Hepatitis C -- Current State of the Art and Future Directions 

Introduction

Hepatitis C, a common blood-borne infection and a frequent reason for visitation to a physician's office, was a major topic of discussion at the recent annual meeting of the American Association for the Study of Liver Diseases (AASLD), held in Boston, Massachusetts, October 30-November 2, 2004.

The current state-of-the-art treatment for previously untreated patients with chronic hepatitis C infection is a once-weekly injection of pegylated interferon in combination with oral ribavirin. Although initially thought to be an asymptomatic disease, numerous studies have now shown that hepatitis C adversely affects patients' quality of life.

The topics of discussion regarding hepatitis C presented at this year's meeting concerned the prevalence and natural history of this viral infection, the treatment of acute hepatitis C, the treatment of African-American populations infected with hepatitis C, the appropriate treatment duration for infection, the treatment of the patient infected with genotype 2 and 3 disease, the re-treatment of nonresponders to standard interferon therapy, and new therapies for the treatment of hepatitis C infection.

This report addresses key highlights in these topical issues, with an emphasis on implications for the treating physician.

Prevalence and Natural History

Trends in Hepatitis C Prevalence in the United States

The Centers for Disease Control and Prevention (CDC)^[1] reported on the prevalence of hepatitis C infection derived from data in the National Health and Nutrition Examination Survey (NHANES), which was conducted during 1999-2002 in 15,079 noninstitutionalized, nonmilitary personnel. The results were then compared with those from a similar survey performed 10 years ago.

They found the prevalence of anti-hepatitis C virus (HCV) antibody to be 1.6%, corresponding to 3.8 million people. The prevalence was 2.1% in men and 1.1% in women. Black individuals had an anti-HCV prevalence rate of 3.0%, which was higher than the rates seen in white individuals (1.5%) and Mexican-American individuals (1.3%). Of all individuals infected with HCV, 69.9% were between the ages of 35 and 54 years. Prevalence was highest among those aged 45-49 years, with 7.1% of men and 2.3% of women infected in this group. Black men aged 45-49 years had an astounding prevalence rate (anti-HCV-positive) of 17.9%. Individuals with a history of injection drug use had a disease prevalence rate of 57.3%.

The study authors compared these data with data from the NHANES III survey performed 10 years ago. They found that the overall incidence of hepatitis C antibody prevalence has not changed over the past 10 years, but that the peak age-specific disease prevalence has increased from the group aged 35-39 years as found a decade ago, to 45-49 years in the current NHANES. These data are consistent with a past epidemic of acute hepatitis C that affected a large cohort of people. One of the major shortcomings of this study is that it reports on the prevalence of the hepatitis C antibody, which may indicate previous exposure or active disease. This study does not report on disease prevalence, as prevalence of hepatitis C infection is defined by the presence of hepatitis C viral RNA in serum. Only 148 of the 15,079 participants had serum available for hepatitis C viral RNA testing, making any statements regarding disease prevalence, and not potential exposure to the disease, invalid.

HCV Prevalence Among Liver Transplant Surgeons

The prevalence of hepatitis C among physicians remains undetermined. Because hepatitis C is the most common indication for liver transplantation, it seems reasonable to assume that liver transplant surgeons would be expected to be at high risk for acquiring the disease.

Thorburn and colleagues,^[2] in an anonymous survey of 117 liver transplant surgeons who attended the 9th Congress of the International Liver Transplantation Society Meeting in Barcelona, Spain, in June 2003, determined that the incidence of hepatitis C infection in this group was 0.8%. The reported prevalence of hepatitis C infection among the transplant recipients in this group was 31% to 40%. Based on these findings, the risk of hepatitis C transmission to transplant surgeons is reassuringly low, despite the particular risks associated with their occupation.

