treated prior to the onset of cirrhosis. Currently, with treatment with PEG-IFN plus ribavirin, 54% to 61% of patients who complete therapy can expect to have sustained virologic responses.

“All patients with chronic HCV are potential candidates for antiviral therapy,” Dr. Howell said. “However, the decision of whether or not to treat depends on several factors including age, viral genotype as predictive of response, the presence and stage of hepatic fibrosis, the presence and severity of comorbid illness (especially hepatic comorbidity), and the patient’s motivation and willingness to tolerate potential side effects.”

Selected patients should be greater than 18 years of age and have both viremia (HCV RNA determined by PCR) and biopsy-determined portal or bridging fibrosis with some inflammation and necrosis. For the most part, these are patients with compensated liver disease and minimal evidence of functional deficit (e.g., mild alterations in bilirubin, serum albumin, and prothrombin times, and no evidence of complications of cirrhosis such as ascites, variceal bleeding, or hepatic encephalopathy). Because treatments are potentially teratogenic, patients should not be pregnant, potentially pregnant during the course of treatment, or partners of women who might become pregnant during treatment. ALT levels are not a definitive criterion, as even patients with normal or near-normal levels who meet the histologic and viremic criteria may benefit from clearing the virus. It is less clear, however, that treatment will affect the long-term disease course in patients without persistently high ALT levels.

Recent evidence suggests that individuals with decompensated liver disease may also benefit from treatment both for clearing the virus and prior to liver transplantation for preventing recurrence of HCV in the graft. The data so far suggest, however, that these patients have a disproportionately high rate of treatment-related complications such as severe peripheral blood cytopenia and thrombocytopenia, and hence their treatment remains experimental and should be undertaken only in the context of clinical trials.

Treatment is contraindicated for individuals with autoimmune conditions, hepatic decompensation, seizure disorders, pregnancy, hemoglobinopathies including thalassemia and sickle-cell anemia, and psychiatric disorders. There is some evidence that patients with retinopathies related to diabetes or hypertension may undergo rapid progression of ophthalmic changes while on IFN treatment, so they should be screened very carefully, as should patients with cardiovascular or cerebrovascular disease.

Predictors of response to therapy are principally viral genotype, the pre-treatment viral load, extent of liver cirrhosis, and body weight. It is important to keep these factors in mind when selecting patients for treatment. Patients who have advanced cirrhosis should be screened for hepatocellular carcinoma before being admitted to antiviral treatment. Patients selected for treatment should be given hepatitis A and hepatitis B vaccines to prevent excess morbidity in the event of subsequent co-infection.

Like Mr. Ingram, Dr. Howell endorsed the use of liver biopsy as the gold standard of diagnosis in HCV and the best predictor of the fibrosis progression rate, provided one knows the approximate duration of infection.

Improving Outcomes in Hepatitis C: The Role of Pegylated Interferons in Combination Therapy

Since 1990, IFN has been the core component of treatment for HCV. However, IFNs, when administered 3 times weekly for 48 weeks, yielded low sustained viral response rates of 13% to 19%. Daily IFN monotherapy met with only limited success, because improved response rates were observed only in genotypes other than genotype 1, the dominant and most difficult to treat HCV organism in North America. More recently, the addition of ribavirin, a nucleoside analogue that appears to have no inhibitory effect on HCV when administered alone, to the standard IFN regimen has resulted in improved response rates (38% to 43%), but also in additional toxicity.

The main reason for the poor response to standard IFN therapy is inherent in its short half-life of 5 to 8 hours. This leads to broad fluctuations in plasma concentrations during the treatment period. Dosing three times weekly results in undetectable blood levels on the other 4 days. This shortcoming of IFN led to the development of longer-lasting alpha IFN compounds by attaching a large polyethylene glycol (PEG) molecule to the IFN protein. These larger molecules lead to prolonged absorption times and elimination half-lives of 40 hours (PEG-IFN alpha-2b) to 80 hours (PEG-IFN alpha-2a). These agents can be administered once weekly with standard IFN dispensed throughout the week. PEG is an inert substance that adds no toxicity to treatment.

The enhanced pharmacokinetics profile of PEG-IFNs has resulted in improved antiviral efficacy. The recently approved combinations of PEG-IFN alfa-2a or PEG-IFN alpha-2b plus ribavirin have become the standard of care for the treatment of patients with HCV. Of the two pegylated IFNs, alfa-2b has the lower molecular weight, is fairly readily degraded, and has somewhat higher immunogenicity and a shorter half-life. Thirty percent of this agent is eliminated through hepatic metabolism. PEG-IFN alpha-2a undergoes more sustained absorption and restricted distribution favoring the liver. It remains at measured concentrations in the serum for up to a week. About 70% of its elimination is through hepatic metabolism, and the remainder is renal.

The efficacy data for pegylated interferons come from two pivotal phase III clinical trials. One of them, a multinational European study, compared sustained virologic response rates in 1,530 patients randomized to initial treatment in three trial arms: (i) IFN alfa-2b 3 million units three times weekly plus ribavirin 1,000 to 1,200 mg daily for 48 weeks; (ii) PEG-IFN alpfa-2b 1.5 mcg/kg weekly for 4 weeks followed by PEG-IFN alfa-2b 0.5 mcg/kg weekly plus ribavirin 1,000 to 1,200 mg daily for 44 weeks; or (iii) PEG-IFN alfa-2b 1.5 mcg/kg weekly plus ribavirin 800 mg daily for 48 weeks. The response rates were 47%, 47%, and 54% in the three arms, respectively, with a statistically significant improvement (p=0.01) in the third arm versus the first. The genotype 1 histologic response was 42% in arm 3 compared with 29% with unmodified IFN alfa-2b after 48 weeks of treatment. Treatment of genotype 1 usually requires a full year. The response rates for genotypes 2 and 3 were similar among treatment groups (79% and 82%) (Manns MP et al. Lancet 2001;358:958).

