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Therapeutic Modalities
Characteristics of a Typical Patient
IFN Monotherapy
Combination IFN and Ribavirin
Peg-IFN With and Without Ribavirin
Candidates for Therapy
Duration of Therapy
Predictors of Response
Monitoring
Retreatment
Management of Side Effects
Use of Growth Factors As an Adjunct To Anti-HCV Therapy
 
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Treatment of Uncomplicated
Chronic HCV Infection

KEY POINTS

  • Pegylated interferon (PEG-IFN) combined with ribavirin is the best currently available therapy for HCV infection.
  • Several predictors of treatment response have been identified, including HCV genotype.
  • An absence of serum HCV RNA 6 months after discontinuation of therapy predicts durable viral eradication.
  • Treatment of patients with chronic HCV infection is associated with significant side effects, although most of these are not serious or life-threatening.
  • Adjunctive use of hematopoietic growth factors shows promise for managing the anemia and neutropenia associated with anti-HCV therapy, but further studies are warranted.

It has been estimated that approximately 3% of the world's population is infected with HCV.59 This represents nearly 170 million persons worldwide.59 In the United States, the prevalence of anti-HCV is 1.8%; 74% of these patients exhibit HCV RNA positivity. This corresponds to 2.7 million chronically infected persons in the United States alone.1

The substantial morbidity, mortality, and economic burden associated with HCV infection are responsible for the striking worldwide public health impact of this condition. Currently, HCV infection is responsible for an estimated 8,000 to 10,000 deaths annually in the United States, and that number is predicted to triple in the next 10 to 20 years. HCV-related disease is the leading indication for liver transplantation in the United States. The decision to treat patients with chronic HCV infection should be made after many factors have been considered and each case has been individualized (see "The Team Approach to Hepatitis C Management").
THERAPEUTIC MODALITIES

Pegylated interferons (PEG-IFNs)—which are produced by the conjugation of IFN and a polyethylene glycol molecule—represent a recent therapeutic advance in the treatment of HCV infection. This modified formulation of IFN has resulted in improved therapeutic effectiveness over unmodified IFN, likely because its sustained action is the result of a long half-life. Trials of PEG-IFN in combination with ribavirin have established its safety and efficacy.

Combination therapy with nonpegylated IFN alfa and ribavirin—until recently considered to be the treatment of choice for chronic hepatitis C—is less convenient and probably less effective. Fewer than 40% of patients achieve a durable benefit, ie, a sustained virologic response, defined as the absence of serum HCV RNA 6 months after the end of treatment, as measured by a sensitive assay with a lower limit of detection of at least 50 IU/mL.

Progress has been slower in the development of non-IFN-based therapies for HCV infection, including protease inhibitors, helicase inhibitors, ribozymes, antisense therapies, cytokine-based therapies, and T-cell-based therapeutic vaccines. Overall, advances in the development of therapies for HCV infection have been hindered by the lack of dependable cell culture systems and an adequate animal model. Furthermore, variations in the response to IFN treatment by different viral genotypes and differences in the type or vigor of immune responses may represent other obstacles to the development of a uniformly effective therapy or vaccine.
CHARACTERISTICS OF A TYPICAL PATIENT

The typical HCV-infected patient for whom therapy is well established is an adult who has chronic infection (ie, evidence of infection for at least 6 months). The typical patient has elevated serum transaminase levels, detectable serum HCV RNA, and histologic evidence of liver injury in the absence of decompensated cirrhosis. In addition, other liver diseases or confounding comorbid conditions have been excluded. For the typical HCV-infected patient, IFN-based therapeutic regimens have been found to be safe and often effective.

IFN MONOTHERAPY

In the 1980s, even before HCV was identified, therapy with IFN alfa was shown to be associated with normalization of transaminase levels in patients with non-A non-B hepatitis.60 In 1989, the results of two controlled clinical trials that evaluated the efficacy of IFN treatment in chronic HCV infection were published.61,62 In both trials, patients received 1 to 3 million IU of IFN alfa-2b three times weekly for 6 months. Complete biochemical remission was achieved in half of these patients. However, in almost 50% of the responders, serum transaminase levels returned to pretreatment levels 6 to 12 months after IFN therapy was discontinued.

In 1997, Carithers and Emerson published a meta-analysis of randomized trials in which IFN alfa-2b—in regimens of at least 2 million IU three times weekly for a minimum of 24 weeks—was given to IFN-naive patients.63 They concluded that IFN alfa is effective in treating chronic HCV infection. A biochemical sustained response—that is, normalization of ALT levels by 6 months following discontinuation of therapy—was achieved in 23% of the treated group, compared with only 2% of the untreated group (p < 0.001).

