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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”


Hepatitis C: Current and Future Treatment

Emmet B. Keeffe, MD, Stanford University Medical Center, Stanford, Calif.


Abstract and Introduction


Interferon alfa-2b, 3 million units tiw, plus ribavirin, 1000 to 1200 mg daily for 6 to 12 months, has shown an improvement of 2-fold or more for all measures of efficacy when compared with interferon monotherapy. In the next year, treatment of chronic hepatitis C will involve pegylated interferons, either alone or in combination with ribavirin. Therapy in 3 to 5 years will likely be multidrug combinations, including inhibitors of the hepatitis C virus (Hepatitis C Virus) protease, helicase, or polymerase, with the aim of reducing serum levels or eradicating Hepatitis C Virus RNA.


Hepatitis C virus (Hepatitis C Virus) infection is the most common type of chronic viral hepatitis in the developed world.[1-3] The prevalence of antibody to Hepatitis C Virus (anti-Hepatitis C Virus) is 1.8% among the US population, with 74% of antibody-positive individuals demonstrating chronic infection with viremia.[4] These prevalence rates suggest that approximately 3.9 million Americans have been infected with Hepatitis C Virus, and 2.7 million are chronically infected.

Chronic hepatitis C impairs health- related quality of life,[5] with natural history studies indicating that progression to cirrhosis occurs in at least 25% of patients, generally over a 10- to 30-year period.[1-3] After the development of cirrhosis, hepatocellular carcinoma occurs in 2% to 5% of these patients each year.[6] However, it is important to keep in mind that most patients with chronic hepatitis C have a relatively benign natural history without development of progressive disease.[7,8]

Chronic hepatitis C is responsible for 8,000 to 10,000 deaths per year in the United States, and it is estimated that this death rate could increase to 38,000 per year by the year 2010. It is now the single most common indication for liver transplantation in the United States and Europe.

The high prevalence and potential morbidity of Hepatitis C Virus infection makes treatment of chronic hepatitis C one of the more urgent priorities in infectious disease control.

Dr Keeffe is professor of medicine, chief of hepatology, and medical director of the liver transplant program at Stanford University Medical Center, Stanford, Calif.




Hepatitis C: Current and Future Treatment

from Infections in Medicine ®

Current Treatment

Interferon-a monotherapy and, more recently, combination interferon-a and ribavirin therapy are the only treatments for chronic hepatitis C shown to be effective, although sustained response rates (normal serum aminotransferase levels and/or undetectable Hepatitis C Virus RNA 6 months after completion of therapy) still occur in fewer than half of treated patients. Interferon-a at the standard dosages of 3 million units, or 9 mg, tiw for 6 months achieves a sustained biochemical and virologic response with histologic improvement in 7% to 20% of treated patients.[9-11]

Continuing interferon-a monotherapy for 12 to 18 months improves the sustained response rate to 15% to 30%. Results of the US and European trials with combination interferon alfa-2b plus ribavirin therapy in previously untreated patients show a doubling of these biochemical and virologic sustained response rates to approximately 40%, making combination interferon/ribavirin the current treatment of choice for chronic hepatitis C.[12,13]

Candidates for Therapy and Pretreatment Considerations

The primary goal of antiviral therapy for chronic hepatitis C is durable viral clearance as evidenced by the absence of Hepatitis C Virus RNA in serum. A secondary goal is reduction of damage to the liver as determined by either persistently normal alanine aminotransferase (ALT) levels or improved liver biopsy results, with the expectation that this will delay or prevent cirrhosis, hepatocellular carcinoma, the need for liver transplantation, and death. Interferon therapy is indicated in patients with chronic hepatitis C who are at the greatest risk for progression to cirrhosis.[2,3] These patients are characterized by the following:

  • Persistently elevated ALT levels for more than 6 months.
  • Detectable serum Hepatitis C Virus RNA by a qualitative or quantitative assay.
  • Liver biopsy demonstrating grade 2 or 3 fibrosis (Table 1).
  • Moderate degrees of liver inflammation and necrosis.

