Gastroenterology & Hepatology Volume 8, Issue 1, Supplement 1 January 2012
A SPECIAL MEETING REVIEW EDITION
Highlights in the Treatment of Hepatitis C Virus Infection From AASLD 2011
The 62nd Annual Meeting of the American Association for the Study of Liver Diseases
November 4–8, 2011 • San Francisco, California
With commentary by
John M. Vierling, MD, FACP
Professor of Medicine and Surgery
Chief of Hepatology
Baylor College of Medicine
Houston, Texas
Special Reporting on:
• HCV RNA Quantification Cutoff Is Significant in Boceprevir-Based Treatment
• Telaprevir-Based Regimens Provide Durable Sustained Virologic Response in Patients with Genotype 1 HCV Infection
• Milk Thistle Extract Is Not Beneficial in Previously Treated
• Patients with HCV Infection
• Boceprevir-Containing Regimens Are Effective in HCV/HIV-Coinfected Patients
PLUS Meeting Abstract Summaries
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HCV RNA Quantification Cutoff Is Significant in Boceprevir-Based Treatment
The addition of the oral hepatitis C virus (HCV) NS3/4A protease inhibitor boceprevir to peginterferon and ribavirin is associated with significant improvements in sustained virologic response (SVR) rates, both in treatment-naïve patients (SPRINT-2 trial) and in previously treated patients (RESPOND-2 trial).1,2 In both of these phase III trials, patients were randomly assigned to 1 of 3 treatment arms: a response-guided treatment regimen containing boceprevir, peginterferon, and ribavirin, in which treatment duration was based on HCV RNA levels at Weeks 8–24; a fixed-duration regimen containing boceprevir, peginterferon, and ribavirin, in which the treatment duration was 48 weeks for all patients; or a regimen containing peginterferon and ribavirin.
In these studies, HCV RNA levels were measured using the TaqMan v2
assay, which has a lower limit of quantification (LOQ) of 25 IU/mL and a lower limit of detection (LOD) of 9.3 IU/mL. In real-world practice, however, assays with differing cutoffs are used. To correlate these clinical trial findings with the assay cutoffs used in clinical practice, Eric J. Lawitz and colleagues analyzed how the response cutoff used affected SVR rates and relapse rates.3 This analysis was presented at the 2011 Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
Patients were categorized into 1 of 3 groups according to on-treatment response: those with HCV RNA levels that were undetectable (below the LOD of 9.3 IU/mL), those with HCV RNA levels that were detectable but below the LOQ (9.3–25 IU/mL), and those with HCV RNA levels that were quantifiable (>25 IU/mL). In a pooled analysis of patients from both the SPRINT-2 and RESPOND-2 trials, the proportion of patients who had an HCV RNA level that was detectable but below the LOQ at Week 8 was 14.5% in the response-guided treatment arm and 17.3% in the fixed-duration boceprevir-treatment arm. Interestingly, the proportion of patients whose responses fell into this intermediate category (detectable but below the LOQ) peaked at Week 8, which is the most critical time point for response-guided therapy. At the end of the follow-up period (24 weeks post-therapy), only 1 of 571 patients (0.2%) had an HCV RNA level that was detectable but below the LOQ.
The use of different cutoffs at Week 8 also appeared to affect SVR rates. SVR rates were 84–89% among patients
with undetectable HCV RNA levels at Week 8, 63–75% in patients with HCV RNA levels that were detectable but below the LOQ at Week 8, and 13–24% in patients with detectable HCV RNA levels at Week 8. In a combined analysis of all treatment arms, SVR rates were 89% in patients with undetectable HCV RNA levels and 67% in patients with HCV RNA levels that were detectable but below the LOQ.
Lawitz also discussed how variability in the timing of the Week 8 blood draw could impact the observed HCV RNA levels, as the Week 8 sample could be collected any time between treatment Weeks 7 and 9. Although most patients submitted samples on Week 8, a minority of patients had blood collected earlier or later; therefore, changes in viral load between Weeks 7 and 9 could be relevant. Indeed, the investigators found that the proportion of patients attaining undetectable HCV RNA levels increased during this period, from 47% at Week 7 to 66% at Week 9, and the proportion of patients with quantifiable HCV RNA levels declined correspondingly, from 36% at Week 7 to 18% at Week 9. However, the proportion of patients in the intermediate group—those with detectable but not quantifiable HCV RNA levels—remained stable at 16–17% between Weeks 7 and 9.
Overall, patients with undetectable HCV RNA levels had high SVR rates (87–89%) regardless of when HCV RNA undetectability was attained. In contrast, among patients in the intermediate response category (detectable but below the LOQ), those who attained HCV RNA undetectability later in the course of therapy had lower SVR rates. In a combined analysis, 67% of patients with HCV RNA levels that were detectable but below the LOQ at Week 8 attained SVR; among patients with HCV RNA levels that were detectable but below the LOQ at Week 20, the SVR rate decreased to 19%.
Similar trends were seen for relapse rates. Relapse rates remained low (6–8%) in patients who attained undetectable HCV RNA levels, regardless of when undetectability was attained. Conversely, the relapse rate among patients whose HCV RNA level was detectable but below the LOQ increased as therapy progressed, from a 15% relapse rate among patients whose HCV RNA level was detectable but below the LOQ at Week 8, to 50% of patients whose HCV RNA level was detectable but below the LOQ at Week 20. A genotype analysis showed no difference in the frequency or impact of SVR according to genotype (1a vs 1b).
Lawitz concluded that the earlier patients attain undetectable levels of HCV RNA, the higher the chances of achieving SVR. Conversely, the later patients attain HCV RNA levels below the LOD, the higher the relapse rate. Thus, more vigilant monitoring of HCV RNA levels in patients with detectable levels of HCV RNA at Week 8 could improve SVR rates. Finally, while SVR can be evaluated using the lower LOQ, decisions regarding the duration of response-guided therapy, which are made at Week 8, should be based on the lower LOD.
References
1. Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.
2. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.
3. Lawitz E, Poordad F, Bronowicki J, et al. The effect of using lower limit of quantitation (LLQ) vs lower limit of detection (LLD) for the definition of undetectable HCV RNA: data from the RESPOND-2 and SPRINT-2 trials. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; November 4–8, 2011; San Francisco, California. Abstract 167.
ABSTRACT SUMMARY Quad Regimen Containing VX-222 and Telaprevir for Treatment-Naïve Patients with HCV Genotype 1 Infection
The ZENITH trial is an ongoing, phase II study evaluating 12-week response-guided treatment with the HCV polymerase inhibitor VX-222 plus telaprevir, in combination with peginterferon and ribavirin, in treatment-naïve patients with genotype 1 HCV infection. A total of 106 patients were originally assigned to 1 of 2 treatment regimens: VX-222 plus telaprevir; or quad therapy with VX-222, telaprevir, peginterferon, and ribavirin. The dual therapy regimens were halted early due to viral breakthrough. The trial was continued using the 4-drug combination plus a newly added 3-drug regimen consisting of telaprevir, VX-222, and ribavirin.
