Current Therapies for Chronic Hepatitis C

McKenzie C. Ferguson, Pharm.D.

Disclosures

Pharmacotherapy. 2011;31(1):92-111. 

In This Article

Therapeutic Management

The management of chronic HCV infection should be individualized. Methods to prevent transmission and the importance of adherence to treatment should be addressed. Treatment is strongly recommended and should be considered in patients with chronic HCV and detectable levels of HCV RNA, elevated aminotransferase levels, and histologic evidence of progressive liver disease.[7,16]

The primary goals of therapy are to prevent complications and death from HCV while reducing adverse events and maintaining quality of life. The difficulty in achieving these goals is complicated by the slow progression of chronic disease and treatment responses that are based on surrogate virologic parameters versus long-term clinical outcomes. Normalization of serum aminotransferase levels, virologic response, and histologic improvement are several short-term outcomes commonly assessed.[7]

Virologic cure is established by a sustained virologic response (SVR), defined as the absence of serum HCV RNA by PCR assay 24 weeks after cessation of therapy.[7] The SVR offers the best prediction of long-term response. Lack of an early virologic response (EVR) can be used to predict nonresponders and a lack of SVR. Evaluation of rapid virologic response (RVR) can be used to assess durations of treatment based on genotype. All virologic responses are defined in Table 4.[7]

α-Interferon or interferon alfa-2b was the first therapy approved for the treatment of HCV.[17] The limitations with conventional, nonpegylated interferon include rapid absorption in subcutaneous tissue, large volume of distribution, rapid renal elimination, short half-life, and variable peak-trough concentrations.[16] These unfavorable characteristics necessitated dosing 3 times/week. The later addition of a polyethylene glycol (pegylated) moiety resolved many of these issues.

Ribavirin, an oral synthetic nucleoside analog, acts synergistically with pegylated interferon and is administered in divided doses. Ribavirin is not effective or indicated as monotherapy for treatment of HCV.[18] The combination of pegylated interferon and ribavirin represents the recommended treatment for HCV.

Safety

Treatment-limiting adverse effects are a common complication of HCV treatment and are experienced by most patients. Adverse events may lead to dosage reductions or treatment discontinuation. The most common adverse effects (occurring in 20–40% of patients) include flu-like symptoms (fatigue, headache, fever), gastrointestinal effects (nausea, anorexia, diarrhea), and psychiatric effects (irritability, depression, insomnia). Psychiatric effects can be managed with frequent assessment and counseling. Selective serotonin reuptake inhibitors can be used to treat depression. Agent selection should address hepatic dysfunction and drug interactions. Laboratory abnormalities such as neutropenia (absolute neutrophil count < 1500 cells/mm3) and anemia also frequently lead to dosage reductions and/or treatment discontinuation. The use of granulocyte colony-stimulating factors is usually not necessary except in cases of advanced cirrhosis. Likewise, growth factors such as erythropoietin and darbepoetin should be used cautiously in light of the potential for serious cardiac and thromboembolic events and increased costs. Their use has not been associated with better clinical outcomes, including attainment of SVR, in patients with HCV.[7,18–20]

Interferon Significant safety concerns exist with all interferon products. A black-box warning highlights the potential for causing or aggravating fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients require careful monitoring and observation while receiving these therapies. Therapy should be discontinued in patients with persistently severe or worsening signs or symptoms of any of the mentioned conditions. Contraindications to the use of interferon include hepatic decompensation as evidenced by a Child-Pugh score greater than 6 (class B or C) in patients with cirrhosis before or during treatment. Routine monitoring of complete blood cell count and liver function tests, including before treatment and routinely thereafter, is necessary. Dose reductions should be considered in patients with hematologic abnormalities, moderate depression, or renal dysfunction, or if transaminase levels flare. Severe depression warrants discontinuation of therapy. Individual prescribing information should be consulted for specific recommendations for dosage reductions associated with each interferon product.[19,20]

Ribavirin Ribavirin carries a black-box warning regarding its potential to cause birth defects and fetal death. It is rated as pregnancy category X and is contraindicated in pregnant women and men whose female partners are pregnant. Women of childbearing age and men must use two effective forms of contraception during the treatment period and for 6 months after treatment. Routine monthly monitoring of pregnancy tests is also required. A toll-free hotline to the Ribavirin Pregnancy Registry was established to monitor maternal and fetal outcomes of pregnant women exposed to ribavirin.[19,20]

