A SPECIAL MEETING REVIEW EDITION: Updates in the Treatment of Hepatitis C Virus Infection From EASL 2012

Safety of Telaprevir or Boceprevir in Combination with Peginterferon α/Ribavirin in Cirrhotic Nonresponders. First Results of the French Early Access Program (ANRS CO20-CUPIC)

Triple therapy with a hepatitis C virus (HCV) NS3/4A protease inhibitor such as telaprevir or boceprevir plus peginterferon α-2a and ribavirin can improve sustained virologic response (SVR) rates in patients infected with HCV. However, few cirrhotic patients were included in the studies that first evaluated these therapies, such as REALIZE (telaprevir) and RESPOND-2 (boceprevir).^1,2 Therefore, Christophe Hézode and associates from the ANRS—a French national agency for research on AIDS and viral hepatitis—conducted another study to determine the safety and efficacy of telaprevir or boceprevir plus peginterferon α-2a and ribavirin in HCV-infected patients with cirrhosis.³ Hézode presented the interim safety and tolerability results of this study at the 2012 European Association for the Study of the Liver (EASL) Annual Meeting, which was held April 18-22 in Barcelona, Spain.

This study included patients from the CUPIC cohort who had compensated, Child-Pugh class A cirrhosis, genotype 1 HCV infection, and a history of relapse or partial response (HCV RNA decline >2 log₁₀ at Week 12 but failure to achieve undetectable HCV RNA levels) when previously treated with peginterferon and ribavirin. Patients received 1 of 2 treatments: 12 weeks of telaprevir, peginterferon, and ribavirin followed by 36 weeks of peginterferon and ribavirin; or 4 weeks of peginterferon and ribavirin followed by 44 weeks of boceprevir, peginterferon, and ribavirin. Hézode noted that the patients were not randomized into treatment groups; therefore, this study cannot provide a direct comparison between telaprevir and boceprevir.

The investigators analyzed safety data from patients who had received at least 16 weeks of antiviral treatment (n=455). The female-to-male ratio was 0.4, and the mean patient age was 57 years. The majority of patients were infected with genotype lb HCV, and portal hypertension was present in 15% of the patients. Compared to the cirrhotic patients included in the REALIZE study, the patients in this study’s telaprevir treatment group (n=296) were older and had lower mean hemoglobin and platelet levels; approximately one third of these patients met at least 1 of the exclusion criteria for the REALIZE study. Similarly, the patients in this study’s boceprevir treatment group (n=159) differed from the cirrhotic patients included in the RESPOND-2 study, with 26% of these patients meeting at least 1 of the exclusion criteria for the RESPOND-2 study.

There was a high rate of serious adverse events in both the telaprevir and boceprevir treatment groups (51% and 40%, respectively). Discontinuation due to adverse events occurred in 14% of the telaprevir group and 7% of the boceprevir group. Anemia (hemoglobin level ≤10 g/dL) was observed in approximately 30% of patients; interventions included administration of erythropoietin (in approximately two thirds of the patients in each treatment group) and blood transfusions (in 15% and 11 % of the telaprevir and boceprevir groups, respectively). Grade 3—4 adverse events included neutropenia (12% and 10% of the telaprevir and boceprevir treatment groups, respectively), thrombocytopenia (22% and 7%), rash (7% and 1%), and severe infection (9% and 2.5%). Hepatic decompensation occurred in 4.4% of the patients in each treatment group. Hézode noted that the occurrences of severe infection and hepatic decompensation were likely due to interferon rather than the protease inhibitor. Additional adverse events occurred in 53% of the telaprevir group and 32% of the boceprevir group. Six patients in the telaprevir group died from sepsis or hepatic decompensation, and 2 patients in the boceprevir group died from sepsis. While the study design did not allow for direct comparisons between telaprevir and boceprevir, there appears to be a trend towards fewer adverse events with boceprevir.

Hézode also presented some preliminary efficacy data from the CUPIC study. In the telaprevir treatment group, the rapid virologic response (RVR) rate was 53%. At Weeks 12 and 16, undetectable HCV RNA levels were achieved by 86% of patients who received telaprevir-based triple therapy. In the boceprevir treatment group, undetectable HCV RNA levels were achieved by 37% of patients at Week 8 and 71% of patients at Week 16.

Hézode concluded that when telaprevir and boceprevir were administered with peginterferon α-2a and ribavirin as part of a triple therapy regimen, both protease inhibitors had poor safety profiles in genotype 1 HCV-infected patients with compensated cirrhosis. The rate of serious adverse events in this population was 40—51%, compared to rates of 9% and 14% in the REALIZE and RESPOND-2 studies, respectively. However, the initial efficacy data suggest that triple therapy can achieve good on-treatment virologic responses in cirrhotic patients. The investigators concluded that triple therapy should be used with caution and close monitoring in patients with cirrhosis and genotype 1 HCV infection.

ABSTRACT SUMMARY In Vitro Characterization of the Pan-Genotype Activity of the HCV NS3/4A Protease Inhibitors Boceprevir and Telaprevir

The peptidyl NS3/4A protease inhibitors boceprevir and telaprevir are approved for the treatment of genotype 1 HCV when used in combination with peginterferon and ribavirin. However, evidence suggests that these protease inhibitors may also be useful for the treatment of other HCV genotypes. Telaprevir has been shown to reduce HCV RNA levels in patients infected with genotype 2 HCV but not in those with genotype 3 HCV.¹ Boceprevir has been associated with a reduction in HCV RNA levels in HCV-infected patients with either genotype 2 or 3.²

At the 2012 EASL Annual Meeting, John Howe and coauthors presented data on the in vitro activity of boceprevir and telaprevir against the 6 major genotypes of HCV.³ To measure the inhibitory activity of these drugs, recombinant his-tagged NS3/4A proteases were expressed and purified for use in a kinetic chromogenic assay. Boceprevir and telaprevir both demonstrated activity against genotypes 1 through 6 in this assay.