While pretreatment liver biopsy has been widely recommended and is standard in clinical trials evaluating new antiviral agents,[2,3] a recent cost-effectiveness analysis showed that routine liver biopsy increased the cost of managing patients without improving outcomes.[14] A potentially acceptable alternative is to offer antiviral therapy to all patients who have chronic hepatitis C without contraindications or decompensated cirrhosis. Liver biopsy would be reserved for the exclusion of concomitant, alternative liver diseases and for management decisions -- for example, in patients not wanting therapy if fibrosis is mild or absent, or in patients who do not respond to standard therapy and are considering future, experimental therapies.

Pretreatment measurement of quantitative Hepatitis C Virus RNA levels and Hepatitis C Virus genotype are useful in forecasting the success rate of therapy and determining the length of combination interferon/ ribavirin treatment -- 6 months for patients with genotypes 2 or 3, 12 months for patients with genotype 1.[12,13]

Patients with histologically mild disease (grade 0 or 1 fibrosis) have a relatively benign natural history[15] and may not require treatment.[2,3] Nevertheless, since nonfibrotic liver disease is associated with a higher likelihood of response to interferon, with treatment resulting in improved survival and cost savings, it may be judicious to offer such patients a trial of antiviral therapy.[12-14]

Several studies have evaluated the clinical status and response to treatment of patients with chronic viremia but persistently normal ALT levels on repeated determinations.[16] Although advanced histologic changes are seen infrequently and cirrhosis is rare, abnormal liver histology is found in the majority of such patients. The results of several treatment trials indicate that a sustained virologic response is uncommon, with elevated ALT levels developing in some patients during treatment and persisting thereafter.[16] The current recommendation is not to perform biopsy or administer treatment in patients with persistently normal ALT levels.[2,3] Further studies are necessary to determine whether combination interferon/ribavirin treatment will result in better outcomes in this subset of Hepatitis C Virus-infected patients.

Patients with compensated cirrhosis have a 29% risk of decompensation and a 21% risk of death over 10 years; once decompensation occurs, the 5-year survival is only 50%.[17] Since the efficacy of interferon in patients with decompensated cirrhosis has not been documented, these patients should be considered for liver transplantation. Patients with compensated cirrhosis secondary to chronic hepatitis C have reduced sustained response rates to interferon therapy.[2,3] However, data from more recent studies suggest that interferon therapy improves liver function and may prevent or delay the onset of decompensation or the development of hepatocellular carcinoma in patients with cirrhosis, particularly those who show a complete response to interferon.[18] Thus, cautious use of interferon with close monitoring for cytopenias may be warranted in patients with chronic hepatitis C who have compensated cirrhosis.

Heavy drinkers with chronic hepatitis C are at risk for more advanced histologic disease secondary to Hepatitis C Virus infection and should be encouraged to abstain from alcohol.[2,3] Recently published retrospective and prospective studies have demonstrated that the occurrence of acute hepatitis A in patients with chronic hepatitis C and other chronic liver diseases is associated with increased morbidity and mortality.[19,20]

Although not directly studied, there is also probably a worse outcome of acute hepatitis B in patients with preexisting chronic liver diseases, including chronic hepatitis C. The safety and efficacy of hepatitis A vaccine in patients with chronic liver disease was recently demonstrated[21]; hepatitis B vaccine also has effectiveness in chronic liver disease, although higher doses of the vaccine may be required.[22]

These observations led to the recommendation by the CDC that all patients with chronic liver disease receive hepatitis A vaccine.[23] The NIH Consensus Development Conference recommended that all patients with hepatitis C be screened for prior immunity and undergo vaccination for both hepatitis A and B if susceptible.[2]


Interferon Monotherapy

Three types of interferon-a have been studied and are approved for the treatment of chronic hepatitis C (Table 2):

  • Interferon alfa-2b.
  • Interferon alfa-2a.
  • Alfacon-1 (consensus interferon).

