State of the Science in Anti-HCV Therapy

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• Utilizing knowledge of early predictors of response, differentiate those HCV patients who are likely to achieve a sustained viral response.
  
  
• Analyzing the differences in the virologic and pharmacokinetic responses to anti-HCV treatment in African Americans compared with Caucasians, examine the factors that may explain the differences.
  
  
• Based on the efficacy and safety of currently available therapies, formulate strategies to improve response rates in patients with chronic HCV (including nonresponders and difficult-to-treat patients).
  
  
• Assess the efficacy and safety of emerging new drugs in the treatment of HCV to determine how they may be integrated in treatment regimens for improved patient responses.

Early determination of which patients are likely to achieve a sustained virologic response (SVR) to treatment of hepatitis C virus (HCV) could allow those unlikely to achieve an SVR to be spared the expense and potential toxicities of continued therapy. Retrospective analyses of patients treated with peginterferon/ribavirin combination therapy^1,2 found that a failure to achieve a ≥ 2-log₁₀ decrease in HCV RNA at week 12 was the best predictor of failure to achieve an SVR after 48 weeks of therapy, a finding that is reflected in current guidelines.³

Conversely, those patients likely to achieve an SVR may need a shorter duration of treatment than previously assumed. Initial reports indicated that the presence of a viral response at 4 weeks has enabled shorter treatment duration (12–16 weeks) with very high levels of efficacy in patients infected with HCV genotype 2 or 3.^4-6

The identification of additional variables that predict the outcome of therapy, including differences in gene expression,⁷ will further aid in early clinical treatment decisions.

Wong et al⁸ investigated whether a rapid viral response to peginterferon alfa-2b/ribavirin (HCV RNA negativity at week 4 of therapy) can predict SVR after a shorter-than-standard 24 weeks of therapy.

Data from two trials were analyzed. Both trials enrolled patients with genotype 1 and low viral load (≤2 x 10⁶, as measured with quantitative PCR), and dosed peginterferon alfa-2b at 1.5 μg/kg/wk. However, they differed in ribavirin dosing: the first⁹ trial administered ribavirin 800 mg/d for 48 weeks and the second¹⁰ gave ribavirin 800 to 1400 mg/d for 24 weeks. Note that patients from the first⁹ trial were only included in this analysis if they had received more than 10.6 mg/kg of ribavirin and had available week 4 PCR results, in addition to low viral load of HCV genotype 1.

The results from the two studies are shown in Table 1. In the 24-week study, 110/235 patients (47%) were viral negative at week 4. Of these, 98 (89%) achieved an SVR, while of 125 patients who failed to clear HCV RNA by week 4, 106 failed to achieve SVR, for a negative predictive value (correct prediction of eventual nonresponse) of 85%. A lower percentage of patients (35%) in the 48-week study were viral negative at week 4, and the negative predictive value was also lower (36%).

Audio Commentary 

Most patients who are infected with a low viral load of genotype 1 and are viral negative at week 4 can thus be treated successfully for just 24 weeks with a high probability of achieving an SVR. However, viral positivity at week 4 does not indicate that the patient will not achieve an SVR and should not be used as a stopping criterion, as it is far less accurate than viral negativity at week 12 for predicting eventual response. Discontinuing treatment in patients who have persistent detectable virus at week 4 would result in inappropriately ceasing therapy early in 16% of patients who would achieve an SVR if treated for 24 weeks¹⁰ or 59% of patients who would achieve an SVR if treated for 48 weeks⁹ (P < .00001). However, limiting treatment to 24 weeks in those who are viral negative at week 4 could result in substantial cost savings. More data are now required to confirm these findings and studies are ongoing.

Audio Commentary 

Interferon gamma-inducible protein 10 (IP-10) is a 10-kD protein involved in recruiting T cells to the liver as part of the host response to hepatitis infection.¹¹ IP-10 can be induced by interferon alfa as well as interferon gamma.

According to a report by Lagging et al,¹² baseline plasma levels of IP-10 predict both viral kinetics and outcome in response to therapy in patients with chronic HCV genotype 1 infection.