Other serious effects with ribavirin highlighted in a black-box warning are the risk of hemolytic anemia, which may result in worsening cardiac disease. Because of this risk, a complete blood cell count should be obtained before treatment and, at a minimum, at weeks 2 and 4 of therapy. Patients with preexisting cardiac disease need to have an echocardiogram before treatment and should be closely monitored. The need for dosage reductions is determined by laboratory values, specifically those showing anemia in the presence or absence of cardiac history. Ribavirin is also contraindicated in patients with a history of hypersensitivity to ribavirin or any component of the formulation and should not be used in patients with a creatinine clearance less than 50 ml/minute.[18]

Treatment Regimens

All patients with chronic HCV infection should be evaluated for treatment with peginterferon and ribavirin. The duration of therapy will be determined depending on HCV genotype. Patients with genotype 1 infection typically have an SVR rate of 40–55%, whereas those with genotype 2 or 3 have higher rates at 70–90%.[21,22] Patients with genotype 1 or 4 require treatment for 48 weeks, whereas those with genotype 2 or 3 can receive 24 weeks of therapy.[7] Given the complexity and breadth of the literature in patients receiving retreatment of HCV after liver transplantation, studies focused in that area of practice are not included in the scope of this review.

Recent clinical studies evaluating various treatment strategies are summarized in Table 5 and Table 6 .[23–38] Most studies were conducted in treatment-naïve patients with detectable HCV RNA, histologic findings consistent with chronic HCV, and elevated ALT levels. Study analyses were conducted as intent to treat unless otherwise noted.

Comparative Efficacy of Pegylated Interferons Two pegylated interferons are FDA approved for treatment of HCV, peginterferon alfa-2a and peginterferon alfa-2b.[17] Although both agents are routinely prescribed for treatment, their dosing regimens and pharmacokinetics differ. Peginterferon alfa-2b is dosed according to body weight, whereas peginterferon alfa-2a is a fixed dose. Both agents are dosed subcutaneously once/week; however, their half-lives are different. Peginterferon alfa-2b has a 40-hour mean elimination half-life, and peginterferon alfa-2a has a plasma half-life of 80–160 hours.[19,20] These differences in half-lives have corresponded to reduced or absent plasma concentrations at 7 days and variable peak:trough ratios with peginterferon alfa-2b.[23] Until the results of recent studies were available, it was uncertain whether these differences significantly impacted treatment outcomes. The efficacy and safety of both pegylated interferons have been studied in several recent prospective, randomized, clinical trials ( Table 5 ).[23–33] Standard dosages of peginterferon alfa-2a at 180 μg and peginterferon alfa-2b at 1.5 μg/kg subcutaneously once/week were used in all studies unless otherwise noted.

A prospective, randomized, open-label study was conducted to compare viral pharmacokinetics and HCV RNA response at 12 weeks between peginterferon alfa-2a and peginterferon alfa-2b, both in combination with ribavirin.[23] Patients with genotype 1 and a viral load of 800,000 IU/ml or greater were evaluated. Ribavirin was dosed according to weight, 1000 mg/day for patients weighing 75 kg or less and 1200 mg/day for those weighing greater than 75 kg. Standard dosing of peginterferon alfa-2a and peginterferon alfa-2b was used. The primary end point, HCV RNA over time, was comparable between both groups at all time points. Similarly, the proportion of patients who achieved RVR was similar. More patients discontinued treatment in the peginterferon alfa-2b group (5.7% vs 1% in the peginterferon alfa-2a group) due to adverse events, such as rash, anemia, suicidal ideation, depression, influenza-like symptoms. However, no significant differences in overall safety outcomes were noted. The peginterferon alfa-2b group experienced more influenza-like illness, chills, fever, rash, and vomiting, whereas the peginterferon alfa-2a group had more dyspnea reported. Neutropenia (≥ grade 3) occurred in 43.4% of patients in the peginterferon alfa-2a group versus 34.8% in the peginterferon alfa-2b group.

Another prospective, randomized, open-label study compared peginterferon alfa-2a and peginterferon alfa-2b, both with ribavirin, for differences in SVR in treatment-naïve patients with chronic HCV.[24] Dosing of ribavirin was based on patient weight: 800 mg/day if less than 65 kg, 1000 mg/day if 65–75 kg, and 1200 mg/day if greater than 75 kg. Duration of treatment was 24 weeks for patients with genotypes 2 or 3 and 48 weeks for those with genotypes 1 or 4. Results showed that SVR rates were similar between groups: 66% in the peginterferon alfa-2a group and 62% with peginterferon alfa-2b (p=0.64). Differences among genotypes according to treatment group were also not significant, with more than 45% of patients with genotype 1 and more than 80% of those with genotypes 2, 3, or 4 achieving SVR.