Although these interferons have demonstrated some differences in efficacy in subgroup analyses, the NIH Consensus Development Conference panel concluded that all 3 interferons have generally comparable safety and efficacy in the treatment of chronic hepatitis C when given at the standard dosages of 3 million units, or 9 µg, tiw for 12 months or longer.[2]

Response rates to interferon therapy vary according to dosage and duration of therapy and baseline characteristics of treated patients. Duration of treatment appears to be more important than the dosage of interferon in achieving a sustained response. Only 7% to 20% of patients have a long-term sustained response after 6 months of therapy; treatment for 12 to 24 months is associated with a sustained virologic response of 15% to 30% and a significantly greater decrease in hepatic inflammation.[2,3,11] The efficacy of higher interferon doses and daily induction therapy is currently under evaluation.

Pretreatment factors associated with a greater likelihood of response to interferon include[24]:

  • Low serum Hepatitis C Virus RNA level (less than 1 to 2 x 106 copies/mL).
  • Hepatitis C Virus genotype 2 or 3.
  • Absence of advanced fibrosis or cirrhosis on biopsy.

A remarkable and unexplained poor response to interferon has been shown in African Americans when compared with white patients, with end-of-treatment and sustained virologic responses of only 5% and 2% versus 33% and 12%, respectively.[25]

Responses to antiviral therapy for chronic hepatitis C are defined by convention on the basis of various outcomes.[26] A biochemical response is defined on the basis of a normal ALT level and a virologic response by an undetectable level of serum Hepatitis C Virus RNA. The time of these findings is expressed either as an end-of-treatment response or as a long-term post-treatment sustained response. Persistence of a biochemical and/or virologic response for 6 months or more after cessation of therapy is the operational definition of a sustained response.

Evidence is now accumulating that a sustained virologic response 6 months after completion of interferon therapy predicts a long-term clinical response over 4 to 10 years.[27,28] In studies by Marcellin and coauthors[27] and Lau and associates,[28] there was permanent loss of serum Hepatitis C Virus RNA in more than 95% of patients and improvement of liver histology, including evidence of regression of hepatic fibrosis, in noncirrhotic patients. These studies suggest that some patients may indeed be cleared of chronic Hepatitis C Virus infection and that a reduction in mortality should be expected if cirrhosis, with its risk of progression to hepatocellular carcinoma, can be prevented.

Nonresponse is defined as persistently elevated ALT levels and/or detectable serum Hepatitis C Virus RNA. A variant of nonresponse called "breakthrough" is defined as an initial decrease of ALT levels into the normal range or the disappearance of detectable Hepatitis C Virus RNA with subsequent elevation of ALT levels or presence of detectable Hepatitis C Virus RNA while the patient is still receiving treatment. Failure to clear Hepatitis C Virus RNA after 12 weeks of interferon monotherapy or 24 weeks of combination therapy predicts the lack of a sustained virologic response and has been considered reason to stop therapy.[2,3,12,13] However, histologic improvement may still occur in nonresponders at the end of a complete course of therapy, and thus continuation of therapy may be beneficial.[18] A large NIH 5-year study of the potential benefit of long-term interferon therapy in nonresponders with advanced fibrosis is currently under way.

Re-treatment With Interferon Monotherapy

Re-treatment studies have been performed on patients with chronic hepatitis C who were nonresponders or relapsers after a course of interferon monotherapy. Re-treatment response rates have been highly variable and depend on the response to the initial course of treatment. The only treatment strategies that have shown some favorable results with interferon monotherapy are using a higher dose for a longer period[29] or using a different interferon.[30] In general, response rates are much higher in patients who previously responded and relapsed than in patients who did not respond to an initial course of therapy.

