Abstract
High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase-inhibitor (GS-9669) or a protease-inhibitor (GS-9451) and after 12 weeks with sofosbuvir + ledipasvir. Here we analyze the viral kinetics observed during these treatments to decipher the origin of the rapid cure and to evaluate the possibility of further reducing treatment duration. We found that viral kinetics were surprisingly slow in all treatment groups and could not reproduce the high SVR rates observed. Based on experimental results suggesting that NS5A- or protease-inhibitors can generate non-infectious virus, we incorporated this effect into a mathematical model. We found that to predict observed SVR rates it was necessary to assume that ledipasvir, GS-9669 and GS-9451 rapidly reduce virus infectivity. We predicted with this model that 4 weeks of triple therapy could be sufficient to achieve SVR in patients with undetectable viremia at week 1, but would be suboptimal in general. In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy.
Highlights
Gov, number NCT01805882) added a third antiviral, either a non-nucleoside polymerase inhibitor (GS-9669) or a protease inhibitor (GS-9451), on top of SOF + LDV
At the end of treatment (EOT), all patients treated with SOF + RBV had hepatitis C virus (HCV) RNA below the limit of detection (LOD), whereas in the SYNERGY trial this proportion was only 65% (13/20), 40% (8/20) and 50% (10/20) in patients treated with SOF + LDV, SOF + LDV + GS-9669 and GS-9451, respectively
Based on experience accumulated with other anti-HCV drugs, our hypothesis was that in order to have a cure rate of 95% or higher in 6 weeks, the viral decline should be faster than seen with previous therapies
Summary
Gov, number NCT01805882) added a third antiviral, either a non-nucleoside polymerase inhibitor (GS-9669) or a protease inhibitor (GS-9451), on top of SOF + LDV. Results of an in vitro experiment suggest that some DAAs, in particular NS5A and protease inhibitors, significantly affect viral infectivity and that infectious titer declines much more rapidly than extracellular viral load in response to these treatments[10]. This mode of action has not been previously integrated into viral kinetic models. In that study involving Chinese patients all infected with HCV genotype 1b without cirrhosis, all 18 patients who achieved a viral load
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