At the 2011 AASLD Annual Meeting, David R. Nelson presented a Week 24 interim analysis of the ZENITH trial, focusing on the 59 patients who received the 4-drug regimen: VX-222 (100 mg [n=29] or 400 mg [n=30] twice daily), telaprevir (1,125 mg twice daily), peginterferon (180 μg/week), and ribavirin (1,000–1,200 mg/day) for 12 weeks.1 In this response-guided approach, patients could stop all treatment at Week 12 if they had undetectable levels of HCV RNA at Weeks 2 and 8 (as measured using the Taqman v2 assay); patients whose HCV RNA levels were detectable at either
Week 2 or Week 8 received a total of 24 weeks of peginterferon and ribavirin.
Among patients who received VX-222 at a dose of 400 mg, 15 of 30 patients (50%) were able to stop treatment at Week 12; SVR was achieved by 14 of 15 of those patients (93%). Of the 15 patients receiving the 400-mg dose of VX-222 who were assigned to 24 weeks of treatment, 13 patients (87%) had undetectable levels of HCV RNA at 12 weeks post-treatment.
Among patients receiving the 100-mg dose of VX-222, 11 of 29 patients (38%) were able to stop treatment at Week 12; 82% of those patients (9/11) attained SVR. Of the 18 patients in the 100-mg VX-222 arm who were assigned to 24 weeks of treatment, 15 patients (83%) had undetectable levels of HCV RNA at 12 weeks post-treatment.
In an intent-to-treat analysis of all patients, undetectable HCV RNA levels at Week 24 were observed in 90% of patients assigned to the 400-mg dose of VX-222 and in 83% of patients assigned to the 100-mg dose of VX-222. Relapses occurred in 3 patients: 2 in the 100-mg VX-222 arm and 1 in the 400-mg VX-222 arm.
In terms of safety, the most frequently reported adverse events included fatigue (56%), nausea (49%), diarrhea (48%), anemia (37%), pruritus (34%), and rash (31%). Severe adverse events occurring in more than 1 patient included neutropenia (5.1%), hypomagnesemia (3.4%), and anemia (3.4%).
Reference
1. Nelson DR, Gane EJ, Jacobson IM, et al. VX-222/telaprevir in combination with peginterferon-alfa-2a and ribavirin in treatment-naïve genotype 1 HCV patients treated for 12 weeks: ZENITH study, SVR12 interim analysis. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; November 4–8, 2011; San Francisco, California. Abstract LB-14.
Telaprevir-Based Regimens Provide Durable Sustained Virologic Response in Patients with Genotype 1 HCV Infection
Recently published, phase III trials have demonstrated high SVR rates in patients with genotype 1 chronic HCV infection who were treated with regimens containing the HCV NS3/4A protease inhibitor telaprevir; this finding has been observed both in previously untreated patients and in patients who were previously treated with peginterferon-a and ribavirin.1-3 Although a high proportion of patients respond to telaprevir, HCV variants that confer a decreased sensitivity to this drug have been detected in patients who do not attain SVR with telaprevir-based regimens.
The EXTEND trial is a multinational, 3-year study of patients enrolled in phase II and phase III studies of telaprevir. This trial was designed to assess the durability of responses in patients who attained SVR, to examine changes in HCV variants over time in patients who do not attain SVR, and to examine long-term clinical outcomes. At the 2011 AASLD Annual Meeting, Kenneth E. Sherman presented the second set of interim results from this trial.4
This analysis included 408 patients, 55% of whom attained SVR. Of these 223 patients, 222 patients (>99%) maintained undetectable levels of HCV RNA over a median follow-up period of 21 months after achieving SVR. The single relapse occurred in a patient who discontinued treatment after receiving only 10 weeks of therapy; this relapse occurred 48 weeks after stopping treatment.
A resistance analysis using population-based sequence analysis was conducted in 185 patients who did not attain SVR. Overall, resistance mutations were no longer detected in 85% of patients after a median follow-up period of 29 months; this rate was 95% among patients with genotype 1b HCV infection and 77% among patients with genotype 1a HCV infection. No severe liver-related clinical events occurred during the follow-up period among patients who attained SVR. In the non-SVR population, 4 of 185 patients (2.2%) developed liver-related events, including 2 cases of hepatocellular carcinoma leading to liver transplantation, 1 case of hepatic encephalopathy, and 1 case of ascites.
Overall, these results continue to show that SVR is durable among patients treated with telaprevir-based regimens; in addition, most patients with resistant variants subsequently revert to wild-type virus. Severe clinical events occurred in a small proportion of patients who did not attain SVR.
References
1. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014-1024.
2. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
3. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
4. Sherman KE, Sulkowski MS, Zoulim F, et al. Follow-up of SVR durability and viral resistance in patients with chronic hepatitis C treated with telaprevir-based regimens: interim analysis of the EXTEND study. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; November 4–8, 2011; San Francisco, California. Abstract 248.
ABSTRACT SUMMARY Boceprevir-Based Therapy Effective in Some Prior Null Responders
The PROVIDE study is an ongoing, multicenter, single-arm rollover study evaluating the efficacy of boceprevir, peginterferon, and ribavirin in patients who previously failed to respond to peginterferon and ribavirin. The PROVIDE study enrolled 168 patients who were previously assigned to the control arm of 1 of 4 boceprevir studies: SPRINT-1, SPRINT-2, RESPOND-2, or
PEG 2a/BOC. Patients were required to have received at least 12 weeks of peginterferon and ribavirin. Failure to achieve SVR could have been due to 1 of 3 reasons: 1) futility, defined as a detectable level of HCV RNA at Week 12 in treatment-experienced patients or at Week 24 in previously untreated patients; 2) virologic breakthrough; or 3) relapse after attaining an end-of-treatment response. The PROVIDE treatment regimen consisted of boceprevir (800 mg 3 times daily), peginterferon a-2b (1.5 μg/kg weekly), and weight-based ribavirin (600–1,400 mg/day in
2 divided doses).
At the 2011 AASLD Annual Meeting, John M. Vierling and colleagues presented results of a subset analysis from the PROVIDE study in which the efficacy of boceprevir, peginterfon, and ribavirin was evaluated in 48 patients classified as prior null responders.1 A null response was defined as a reduction in HCV RNA level less than 2 log10 from baseline to Week 12 while receiving peginterferon and ribavirin treatment in the prior study. All patients in this subanalysis received 4 weeks of peginterferon and ribavirin, followed by boceprevir plus peginterferon and ribavirin for up to 44 weeks.