A replicon assay was then performed to measure the cell-based activity of boceprevir and telaprevir against all 6 HCV genotypes. Replicon cell lines (genotype la, lb, 2a, 2b, 3a, 5a) were treated with boceprevir or telaprevir for 3 days. HCV RNA levels were measured using a real-time polymerase chain reaction assay (Taq-man) to determine the potency of the drugs. Both boceprevir and telaprevir were found to be active against the assayed genotypes.

Finally, in a cell-based NS3/4A phenotype assay, genotype la, lb, 2a, 2b, 3a, 4a, 5a, and 6a NS3/4A sequences were cloned from patient isolates and inserted into an expression vector. The expression vectors were coexpressed in cells with a modified secreted alkaline phosphatase (SEAP) reporter plasmid that contained a NS3/4A cleavage site. Measurement of SEAP activity revealed boceprevir and telaprevir potency. With boceprevir, there was a 2.2-fold shift for genotype 3a compared to genotype 1a and a 3.2-fold shift for genotype 4a compared to genotype la. With telaprevir, there was an 8-fold shift for genotype 3a and a 5.9-fold shift for genotype 4a, both compared to genotype 1a. Structural modeling and sequence alignment determined that the nonconserved NS3 amino acids R123T, D168Q, and I132L might play an important role in boceprevir and telaprevir interactions with genotype 3 HCV; this hypothesis is currently under investigation.

The authors concluded that use of boceprevir for the treatment of genotypes 3 and 4 and use of telaprevir for the treatment of genotypes 2,5, and 6 should be further evaluated in the clinical setting.

Sustained Virologic Response (SVR) in Prior Peginterferon/Ribavirin (PR) Treatment Failures After Re-treatment with Boceprevir (BOC) + PR: The PROVIDE Study Interim Results

Addition of boceprevir to peginterferon and ribavirin significantly improves SVR rates in both treatment-naïve and previously treated patients. The PROVIDE study was conducted to determine SVR rates among prior null responders, prior partial nonresponders, and prior relapsers when these patients were re-treated with triple therapy consisting of boceprevir, peginterferon, and ribavirin. Jean-Pierre Bronowicki presented interim efficacy and safety data from the PROVIDE study at the 2012 EASL Annual Meeting.¹

The PROVIDE study enrolled patients from the control arms of phase II and phase III clinical trials of boceprevir; these patients had all received at least 12 weeks of peginterferon and ribavirin but failed to achieve SVR due to futility, virologic breakthrough, or relapse. As part of the PROVIDE study, patients received 4 weeks of lead-in therapy with peginterferon and ribavirin if it had been more than 2 weeks since their last treatment. Patients then received boceprevir (800 mg three times daily), peginterferon (1.5 μg/kg/week), and weight-based ribavirin (600-1,400 mg/day) for up to 44 weeks. Treatment was stopped due to futility if patients had a detectable HCV RNA level at 12 weeks. The primary end-point of the analysis was undetectable HCV RNA levels 24 weeks after the end of treatment (SVR24).

The study enrolled 168 patients from the control arms of the SPRINT-1, SPRINT-2, RESPOND-2, and boceprevir/Pegasys trials; 51% of patients were partial responders, 31% were null responders (<2 log₁₀ decline in HCV RNA level at Treatment Week 12), and 15% were relapsers. The majority of patients were white (84%) and male (67%), and the mean patient age was 52 years. A high viral load (>800,000 IU/mL) was present in 77% of patients, and 61% of patients were infected with genotype la HCV. The proportion of patients with severe fibrosis (Metavir score of F3 or F4) ranged from 8% among prior relapsers to 22% among prior partial responders.

Four patients discontinued therapy during the lead-in phase; of the 164 patients who received triple therapy, 94 patients completed treatment, 53 discontinued treatment, and 17 patients were on-therapy at the time of this analysis. Reasons for discontinuation included adverse events (n=11), treatment failure (n=32), and nonmedical reasons (n=10). Thus, 138 patients were included in the interim analysis presented by Bronowicki.

After the lead-in phase, 78% of prior null responders and 24% of prior partial responders/relapsers had a less-than-1 log₁₀ decline in HCV RNA level; among these patients, SVR rates were 36% in prior null responders and 64% in prior partial responders. Among patients with at least a 1 log₁₀ decline in HCV RNA level, the overall SVR rate was 68%: 55% in prior null responders, 72% in prior partial responders, and 56% in relapsers. The overall SVR rate at the end of the follow-up period was 59% (81 of 138 patients): 40% in prior null responders, 68% in prior partial responders, and 56% in relapsers. Bronowicki noted that few relapsers were included in this analysis; while 26 relapsers were enrolled in the study, only 9 of these patients were included in the interim analysis. A multivariate analysis found that prior nonresponder status, baseline platelet levels, gender, and high viral load were independent predictive factors for SVR.

