Boceprevir Improves Response to Interferon-Based HCV Therapy

The HCV protease inhibitor boceprevir improved sustained response rates when combined with pegylated interferon plus ribavirin in both previously untreated patients and prior non-responders, according to findings from 2 studies published in the March 31 New England Journal of Medicine.

The advent of direct-acting antiviral agents that interfere with various steps of the hepatitis C virus (HCV) lifecycle will usher in a new era of treatment. The current standard of care, pegylated interferon plus ribavirin, leads to sustained virological response (SVR) less than half the time for hard-to-treat HCV genotype 1.

The first of these drugs -- 2 HCV protease inhibitors currently undergoing review by the U.S. Food and Drug Administration (FDA) -- are Merck's boceprevir (recently given the brand name Victrelis) and Vertex's telaprevir. Initially they will be used in combination with standard therapy, making it both more effective and potentially shorter.

This week's New England Journal of Medicine featured reports from 2 pivotal Phase 3 studies of telaprevir: SPRINT-2, which enrolled previously untreated patients, and RESPOND-2, which enrolled prior non-responders and relapsers. These findings were previously presented at the American Association for the Study of Liver Diseases (AASLD) meeting last fall. [Telaprevir findings from the treatment-naive ADVANCE and treatment-experienced REALIZE trials appeared in the June, 23, 2011 issue of the same journal.)

SPRINT-2

SPRINT-2 included 1097 treatment-naive genotype 1 patients. Participants were divided into cohorts according to race, as people of African descent do not respond as well to interferon-based therapy. One cohort included 159 black patients, while the other included 938 people of other racial/ethnic groups (dubbed "non-black").

All participants started a regimen of 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) plus 600-1400 mg/day weight-adjusted ribavirin for a 4-week lead-in period. They were randomly allocated to subsequently either continue on pegylated interferon/ribavirin plus placebo for 44 more weeks (control group) or to add 800 mg 3-times-daily boceprevir.

Boceprevir recipients were further randomized to receive the triple combination either for a fixed duration of 44 more weeks or using response-guided therapy. In the latter group participants with undetectable HCV viral load between weeks 8 and 24 stopped boceprevir early. People who still had detectable viral load at week 24 discontinued all therapy due to likely futility of continued treatment.

Results

• SVR rates 24 weeks after completion of treatment were significantly higher in the boceprevir arms than in the standard therapy control group.
• In an intent-to-treat analysis, 68% of non-black patients receiving fixed-duration triple therapy and 67% receiving response-guided therapy achieved SVR, compared with 40% in the control group.
• Among black patients the corresponding SVR rates were 53%, 42%, and 23%, respectively.
• Relapse rates in both fixed duration and response-guided boceprevir arms were significantly lower than in the standard-therapy control group.
• Almost all boceprevir recipients with undetectable HCV RNA during weeks 8 through 24 went on to achieve SVR.
• The most common treatment-related adverse events across arms were fatigue, headache, and nausea.
• Anemia and dysgeusia (odd taste sensations) were significantly more common among boceprevir recipients.
• Overall rates of discontinuation due to adverse events were similar across treatment arms.
• More people in the boceprevir arms, however, discontinued therapy (2% vs 1% in the control group), reduced drug doses (21% vs 13%), or used erythropoietin (43% vs 24%) due to anemia.

Based on these findings, the study authors concluded, "The addition of boceprevir to standard therapy with peginterferon/ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection."

SVR rates were similar with 24 weeks or 44 weeks of boceprevir, they added.

"Among non-black patients, the combination therapy with boceprevir was associated with a relative increase of approximately 70% in the rates of sustained virologic response over standard therapy," they elaborated in their discussion. "Although lower among black patients than among non-black patients, the rates of sustained virologic response with the boceprevir regimens were nearly double those with the standard of care."

RESPOND-2

RESPOND-2 included 403 treatment-experienced genotype 1 patients, both prior non-responders and relapsers; about 12% were black.

Again, all participants initially received pegylated interferon/ribavirin for a 4-week lead-in period. They were randomly assigned to subsequently continue on pegylated interferon/ribavirin plus placebo for 44 more weeks or to add 800 mg 3-times-daily boceprevir.