Of the 48 patients in the analysis, 3 patients discontinued therapy during the 4-week lead-in period, 45 patients received at least 1 dose of boceprevir, and 19 patients completed treatment. Patients’ mean age was 51 years; 65% of patients were male; 69% were white; 88% had a baseline viral load above 800,000 IU/mL; and 4% had evidence of cirrhosis. The primary study endpoint was SVR, which was defined as an undetectable HCV RNA level at 24 weeks post-therapy; SVR was attained in 16 of 42 evaluable patients (38%). End-of-treatment responses were attained in 20 of 43 patients (47%), and relapses following end-of-treatment response were detected in 3 of 19 patients (16%).
The investigators noted an association between declines in HCV RNA level after the 4-week lead-in period and the likelihood of subsequent SVR. Fifty percent of patients with a decline in HCV RNA level of at least 1 log10 at Week 4 achieved SVR, compared to an SVR rate of 34% among patients whose HCV RNA decline at Week 4 was less than 1 log10. Moreover, responses to peginterferon and ribavirin during the prior trial appeared to predict responses during the lead-in period of the PROVIDE study: 32 of the 42 patients (76%) who failed to attain a 2 log10 decline in HCV RNA levels at Week 12 in the SPRINT-2 or RESPOND-2 study also failed to attain a 1 log10 decline after the 4-week lead-in period in the PROVIDE study.
Due to the small number of patients in this analysis, the investigators were unable to evaluate baseline characteristics associated with SVR. Nonetheless, these results suggest that a treatment regimen consisting of boceprevir, peginterferon, and ribavirin can be effective in a group of well-documented prior null responders.
Reference
1. Vierling J, Flamm S, Gordon S, et al. Efficacy of boceprevir in prior null responders to peginterferon/ribavirin: the PROVIDE study. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; November 4–8, 2011; San Francisco, California. Abstract 931.
Milk Thistle Extract Is Not Beneficial in Previously Treated Patients with HCV Infection
Silymarin, an extract from the seeds of the milk thistle plant Silybum marianum, contains the major flavonolignans silybin A and silybin B and has been used for centuries as a treatment for patients with liver disorders. The compound has demonstrated anti-inflammatory, immunomodulatory, and antiviral activity in vitro.1,2 However, clinical studies of silymarin in patients with hepatitis have yielded inconclusive results.
At the 2011 AASLD Annual Meeting, Michael W. Fried presented final results of the randomized, double-blind, placebo-controlled SyNCH trial, which was designed to evaluate the efficacy and safety of silymarin as a treatment for chronic HCV infection.3 Conducted at 4 centers in the United States, this trial enrolled patients who were at least 18 years of age, had quantifiable levels of HCV RNA, and had not attained SVR following treatment with a prior interferon-based regimen. Patients also were required to have an alanine aminotransferase (ALT) level of at least
65 IU/L. Exclusion criteria included evidence of decompensated cirrhosis, moderate or severe steatosis or steatohepatitis, co-infection with HIV or hepatitis B virus, use of milk thistle within 30 days of study entry, and lactose intolerance (due to the composition of the placebo capsules).
A total of 154 patients were randomly assigned to 1 of 3 groups: silymarin at a dose of 420 mg 3 times daily, silymarin at a dose of 700 mg 3 times per day, or placebo. All treatments were given for 24 weeks. The silymarin preparation used in the study was a standardized 140-mg capsule that is approved in some countries in Europe and Asia. The doses used in this trial were 3–5-fold higher than the customary oral dose of 140 mg 3 times per day; these doses were selected based on findings from a phase I dose-escalation study.4 In this phase I study, silybin A and silybin B had low bioavailability at a dose of 140 mg 3 times daily, but these compounds exhibited nonlinear pharmacokinetics, suggesting that doses above 700 mg would improve bioavailability.
The median age of patients enrolled in the SyNCH trial was 54 years; the median ALT level was 106 IU/L; 71% of patients were male; 10–15% of patients reported a history of diabetes; and 21–35% of patients showed evidence of cirrhosis. Most patients were white, and the placebo group had a somewhat larger proportion of whites than the treatment groups. Approximately half of patients had used milk thistle prior to the study.
Overall, 138 patients completed the 24-week evaluation period, including 44 patients in the 420-mg silymarin group, 44 patients in the 700-mg silymarin group, and 50 patients in the placebo group. To meet the primary endpoint of the study, patients had to meet 1 of the following criteria: either an ALT level less than 45 IU/L; or an ALT level less than 65 IU/L, provided this was at least a 50% decline from baseline. The investigators found no significant difference between groups for this endpoint, with a total of 6 patients (2 in each of the 3 arms) achieving either of these criteria.
The SyNCH study also found no significant differences in terms of secondary endpoints, including change in serum ALT levels, change in serum HCV RNA levels, or differences in quality of life. Subset analyses also did not reveal any differences in ALT outcomes between groups; these analyses looked at the subset of patients with a complete ALT data set and the subset of patients with greater-than-80% adherence.
Adherence to the prescribed medication, which was assessed using returned dose cups, was found to be excellent; more than 90% of patients maintained greater-than-80% adherence. Silymarin was also well tolerated, with the most common adverse events being mild or moderate gastrointestinal effects. There was no significant difference in the incidence of serious adverse events, which were reported in 5–6 patients in the silymarin arms and 1 patient in the control group. One patient in the low-dose silymarin group committed suicide 12 weeks after discontinuing the drug.
A pharmacokinetic analysis yielded results similar to the results of the phase I study, with random plasma concentrations of silybin A varying from 2 ng/mL to 2,000 ng/mL. The median and highest steady-state silybin A concentrations were increased 2-fold in the higher-dose versus the lower-dose group.
Based on the results of this well-controlled study, the investigators concluded that silymarin did not appear to significantly affect biochemical or virologic outcomes in a select group of previously treated patients with chronic HCV infection.
References
1. Morishima C, Shuhart MC, Wang CC, et al. Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection. Gastroenterology. 2010;138:671-681.
2. Wagoner J, Negash A, Kane OJ, et al. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology. 2010;51:1912-1921.
3. Fried MW, Navarro VJ, Afdhal NH, et al. A randomized, placebo-controlled trial of oral silymarin (milk thistle) for chronic hepatitis C: final results of the SYNCH multicenter study. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; November 4–8, 2011; San Francisco, California. Abstract 228.