A third arm of the Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study was undertaken to evaluate the safety and efficacy of standard-dose peginterferon alfa-2a, standard-dose peginterferon alfa-2b, and low-dose peginterferon alfa-2b (1.0 μg/kg/wk) in 3070 treatment-naïve patients with genotype 1 HCV.[25] All regimens included weight-based ribavirin; however, the dose differed according to which interferon product was used. For the peginterferon alfa-2b group, ribavirin was dosed based on patient weight: 800 mg/day if 40–65 kg, 1000 mg/day if more than 65 kg but less than 85 kg, 1200 mg/day if more than 85 kg but less than 105 kg, and 1400 mg/day if more than 105 kg but less than 125 kg, . The peginterferon alfa-2a group received ribavirin 1000 mg/day for weight less than 75 kg, and 1200 mg/day for weight of 75 kg or more. Different ribavirin regimens were used based on the current prescribing information at the time of the study. The treatment duration was 48 weeks. The primary end point was SVR, and two superiority analyses were conducted to compare the two dosage regimens of peginterferon alfa-2b and standard-dose peginterferon alfa-2b versus peginterferon alfa-2a.

Rates of SVR were similar among all three groups: 39.8% for standard-dose peginterferon alfa-2b versus 38% for low-dose peginterferon alfa-2b (p=0.20), and 40.9% for standard-dose peginterferon alfa-2a versus standard-dose peginterferon alfa-2b (p=0.57). Adverse events were also similar in type and frequency among all groups. Two deaths were considered to be possibly related to treatment, one with standard-dose peginterferon alfa-2b (suicide) and one with peginterferon alfa-2a (myocardial infarction).

Duration of Therapy According to Genotype Given that peginterferon and ribavirin represent the established treatment for chronic HCV, much of the current research focuses on duration of therapy. Genetic differences have been heavily studied in relation to HCV. The standard of evidence-based HCV care has been to treat patients with genotype 1 or 4 for 48 weeks and those with genotype 2 or 3 for 24 weeks. More recently, studies have focused on individualizing the duration according to RVR or EVR. The following studies highlight some of these recent findings.

Analysis of common predictors of SVR was conducted in several of these studies. Factors such as age 45 years or younger, genotype 2, baseline HCV RNA level of 400,000 IU/ml or lower, weight of 80 kg or less, ALT levels, and degree of fibrosis were all predictive of SVR.[26,28–30,32]

It is important to note that with many of these studies, the overall SVR rates may not differ, but the relapse rates and rates of discontinuation may be balancing the results. This, in addition to differences in study design, may contribute to the lack of consistent results regarding the optimal durations of treatment according to genotype.

Genotype 1. A prospective, open-label German study of patients with genotype 1 randomly assigned to standard-dose peginterferon alfa-2a in addition to ribavirin 800 mg/day for either 48 weeks (group A) or 72 weeks (group B) aimed to evaluate differences in SVR and relapse rates.[26] The primary efficacy measure, SVR, was similar in both groups (53% at 48 wks [group A] and 54% at 72 wks [group B], p=0.8), highlighting that duration of therapy did not translate into higher SVR rates. In addition, a significantly higher proportion of patients in group B prematurely discontinued therapy (p<0.001).

Patients who had detectable HCV RNA levels at week 12 achieved significantly higher SVR rates with 72 weeks of treatment versus 48 weeks (29% vs 17%, p=0.04), whereas those who had undetectable levels at weeks 4 or 12 reached SVR rates as high as 84%, independent of treatment duration. This demonstrated that patients considered "slow responders" to therapy may benefit from extended treatment. Benefits of extended treatment on relapse rates were also noted in patients who were considered slow responders (HCV RNA detectable at wks 4 or 12). Relapse rates were lower in patients with HCV RNA first undetectable at week 12 (group A 37% vs group B 23%, p=0.016) and at week 24 (64% vs 40%, p=0.021). Rates of relapse were similar between groups (group A 29% vs group B 21%, p=0.13). The frequency of adverse events was not significantly different between treatment groups; however, a higher proportion of patients treated for 72 weeks discontinued therapy compared with those treated for 48 weeks.