Boceprevir recipients either stayed on triple therapy for 44 more weeks or used response-guided therapy. The latter group stopped boceprevir at week 36; those who had detectable HCV RNA at week 8 continued on pegylated interferon/ribavirin through week 48.

Results

• In an intent-to-treat analysis, patients in the boceprevir arms again had significantly higher SVR rates -- 66% with fixed-duration therapy and 59% with response-guided therapy -- than those in the standard therapy control group (21%).
• Among people with undetectable HCV RNA at week 8, SVR rates were 86% after 32 weeks and 88% after 44 weeks of triple therapy.
• Among participants who had less than a 1 log IU/mL decrease in HCV RNA at week 4, one-third of boceprevir recipients still achieved SVR, compared with none in the control group.
• Here too, the most common adverse events were fatigue, headache, and nausea.
• Anemia again occurred about twice as often in the boceprevir arms than in the control group.

"The addition of boceprevir to peginterferon/ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon/ribavirin alone," the investigators concluded, noting that fixed-duration and response-guided therapy were similarly effective.

Patients who previously relapsed after receiving standard therapy had SVR rates of up to 75% on boceprevir triple therapy, while previous non-responders had sustained response rates of 40% to 52%, they added in their discussion.

In summary, they wrote, the results of this trial "show that boceprevir, when added to peginterferon alfa-2b and ribavirin, leads to high rates of sustained virologic response in difficult-to-treat patients."

Editorial

In an accompanying editorial, Donald Jensen from the University of Chicago Medical Center wrote that, "A new era of therapy for hepatitis C virus (HCV) infection is dawning with the development of 2 effective HCV protease inhibitors, boceprevir and telaprevir."

While HCV protease inhibitors represent a "major advance in our ability to treat chronic HCV infection," he continued. "Future therapy will be more complex, not easier, but the improvement in the rate of sustained virologic response with boceprevir, to nearly 70% in the SPRINT-2 trial and to more than twice the rate in previously treated patients in HCV RESPOND-2, have been eagerly awaited."

Investigator affiliations:

SPRINT-2: Cedars-Sinai Med Ctr, Los Angeles, CA; Gastroenterology-Hepatology-Certified Endoscopy Ctrs, Alexandria, VA; St Louis Univ School of Medicine, St Louis, MO; Azienda Ospedaliera Fatebenefratelli e Oftalmico, Milan, Italy; Hannover Medical School, Hannover, Hannover, Germany; John Hopkins Univ School of Medicine, Baltimore, MD; Ctr for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY; Univ of Pennsylvania, Philadelphia, PA; Inova Fairfax Hospital and the Betty and Guy Beatty Center for Integrated Research, Falls Church, VA; Merck, Whitehouse Station, NJ; Ctr Hosp Univ de Nancy, Univ Henri Poincaré Nancy 1, Vandoeuvre-lès-Nancy, France. RESPOND-2: St Louis Univ School of Medicine, St Louis, MO; Henry Ford Hosp, Detroit, MI; Alamo Medical Research, San Antonio, TX; Univ Paris-Diderot, Hosp Beaujon, Clichy, France; Baylor College of Medicine, Houston, TX; Department of Medicine, J.W. Goethe University Hospital, Frankfurt, Germany; Cedars-Sinai Medical Ctr, Los Angeles, CA; Inova Fairfax Hospital and the Betty and Guy Beatty Center for Integrated Research, Falls Church, VA; Merck, Sharp & Dohme, Whitehouse Station, NJ; Hospital General Universitario Vall d'Hebron and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas del Instituto Carlos III, Barcelona, Spain.

Both SPRINT-2 and RESPOND-2 were funded by Schering-Plough, now part of Merck.

4/1/11

References

F Poordad, J McCone, BR Bacon, et al. (SPRINT-2 Investigators). Boceprevir for Untreated Chronic HCV Genotype 1 Infection. New England Journal of Medicine 364: 1195-1206 (abstract). March 31, 2011.

BR Bacon, SC Gordon, E Lawitz, et al. Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection (HCV RESPOND-2 Investigators). New England Journal of Medicine 364: 1207-1217 (abstract). March 31, 2011.

DM Jensen. A New Era of Hepatitis C Therapy Begins (editorial). New England Journal of Medicine 364: 1272-1274. March 31, 2011.