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Hepatitis C Treatment
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The management of side-effects during therapy for hepatitis C
Alimentary Pharmacology & Therapeutics
Volume 20 Issue 9 Page 917 - November 2004
R. J. Aspinall & P. J. Pockros
Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA, USA
http://www.natap.org/2004/HCV/120304_01.htm
--Although the article below is about treatment for patients with HCV monoinfection, much of the information also applies to patients with coinfection. There are several key differences between coinfection & monoinfection: (1) HIV accelerates HCV disease progression, so in monoinfection 20% of individuals can progress to cirrhosis or serious complications on average in 20-30 yrs; but progression to serious disease stage can take half the time in coinfection. (2) studies of treatment in coinfected patients has found response rates to therapy has been lower compared to monoinfected patients.
Current Treatment for Chronic Hepatitis C
Peter Ferenci, MD
Current Treatment Options in Gastroenterology Dec 2004
TABLE OF CONTENTS
Introduction
• CURRENT GUIDELINES
• PATIENT AND VIRAL CHARACTERISTICS THAT INFLUENCE SUSTAINED VIROLOGIC RESPONSE RATES
• MANAGEMENT OF GENOTYPE 1 INFECTION
• MANAGEMENT OF GENOTYPE 2 and 3 INFECTIONS
• IMPORTANT EVOLVING ISSUES (Early Viral Response, EVR
Treatment
Diet, lifestyle, and adjunctive treatments
Pharmacologic (drug) treatment
Interferon-based therapies
• Pegylated interferons
• Conventional interferons
• Ribavirin
Emerging therapies
References and Recommended Reading
Opinion Statement
The number one choice for treatment of chronic hepatitis C is the combination of once weekly subcutaneous pegylated interferon plus daily oral ribavirin. The duration of treatment and dose of ribavirin must be tailored to the hepatitis C virus (HCV) genotype. Patients infected with HCV genotype 1 should be treated for 48 weeks with a standard dosage of ribavirin (1000 or 1200 mg/d). This ribavirin dosage regimen is 'off-label' when used in conjunction with pegylated interferon alfa-2b (12 kD). The approved dosage for use in combination with this agent is 800 mg daily. The appropriate duration of treatment and dosage of ribavirin for patients infected with HCV genotype 2 or 3 differs depending on the pegylated interferon that is chosen. It is important to note that the treatment paradigm for these individuals is quickly evolving. When using peginterferon alfa-2a (40 kD) [Pegasys] in patients with HCV genotype 2 or 3, the duration of treatment should be 24 weeks in combination with a low dose of ribavirin (800 mg/d). When using pegylated interferon alfa-2b (12 kD) [PegIntron] in patients infected with HCV genotype 2 or in patients infected with genotype 3 and hepatitis C virus RNA less than 600,000 IU/mL, the duration of treatment should be 24 weeks. However, recent data suggest such treatment may not be optimal for patients infected with HCV genotype 3 and hepatitis C virus RNA at levels greater than or equal to 600,000 IU/mL; treatment duration may need to be greater than 24 weeks. When using pegylated interferon alfa-2b (12 kD) in patients infected with HCV genotype 3 and high viral load, the optimal dosage of ribavirin appears to be 800 to 1400 mg/d based on bodyweight.
Introduction
Treatment of chronic hepatitis C has evolved rapidly in the past 15 years because hepatitis C virus was isolated and characterized. Before the isolation of hepatitis C virus (HCV) RNA, the diagnosis was one of exclusion ('non-A, non-B hepatitis') that relied heavily on elevations in serum alanine aminotransferase (ALT) levels, which is a crude indicator of HCV infection. Until the advent of sensitive and specific HCV RNA assays successful treatment outcome was defined by normalization of ALT levels. Because treatment with a 24-week course of conventional interferon alfa has been minimally effective since its start, we have advanced to the point at which HCV RNA can be eradicated in more than 50% of patients with the combination of pegylated interferon plus ribavirin [1**, 2**, 3**]. The use of ALT levels as a basis for treatment decisions and outcomes has been largely replaced by HCV RNA testing and the suitability of 'watchful waiting' as a management strategy for patients with persistently 'normal' ALT levels has been discounted [4]. Contemporary management of chronic hepatitis C is based on many factors such as HCV genotype, viral load, and patient age/duration of infection, in addition to patient preferences, motivation, and health-related quality of life [5*, 6**].
