Administration of the 3D regimen (an oral, interferon-free combination of ritonavir-boosted ABT-450, ombitasvir and dasabuvir) with or without ribavirin achieved a sustained virologic response 12 weeks post treatment (SVR12) in 99% of patients with chronic hepatitis C (HCV) genotype-1b infection (GT1b) without cirrhosis, according to an analysis of data pooled from the PEARL-II and PEARL-III studies presented at ICAAC 2014 in Washington, D.C., by David Bernstein, M.D. of the Hofstra North Shore-LIJ School of Medicine. In fact, only one participant could be qualified as experiencing treatment failure.
The response was similar regardless of baseline characteristics sometimes associated with poor treatment responses (such as age, baseline viral load, gender, body mass index [BMI], treatment history and mental health issues). In addition, there were few serious adverse events on the regimen, even with ribavirin.
The combination of interferon and ribavirin used to be the mainstay of HCV treatment, but was poorly tolerated and only achieved sustained viral suppression in a small proportion of chronically infected patients -- and baseline host and viral factors often affected response rates. Recently, however, treatment of HCV has been dramatically improved with the development of potent new oral agents that directly attack HCV viral targets.
The 3D regimen contains three of these: ABT-450, an HCV NS3/4A protease inhibitor; ombitasvir (ABT-267) that targets NS5A (a viral protein essential for HCV replication and assembly); and dasabuvir (ABT-333), an NS5B RNA polymerase inhibitor. Ritonavir-boosted ABT-450 has been co-formulated with ombitasvir as a once-daily tablet. Dasabuvir is dosed at 250 mg orally twice a day.
To date, the 3D regimen has been studied in over 2,700 individuals and appears to be very well tolerated, with only a 2% treatment discontinuation rate, and highly effective in people with HCV genotype-1 (GT1) infections. In one study, just 12 weeks of 3D plus ribavirin achieved SVR12 in 96% of treatment-naive and -experienced HCV-GT1-infected patients without cirrhosis, while in HCV GT1-infected patients with compensated cirrhosis, 12 to 24 weeks of 3D plus ribavirin achieved SVR12 in 92% to 96% of trial participants.
PEARL II and III
The large multicenter PEARL trials were performed to assess the contribution of ribavirin, 1,000 to 1,200 mg daily according to body weight (<75 kg and ≥75kg, respectively), to 12 weeks of the 3D regimen when given to treatment-naive HCV-GT1b patients (PEARL-III) and HCV- GT1b patients with prior treatment experience on pegylated interferon/ribavirin (PEARL-II).
The study enrolled 605 adults (aged 18-70) with chronic HCV-GT1b infection, but without cirrhosis and with BMIs between 18 and 38 kg/m2. The study excluded anyone with HIV or hepatitis B coinfection or liver disease due to causes other than hepatitis C.
The analysis reported at ICAAC pooled the data from PEARL II and III, and looked at safety and SVR12 rates according to baseline parameters previously associated with poorer outcomes on interferon-ribavirin treatment. The safety analysis included all 605 patients; the efficacy analysis was performed in 598, as it excluded six patients who received a non-coformulated version of the 3D regimen, and one patient whose HCV genotype could not be confirmed.
The baseline characteristics were fairly well matched:
- An approximately equal proportion of men and women.
- More than half of the participants were from Europe, with the remainder split between participants from the U.S. and those from the rest of the world.
- More than 93% were white. (Only about 5% were black -- all from the U.S.)
- The mean age was 50. (Over 40% were above the age of 55.)
- The mean BMI was ~26 kg/m2 -- 15.3% to 20.7% (in the 3D plus ribavirin and the 3D alone arms, respectively) had BMIs above 30 kg/m2.
- 12.3% and 9.2% in the 3D plus ribavirin and the 3D alone arms, respectively, had a history of depression or bipolar disorder.
- Of the 598 patients included in the efficacy analysis (419 treatment-naive and 179 treatment-experienced), 98.7% (294/298) and 99.3% (298/300) receiving 3D plus ribavirin or 3D alone, respectively, had an SVR12.
- There was only one patient who experienced treatment failure -- a viral rebound at week 10. A subsequent genotypic analysis found a mutated virus (a Y93H variant detected in NS5A), which had not been detectable at baseline.
- Two patients had to prematurely discontinue treatment in the 3D plus ribavirin arm.
- Three patients were classified as having experienced treatment failure in the intent-to-treat analysis, because they did not come in for their 12-week post-treatment visit. However, they came in subsequently and had undetectable HCV viral loads.
- No patient has experienced a virologic relapse.
- None of the baseline characteristics of the host and virus seemed to predict non-response.
Most of the adverse events were mild or moderate. There were a couple of severe adverse events in two patients in each arm and serious adverse events were reported in each arm, only one of which, arthritis, was considered to possibly be due to treatment. Two patients discontinued treatment, but only one of these was due to adverse events that were possibly related to study drug (anxiety, tachycardia, fever and dyspnea on day 36). Nausea, pruritus, asthenia and insomnia were significantly more common on the 3D-plus-ribavirin arm, but were only reported by 10% to 14% of the participants.
No patient discontinued treatment due to laboratory abnormalities. Only a couple of patients had significantly increased liver function tests and these resolved on treatment, and a small number had hyperbilirubinemia that resolved spontaneously.
Overall, the ribavirin dose was reduced due to anemia or adverse events in 24 patients, but all experienced an SVR12.
More than 99% of the participants were HCV RNA negative at just four weeks of treatment, leading some in the audience to question whether it might even be possible to further shorten the duration of treatment.
"I think that is being looked at," said Bernstein, "but these are the data we have."
Theo Smart is an HIV activist and medical writer who joined ACT UP New York in 1988 and moved to Cape Town, South Africa, in 2000. As a writer and editor, he has more than 20 years of experience writing and editing about HIV treatment for organizations including ACT UP's Treatment & Data Committee, TAG, the PWA Health Group, GMHC, the Physician's Research Network in New York, amfAR, HIV and AIDS Treatment in Practice (HATIP) and NAM/AIDSmap. He covers human rights, the scale up and delivery of HIV and TB care and treatment services, maternal and child health and revitalizing primary health care and health systems strengthening in resource-limited settings. He also follows the development of targeted health services for people who inject drugs, sexual minorities and commercial sex workers in concentrated epidemics.