Natural History of Chronic Hepatitis C Among Plasma Donors

The natural history of hepatitis C infection is difficult to assess because of the inability to determine the initial exposure to the disease. Ferenci and colleagues^[3] reported on the Austrian experience following several outbreaks of hepatitis C infection in plasmapheresis centers in Austria in the 1970s and 1980s; 435 individuals have been identified as having contracted hepatitis C at these centers. All patients were infected with genotype 1 disease; 39 are women and 396 are men. The mean age of infection was 22 years. The mean follow-up in this study was 27 years. Nine of the 435 individuals (2.1%) have died of liver disease, including 1 following a liver transplantation. Fifteen subjects (3.4%) developed hepatocellular carcinoma; 22 subjects (5.1%) underwent liver transplantation; and 93 individuals (21.4%) have compensated cirrhosis. A total of 110 (25.3%) noncirrhotic patients were nonresponders to antiviral therapy. Thirty-one subjects (9%) cleared the virus either spontaneously (3 people) or with antiviral therapy (28 people). The study authors concluded that within 27 years of exposure, 29.7% of the plasma donors developed advanced liver disease, with an overall mortality rate of 2.1%. These data underscore the progressive nature of this disease.

HCV Genotype 3a

The origin and worldwide spread of disease is always fascinating to those in the medical field. Morice and colleagues^[4] reported on the worldwide spread of HCV genotype 3a disease, using nucleotide sequencing of the nonstructural 5B component of the hepatitis C genome. It is believed that genotype 3a probably originated in the Indian subcontinent and/or Southeast Asia, and has spread to the rest of the world among intravenous drug users. This study evaluated samples from 93 patients infected with genotype 3a from around the globe.

These investigators found that the phylogenetic tree topologies showed no specific clustering according to the continent or area of origin, suggesting a homogeneous spread of genotype 3a infection, and small, noninclusive clusters of viral sequences from South America, California, or Australia were noted. These data are consistent with the concept that genotype 3a infection had a common origin and that genetic diversification may occur among local areas of infection.

Impact of Marijuana on Fibrosis Progression in Hepatitis C

Most hepatitis C experts agree that factors such as alcohol intake, coinfection with either hepatitis B or the human immunodeficiency virus, and age at infection may lead to the development of significant fibrosis. Other factors remain elusive and not proven. Of particular interest is the effect of Cannabis sativa, or marijuana, on disease progression. Many patients use marijuana for pleasure or to combat complaints of nausea associated with antiviral therapy. Marijuana is known to exert its effects via the CB1 and CB2 receptors. An upregulation of CB1 receptors has been found to be present in cirrhosis.

Hezode and colleagues^[5] investigated the effects of marijuana use on the development of fibrosis in 211 consecutive untreated patients with chronic hepatitis C infection. Forty-nine percent of patients admitted to marijuana use. For purposes of the study, marijuana cigarette use was classified into the following 3 categories: (1) nonsmokers; (2) occasional smokers (< 1 cigarette per day); and (3) daily smokers (at least 1 daily marijuana cigarette).

By both univariate and multivariate analyses, daily marijuana smoking was found to be associated with the development of significant hepatic fibrosis. Thus, this study reports a strong association between daily marijuana use and fibrosis progression; the underlying mechanism needs to be further determined, although current data would suggest a role in the upregulation of the CB1 receptor. These findings should encourage physicians to advise their patients with hepatitis C infection to avoid marijuana use. Further studies regarding this important and controversial topic need to be addressed.

Hepatitis C and Sleep Disorders

Hepatitis C has been previously shown to adversely affect patients' quality of life. The prevalence of sleep disorders and fatigue in 59 patients with chronic hepatitis C was addressed by Carlson and colleagues.^[6]

Patients with hepatitis C were found to have an increased incidence of fatigue vs normal historical controls. The majority of patients with hepatitis C (64%) were found to be "poor sleepers," as defined by a Pittsburgh Sleep Quality Index score of greater than 5. With respect to the presence of sleep disorders and fatigue, no difference was noted between men and women or between patients with and without cirrhosis. However, weekly use of sleeping medications was reported in 33% of patients without cirrhosis and in 9.7% of those with cirrhosis.

The study authors concluded that patients with chronic hepatitis C infection suffer from poor quality of sleep, regardless of their disease stage, and that fatigue is significantly correlated to poor sleep quality.

Acute Hepatitis C

Acute hepatitis C is not commonly seen in clinical practice; therefore, there is a paucity of well-designed, randomized, controlled trials for the treatment of this patient group. Approximately 15% to 30% of patients with acute hepatitis C will spontaneously clear the infection, whereas the remainder of patients will develop chronic disease. Although most clinicians agree that acute hepatitis C should be treated, when therapy should be initiated, how long it should be given, and which therapy to use remain unclear. Two studies presented during this year's AASLD meeting evaluated 3-month regimens of pegylated interferon for the treatment of acute hepatitis C.