4. Hawke RL, Schrieber SJ, Soule TA, et al. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol. 2010;50:434-449.
ABSTRACT SUMMARY Concomitant Use of Boceprevir and CYP3A4/5-Interacting Drugs in Patients with Genotype 1 HCV Infection
Boceprevir is metabolized primarily by aldo-ketoreductase and, to a lesser extent, by CYP3A4/5. Boceprevir also inhibits CYP3A4/5; therefore, coadministration of boceprevir may affect levels of drugs metabolized by CYP3A4/5. In a study presented at the 2011 Annual Meeting of the AASLD, Fred Poordad and colleagues evaluated the pharmacokinetic effects of coadministering boceprevir with other drugs; this study also analyzed adverse events and SVR rates in patients receiving concomitant medications.1
This analysis included patients from 3 boceprevir studies: SPRINT-1, SPRINT-2, and RESPOND-2. A total of 1,548 patients received boceprevir, peginterferon, and ribavirin; 547 patients received peginterferon and ribavirin alone. The most commonly used concomitant medications were antidepressants (used by 42% of patients), followed by benzodiazepines (31%) and steroids (20%). Less commonly used medications included calcium channel blockers (6%) and oral contraceptives (6%). Use of methadone was reported in only 1% of patients in SPRINT-2 and RESPOND-2.
Coadministration of other drugs had no clinically concerning effect on exposure to boceprevir, as assessed by the area under the concentration-time curve (AUC). In terms of boceprevir’s effects on coadministered drugs, boceprevir did increase exposure to midazolam, which is a CYP3A4 substrate. The mean AUC(τ) ratio for the drug alone versus with boceprevir was 5.30, indicating that boceprevir is an inhibitor of CYP3A4.
Boceprevir did not affect the metabolism of drugs that are not primarily metabolized by CYP3A4. However, exposure to the contraceptive drospirenone/ethinyl estradiol was increased by boceprevir (mean AUC(τ) ratio, 1.99), although CYP3A metabolism of drospirenone is thought to be modest. There were no clinically concerning interactions between boceprevir and the HIV drugs ritonavir, efavirenz (EFV), and tenofovir.
A toxicity analysis showed that boceprevir can be safely coadministered with many commonly prescribed drugs, including antidepressants and methadone. Adverse event rates were similar in the subgroup of boceprevir-treated patients receiving antidepressants compared to the overall population. Likewise, adverse event rates did not appear to be affected by various CYP3A4/5 substrates, including statins, phosphodiesterase-5 inhibitors, benzodiazepines, calcium channel blockers, methadone, oral contraceptives, pioglitazone, or steroids.
Among patients taking boceprevir plus a CYP3A4/5 substrate and/or inhibitor, several adverse events occurred more often in patients taking specific concomitant medications. Compared to patients who were not taking concomitant medications, patients taking macrolide antibiotics were more likely to experience anemia (49% vs 68%) and gastrointestinal effects (82% vs 100%), patients taking azole antifungals were more likely to experience dysgeusia (37% vs 43%) and paresthesia (4% vs 13%), women taking oral contraceptives were more likely to experience gastroesophageal reflux disease (6% vs 12%), patients receiving statins were more likely to experience rash (17% vs 27%), and patients receiving calcium channel blockers were more likely to experience gastrointestinal effects (9% vs 15%). SVR rates were not affected by use of concomitant medications.
The investigators caution that the number of patients in each category was small, so these results should not be considered conclusive. Other drug-drug interaction studies are ongoing, including a study investigating potential interactions in HIV-infected patients receiving protease inhibitors.
Reference
1. Poordad F, Lawitz E, Gordon SC, et al. Concomitant medication use in patients with hepatitis C genotype 1 treated with boceprevir (BOC) combination therapy. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; November 4–8, 2011; San Francisco, California. Abstract 937.
ABSTRACT SUMMARY Efficacy and Safety of Boceprevir-Based Regimens in Treatment-Naïve Black Patients
Because black patients typically show lower response rates to therapy, the SPRINT-2 study enrolled and analyzed black patients separately from nonblack patients. At the 2011 AASLD Annual Meeting, Jonathan McCone, Jr., and colleagues presented data on the efficacy and safety of boceprevir-based therapy in black patients enrolled in the SPRINT-2 trial.1
Of the 159 treatment-naïve black patients who were enrolled in this study, 52 patients were assigned to receive peginterferon and ribavirin for 48 weeks; 52 patients were assigned to receive response-guided therapy with boceprevir, peginterferon, and ribavirin; and 55 patients were assigned to receive boceprevir, peginterferon, and ribavirin for 48 weeks. Patients in all treatment groups received peginterferon and ribavirin alone for 4 weeks before the addition of boceprevir or placebo.
The addition of boceprevir to peginterferon and ribavirin was associated with a significant improvement in SVR rates. Among the 154 patients without cirrhosis, SVR rates were 54% for patients treated with boceprevir plus peginterferon and ribavirin for 48 weeks, 50% for patients treated with response-guided boceprevir plus peginterferon and ribavirin, and 26% for patients treated with peginterferon and ribavirin alone. In patients without cirrhosis who had an undetectable HCV RNA level at Weeks 8–24, boceprevir-containing treatment regimens yielded SVR rates of 92–95%. Among patients without cirrhosis who were late responders—defined as having an HCV RNA level that was detectable at Week 8 but undetectable at Week 24—SVR rates were 58–86%. Due to small patient numbers, the authors were unable to draw conclusions about the efficacy of boceprevir-containing therapy in the subset of patients with cirrhosis. However, the authors recommended that these patients be given boceprevir plus peginterferon and ribavirin for 48 weeks.
In terms of adverse events, patients who received 48 weeks of boceprevir-based treatment or response-guided boceprevir-based treatment had higher rates of anemia than patients in the control group (71%, 63%, and 31%, respectively) and a higher requirement for erythropoietin (mean days of use: 148, 82, and 93 days, respectively). Dysgeusia was also more common among patients who received boceprevir-containing regimens: 40% among patients who received the 48-week boceprevir-based regimen, 29% among patients who received the response-guided boceprevir-based regimen, and 12% in the control group. Rates of neutropenia were similar across all 3 arms (31%, 35%, and 35%, respectively).
Reference
1. McCone J, Jacobson IM, Bacon BR, et al. Treatment-naive black patients treated with boceprevir combined with peginterferon alfa-2b + ribavirin. Results from HCV SPRINT-2. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; November 4–8, 2011; San Francisco, California. Abstract 981.