CURRENT GUIDELINES
Current treatment recommendations are based on data from randomized, multinational phase III trials [6**, 7, 8]. Pegylated interferon plus ribavirin is the number one choice for treatment, as it is significantly more effective than the combination of conventional interferon alfa plus ribavirin [1**, 3**]. The overall sustained virologic response (SVR) rate after 48 weeks of treatment with pegylated interferon alfa-2b (12 kD) plus ribavirin was 54% in the one pivotal trial conducted with this combination [3**]; the range was 52% to 63% in pivotal trials with peginterferon alfa-2a (40 kD) plus ribavirin [1**, 2**, 4]. Monotherapy with a pegylated interferon is significantly less effective than either conventional or pegylated interferon alfa plus ribavirin [1**]. Therefore, monotherapy should only be used when patients cannot tolerate ribavirin because of intolerance or a contraindication.
In everyday clinical practice, treatment is tailored to the infecting HCV genotype because SVR rates in clinical trials have been heterogeneous [9*]. Patients infected with HCV genotype 1 must be treated for 48 weeks with a pegylated interferon and a standard dose of ribavirin (1000 or 1200 mg/d). A randomized trial of duration of treatment and dose information of ribavirin, based on the combination of peginterferon alfa-2a (40 kD) plus ribavirin, demonstrated that the 48-week standard dose regimen was significantly more effective than shorter regimens (ie, 24 weeks) and/or a lower ribavirin dose (800 mg/d) [2**].
The highest SVR rates have consistently been obtained in patients infected with HCV genotypes 2 and 3. In the study by Hadziyannis et al. [2**] the rate of patients cured with peginterferon alfa-2a (40 kD) plus ribavirin across four treatment groups varied according to treatment duration (24 vs 48 weeks) and ribavirin dose (800 vs 1000/1200 mg/d). The highest SVR rate (84%) and lowest adverse event rate occurred in the group treated with the least-intensive regimen (24 weeks combined with low-dose ribavirin). Therefore, the current recommendation for patients infected with genotype 2 or 3 infection is combination therapy with a pegylated interferon plus a low dose of ribavirin (800 mg/d) for 24 weeks [6**, 8]. However, recent data have raised questions as to the appropriate dose of ribavirin and duration of treatment when using pegylated interferon alfa-2b (12 kD) [10, 11*].
PATIENT AND VIRAL CHARACTERISTICS THAT INFLUENCE SUSTAINED VIROLOGIC RESPONSE RATES
A number of patient and viral factors influence SVR rates in patients with chronic HCV [11*]. The most important factors are the genotype of the infecting HCV strain and baseline HCV RNA level. Patients infected with HCV genotype 1 have significantly lower SVR rates than those infected with HCV genotypes 2 or 3. Patients with a high baseline HCV RNA level (> 800,000 IU/mL) also respond less well than those with lower titers [11*].
Patient age, gender, ethnicity, body mass index, and the extent of hepatic fibrosis all influence SVR rates [11*]. Unfavorable characteristics include older age, male gender, African-American heritage, increased body mass index, and advanced fibrosis [9*]. It is not clear why SVR rates are lower in African-American patients than they are in white patients [12, 13*]; viral kinetic factors are likely involved [14]. Treating patients at a younger age and encouraging obese patients to lose weight may improve the chance of an SVR. In contrast, delaying treatment is likely to reduce the chance of a favorable outcome.
Patients who failed to respond to a previous antiviral therapy are less likely to achieve an SVR with subsequent treatment [15].