Re-treatment of relapsers with interferon alfacon-1 at a higher dosage of 15 mg tiw for 12 months achieved a 58% sustained virologic response,[30] similar to the re-treatment response rate of combination interferon alfa-2b and ribavirin.[31] The substantially higher tolerability of interferon monotherapy compared with combination therapy -- rates of discontinuation of approximately 5% to 10% versus 15% to 20%, respectively -- makes monotherapy an excellent re-treatment option for those who relapsed following prior therapy.

In contrast to the reasonably good results with re-treatment of relapsers, the cumulative data indicate that nonresponders to interferon therapy achieve only modest responses with re-treatment, as shown by a 13% sustained virologic response to interferon alfacon-1 at a dosage of 15 mg tiw for 12 months.[30] However, approximately 30% of nonresponders have the breakthrough subtype of nonresponse. With re-treatment with interferon alfacon-1 at 15 mg tiw for 12 months, 27% of those with a viral breakthrough had a virologic sustained response, compared with 8% of nonresponders without breakthrough.[32] Therefore, prior nonresponders with breakthroughs have a better chance of responding to re-treatment.

Combination Interferon With Ribavirin

Since therapy for chronic hepatitis C with interferon-a is less than ideal, numerous other approaches have been studied. Results of recently concluded trials comparing standard interferon-a monotherapy with interferon alfa-2b/ribavirin combination therapy have shown an approximate doubling in response rate for all measures of efficacy.[12,13] Although the rate of drug-induced adverse effects is higher, the overall safety profile of combination therapy is acceptable.[12,13]

Ribavirin is a nucleoside analogue typically given orally, 1000 to 1200 mg/d. Combination therapy with ribavirin and interferon-a initially showed promise in uncontrolled pilot studies, with later confirmation in randomized trials. Results of the recently concluded US and European trials comparing standard interferon-a monotherapy with interferon alfa-2b plus ribavirin have shown significant improvement in response rates for all measures of efficacy in treatment-naive patients with chronic Hepatitis C Virus infection,[12,13] including:

  • Clearance of Hepatitis C Virus RNA.
  • Normalization of ALT levels.
  • Improved histology.

These studies have also shown important differences in outcome based on genotype. Patients with genotype 1 had increased rates of sustained virologic response with 48 weeks versus 24 weeks of combination therapy, while patients with other genotypes derived no added benefit after the additional 24 weeks of combination therapy (Table 3).

In patients who relapse after an end-of-treatment response with interferon-a alone, combination treatment with interferon/ribavirin for 24 weeks has achieved a 49% response rate compared with 4% with interferon alone at standard dosage.[31] However, nonresponders to interferon-a alone rarely achieve a sustained response with combination treatment.

The chief side effect of ribavirin therapy is a dose-dependent hemolytic anemia, which is reversible and usually stabilizes after 4 to 8 weeks of treatment. Most patients experience a drop in hemoglobin level of 2 g/dL, and some patients may become severely anemic, necessitating discontinuation of therapy. Other common side effects associated with ribavirin treatment are respiratory symptoms (cough, dyspnea); skin disorders (pruritus, rash, dry skin); neuropsychiatric symptoms (insomnia, depression, anxiety); and GI disorders (anorexia, dyspepsia). Ribavirin is potentially teratogenic, and contraception is mandatory during treatment and for 6 months after therapy.

In the US multicenter study of combination therapy, discontinuation of therapy was necessary in 8% to 21% of patients in the 4 treatment groups and more common in the combination groups. In the 2 combination-treatment groups, dose reduction was required in 7% to 9% of patients because of anemia and 13% to 17% for other reasons.[13] The most frequent reason for discontinuation of therapy in all groups in the US trial was the development of psychiatric symptoms, primarily depression.

