Elsevier Global Medical News
BY DENISE NAPOLI
Therapy with a novel nonnucleoside polymerase inhibitor,in combination with a protease inhibitor and ribavirin,achieved a 100% virologic response rate at 29 days among patients with hepatitis C genotype 1,Dr. Stefan Zeuzem and colleagues reported in the December issue of Gastroenterology.
Moreover, this novel alternative to the standard regimen was safe,with no serious adverse events,and was highly tolerable, the investigators said.
Dr. Zeuzem, of the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, and colleagues studied 34 adult patients (mean age 51) who were naive to interferon,peg-interferon, ribavirin,or any direct-acting antiviral for acute or chronic hepatitis C. All patients had plasma HCV RNA levels of at least 100,000 IU/mL at screening and did not have cirrhosis.
Participants were randomized to receive 400 mg t.i.d.or 600 mg t.i.d. of BI 207127,“an orally bioavailable, reversible, thumb pocket 1 nonnucleoside inhibitor of the HCV NS5B polymerase with potent and specific antiviral activity in vitro.”
All participants also received BI 201335, “a second-generation HCV NS3/4A protease inhibitor with highly potent in vitro activity against GT-1a/1b subtypes,” at a dose of 120 mg/day, as well as daily weight dosed ribavirin, for 4 weeks, the authors wrote.
The cohort taking 600-mg doses of the polymerase inhibitor BI 207127 had virologic response rates (defined as plasma HCV RNA levels of less than 25 IU/mL) of 18%, 82%, 100%,and 100% at days 8, 15, 22, and 29.
Slightly less impressive results were seen in the 400-mg group, with rates of 27%,47%, 67%, and 73% at days 8, 15,22, and 29, respectively. “Most patients in the 600-mg t.i.d. dose group even had undetectable HCV RNA at days 22 and 29 (53% and 71%, respectively), while these rates did not exceed 20% in the 400 mg t.i.d. dose group,” added the investigators.
There were no serious adverse events (AEs),or premature treatment discontinuations due to AEs within the 4-week study period. Most patients in both dosing cohorts reported mild diarrhea,nausea,and vomiting. Also, at the 600-mg dose, 42% developed mild rashes or hotosensitivities, and four patients developed transient, mild paresthesias.
The “crucial next step,” according to the investigators, will be achievement of longer-term sustained virologic response on the novel peginterferon-free regimen.
Dr. Zeuzem, along with several of his coinvestigators, disclosed financial and consulting relationships with multiple pharmaceutical companies, including the maker of the novel drugs used in this study,Boehringer Ingelheim.
Novel Interferon-Free Hep C Regimen Promising
Dr. Stuart C. Gordon, AGAF, comments:
The holy grail of hepatitis C antiviral therapy is a virologic cure using a pill
or combination of pills,with no side effects, for as brief a period of time as possible. After the development and use as monotherapy of the first NS3/4A HCV protease inhibitors,resistance mutations unfortunately emerged quickly, resulting in the need for our present triple-therapy regimens that include interferon and often still span 48 weeks. And the adverse event profiles of such therapy have worsened, not lessened.
The present study sought to determine whether HCV RNA negativity was an attainable goal after an all-oral antiviral regimen that omitted interferon injections.
Using one dose of an HCV protease inhibitor and two different doses of an HCV non-nucleoside NS5B polymerase inhibitor, together with weight-based ribavirin, the investigators found that use of the higher-dose polymerase led to 100% of patients achieving viral negativity in 30 days, representing an historical first step toward interferon-free HCV antiviral therapy.
Whether this study’s impressive 100% viral negativity at day 28 with 3 oral drugs persists beyond week 4 – or whether ribavirin can be eliminated – will not be answered by the present cohort, because all of them went on to receive standard peginterferon and ribavirin.
The clinical importance of the landmark Zeuzem study is that it helps elucidate pathways toward overcoming emergence of preexisting HCV viral variants, arguably the greatest frustration of the all-oral cocktails.
While today the addition of ribavirin to such a regimen is the safest way to obviate development of resistance, the next hurdle – and the current high-stakes gamble in clinical trials
– remains whether ribavirin can become the next dinosaur to face extinction.
The Zeuzem study helps change the present landscape because there is now greater promise of transition away from the current toxic therapies.
Several all-oral, interferon-free trials are now in progress, and if these virologic responses persist after treatment discontinuation,such studies will usher in yet a new era that will likely overwhelm the global medical system with millions of HCV infected persons,now nearing epidemic proportions.
However, considerable challenges remain unaddressed. Ribavirin-induced anemia precludes many patients from ever attempting treatment, including the renal failure population. Gastrointestinal and dermatologic side effects in the current study may be formidable. Additionally, many of the second-generation HCV protease inhibitors, including the one studied in the present report, cause a rapid hyperbilirubinemia that is probably attributable to inhibition of bilirubin transporters, a heretofore-uncommon drug-induced phenomenon.
It remains untested and potentially problematic that these high bilirubin levels will necessarily remain benign among cirrhotics.Nevertheless, with the present report, the close of 2011 has witnessed dramatic advances that bode well for the treatment of chronic hepatitis C infection.
STUART C. GORDON, M.D., AGAF, is Professor of Medicine, Wayne State University School of Medicine, and Director of Hepatology, Henry Ford Health Systems,Detroit. His relevant disclosures are research support/speaking/consulting for Merck, and research support/speaking for Vertex.
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