Plasma samples were obtained from 178 patients infected with HCV genotype 1 who were participating in a large treatment trial with peginterferon alfa-2a and ribavirin. Plasma IP-10 was measured at baseline, day 7 and week 6 of treatment, and at follow-up 12 weeks after treatment. The rapidity of the initial viral response correlated with baseline IP-10 levels: patients with the lowest levels (<150 pg/mL) had a more rapid decline in HCV RNA than those with higher levels (Fig. 1). The same pattern held true when the data were analyzed from patients with body mass index (BMI) > 25, baseline HCV RNA > 2 x 10⁶ IU/mL, or both. In all groups analyzed, patients who achieved an SVR had significantly lower baseline IP-10 levels than those who did not respond or who relapsed. In a logistic regression model, log₁₀ IP-10 at baseline (odds ratio 14.07, P < .0001) and log₁₀ HCV RNA at baseline (odds ratio 2.02, P = .0081) were predictors of a ≥ 2-log₁₀ reduction of HCV RNA during the first 4 weeks of therapy. Log₁₀ IP-10 (pg/mL) at baseline, log₁₀ HCV RNA (IU/mL) at baseline, gender, and BMI were all significantly associated with a higher likelihood of SVR; of these, IP-10 had the largest odds ratio (3.5, P = .017).

In the future, if new studies can verify the results of this study, baseline IP-10 serum concentrations may aid in making treatment decisions in difficult-to-treat patients.

The rates of SVR and histologic improvement following anti-HCV treatment depend on the dosing of peginterferon and ribavirin.^9,13,14 Higher doses of peginterferon have been shown to be more efficacious,^9,15 and increasing the dosage of ribavirin based on the weight of the patient also increases response in patients infected with genotype 1.¹⁶

Maintenance of dosing is also important for successful anti-HCV treatment,¹⁷ but adverse events can lead to reductions in dose or discontinuations. Anemia is a common adverse event with peginterferon/ribavirin therapy that frequently necessitates a lowered dose or discontinuation of ribavirin. Epoetin alfa stimulates the production and release of red blood cells, thereby alleviating anemia. The addition of epoetin alfa can significantly increase hemoglobin levels in patients experiencing interferon/ribavirin-related anemia.¹⁸ In a recent trial, epoetin alfa in combination with interferon alfa/ribavirin therapy resulted in higher rates of ribavirin dose maintenance (88% versus 60%, P < .001) and greater improvement in fatigue and quality of life than placebo.¹⁴ No SVR data were reported from this trial.

Mitchell Shiffman, MD, presented data on whether using epoetin alfa at the onset of treatment with peginterferon and ribavirin would reduce the frequency of anemia, thus allowing higher ribavirin dosing and resulting in improved rates of SVR.¹⁹

In this prospective single-center trial, 150 patients infected with HCV genotype 1 were randomized into three study arms: 1) peginterferon alfa-2b plus weight-based ribavirin (800–1400 mg/d, mean dose of 13.3 mg/kg/d); 2) peginterferon alfa-2b plus weight-based ribavirin (800–1400 mg/d, mean dose of 13.3 mg/kg/d) plus epoetin alfa (40,000 U/wk); and 3) peginterferon alfa-2b plus high-dose ribavirin (1000–1600 mg/d, mean 15.2 mg/kg/d) plus epoetin alfa. The dose of ribavirin was reduced in 200-mg steps if hemoglobin decreased to below 10 g/dL or if other ribavirin-associated adverse events developed. Ribavirin was discontinued if the hemoglobin fell below 8.5 g/dL. The dose of epoetin alfa was also adjusted to maintain hemoglobin concentrations between 12 and 15 g/dL.

Shiffman reported results from 146 patients. Group 2 (peginterferon/weight-based ribavirin/epoetin alfa) had slightly higher proportions of patients who had cirrhosis or patients who were African Americans; otherwise, the demographics were similar among the groups. In an intent-to-treat analysis, a higher percentage of those receiving the high-dose ribavirin plus epoetin alfa (49%) achieved an SVR than those receiving the lower dose of ribavirin plus epoetin alfa (19%) or those receiving no epoetin alfa (29%) (P < .05, Group 3 versus Groups 1 and 2) (Fig. 2). The higher SVR in Group 3 was due to a dramatically lower relapse rate (8%) than in Group 1 (36%) or Group 2 (40%) (P < .05).