Serious adverse events were observed in 10% of patients. No life-threatening adverse events or deaths occurred during the study, but 7% of patients discontinued the study drug due to adverse events. The most common adverse event was anemia, which occurred in 48% of patients; severe anemia (hemoglobin level <8.5 g/dL) occurred in 11% of patients, with 1 patient discontinuing the study drug for this reason. Forty percent of patients were treated with erythropoietin for management of anemia, and 2% of patients required blood transfusions. Other common adverse events included fatigue (47%), dysgeusia (34%), nausea (30%), and neutropenia (22%). Bronowicki noted that this safety profile is similar to the safety profile observed in other studies of triple therapy with boceprevir, peginterferon, and ribavirin.

In conclusion, Bronowicki stated that triple therapy with boceprevir, peginterferon, and ribavirin achieved high SVR rates among patients in whom prior therapy with peginterferon and ribavirin alone had led to null response, partial response, or relapse.

Futility Rules in Telaprevir Combination Treatment

For patients treated with direct-acting antiviral drugs such as telaprevir, the application of futility rules limits the emergence or selective expansion of drug-resistant HCV variants and avoids prolonged exposure to side effects in patients who are unlikely to respond to therapy. According to the stopping rules used in phase III clinical trials of telaprevir, this drug was discontinued if a treatment-naïve patient’s HCV RNA level was greater than 1,000 IU/mL at Week 4 or if a treatment-experienced patients HCV RNA level was greater than 100 IU/mL at Week 4, 6, or 8.^1-3

In addition, all study drugs were discontinued if the patient had a less-than-2 log₁₀ decrease in HCV RNA level at Week 12 or if HCV RNA was detectable at Week 24. To ensure that these futility rules are appropriate for clinical use, an international group of investigators performed retrospective analyses of the major phase III studies of telaprevir. Ira M. Jacobson presented results of this analysis at the 2012 EASL Annual Meeting.⁴

This retrospective analysis included data from 2 phase III trials of treatment-naïve genotype 1 HCV-infected patients (ADVANCE and ILLUMINATE) and a phase III trial of prior relapsers, partial responders, and nonresponders (REALIZE).^1-3 The analysis was restricted to patients from the ADVANCE and ILLUMINATE studies who received 12 weeks of telaprevir, peginterferon, and ribavirin followed by 12 or 36 weeks of peginterferon and ribavirin and patients from the REALIZE study who received 12 weeks of telaprevir, peginterferon, and ribavirin followed by 36 weeks of peginterferon and ribavirin. On-treatment HCV RNA levels were measured at Weeks 4 and 12 for the treatment-naïve patients (ADVANCE and ILLUMINATE) and at Weeks 4, 6, 8, and 12 for treatment-experienced patients (REALIZE). HCV RNA thresholds for futility were defined as greater than 1,000 IU/mL or between 100 IU/mL and 1,000 IU/mL.

ABSTRACT SUMMARY 100% SVR in IL-28B CC Patients Treated with 12 Weeks of Telaprevir, Peginterferon, and Ribavirin in the PROVE2 Trial

In the ADVANCE trial, 90% of patients with genotype 1 HCV infection and the interleukin (IL)-28B CC genotype achieved SVR when treated with telaprevir, peginterferon, and ribavirin. To investigate SVR rates in patients with IL-28B genotype CC versus non-CC, Bronowicki and associates performed a retrospective analysis of data from the PROVE2 study; their results were presented at the 2012 EASL Annual Meeting.¹

The PROVE2 study enrolled non-cirrhotic, treatment-naïve patients who were infected with genotype 1 HCV. In this trial, patients were assigned to 1 of 4 treatment regimens: telaprevir, peginterferon α-2a, and ribavirin for 12 weeks; telaprevir, peginterferon α-2a, and ribavirin for 12 weeks followed by peginterferon α-2a and ribavirin for an additional 12 weeks; telaprevir and peginterferon α-2a for 12 weeks; or peginterferon α-2a and ribavirin for 48 weeks (control group).

Samples from treatment-naïve patients with genotype 1 HCV infection were analyzed for the presence of the IL-28B CC genotype at polymorphic site rs12979860. Of the 156 patients who consented to genetic testing, data were available for 141 patients.The mean age of the patients was 44.5 years, the mean body mass index was 23.7 kg/m², and 64% were male. Patients had a mean baseline viral load of 6.5 log₁₀ IU/mL, and 52% of patients had genotype 1 b HCV infection. In terms of IL-28B genotype, 43 patients (30%) had genotype CC, 83 patients (59%) had genotype CT, and 15 patients (11%) had genotype TT.

All of the patients with IL-28B genotype CC who received telaprevir, peginterferon, and ribavirin for 12 weeks achieved SVR (n=12). SVR was also achieved in the majority of patients with IL-28B genotype CC who received other treatment regimens: 94% (15/16) of patients who were treated with telaprevir, peginterferon, and ribavirin for 12 weeks followed by peginterferon and ribavirin for an additional 12 weeks; 75% (3/4) of patients treated with telaprevir and peginterferon for 12 weeks; and 64% (7/11) of patients in the control group. The investigators concluded that 12 weeks of treatment with telaprevir, peginterferon α-2a, and ribavirin was a successful therapy for treatment-naïve, noncirrhotic, white patients with genotype 1 HCV and IL-28B genotype CC.The CONCISE trial is currently being conducted to investigate SVR rates in IL-28B genotype CC patients treated with telaprevir, peginterferon α-2a, and ribavirin for 12 or 24 weeks.

