BMS Files NDA with FDA
On March 12, 2015 Bristol-Myers Squibb (BMS)
announced that the Food and Drug Administration (FDA) had accepted
their new drug application (NDA) for the combination of daclatasvir
plus sofosbuvir for the treatment of HCV genotype 3. In BMS’s phase 3
studies of genotype 3 patients—101 treatment-naïve, 51
treatment-experienced—the cure rates were 90% and 86% respectively.
However, in people who had cirrhosis (F-4) the cure rates were 63% to
73% leaving an unmet need for these patients.
The Conference on Retroviruses and Opportunistic
Infections (CROI) 2015 held in Seattle, WA, had a wealth of information
about the treatment of people with HIV and HCV coinfection. Since the
introduction of interferon-free therapy the cure rates of HCV in
people who are coinfected with HIV and HCV are the same as the cure
rates in people who are HCV mono-infected, and importantly the studies
presented at CROI reinforce this information.
DL Wyles et al., presented “Daclatasvir in
Combination with Sofosbuvir for HIV/HCV Coinfection: ALLY-2 Study.”
The study included patients with HCV genotype 1 (1a-139 pts; 1b-29
pts), genotype 2 (19 pts), genotype 3 (19 pts) and genotype 4 (3
pts). There were three arms in the study—two arms with 12 weeks
treatment duration and one arm with an eight-week treatment
period—there were no genotype 4 patients in the eight-week treatment
arm. Most of the patients were male (83-91%);
White (56-65%); and
there were 29 patients with cirrhosis in the study.
The cure rates were 97% in
genotype 1, and 100% in genotypes 2, 3, and 4 in the groups treated for
12 weeks. In the groups treated for eight weeks, the cure rates fell
to 76%. There was no impact based on genotype or type of prior
are remarkable cure rates regardless of genotype, viral load, and
other factors at least in the 12-week group. Based on this data 8
weeks of Daclatasvir plus sofosbuvir is not effective.
An unmet medical need is
treatment of people with genotype 3 with cirrhosis—this information was
not available. Additionally, there were very few genotype 3 patients
in the study to draw any conclusions.
Given the results of Harvoni
(below) the niche for this combination may be narrow. However, it was
noted that, if approved, adjusting the dosing would be easier since
these drugs are dosed separately especially for some people on HIV
S Naggie et al., present data from
“Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected with HCV and
HIV-1: ION-4.” This study was a phase 3 clinical trial of Harvoni
(sofosbuvir/ledipasvir) for the treatment of HCV genotype 1 and 4 in
people who are coinfected with HIV and hepatitis C. A total of 335
patients were included in the trial—75% were genotype 1a; 23% genotype
1b; 2% genotype 4. The study included 45% treatment-naïve patients, 55%
treatment-experienced patients, and 20% of the patients had
compensated cirrhosis. The mean age of the patients was 52yo; 82% were
male, 34% were Black.
The overall cure rate was 96%.
There was little difference in cure rates between treatment naïve and
treatment experienced (95% vs. 97%) and those with and without
cirrhosis (94% vs. 96%). There was a difference in cure rates between
Blacks (90%) and non-Blacks (99%). The most common side effects were
headache, fatigue and diarrhea.
Gilead is trying to determine
the difference in the cure rates between Blacks and non-Blacks. They
have ruled out drug concentration levels in the blood and the possible
interaction of the HIV medications. During the question and answer
period there were a couple of interesting comments about the lower
response rates in Blacks:
Perhaps Black patients coinfected with HIV and HCV may need to be treated longer
Previous clinical trials
have had lower Black patient populations that may not have given us a
true picture of treatment cure in Blacks—more Blacks are needed in
clinical trials period. In the days of pegylated interferon and
ribavirin therapy the cure rates were much lower.
Gilead stated that they are
planning to file a New Drug Application (NDA) with the FDA based on the
phase 3 data for the treatment of HCV in people with HIV.
cure rates and low side effects regardless of prior treatment response
or degree of liver damage. Once we learn more about the reason for
the lower response rates in Blacks we will keep our readers informed.
Delaying Treatment = More Deaths
Everyone is trying to come to terms with the impact
of treating people who are the sickest. Lately, there have been
studies showing this approach may not be cost effective. It certainly
isn’t patient centered or tied to improving the quality of life for
people living with hepatitis C. A study presented at CROI—“Impact of
Deferring HCV Treatment on Liver-Related Events in HIV+ Patients, by C
Zahnd et al.”—sheds some light on the long-term health risk of
The researchers in the study
used a model to predict health outcomes from the Swiss HIV Cohort Study
to simulate HIV/HCV patients from the time of acute infection through
chronic infection and fibrosis stages using the Metavir system for
staging fibrosis/cirrhosis (F0 through F4), decompensated cirrhosis,
liver cancer, and death. They assumed that 100% of patients were
treated with interferon-free therapies and of these patients 90% were
The highlights of their findings included:
It is a known fact that people cured of hepatitis C still have liver
disease progression especially in later stages of cirrhosis. The
authors of the study believe that HIV/HCV coinfection may contribute to
liver disease progression even after being cured. This study and other
studies which show the benefits of early treatment should be an
important part of the discussion on evaluating the cost-effectiveness
of treatment. There is also a matter of public health: Treating HCV
can stop the transmission of HCV.
If patients were treated one month or 1 year after diagnosis—3% would die from liver-related deaths
If HCV treatment was delayed
until later stages, the percentages of patients who were predicted to
die dramatically increased: Treated at F-2 a 5% death rate; treated at
F-3 a 10% death rate; treated at F-4 a 25% death rate.
Labels: CROI, daclatasvir plus sofosbuvir, HCV Drugs