ABSTRACT SUMMARY Efficacy of Telaprevir-Based Regimens in HCV/HIV–Co-infected Patients
In a late-breaking abstract at the 2011 AASLD Annual Meeting, Kenneth E. Sherman and colleagues presented interim results of a phase II study evaluating telaprevir, peginterferon a-2a, and ribavirin in genotype 1 HCV treatment-naïve patients who were co-infected with HIV.1
The study was divided into 2 parts; in both parts, patients were randomly assigned to 1 of 2 antiviral treatment regimens: telaprevir (750 mg every 8 hours), peginterferon a-2a (180 μg/week), and ribavirin (800 mg/day) for 12 weeks, followed by 36 weeks of peginterferon and ribavirin; or 48 weeks of placebo plus peginterferon and ribavirin. In Part A, patients received no concurrent antiretroviral therapy (ART). In Part B, patients received their assigned antiviral therapy plus a stable, predefined ART: either an EFV-based regimen or an atazanavir/ritonavir (ATV/r)-based regimen. Patients assigned to telaprevir and an EFV-based regimen received telaprevir at a dose of 1,125 mg every 8 hours.
The investigators assessed virologic responses during therapy using the TaqMan v2 assay, which has a lower LOQ of 25 IU/mL and a LOD below 10–15 IU/mL. Of the 62 randomized patients, 60 received at least 1 dose of study medication, including 13 patients in Part A (no ART) and 47 patients in Part B (with ART). The mean age of enrolled patients was 46 years; 88% were male; 27% were black; 68% had genotype 1a HCV infection; and 3.3% had cirrhosis. HCV RNA levels at or above 800,000 IU/mL were observed in 92% of patients in Part A and 81% of patients in Part B. Mean CD4+ T-cell counts were 690 cells/mm3 for patients in Part A and 562 cells/mm3 for patients in Part B.
On-treatment virologic responses were higher among patients receiving the telaprevir-based antiviral regimen than among patients receiving peginterferon and ribavirin alone. Early virologic response, defined as an undetectable level of HCV RNA at Weeks 4 and 12, was observed in 63% of patients receiving the telaprevir-based regimen compared to 4.5% of patients receiving peginterferon and ribavirin alone. Of the 60 patients evaluable at Week 24, undetectable HCV RNA levels were observed in 74% of telaprevir-treated patients and 55% of patients who received peginterferon and ribavirin.
Two HCV breakthroughs were detected in patients receiving telaprevir-based therapy and ART, including 1 patient receiving an EFV-based regimen and 1 patient receiving an ATV/r-based regimen. No HIV viral breakthroughs were detected. The absolute number of CD4+ T cells declined while patients were on therapy, although the relative proportion of CD4+ T cells remained stable.
In regard to toxicity, the safety profile of telaprevir in this study was similar to that seen in HCV monoinfected patients. Adverse events that occurred more often (≥10% higher) in the telaprevir-treated group versus the control group were abdominal pain, vomiting, nausea, pyrexia, dizziness, depression, and pruritis. No severe rashes were noted.
Comparing the 2 ART regimens, the incidence of bilirubin adverse events was higher among patients who received the ATV/r regimen than among patients who received the EFV regimen (27% vs 0%); the incidence of indirect hyperbilirubinemia was also higher in patients who received the ATV/r regimen. Among patients who received ART and telaprevir, 3 patients discontinued at least 1 study drug due to an adverse event. The adverse events that prompted discontinuation included cholelithiasis, jaundice, and hemolytic anemia.
Finally, the ART regimen did not appear to affect the pharmacokinetics of telaprevir. The effects of telaprevir on ART pharmacokinetics were consistent with previous reports in healthy individuals.
Reference
1. Sherman KE, Rockstroh JK, Dieterich DT, et al. Telaprevir combination with peginterferon alfa-2a/ribavirin in HCV/HIV coinfected patients: 24-week treatment interim analysis. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; November 4–8, 2011; San Francisco, California. Abstract LB-8.
Boceprevir-Containing Regimens Are Effective in HCV/HIV–Co-infected Patients
At the 49th Annual Meeting of the Infectious Diseases Society of America, Mark S. Sulkowski presented results of a phase IIb trial designed to evaluate the efficacy and safety of a boceprevir-containing regimen in patients who were co-infected with HCV and HIV-1.1 Between November 2009 and December 2010, this study enrolled 100 patients with untreated genotype 1 HCV infection, HIV RNA levels less than 50 copies/mL, and stable HIV disease. Patients were excluded if they were receiving non-nucleoside reverse transcriptase inhibitors, unboosted protease inhibitors, zidovudine, or didanosine.
Patients were stratified by presence of cirrhosis and by baseline HCV RNA level (<800,000 IU/mL vs ≥800,000 IU/mL). During the 4-week lead-in period, all patients received peginterferon a-2b (1.5 μg/kg/week) and weight-based ribavirin (600–1,400 mg/day) alone. Patients were then randomly assigned to 44 weeks of treatment with peginterferon and ribavirin plus either boceprevir (800 mg 3 times daily) or placebo. Ninety-eight patients received at least 1 dose of medication: 64 patients in the boceprevir arm and 34 patients in the control arm. Patients’ median age was 43 years; 82% were white, 69% were male, 88% had high HCV RNA levels, 65% had genotype 1a HCV infection, and 5% had cirrhosis.
In an interim analysis of 93 patients who had evaluable Week 24 data, 70.5% of patients receiving boceprevir plus peginterferon and ribavirin had undetectable levels of HCV RNA (using the Taqman v2 assay, with a LOD of 9.3 IU/mL), compared to 34.4% of patients in the control group. Virologic response rates were also higher in the boceprevir-treated group at Week 8 (37.5% vs 14.7%) and Week 12 (56.5% vs 25.0%).
In terms of adverse events, boceprevir-treated patients were more likely than control patients to have pyrexia (34% vs 21%), anorexia (30% vs 18%), headache (28% vs 12%), dysgeusia (25% vs 15%), vomiting (25% vs 15%), and neutropenia (13% vs 3%). Other adverse events, including anemia, occurred at similar rates in both arms (<10% difference). Serious clinical events occurred in 8% of patients in the boceprevir-treated group and 21% of patients in the control group; dose modifications due to adverse events were required in 19% and 21%, respectively; and study discontinuations were required in 14% and 9%, respectively. The study investigators reported no differences between arms in terms of HIV-related parameters, including CD4+ T-cell count or the proportion of patients with an HIV RNA level less than 50 copies/mL.
Reference
1. Sulkowski M, Pol S, Cooper C, et al. Boceprevir plus peginterferon/ribavirin for the treatment of HCV/HIV co-infected patients: interim on-treatment results. Presented at the Annual Meeting of the Infectious Diseases Society of America; October 20–23, 2011; Boston, Massachusetts. Abstract LB-37.