At Week 4, a total of 25 patients had HCV RNA levels greater than 1,000 IU/mL: 1.7% (14/844) of treatment-naïve patients, 0.7% (1/138) of prior relapsers, 0% (0/46) of prior partial responders, and 14% (10/70) of prior null responders. None of these patients subsequently achieved SVR. Twenty-three of these 25 patients reached their lowest HCV RNA levels around Week 2, after which HCV RNA levels increased by Week 4. This pattern was observed in both treatment-naïve and treatment-experienced patients. At least 1 resistance variant was present in 23 of the 25 patients. Twelve treatment-naïve patients and 8 treatment-experienced patients had the V36M+R115K variant, 1 treatment-naïve patient had theA156S/T/V variant, and 2 treatment-experienced patients had the R155K variant. Jacobson underscored the fact that most patients who had an HCV RNA level above 1,000 IU/mL at Week 4 were already experiencing viral rebound and harboring viral variants.

A second subset of patients had HCV RNA levels between 100 IU/mL and 1,000 IU/mL at Week 4: 1.9% (16/844) of treatment-naïve patients, 0% (0/138) of prior relapsers, 2.2% (1/46) of prior partial responders, and 8.6% (6/70) of prior null responders. Of these 23 patients, 5 (22%) achieved SVR; 4 of these patients were treatment-naïve and 1 patient was treatment-experienced. Thus, Jacobson noted that there was a low but persistent chance for SVR in both treatment-naïve and treatment-experienced patients who had HCV RNA levels between 100 IU/mL and 1,000 IU/mL at Week 4.

At Week 12, HCV RNA levels over 1,000 IU/mL were detected in 1.5% (9/605) of treatment-naïve patients, 0.8% (1/119) of prior relapsers, 0% (0/39) of prior partial responders, and 3.9% (2/51) of prior null responders. None of these patients achieved SVR. HCV RNA levels between 100 IU/mL and 1,000 IU/mL were detected in 1.2% (7/605) of treatment-naïve patients and 12% (6/51) of prior null responders at Week 12; 2 of the 7 treatment-naïve patients achieved SVR, but none of the treatment-experienced patients achieved SVR. At Week 24, 32 (3.5%) treatment-naïve patients and 12 (17%) treatment-experienced patients had detectable HCV RNA levels; none of these patients achieved subsequent SVR.

In summary, none of the patients in this retrospective analysis achieved SVR if their HCV RNA levels were above 1,000 IU/mL at Week 4 or Week 12, but some patients with HCV RNA levels between 100 IU/mL and 1,000 IU/mL at these time points did achieve SVR. Thus, the refined futility rules for telaprevir, peginterferon, and ribavirin therapy are as follows: (1) stop all therapy if HCV RNA levels are greater than 1,000 IU/mL at Week 4 or Week 12, and (2) stop all therapy if detectable virus is present at Week 24. Jacobson added that this analysis should increase practicing clinicians’ confidence that these stopping rules are appropriate for their patients.

ABSTRACT SUMMARY Burden of Illness in Treatment-Naïxve Hepatitis C (HCV) Patients in the US

At the 2012 EASL Annual Meeting, Antoine El Khoury and colleagues presented the results of a study that examined work productivity, daily activities, healthcare resource use, economic costs, and health-related quality of life among treatment-naïve, HCV-infected patients in the United States.¹ Patient data were collected using the 2010 US National Health and Wellness Survey. The analysis was restricted to patients who reported physician-diagnosed HCV infection, no HIV/AIDS or hepatitis B co-infection, and no prior or current treatment for HCV infection (n=306). The HCV-infected group was compared to an unmatched control group (n=73,586) and to a matched control group (n=306).

The Work Productivity and Activity Impairment questionnaire was used to assess impairment in work and nonwork activities. This questionnaire revealed that activity impairment was significantly greater in untreated HCV-infected patients (42.2%) than in matched controls (27.3%;P<.001). Impairment at work was assessed among employed HCV-infected patients (n=121) and matched controls (n=141) in terms of absenteeism (the percentage of work time missed due to the patient’s health in the past 7 days), presenteeism (the percentage of impairment at work due to the patient’s health in the past 7 days), and overall work impairment (combination of absenteeism and presenteeism).There was no significant difference in absenteeism between untreated HCV-infected patients and matched controls (5.0% vs 2.8%; P=.089); however, untreated HCV-infected patients had increased rates of presenteeism (23.2% vs 13.1 %; P<.001) and overall work impairment (26.2% vs 14.9%; P<.001). A cost analysis showed that estimated average indirect costs were higher in the untreated HCV-infected group, although this difference was only significant for indirect costs related to presenteeism (P<.001).

In terms of healthcare resource utilization, untreated HCV patients had significantly more physician visits annually than matched controls (12.2 vs 8.2; P<.001), as well as more emergency room visits (0.76 vs 0.54; P=.023); however, there was no significant difference in hospitalizations (0.42 vs 0.25; P=.071). Associated direct costs were all higher among untreated HCV-infected patients. Additionally, health-related quality of life in untreated HCV-infected patients was poorer than in matched controls as shown by a lower mean Mental Component Summary score (43.7 vs 48.6; P<.001), a lower mean Physical Component Summary score (40.2 vs 44.9; P<.001), and a lower Health Utility score (0.65 vs 0.73; P<.001).

ABSTRACT SUMMARY A Randomized Trial Comparing Ribavirin Dose Reduction Versus Erythropoietin for Anemia Management in Previously Untreated Patients with Chronic Hepatitis C Receiving Boceprevir Plus Peginterferon/Ribavirin.

