- Category: Experimental HCV Drugs
- Published on Monday, 14 April 2014 00:00
- Written by Keith Alcorn
The largest study of new direct-acting antivirals yet conducted for genotype 1 hepatitis C patients with compensated cirrhosis has shown that it is possible to cure between 92% and 96%, regardless of previous treatment history, within 12 to 24 weeks using AbbVie's 3D triple regimen plus ribavirin, according to results of the TURQUOISE-II study presented at the 49th EASL International Liver Congress last week in London.
The investigational therapy evaluated in the TURQUOISE-II study consisted of the protease inhibitor ABT-450 with ritonavir booster (150 /100 mg once-daily), the NS5A inhibitor ombitasvir (ABT-267) (250 mg once-daily), and the non-nucleoside NS5B polymerase inhibitor dasabuvir (ABT-333) (250 mg twice-daily), plus ribavirin.
This regimen was also evaluated in treatment-experienced patients with genotype 1 infection. The results of that study, SAPPHIRE II, were reported on the opening day of the congress.
Historically, people with hepatitis C whose liver disease has progressed to cirrhosis have responded less well to interferon-based regimens. New interferon-free DAA regimens are being tested in a wide range of patient populations, and have displayed very high cure rates.
Cirrhotic patients have been under-represented in earlier studies, despite being one of the highest-priority populations for hepatitis C treatment. People with compensated cirrhosis are at high risk of progression to decompensated liver disease and require a high level of medical management even when liver function remains compensated. Antiviral treatment that can cure hepatitis C may halt further liver damage and permit some regression in liver disease, improving life expectancy for this patient group.
TURQUOISE-II recruited patients with compensated cirrhosis (Child Pugh A) documented by liver biopsy orFibroscan. Patients with ascites (abdominal fluid accumulation) and with varices (varicose veins in the esophagus or stomach) were permitted to join the study. People with prior treatment experience using pegylated interferon and ribavirin were also eligible to join, as were previously untreated patients.
The study enrolled 380 participants at 78 sites in Europe and North America. Participants were randomized to receive 12 or 24 weeks of treatment. The primary endpoint of the study was sustained virological response 12 weeks after the conclusion of treatment (SVR 12), considered to be a cure for hepatitis C infection.
70% of participants were male, with a mean age of approximately 57 years. The study population was overwhelmingly Caucasian (93%). The population included a high proportion of patients with multiple predictors of poor response to hepatitis C treatment. As well as being cirrhotic, 67% of participants in the 12-week arm and 70% in the 24-week arm had HCV genotype 1a infection. 59% in the 12-week arm and 57% in the 24-week arm were treatment-experienced, predominantly previous null responders (36% of all study participants).
The primary analysis showed no significant difference in treatment outcome according to the length of treatment. 92% of participants in the 12-week treatment group achieved SVR12 compared to 96% of the 24-week group.
Patients with genotype 1a were marginally less likely to achieve SVR12 than those with genotype 1b (87% vs 99% in the 12-week arm, 94% vs 100% in the 24-week arm). This difference in response by HCV subtype was largely driven by a slightly poorer rate of response in previous null responders with genotype 1a. In this group, 80% in the 12-week arm (40 out of 50) achieved SVR12, compared to 93% in the 24-week arm (39 out of 42). In comparison, 92% of participants in the 12-week (59 out of 64) and 93% in the 24-week arm (52 out of 56) who were previously untreated achieved SVR12.
Analysis by indicators of severity of liver disease (portal hypertension and hepatic function) showed that patients with lower baseline serum albumin (<35 g/L) tended to have slightly poorer response regardless of duration of therapy (84% and 89% in the 12- and 24-week arms, compared to 93% and 97%, respectively, among those with serum albumin >35 g/L). Responses were also somewhat poorer in those with baseline platelet counts <100 who received treatment for 12 weeks compared to the 24-week group (89% vs 97%).
A total of 17 participants experienced virological failure during or after treatment. Virological breakthrough during treatment was rare (1 in the 12-week arm and 3 in the 24-week arm), but the proportion of patients who experienced viral relapse after the completion of treatment was significantly higher in the 12-week arm compared with the 24-week arm (5.9% vs 0.6%). Of the 12 relapses in this arm, 7 occurred in patients with genotype 1a who had been null responders to previous treatment.
Treatment was well tolerated. 1.9% of patients in the 12-week arm and 2.3% in the 24-week arm discontinued treatment due to a serious adverse event; the nature of these events was unspecified. The most common adverse events were fatigue, headache, and nausea. While 8.9% of patients required ribavirin dose reduction due to anemia, all patients who underwent dose reduction achieved SVR12.
A total of 4 cases of hepatic decompensation occurred during the study but none were considered related to treatment. Transient increases in ALT and bilirubin were observed more frequently in the 12-week arm, but in all cases these elevations were transient and did not result in treatment discontinuation.
Presenting the results, Fred Poordad from the Texas Liver Institute at the University of Texas concluded that there was no statistical difference in cure rates between patients treated for 12 or 24 weeks, and that the duration of treatment required was likely to be a matter of clinical judgment based on the individual characteristics of a patient.
F Poordad, C Hezode, R Trinh, et al. TURQUOISE-II: SVR12 rates of 92%-96% in 380 hepatitis C virus genotype 1-infected adults with compensated cirrhosis treated with ABT-450/r/ABT-267 and ABT-333 plus ribavirin (3D+RBV). 49th European Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O163.
AbbVie. AbbVie to Present Late-Breaking Results from TURQUOISE-II Study in Chronic Hepatitis C Patients with Cirrhosis at the 2014 International Liver Congress. Press release. April 12, 2014.
AbbVie. AbbVie to Present Detailed Results from Phase III Studies in Patients with Chronic Hepatitis C at the 2014 International Liver Congress. Press release. March 24, 2014.
European Association for the Study of the Liver. New Interferon-Free, All-Oral 3D Treatment Regimen Achieves High Rates of Virological Response in Patients Chronically Infected with HCV Genotype 1. Press release. April 12, 2014.