Significantly fewer patients treated with epoetin alfa had hemoglobin levels decline to < 10 g/dL (9% and 6% in Groups 2 and 3, respectively, versus 34% in Group 1). Significantly fewer patients receiving standard therapy plus epoetin alfa (Group 2) needed the dose of ribavirin reduced (10% versus 40% in Group 1) and the mean dose reduction was smaller (27 versus 179 mg/d). Thirty-one percent of those receiving the high-dose ribavirin (Group 3) required a dose reduction, with a mean reduction of 102 mg, but this still resulted in a higher mean dose in Group 3 than in Groups 1 and 2 (Table 2).

Although Caucasians had both higher early virologic response (EVR) and SVR rates than African Americans, the SVR rate was higher in the high-dose ribavirin group than the other groups, regardless of race. SVR was also higher in the high-dose group across all body weights.

About 30% of patients in each group discontinued therapy because of nonresponse, and 25%, 36%, and 18% in Groups 1, 2, and 3, respectively, discontinued for systemic side effects. Anemia was the reason for discontinuation in 4%, 2%, and 0% of patients in Groups 1, 2, and 3, respectively.

Thus, use of epoetin alfa itself did not significantly affect mean ribavirin dose or EVR rate, but the use of epoetin alfa in conjunction with high-dose ribavirin significantly increased SVR in these patients infected with HCV genotype 1. The incidence of relapse was lower in the group receiving high-dose ribavirin plus epoetin alfa despite the need to reduce the dose in 31% of patients, suggesting that the ability of ribavirin to reduce relapse occurs early in the course of treatment.

Audio Commentary 

The final results of the Weight-based Interferon and Ribavirin (WIN-R) Trial, reported by Ira Jacobson, MD, indicated that weight-based dosing of ribavirin increases rates of SVR over fixed-dose ribavirin, particularly for difficult-to-treat patients, such as African Americans and those infected with HCV genotype 1.²⁰ In this large, prospective trial, 4913 patients at 225 sites were randomized into two study arms: ribavirin 800 mg/d or ribavirin based on weight (<65 kg, 800 mg/d; 65 to <85 kg, 1000 mg/d; 85 to <105 kg, 1200 mg/d; and 105 to 125 kg, 1400 mg/d); patients in both arms also received peginterferon alfa-2b 1.5 μg/kg QW. Patients with HCV genotype 1 infection were treated for 48 weeks, whereas those infected with genotype 2 or 3 were randomized to receive 24 or 48 weeks of treatment.

The per-protocol analysis included all patients ≥65 kg, who made up 86% of the study population. There was no significant difference between the groups in end-of-treatment (EOT) response, but significantly more patients treated with weight-based ribavirin achieved an SVR (44.3% versus 40.6%, P = .02) (Fig. 3). This advantage of weight-based over fixed-dose ribavirin was maintained when the responses of all patients (including those <65 kg) were analyzed (SVR 45% versus 42%, P = .028).

Weight-based dosing was also superior in patients infected with genotype 1 (34% versus 29%, P = .004), in patients with high viral load and genotype 1 (32% versus 27%, P = .047), and in African-American patients with genotype 1 infection at both EOT (29% versus 16%, P = .006) and week 24 of follow-up (SVR, 21% versus 10%, P = .004) (Table 3).¹⁶ Patients with genotypes 2 and 3 received no significant benefit from weight-based ribavirin dosing and there was no difference between 24 and 48 weeks of treatment in patients infected with genotypes 2 and 3, indicating once again that these patients can be treated effectively in 24 weeks with fixed dosing.

Audio Commentary 

Predictably, anemia (nadir hemoglobin <10 g/dL) rates were higher in the weight-based group than in the fixed-dose group (19% versus 12%, respectively); however, anemia was no more frequent in the heavier patients taking 1400 mg/d ribavirin than in patients taking other doses. There were more dose reductions (of either drug) in the weight-based ribavirin group.

Consensus interferon (CIFN) is a genetically engineered molecule derived from interferon alfa²¹ that has demonstrated enhanced biologic potency compared with the naturally occurring interferon alfas, such as interferon alfa-2a or alfa-2b. CIFN exhibits increased antiviral activity in vitro, and improved response rates at EOT compared with interferon alfa-2b.²²

The interferon alfa isoforms are type I interferons. A naturally occurring type II interferon, interferon gamma mediates the clearance of HCV by the host during acute infection.²³ Preclinical studies perhaps suggest that interferon alfa and interferon gamma may act synergistically against HCV infection when delivered in combination.^24,25

In a randomized, open-label pilot study, Kaiser et al tested whether combining CIFN with interferon gamma, with or without ribavirin, can improve response rates in treatment-naive patients infected with HCV genotype 1.²⁶

Sixty patients received CIFN 9 μg QD for 48 weeks and were randomized to also receive interferon gamma 50 μg TIW, weight-based ribavirin 11 mg/kg, or both. Rates of both EOT response and SVR were higher in the triple-therapy group than in either of the other groups, although the only significant difference was between the rate of SVR in the triple therapy group and the CIFN/interferon gamma group (Table 4).