Kamal and colleagues^[7] compared the use of once-weekly pegylated interferon alfa-2b vs 3 times weekly interferon alfa-2b plus ribavirin in 68 patients acutely infected with either hepatitis C genotype 1 or 4. Treatment was randomized to begin 8 weeks, 12 weeks, or 20 weeks after presumed disease exposure. Patients were treated for an initial 12 weeks of therapy, and if a virologic response was not achieved at this point, therapy was continued for an additional 12 weeks. The primary end point of therapy was an undetectable HCV-RNA at 24 weeks after the end of therapy; this was termed a sustained viral response. Seven patients (10%) had a spontaneous clearance of virus without treatment. The sustained viral response rates for the groups receiving pegylated interferon monotherapy initiated at 8, 12, or 20 weeks were 90%, 90%, and 80%, respectively. The sustained viral response rates for the groups receiving combination interferon and ribavirin 3 times per week were 63%, 70%, and 60%, respectively. The study authors concluded that in patients with acute hepatitis C infection, once-weekly pegylated interferon alfa-2b was better than standard combination interferon plus ribavirin therapy, and that the pegylated interferon was safer and more cost effective. There appears to be a trend toward higher sustained viral response rates when pegylated interferon is started earlier after disease exposure, although this difference was not statistically significant. It also appears from this study that patients with genotype 1 disease require 24 weeks of therapy, whereas those with genotype 4 require only 12 weeks of treatment.

In the second of these studies, Calleri and colleagues^[8] evaluated the use of pegylated interferon alfa-2b at a dose of 1.5 mcg/kg weekly for 3 months in 43 patients with acute hepatitis C. Overall, 30 of 43 (69.8%) subjects had a sustained viral response. When evaluated by genotype, 10 of 16 (62%) patients with genotype 1 and 4 disease had a sustained viral response, and 11 of 14 (79%) genotype 2 and 3 patients had a sustained viral response. There was a trend toward higher response rates in men, non-intravenous-drug users, and patients with low levels of virus, although none of these factors were independently predictive of response. Hepatitis C viral persistence at 4 weeks of therapy was predictive of nonresponse to therapy.

Persistence of Virus Following Successful Therapy

Sustained viral response to hepatitis C therapy is defined as an undetectable serum HCV-RNA 6 months after stopping treatment, regardless of the therapy used. This definition has become the cornerstone of hepatitis C treatment because its attainment has a significant impact upon both the patient and the treating physician.

An important study was presented by Radkowski and colleagues^[9] during these meeting proceedings that places into question our definition of response. They evaluated for the presence of hepatitis C viral RNA in either stimulated lymphocytes, cultured macrophages, or posttreatment liver biopsy samples from 17 sustained viral responders to combination interferon and ribavirin therapy. HCV-RNA was detectable in the macrophages of 11 (65%) patients and in the lymphocytes of 7 (41%) patients. Three patients had HCV-RNA detectable in liver tissue. Overall, only 2 of the 17 (12%) sustained viral responders were negative for the presence of HCV-RNA in all analyzed specimens.

These findings are important because they bring into question the current definition of sustained viral response. These findings need to be further evaluated in larger series because the persistence of virus may have significant implications on future disease progression, disease activation, disease transmission, and the development or persistence of hepatic fibrosis.

Treatment of Hepatitis C

Comparison of Pegylated Interferons

The current standard of care for the treatment of chronic hepatitis C infection is a combination of pegylated interferon and ribavirin. Two types of pegylated interferon, pegylated interferon alfa-2a and pegylated interferon alfa-2b, are approved for use in the United States. Many investigators have publicly compared these 2 compounds, but to date, all of these comparisons have been based on opinion, without the benefit of unbiased comparative data. This lack of data renders all comparisons as being without true scientific merit.