ABSTRACT SUMMARY SVR Rates and Viral Resistance Profiles Following Telaprevir-Based Therapy Are Similar Across Liver Fibrosis Stage
Two randomized, double-blind, placebo-controlled, phase III trials—ADVANCE and ILLUMINATE—demonstrated the efficacy of telaprevir-based therapy in treatment-naïve patients with genotype 1 HCV infection.1,2 At the 2011 AASLD Annual Meeting, Patrick Marcellin and colleagues presented results of a pooled analysis of these 2 trials in which they evaluated whether liver fibrosis stage affects responses to telaprevir-based therapy and the development of resistant variants.3
This analysis included a total of 1,443 patients: 903 patients from the ADVANCE trial and 540 patients from the ILLUMINATE trial. Of the 1,264 evaluable patients, 903 had received telaprevir-based therapy and 361 had received peginterferon and ribavirin alone. Overall, 77% of patients had no/minimal or portal fibrosis (F0–F2) and 23% had bridging fibrosis or cirrhosis (F3–F4). Analyzed separately according to the type of treatment they received, 75% of telaprevir-treated patients had F0–F2 fibrosis, and 80% of patients receiving peginterferon and ribavirin alone had F0–F2 fibrosis. The investigators reported no differences in SVR rates according to pretreatment fibrosis stage, and the increases in SVR rates observed when telaprevir was added to peginterferon and ribavirin were comparable regardless of fibrosis stage. However, relapse and virologic failure were more likely in patients with advanced fibrosis.
The presence of resistant variants was evaluated in 223 patients who did not attain SVR. The incidence of low-level resistant variants was 40% and 43% in patients with F0–F2 and F3–F4 fibrosis, respectively; the incidence of high-level resistant variants was 35% and 41%, respectively. The median time to loss of resistant variants, which was assessed in 152 patients, was similar for patients with F0–F2 fibrosis (9 months) versus patients with F3–F4 fibrosis (10 months).
The authors concluded that, in terms of SVR rate or viral resistance profiles, pretreatment fibrosis score did not appear to affect the benefit of telaprevir-based therapy over peginterferon and ribavirin. However, patients with more advanced fibrosis were more likely to have virologic failure or relapse compared to patients with no/minimal or portal fibrosis.
References
1. Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naive patients: final results of phase 3 ADVANCE study. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; October 29–November 2, 2010; Boston, Massachusetts. Abstract 211.
2. Herman KE, Flamm SL, Afdhal NH, et al. Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: final results of phase 3 ILLUMINATE study. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; October 29–November 2, 2010; Boston, Massachusetts. Abstract LB2.
3. Marcellin P, Sullivan J, Fried MW, et al. Sustained virologic response rates and viral resistance profiles were similar in patients treated with a telaprevir-based regimen regardless of liver fibrosis stage. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; November 4–8, 2011; San Francisco, California. Abstract 2105.
ABSTRACT SUMMARY Peginterferon a-2a Comparable to Peginterferon a-2b in Boceprevir-Based Regimens
Boceprevir-based regimens have demonstrated significant efficacy in patients who failed prior treatment for HCV infection. In the RESPOND-2 trial, the addition of boceprevir to peginterferon a-2b and ribavirin was associated with an SVR rate of 59–66%, compared to an SVR rate of only 21% in patients treated with peginterferon and ribavirin alone.1
To evaluate whether the addition of boceprevir was also effective when combined with the alternative peginterferon (a-2a) in combination with ribavirin in patients with previously treated infection, Steven L. Flamm and colleagues designed a randomized, double-blind, placebo-controlled, phase III trial.2 The entry criteria for this study were identical to those of the RESPOND-2 trial: Patients must have responded to interferon for at least 12 weeks but failed to achieve SVR. Patients were stratified by historical response (nonresponse vs relapse) and by HCV genotype (1a vs 1b).
This study enrolled 201 patients who were randomly assigned to 1 of 2 treatment regimens; 134 patients received boceprevir (800 mg 3 times daily), peginterferon a-2a (180 μg weekly), and weight-based ribavirin (1,000–1,200 mg/day in a divided dose); 67 patients received peginterferon and ribavirin plus placebo. All patients received 4 weeks of peginterferon and ribavirin prior to the 44-week treatment period. Patients with detectable HCV RNA levels at Week 12 discontinued treatment due to futility.
In an earlier report presented at the 2011 Digestive Disease Week meeting, SVR rates in this study were found to be similar to those in the RESPOND-2 trial (64% with boceprevir-based triple therapy vs 21% with peginterferon and ribavirin alone); however, some adverse events were observed more frequently in the boceprevir arm of this trial.3 At the 2011 AASLD Annual Meeting, Dr. Flamm and colleagues presented a safety analysis to address this latter issue.2
Overall, boceprevir plus peginterferon a-2a and ribavirin was well tolerated, and there were no new safety findings compared with peginterferon a-2b–containing therapy. Compared with peginterferon and ribavirin alone, the boceprevir-based regimen was associated with higher rates (>10% difference between arms) of anemia (50% vs 33%), nausea (39% vs 27%), dysgeusia (39% vs 15%), neutropenia (31% vs 18%), diarrhea (25% vs 7%), and rash (23% vs 7%). Compared to treatment with peginterferon and ribavirin alone, boceprevir-based treatment was associated with a higher rate of dose modifications due to adverse events (43% vs 22%) and a higher rate of discontinuations due to adverse events (17% vs 4%).
Serious adverse events occurred in 13% of patients receiving boceprevir-based therapy compared to 10% of patients receiving peginterferon and ribavirin alone. The only serious adverse event occurring in more than 1 patient was neutropenia, which was reported in 2 boceprevir-treated patients. Grade 3/4 neutropenia, which was reported more often after Week 12, was not associated with an increased risk of infections. Overall, the findings from this trial provide evidence that boceprevir is effective and safe when administered in combination with either of the commercially available pegylated interferons.
References
1. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.
2. Flamm S, Lawitz E, Jacobson I, et al. Overall safety profile of boceprevir plus peginterferon alfa-2a/ribavirin in genotype 1 previous nonresponders and relapsers to peginterferon/ribavirin. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases; November 4–8, 2011; San Francisco, California. Abstract 1010.
3. Flamm SL, Lawitz EJ, Jacobson IM, et al. High sustained virologic response (SVR) among genotype 1 previous non-responders and relapsers to peginterferon/ribavirin when re-treated with boceprevir (BOC) plus peginterferon alfa-2A/ribavirin. Presented at Digestive Disease Week; May 7–10, 2011; Chicago, Illinois. Abstract 903.