No serious adverse events were reported in any of the patients. Patients treated with interferon gamma experienced significantly more side effects, specifically flu-like symptoms, and also fatigue and myalgias, than those in the interferon alfa/ribavirin arm. 100% of these patients experienced flu-like symptoms, compared with 82% in the interferon alfa/ribavirin arm. Seven patients receiving interferon gamma had grade 3 neutropenia. All arms experienced similar interferon-related adverse events.

The dose of 50 μg interferon gamma TIW was chosen for this study because of safety data available at the time the study protocol was developed. Other studies have looked at higher doses of 100 or 200 μg, and dose-finding studies are now under way to determine the optimal dose for interferon gamma.

The effect of interferon gamma by itself appears to be rather small, and in this small pilot study was not significant compared with standard therapy with interferon/ribavirin. Further studies are now required to delineate response rates and to carefully evaluate the tolerability of this combination therapy.

There is a higher prevalence of HCV infection among African Americans than among Caucasians.²⁷ Although African Americans have historically been underrepresented in clinical trials, they have consistently been shown to have lower response rates to anti-HCV treatment with interferon monotherapy^28,29 or (peg)interferon/ribavirin combination therapy^30-32; a recent study also showed a trend toward lower responses in African Americans treated with CIFN.³³ African Americans have a higher prevalence of genotype 1 infection,^28,34 but the difference in response to anti-HCV therapy persists when Caucasian and African-American patients with genotype 1 infections are compared,^31,34 and the difference in response rate is also independent of the severity and duration of disease, compliance, and other demographic factors.^31,34

Hari Conjeevaram, MD, MS, reported on the prospective, multicenter Virahep-C Study, which was designed to investigate the difference between African-American and Caucasian patients in their response to peginterferon/ribavirin and to identify factors that predict a lack of response.³⁵

The study enrolled 196 African-American and 205 Caucasian patients infected with HCV genotype 1. The patients were all treatment-naive and were treated with 180 μg/wk peginterferon alfa-2a and 1000 to 1200 mg/d ribavirin. Patients who were HCV RNA negative at week 24 were treated for an additional 24 weeks and then followed to week 72 to determine the SVR rate (the primary endpoint).

At baseline, the African Americans had significantly higher average BMI, higher rates of diabetes and hypertension, and lower mean alanine aminotransferase, neutrophil, and hemoglobin levels (P < .001 for all). African Americans were also significantly more likely to be infected with HCV subtype 1b (47% versus 28%, P = .0004) and less likely to have subtype 1a (46% versus 58%, P = .04). HCV RNA levels, mean age, gender ratios, and histologically determined disease severity were similar between the groups.

Racial differences in response were apparent as early as week 4, when 10% of African Americans and 22% of Caucasians were HCV RNA negative (P = .0015). This discrepancy continued throughout the course of treatment (Table 5). At week 72, 28% of African Americans and 52% of Caucasians had achieved an SVR (P < .0001). Breakthrough responses during treatment occurred more frequently in African Americans (13% versus 6%), but relapse rates following treatment were similar between the groups (32% versus 25%). An EVR, defined as HCV RNA negativity or a ≥2-log drop in HCV RNA at week 12, was present in 61% of African Americans and 78% of Caucasians (P = .003).

Multiple regression analysis revealed that Caucasian race, male gender, fibrosis score, and baseline viral load all predicted SVR; moreover, there was an interaction between race and viral level, such that as baseline viral load increased the difference in response between the races also increased. Although compliance rates were lower among African Americans (53.8% took 80% of the doses of each drug, compared with 73% for Caucasians), this did not affect the study outcome: when those in each group who took 100% of the doses were compared, there was still a difference in response between the races. The proportion of patients with serious adverse events, dose reductions, and dose discontinuations were similar between the groups.

