A two-drug combination of direct-acting
antivirals developed by Merck achieved very high cure rates, with and without
ribavirin, in patients with genotype 1 hepatitis C infection in a small study
presented on Sunday at the 64th Meeting of the American Association
for the Study of Liver Diseases (the Liver Meeting) in Washington DC.
The study compared a combination of two
drugs with and without ribavirin in patients with genotype 1a and 1b hepatitis
C infection. Merck is slightly behind several other pharmaceutical companies in
progress towards the development of interferon-free drug combinations for
treatment of hepatitis C.
Current hepatitis C treatment is based on
the use of a direct-acting antiviral in combination with pegylated interferon
and ribavirin. Both pegylated interferon and ribavirin are poorly tolerated by
many people, especially in extended courses of treatment that may last more
than one year in some cases. Numerous pharmaceutical companies are working to
develop interferon-free regimens that can cure hepatitis C within 12 to 24
weeks.
The role of ribavirin in future treatment
is less clear.
Phase II studies of other direct-acting
antivirals have indicated that, for genotype 1a at least, ribavirin improves
the cure rate. It is less clear that ribavirin treatment will be necessary for
patients with genotype 1b infection.
Genotype 1b HCV has a higher barrier to the
development of drug resistance than genotype 1a. This raises the possibility
that patients with genotype 1b infection may be able to use two highly potent
direct-acting antivirals without ribavirin to achieve a cure with 12 weeks of
treatment, potentially reducing the risk of side-effects.
The C-WORTHY study tested a combination of
the HCV protease inhibitor MK-5172 and the NS5A inhibitor MK-8742 with or
without ribavirin for 12 weeks. The study recruited patients with less advanced
liver disease (F0 to F2 fibrosis) and no previous experience of treatment, a
population with a higher prospect of responding to treatment than patients with
cirrhosis.
The study compared three 12-week regimens:
- Arm 1: MK-5172 (100 mg once daily), MK-8742 (20 mg once daily) plus
ribavirin (600-1400 mg/d) (stratified by genotype 1a vs 1b)
- Arm 2: MK-5172 (100 mg once daily), MK-8742 (50 mg once daily) plus
ribavirin (stratified by genotype 1a vs 1b)
- Arm 3. MK-5172 (100 mg once daily) and MK-8742 (50 mg once daily)
(genotype 1b only).
All treatment was given for 12 weeks.
The study enrolled 65 patients, but seven
patients were excluded from the primary analysis because they received incorrect
doses of ribavirin (4) or because they discontinued study medication for
protocol violations or due to withdrawal of study consent. Primary results are
detailed in the table below.
Study arm
|
Regimen
|
N
|
GT1a / GT1b
|
SVR12
|
1
|
MK-5172 (100mg) + MK-8742 (20mg) + ribavirin
|
22
|
76% / 24%
|
21/21 (100%)
|
2
|
MK-5172 (100mg) + MK-8742 (50mg) + ribavirin
|
24
|
70% / 30%
|
23/24 (96%)
|
3
|
MK-5172 (100mg) + MK-8742 (50mg)
|
12
|
0% / 100%
|
11/11 (100%)
|
One case of virological relapse occurred
within four weeks of completion of treatment. Drug level testing revealed that
despite achieving an undetectable viral load at week 2 of treatment, the
patient had low drug levels, resulting in viral rebound.
Eric Lawitz of Texas Liver Institute noted
that the addition of ribavirin made little difference to the speed at which
virus levels declined after starting treatment.
Almost one-in-five patients in the
ribavirin-containing arms developed anaemia (haemoglobin < 10mg/dL) (19%) in
this 12-week study, but no trial participants either stopped treatment or
required treatment as a consequence of developing anaemia. Seven cases of rash
were observed in the ribavirin-containing arms but not all were attributable to
ribavirin, said the investigators.
Other common side-effects included fatigue
(26%), headache (22%), nausea (18%), diarrhoea (12%), dizziness (11%) and rash
(11%).
The C-WORTHY study is also testing the two
drugs, with and without ribavirin, in people with cirrhosis and people with HIV co-infection,
as well as in previous non-responders to pegylated interferon and ribavirin.
Results from these study arms will be presented at future scientific
conferences in 2014.