The addition of an HCV protease inhibitor to peginterferon and ribavirin therapy can increase the risk for anemia. Management strategies for combating anemia include ribavirin dose reduction and administration of erythropoietin. At the 2012 EASL Annual Meeting, Fred Poordad and colleagues presented the results of a study that sought to determine the efficacy, safety, and tolerability of erythropoietin administration versus ribavirin dose reduction for the treatment of anemia in patients receiving boceprevir, peginterferon, and ribavirin.¹

Treatment-naïve patients with chronic, genotype 1 HCV infection were enrolled in this study. Participants were at least 18 years of age, showed no evidence of hepatocellular carcinoma (HCC) or co-infection, and had normal baseline hemoglobin levels(12-15 g/dL for female patients; 13-15 g/dL for male patients). Patients received 4 weeks of lead-in therapy with peginterferon (1.5 µg/kg/week) and ribavirin (600-1,400 mg/day) fol lowed by boceprevir (800 mg three times daily) plus peginterferon and ribavirin for a total treatment duration of either 28 or 48 weeks.

Hemoglobin levels at or below 10 g/dL after the 4-week lead-in period occurred in 73% (500/687) of patients; these patients were randomly assigned to either a 200-400 mg/day reduction in ribavirin dose (n=249) or 40,000 lU/week erythropoietin (n=251). If hemoglobin levels dropped to 8.5 g/dL or lower, secondary intervention was allowed. If hemoglobin levels dropped to 7.5 g/dL or lower, the patient was discontinued from the study.

Comparison of the ribavirin dose-reduction arm and the erythropoietin arm revealed no differences in end-of-treatment virologic response rates (82% in both groups), relapse rates (10% in both groups), or SVR rates (71% in both groups). A multivariate logistic regression analysis that assessed race, gender, body weight, fibrosis score, and IL-28B genotype found similar SVR rates in the ribavirin dose-reduction arm and the erythropoietin arm regardless of subgroup. Statistical analyses also revealed that the probability of achieving SVR was similar for patients managed with ribavirin dose reduction and those given erythropoietin (P=.769), and SVR was not associated with the degree of hemoglobin decline among patients who developed anemia. Finally, the rates of serious adverse events and study discontinuations were similar for patients who were managed with ribavirin dose reduction and those who received erythropoietin.

Boceprevir Plus Peginterferon/Ribavirin for the Treatment of HCV/HIV Co-Infected Patients: End-of-Treatment (Week 48) Interim Results

One third of all HCV-infected patients are co-infected with HIV, but few studies have examined the safety and efficacy of protease inhibitors in this population. Thus, a double-blind, phase II trial was conducted to determine the efficacy and safety of triple therapy with boceprevir, peginterferon, and ribavirin in patients who were co-infected with genotype 1 HCV and HIV (<50 copies/mL).

After a 4-week lead-in period during which patients received peginterferon α-2b (1.5 µg/kg/week) and weight-based ribavirin (600-1,400 mg/day), patients were randomized (2:1) to receive either boceprevir (800 mg three times daily) or placebo plus peginterferon and ribavirin for an additional 44 weeks. All patients were on combination antiretroviral therapy, but zidovudine, didanosine, stavudine, efavirenz, etravirine, and nevirapine were not permitted, and patients had not received previous treatment for HCV. The primary efficacy endpoint for this study was SVR24. Josep Mallolas presented interim results of this ongoing study at the 2012 EASL Annual Meeting.¹

Most of the enrolled patients were noncirrhotic (95%), white (82%), and male (69%); patients had a median age of 43 years; 88% of patients had high baseline HCV RNA levels; and 65% of patients were infected with genotype la HCV. Overall, patients’ HIV infection was well controlled; patients had median CD4+ T-cell counts of at least 200 cells/mm³ and stable undetectable HIV viral loads.

The full 48-week treatment regimen was completed by 61 % of the patients assigned to boceprevir plus peginterferon and ribavirin (boceprevir group) and by 32% of patients treated with peginterferon and ribavirin alone (control group). Mallolas noted that the high rate of discontinuation in the control group was primarily due to virologic treatment failure (41%), whereas discontinuation in the boceprevir group was largely due to adverse events (20%).

Undetectable HCV RNA levels were observed in 42.2% of patients in the boceprevir group and 14.7% of patients in the control group by Treatment Week 8. By the end of treatment, undetectable HCV RNA levels were observed in 63.9% of patients in the boceprevir group and 29.4% of patients in the control group. At the time of this interim analysis, SVR24 had not yet been reached; however, 62.5% of the boceprevir group and 26% of the control group had achieved SVR12.

ABSTRACT SUMMARY Development and Validation of Prediction Models for Risk of Hepatocellular Carcinoma Among Hepatitis C Virus-Infected Patients

At the 2012 EASL Annual Meeting, Mei-Hsuan Lee and colleagues presented the results of a study that sought to develop and validate a tool for estimating the risk of HCC among patients infected with HCV.¹ Two cohorts of patients were used for the study: (1) a model development cohort of 975 anti-HCV seropositive patients and (2) the external validation cohort of 562 anti-HCV seropositive patients. The investigators developed 3 models for predicting the 5-year risk of HCC. Model 1 included age, alanine aminotransferase (ALT) level, the ratio of aspartate aminotransferase to ALT (AAR), and the presence of cirrhosis. Model 2 included age, ALT, AAR, cirrhosis, and serum HCV RNA level. Model 3 included age, ALT, AAR, cirrhosis, serum HCV RNA level, and HCV genotype. To estimate regression coefficients for each HCC risk factor in the model development cohort, the investigators used Cox proportional hazards models. The coefficient was then converted to a risk score that was applied to patients in the validation cohort.

