The largest study of new direct-acting antivirals yet
conducted in people with hepatitis C genotype 1 who have compensated cirrhosis has
shown that it is possible to cure between 92 and 96% of people with
cirrhosis, regardless of previous treatment history, within 12 to 24 weeks,
according to results of the TURQUOISE-II study presented at the 49th Annual Meeting of the European Association for the Study of the Liver (EASL) on 11 April in London.
The TURQUOISE-II study evaluated a regimen of three
direct-acting antivirals developed by AbbVie. The investigational therapy
consisted of the protease inhibitor ABT450 with ritonavir booster (150mg/100mg
once daily), the NS5A inhibitor ombitasvir (ABT-267) (250mg once daily) and the
non-nucleoside NS5B polymerase inhibitor dasabuvir (ABT-333) (250mg twice
daily), and 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 regimens are being tested in a wide range of
patient populations, and have displayed very high cure rates. People with cirrhosis have been under-represented in earlier studies, despite forming 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
is being maintained in the compensated state. Antiviral treatment that can cure
hepatitis C infection 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 grade) documented by liver biopsy or Fibroscan. Patients with ascites and with varices were permitted
to join the study. Patients with prior experience of treatment with pegylated
interferon and ribavirin were eligible to join the study, as were previously
The study enrolled 380 patients at 78 sites in Europe and
North America. Participants were randomised 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 of
hepatitis C infection.
Seventy per cent of participants were male, with a mean age of
approximately 57 years. The study population was overwhelmingly Caucasian
(93%). The study population included a high proportion of patients with
multiple predictors of poor response to hepatitis C treatment: as well as having cirrhosis, 67.3% of the 12-week arm participants and 70.3% of 24-week arm
participants had genotype 1a infection. 58.7% of participants in the 12-week arm and 57% of 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. In the 12-week
treatment group, 91.8% of participants achieved SVR12 compared to 95.9% of the 24-week treatment group
(p = 0.89). Patients with genotype 1a infection were marginally less likely to
achieve SVR12 than those with genotype 1b infection (88.6 vs 98.5% in the
12-week arm, 94.2 vs 100% in the 24-week arm).
This difference in response by sub-genotype was largely
driven by a slightly poorer rate of response in previous null responders with
genotype 1a infection. In this group of patients, 80% of the 12-week arm (40 out
of 50) achieved SVR12, compared to 92.9% of the 24-week arm (39 out of 42). In
comparison, 92.2% of the 12-week (59/64) and 92.9% of the 24-week arm
participants (52/56) 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 responses regardless
of duration of therapy (84 and 88.9% in the 12- and 24-week arms, compared to
92.9 and 96.8% respectively in 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 (88.9 vs 97%).
A total of 17 people experienced virologic failure during
or after treatment. Virologic failure during treatment was rare (1 in the
12-week arm and 3 in the 24-week arm) but the proportion of participants who
experienced viral relapse after the completion of treatment was significantly
higher in the 12-week arm (5.9% vs 0.6%). Seven of the twelve relapses in this arm
occurred in people with genotype 1a who had been null responders to previous
Treatment was well-tolerated; 1.9% of the 12-week arm and
2.3% of 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. 8.9% of patients required a ribavirin dose
reduction due to anaemia, but all patients who underwent dose reduction
Four cases of hepatic decompensation occurred during the
study but none were considered related to the study 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, Professor Fred Poordad of 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 judgement based on the individual characteristics of the patient.