A similar study was conducted in the United States to evaluate extended treatment (48 vs 72 wks) in treatment-naïve patients with genotype 1 treated with peginterferon alfa-2b in combination with weight-based ribavirin (≤ 64 kg, 800 mg; 65–84 kg, 1000 mg; 85–104 kg, 1200 mg; ≥ 105 kg, 1400 mg).[27] Before randomization, patients were determined to be slow responders, defined as at least a 2-log reduction in HCV RNA and undetectable levels at week 24. The primary end point, SVR, was statistically significantly higher in the extended treatment group receiving 72 weeks of treatment (38%) versus those treated for a total of 48 weeks (18%, p=0.03). A lower relapse rate was also found with the extended duration (20% vs 59%, p=0.004). The rates of adverse effects and discontinuation did not differ significantly between groups.

A noninferiority study conducted in Italy evaluated the efficacy of peginterferon alfa-2a or peginterferon alfa-2b combined with ribavirin for a standard treatment duration (48 wks) versus an extended treatment duration in patients with genotype 1.[28] Weight-based ribavirin was dosed at 1000 mg/day for patients weighing 75 kg or less and 1200 mg/day if weight was more than 75 kg. Patients randomized to the extended-treatment group received the drugs for an individualized duration based on virologic response during the initial 12 weeks of therapy. Patients in this group who achieved undetectable HCV RNA levels (RVR) at 4 weeks were treated for 24 weeks, and those achieving RVR at 8 and 12 weeks were treated for 48 and 72 weeks, respectively.

Sustained virologic response occurred in 45.1% of patients in the standard-duration group and 48.8% in the individualized group (p=0.37). This met the criteria for establishing noninferiority. Patients who achieved RVR at 4 weeks had SVR rates of 87% after receiving therapy for the standard treatment duration (48 wks) and 77.2% after 24 weeks of treatment in the individualized group (p=0.12). Patients achieving undetectable HCV RNA levels at week 12 showed a greater overall SVR when randomized to the 72-week duration rather than 48 weeks (63.4% vs 38.1%). Relapse rates, adverse events, and virologic responses according to duration and peginterferon were also similar. More patients in the individualized group discontinued therapy. The authors concluded that these findings warrant larger studies to determine the benefit of individualized therapy based on 12-week response.

Finally, a study was conducted in Austria in patients with genotype 1 or 4; patients received peginterferon alfa-2a plus ribavirin 1000–1200 mg/day.[29] Patients who achieved RVR were assigned to 24 weeks of therapy. Results showed an overall SVR rate of 76.7%. These results were the first reported of a larger study involving 516 patients that will also evaluate treatment durations of 48 and 72 weeks depending on virologic response.

Cumulatively, the results of these recent studies recognize possible alternative durations of therapy in patients with HCV genotype 1, depending on virologic response, both RVR and EVR. For slow-responding patients, commonly determined by week 12 and 24, a longer duration of treatment, up to 72 weeks, may be beneficial. Those patients with genotype 1 who achieve RVR may be candidates for 24 weeks of treatment. However, more conclusive evidence and larger studies need to be conducted to confirm these findings.

Genotypes 2 and 3. Several small studies have found SVR rates of 80% or higher in patients with genotype 2 or 3 HCV after achieving RVR at 4 weeks and being treated with 12–16 weeks of therapy.[39–42] Differences in these studies, including treatment duration, ribavirin dosage, population characteristics, and study design have made it difficult to use these findings as evidence to support a shortened duration of therapy for these patients. Although the concept of a shortened duration based on genotype and virologic response aims at reducing unnecessary treatment and adverse effects, some recent studies have shown attenuated efficacy when compared with the standard 24 weeks of therapy.

A randomized, open-label, phase III, multicenter study sought to compare the efficacy of 12 or 24 weeks of therapy in patients with genotype 2 or 3.[31] Peginterferon alfa-2a and ribavirin 800 mg/day were administered. Results showed that 12 weeks of therapy was inferior to 24 weeks in relation to SVR rates (59% vs 78%, p<0.0001). Also, a higher relapse rate was noted with 12 weeks (33% vs 12%, p<0.0001). Adverse events leading to discontinuation of therapy occurred more frequently in the 24-week group (p<0.0001).