Adherence is important in maximizing SVR rates. Poor adherence and dose reductions reduce overall 'exposure' to therapy and are associated with lower SVR rates [16, 17]. Maintaining exposure to ribavirin, especially during the first 12 weeks of treatment, significantly increases SVR rates [15, 17].
Coinfection with HIV is a poor prognostic factor, although the combination of peginterferon alfa-2a (40 kD) plus ribavirin was recently shown to be effective in this population, achieving an overall SVR rate of 40% and with a pattern of outcomes that mirrors those in HCV mono-infected patients [18**].
MANAGEMENT OF GENOTYPE 1 INFECTION
Genotype 1 infection is the most difficult HCV genotype to treat and substantial research has been devoted to improving treatment outcomes. Concurrent treatment with ribavirin is required throughout the full 48-week duration of treatment to prevent relapse and maximize SVR rates in this subgroup [19]. Extending the duration of treatment may potentially improve SVR rates, although simply extending the duration of treatment does not cure more patients. However, tailoring the duration of treatment to individual virologic response is promising. In a Spanish study (TeraViC-4) [20], patients with detectable HCV RNA who were treated for 4 weeks with peginterferon alfa-2a (40 kD) plus ribavirin and who were randomized to a total treatment duration of 72 weeks had significantly lower relapse rates and higher SVR rates compared with those who were treated for 48 weeks. The bulk of patients randomized in the study had genotype 1 infection and high viral loads. Duration of treatment guided by the results of viral kinetic studies may thus become part of routine clinical practice in the near future. (note from Jules Levin: Clearly, it is important to first see a viral load response (HCV RNA) before deciding to continue to 48 weeks and further to 72 weeks. If HCV RNA is not undetectable by 12 weeks or certainly by 24 weeks the chance of achieving undetectable HCV RNA by week 48 is low, therefore extending therapy beyond 48 weeks is not useful in such a situation).
MANAGEMENT OF GENOTYPE 2 and 3 INFECTIONS
Recent data suggest that different treatment regimens may be required for HCV genotypes 2 and 3 depending on the pegylated interferon. Based on the results of Hadziyannis et al. [2**], a 24-week regimen of peginterferon alfa-2a (40 kD) plus a fixed low dose of ribavirin (800 mg/d) has been recommended for use in genotype 2 and 3 patients, regardless of the baseline HCV RNA level.
Similar data are not available to guide therapy with pegylated interferon alfa-2b (12 kD); however, the results of a recently published noncomparative study provide insight into the suitability of a 24-week regimen with pegylated interferon for HCV genotype 2 or 3 [11*]. Patients with genotype 3 and a moderately high baseline HCV RNA level (> 600,000 IU/mL) had a significantly higher relapse rate than the patients with genotype 3 who had low HCV RNA levels; all patients with genotype 2 (23% vs £ 9%) were treated for 24 weeks with pegylated interferon alfa-2b (12 kD) plus an investigational weight-based ribavirin regimen (800 to 1400 mg/d). Moreover, if using pegylated interferon alfa-2b (12 kD), it is prudent to recommend a full 48-week regimen in patients infected with HCV genotype 3 and to consider using the investigational weight-based ribavirin regimen rather than the licensed dose of 800 mg/d [10].
IMPORTANT EVOLVING ISSUES
Individualizing treatment and maximizing outcomes with viral kinetic studies (note from Jules Levin: this section reviews the importance of viral load response to therapy & how it can be used to help in predicting response to therapy & in designing an approach to duration of therapy).