There were varying total risk scores for each of the 3 models; overall, patients were at an increased risk for HCC if they had higher total risk scores. The total risk score for each patient in the validation cohort was calculated by using the scoring system; patients were then categorized as having a low, medium, or high risk for HCC. For model 1, the cumulative risks for these 3 groups were 3%, 14%, and 27%, respectively. For model 2, the cumulative risks were 5%, 13%, and 19%, respectively. For model 3, the cumulative risks were 6%, 13%, and 23%, respectively. The performance of each model was evaluated by the area under the receiver operating curve (AUROC). For all 3 models, the AUROCs in the validation cohort ranged from 0.71 to 0.75.

ABSTRACT SUMMARY High Sustained Virologic Response Rates with Response-Guided Danoprevir Plus Peginterferon α-2A (40KD) and Ribavirin in Treatment-Naïve, HCV Genotype 1 Patients: ATLAS Study Final Results

The ATLAS study was a multicenter, phase II trial that evaluated the safety, efficacy, and tolerability of response-guided treatment with danoprevir (a second-generation HCV protease inhibitor), peginterferon α-2a, and ribavirin in treatment-naïve patients with chronic, genotype 1 HCV infection. Patients were randomized to receive 1 of 3 doses of danoprevir (300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours) or placebo plus peginterferon (180 µg/week) and ribavirin (1,000-1,200 mg/day) for 12 weeks. Response-guided peginterferon and ribavirin therapy was continued for a total treatment duration of 24 weeks in those patients who achieved extended RVR (HCV RNA level <15 lU/mL); patients who did not achieve extended RVR continued therapy for a total treatment duration of 48 weeks. Due to reversible grade 4 elevations in ALT levels, treatment with 900 mg danoprevir was terminated early.

At the 2012 EASL Annual Meeting, Patrick Marcellin and coauthors presented the final efficacy and safety data from the ATLAS study.¹ During the first 24 weeks of treatment with danoprevir, peginterferon, and ribavirin, patients showed a rapid and sustained reduction in serum HCV RNA levels. Extended RVR was achieved in 65% of patients treated with 300 mg danoprevir, 79% of patients treated with 600 mg danoprevir, and 18% of patients treated with 900 mg danoprevir; 87-96% of these patients achieved SVR. Rates of SVR24 were higher in patients treated with danoprevir compared to placebo (68-85% vs 42%, respectively). The highest SVR rate (100% across all treatment arms) was achieved in patients with the IL-28B CC genotype and HCV genotype 1b (n=16). Among patients who achieved end-of-treatment virologic response, relapse occurred in 38% of patients in the placebo group compared to 18%, 8%, and 11% of patients in the 300 mg, 600 mg, and 900 mg danoprevir-treatment groups, respectively.

Viral resistance-related breakthrough or partial response occurred in 4% (8/194) of patients; all of these patients were receiving danoprevir as part of their treatment regimen. All of these patients were infected with HCV genotype 1a and harbored the R155K variant, and none of these patients showed evidence of danoprevir resistance mutations at baseline. Of the danoprevir-treated patients with undetectable HCV RNA levels at the end of treatment, viral relapse occurred in 12% (21/172); 9 of these patients harbored the R155K variant and were infected with HCV genotype 1a.

The safety profile of danoprevir plus peginterferon and ribavirin was comparable to that of peginterferon and ribavirin alone, with the exception of reversible grade 4 elevations in ALT levels (4/194 patients in the danoprevir arms). The most common adverse events were fatigue, headache, nausea, insomnia, myalgia, and chills. Nineteen patients withdrew from the study due to adverse events; these patients included 23% of the placebo group and 12% of the 900 mg danoprevir arm.

Recent findings suggest that concomitant use of boceprevir and ritonavir-boosted HIV protease inhibitor therapy may cause significant drug-drug interactions, thereby reducing the effective levels of these drugs.² In this study, HCV therapy appeared to remain effective—as shown by high rates of SVR12 (approximately 67%)—regardless of the specific HIV protease inhibitor used (primarily atazanavir, lopinavir, or darunavir). In addition, rates of HIV breakthrough were similar in the boceprevir and control groups; HIV virologic failure (defined as >50 copies/mL at 2 consecutive visits) occurred in 2 patients in the boceprevir group and in 3 patients in the control group by Treatment Week 48. One additional patient in each group showed HIV breakthrough during the first 12 weeks post-treatment. While pharmacokinetic analysis of the HIV protease inhibitors was not performed in this study, Mallolas noted that no clinically evident drug-drug interactions between boceprevir and ritonavir-boosted HIV protease inhibitors were observed.

All of the patients in the control group and 98% of patients in the boceprevir group experienced at least 1 adverse event during the study. The incidences of serious adverse events were similar in both groups (17-21%). Patients in the boceprevir group were more likely to experience decreased appetite, pyrexia, dysgeusia, vomiting, asthenia, anemia, and neutropenia. Also, more patients in the boceprevir group discontinued treatment due to adverse events (20% in the boceprevir group vs 9% in the control group). Discontinuation of treatment due to anemia was very low in each group (2—3%), but erythropoietin administration occurred more frequently in the boceprevir group.