Another study randomly assigned patients with genotype 2 or 3 to receive peginterferon alfa-2b plus weight-based ribavirin (800 mg/day if < 65 kg, 1000 mg/day if 65–85 kg, 1200 mg/day if 86–105 kg, and 1400 mg/day if > 105 kg) for a treatment duration of 14 or 24 weeks dependent on virologic response.[32] Patients who achieved RVR were randomly assigned to either 14 weeks (group A) or 24 weeks (group B) of treatment, and patients not achieving RVR received 24 weeks (group C) of therapy. This was an open-label, noninferiority study to evaluate SVR. Noninferiority could be established if the upper limit of the 95% confidence interval (CI) was below the margin of 10%. Most patients (80%) were infected with genotype 3. Results showed that group A had an SVR rate of 81.1% and group B achieved SVR in 90.7% (difference 9.6%, 95% CI 1.7–17.7%), not establishing noninferiority. Group C achieved SVR in 55% of patients. When adjusted to include only patients with an HCV RNA determination 24 weeks after the end of treatment, SVR rates were similar (86.3% in group A and 93.2% in group B). Patients in group A experienced higher relapse rates over group B (10.8% vs 5.3%), but group B had higher rates of discontinuation. The occurrence of adverse effects did not differ significantly between groups.

The ACCELERATE trial is the largest study to our knowledge that evaluated a shortened duration of treatment in patients with genotype 2 or 3.[30] Efficacy was assessed in this large international study conducted in 1469 patients. Patients were randomly assigned to receive 16 or 24 weeks of therapy with peginterferon alfa-2a and ribavirin 400 mg twice/day. The study was designed as a per-protocol, noninferiority analysis with a margin for noninferiority set at 6%. Overall results failed to demonstrate noninferiority. The SVR rates were 65% in the 16-week group versus 76% in the 24-week group (p<0.001). A significantly higher relapse rate occurred in the 16-week group as well (31% vs 18%, p<0.001). Anemia and neutropenia were the most common causes of dosage reductions. More patients in the 24-week group required ribavirin dosage reductions (23% vs 17%, p=0.01).

Genotypes 4 and 5. Few robust studies were conducted solely in patients with genotype 4 or 5. Although genotypes 1 and 4 are thought to be similar, a recent prospective, uncontrolled study in 30 patients from the Middle East with genotype 4 demonstrated that treatment with peginterferon alfa-2a in combination with weight-based ribavirin 1000 mg/day for patients weighing less than 75 kg and 1200 mg/day if weight was more than 75 kg, for 48 weeks resulted in an SVR in 63.6% of patients, which was slightly higher than normally observed SVR rates for patients with genotype 1.[15]

A 2008 retrospective study conducted in Syrian patients with genotype 5 evaluated virologic response in 26 patients who received ribavirin 1000–1200 mg/day in combination with interferon alfa-2a 3 million units 3 times/week or peginterferon alfa-2a at standard dosages.[43] Patients were treated for 24 or 48 weeks. More patients received conventional interferon (65%) than pegylated interferon (35%). Results showed SVR was attained in 47% of patients receiving interferon versus 67% receiving pegylated interferon (p=0.43). Higher rates were also achieved with 48 weeks of treatment.

Genotype 6. Limited evidence exists regarding the appropriate duration of therapy for patients with genotype 6. One small, retrospective cohort study evaluated peginterferon plus ribavirin for 24 or 48 weeks in this population.[33] Dosing was as follows: interferon alfa-2b 3 million units 3 times/week plus ribavirin 1000 mg/day; weight-based peginterferon alfa-2b 80–150 μg/day with weight-based ribavirin 800–1200 mg/day; or peginterferon alfa-2a 180 μg/week with ribavirin 1000–1200 mg/day. In total, 23 patients were treated for 24 weeks, and 12 patients completed 48 weeks. Most patients were Asian-American. Results showed SVR rates of 39% versus 75% for those treated for 24 and 48 weeks, respectively (p=0.044). The results of this study need to be confirmed with larger, prospective studies in this population.

Overall the results of studies in patients with HCV genotype 2, 3, or 6 indicate that a treatment duration of 24 weeks remains the most appropriate. Shorter durations are associated with relapse and lower SVR rates.

Relapse and Nonresponse Few studies have assessed patients who do not respond to the current standard of therapy. Early studies evaluated clinical response to peginterferon plus ribavirin in patients who failed treatment with interferon, and more recent studies aim to evaluate retreatment after treatment failure with pegylated interferon.[44] Current U.S. guidelines do not strongly advocate retreatment of patients who previously fail to respond to initial therapy.[7] Although consistent results are lacking and need to be confirmed with larger studies, potential situations for retreatment exist, including in those patients who previously failed therapy with nonpegylated interferon.