Commentary
John M. Vierling, MD, FACP
The regulatory approval of combination therapy with the HCV-specific NS3/4A protease inhibitors boceprevir and telaprevir, in combination with peginterferon-α and ribavirin, has revolutionized therapy for patients with genotype 1 HCV infection who are either treatment-naïve or who failed prior therapy with peginterferon and ribavirin. Post–hoc analyses of the phase III registration trials of boceprevir and telaprevir continue to refine our understanding of the genetic, virologic, clinical, and histologic variables that affect SVR rates. Studies are now exploring the safety and efficacy of newer protease inhibitors; inhibitors of the NS5A and NS5B components of the polymerase replication complex; host cyclophilin inhibitors of NS5A function; dual, triple, and quadruple combinations of direct-acting antivirals (DAAs) plus peginterferon and ribavirin; and peginterferon-λ and immunomodulators. Currently, there are 10 active phase I trials, 19 phase II trials, and 4 phase III registration trials ongoing in the United States and other countries. Given this research activity, it is no surprise that HCV treatment studies were prominent at both the 49th Annual Meeting of the Infectious Diseases Society of America and the 62nd Annual Meeting of the AASLD. This Special Meeting Review highlights advances in the treatment of HCV infection by summarizing presentations from both meetings.
While combination therapy including either boceprevir or telaprevir has unequivocally increased SVR rates in patients with genotype 1 HCV infection, key questions remain about the long-term durability of SVR, the impact of SVR on liver-related events, and changes in populations of resistance-associated variants (RAVs). To address these questions, patients participating in phase II and phase III studies of telaprevir were eligible for enrollment in the EXTEND trial to observe patients for an additional 3 years. The interim results indicated that over 99% of patients who achieved SVR maintained undetectable levels of HCV RNA long term. Importantly, no liver-related events occurred. In contrast, liver-related events related to portal hypertension or hepatocellular carcinoma occurred in 2.2% of patients who did not achieve SVR. Thus, SVR was durable and appears to reduce the risk of liver-related complications. Population sequence analysis (with a lower LOD of approximately 20%) was used to assess the persistence of RAVs. Overall, 85% of RAVs were no longer detectable after a median period of 29 months. Undetectability was greater in patients with genotype 1b HCV infection (95%) versus genotype 1a HCV infection (77%). Deep sequencing analyses will be required to determine if RAVs revert to their pretreatment levels among the quasispecies. Overall, the loss of detectable RAVs after telaprevir or boceprevir therapy bodes well for re-treatment using DAAs of the same or different classes.
With the advent of DAA therapies, clinicians must interpret the results of sensitive HCV RNA polymerase chain reaction assays and use both LOQ and LOD to make on-treatment decisions about response-guided therapy. The clinical importance of LOQ and LOD was illustrated by results of a pooled analysis of the phase III trials of boceprevir-based combination therapy in treatment-naïve and treatment-experienced patients. Patients were divided into 3 groups based on HCV RNA level: undetectable (below the LOD of 9.3 IU/mL); detectable but below the LOQ (between 9.3 IU/mL and 25 IU/mL); or at or above the LOQ. SVR rates varied according to HCV RNA level at Week 8 (after 4 weeks of peginterferon and ribavirin therapy followed by 4 weeks of boceprevir-based combination therapy): 84–89% when the HCV RNA level was undetectable, 63–75% when it was detectable but below the LOQ, and 13–24% if it was at or above the LOQ. Timing of HCV RNA testing also played a role, since the proportion of patients attaining undetectable HCV RNA levels increased from Weeks 7–9, while the proportion of patients with HCV RNA levels that were detectable but below the LOQ remained constant. These results indicate that the faster a patient achieves HCV RNA undetectability, the higher the SVR rate. Thus, clinicians using DAA therapies must pay close attention to whether HCV RNA levels below the LOQ are detectable or undetectable. This is particularly true for determining a patient’s eligibility for the shorter duration of response-guided therapy.
In the era of ART, patients with HIV infection are less likely to succumb to complications of AIDS, but those who are co-infected with HCV disproportionately develop cirrhosis, liver failure, and hepatocellular carcinoma. Previous trials of peginterferon and ribavirin in HIV/HCV co-infected patients showed poor tolerability and inferior SVR rates compared to patients with HCV infection alone. Ongoing, randomized, placebo-controlled, phase IIb trials of combination therapy with boceprevir or telaprevir in patients who are co-infected with HIV and genotype 1 HCV demonstrate significant improvements in SVR rates in this difficult-to-treat population. Studies presented in this supplement provide interim results regarding the proportion of HIV/HCV co-infected patients with undetectable HCV RNA levels (LOD, 9.3–10.0 IU/mL) among patients treated with boceprevir-based combination therapy, telaprevir-based combination therapy, or peginterferon and ribavirin. HCV RNA levels were undetectable in 70.5% of co-infected patients treated with boceprevir-based therapy, compared to 34.4% of patients treated with peginterferon and ribavirin alone. The 24-week interim analysis of the telaprevir-based triple therapy trial showed that 74% of patients treated with telaprevir-based combination therapy had undetectable HCV RNA levels, compared to 55% of patients treated with peginterferon and ribavirin. It is important to note that only predefined ART regimens were allowed in each of these trials, and the designs of the boceprevir and telaprevir trials differed significantly. Data on SVR rates, tolerability, adverse events, and drug-drug interactions are eagerly awaited. Results of ongoing drug-drug interaction studies with boceprevir and telaprevir plus different ART regimens should lead to a better understanding of how ART doses can be safely adjusted to maintain control of HIV and achieve high rates of SVR.
Other difficult-to-treat patients include those with a null response to prior peginterferon and ribavirin therapy (defined as a less-than-2 log10 decline in HCV RNA level from baseline after 12 weeks of peginterferon and ribavirin therapy) and those with advanced fibrosis. Since null responders were excluded from the phase III RESPOND-2 study, which assessed boceprevir-based combination therapy in patients who had failed previous peginterferon and ribavirin therapy, the efficacy of boceprevir-based therapy in null responders is of particular interest. The PROVIDE study, which allowed patients in the control arms of 4 boceprevir trials to enroll for boceprevir-based triple therapy, provided an opportunity to assess SVR rates in prior null responders. The interim analysis of 42 evaluable null responders who had completed SVR testing showed that 16 (38%) had achieved SVR. Declines in HCV RNA levels during the 4-week peginterferon and ribavirin lead-in period predicted SVR rates: Patients with a decline greater than 1 log10 had an SVR rate of 50%, while those with a decline less than 1 log10 had an SVR rate of 34%.
