—Alan Franciscus, Editor-in-Chief
This year’s American Association
for the Study of Liver Diseases (AASLD) conference was nothing short
of amazing for the incredible information about hepatitis C (HCV)
treatment—the cure rates were in the range of 80 to 100%. The high
rates even included people who we would normally characterize as having
negative predictors of treatment response—cirrhosis, prior null
responders, pre- and post liver transplant patients, genotype 3 and
others. In part 1 of our AASLD coverage, we will feature the current
drugs to treat HCV as well as some of the drugs in the pipeline.
In December, 2014, the Food and Drug Administration
(FDA) is expected to approve AbbVie’s 3D combination to treat
hepatitis C genotype 1. Many of the presentations that are summarized
in this issue include results from 3D treatment in people with
cirrhosis, on opioid substitution, people with a history of
depression/bipolar disease, and a pooled analysis of HCV genotype 1a.
*The 3D combination consists of paritaprevir (ABT-450)/ritonavir, ombitasvir and dasabuvir with and without ribavirin.
Regimens of Paritaprevir (ABT-450)/r/Ombitasvir and Dasabuvir with
Ribavirin achieve high SVR12 rates in HCV Genotype 1-infected Patients
with Cirrhosis, Regardless of Baseline Characteristics—M. Fried et al.
In the TURQUOISE-II trial
treatment-naïve and experienced patients with compensated cirrhosis
received the 3D combination plus ribavirin for 12 weeks (208 patients)
or 24 weeks (172 patients). The characteristics of patients were evenly
divided between the two arms. Most of the patients were male, white,
average age ~57 yo, HCV genotype 1a, and treatment experienced
The overall cure rates were 92%
(1a-89%, 1b-99%) in the 12-week arm, and 97% (1a-95%, 1b-100%) in the
24-week arm. Three factors were found to be associated with lower
rates of cure: IL28B TT (p= 0.021 p=value); response (p= 0.038); HCV
genotype 1a (p=0.046).
Typically, treatment response (even with all oral regimes) has somewhat
lower cure rates in people with cirrhosis, but in the 3D combination
it appears that the only significant difference is subtype.
+ Dasabuvir With and Without Ribavirin in HCV Genotype 1-infected
Patients Receiving Stable Opioid Substitution Treatment: Pooled
Analysis of Efficacy and Safety in Phase 2 and Phase 3 Trials –M. Puoti et al.
A pooled analysis of data from a
phase 2 and phase 3 clinical study of 56 patients (44 genotype 1a; 12
genotype 1b) who received the 3D combination therapy with and without
ribavirin revealed overall cure rates of 96% (1a-96%; 1b-100%). The
majority of the patients were male, white, genotype 1a, average age ~48
Although this sub-analysis had a small patient population it is
important since there are many people with hepatitis C who are on
opioid substitution and are in need of HCV treatment. This information
should help to guide the medical establishment to treat this important
population of people infection with hepatitis C.
ABT-450/r/Ombitasvir + Dasabuvir With and Without Ribavirin in HCV Genotype 1-infected Patients with History of Depression or Bipolar Disorder: Pooled Analysis of Efficacy and Safety in Phase 3 Trials—D. Nelson et al.
A pooled analysis of six phase 3 studies of 2052
treatment-naïve and treatment-experienced patients was conducted. Of
those who were treated for 12 weeks or 24 weeks 357 (17.4%) had a
history of depression or bipolar disorder.
The patient characteristics of
those on the 3D regimen with or without RBV who had a history of
depression or bipolar disorder were HCV genotype 1a (62-67%); genotype
1b (33-38%); female (53-59%); white (89-93%); prior null responders
Approximately, 61% were
receiving at least one antidepressant (33% serotonin reuptake inhibitor
antidepressants; 22% benzodiazepines (anti-anxiety drugs)).
The cure rates were 96% in the
groups that did and did not receive ribavirin. Depression as a side
effect occurred more frequently in the group that had a history of
depression/bipolar—(11.3/8.2% in people with a history compared to
3.5/4.2% in people with no history).
is also great news that should help ease medical providers’ and
patients’ fears about treating with HCV inhibitors since the results
demonstrated high cure rates even in prior null-responders, but with a
low side effect profile. The rate of treatment-induced depression was
higher in the group with a history of people with depression/bipolar
disorder. In the past most people with psychiatric disease were
excluded from treatment because of interferon-related depression. Now
this barrier should be removed.