COMBINATION IFN AND RIBAVIRIN

Ribavirin is an oral nucleoside analog with activity against a broad spectrum of DNA and RNA viruses. When used alone, it has little or no activity against HCV. Both direct antiviral and immune modulatory effects have been proposed as mechanisms of action.64 Placebo-controlled studies of ribavirin monotherapy in patients with chronic HCV infection found that although 20% to 40% of patients had a biochemical response at the end of therapy, none had a virologic response.65

In the mid-1990s, small pilot studies suggested that treatment with IFN and ribavirin for 6 months was more effective than treatment with IFN alone. A meta-analysis of individual patient data from four European centers found that the efficacy of IFN and ribavirin combination therapy was two- to three-fold greater than the efficacy of IFN alone.66 Also, two randomized controlled trials published in 1998 showed that the combination of IFN alfa-2b and ribavirin produced better rates of sustained virologic and biochemical response in patients with HCV infection who were given it as initial treatment (IFN-naive patients) and in those who had experienced a virologic relapse after a previous course of IFN monotherapy.67 68 Sustained virologic response rates ranged from 31% to 38% when combination therapy was given as the initial treatment, and the sustained virologic response rate was 49% when it was given for relapse. These rates are three to five times as high as those achieved with monotherapy.
PEG-IFN WITH AND WITHOUT RIBAVIRIN

PEG-IFNs were recently approved in the United States and Europe for the treatment of chronic HCV infection. The rationale for developing anti-HCV agents that have a longer half-life (which PEG-IFN does) is based on the dynamics of the viral response to IFN. A substantial decrease in viral load occurs during the first 24 hours following a single injection of IFN alfa-2b. However, viral counts begin to rebound at 48 hours, suggesting that longer-acting medications may be more appropriate for these patients.52 Because pegylation prolongs the half-life of IFN, only one dose per week is required to maintain effective levels in the blood (vs. three doses per week with standard IFN).52

The results of three large trials of PEG-IFN alfa-2a and alfa-2b therapy in patients with chronic HCV infection established its superiority over conventional IFN alfa.45 69 70. Overall, sustained viral eradication was achieved in 25% to 39% of patients who were treated with PEG-IFN (alfa-2a or alfa-2b) monotherapy, compared with only 7% to 19% of those who received standard IFN. In all trials, the incidence of adverse effects among patients who received PEG-IFN was similar to that among patients who received standard IFN.

In one of these trials, Zeuzem et al randomly assigned 531 HCV RNA-positive patients with chronic HCV infection without cirrhosis to receive either PEG-IFN alfa-2a (180 µg weekly for 48 weeks) or IFN alfa-2a (6 million IU three times weekly for 12 weeks, followed by 3 million IU three times weekly for 36 weeks).69 PEG-IFN alfa-2a was associated with a significantly greater virologic response than standard IFN. Sustained virologic and biochemical responses were achieved in 38% of the patients treated with PEG-IFN (compared with only 17% of those treated with standard IFN), which was similar to the results seen in patients who were given the combination of standard IFN and ribavirin.

In the second trial, Heathcote et al randomly assigned patients with chronic HCV infection who had cirrhosis to receive either 90 or 180 µg of PEG-IFN alfa-2a weekly or standard IFN alfa-2a (3 million IU three times weekly) for 48 weeks.45 They found that a sustained virologic response was achieved by 30% of the patients who received PEG-IFN at 180 µg weekly.

The third trial of PEG-IFN included 1,219 patients with chronic HCV infection who were assigned to receive standard IFN alfa-2b (3 million IU three times weekly) or PEG-IFN alfa-2b given in one of three doses (0.5, 1.0, or 1.5 µg/kg body weight once weekly).70 Sustained virologic response was substantially greater with PEG-IFN alfa-2b at the doses of 1.0 or 1.5 µg/kg compared with standard IFN alfa-2b (23% to 25% vs. 12%).

Similarly, three large trials of PEG-IFN and ribavirin combination therapy established its role in treating patients with chronic HCV infection.49 50 71 Sustained viral eradication rates in patients who received PEG-IFN and ribavirin ranged between 48% and 56%, compared with rates of 29% to 47% among those who received standard IFN and ribavirin.
CANDIDATES FOR THERAPY

Theoretically, all patients with chronic HCV infection are candidates for antiviral therapy. However, only a subgroup of patients has a clear indication for treatment. The restriction of treatment is justified because of the naturally slow course of the infection, the expense of the treatment, the occurrence of adverse effects, and the relative ineffectiveness of treatment. Previously untreated patients with detectable levels of HCV RNA who have persistently elevated aminotransferase levels and whose liver biopsy specimens show fibrosis (or at least moderate necrosis and inflammation) are at high risk for disease progression. Therefore, combination therapy is recommended for this group if there are no contraindications to either IFN or ribavirin.22 72

The current standard recommended therapy is a weekly dose of PEG-IFN alfa-2a or PEG-IFN alfa-2b and ribavirin at 1,000 to 1,200 mg daily for 6 to 12 months. For other groups of patients, indications for treatment are less clear, and decisions should be made on a case-by-case basis.