The Evaluation of PegIntron in Control of Hepatitis C (EPIC) study was a large, international, multicenter, open-label study conducted to evaluate the retreatment of patients with chronic HCV who previously failed therapy with peginterferon or nonpegylated interferon therapy in combination with ribavirin.[45] Patients qualified for retreatment if they had significant hepatic fibrosis or cirrhosis at presentation and needed to receive at least 12 weeks of combination therapy without achieving SVR. Patients received standard-dose peginterferon alfa-2b plus weight-based ribavirin for 48 weeks. Most patients were Caucasian men with genotype 1 HCV and viral loads greater than 600,000 IU/ml, and who did not respond to previous treatment with interferon therapy in combination with ribavirin. Overall, 22% of patients achieved SVR, with a greater response observed in patients who relapsed versus those who did not respond (38% vs 14%) regardless of previous treatment. Furthermore, patients who previously received interferon therapy responded better than those who received pegylated interferon (25% vs 17%). Genotype, viral load at baseline, stage of fibrosis, previous treatment regimen, and previous response were found to be significant predictors of response.

Extending the treatment duration of therapy may be a feasible option in patients with HCV who did not respond after treatment with peginterferon and ribavirin. One study investigated the use of peginterferon alfa-2a with ribavirin to retreat nonresponders to peginterferon alfa-2b plus ribavirin.[46] This parallel-group, international study randomly assigned patients to one of four possible open-label treatment groups: peginterferon alfa-2a 360 μg/week for 12 weeks followed by 180 μg/week to complete 72 weeks of treatment (group A) or 48 weeks of treatment (group B), or peginterferon alfa-2a 180 μg/week for 72 weeks (group C) or 48 weeks (group D). All patients received ribavirin 1000 or 1200 mg/day. Most patients had genotype 1. The rate of SVR in group A was 16% versus 9% in group D (p=0.006). The SVR rates were 7% in group B and 16% in group C. More patients in treatment groups A and C benefited from extended durations but withdrew from the study. In addition, the overall rate of serious adverse events was higher in patients assigned to 72 weeks of therapy. The results of this study demonstrate the possibility of extended treatment in nonresponders to peginterferon therapy; however, the withdrawal rate and risk of adverse events need to be considered.

Patients who relapse or those who do not respond to initial peginterferon and ribavirin therapy need to be adequately assessed before starting retreatment. Previous response (non-response, relapse, and breakthrough) needs to be assessed. Also, modifiable risk factors affecting treatment should be identified, including adherence to treatment, body weight, and alcohol abuse.[44]

Alternative and Investigational Therapies

Several new therapies are in development for the treatment of HCV infection (Table 6).[34–38] In addition, targeted HCV inhibitors are promising agents for future treatment.[47]

Albinterferon A new interferon product, albinterferon, consists of interferon alfa-2b genetically fused to recombinant human albumin, allowing for a more convenient dosing schedule (once or twice/mo).[34,47] Albinterferon alfa-2b is an 85.7-kilodalton protein with an estimated half-life of 150 hours.[34,35] Albinterferon is in phase I studies in the United States for the treatment of HCV infection in patients with HIV coinfection. No studies, to our knowledge, have evaluated the use of albinterferon in patients with renal dysfunction. Several other countries are in phase III of development for the use of albinterferon as combination therapy in treatment-naïve patients with HCV.[48]

An open-label, phase III, multicenter trial investigated dosing strategies, efficacy, safety, and patient-reported health-related quality of life with albinterferon alfa-2b compared with peginterferon alfa-2a in previously untreated patients with genotype 1.[34] Patients were randomly assigned to one of four treatment groups: albinterferon 900 μg subcutaneously once every 2 weeks, albinterferon 1200 μg once every 2 weeks, albinterferon 1200 μg once every 4 weeks, or peginterferon alfa-2a 180 μg subcutaneously once/week (active control). In addition, all patients received ribavirin 1000 mg/day if their weight was less than 75 kg or 1200 mg/day if their weight was 75 kg or more. The duration of treatment was 48 weeks.

Results of the primary and secondary efficacy end points, including SVR, relapse rate, and breakthrough rate, demonstrated no significant difference between the albinterferon groups and peginterferon alfa-2a. The SVR ranged from 55–58% in the intent-to-treat analysis of all groups (p=0.64). Rates of adverse events were similar among all groups with the exception of the albinterferon 1200 μg every 2 weeks group, which experienced a higher frequency and more severe adverse effects. The rate of discontinuation was also higher in this group (p=0.04). Hematologic abnormalities were comparable across groups except for the albinterferon 1200 μg every 4 weeks group, which had a significantly lower rate of events (p<0.05). Health-related quality of life was significantly more favorable in the albinterferon 900 μg every 2 weeks treatment group compared with the peginterferon alfa-2a group in terms of scores and missed workdays (p<0.05).