One of the most promising areas of investigation is individualized treatment based on the initial viral kinetic response to treatment. The study of HCV dynamics has been facilitated by the widespread availability of sensitive and specific quantitative assays for HCV RNA. Fluctuations in serum HCV RNA level over time reflect the shifting balance of production and elimination of HCV, and the sensitivity of HCV to conventional interferon alfa is potentially useful in predicting the outcome of therapy [21]. On-treatment assessment of the virologic response to therapy is useful in identifying potential nonresponders and may be useful in identifying individuals who require a longer duration of treatment to eradicate HCV. Analysis of data from a randomized multinational study with peginterferon alfa-2a (40 kD) plus ribavirin demonstrates that the probability of achieving an SVR in patients with genotype 1 increases inversely with the time taken to clear HCV after the start of treatment [22]. Patients who were cleared of HCV by week 4 using combination therapy achieved an SVR rate of 91% and no patient relapsed during the follow-up phase [22]. Analysis of data from the same trial has shown that the absence of an early virologic response (EVR), defined as undetectable HCV RNA or a greater than or equal to 2-log10 decrease in HCV RNA at week 12, has a 97% negative predictive value for an SVR [1**]. In other words, patients who fail to achieve an EVR are unlikely to achieve an SVR after 48 weeks of treatment. The results of the TeraViC-4 study demonstrate that such patients may still be able to achieve an SVR but prolonged treatment is required.
Management of patients with persistently normal serum alanine aminotransferase levels
Historically serum ALT levels were used as the basis for treatment decisions in patients with chronic hepatitis C. As a result, little research has been done in this large group of patients. A randomized multinational trial has demonstrated that 48 weeks of treatment with the combination of peginterferon alfa-2a (40 kD) plus ribavirin produces SVRs in 52% of patients overall [4]. Consistent with findings in patients with elevated ALT levels, 24 weeks of combination therapy produced optimal outcomes in patients with normal ALT levels infected with genotype 2 or 3, but 48 weeks was required to maximize SVR rates in patients with genotype 1 infection. No patient in an untreated control group was cleared of HCV during 72 weeks of watchful waiting [4]. Opinions are divided on whether it is necessary to perform liver biopsies on patients with normal ALT levels considering the availability of effective therapy. The likelihood of disease progression and patient preference should be considered when making a decision on treatment [5*].
Nonresponders to previous interferon-based treatment
How to manage nonresponders on interferon-based therapy is an important but unanswered question. The ongoing Hepatitis C Antiviral Treatment Against Cirrhosis (HALT-C) trial is addressing this problem. Patients who fail to achieve a virologic response after 20 weeks of peginterferon alfa-2a (40 kD) plus ribavirin have been randomized to a total of 3.5 years of treatment with half the standard dose of peginterferon alfa-2a (40 kD) monotherapy or no treatment [15]. The trial will determine whether maintenance therapy can prevent development or progression of cirrhosis in patients with detectable HCV RNA levels in serum.
Current guidelines recommend against re-treatment of patients who fail to respond to an adequate course of combination pegylated interferon plus ribavirin therapy [6**]. Future therapies in clinical development may be necessary for these individuals. (note from Jules Levin: for non-responders to interferon/RBV or peginterferon/RBV there are several options. One is Maintenance therapy as outlined above, which is being studied in the HALT-C Study, Co-Pilot Study, and in SLAM-C for coinfected patients. Numerous studies and preliminary results from ongoing studies show Maintenance Therapy can slow HCV disease progression. This can be very useful in perhaps preventing progression of disease to a severe situation, until new therapies are developed. Perhaps, retreatment with higher doses of peginterferon may be successful. Nonresponders to interferon+RBV can use peginterferon+RBV, as studies find a percentage of patients can be successful doing this. You can consider enrolling in a study of new HCV drugs such as NM283, (polymerse inhibitor, Idenix Pharmaceuticals), or a HCV protease inhibitor study. Another option currently being studied in phase III clinical trials is the use of Consensus Interferon at high dosing. Results from several pilot studies find that patients who were not able to achieve success with peginterferon+RBV may have success with Consensus Interferon at high doses. The high dose may be difficult to tolerate, but some doctors use a unique approach. If a patient does not have an undetectable HCV RNA by week 12 or perhaps week 24, the patient was switched immediately to high dose Consensus Interferon. As mentioned, phase III studies are still ongoing so this approach is experimental until results from the phase III studies.
