David Wyles from University of California at San Diego presented results
from the ALLY-2 trial looking at sofosbuvir in combination with a different
NS5A inhibitor, Bristol-Myers Squibb's daclatasvir.
The sofosbuvir plus daclatasvir combination performed
well in early studies, but Gilead decided to halt development of this
regimen in order to focus on its own NS5A drug, ledipasvir. Once sofosbuvir was
approved and on the market, however, Bristol-Myers was able to move forward with
phase 3 clinical trials.
ALLY-1 tested the sofosbuvir plus daclatasvir regimen plus ribavirin for
12 weeks in patients with cirrhosis or liver transplant recipients with HCV
genotypes 1-6, ALLY-2 tested sofosbuvir plus daclatasvir without ribavirin for
8 or 12 weeks in people with HIV and HCV co-infection who had HCV genotypes
1-6, and ALLY-3 tested the
combination for 12 weeks in people with HCV genotype 3.
An advantage of daclatasvir is that it is active against multiple HCV
genotypes (known as 'pangenotypic') while ledipasvir is primarily active
against genotype 1. This is important because while genotype 1 is most common
in Europe and the US, other genotypes predominate in other countries with high
hepatitis C burdens.
All participants received once-daily 400mg sofosbuvir plus daclatasvir. ALLY-2
enrolled two cohorts: 151 previously untreated patients (including prior use of
sofosbuvir) who received the regimen for 8 or 12 weeks, and 52
treatment-experienced patients all of whom received the 12-week course.
Overall, nearly 90% were men, about 60% were white, about 35% were black
and the median age was approximately 55 years. A majority (63-70% across
treatment arms) had harder-to-treat HCV subtype 1a, 12-21% had subtype 1b,
4-12% had genotype 2, 6-8% had genotype 3 and 0-4% had genotype 4. About 10% of
treatment-naive patients had cirrhosis, rising to 29% for the
treatment-experienced.
Participants could either be on HIV treatment with undetectable viral
load and a CD4 count of at least 100 cells/mm3, or not yet on HIV
treatment with a CD4 count of at least 350 cells/mm3. Median CD4
counts were in the 500-600 cells/mm3 range. Those on HIV treatment
were permitted to take a wide range of antiretrovirals. The standard 60mg
daclatasvir dose was adjusted down to 30mg with ritonavir-boosted HIV protease
inhibitors or up to 90mg with most NNRTIs to account for drug interactions (all
doses were combined in the analysis).
SVR12 rates were high in the 12-week arms: 96% for treatment-naive
patients and 98% for treatment-experienced. The cure rate fell to just 76%,
however, for treatment-naive people who took treatment for only 8 weeks. These
rates were nearly the same whether looking at just people with genotype 1 or at people with all
genotypes together.
There was one relapse in both of the 12-week arms, but 10 in the 8-week
arm. Both relapsers treated for 12 weeks had HCV 1a; everyone with genotypes 2,
3 or 4 treated for this duration were cured. People with cirrhosis had a lower cure rate than those without cirrhosis
in both the 8-week arm (60% vs 77%) and in the treatment-naive (89% vs 99%) and
treatment-experienced (93% vs 100%) 12-week arms.
In the 8-week arm, SVR12 rates also varied by ART regimen, with those
taking darunavir/ritonavir (Prezista)
doing worse. Wyles suggested this might be due to sub-therapeutic drug levels,
as the ritonavir did not boost daclatasvir as much as expected. There was no
difference, however, in the 12-week arms.
Here too, treatment was generally safe and well-tolerated. There were no
deaths or adverse events leading to treatment discontinuation and serious
adverse events were uncommon (0-3%). Most participants maintained HIV suppression
and stable CD4 counts.
Speaking at a CROI press conference, both Naggie and Wyles noted that
their studies saw response rates in these participants with HIV and HCV co-infection
as high as those for people with HCV mono-infection in other trials. This
supports recent hepatitis C treatment guidelines recommending that HIV-positive
and HIV-negative people should be treated the same for hepatitis C.
"These are really exceptional cure rates and they
are very safe regimens," Naggie said. "ION-4 and ALLy-2 offer great
options for people who are co-infected."
It remains unclear how sofosbuvir plus daclatasvir will be used in
clinical practice, given the availability of Harvoni. The difference between the full (non-discounted) US cost of
sofosbuvir alone and Harvoni for 12
weeks is US$10,500 – likely less than the price of daclatasvir. Wyles suggested
that it may be beneficial, especially for people with co-infection, to use two
separate pills rather than a coformulation so that drug doses can be adjusted
independently.
Daclatasvir appears to be active against a wider range of HCV genotypes
than ledipasvir, though press conference moderator David Thomas of Johns
Hopkins suggested that there have been too few patients with other genotypes in
clinical trials to get definitive answers. People with genotype 3 who have
cirrhosis remain a difficult-to-treat population. Further, Gilead is working on
a new coformulation of sofosbuvir and a next-generation NS5A inhibitor with
pangenotypic activity (GS-5816).