Trial: Subgroup Analysis of Genotype 1a-infected Patients Treated with
Dasabuvir Plus Ombitasvir/ABT-450/r With or Without Ribavirin—D Bernstein.
This analysis of a phase 3 study included
non-cirrhotic genotype 1a treatment-naïve patients who received the 3D
combination without ribavirin (205 patients) and with ribavirin (100
patients). A majority were male, age ~51, white, liver disease stage
The overall cure rates were 97%
in the 3D group that received ribavirin and 90% in the group that did
not receive ribavirin. Most of the side effects were mild, and only
two patients (1%) discontinued treatment due to side effects, but the
researchers did not believe they were related to the study drugs. The
most common side effects were fatigue, headache, nausea, insomnia,
diarrhea, and pruritus.
This analysis showed that there was a very high cure rate with and
without ribavirin, low rate of side effects and treatment
discontinuation. It is likely that FDA approval of this 3D combination
with ribavirin will be recommended for this patient population.
Bristol-Myers Squibb (BMS)
Unity 1 and 2: Daclatasvir plus
asunaprevir plus beclabuvir co-formulated into a fixed dose pill taken
twice daily. Interferon- and ribavirin-free regime. Treatment duration
was 12 weeks.
Fixed-Dose Combination Therapy with Daclatasvir/Asunaprevir/Beclabuvir
for Non-Cirrhotic Patients With Chronic HCV Genotype 1 Inection:
Unity-1 Phase 3 SVR12 Results—F. Poordad et al.
There were 312 treatment-naïve and 103
treatment-experienced patients treated with the fixed dose of DCV-TRIO
in this phase 3 study. Seventy-three percent were HCV 1a; the
majority were white and the average age was 54-57 yo.
The overall cure rate in
treatment-naïve group was 92% (1a-90%; 1b-98%), and 89% in the
treatment- experienced group (1a-85%; 1b-100%).
There were eight patients who
discontinued treatment due to lack of treatment success; three patients
discontinued treatment due to side effects (but did go on to achieve a
cure). Two percent of patients had serious side effects, but the
researchers did not consider them related to the study drugs. The
majority of side effects were mild—headache, fatigue, diarrhea and
this trial of genotype 1 treatment-naïve non-cirrhotic patients,
DCV-TRIO without ribavirin for 12 weeks produced high cure rates and
low side effects. BMS is expected to file for FDA approval sometime in
Fixed-Dose Combination Therapy With
Daclatasvir/Asunaprevir/Beclabuvir, ±Ribavirin, for Patients with
Chronic HCV Genotype 1 Infection and Compensated HCV Cirrhosis: Unity-2
Phase 3 SVR12 Results.
There were 112 treatment-naïve and 90
treatment-experienced patients treated with DCV-TRIO (with and without
ribavirin) for 12 weeks in a phase 3 study. The average age was ~59
yo; mostly white males, HCV genotype 1a.
The cure rates were 93% in the
DCV-TRIO without ribavirin group (naïve 93%; experienced 87%), and 98%
in the DCV-TRIO plus ribavirin group (naïve 98%; experienced 93%).
Table 1:Cure rates by subtype:
90% (36 of 40 pts)
100% (17of 17 pts)
86% (30 of 35 pts)
90% (9 of 10 pts)
97% (38 of 39 pts)
100% (15 of 15 pts)
91% (32 of 35 pts)
100% (10 of 10 pts)
are very good results from a small population of HCV genotype 1a/b
patients with compensated cirrhosis. The combination appears to work
best in people with genotype 1b, but these results could possibly be a
factor of the small patient size.
12-Week Combination Treatment With Daclatasvir and Sofosbuvir in
Patients Infected with HCV Genotype 3: Ally-3 Phase 3 Study—D. Nelson et al.
This was a phase 3 study of 152 patients: 101
treatment-naïve and 51 treatment-experienced. The patients received the
combination of daclatasvir plus sofosbuvir for a treatment period of 12
weeks. The majority of patients were white males, average age
~53-58; 19% to 25% had cirrhosis.