Therapy for special groups of patients—for example, children, liver transplant recipients, and patients who have persistently normal aminotransferase levels, cirrhosis, coinfection with HIV or HBV, or extrahepatic manifestations of hepatitis C—is discussed later in this monograph.
DURATION OF THERAPY

In principle, patients with genotype 1, 4, or 6 virus should be given at least 12 weeks of treatment and then checked for early virologic response. Early virologic response—defined as the lack of detectable HCV RNA or a greater than 2-log drop (99% reduction) in the level of HCV RNA—is believed to be the most reliable factor in predicting sustained virologic response.22 If there has been less than a 2-log drop in HCV RNA after 12 weeks of therapy in patients with genotype 1 HCV, therapy should be discontinued. Because of the random fluctuation of viral levels, a decision to discontinue therapy when a nearly 2-log drop is encountered needs to be individualized. For genotype 1 patients who have a 2-log drop in viral load after 12 weeks of therapy, treatment should be continued for a year. For those with genotype 2 or 3 HCV, no interim viral load testing is needed, and a total of 24 weeks of therapy is given.

PREDICTORS OF RESPONSE

Independent predictors of a favorable response to combination therapy have been determined from an analysis of the combined data from three major trials.49 50 70 The most consistent factors were non-1 genotype, lower levels of HCV RNA (<800,000 IU/mL), and lower body mass index. Among patients with genotype 2 or 3, sustained virologic response rates with standard IFN and ribavirin were similar to those seen with PEG-IFN and ribavirin. Furthermore, a 24-week course of PEG-IFN and ribavirin was found to be as effective as a 48-week course in patients with genotype 2 or 3, but not in patients with genotype 1. Finally, a lower dose of ribavirin (800 mg/d) appeared to be adequate for patients with genotype 2 or 3, but a higher dose yielded better results in patients with genotype 1.71

MONITORING

Because of the potential adverse effects of IFN treatment, careful screening and monitoring of the patient's condition is needed. Monitoring should include a complete blood count, serum chemistry panel, and liver function tests performed monthly. The level of thyroid-stimulating hormone should be checked periodically. For women of childbearing age, a serum pregnancy test should be performed while the patient is receiving ribavirin. If pregnancy occurs at any time during treatment, as demonstrated by a positive pregnancy test, treatment should be discontinued immediately. The patient should be counseled about the risks to the fetus posed by ribavirin. An assessment of neuropsychiatric side effects, especially depression, should be undertaken at each visit during therapy. Psychiatric complications of HCV infection are discussed later in this monograph.

RETREATMENT

With the improved efficacy of treatment for HCV infection, patients who failed to achieve viral eradication after previous therapy with IFN with or without ribavirin are being considered for retreatment with PEG-IFN. In general, patients who failed to achieve viral eradication with previous therapy can be classified into two broad categories: nonresponders and relapsers. Nonresponders are those who are not HCV RNA-negative at the end of therapy; these include several subcategories, as outlined in Table 9. In contrast, relapsers are patients who become HCV RNA-negative by the end of therapy only to redevelop HCV RNA after stopping therapy. Approximately 20% of patients with undetectable viral levels at the end of therapy will relapse after treatment discontinuation.73

Table 9
Categories of nonresponse to anti-HCV therapy
Nonresponders Patients who are not HCV RNA-negative at the end of therapy
  Null
  responders
Patients with no significant decline in HCV RNA
during therapy
  Partial
  responders
Patients with a first-phase viral response but a poor
second-phase response
  Breakthrough   responders Patients with temporary disappearance of circulating virus followed by reemergence of virus while still on therapy
Relapsers Patients who become HCV RNA-negative by the end of therapy only to redevelop HCV RNA after stopping therapy
  

The first step when considering retreatment in a patient without sustained response to prior therapy is to determine whether the patient experienced true nonresponse or relapse after an adequate course of therapy. It is important to identify the reasons for the previous lack of response. These may involve patient issues, such as poor treatment adherence or poor timing of therapy in the context of other life events (eg, a new job, a change in insurance status). They also may involve provider issues, particularly poor side effect management during initial therapy, which may have resulted in dose reductions or early withdrawal from treatment. These considerations should be aimed at identifying interventions—such as use of growth factors to avoid dose reductions or prophylactic antidepressant therapy if severe depression was a problem during prior therapy—that might increase the chance of success with retreatment.