In an effort to compare these 2 interferons, Silva and colleagues^[10] compared the pharmacokinetic and pharmacodynamic properties of pegylated interferon alfa-2a and pegylated interferon alfa-2b in 36 genotype 1 patients during the first 4 weeks of therapy. (Author's note: The study was presented by Dr. Mark Laughlin, an employee of Schering-Plough, the manufacturer of pegylated interferon alfa-2b.). Laughlin reported that this study found a significantly greater viral load reduction in the first 4 weeks of therapy in those patients treated with pegylated interferon alfa-2b. While this finding is intriguing, this finding was not related by the investigators to clinical efficacy, side effects, or quality of life while on therapy. Because pegylated interferon monotherapy is not used as the standard of care for the treatment of chronic hepatitis C infection, this report offers no statement regarding the clinical efficacy of either pegylated interferon and should not influence drug selection. A head-to-head comparison of the 2 pegylated interferons in combination with a controlled ribavirin dose is required to appropriately compare these medications. Such a trial is underway.

African-American Population

The prevalence of hepatitis C in the African-American population in the United States, is roughly 2-3 times that seen in the white population in this country. Despite this finding, African-American patients have been underrepresented in the numerous large published hepatitis C treatment trials. Initial reports indicate that response rates to interferon and ribavirin-based therapies are lower in African-American individuals than in white or Asian individuals. The factors, such as the high prevalence of genotype 1 disease in this population, behind these differences are uncertain.

Jacobson and colleagues^[11] reported on the use of weight-based ribavirin vs flat-dose ribavirin in combination with pegylated interferon alfa-2b in 387 African-American patients infected with hepatitis C genotype 1. All patients received pegylated interferon alfa-2b 1.5 mcg/kg weekly. Patients were randomized to either a fixed dose of 800 mg of ribavirin or a weight-based dosing regimen.* In the weight-based dosing regimen, patients received 800 mg per day if they weighed < 65 kg, 1000 mg of ribavirin if they weighed between 65 kg and 85 kg, 1200 mg of ribavirin if they weighed between 86 kg and 104 kg, and 1400 mg of ribavirin if they weighed between 105 kg and 124 kg. Because of the higher dosages of ribavirin, both dose reductions and hematopoietic growth factors were allowed. In an analysis of patients who had received at least 1 dose of medication, a sustained viral response was seen in 21% of those in the weight-based dose arm and in 10% of those in the fixed-dose arm. Anemia, defined as a hemoglobin drop to below 11 g, occurred in 47% of patients in the weight-based dose arm and in 29% of those in the fixed-dose arm. Dose reductions and growth factor use were greater in the group receiving weight-based dose ribavirin. While dose reductions and anemia were more common in the group receiving weight-based ribavirin dosing, dose discontinuation rates were similar in both groups.

The results of this study are very important and support the use of weight-based dosing over fixed dosing of ribavirin in African-American patients infected with genotype 1 disease. This study is equally important because it is one of the largest cohorts of African-American patients studied to date with hepatitis C infection.

Treatment Duration

The current approved treatment for hepatitis C is pegylated interferon plus ribavirin for a total of 48 weeks. Some studies have suggested that a longer treatment period may be warranted in those patients who have a late documented viral clearance while on therapy. Currently, a 12-week time point is used to determine the presence of an early viral response; however, many studies indicate that a 4-week point may also be useful in predicting a response to 48 weeks of therapy.

The TeraVIC-4 study^[12] evaluated the treatment of patients whose 4-week on-treatment HCV-RNA was positive, for a total course of either 48 weeks or 72 weeks of continued therapy.* All patients were treated with pegylated interferon alfa-2a at a dose of 180 mcg per week plus ribavirin 800 mg per day; 327 patients were included in the analysis, and 90% were genotype 1. The end-of-treatment response in the group receiving 48 weeks vs the group receiving 72 weeks of therapy, was 61% and 52%, respectively. The sustained viral response rate in the group receiving 48 weeks vs 72 weeks of therapy was 32% and 46%, respectively. The relapse rate in the group receiving 48 weeks vs 72 weeks of therapy was 48% and 13%, respectively.

The study authors concluded that the increased duration of therapy in this select population resulted in an increase in sustained viral response rate and a decrease in the relapse rate. Although this study is interesting and supports longer duration of therapy in this group of patients, one cannot help but wonder if the ribavirin dose used in this study was too low. Because higher ribavirin dosages have been shown to decrease relapse rates, perhaps the same effect may have been achieved with higher ribavirin doses for a treatment period of 48 weeks. Although there were no increased adverse events noted in the group treated for 72 weeks, the investigators do not comment upon the quality of life of these patients during this treatment period.

