An all-oral regimen of
telaprevir, VX-222 and ribavirin for 12 weeks was generally well-tolerated and
produced sustained virological response in approximately 70% of previously
untreated chronic hepatitis C patients, according to findings from the ZENITH
study presented at The Liver Meeting 2012, the 63rd Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD) last month in Boston.
recent approval of the first direct-acting antiviral drugs for hepatitis C has brought
about a new era of treatment, but many patients and providers are awaiting
all-oral regimens without interferon and its difficult side-effects.
ZENITH trial evaluated the safety, tolerability, and antiviral activity of
telaprevir (Incivo/Incivek) –
one of the HCV protease inhibitors approved last year –
plus the experimental non-nucleoside HCV polymerase inhibitor VX-222, both
developed by Vertex Pharmaceuticals.
received these two drugs either alone in a dual regimen, in combination with
ribavirin in a triple regimen or with both ribavirin and pegylated interferon
alfa-2a (Pegasys) in a quadruple
Ira Jacobson from Weill Cornell Medical College presented data
from an interim analysis of people receiving the all-oral triple regimen.
Investigators previously reported that the quadruple regimen produced sustained
virological response rates up to 90% at 12 weeks post-treatment (SVR12).
The dual regimen was less effective and led to a significant number of viral
break-throughs, and this arm was therefore discontinued early.
this analysis of the triple regimen, participants were stratified according to
HCV subtype 1a or 1b, the latter being easier to treat. They received 1125mg
twice-daily telaprevir plus 400mg twice-daily VX-222 plus ribavirin. People with
undetectable HCV RNA at weeks 2 and 8 and no viral break-through were eligible
to stop all treatment at that point; others continued on pegylated interferon
plus ribavirin alone for 24 more weeks.
analysis included 23 participants with HCV 1a and 23 patients with HCV 1b. All
were treatment-naive and did not have liver cirrhosis. About 75% of the
combined study population consisted of men, about 80% were white and the median
age was approximately 50 years. One-third had the favourable IL28B 'CC' host genotype
associated with good interferon response. Nearly 90% in both groups had high
baseline viral load (HCV RNA > 800,000 IU/mL).
four weeks of treatment, 91% of people in both the HCV 1a and 1b groups had viral
load below the level of quantification (< 25 IU/mL), but the rate of
undetectable viral load (< 15 IU/mL) was lower in the 1a group, at 57%.
After 12 weeks, however, 83% of participants in both the 1a and 1b groups had
undetectable HCV RNA.
participants (26%) in the HCV 1a group and five (22%) in the 1b group were
eligible to stop treatment at week 12. Overall SVR12 rates were 73%
for 1a patients and 70% for 1b patients.
participants eligible to stop treatment at week 12, the SVR12 rates
were 67% for patients with HCV 1a and 100% for those with 1b. Amongst those who
continued on pegylated interferon/ribavirin through week 36, SVR12
rates were 93 and 85%, respectively.
people experienced viral break-though prior to week 12; all had IL28B non-'CC' host
genotypes and were found to have resistant virus.
triple regimen was generally safe and well tolerated. No participants
experienced serious adverse events during the first 12 weeks on triple therapy
and only one person discontinued treatment due to side-effects. The most common
adverse events were diarrhoea (50%), rash (37%), nausea (30%), itching (30%)
and fatigue (24%). Although 15% of patients developed mild anaemia (hemoglobin
< 10 g/dL), none had severe anaemia (< 8.5 g/dL).
results, the researchers concluded, "support further study of the
combination of VX-222 plus telaprevir as part of an all oral, interferon-free
treatment for patients infected with HCV genotype 1".
pointed out that people with genotype 1a took longer to clear HCV RNA than
those with genotype 1b. Although overall sustained response rates were similar,
the 1b group did better on the 12-week all-oral regimen, whilst those with 1a
did better with interferon/ribavirin added. Studies are underway to test a
longer course of all-oral triple therapy, he said.
related study, Maria Rosario and colleagues from Vertex assessed whether
impaired liver function affects the pharmacokinetics and tolerability of
VX-222. They found that administration of multiple oral doses of VX-222 were
safe and well-tolerated for people with mild or moderate liver impairment.
VX-222 exposures were higher than those seen in healthy volunteers, "but
this increase would not be expected to impact virologic response", they