—Alan Franciscus, Editor-in-Chief
The Conference on Retroviruses and Opportunistic
Infections (CROI) was recently held in Boston, MA. This year there were
quite a few presentations about hepatitis C (HCV) and HIV/HCV
coinfection. In this month’s HCV Advocate newsletter I will discuss data on HCV inhibitor therapy (direct-acting antivirals (DAAs)) to treat HCV.
The results of a study from Abbvie were released at CROI
that included a combination of different HCV inhibitors (with and
without ribavirin) for the treatment of HCV genotype 1b treatment-naïve
patients. The treatment duration was 12 weeks. Three HCV inhibitors
–ABT-450/r (boosted with ritonavir), ABT-267 and ABT-333–with ribavirin
(210 patients) and without ribavirin (209 patients) were given.
The stage of liver damage of patients in
the study included those with F0-F1 (68-72%), F2 (18-23%) or F3 (21%).
There were no patients with cirrhosis. The average age was about 48
yo. Most were white race and the gender was about equal between
females and males.
The cure rates were 99.5% in the group
that received ribavirin and 99% in the group that did not receive
ribavirin. One patient had virologic breakthrough at week 10 and 2
patients were lost to follow-up.
The most common side effects were
mild—headache, fatigue, pruritus (itching), nausea, and weakness.
Itching, anemia and rash were higher in the ribavirin containing
groups. There were no treatment discontinuations.
Dr. Reddy, an author and a presenter,
concluded that “For treatment-naïve GT1b patients without cirrhosis,
ABT-450/r, ABT-267 and ABT-333 is well tolerated and highly efficacious
with or without ribavirin.”
Comment: Abbvie’s combination of HCV
inhibitors continues to impress with cure rates exceeding 90% with and
without ribavirin for a treatment period of 12 weeks in both genotype 1a
and 1b. Abbvie has noted that they expect to apply for marketing
approval to the Food and Drug Administration (FDA) this year so these
drugs could hit the market within the year. Great news for patients
especially since it appears that ribavirin can be dropped from this
therapy for genotype 1.
Another interferon- and ribavirin-free study
presented at CROI was on three HCV inhibitors that have been developed
by Bristol-Myers Squibb. In the current study a total of 168 treatment
naïve HCV genotype 1a and 1b patients were treated with a three drug
combination of daclatasvir, asunaprevir, and BMS-791325. There were two
arms in the study—the drugs in the two arms were the same except the
dose of BMS-791325 was 75mg (80 patients) in one arm and 150mg (86
patients) in the other arm. The treatment duration was 12 weeks. The
demographics of the people in the study were: average 54 yo; men (67%);
white race (83%); HCV genotype 1a (82%); F0-F1(46%), F2 (13%), F3
(20%), F4 (18% with biopsy confirmed cirrhosis); unknown grade (2%).
The overall cure rates were 92% and the
cure rates were similar cure between the arms and by patient
demographics. There were 8 treatment discontinuations, due mainly to
lack of efficacy (3 patients) and adverse event (2 patients). The most
common side effects reported were headache, diarrhea, fatigue, and
Dr. Hawkins commented “The 12-week,
interferon- and ribavirin-free, all oral 3-DAA regime achieved SVR12 in
>90% of patients despite high prevalence of genotype 1a, advanced
fibrosis/cirrhosis, and IL28B non-CC genotypes.”
Comments: The results in
this early trial are very encouraging for interferon- and
ribavirin-free therapy for 12 weeks of treatment. This combination has
also been designated as a ‘Breakthrough Therapy” by the FDA which
means the FDA will help guide BMS through the clinical trial process
and the designation will help to accelerate the approval process.
The combination of BMS’s daclatasvir and Janssen’s
simeprevir with and without ribavirin to treat HCV genotypes 1a and 1b
was presented. In the study, the subtypes (1a and 1b) were divided
into different arms.
The first data presented was on subtype
1b—147 (104 treatment naive; 43 prior null responders). The patient
characteristics were age 53-59 yo; male (42-52%); white race (85-100%);
liver histology F0-F2 (39-77%), F3 (10-22%); F4 (11-39%).