Berg and colleagues^[13] also looked at relapse rates in patients treated for 48 vs 72 weeks with pegylated interferon alfa-2a 180 mcg/week plus ribavirin 800 mg per day. This study focused on the late virologic responder, which was defined as those patients whose serum HCV-RNA was positive at 12 weeks but became negative at 24 weeks. In this particular population, there was a significant reduction in relapse rates when treatment was extended to 72 weeks. This study supports a longer duration of therapy in this patient population. However, as in the TeraVIC-4 study,^[12] one cannot help but wonder why a higher dose of ribavirin was not chosen as the baseline dosage.

Genotype 2 and 3 Disease

Patients infected with HCV genotype 2 and 3 have been shown to have better responses to pegylated interferon and ribavirin-based regimens than those infected with genotype 1. (The response rates of these 2 genotypes are usually reported together.)

Efficacy of treatment. Rizzetto and colleagues^[14] reported the results of a subanalysis of 2 previously published studies assessing the efficacy of pegylated interferon alfa-2a plus ribavirin in the treatment of patients with genotype 2 and 3 infection; 258 patients with genotype 2 disease and 374 patients with genotype 3 disease were included in the analysis. Sustained viral response rates were found to be higher in genotype 2 patients than in those with genotype 3 disease. The response rates for genotype 2 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 800 mg per day for 24 weeks with low and high viral levels were 100% and 84%, respectively. The response rates for genotype 2 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 1000-1200 mg per day for 24 weeks with low and high viral levels were 82% and 86%, respectively. The response rates for genotype 2 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 800 mg per day for 48 weeks with low and high viral levels were 93% and 84%, respectively. The response rates for genotype 2 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 1000-1200 mg per day for 48 weeks with low and high viral levels were 75% and 77%, respectively.

The response rates for genotype 3 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 800 mg per day for 24 weeks with low and high viral levels were 75% and 84%, respectively. The response rates for genotype 3 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 1000-1200 mg per day for 24 weeks with low and high viral levels were 83% and 76%, respectively. The response rates for genotype 3 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 800 mg per day for 48 weeks with low and high viral levels were 83% and 66%, respectively. The response rates for genotype 3 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 1000-1200 mg per day for 48 weeks with low and high viral levels were 78% and 75%, respectively.

Based on these findings, the study authors concluded that patients with genotype 2 infection responded better than those with genotype 3. The study authors also concluded that in all groups of patients with genotype 3 disease, a treatment course of low-dose ribavirin plus pegylated interferon for 24 weeks is sufficient. This is a very provocative report because there does appear to be a difference in response rates between genotype 2 and 3 patients. Further studies need to be performed that include variables such as viral load, the presence of steatosis, and the presence of fibrosis to better evaluate the response rates of each individual genotype. This represents an important clinical area in which new information should be obtained.

Duration of treatment. The duration of treatment for patients with genotype 2 and 3 infection also needs to be addressed. Although most physicians use a treatment duration of 24 weeks in this population, studies are being performed to determine the ideal length of treatment.

Dalgard and colleagues^[15] studied the efficacy of 14-week treatment duration in patients infected with hepatitis C genotypes 2 and 3; 122 previously untreated patients were treated with pegylated interferon alfa-2b 1.5 mcg/kg once weekly plus weight-based ribavirin dosing at 800-1400 mg per day.* Patients who achieved an undetectable HCV-RNA level at weeks 4 and 8 were continued for a total course of 14 weeks. Those patients who were positive at 8 weeks were treated for a total of 24 weeks; 95 (78%) patients were treated for 14 weeks and the remaining 27 were treated for 24 weeks. The sustained viral response rate was 90% in the group treated for 14 weeks and 56% in the group treated for 24 weeks. The overall sustained viral response rate was 82%. The study authors concluded that 14 weeks of therapy is sufficient for those patients with genotype 2 and 3 infection who have had an early viral response at 4 and 8 weeks.

This finding has wide-reaching implications because it questions both our current accepted time point for early viral response of 12 weeks and our current recommended duration of therapy for genotype 2 and 3 disease. Additional studies in this area must be performed to validate these findings. As we postulate that there may be a difference in response rates between genotype 2 and 3 infection, it would be nice to learn from these investigators the individual sustained viral response rates of those patients infected with genotype 2 and 3 disease.

