combination of direct acting antivirals (DAAs) is effective and safe in HCV-genotype-1-infected
patients who did not respond to previous DAA therapy, according to research
presented to the recent International Liver Congress in Barcelona.
involved 50 adult patients without cirrhosis who did not achieve a sustained
virological response (SVR) with previous DAA-containing therapy. They were
randomised to receive one of three doses of ABT-493 (NS3/4A protease inhibitor)
and ABT-530 (NS5A inhibitor). Most of the patients had pre-existing resistance
to drugs in these classes. Between 86 and 100% of patients had a SVR 12
weeks after the completion of therapy (SVR12) and there were only two virologic
failures. The combination worked well in the context of pre-existing resistance
mutations. There were no serious side effects or laboratory abnormalities.
The development of
oral DAAs has revolutionised the treatment of HCV infection. Response rates of
90% or more have been observed in both clinical trials and real-world settings. The
failure of DAA treatment is often associated with the presence of
drug-resistant strains of virus. The majority of resistance-associated variants
(RAVs) can persist for more than two years after treatment with agents in the
NS5A class of DAAs.
- intent to treat analysis
All participants in a clinical trial are included in the final analysis, in the groups they were originally assigned to, whether or not they actually completed their course of treatment. Provides a better estimate of the real world effect of a treatment than an ‘on treatment analysis’.
ABT-530 are investigational next generation DAAs. ABT-493 is an HCV NS3/4A protease inhibitor active against
all genotypes of hepatitis C. ABT-530 is an NS5A inhibitor also active against
all genotypes of HCV. Both agents are active against common variants that
confer resistance to first-generation agents of their classes. Laboratory studies show they
have a high barrier to resistance and are potent in the presence of common NS3A
and NS5A RAVs. The combination also has the advantage of once-daily oral dosing.
designed a phase 2 study (Magellan-1) to explore the efficacy and safety of ABT-493
and ABT-530 in combination for the treatment of non-cirrhotic HCV genotype-1
infected patients who did not had a sustained virologic response to previous DAA
The study was open
label. Patients were randomised to receive one of three doses:
- ABT-493/ABT-530 200/80mg (six
- ABT-493/ABT-530 300/120mg with
ribavirin 800mg (22 patients)
- ABT-493/ABT-530 300/120mg (22
recruitment to the low dose arm was halted on the basis of dose-finding studies
and patients already recruited to this arm were randomised to the remaining
Most of the
patients were male, approximately a third were black and over half were aged
between 39 and 70 years. Baseline HCV viral load was between 6.1-6.7 log10 IU/ml. The majority of patients had genotype-1a infection and had fibrosis
Half the patients
had experience of NS5A-containing therapy and 84% had previously taken a HCV protease
A baseline NS3 or
NS5A resistance mutation was detected in between 77 and 86% of patients.
all 50 randomised patients (intent to treat analysis) showed that SVR12 was
achieved by all six patients in the low dose arm, by 91% of patients treated
with ABT-493/ABT-530 300/120mg and ribavirin, and by 86% of patients in the ABT-493/ABT-530
There was one case
of viral breakthrough (ABT-493/ABT-530 300/120mg arm) and one patient relapsed
(ABT-493/ABT-530 300/120mg ribavirin arm). Three patients were lost to
Exclusion of the
patients lost to follow-up (modified intent-to-treat analysis) showed SVR12
rates of 95% on both ABT-493/ABT-530 300/120mg study arms.
well in the context of common NS3 and NS5A resistance mutations.
reported by between 77 and 86% of patients, and 83% of these adverse events were
mild in severity. There were no serious laboratory abnormalities, but three
patients in the ABT-493/ABT-530 300/120mg ribavirin arm experienced a mild
elevation in bilirubin.
conclude that the investigational therapy was associated with high SVR12 rates
with only two virologic failures. Baseline resistance did not appear to impact
on the efficacy of therapy and the addition of ribavirin did not increase SVR12