ABSTRACT SUMMARY Low Vitamin D Serum Levels Are Associated with Liver Fibrosis and Impaired Virologic Response to Antiviral Therapy with PEG IFN+RBV in HIV/HCV Co-Infected Patients

Patients who are co-infected with HIV and HCV often exhibit low levels of 25-hydroxy vitamin D [25(OH)D], which has been associated with liver fibrosis. At the 2012 EASL Annual Meeting, Mattias Mandorfer and coworkers presented the results of a study that sought to determine whether 25(OH)D levels were associated with virologic response to peginterferon α-2a/2b plus ribavirin in HIV/HCV co-infected patients.¹

Epidemiologic data, infection parameters, and liver biopsies were analyzed from 93 patients with HIV/HCV co-infection. Patients were grouped according to their 25(OH)D levels: 16 patients (17%) had normal 25(OH)D levels (>30 ng/mL); 53 patients (57%) had 25(OH)D insufficiency (10-30 ng/mL); and 24 patients (26%) had 25(OH)D deficiency (<10 ng/mL). The proportion of patients with advanced liver fibrosis (Metavir score F3 or F4) was significantly higher in the group with 25(OH)D deficiency (63%) and the group with 25(OH)D insufficiency (40%) compared to the group with normal 25(OH)D levels (13%). Low levels of 25(OH)D were also associated with a higher rate of liver fibrosis progression; the group with normal 25(OH)D levels progressed at a rate of 0.108 U/yr compared to a rate of 0.182 U/yr for the group with 25(OH)D insufficiency and 0.191 U/yr for the group with 25(OH)D deficiency (P=.001).

Information regarding virologic response was available for 65 patients who were receiving chronic HCV therapy with peginterferon plus ribavirin. Significantly more patients in the group with normal 25(OH)D levels versus the 25(OH)D deficiency group achieved cEVR (92% vs 47%; P=.016) and SVR (85% vs 40%; P=.024). Of the patients with 3-4 risk factors for treatment failure at baseline (HCV genotype 1 or 4, high HCV RNA viral load, advanced liver fibrosis, and IL-28B rs12979860 non-C/C single nucleotide polymorphism), patients with 25(OH)D deficiency had lower SVR rates than patients with normal 25(OH)D levels (0% vs 52%; P=.012). Of the patients with 0-2 risk factors for treatment failure at baseline, SVR rates were comparable between the group with 25(OH)D deficiency and the group with normal 25(OH)D levels.

The authors concluded that low levels of 25(OH)D were associated with advanced liver fibrosis, progression of fibrosis, and impaired virologic response to peginterferon plus ribavirin therapy. Based on these data and the findings of other studies, vitamin D supplementation may improve virologic response rates and attenuate liver fibrosis in patients co-infected with HIV/HCV.

Given these interim results, Mallolas concluded that patients co-infected with HCV and HIV achieved higher rates of HCV response when treated with boceprevir-based triple therapy versus treatment with peginterferon and ribavirin alone. In addition, the preliminary safety profile of boceprevir-based triple therapy in HCV/HIV co-infected patients was comparable to the safety profile observed in HCV-monoinfected patients. Importantly, rates of viral breakthrough in HCV/ HIV co-infected patients who were treated with boceprevir were not higher than rates of viral breakthrough in the control group.

Commentary

Jean-Pierre Bronowicki

The 47th Annual Meeting of EASL was held in Barcelona, Spain in April 2012. Again this year, treatment of HCV infection was a major topic of the congress. The main highlights were the many abstracts that reported the first efficacy and safety results of combination therapy involving different direct-acting antiviral (DAA) agents with or without ribavirin and with or without peginterferon. Some results look very promising. However, these results are very preliminary and should be confirmed in a greater number of patients and in patients with more advanced liver disease. Several studies whose results may have a direct impact on current clinical practice were selected for inclusion in this supplement.

Relatively few cirrhotic patients were included in the phase III studies that assessed the efficacy and tolerance of telaprevir and boceprevir. It was shown that cirrhosis negatively impacts the probability of achieving SVR; however, no safety data on triple therapy are available in cirrhotic patients. Christophe Hézode and colleagues (abstract #8) reported the interim safety and efficacy analysis of the CUPIC study, which is a multicenter, observational French study. Patients included in CUPIC were all cirrhotic patients who failed to respond to prior treatment with peginterferon and ribavirin and who were treated with triple therapy including boceprevir or telaprevir as part of the French early access program, which was started in January 2011. A total of 455 patients who received at least 16 weeks of antiviral treatment were included in the analysis. All patients had Child-Pugh class A cirrhosis, but comparing these patients with the cirrhotic patients included in the pivotal studies (such as REALIZE and RESPOND-2) showed that the mean age was greater and the mean platelet count was lower in the CUPIC population. Moreover, 15% of patients had esophageal varices, and some had a history of liver decompensation. The major conclusion of this work is that the safety profile of DAAs among compensated cirrhotic patients was poor but compatible with their use in real-world practice. The rates of serious adverse events and discontinuations due to adverse events were higher compared to the pivotal studies. Indeed, despite widespread use of erythropoietin (56-66%), severe anemia (hemoglobin level <8 g/dL) occurred in 10% of patients, and 10—15% of patients received blood transfusions. Moreover, 8 deaths were reported, mainly due to infection. In terms of efficacy, the early virologic response looks relatively good. These results should be compared to the tolerance of dual therapy with peginterferon and ribavirin in cirrhotic patients. In a retrospective analysis of 68 treated HCV cirrhotic patients, Dultz and coauthors (abstract #1105) showed that the risk of hepatic decompensation was 83% in patients with a Model for End-Stage Liver Disease score above 13 and 59% in patients with a platelet count below 120,000. Therefore, it is important to define the subgroup of cirrhotic patients who are at risk of serious or life-threatening adverse events while on antiviral therapy. In the meantime, patients with cirrhosis should be treated cautiously and should be carefully monitored during treatment, maybe exclusively at expert centers.