Contraindications to combination therapy with interferon and ribavirin are listed in Table 4. Some of these contraindications relate primarily to ribavirin therapy. For example, patients with preexisting anemia usually cannot tolerate the degree of hemolysis that occurs with ribavirin. Patients with significant cardiovascular disease are also at risk if severe anemia develops during therapy. Patients with chronic hepatitis C and the above baseline conditions should be treated with interferon monotherapy rather than combination therapy.[11]

Section 2 of 3




Hepatitis C: Current and Future Treatment

from Infections in Medicine ®

Future Therapies

Induction Interferon Therapy

The failure of interferon-a monotherapy may be associated with increased quasispecies diversity and high viral load. (Quasispecies are closely related but distinct genomes within the same Hepatitis C Virus genotype that occur over time from viral mutations.) Therefore, as in HIV infection, aggressive initial therapy for chronic hepatitis C with interferon may be appropriate.

Interferon-a, 10 to 15 million units daily, has shown significantly better early antiviral efficacy than a dosage of 5 million units daily or the standard dosage of 3 million units tiw.[33,34] Initial intervention with a high-dose induction interferon regimen, resulting in a rapid exponential decline in the Hepatitis C Virus RNA level, is likely to show enhanced effectiveness in determining the initial response and may prove to be the most effective way to achieve sustained Hepatitis C Virus clearance. However, current studies are too limited to determine whether early viral clearance will increase the ultimate sustained virologic response rate.

Pegylated Interferon

Based on the similar hypothesis of induction therapy, a long-acting pegylated formulation of interferon (PEG-IFN) (formed by the attachment of the inert polymer polyethylene glycol to interferon) may help reduce the fluctuating effects seen with the 3-times-per-week dosing regimen with standard interferon, which has a serum half-life of 4 to 6 hours. PEG-IFN has a decreased renal clearance with a half-life of more than 90 hours and is administered once a week subcutaneously.

A major research program is being conducted to assess the safety and efficacy of PEG-IFN alfa-2a or alfa-2b in the treatment of chronic Hepatitis C Virus infection. Data from ongoing studies indicate that the safety profile of PEG-IFN alfa-2a (180 mg once a week) is comparable to that of standard regimens using interferon alfa-2a (3 million units tiw), but the sustained virologic response rate of 36%[35] is equivalent to that with treatment with combination interferon and ribavirin.[12,13] Studies are also under way to assess the safety and efficacy of PEG-IFN combined with ribavirin.

Future Antiviral, Immunomodulatory, and Combination Treatments

Although current interferon-based combination therapy can achieve sustained virologic response rates of up to 40%, the remaining 60% of treated patients do not experience significant long-term benefits. Clearly, better therapies are needed, especially for the interferon nonresponders. A number of newer approaches to the eradication or control of Hepatitis C Virus infection are undergoing laboratory testing or have shown some efficacy in the control of other viral infections[36] but have not reached the stage of clinical trials in patients with chronic hepatitis C.

One promising approach, which has demonstrated success in the control of HIV infection, is the inhibition of viral replication by the use of enzyme inhibitors to Hepatitis C Virus protease, helicase, or replicase.[36] While this approach appears to effectively suppress viremia, a potential limitation is the emergence of drug-resistant mutations. Inhibition of viral replication might also be achieved by:

  • Antisense oligonucleotides that bind to specific sequences in the Hepatitis C Virus RNA.
  • Ribozymes that catalyze cleavage of Hepatitis C Virus RNA.
  • Gene transfer of interfering proteins that specifically interrupt virion assembly in the hepatocyte.

Other potential future approaches to the treatment of chronic Hepatitis C Virus infection involve modulation of the host immune response. There is speculation that patients who develop chronic Hepatitis C Virus infection have a weak TH1 cytokine response and strong TH2 response, and are thus unable to clear the virus. Therefore, treatments that might alter this balance to create a stronger TH1 response are under exploration.[36]

Most probably, future treatment with the goal of controlling or eradicating chronic Hepatitis C Virus infection will include several of the above approaches -- multidrug regimens to inhibit viral entry into the hepatocyte, suppress viral replication, and alter immune response to the virus.