It is also important to identify the patient's HCV genotype, since retreatment is more likely to yield a sustained virologic response in nonresponders with genotypes 2 or 3 than in those with genotype 1.

Current options for retreatment are limited to PEG-IFN plus ribavirin, or the use of consensus IFN. Available data suggest that approximately 25% to 40% of nonresponders to IFN monotherapy will achieve a sustained virologic response with PEG-IFN and ribavirin combination therapy, while only 10% to 12% of nonresponders to combination IFN and ribavirin therapy will achieve a response with PEG-IFN and ribavirin.74 75 These modest results suggest that physicians should be selective when deciding which patients should be retreated, at least to the extent that sustained virologic response is the treatment goal.

Fewer data are available on the effectiveness of combined PEG-IFN and ribavirin for the treatment of patients who relapsed following IFN or IFN-ribavirin therapy. Preliminary data suggest that sustained viral eradication in this group of patients is as high as 60%.74

In addition to the patient's prior therapy and the nature of response to that therapy, the factors that are predictive of sustained virologic response with retreatment are similar to the predictors of response in treatment-naïve patients (Table 10).76

Table 10
Factors that should influence retreatment decisions*
Factor
Favorable to Retreatment
Unfavorable to Retreatment
Prior treatment IFN monotherapy IFN + ribavirin
Prior response to therapy Relapse or partial response Null response
Genotype 2 or 3 1
Serum HCV RNA level Low High (>850,000 IU)
Race Caucasian, Hispanic, Asian African-American
Adherence Poor (if reversible factors are identified) Complete
*All retreatment decisions should be individualized.
Adapted from Shiffman.76

Intriguing preliminary data have indicated that the combination of consensus IFN and ribavirin may yield impressive sustained virologic response rates of approximately 40% in nonresponders to previous IFN-ribavirin therapy,77 but these findings must be validated in large, well-controlled trials, which are currently under way.

The potential role of maintenance therapy with PEG-IFN alone in preventing further progression of liver disease—including hepatic decompensation and hepatocellular carcinoma—is currently under investigation.
MANAGEMENT OF SIDE EFFECTS

In addition to its suboptimal efficacy, IFN-based therapy has other shortcomings. It is expensive, it must be administered subcutaneously, and it is associated with numerous side effects (Table 11). The most common IFN-related side effects are symptoms consistent with a flu-like illness. This flu-like syndrome usually disappears after 2 to 4 weeks of therapy. These symptoms can be ameliorated by acetaminophen given before IFN is injected. Long-term side effects include fatigue, weight loss, reversible alopecia, hematologic abnormalities, and neuropsychiatric symptoms. Autoimmune phenomena may develop, especially in patients who have an underlying autoimmune disorder. Antithyroid antibodies and autoimmune thyroiditis may develop in some cases and may not be reversible after treatment is stopped.

Table 11
Frequency of side effects in patients with
chronic hepatitis C treated with IFN
Side Effect % of Patients
Flu-like syndrome: fever, headache, chills, myalgia, fatigue 60 to 80
Gastrointestinal disorders: nausea, anorexia, diarrhea 15 to 25
Neuropsychiatric disorders: depression, irritability 10 to 30
Skin disorders: alopecia, pruritus, rash, dry skin 5 to 15
Bone marrow hypoplasia requiring dose modification, anemia, neutropenia 10 to 20
Cardiovascular disorders: arrhythmia, cardiomyopathy, congestive heart failure, angina <5
Endocrine disorders: exacerbation of diabetes mellitus, hypothyroidism, hyperthyroidism, gynecomastia <5
Liver and biliary diseases: liver failure/encephalopathy, jaundice <5
Musculoskeletal disorders: arthritis, leg cramps, muscle weakness <5
Reproductive system disorders: amenorrhea, impotence, uterine bleeding <5
Other: respiratory, urinary, vision disturbances, hearing loss <5
Adapted from data in references 67 and 68 and the package inserts of IFN alfa-2b and PEG-IFN alfa-2a and -2b.

Overall, the spectrum of side effects associated with PEG-IFN appears to be similar to that seen with standard IFN therapy.78 Ribavirin treatment is universally associated with varying degrees of hemolytic anemia, which may increase fatigue and decrease quality of life during therapy; as a result, dose adjustment may be necessary.

