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Boceprevir Improves SVR With PegIFN/RBV After Failure or Relapse With HCV-1
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
Adding the HCV-NS3 protease inhibitor boceprevir to pegylated interferon plus ribavirin (PegIFN/RBV) significantly improved sustained virologic response (SVR) rates in HCV genotype 1-infected people with a history of nonresponse or relapse with PegIFN/RBV [1]. SVR rates were higher among relapsers than nonresponders, though 40% to 50% of nonresponders attained SVR with boceprevir plus PegIFN/RBV.
Among the six major genotypes of hepatitis C virus, genotype 1 responds most poorly to PegIFN/RBV, with about half of patients achieving SVR (undetectable HCV RNA 24 weeks after treatment ends). RESPOND-2 aimed to track SVR rates in people who added boceprevir to PegIFN/RBV after nonresponse to PegIFN/RBV (defined as at least a 100-fold drop in HCV RNA by week 12 but detectable HCV RNA throughout therapy) or relapse after response to PegIFN/RBV.
This double-blind, placebo-controlled trial randomized HCV genotype 1-infected participants to one of three arm:
Four weeks of PegIFN/RBV then:
Arm 1 (n = 80): PegIFN/RBV plus placebo through week 48
Arm 2 (n = 162): PegIFN plus boceprevir through week 36, then continued PegIFN/RBV in people with detectable HCV RNA at week 8, or follow-up without further therapy if undetectable at week 8; called response-guided treatment
Arm 3 (n = 161): PegIFN plus boceprevir through week 48
Anyone with detectable HCV RNA at week 12 discontinued treatment.
Study participants from the United States, Canada, and Europe averaged 53 years of age in the three treatment arms. About 70% were men and 12% black. About half had HCV genotype 1a and half 1b. Proportions with a pretreatment HCV load above 800,000 IU/mL were 81% in arm 1, 91% in arm 2, and 88% in arm 3. Proportions with a METAVIR F3/F4 score were 19% in the three arms. About one third of enrollees in each arm were nonresponders and about two thirds were relapsers.
SVR rates were significantly greater in either boceprevir arm than in the placebo arm:
Arm 1: SVR 21%, relapse 32%
Arm 2: SVR 59% (P < 0.0001 versus arm 1), relapse 15%
Arm 3: SVR 66% (P < 0.0001 versus arm 1), relapse 12%
SVR rates did not differ significantly between the two boceprevir arms (odds ratio 1.4, 95% confidence interval 0.9 to 2.2). In arm 2, 46% of participants were eligible for briefer therapy.
Among people with undetectable HCV RNA at week 8, 7 of 7 in arm 1, 64 of 74 (86%) in arm 2, and 74 of 84 (88%) in arm 3 achieved SVR. SVR rates were substantially higher among relapsers than previous nonresponders in all three treatment arms: 29% versus 7% in arm 1, 69% versus 40% in arm 2, and 75% versus 52% in arm 3. People with less than a 10-fold decline in HCV RNA after 4 weeks of PegIFN/RBV had lower SVR rates in all three arms: 0 versus 25% in arm 1, 33% versus 73% in arm 2, and 34% versus 79% in arm 3.
A multivariate model to determine independent predictors of SVR considered gender, age, treatment arm, prior response, statin use before treatment, region, and baseline HCV RNA, cirrhosis, weight, body mass index, platelets, steatosis, and alanine aminotransferase. Five predictors of SVR emerged at the following odds ratios (OR) (and 95% confidence intervals):
-- Arm 3 versus arm 1: OR 10.7 (5.3 to 21.6), P < 0.001
-- Arm 2 versus arm 1: OR 7.3 (3.6 to 14.5), P < 0.001
-- Prior relapse versus nonresponse: OR 3.1 (1.9 to 4.9), P < 0.001
-- Baseline HCV RNA below 800,000 versus higher: OR 2.4 (1.2 to 5.3), P = 0.02
-- No cirrhosis: OR 2.1 (1.1 to 4.2), P = 0.03
Median treatment duration was 104 days in arm 1, 252 days in arm 2, and 336 days in arm 3. Respective rates of serious adverse events and dropouts for adverse events were 5%, 10%, and 14%, and 3%, 8% and 12%. Dose modification rates were 14% in arm 1, 29% in arm 2, and 33% in arm 3. Two side effects occurred much less often in arm 1 than in arm 2 or 3: anemia (20% in arm 1, 43% in arm 2, and 46% in arm 3) and dysgeusia (abnormal taste) (11% in arm 1, 43% in arm 2, and 45% in arm 3).
The RESPONSE-2 team concluded that boceprevir "can be used to treat patients with all categories of interferon responsiveness." They noted that response-guided boceprevir therapy (arm 2) was as effective as continuous therapy (arm 3) for these patients. The 4-week PegIFN/RBV lead-in allowed for real-time assessment of interferon responsiveness, which predicted SVR.
Also at this conference, SPRINT-2 investigators reported that adding boceprevir to PegIFN/RBV significantly improved SVR rates compared with PegIFN/RBV alone in previously untreated people HCV genotype 1 [2]. NATAP reviews SPRINT-2 separately.
References
1. Gordon S, Bacon B, Lawit E, 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. February 27-March 2, 2011. Boston. Abstract 116.
2. Sulkowski M, Poordad F, McCone J, 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. February 27-March 2, 2011. Boston. Abstract 115.
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