Nonresponders

Re-treatment of patients unresponsive to standard interferon plus ribavirin therapy has been disappointing.

Re-treatment with pegylated interferon-based therapy. Poynard and colleagues^[16] reported preliminary results of the EPIC (Early viral response with Peg-intron/rebetol weight based dosing in previous Interferon/ribavirin HCV treatment failures) trial's attempts to address the issue of re-treatment of patients previously unresponsive to standard interferon and ribavirin, with pegylated interferon and ribavirin-based therapy. In this trial, patients are treated with pegylated interferon alfa-2b 1.5 mcg/kg per week plus a weight-based ribavirin regimen of 800-1400 mg per day.* Data were presented on the early virologic response in more than 1400 patients enrolled in the trial. Early virologic response was defined as a decrease in HCV-RNA level by greater than 2 logs from baseline or an undetectable HCV-RNA at 12 weeks of therapy. Based on these criteria, 65% of treated patients have achieved an early virologic response. The early virologic response in genotype 2/3 patients and genotype 1 patients was 88% and 49%, respectively. Even more interesting is that 40% of patients were HCV-RNA negative at week 12 of therapy. These data are very preliminary, and we eagerly await the sustained viral response data from this trial.

Re-treatment with consensus interferon. Daily consensus interferon plus ribavirin is another regimen currently being evaluated for the treatment of patients who have failed to respond to combination interferon and ribavirin therapy.

Kaiser and colleagues^[17] reported preliminary data comparing the use of either consensus interferon 18 mcg per day for 4 weeks followed by 9 mcg per day for 8 weeks, vs the use of consensus interferon 27 mcg per day for 4 weeks followed by 18 mcg per day for 8 weeks. After this initial 12-week treatment course, all patients received consensus interferon 9 mcg per day plus weight-based dosing of ribavirin for another 36 weeks.* A total of 120 patients were evaluated; 91% had genotype 1 infection and 28% had either bridging fibrosis or cirrhosis. The end-of-treatment viral response rates in the group receiving the higher-dose consensus interferon vs the lower-dose consensus interferon were 66% and 59%, respectively. The sustained viral response rates in the group receiving the higher dose consensus interferon vs the lower dose consensus interferon were 44% and 39%, respectively. Consensus interferon had to be dose reduced in 17% of patients and discontinued in 6%. The most common reason for dose reduction was thrombocytopenia. There was no difference in the drop-out rates between the 2 treatment arms.

This trial reports the highest sustained viral response rates yet in patients previously unresponsive to interferon and ribavirin-based therapy. Relapse rates in this group, however, still continue to be significant.

Future Therapies

The current standard of care for the treatment of previously untreated hepatitis C infection is once-weekly pegylated interferon plus ribavirin. These therapies have overall sustained response rates of between 52% and 54%, meaning that approximately 50% of patients do not respond to therapy. Because of these response rates, many new therapies are being evaluated to treat hepatitis C infection. This year, phase 1/2 data were reported for a new polymerase inhibitor named NM283* and a recombinant alfa interferon genetically fused to human serum albumin.*^[18,19] While preclinical data suggest antiviral synergy for NM283 and interferon, and phase 1/2 data with the recombinant alfa interferon show a favorable safety profile and biphasic viral decline, both compounds are early in development and expanded clinical testing is warranted.

Concluding Remarks

The annual meeting of the AASLD brought some interesting topics regarding hepatitis C to the forefront. The CDC NHANES data showed that the prevalence of the antibody for hepatitis C has remained constant over the past decade, while the cohort of people with the disease has aged. New advances have also been made in understanding the natural history of the disease. Although response rates to therapy have improved, we continue to refine our approach to patients with HCV genotypes 2 and 3. The issue of longer duration of therapy has also been discussed for those patients who do not demonstrate an early virologic response. Lastly, although many new therapies are being evaluated, they remain in early clinical development. Therefore, the best approach to maximizing current therapies appears to be improved familiarity with pegylated interferon and ribavirin and improved management of the adverse events associated with this combination therapy.

*The US Food and Drug Administration has not approved this medication for this use.

Supported by an independent educational grant from Gilead.

References

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