Many, but not all, of these side effects are dose-dependent and reversible, but they can lead to nonadherence by some patients and decrease the likelihood of a response. The rate of nonadherence has been estimated to range between 5% and 10%.79 Based on results from a large phase III clinical trial of PEG-IFN alfa-2a and ribavirin,50 the rate of premature withdrawal of therapy due to laboratory abnormalities or adverse events was 10%, while dose reduction occurred in 32% of patients. Hematologic abnormalities including anemia, neutropenia, and thrombocytopenia were the most frequent indication for dose reduction. Emerging strategies for the management of these hematologic abnormalities are discussed in the following subsection.

The wakefulness-promoting agent modafinil is increasingly being used for the management of IFN-associated fatigue, at a dosage of 50 to 100 mg daily. Its potential benefits must be weighed, however, against any potential addictive tendencies and the fact that modafinil may reduce the effectiveness of steroidal contraceptives. Further study of the safety and potential benefits of modafinil in this patient population is encouraged.
USE OF GROWTH FACTORS AS AN ADJUNCT TO ANTI-HCV THERAPY

No uniform approach has been proposed for managing the hematologic adverse effects of IFN and ribavirin therapy in patients with hepatitis C, which continues to evolve.

Anemia. Anemia related to anti-HCV therapy is attributed largely to ribavirin, although IFN (and, to a lesser extent, PEG-IFN) also is believed to play a role. Research on the management of anemia related to anti-HCV therapy has focused on erythropoietic growth factors. Two randomized trials have shown that epoetin alfa therapy (40,000 IU weekly) was associated with increased hemoglobin values and maintenance of ribavirin dose levels in HCV-infected patients whose hemoglobin level fell below 12 g/dL during combination therapy with IFN or PEG-IFN plus ribavirin.80 81 In the first trial, hemoglobin levels rose by 2.8 g/dL in the epoetin alfa group compared with 0.4 g/dL in the control group, which received "standard of care" (ribavirin dose reduction).80 More patients in the epoetin alfa group were able to maintain a ribavirin dose greater than 800 mg/d (83% vs. 54%). In the second trial, the ribavirin dose was maintained at a level equal to or greater than the dose at randomization in 88% of patients who received epoetin alfa for 8 weeks compared with 60% of patients who received placebo for 8 weeks.81 Quality-of-life scores also improved significantly over the course of therapy in the epoetin alfa group.

Despite these promising findings, no published prospective studies have yet demonstrated a direct relationship between the use of erythropoietic growth factors in HCV-infected patients and an increase in sustained virologic response rates. Additionally, no cost-effectiveness analyses of growth factors in this patient population have yet been published that take into account sustained virologic response. Finally, because erythropoietic growth factors are not currently approved by the FDA for use in patients with HCV infection, insurance coverage of these therapies may be a challenge. This panel recommends that erythropoietic growth factors be considered on an individualized basis for patients with symptomatic anemia during antiviral therapy for HCV infection.

Neutropenia. Neutropenia is attributed to the IFN component of anti-HCV therapy and appears to occur at higher rates with PEG-IFN than with standard IFN. Reduction of the dose of PEG-IFN has been recommended for patients with neutrophil counts of less than 750 cells/mm3 based on data from cancer patients undergoing chemotherapy. Neutropenia induced by anti-HCV therapy may be particularly pronounced in liver transplant recipients and patients with cirrhosis or HIV coinfection. However, neutropenia in the HCV-infected population has not been associated with sepsis.

Research on the management of neutropenia in HCV-infected patients has centered on granulocyte colony-stimulating factor (GCSF) and granulocyte-macrophage colony-stimulating factor (GMCSF), although data are rather limited. Several small studies suggest that these therapies can safely maintain neutrophil counts above 750 cells/mm3 in HCV-infected patients during IFN-based therapy.82-84 Given these limited data and the generally benign outcome of neutropenia in HCV-infected patients during therapy, it is difficult to recommend the routine use of GCSF or GMCSF at this time. However, GCSF may be considered, at a dosage of 300 µg subcutaneously one to three times weekly, in selected patients with neutrophil counts less than 500 cells/mm3. Notably, the response to GCSF is immediate and does not require discontinuation of IFN or PEG-IFN therapy.

Thrombocytopenia. A reduction in platelet count may be observed in patients receiving IFN or PEG-IFN, although it is rarely a cause of dose reduction or treatment discontinuation. Recombinant human interleukin-11, or oprelvekin, has been studied for efficacy against thrombocytopenia in a small number of HCV-infected patients but appears to be limited by safety concerns and is generally not recommended.85

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