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CROI 2011: HCV Protease Inhibitor Boceprevir Improves Response for Treatment-Naive and Non-responders

Merck's investigational hepatitis C virus (HCV) protease inhibitor boceprevir improved sustained response rates when combined with pegylated interferon plus ribavirin in both previously untreated patients and those who were non-responders or relapsers after prior therapy, according to 2 Phase 3 studies presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) this month in Boston.

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

The first such drugs -- boceprevir and Vertex's HCV protease inhibitor telaprevir -- are expected to be approved this year. Initially, they will be used in combination with standard-of-case therapy, but all-oral regimens without interferon are currently being studied.

At CROI, researchers presented final data 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 results were previously presented at the American Association for the Study of Liver Diseases (AASLD) meeting this past fall.

SPRINT-2 and RESPOND-2 did not include people with HIV -- making these presentations unusual for CROI -- but HIV specialists recognize the need to get up to speed on hepatitis C treatment, since many HIV positive people are coinfected with HCV. As recently reported, the conference also featured the first data on telaprevir for HIV/HCV coinfected individuals.

SPRINT-2

SPRINT-2 included 1097 treatment-naive HCV genotype 1 patients (about 60% men). 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 ("non-black"). Most had high HCV viral load and nearly 10% had advanced liver fibrosis.

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. After this, they were randomly assigned to continue on pegylated interferon/ribavirin, either alone or in combination with 800 mg boceprevir 3-times-daily.

Boceprevir recipients were further allocated to receive either the triple combination for a fixed duration of 48 total weeks or response-guided therapy. In the latter arm, all participants stopped boceprevir at week 28. Those with undetectable HCV RNA during weeks 8-24 stopped all drugs, while those with continued detectable HCV viral load stayed on pegylated interferon/ribavirin through week 48.

Results

• In an intent-to-treat analysis, SVR rates were significantly higher in the boceprevir arms -- 66% with fixed-duration treatment and 63% with response-guided therapy -- compared with the standard therapy arm (38%).
• In all arms, white patients had higher response rates than blacks: 68% vs 53% in the fixed duration boceprevir arm, 67% vs 42% in the response-guided therapy arm, and 40% vs 23% in the standard therapy arm.
• The relapse rate was 9% in both boceprevir arms, compared with 22% in the standard therapy group.
• Almost all boceprevir recipients with undetectable HCV RNA during weeks 8-24 achieved SVR: 96% with fixed-duration boceprevir, 97% with response-guided therapy.
• Among boceprevir participants who had detectable HCV viral load at least once during weeks 8-24, still 74% achieved SVR in both arms.
• The most common treatment-related adverse events across arms were fatigue, headache, and nausea.
• Anemia and dysgeusia (odd taste sensations) were more common in the boceprevir groups than in the standard therapy group.
• Rates of discontinuation due to adverse events, however, were similar across arms: 16% in the standard therapy arm, 16% in the boceprevir fixed-duration arm, and 12% in the response-guided therapy arm.

Based on these findings, the researchers concluded that a regimen of boceprevir plus pegylated interferon/ribavirin "significantly increased SVR" compared with standard therapy alone, and HCV RNA at week 8 could be used to determine duration of pegylated interferon/ribavirin.

RESPOND-2

RESPOND-2 enrolled 400 treatment-experienced genotype 1 patients, both prior non-responders and relapsers (undetectable at the end of treatment followed by viral rebound). About two-thirds were men, 12% were black, and 12% had liver cirrhosis.

Again, all participants initially received pegylated interferon/ribavirin standard therapy for a 4-week lead-in period. They were then randomly assigned to continue on pegylated interferon/ribavirin either alone or in combination with 800 mg 3-times-daily boceprevir.

Boceprevir recipients were assigned to either stay on triple therapy through week 48 or use response-guided therapy. In the latter group, participants stopped boceprevir at week 36; those with undetectable HCV RNA at week 8 stopped all treatment, while those with detectable viral load continued on pegylated interferon/ribavirin through week 48.

Results

• In an intent-to-treat analysis, patients in the boceprevir arms had significantly higher SVR rates -- 67% with fixed-duration therapy and 59% with response-guided therapy -- than those in the standard therapy arm (21%).
• People with undetectable HCV RNA at week 8 had high SVR rates in all arms: 88% with fixed-duration boceprevir, 86% with response-guided boceprevir, and 100% with standard therapy.
• People taking boceprevir, however, were about 6 times more likely to have undetectable HCV RNA at week 8 (46%-52% vs 9%).
• In all arms, previous relapsers had higher SVR rates than prior non-responders: 75% vs 52% with fixed-duration boceprevir, 40% vs 69% with response-guided boceprevir, and 29% vs 7% with standard therapy.
• Here too, the most common adverse events were fatigue, headache, and nausea.
• Anemia occurred about twice as often in the boceprevir arms: 46% with fixed-duration boceprevir, 43% with response-guided boceprevir, and 20% with standard therapy.
• Serious adverse events likewise occurred about twice as often in the boceprevir arms: 14%, 10%, and 5%, respectively.

The investigators concluded that boceprevir added to pegylated interferon/ribavirin "significantly increased SVR."

They added that boceprevir could be used to treat patients with all types of interferon non-responsiveness, and that fixed-duration and response-guided therapy were "equally effective."
Investigator affiliations:

Abstract 115: John Hopkins Univ School of Medicine, Baltimore, MD; Cedars-Sinai Med Ctr, Los Angeles, CA; Gastroenterology/Hepatology/Certified Endoscopy Ctrs, Alexandria, VA; St Louis Univ School of Medicine, St Louis, MO; AO Fatebenefratelli e Oftalmico, Milan, Italy; Hannover Medical School, Hannover, Germany; Ctr for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY; Univ of Pennsylvania, Philadelphia, PA; Merck, Whitehouse Station, NJ; Ctr Hosp Univ de Nancy, Univ Henri Poincaré Nancy 1, Vandoeuvre-lès-Nancy, France.

Abstract 116: Henry Ford Hosp, Detroit, MI; St Louis Univ School of Medicine, St Louis, MO; Alamo Medical Research, San Antonio, TX; Univ Paris, Hosp Beaujon, Clichy, France; Baylor College of Medicine, Houston, TX; Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Cedars-Sinai Med Ctr, Los Angeles, CA; Merck, Whitehouse Station, NJ; Hosp Univ Vall d'Hebrón, Barcelona, Spain.

3/15/11

References

M Sulkowski, F Poordad, J McCone, et al. BOC Combined with P/R for Treatment-naive Patients with HCV Genotype-1: SPRINT-2 Final Results. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 115.

S Gordon, B Bacon, E Lawitz, et al. HCV RESPOND-2 Final Results: High Sustained Virologic Response among Genotype-1 Previous Non-responders and Relapsers to pegIFN/RBV when Re-treated with BOC + PEGINTRON/RBV
18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 116.