High-dose induction therapy
The use of high-dose induction therapy with conventional interferon plus ribavirin showed promise in improving outcomes in patients with genotype 1 infection [23]. Preliminary results of a pilot study show that the combination of a high dose (ie, 360 mg/week) of peginterferon alfa-2a (40 kD) plus ribavirin during the first 12 weeks of therapy increases the proportion of patients with an early virologic response [24]. Incorporating these findings into a comprehensive strategy to improve SVR rates in patients with difficult-to-treat characteristics is one of the challenges for clinical researchers.
Hepatitis C virus infection in transplant recipients
Chronic hepatitis C and decompensated liver disease are the leading indications for liver transplantation in the United States. As a result, effective prophylaxis to prevent reinfection after transplantation and effective treatment for HCV recurrence in transplant recipients is a priority. The balance between efficacy and tolerability of interferon-based treatments is less favorable in this population than in immunocompetent patients. Ongoing trials with pegylated interferons and ribavirin will provide guidance in the future management of these patients [6**].
Treatment
Diet, lifestyle, and adjunctive treatments
• Sustained virologic response rates are higher in patients with low body mass index; therefore, weight loss is advised in all patients who are overweight [6**].
• Excessive alcohol consumption can exacerbate hepatic fibrosis. Patients should abstain from alcohol and illicit drugs. Addiction treatment programs should be offered [6**].
• Use of effective contraception is mandatory during treatment with ribavirin [6**].
• Use of antidepressants may be considered in patients with a history of clinically significant depression as treatment is contraindicated in those with uncontrolled major depression [6**].
• Patients who develop anemia during treatment may benefit from adjunctive treatment with erythropoietin in order to maintain the dose of ribavirin [25].
• Herbal remedies that are popular in patients with chronic hepatitis C include those with antioxidant properties as well as licorice (Glycyrrhiza glabra) and milk thistle extract (Silybum marinum) [26]. Large, well-designed efficacy trials are required to confirm the benefit of such remedies. Herbal products are not alternatives to evidence-based pharmacologic treatment. Patients should be encouraged to discuss their use of alternative therapies.
Pharmacologic (drug) treatment
• The primary goal of therapy is eradication of HCV to prevent complications of chronic hepatitis C infection, including cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.
• Treatment decisions involve consideration of HCV genotype and HCV RNA level as well as specific patient characteristics, including preference for treatment and motivation.
• SVR is equated with the eradication of HCV and is associated with significant improvements in health-related quality of life [16, 27, 28, 29, 30], improvements in hepatic histology [31, 32, 33, 34], and reductions in the incidence of liver-related death [31, 35, 36, 37, 38].
Interferon-based therapies
• Interferon based therapies include the conventional interferons and pegylated interferons. The adverse event profile of these agents is generally similar and includes flu-like symptoms (fatigue, pyrexia, myalgia, arthralgia, headache, and rigors). Mild to moderate psychiatric reactions, including depression, irritability, and anxiety, may also occur. Other adverse events include alopecia, pruritus, rash, nausea/vomiting, diarrhea, skin reactions, and injection site reactions. Alfa interferons suppress bone marrow function and may result in cytopenias (neutropenia and thrombocytopenia). The manufacturers' prescription information should be consulted for the specific incidence of adverse events.
Pegylated interferons
• Pegylated interferons are superior to conventional interferons when these agents are given alone or in combination with ribavirin. The combination of pegylated interferon plus ribavirin is recognized as the treatment of choice in contemporary guidelines. The two commercially available pegylated interferons differ in the size and attachment of the polyethylene glycol moiety, and as a result there are important differences in the pharmacokinetics and viral kinetic response to treatment with these agents.
Peginterferon alfa-2a (Pegasys)
Standard dosage: Monotherapy or in combination with ribavirin dosage is 180 mg subcutaneously (SC) once a week.