The IL-28B genotype is the strongest predictor of SVR to peginterferon and ribavirin therapy. The impact of IL-28B seems to be less pronounced in the case of triple therapy. However, 80-90% of genotype 1 patients with IL-28B genotype CC who received triple therapy based on boceprevir or telaprevir achieved SVR. Moreover, 80-90% of patients were eligible for a shortened duration of therapy (24-28 weeks). The PROVE2 study was a phase II study assessing the efficacy of telaprevir in noncirrhotic, European, treatment-naïve patients infected with HCV genotype 1. In 1 arm, patients were treated with only 12 weeks of triple therapy. In this arm, the SVR rate was 60%. The aim of the study conducted by my colleagues and I (abstract #1094) was to evaluate the SVR rates in IL-28B genotype CC and non-CC French patients who received 12 weeks of telaprevir in combination with peginterferon and ribavirin. The SVR rate was 100% in the 12 genotype CC patients, 44% in the 27 genotype CT patients, and 20% in the 5 genotype TT patients. These results suggest that a very short treatment duration may be sufficient to cure IL-28B genotype CC, white, noncirrhotic, treatment-naïve patients infected with genotype 1 HCV. The same results were observed in the Austrian patients who were included in PROVE2 and also in 3 French patients treated in real-world practice (data not included in abstract). A randomized multicenter clinical trial, CONCISE, is ongoing in the United States and Europe with the aim of determining the SVR rate in IL-28B genotype CC patients who are treated with triple therapy for a total of 12 weeks compared to those treated for 24 weeks. Because of the cost of protease inhibitor therapy, some countries recommend that genotype CC, treatment-naïve patients receive only peginterferon and ribavirin without a protease inhibitor. This strategy may be reconsidered if a very short treatment duration of triple therapy may be applied to these patients, because it is probable that the overall cost (direct plus indirect costs) of this strategy may be less. At this time, this strategy should be reserved for white patients without cirrhosis who are not overweight. Therefore, it is unclear whether it can be fully applicable to the general American population.

Triple therapy including telaprevir or boceprevir significantly increases the incidence of anemia (hemoglobin level <10 g/dL). The management of anemia may have an impact on SVR rates and the overall cost of the treatment. Indeed, ribavirin dose reduction may negatively impact SVR rates, whereas the use of erythropoietin will significantly increase the cost of treatment. In this randomized controlled trial, Poordad and colleagues (abstract #1419) compared the impact of anemia management strategy on the SVR rate. More than 680 genotype 1, treatment-naïve patients were treated with boceprevir-based triple therapy. In cases of anemia (hemoglobin level <10 g/dL), patients were randomized either to erythropoietin or ribavirin dose reduction as the primary anemia management strategy. The main objective was to compare SVR rates in the 2 arms. The end-of-treatment response and SVR rates were strictly similar in the 2 arms: 82% and 71%, respectively. The efficacy of erythropoietin seems to be weak in this case. Indeed, a second anemia management strategy (erythropoietin or ribavirin dose reduction) was necessary in 38% of the patients who received erythropoietin first, compared to only 18% of patients in whom anemia was first managed by ribavirin dose reduction. In this trial, the recommendation was to reduce the dose of ribavirin by 200—400 mg/day. In a post—hoc analysis of the telaprevir phase III studies, Sulkowski and coauthors (abstract #1162) assessed the efficacy of outcomes based on ribavirin dose reduction. There was no clear negative impact of ribavirin dose reduction on SVR rates even in patients who received a daily ribavirin dose less than or equal to 600 mg. SVR rates were 71% in patients with no ribavrin dose reduction, 77% in patients in whom ribavirin was reduced to 800-1,000 mg/day, and 68% in patients in whom ribavirin was reduced to 600 mg/day or lower. However, the SVR rate seems to be slightly lower (10—15% difference) in patients in whom ribavrin dose reduction occurred within the 4 first weeks of treatment. These 2 studies strongly suggest that anemia can be managed by ribavrin dose reduction without a real negative impact on SVR. Erythropoietin should be reserved as a second-line intervention. Finally, studies presented at EASL addressed HIV/HCV co-infected patients, a group of patients who are difficult to cure. Therefore, there is an urgent need for new therapeutic strategies in this population. Mallolas and colleagues (abstract #50) reported the interim results of a randomized controlled trial in HIV/HCV co-infected treatment-naïve patients. The efficacy and tolerance of boceprevir triple therapy were assessed. Triple therapy increased rates of SVR12 (63% vs 26%). The safety profile seems comparable to that reported in monoinfected patients. HIV breakthroughs were observed in 3 of 64 patients in the boceprevir group and 4 of 34 patients in the control group. A drug interaction study showed that taking boceprevir with ritonavir in combination with atazanavir or darunavir, or with lopinavir/ritonavir, reduced the blood levels of the HIV medicines and boceprevir. The US Food and Drug Administration updated the label for boceprevir to include information about these drug interactions. Based on outcomes in clinical trials, however, some experts think these drugs can be used together safely if HIV and HCV viral loads are carefully monitored. Further studies are needed to reconcile these conflicting findings.