The impact of advanced fibrosis on SVR rates was assessed in a pooled analysis of 2 phase III trials of telaprevir—ADVANCE and ILLUMINATE. While SVR rates were lower among patients with bridging fibrosis (F3) or cirrhosis (F4), the percent increase in SVR rates above the SVR rate in the peginterferon and ribavirin group was comparable across all fibrosis stages. However, patients with F3–F4 fibrosis were more likely to experience virologic failure or relapse. No significant differences were noted between patients with F0–F2 fibrosis versus those with F3–F4 fibrosis in terms of the frequency of RAVs or the duration of their detectability using population sequencing methods.
Coadministration of bocepreivr and drugs metabolized through CYP3A or aldo-keto reductases has the potential to alter their metabolism. Boceprevir is metabolized primarily through aldo-keto reductases and, to a lesser extent, through CYP3A4; however, boceprevir is an inhibitor of CYP3A4/5. Telaprevir is both a substrate and an inhibitor of CYP3A4. Retrospective analyses of phase II and phase III trials of boceprevir assessed the pharmacokinetic effects of boceprevir coadministration on concomitant medications and the impact of concomitant medications on rates of adverse events and SVR. Of note, both boceprevir and telaprevir increase exposure to midazolam, a CYP3A4 substrate, which has important implications for its use in moderate sedation. Coadministration of boceprevir increases the AUC of midazolam 5.3-fold, indicating a need for dose reduction. Boceprevir also increased the AUC of the oral contraceptive drospirenone/ethinyl estradiol 1.99-fold, even though drospirenone does not appear to be a CYP3A4 substrate. Importantly, no drug-drug interactions were identified between boceprevir and the HIV ART drugs ritonavir, EFV, and tenofovir. Coadministration of boceprevir with antidepressants and methadone appeared to be safe. The frequency of several adverse events was increased with specific concomitant medications: Anemia was more frequent in patients taking macrolide antibiotics, dysgeusia and paresthesias were more common in patients taking azole antifungal medications, gastroesophageal reflux disease was more prevalent in women taking oral contraceptives, rash was more common in patients receiving statins, and gastrointestinal symptoms were more likely in patients on calcium channel blockers. However, concomitant medications did not affect SVR rates. Healthcare providers should be sure to obtain detailed information about all medications, including complementary and alternative medications, before initiating therapy with either boceprevir or telaprevir. The package inserts for these drugs contain useful information regarding drug-drug interactions and dose modifications, as does the website www.hep-druginteractions.org.
Black patients have a higher prevalence of HCV infection, especially genotype 1 HCV infection, and lower rates of SVR with peginterferon and ribavirin therapy, boceprevir-based triple therapy, or telaprevir-based triple therapy. The efficacy and safety of boceprevir-based triple therapy in treatment-naïve black patients was analyzed in the phase III SPRINT-2 trial, which prespecified an enrollment of black patients exceeding that expected by chance alone. However, the study was not powered to compare SVR rates between black and nonblack patients. SVR rates with boceprevir-based therapy were significantly higher than the SVR rates achieved with peginterferon and ribavirin. In noncirrhotic patients, SVR rates of 92–95% were achieved if HCV RNA levels were below the LOD of 9.3 IU/mL at Weeks 8–24. In contrast, noncirrhotic patients who were late responders (defined as a detectable level of HCV RNA at Week 8 and an undetectable level at Week 24) had SVR rates of 58–86%. Unfortunately, the number of patients with cirrhosis was too small for meaningful analysis. No racial differences were noted for anemia or dysgeusia associated with boceprevir-based therapy.
Previous analyses of the phase II and phase III trials of boceprevir and telaprevir indicated that SVR rates in treatment-naïve patients correlate with interferon responsiveness. The safety and efficacy of boceprevir and ribavirin when combined with either peginterferon α-2a or peginterferon α-2b were investigated in a randomized, double-blind, placebo-controlled phase III trial. As also reported at Digestive Disease Week 2011, SVR rates were comparable when boceprevir and ribavirin were combined with either peginterferon α-2a or peginterferon α-2b, and no differences in adverse events or serious adverse events were noted. Thus, boceprevir is both safe and effective when used with either peginterferon.
Goals of newer antiviral therapies include an increase in SVR rates, a decrease in the duration of therapy, and possible elimination of peginterferon and/or ribavirin in order to minimize adverse events. Working toward these goals, the ongoing, phase II ZENITH study was designed to assess 12-week response-guided therapy using a combination of telaprevir and the NS5B polymerase inhibitor VX-222—with or without peginterferon and ribavirin—in treatment-naïve patients with genotype 1 HCV infection. Patients were randomized to receive dual therapy with telaprevir and VX-222 (without peginterferon and ribavirin) or quad therapy with all 4 drugs. The dual regimen was aborted due to unacceptable viral breakthrough, and the trial was continued using the quad regimen and a triple drug regimen consisting of telaprevir, VX-222, and ribavirin. The interim analysis of the Week 24 responses focused on the results of the quad therapy regimen, which allowed patients to discontinue all therapy at Week 12 if they had undetectable levels of HCV RNA (LOD, 10 IU/mL) at Weeks 2 and 8. If the level of HCV RNA was detectable at either Week 2 or Week 8, then peginterferon and ribavirin therapy was extended for an additional 12 weeks. Among patients treated with the highest dose of VX-222, 50% were eligible to stop therapy after 12 weeks and 93% achieved SVR. Of those requiring an additional 12 weeks of peginterferon and ribavirin, 87% had undetectable levels of HCV RNA 12 weeks after cessation of therapy. The most frequent adverse events were similar to those observed with telaprevir, peginterferon, and ribavirin therapy. While it is disappointing that a dual regimen consisting of a protease inhibitor and a polymerase inhibitor was ineffective, the outstanding SVR rates among patients who received the quad regimen and the study’s ability to use a response-guided approach to shorten therapy are encouraging.
Despite objective proof of the safety and efficacy of antiviral therapies, patients remain enamored by complementary and alternative therapies for chronic HCV infection. Proponents of the milk thistle plant tout evidence of the anti-inflammatory, immunoregulatory, antioxidant, and antiviral properties of its active ingredient, silymarin, as rationales for its use. It is gratifying that the final results of a randomized, double-blind, placebo-controlled trial assessing the safety and efficacy of pharmaceutical-grade silymarin for the treatment of chronic HCV infection are now available. The trial was limited to adults who had quantifiable levels of HCV RNA, had not achieved SVR with prior interferon-based therapies, and had elevated ALT levels. The results of this study were unequivocal: There were no differences between patients treated with silymarin versus placebo with respect to either the primary study endpoint (reduction in ALT level) or secondary endpoints (including changes in ALT level, HCV RNA level, and quality of life). Silymarin was well tolerated, although 1 patient committed suicide 12 weeks after taking the drug. This carefully designed, rigorously conducted study should serve as a model of future studies of complementary and alternative therapies.