ABT-450/r plus ABT-072 - Two Oral Drugs Clear HCV Without Interferon

From Medscape Medical News

Two Oral Drugs Clear HCV Without Interferon

 Daniel M. Keller, PhD

May 2, 2012 (Barcelona, Spain) — Twelve weeks of treatment with a combination of 2 direct-acting antiviral drugs plus ribavirin achieved a sustained virologic response rate of more than 80% in patients chronically infected with genotype 1 hepatitis C virus (HCV), Eric Lawitz, MD, from Alamo Medical Research in San Antonio, Texas, reported here at the International Liver Congress 2012.

In a pilot study of 11 treatment-naive noncirrhotic patients, 91% achieved a sustained virologic response at 12 weeks after the end of treatment (SVR12), and 82% had a sustained virologic response at 36 weeks (SVR36).

Currently, the only approved regimens for the treatment of patients with genotype 1 HCV contain interferon. For patients who cannot tolerate interferon, there are no other options.

The 2 direct-acting antiviral drugs are ABT-450, a potent inhibitor of the HCV NS3 protease, and ABT-072 (Abbott Labs), a nonnucleoside inhibitor of HCV NS5B RNA polymerase. Both drugs are dosed orally once daily. ABT-450 is boosted with ritonavir (ABT-450/r) to maintain high ABT-450 exposure and to allow once-daily dosing.

This trial is the first to evaluate the 2 drugs plus ribavirin in an interferon-free regimen for the treatment of HCV genotype 1. The researchers enrolled only patients who were of the interleukin-28B CC genotype, which is the genotype most amenable to treatment with pegylated interferon and ribavirin, in case the trial regimen failed.

Patients were treated with ABT-450/r plus ABT-072 daily plus ribavirin for 12weeks and then followed for 48 weeks after the end of treatment. To be eligible for the study, patients had to be 18 to 65 years of age; had to have HCV genotype 1 infection for at least 6 months, no evidence of cirrhosis or bridging fibrosis, and no coinfection with hepatitis B or HIV; and had to be eligible for treatment with pegylated interferon plus ribavirin.

Baseline characteristics were similar in the the 2 groups (mean age, 56.4 years; mean weight, 79.6 kg). Mean HCV RNA level was 6.93 ± 0.22 log10 IU/mL, and all patients had HCV RNA levels above 800,000 IU/mL.

Rapid, Sustained Virologic Responses

All 11 patients achieved a rapid virologic response and an extended rapid virologic response. Sustained virologic responses at 12, 24, and 36 weeks occurred in 91%, 91%, and 82% of the cohort,respectively.

There were no virologic breakthroughs on therapy, but 2 patients relapsed after therapy ended — one at week 12 and the other at week 36.

All patients experienced adverse effects, but most were mild and included headache, nausea, fatigue, dry skin, and rash. One person had a fasting glucose level above 250 mg/dL, and 2 had indirect bilirubin elevations without concomitant transaminase elevations 1 week after treatment initiation, which resolved with continued dosing. The elevation was consistent with the known effect of ABT-450 on the OATP1B1 bilirubin transporter.

The were no study drug interruptions or discontinuations and no early trial discontinuations. There were also no deaths or serious adverse effects.

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the European Association for the Study of the Liver Governing Board Scientific Committee, told Medscape Medical News that in light of the small sample size, the 1 late relapse at 36 weeks may or may not be important.

"If these very late relapsers are just 1% or 2%, then it will be of no clinical relevance.... If it's really 1 of 11 (so close to 10%), these late relapsers will be very important," he said. "Because these are new regimens, we don't know how the responders will behave in the long term, so I think the SVR12 should be the gold standard for reporting the results of the trials. [In addition], all trials should still have at least 1 HCV RNA follow-up...1 year after these SVR12 determinations."

Dr. Lawitz reports financial relationships with Abbott, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer  Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, sanofi-aventis, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, and ZymoGenetics. Dr. Papatheodoridis has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 13. Presented April 19, 2012.