PEG-IFN alfa-2a was the subject of the second pivotal trial. In it, 1,121 patients were randomized to three arms for 48 weeks of treatment with (i) PEG-IFN alfa-2a 180 mcg plus placebo, (ii) unmodified IFN alfa-2a 3 million units plus ribavirin 1,000 to 1,200 mg, and (iii) PEG-IFN alfa-2a 180 mcg plus ribavirin 1,000 t0 1,200 mg. Patients’ livers were biopsied prior to randomization and at week 72. Among patients treated with PEG-IFN alfa-2a plus ribavirin (arm 3), the sustained virologic response rate was 56% compared with 44% for patients in arm 2 and 29% in arm 1 (p<0.001 for each comparison). Of all patients with HCV genotype 1, 46% had sustained response with PEG-IFN alfa-2a plus ribavirin compared with 36% for standard IFN alfa-2a plus ribavirin and 21% for PEG-IFN alfa-2a plus placebo. For genotypes 2 and 3, response rates were 76%, 61%, and 45%, respectively (Fried MW et al. N Engl J Med 2002;347:975).

These and other studies confirm that PEG-IFNs plus ribavirin are more effective than standard IFN and/or ribavirin therapies, and they should probably be considered for patients with compensated cirrhosis. In addition, in the study by Fried et al., data were analyzed to determine if improving viremia by a two log decrease significantly improved the durability of response. Such a drop after 12 weeks of treatment occurred in 86% of patients receiving PEG-IFN alfa-2a plus ribavirin, and their sustained virologic response rate was 65%. In contrast, among the 14% of patients who did not experience two log drops in viremia, 97% failed to achieve sustained responses. When treatment was continued out to 12 months, only 3% of these patients had sustained responses, suggesting that treatment beyond 3 months may increase toxicity without significantly improving efficacy.

Recognizing and Managing the Side Effects of Hepatitis C Therapy

Addressing the audience a second time, Dr. Howell noted that HCV therapy is associated with a wide range of side effects, and that managing them effectively is critical to maintaining patients on treatment. Without effective prophylaxis and intervention, between 13% and 22% of patients would discontinue treatment and approximately 40% would need dose reductions of either the IFN or the ribavirin component. In a data review designed to determine the minimum criteria for successful treatment, it was shown that patients who received 80% of the intended dosages of both agents 80% of the time experienced significantly higher sustained virologic response, around 66%, than patients who did not. This was especially the case with patients with HCV genotype 1. In that group, meeting the 80-80-80 criterion resulted in a 50% sustained response rate compared with 37% for patients who did not. Adherence, therefore, is a major component of clinical outcomes, underscoring the importance of symptom management.

IFN and ribavirin each has a characteristic side-effects profile, and no additional side effects have been observed in trials involving PEG-IFNs with or without ribavirin. The treatment-related adverse events associated with IFN are flu-like symptoms in the first few weeks of treatment, nausea and diarrhea, psychiatric symptoms such as depression and irritability, insomnia, and some less common effects such as alopecia, injection site reactions, thyroiditis, and autoimmunity. Leukopenia and thrombo- cytopenia are quite common, though severe thrombocytopenia is not. With the exception of thyroiditis, all of these side effects are reversible with dose reduction or discontinuation. The most troubling side effect of ribavirin is hemolytic anemia, which occurs in about half of patients and requires dose reduction in 10% to 20% of patients. Other side effects are cough, skin rash, dyspnea, insomnia, anorexia, and
teratogenicity.

In the Fried study of PEG-IFN alfa-2a plus ribavirin, 11% of patients withdrew for the following reasons in declining order: psychiatric symptoms, flu-like symptoms (especially fatigue), skin changes, and gastrointestinal side effects. The results were similar in the Manns study of PEG-IFN alfa-2b plus ribavirin (see reference above). Dose reductions due to side effects were required in 36% of patients in the Fried study and 36% of patients in the Manns study depending on the regimen, as side effects are apparently dose-dependent. PEG-IFN alfa-2b plus ribavirin is associated with a higher incidence of neutropenia (18%) than is unmodified IFN alfa-2b plus ribavirin (8%).

Dr. Howell turned to the management of side effects associated with HCV therapy. IFN-related psychiatric symptoms are resolved without sedation by selective serotonin reuptake inhibitors (SSRIs) in up to 85% of patients (Kraus MR et al. Aliment Pharmacol Ther 2002; 16:1091; Gleason OC et al. J Clin Psychiat 2002;63:194). In patients who experience anemia, the most dramatic effects occur in the first few weeks of treatment. It is treated with ribavirin dose reduction at approximately 10 gm/dL and ribavirin discontinuation at 8.5 gm/dL. Results of recent pilot study suggest that weekly recombinant erythropoietin for HCV treatment-related anemia may increase hemoglobin levels by almost 1.5 gm/dL (Dieterich DT et al. Gastroenterol 2001;124:A64). PEG-IFN dose reduction is the appropriate treatment for neutropenia at levels 750 cells/mm3 and for thrombo- cytopenia at levels below 50,000/mm3. Discontinuation is appropriate for neutrophil levels below 500 cells/mm3 and for thrombocytopenia at levels below 25,000/mm3. As the cell counts recover, treatment at lower IFN doses may be possible. Treatment with hematopoietic growth factors may enable patients with these side effects to adhere to
antiviral therapy.