Contraindications: Hypersensitivity to alfa interferons or excipients included in the formulation, neonates and infants (contains benzyl alcohol), autoimmune hepatitis, hepatic decompensation.
Main drug interactions: Inhibits CYP450 1A2 but not 3A4, 2C9, 2C19, or 2D6. Theophylline exposure may increase by approximately 15%. Serum methadone levels may increase by approximately 10% to 15% (clinical significance unknown).
Main side effects: See class effects statement above.
Peginterferon alfa-2b (PegIntron)
Was not reviewed here. It is dosed by weight & has similar side effects.
Special points
Approved for use as monotherapy and in combination with ribavirin. (note from Jules Levin: Roche applied to the FDA approval for Coinfection use approval & an announcement of approval is expected very soon). The combination of peginterferon alfa-2a (40 kD) plus ribavirin is significantly more effective than peginterferon alfa-2a (40 kD) monotherapy. Thus, monotherapy is suitable only in patients who cannot tolerate ribavirin or who have a contraindication to it. Combination therapy should be administered for 48 weeks in patients infected with HCV genotype 1 or 4, and for 24 weeks in patients infected with HCV genotype 2 or 3. Peginterferon alfa-2a (40 kD) plus ribavirin has been evaluated in patients with HIV-HCV coinfection and in patients with persistently 'normal' ALT levels in randomized, controlled, and multinational studies [4, 18**].
Cost effectiveness
Single-dose (180 mg) vial is ($349.20). Monthly convenience pack including syringes is ($1396.80).
Conventional interferons
• Conventional interferons are inferior to pegylated interferons when these agents are given alone or in combination with ribavirin.
Interferon alfa-2a
Standard dosage: 3 million international units (MIU) SC or intramuscularly (IM) three times per week for 48 to 52 weeks or, 6 MIU three times per week for 12 weeks followed by 3 MIU three times per week for 36 weeks. Interferon alfa-2a is not approved for use in combination with ribavirin.
Contraindications: Hypersensitivity to alfa interferons or excipients included in the formulation, neonates and infants (contains benzyl alcohol), autoimmune hepatitis, hepatic decompensation, and immunosuppressed transplant recipients.
Main drug interactions: Reduces clearance of theophylline.
Main side effects: See class effects statement.
Cost effectiveness $36.72 per prefilled syringe containing 3 MIU ($440.64 for a month of therapy) and $73.42 per prefilled syringe containing 6 MIU ($881.04 for a month of therapy).
Interferon alfa-2b
Standard dosage: 3 MIU administered SC or IM three times a week for 72 to 96 weeks.
Contraindications: Hypersensitivity to alfa interferons or to any excipients in the formulation, preexisting psychiatric conditions, especially depression, or a history of severe psychiatric disorders, autoimmune disease, immunosuppressed transplant recipients, and decompensated liver disease.
Main drug interactions: Interactions between interferon alfa-2b and other drugs have not been fully investigated. In general, should be used cautiously in patients who are receiving agents that are known to cause myelosuppression or agents known to be metabolized via the cytochrome P (CYP) 450 pathway.
Main side effects: See class effects statement above.
Special points
Approved for use as monotherapy and in combination with ribavirin.
Cost effectiveness: $281.87 for 6 doses ($563.73 per month of treatment) of 3 MIU, including a multidose pen and disposable needles.
Interferon alfacon-1 (Consensus Interferon)
Standard dosage: 9 mg SC three times a week for 24 weeks, 15 mg three times per week for 48 weeks in nonresponders or relapsers to a previous course of conventional interferon.
Contraindications: Hypersensitivity to alfa interferons or to any component in the formulation, decompensated liver disease, autoimmune hepatitis, and history of severe psychiatric disorders.
Main drug interactions: May inhibit CYP450; however, no formal drug interaction studies have been conducted. Caution is advised in patients who are receiving agents that are known to cause myelosuppression or agents known to be metabolized via the CYP450.