The cure rates were 90% (91 of
101 pts) in the treatment-naïve arm and 86% (44 of 51pts) in the
treatment-experienced arm. The cure rates—based on liver biopsy—for
those with no cirrhosis were: treatment- naïve (97%);
treatment-experienced (94%). The cure rates in those with cirrhosis
were: treatment- naïve (58%); treatment-experienced (69%). Breaking it
down by FibroTest (F4) the cure rates were 73% in the treatment-naïve
and 63% in the treatment-experienced arms.
is an unmet need for medications to treat HCV genotype 3 since the
current standard of care is the combination of Sovaldi (sofosbuvir)
plus ribavirin for a treatment period of 24 weeks. The 24-week
treatment period comes with a hefty price tag, and the cure rate is
84%. This combination, if priced right, could be an alternative
therapy for treatment-naïve and -experienced patients who have little
or no liver damage. But for those with liver damage (at least in this
study) the cure rates are lower than expected. Perhaps the addition of
another inhibitor could increase the cure rates in a population that
needs more treatment options.
Fixed-Dose Combination is Safe and Efficacious in Cirrhotic Patients
Who Have Previously Failed Inhibitors-Based Triple Therapy ± —M Bourliere et al.
This study from France treated HCV cirrhotic genotype 1a/b patients with Harvoni. There were two treatment arms:
Arm 1. 77 patients in a 12-week lead-in placebo arm followed by 12 weeks of treatment with ledipasvir, sofosbuvir plus ribavirin.
Arm 2. 78 patients in a ledipasvir, sofosbuvir plus placebo arm who were treated for 24 weeks.
The mean age was ~56-57 yo, mostly white males, genotype 1a (62-64%); prior protease inhibitor therapy failures.
The side effects were mild to moderate—headache and fatigue were the most common.
results of this trial of ledipasvir and sofosbuvir (Harvoni) with and
without ribavirin were
remarkable given that the patient population is the
most difficult to treat—prior treatment failures of protease inhibitor
therapy with compensated cirrhosis. Including ribavirin for 12 weeks
produces response rates similar to 24 weeks without ribavirin, but it
would be interesting to see if the same patient population would
benefit with 12 weeks of ledipasvir and sofosbuvir without ribavirin.
Integrated Safety and Efficacy Analysis of >500 Patients With
Compensated Cirrhosis Treated With Ledipasvir / Sofosbuvir With and
The study was a pooled analysis of 513 patients who
received ledipasvir plus sofosbuvir (Harvoni) with ribavirin (251 pts)
and without ribavirin (262 patients). The mean age was ~58, mostly
white male, genotype 1a, treatment naïve (161 pts), treatment
experienced (362 pts) of whom 240 pts were prior protease inhibitor
treatment failures. Cirrhosis was diagnosed by liver biopsy (47%);
FibroScan (44%) and FibroTest (9%).
The overall cure rates were
96%. Among treatment-experienced patients treated for 12 weeks with
ledipasvir plus sofosbuvir the cure rates were 90%. Adding ribavirin
increased the cure rated by 6% but adding ribavirin also increased the
rate of side effects including anemia by 10%.
results are, again, remarkable for people with genotype 1 and
compensated cirrhosis. The addition of ribavirin did not add much
benefit especially if you have to endure additional side effects.
Sofosbuvir With GS-5816 for 8 Weeks With and Without Ribavirin in
Patients With HCV Genotype 3 Without Cirrhosis Result in High Rates of
SVR12: The Electron-2 Study
The study was conducted in HCV
genotype 3 treatment-naïve patients without cirrhosis using sofosbuvir
(sof) plus GS-5816 with and without ribavirin (RBV) for a treatment
duration of 8 weeks. There were 4 arms. The mean age was 47 to 50;
the majority were white males, genotype 3a.
The cure rates in the 4 arms were as follows:
SOF, GS-5816 (25mg), (27 pts): 100%
SOF, GS-5816 (25mg), RBV (24 pts): 88%
SOF, GS-5816 (100mg), (27 pts): 96%
SOF, GS-5816 (100mg), RBV (26 pts): 100%
cure rates are impressive. Now we need larger studies in this patient
population and in people who have more severe liver disease. The
authors noted that the combination of sofosbuvir and GS-5816 is being
co-formulated as a fixed-dose combination and it is advancing into
phase 3 clinical trials.
The data above speaks for itself
and it is the “The New Normal” of treatment for hepatitis C—which
means that almost everyone with hepatitis C can be cured of hepatitis C
regardless of liver disease stage. Now, if we could just get these
drugs to everyone with hepatitis C, we might be able to to put an end
to this horrible disease.
In the Mid-Month edition of the HCV Advocate newsletter I will write on more information released at AASLD.
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