Although the racial difference in response rate that was apparent at 4 weeks could not be accounted for by known factors, Conjeevaram speculated that there may be differences in host immune responses or in interferon signaling pathways. A companion analysis of a subset of the African Americans and Caucasians in the Virahep-C study³⁶ found slightly different peginterferon alfa-2a pharmacokinetics between the racial groups: the African Americans had a shorter time to maximum peginterferon concentration and a higher adjusted peginterferon concentration at day 28 than Caucasians; however, the relationship between these pharmacokinetic differences and the differences in treatment response remain to be elucidated.

Audio Commentary 

Despite advances in anti-HCV treatment, about half of patients treated with peginterferon/ribavirin will not achieve an SVR. Retreatment of patients who did not respond to standard interferon/ribavirin combination therapy with peginterferon/ribavirin therapy yields an SVR in no more than 14% of patients,^15,37-40 although a higher SVR rate was reported in patients re-treated using CIFN.⁴¹ Clearly, new strategies are needed to effectively treat this refractory population. Until new drugs are available to meet this growing need, different dosing schedules of currently available drugs are also being evaluated.

John Gross, MD, presented the final results of the REtreatment of Nonresponders with Escalating Weight-based therapy (RENEW) trial,⁴² a trial evaluating the efficacy and safety of higher doses of peginterferon alfa-2b and a weight-based ribavirin schedule in patients with compensated liver disease who had failed to clear HCV RNA during previous treatment with interferon/ribavirin. The RENEW trial was carried out at 100 academic and community sites in the United States.

Patients were randomized into three study arms: peginterferon alfa-2b at 0.5, 1.5, or 3 μg/kg plus ribavirin 800 to 1400 mg/d, stratified by gender, race (African American versus other), genotype (1 versus non-1), and degree of fibrosis (F0/1 versus F2/3/4). If patients were HCV RNA negative at week 24, treatment was continued to week 48, with follow-up to week 72. A total of 963 patients were enrolled, but enrollment into the peginterferon alfa-2b 0.5 group was stopped at 137 patients when the FDA approved the 1.5 μg/kg peginterferon dose. Enrollment in the two other arms continued, and 352 patients started therapy in each; analysis of these two arms was presented.

The rate of HCV RNA negativity at the end of treatment was 24% in both groups, but significantly more patients in the 3 μg/kg group than the 1.5 μg/kg group achieved an SVR (17% versus 12%, P = .03) (Fig. 4). Low fibrosis scores of F0 to F2, Caucasian race, and body weight ≤85 kg were all associated with higher rates of SVR, but patients with Stage 3 to 4 fibrosis (N = 283) and African-American patients (N = 113) did have higher rates of SVR with the double dose of interferon than with the standard dose of 1.5 μg/kg (F3/4: 12% versus 8%; African American: 16% versus 4%). When the data from all patients in both groups were combined, the rate of SVR showed a trend towards increasing with body weight across four stratifications, <65 kg, 65 to 85 kg, >85 to 105 kg, and >105 kg, but this was not significant.

Audio Commentary 

Adverse events were very similar between the two groups, although there were slightly (but not significantly) higher rates of irritability/depression and myalgia/arthralgia in the double-dose group. The rates of dose reduction were somewhat higher in the double-dose group (33% versus 25% in the first 12 weeks and 45% versus 37% overall).

Gross concluded that, among previous nonresponders to interferon/ribavirin, double-dose (3 μg/kg) peginterferon alfa-2b is more effective than 1.5 μg/kg peginterferon in combination with ribavirin, even among hard-to-treat patients, and has a similar safety profile.

Results from the induction period of the REtreatment with PEgasys^® in pATients not responding to prior peginterferon alfa-2b/ribavirin therapy (REPEAT) trial, presented by Patrick Marcellin, MD, indicated that a higher fixed dose of peginterferon alfa-2a (360 μg/wk) is more effective than therapy with the standard dose (180 μg/wk) in previous nonresponders to peginterferon alfa-2b.⁴³ Nine hundred fifty patients were randomized into four study arms of an ongoing study (2:1:1:2). Patients in the first two arms received an initial 12 weeks of therapy with high-dose peginterferon plus ribavirin, followed in Group A by therapy with standard-dose peginterferon for 60 weeks (for a total of 72 weeks of treatment) and in Group B with standard-dose peginterferon for 36 weeks (for a total of 48 weeks of treatment). Patients in Groups C and D received 72 and 48 weeks of therapy, respectively, with 180 μg/wk peginterferon plus ribavirin. All patients will be followed up for 24 weeks.⁴⁴