Main side effects: See class effects statement.
Special points: Approved for use as monotherapy only.
Cost effectiveness: $232.80 for 6 doses ($456.60 per month) of 9 mg, including disposable syringes and needles.
Ribavirin
Ribavirin (Copegus, Roche Pharmaceuticals, Nutley, NJ)
Standard dosage: 800 mg/d to 1200 mg/d administered orally in two divided doses with food. Patients with HCV genotype 1 or 4 should be treated for 48 weeks (1000 mg/d in those weighing < 75 kg and 1200 mg/day in those weighing ³75 kg). Patients with HCV genotype 2 or 3 should be treated for 24 weeks with 800 mg/d.
Contraindications: Hypersensitivity to ribavirin or any component of formulation, pregnancy, men whose female partners are pregnant, patients with hemoglobinopathies such as thalassemia major or sickle-cell anemia, significant or unstable cardiac disease, and creatinine clearance (< 50 ml/min).
Main drug interactions: Inhibits phosphorylation of zidovudine and stavudine in vitro. Increases exposure to didanosine or its active metabolite.
Main side effects: Hemolytic anemia.
Special points: Ribavirin is not effective as monotherapy for the treatment of HCV and should only be used in combination with a conventional or pegylated interferon. Patients are advised to take ribavirin with food.
Cost effectiveness: $1020.84 for a packet of 168 200-mg tablets.
Ribavirin (Rebetol, Schering-Plough Corporation, Kenilwoth, NJ)
Standard dosage: When combined with interferon alfa-2b use 1000 mg/d in patients weighing less than or equal to 75 kg and 1200 mg/d in patients weighing over 75 kg. When combined with pegylated interferon alfa-2b (12 kD) the dosage is 800 mg/d (in Europe the higher dose is licensed; (note from Jules Levin: in USA dosing is not licensed for above 800mg but 1000 & 1200 mg is dosing being used).
Contraindications: Hypersensitivity to ribavirin or any component of the formulation, pregnancy, males whose female partners are pregnant, patients with hemoglobinopathies, such as thalassemia major or sickle-cell anemia, significant or unstable cardiac disease, and creatinine clearance (< 50 ml/min).
Main drug interactions: Inhibits phosphorylation of zidovudine and stavudine in vitro. Increases exposure to didanosine or its active metabolite.
Main side effects: Hemolytic anemia.
Special points: Ribavirin is not effective as monotherapy for the treatment of HCV and should only be used in combination with a conventional or pegylated interferon. Patients are advised to administer ribavirin with food.
Cost effectiveness: For a pack of 42, 56, 72, or 84 200-mg tablets, the cost is $445.04, $593.39, $741.74, and $890.09, respectively.
Emerging therapies
• In Europe, amantadine has been investigated for use in combination with conventional and pegylated interferon with and without ribavirin. Amantadine may or may not provide some advantages to conventional combination therapy; further trials are required [39]. Amantadine provides very modest benefit, if any, above that provided by pegylated interferon plus ribavirin [40].
• Thymalfasin is under investigation in combination with peginterferon alfa-2a (40 kD) in phase III trials.
• Viramidine, a prodrug of ribavirin, appears to be as effective as ribavirin in combination with peginterferon alfa-2a (40 kD), but is associated with a significantly lower incidence of anemia [41].
• In a small pilot study in patients with chronic hepatitis C, vaccination and HCV envelope protein (E1) resulted in improvements in hepatic histology [42]. Further studies are ongoing.
Note from Jules Levin: although not mentioned by the author, NM283 is a polymerase inhibitor in clinical study that has shown to reduce HCV RNA in patients & is being studied in combination with peginterferon. As well, several HCV protease inhibitors are in early stages of development by several companies. Vertex Pharmaceuticals is the furthest along in studying an HCV protease inhibitor, as the clinical study of this drug in patients has just started.