Another phase II, open-label, multicenter trial conducted in 43 treatment-naïve patients with genotype 2 or 3 evaluated different dosages of albinterferon alfa-2b in combination with ribavirin.[35] In contrast to the previous study, a higher dose of albinterferon of 1500 μg every 2 or 4 weeks was used. In addition to assessing efficacy and safety, this study sought to determine if an association exists between insulin resistance and antiviral response in patients with genotype 2 or 3. The treatment duration was 24 weeks.

Rates of SVR were 77.3% for the every 4 week treatment arm versus 61.9% for the every 2 week arm (p=0.27). The lower response in the every 2 week arm was attributed to a higher discontinuation rate unrelated to treatment. Insulin resistance, estimated by homeostasis model assessment of insulin resistance (HOMA-IR), was diagnosed when the HOMA-IR score was greater than 2. Patients who demonstrated insulin resistance according to these methods exhibited a lower SVR compared with those patients without insulin resistance (42.9% vs 88.2%, p=0.02).

No significant differences were found between dosage regimens in terms of safety and tolerability. Some of the most frequently reported moderate-to-severe adverse events were headache, fatigue, chills, myalgia, nausea, pyrexia, decreased weight, back pain, altered mood, and arthralgia; their rates of occurrence did not significantly differ between groups. In addition, the rate of hematologic abnormalities did not significantly differ; however, a higher frequency of low absolute neutrophil count (≤ 750 cells/mm3) was found in the 1500 μg every 2 weeks treatment group compared with the every 4 weeks group (23.8% vs 9.1%, p=0.24). No reductions in hemoglobin level less than 10 g/dl or platelet count less than 50 x 103/mm3 occurred. In addition, no patients in the every 4 weeks treatment group required dosage reductions due to hematologic effects.

Taribavirin Taribavirin (formerly known as viramidine), a prodrug of ribavirin, is also being studied for the treatment of chronic HCV with the benefit of a lower frequency of anemia.[47,49] The major conversion site of taribavirin is in the liver, enabling this drug to concentrate in this location. Taribavirin contains a positively charged 3-carboxymide group, which prohibits its uptake in red blood cells and is thus associated with less hemolytic anemia.[36,49,50] Taribavirin is in phase II testing in the United States for treatment of chronic HCV, in combination with peginterferon.[48,50]

A phase II noninferiority study evaluating the use of taribavirin 800–1600 mg/day versus ribavirin 1000–1200 mg/day, all in combination with peginterferon, resulted in lower SVR rates with taribavirin; however, it did prove to be noninferior to ribavirin (23–37% vs 44%, p=0.155).[36,49] Lower rates of severe anemia were noted with taribavirin versus ribavirin (4% vs 27%).

Subsequent phase III studies (Viramidine's Safety and Efficacy versus Ribavirin [VISER] 1 and VISER 2) compared taribavirin 600 mg twice/day with ribavirin 1000–1200 mg/day (based on weight), both combined with peginterferon alfa-2a, in treatment-naïve patients with any genotype.[37,49,51] Results of these studies failed to demonstrate noninferiority of taribavirin to ribavirin in the intent-to-treat analysis. The SVR rates were 38% with taribavirin and 52% with ribavirin in VISER 1 and 40% versus 55% in VISER 2, respectively. In both studies, taribavirin did have lower rates of anemia (5% vs 24% and 6% vs 22% in VISER 1 and 2, respectively); however, in VISER 2, more patients receiving taribavirin experienced moderate-to-severe diarrhea (29.5% vs 15.7%, p<0.0001). Although these studies were powered based on phase II SVR rates, the authors concluded that noninferiority may not have been established due to suboptimal dosing of taribavirin. Because ribavirin is most appropriately dosed based on weight, the theory that taribavirin may prove more effective with weight-based dosing has yet to be proven.

An unpublished phase IIb study was initiated based on post hoc findings that weight-based taribavirin may prove more effective than standard dosing.[49,52] This study evaluated 275 treatment-naïve patients with genotype 1 HCV. Taribavirin at dosages of 20, 25, or 30 mg/kg/day were compared with ribavirin in addition to peginterferon. End-of-treatment response rates after 48 weeks of treatment were reported as 43.4%, 32.9%, and 29.4% for taribavirin doses, respectively, and 32.9% for ribavirin. Rates of anemia were also lower in the taribavirin groups (13.4%, 15.7%, and 27.9% for taribavirin and 32.9% for ribavirin). The results of this study are promising and need to be confirmed in larger, well-designed studies.