Marcellin presented the results from the first 12 weeks of therapy (the induction period). For this analysis, Groups A and B were combined into a high-dose group, and Groups C and D were combined into a standard-dose group. The baseline characteristics of the high-dose and standard-dose groups were similar; the majority of the patients (91%) were infected with HCV genotype 1 and just over one quarter had cirrhosis. Significantly more patients in the high-dose group (62%) than in the standard-dose group (45%) achieved a ≥2-log decrease in HCV RNA (P < .001); this pattern held true whether or not the patients had cirrhosis or advanced fibrosis.

The safety profile reported to date was similar between the groups. Dose modification or discontinuation of interferon was necessary for 13% of the standard-dose group and 19% of the high-dose group; 3% of the patients receiving the standard dose withdrew from the study, compared with 5% of those receiving the higher dose. Platelet and neutrophil counts were not significantly different between the groups.

Thus, significantly more patients in this preliminary report had an early response to retreatment with double-dose peginterferon alfa-2a plus ribavirin than to retreatment with the standard dose. SVR and further safety data are now awaited.

Audio Commentary 

The efficacy and safety of high-dose daily CIFN and ribavirin were evaluated in 38 patients with advanced liver disease who had tolerated previous therapy with peginterferon and ribavirin but had not achieved an SVR.⁴⁵ Patients were given 27 μg CIFN daily and 400 mg ribavirin BID for 4 weeks, followed by 8 weeks of 18 μg CIFN daily and ribavirin 400 mg BID, and then 36 weeks of 15 μg CIFN daily and 1000 to 1200 mg ribavirin daily. Of the 38 patients, 74% were male, 97% had HCV genotype 1 infection, 79% had Stage 3 or greater fibrosis, and 55% had cirrhosis.

At EOT (week 48), 42% of the patients had become HCV RNA negative, and 18% of the 17 patients who had reached week 72 had achieved an SVR (Fig. 5).

Audio Commentary 

The most common adverse effects, in decreasing order of frequency, were fatigue, headaches, irritability, weight loss, bone pain, and depression. Rare adverse effects were alopecia and tinnitus. Eighteen percent of patients (n = 7) discontinued, but only two of the discontinuations were due to adverse events from the therapy. Dose reductions were necessary for 34% of patients (n = 13). These rates are similar to those seen in nonresponder trials using peginterferon and ribavirin.

As also suggested by other single-center studies of CIFN and ribavirin in nonresponders to peginterferon plus ribavirin,^33,46 the combination of CIFN and ribavirin may prove to be an effective option for HCV patients with advanced fibrosis who did not respond to previous therapy with peginterferon and ribavirin. A large multicenter study of CIFN and ribavirin is currently in progress.

Audio Commentary 

Audio Commentary 

Recent developments in molecular and laboratory techniques^47,48 have enabled the development of novel anti-HCV drugs that specifically inhibit the HCV NS3/4 proteases (eg, SCH 503034, VX-950) or the NS5B polymerase (eg, NM283) that are necessary for viral replication.^47,49 Because inhibitors of the HCV protease can reverse the inactivation of IRF3, such agents may theoretically restore the antiviral host innate immune response, while at the same time inhibiting replication of the virus.^49,50 These novel antivirals in development have the added advantage that they are orally bioavailable.

Stefan Zeuzem, MD, reported the results of a double-blind, placebo-controlled, phase Ib trial of SCH 503034, an HCV-specific protease inhibitor, as monotherapy in patients infected with HCV genotype 1.⁵¹ These patients had not achieved a ≥2-log decline of HCV RNA with at least 12 weeks of previous therapy with peginterferon. Twelve patients were enrolled at each dose level of SCH 503034 (100, 200, and 400 mg BID and 400 mg TID); four additional patients in each group received placebo. Study drug was given orally for 14 days.

Baseline demographics were similar between the groups. Extensive pharmacokinetic analyses were performed on days 1 and 14, and trough levels were also determined on days 11 and 15. The drug was rapidly absorbed, with a T_max of -1 to 2 hours, and C_max and AUC increased with dose. Biphasic clearance occurred with a t_1/2 of 7 to 15 hours.