The patients were randomized to receive
12 weeks (76 patients) of daclatasvir plus simeprevir either without
ribavirin (76 patients) or with ribavirin (71 patients). At the end of
the 12 weeks the patients were again randomized to receive either no
additional treatment or an additional 12 weeks of daclatasvir,
simeprevir with and without ribavirin.
The cure rates in the genotype 1b
treatment patients was 85% in the group that received daclatasvir plus
simeprevir and 75% in the group that received the triple combination of
daclatasvir, simeprevir plus ribavirin. There was little difference
in cure rates between the groups that were treated for 12 or 24 weeks.
However, higher rates were seen in the ribavirin arms especially in
the patients who were prior null responders.
Twenty-two people discontinued mainly due to lack of efficacy.
In the group of patients with genotype
1a the results were disappointing. There were only 21 patients in the
two genotype 1a arms (12 treatment naïve; 9 null responders). Most
were white males aged 49 to 55yo, liver histology
—F0-F2 (9 patients); F3 (6 patients); F4 (6 patients).
The cure rate was 67% in the treatment-naïve patients. None of the null responders achieved a cure.
There were two treatment discontinuations in each group due to adverse events.
Dr. Hézode commented that the low dose of
daclatasvir (30 mg) might have been a factor in the low response rates
in prior null responders, and going forward BMS would use the
daclatasvir at the 60 mg dose.
Comments: The cure
rates in the study were good for genotype 1b but dismal for genotype
1a. However, the study of HCV genotype 1a was small, so it’s hard to
draw solid conclusions. Still, there have been higher cure rates with
other combinations of HCV medications, including BMS DAA combinations
and other all-DAA combinations with and without interferon or
A study conducted in Washington D.C. by the
National Institutes of Allergy and Infectious Diseases is shedding some
light on interferon- and ribavirin-free DAA therapy in a real world
setting to treat people with HCV genotype 1. The clinical trial was
conducted in Washington D.C., and the trial participants were mostly
low-income HCV genotype 1 patients. Many of the patients in the
study had negative predictors of treatment response—65-80% male, 80-95%
African Americans, 55-85% genotype 1a. The study was interferon-free
and ribavirin-free. About a quarter of the patients in the study had
severe fibrosis or cirrhosis. All of the patients with cirrhosis were
treated for 12 weeks (arm 1). The three treatment arms (20 patients
each) and the cure rates are listed below:
Sovaldi, ledipasvir – 12 weeks –100% cure rates
Sovaldi, ledipasvir, GS-9669 –6 weeks
—95% cure rate
Sovaldi, ledipasvir, GS-9451 –6 weeks—100% cure rate
The most common side effects were
headache and fatigue, but they occurred in only the minority of
patients. There were no serious side effects and no treatment
discontinuations. The study was designed as an 8 arm study. The other
arms will include triple therapy combinations for people with
In conclusion, Dr. Kohli stated,
“Hepatitis C can be successfully and safely treated in six weeks using
three direct acting agents with different mechanisms of action.”
Dr. Kohli also stated that they are currently enrolling patients in a 4-week treatment arm.
study is a valuable piece of the treatment response puzzle with only
DAA therapy. Unlike other studies that usually have a higher
percentage of the easier to treat HCV population—the population in this
study are more typical of the HCV population and are also the more
difficult to cure. It is also an indication that the results can be
replicated out in the real world of hepatitis C.
The table below lists HCV inhibitors currently in interferon-free studies to treat HCV.
*Adapted from Pawlotsky JM. Gastroenterology 2012: in press
Generic names of HCV inhibitors are given a suffix
to identify the mechanism of action or what enzyme of the hepatitis C
virus that drug inhibits:
HCV protease inhibitors suffix “previr”
HCV polymerase inhibitors suffix “buvir”
HCV NS5A inhibitors suffix “asvir”
Source: HCV Advocate Newsletter, April 2014