REFERENCES & RECOMMENDED READING
Recently published papers of particular interest have been highlighted as:
* Of importance
** Of major importance
1.** Fried MW, et al.: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002, 347:975-982.
Randomized, controlled, multinational phase III registration trial. The combination of peginterferon alfa-2a (40 kD) plus ribavirin was significantly more effective than conventional interferon plus ribavirin or peginterferon alfa-2a (40 kD) monotherapy
2.** Hadziyannis SJ, et al.: Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004, 140:346-355.
Randomized, controlled, multinational phase III registration trial of peginterferon alfa-2a (40 kD) plus ribavirin that employed an innovative 2 x 2 factorial design. The study examined the effect of treatment duration and ribavirin dose on SVR rates according to HCV genotype. Current treatment recommendations are based on the results of this trial.
3.** Manns MP, et al.: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001, 358:958-965.
The first randomized, controlled, multinational phase III registration trial of a pegylated interferon plus ribavirin. The combination of pegylated interferon alfa-2b (12 kD) plus ribavirin was significantly more effective than conventional interferon plus ribavirin.
4.Zeuzem S, et al.: International, multicenter, randomized, controlled study for the treatment of patients with chronic hepatitis C and persistently normal ALT levels with peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS) [abstract 106]. Hepatology 2003, 38(4 Suppl 1):208A.
5.* Ahmed A: Chronic hepatitis C with normal aminotransferase levels. Gastroenterology 2004, 126:1409-1415. Excellent recent review.
6.** Strader DB: Diagnosis, management, and treatment of hepatitis C. Hepatology 2004, 39:1147-1171.
Recent evidence-based practice guideline endorsed by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.
7.EASL International Consensus Conference on Hepatitis C. Paris, 26-28, February 1999, Consensus Statement. European Association for the Study of the Liver. J Hepatol 1999, 30:956-961.
8.National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002-June 10-12, 2002. Hepatology 2002, 36:S3-S20.
9.* Zeuzem S: Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well? Ann Intern Med 2004, 140:370-381. Excellent recent review.
10.Alberti A: Optimizing PEG-interferon and ribavirin combination therapy for patients infected with HCV-2 or HCV-3: is the puzzle completed? J Hepatol 2004, 40:1032-1035.
11.* Zeuzem S, et al.: Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004, 40:993-999.
Recent study that points to the most appropriate strategy for managing HCV genotype 2 or 3 patients with pegylated interferon alfa-2b (12 kD) plus ribavirin.
12.Jeffers LJ, et al.: Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology 2004, 39:1702-1708.
13.* Muir AJ: Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004, 350:2265-2271.
Recent study of pegylated interferon alfa-2b (12 kD) plus ribavirin that demonstrated that SVR rates are significantly lower in blacks than non-Hispanic whites.
14.Layden-Almer JE, et al.: Viral dynamics and response differences in HCV-infected African American and white patients treated with IFN and ribavirin. Hepatology 2003, 37:1343-1350.
15.Shiffman ML, et al.: Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment [discussion 947]. Gastroenterology 2004, 126:1015-1123.
16.McHutchison JG, et al.: The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity. J Hepatol 2001, 34:140-147.
17.Reddy KR, et al.: The influence of cumulative exposure to combination peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin on sustained virologic response (SVR) rates in patients with genotype 1 chronic hepatitis C [abstract 505]. J Hepatol 2004, 40(suppl 1):149.
18.** Torriani FJ, et al.: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004.
Randomized controlled multinational phase III registration trial of peginterferon alfa-2a (40 kD) plus ribavirin in patients with HIV-HCV coinfection. The results are consistent with those of Fried et al. [1**] and support extension of the chronic hepatitis C treatment paradigm to patients with HIV-HCV coinfection.
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41.Gish R, et al.: Safety and efficacy of viramidine in combination with pegylated interferon alfa-2a for treatment of hepatitis C in therapy-naive patients [abstract 479]. J Hepatol 2004, 40(Suppl 1):141.
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