HCV RNA declined over the 14 days of treatment, with the most pronounced decline—a mean of 1.5 to 2 logs—occurring in the 400 mg TID group (Fig. 6). More than half of the patients in the 400 mg BID group had a decline of 1 to 2 logs, and six of ten patients in the 400 mg TID group had a decline in HCV RNA of > 2 to 3 logs. The decrease in viral load correlated with the trough serum concentrations of SCH 503034. ALT levels also decreased from baseline in the groups receiving the highest dosages, and all but one patient in the 400 mg TID group achieved normal ALT levels during the treatment period.

Early sequencing of the HCV protease indicated that no variant emerged in 42 of the 43 patients who received the active drug. In the remaining patient, a single variant known to cause resistance in vitro, V170A, was detected on days 14 (EOT) and 16 (beginning of follow-up), but disappeared by day 28.

SCH 503034 was well tolerated at all dosages. Adverse events did not increase with dosage, were mild or moderate, and most did not differ between active drug and placebo. The most frequently reported adverse event was headache, which occurred in 12% of patients taking active drug and 29% of patients taking placebo. Clinical laboratory tests were not different between active drug and placebo.

SCH 503034 thus shows promise as an antiviral agent. Toxicology data support further dose escalation of the drug, and a phase II trial of combination therapy for 48 weeks in prior nonresponders is now under way.

Audio Commentary 

The results of a phase 1b study reported by Stefan Zeuzem, MD, indicate that combination therapy with peginterferon and the protease inhibitor SCH 503034 has strong antiviral activity.⁵²

This multicenter, open-label study used a three-way crossover design (with at least a 2-week washout between treatments) to compare monotherapy with two doses of SCH 503034 (200 mg or 400 mg TID) for 7 days, monotherapy with 1.5 μg/kg QW peginterferon for 14 days, and combination therapy with SCH 503034 and peginterferon for 14 days. Monotherapy with SCH 503034 was given for only 7 days to avoid selecting for viral mutants.

The study enrolled 22 patients infected with HCV genotype 1 who had not responded to previous therapy with peginterferon plus ribavirin. Fourteen patients received the 200 mg dosage of SCH 503034 (12 completed the study, one discontinued due to an adverse event, and one withdrew) and 12 received the 400 mg dosage (10 completed the study, and two discontinued because of adverse events attributed to peginterferon).

Monotherapy with the 200 mg TID dosage of SCH 503034 reduced HCV RNA by 0.4 to 1.77 log₁₀ and with the 400 mg TID dosage reduced HCV RNA 0.5 to 2.5 log₁₀. Combination therapy substantially reduced HCV RNA, and 4 of 10 patients receiving peginterferon plus the higher dose of SCH 503034 became RNA negative during treatment. In contrast, none of the 22 patients receiving peginterferon or SCH 503034 monotherapy became RNA negative. The combination also did not affect the oscillatory pharmacodynamic pattern seen with peginterferon alfa-2b alone (Fig. 7).

The viral RNA was sequenced at baseline, EOT, and at follow-up. Of the available sequences from 19 patients, a single variant (T54) was detected in one patient; however, this variant became undetectable after the washout period.

The most common adverse events were headache, myalgia, and fever; the incidence of headache was slightly higher with the combination treatment than with peginterferon alone. One patient discontinued due to a serious adverse event (a seizure) that was thought to be related to treatment with peginterferon.

Phase II studies are under way to assess 24 and 48 weeks of combined treatment as well as to determine the optimal dosage of SCH 503034.

Christopher O'Brien, MD, presented interim results from a randomized, open-label, phase IIb trial comparing the safety and tolerability of the HCV polymerase inhibitor NM283, either alone or in combination with peginterferon, to retreatment with peginterferon plus ribavirin in patients with chronic HCV genotype 1 infection who had previously failed to respond to ≥3 months of treatment with peginterferon plus ribavirin.⁵³

The study comprised five treatment arms (Table 6): NM283 monotherapy, three dosage regimens of NM283 plus peginterferon, and peginterferon plus ribavirin. The peginterferon was dosed at 180 μg/week and ribavirin was given at 1000 to 1200 mg daily. Patients without a sufficient response (decrease in HCV RNA of 0.5 logs at week 4, 1 log at week 12, and 2 logs at week 24) were discontinued from the study.

