A triple combination of Gilead Sciences'
sofosbuvir/ledipasvir (Harvoni) plus
the experimental HCV protease inhibitor vedroprevir cured 96% of
treatment-experienced genotype 1 hepatitis C patients with cirrhosis, without the
need for ribavirin, according to study findings presented on Tuesday at the 2015 AASLD Liver Meeting in San Francisco.
Interferon-free direct-acting antiviral (DAA)
therapy works by targeting different steps of the hepatitis C virus lifecycle.
Combining drugs from different classes produces more potent antiviral activity
and reduces the risk of developing drug resistance.
Eric Lawitz of the Texas Liver Institute and
colleagues evaluated a regimen consisting of agents from three different
classes with or without ribavirin. Sofosbuvir is a nucleotide HCV NS5B
polymerase inhibitor, ledipasvir is a NS5A inhibitor and vedroprevir (formerly
GS-9451) is an investigational NS3/4A protease inhibitor.
Glossary
- albumin
A protein made in the liver, needed to maintain a balance of the fluids in the body. In a blood test, lower than normal levels of albumin and total protein may indicate liver damage or disease. If there is not enough albumin, fluid may accumulate in the abdomen (ascites).
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
- direct-acting antiviral (DAA)
A drug which prevents hepatitis C from reproducing by blocking certain steps in its lifecycle.
- IL28B
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
- sinusitis
Inflammation or infection of the sinuses, which are cavities behind the forehead and cheekbones.
Sofosbuvir/ledipasvir taken alone for 8 weeks
is effective for many easier-to-treat people with HCV genotype 1. Some,
however, do not achieve sustained response with such a short course of therapy,
with prior treatment failure and cirrhosis being important predictors of
suboptimal response. This phase 2 trial assessed whether adding a third DAA
could improve response rates for more difficult-to-treat patients and allow
them to shorten therapy.
This single-centre study included 46
participants with HCV genotype 1, including 70% with harder-to-treat subtype
1a. Two-thirds were men, almost all were white, 87% had unfavourable IL28B non-CC gene
variants and the median age was 57 years. They had compensated cirrhosis
without serious functional impairment as reflected in platelet counts and
albumin levels. At baseline the mean HCV viral load was about 6 log10
IU/ml. All had previously been treated with pegylated interferon and ribavirin,
but people with prior DAA use were excluded.
Participants in this open-label study were randomly assigned (1:1) to
receive sofosbuvir/ledipasvir (400/90mg co-formulation) plus vedroprevir (80mg)
once-daily, either alone or with ribavirin, for 8 weeks. Participants were then
followed for 12 more weeks after the end of treatment to determine sustained
virological response (SVR12), or continued undetectable HCV RNA.
SVR12 rates were 96% in the sofosbuvir/ledipasvir plus vedroprevir arm
and 88% in the arm that also added ribavirin. There was one relapse in the
first arm, and two relapses and one loss to follow-up in the
ribavirin-containing arm.
Viral reduction was rapid after starting treatment, with most people
having HCV RNA below of the limit of quantification by week 2 – faster than the
decline seen with sofosbuvir/ledipasvir alone.
Viral sequencing revealed that 53% of participants had NS3
resistance-associated variants (RAVs) at baseline, while just 7% and 5%,
respectively, had NS5A or NS5B RAVs. Presence of NS3 or NS5B RAVs did not have
much effect on treatment response, but people with NS5A RAVs were less likely
to achieve SVR12 (33% of patients with these RAVs vs 98% of those without).
Deep sequencing showed that two of the relapsers had the L31M NS5A RAV
(associated with reduced susceptibility to ledipasvir) at baseline, and this
was enriched post-treatment; one also had a Q30R variant at baseline but not
post-treatment. The third relapser had no RAVs at baseline, but Q30R was
detected post-treatment.
Treatment with sofosbuvir/ledipasvir
plus vedroprevir was generally safe and well-tolerated, with no serious
adverse events or discontinuations for this reason. The most common adverse
events were headache, rash, sinusitis, cough and fatigue, all occurring more
often in the ribavirin arm. One person taking the triple DAA regimen alone and two
who added ribavirin developed anaemia (haemoglobin < 10 g/dl). There were no
moderate or worse (> grade 2) ALT or AST liver enzyme elevations.
Ledipasvir/sofosbuvir
plus vedroprevir for 8 weeks "achieved high SVR rates in
treatment-experienced genotype 1 patients with cirrhosis" and
"ribavirin did not enhance SVR rates," the researchers summarised.
Dr Lawitz noted that all three relapsers had HCV subtype 1a, but there
were no other obvious factors associated with treatment failure. RAVs were the
most important predictor, with two of the three relapsers having dual-class
(NS3 and NS5A) RAVs at baseline.
The investigators concluded that "The three-drug combination of a
NS5B nucleotide inhibitor + NS5A inhibitor + NS3 protease inhibitor may allow
shortening treatment duration to 8 weeks for patients with more advanced liver
disease."