Protease Inhibitors Two protease inhibitors targeted against chronic HCV are in development.[47] Boceprevir (SCH 503034) and telaprevir (VX-950) are oral agents in phase III development in the United States. Both antiviral therapies are reversible, selective NS3 protease inhibitors; NS3 is an enzyme responsible for viral replication.[53–55] Both agents have shown substantial reductions in viral load in phase I clinical studies. All studies thus far have been conducted in patients with genotype 1. More recent studies have evaluated the use of these agents as a retreatment option for patients previously unable to achieve or maintain SVR.[38,56] Additive and synergistic effects in viral reduction and SVR have been noted with the combination of peginterferon, ribavirin, and a protease inhibitor. In addition, combination therapy has decreased the emergence of resistance with these agents.[53,57,58] Adverse events noted to be more common with telaprevir include rash and pruritis.[53,55,57,58]

A phase I clinical study conducted in 26 patients with genotype 1, who previously did not respond to therapy, evaluated the safety and tolerability of boceprevir in combination with peginterferon alfa-2b.[56] This randomized, open-label, crossover study evaluated two dosages of boceprevir over three dosing periods. One week of boceprevir monotherapy was followed by monotherapy with peginterferon alfa-2b for 2 weeks and then combination therapy of both agents for 2 weeks. A minimum 2-week washout period was incorporated between each dosing period. The two dosage regimens of boceprevir evaluated were 200 mg 3 times/day and 400 mg 3 times/day. Peginterferon alfa-2b was administered at standard dosing of 1.5 μg/kg once/week. Results of this study showed that boceprevir was well tolerated. Combination therapy was associated with a higher frequency of headache, rigor, and myalgia. Pharmacokinetic analyses showed only a slight increase in bioavailability for combination therapy as compared with low-dose boceprevir monotherapy, and no increase in area under the concentration-time curve was noted during combination therapy with high-dose boceprevir versus monotherapy.

A recently published international phase II study evaluated the use of telaprevir in patients with genotype 1 who did not achieve or maintain SVR with previous therapy (Table 6).[38] The study was a randomized, stratified study evaluating one of four possible treatment regimens on achievement of SVR. Telaprevir was administered as a single initial oral dose of 1125 mg followed by 750 mg every 8 hours, peginterferon alfa-2a was dosed at 180 μg/week subcutaneously, and ribavirin was dosed according to weight (1000 mg/day for weight less than 75 kg and 1200 mg/day if weight was 75 kg or more). One group (T12PR24) received telaprevir in combination with peginterferon alfa-2a and ribavirin for 12 weeks followed by placebo, peginterferon alfa-2a, and ribavirin for an additional 12 weeks. Another group (T24PR48) received telaprevir in combination with peginterferon alfa-2a with ribavirin for 24 weeks followed by peginterferon alfa-2a and ribavirin for an additional 24 weeks. The T24P24 group received telaprevir and peginterferon alfa-2a for 24 weeks, and the PR48 group received placebo plus peginterferon alfa-2a in combination with ribavirin for 24 weeks, followed by peginterferon alfa-2a and ribavirin for an additional 24 weeks (control group). Most patients were Caucasian men, aged 51 years, who had previously not responded to therapy.

Results showed that SVR was statistically significantly higher in each telaprevir group than in the control group.[38] In addition, SVR rates were higher among patients who previously experienced relapse versus nonresponders. Logistic regression analyses revealed SVR was associated with assignment to the shorter telaprevir courses combined with longer peginterferon-ribavirin courses, previously undetectable HCV RNA levels, and low baseline viral load. Maculopapular rash and pruritis were more common in groups that received telaprevir. The median time to rash appearance was 7–28 days, and 18 patients (5%) in the telaprevir group discontinued treatment due to rash. Also, patients in the telaprevir group were more likely to discontinue treatment due to adverse effects, with skin disorders the most common reason for discontinuation. A decrease in hemoglobin levels was observed more frequently in the telaprevir-based groups versus the control group.

Overall, protease inhibitors hold promise in treating patients with chronic HCV. To our knowledge, all studies have focused on genotype 1, and more studies are beginning to evaluate the use of protease inhibitors as an option for retreatment versus initial therapy. Broader patient populations and larger studies in the future will help to clarify the exact role of these agents in the treatment of HCV.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....