Baseline demographics were similar in each arm. Importantly, 81% of patients in each treatment arm had not had an EVR to previous therapy. O'Brien presented the responses at week 12 from 178 patients who had received study medication. Response to treatment with NM283 was dose-dependent, and the two higher dosages of NM283 combination therapy produced significantly greater declines in HCV RNA and significantly higher percentages of patients with early viral responses than the peginterferon/ribavirin control arm (Table 6).

An a priori decision had been made to combine the two best NM283/peginterferon arms for comparison with the interferon/ribavirin arm in categorical declines in HCV RNA. The combined NM283 400 to 800 mg ramp arm and the NM283 800 mg arm had a significantly greater percentage of patients achieving >2-log, >3-log, and >4-log declines in HCV RNA than patients in the control arm (Fig. 8).

Patients in the combination groups experienced more gastrointestinal-related toxicities than the monotherapy groups, but overall the adverse events were mild, not dose limiting, and tended to resolve spontaneously. NM283 was not associated with hematologic toxicities. Four percent of the patients discontinued by week 12 due to adverse events. Serious adverse events occurred in 3% of patients; four of these involved gastrointestinal symptoms, two of which were related to study drugs and resulted in anemia and dehydration. All of the adverse events resolved.

NM283 in combination with peginterferon thus had a dose-dependent antiviral effect that was proportionally greater than the effect of peginterferon plus ribavirin. No evidence of viral breakthrough has been observed to date. Further studies are ongoing.

Audio Commentary 

Henk Reesink, MD, presented the final results from a single-agent phase 1b dose-escalation trial of VX-950.⁵⁴ Thirty-six HCV-infected patients were divided into three groups; in each group, 10 patients received active drug and two received placebo. The dosing levels were 450 mg TID, 750 mg TID, or 1250 mg BID for 14 days. More females than males were in the 750 mg arm; otherwise, demographics were similar.

Twenty-eight patients received VX-950, five of whom were treatment-naive, and all patients took 100% of the intended dose. Safety was the primary outcome of the study. The most common adverse events thought to be related to VX-950 were headache and gastrointestinal symptoms, all of which were mild. Three adverse events of moderate severity were not considered to be related to VX-950.

The antiviral effect of VX-950 was a secondary outcome. Most patients had normalized ALT levels by the end of the study. All patients responded to VX-950 with a ≥2-log drop in HCV RNA; 26 of the 28 patients who received VX-950 had a >3-log decrease and seven had a >4 log decrease (Table 7). In four of the eight patients in the 750 mg TID group, HCV RNA fell to <30 IU/mL, and in two of the eight, it fell to <10 IU/mL.

The patients receiving 750 mg TID had the highest trough concentrations at steady state, and continued to show declines in HCV RNA through the end of the study. In contrast, patients receiving 450 mg TID or 1250 mg BID had RNA levels that remained stable after the first few days, or even began to increase again. The trough level at steady state was thus a determinant of the second slope of viral decline. Sequence variants with varying resistance to VX-950 were identified, but the variant that was least sensitive to VX-950 also had reduced replicative capacity.

VX-950 thus produces the most marked antiviral response of any single agent to date. Combination therapy with this agent, as with others, will be required to prevent viral resistance and to enhance the sustained response rates. A small combination study of VX-950 and peginterferon is in progress and two phase II studies will begin shortly: a 28-day study, and 12-week study of therapy with VX-950 and peginterferon. Modeling indicates that 12 weeks of therapy with VX-950 might be sufficient for long-term viral eradication.

Understanding the effects on treatment outcome of patient characteristics, such as race, baseline levels of biomarkers, HCV genotype, and early viral response to treatment, will allow the development of more effective anti-HCV treatments that can be tailored to each patient's needs. Treatment strategies might include adjustments in the dosing of peginterferon/ribavirin, the inclusion of epoetin alfa or alternative interferons as components of the anti-HCV therapy, or shorter treatment regimens.

The future of anti-HCV treatment most likely lies in the development of novel therapeutic approaches that disrupt viral infectivity or replication. The goal of therapy will be to improve clinical outcomes through multiple drug strategies affecting different mechanisms of action while minimizing or eliminating clinically significant resistance. However, these novel agents are still in the early stages of development.

Although challenges remain in implementing successful anti-HCV treatment, data on many new therapies, dosing regimens, and predictors of outcome were presented at the 56th Annual Meeting of the AASLD. Keeping apprised of the latest research findings and expert recommendations will help the clinician provide the most effective anti-HCV therapy and education for his or her patients.

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