HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir

Abstract

Background&Aims Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained-virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost. Methods 58 chronic-HCV patients were treated with 12-week sofosbuvir+simeprevir(n=19), sofosbuvir+daclatasvir(n=19), or sofosbuvir+ledipasvir in three French referral centers. HCV was measured at baseline, day 2, every other week, EOT and 12 weeks post EOT. Mathematical modeling was used to predict the time to cure,i.e,<1 virus copy in the entire extracellular-body fluid. Results All but one patient who relapsed achieved SVR. Mean age was 60±11 years, 53% were male, 86% HCV genotype-1, 9% HIV coinfected, 43% advanced fibrosis (F3), and 57% had cirrhosis. At weeks 2, 4 and 6, 48%, 88% and 100% of patients had HCV<15 IU/ml, with 27%, 74% and 91% of observations having target-not-detected, respectively. Modeling results predicted that 32(43%), 16(23%), 7(13%), 5(9%) and 3(5%) subjects were predicted to reach cure within 6, 8, 10, 12 and 13 weeks of therapy, respectively. The modeling suggested that the patient who relapsed would have benefitted from an additional week of sofosbuvir+ledipasvir. Adjusting duration of treatment according to the modeling predicts reduced medication costs of 43%-45% and 17%-30% in subjects who had HCV<15 IU/ml at weeks 2 and 4, respectively. Conclusions The use of early viral-kinetic analysis has the potential to individualize duration of DAA therapy with a projected average cost-saving of 16%-20% per 100-treated persons.

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

“…The best‐fit parameter values (Table 1) are consistent with previous estimates. For instance, the viral clearance rate, c  =   6.3 day −1 , is close to the reported38 average of 6.2 ± 1.8 day −1 ; the drug efficacy, ε = 0.9991, is consistent with the mean of 0.997 estimated for sofosbuvir‐based treatments14, 18; and the death rate of infected cells, δ = 0.06 day −1 and 0.2 day −1 for the two patients, is in the range of values, 0.01–0.4 day −1 , reported earlier 20…”

“…The achievement of SVR despite detectable viremia at the EOT, a phenomenon termed EOT + /SVR, suggests that DAA treatments can be terminated much earlier than the currently prescribed duration of 12 weeks, even if virus is detectable, at least in some patient subpopulations. The benefits of reduced costs and toxicities are expected to be tremendous 14. Identifying suitable patient subpopulations and the corresponding reduced treatment durations requires an understanding of the mechanism(s) by which DAA treatments lead to EOT + /SVR.…”

Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report

“…The time to reach cure, or SVR, was previously defined as the time to reach less than one hepatitis C virion in the extracellular fluid volume (approximately 13.5-15 L) [9][10][11][12] . Thus a value of approximately 3 × 10 -5 IU/mL is the threshold for viral clearance (termed here cure boundary).…”

“…The fact that the patient achieved SVR despite a very short course of therapy (24 d) was striking since her viral load level 10 d before DAA therapy stopped (3/15/15) was 97 IU/mL, which is several log IU/mL higher than the cure boundary. To estimate, retrospectively, when the patient reached cure we used the standard biphasic HCV treatment model [11,12] and the multiscale HCV treatment model [13,14] . Both these models predicted that cure occurred 3 to 6 wk after therapy was stopped (not shown).…”

A Robust and Efficient Numerical Method for RNA-Mediated Viral Dynamics

“…The standard model for HCV kinetics during treatment provided many insights into the effectiveness and mechanism of action of IFN and ribavirin (reviewed in [29,30]). This model has been able to retrospectively predict the duration of treatment needed for HCV eradication (cure) [31][32][33][34][35] and more recently was used in real-time (on treatment) to predict the duration of therapy needed to achieve cure with an IFN-free regimen of silibinin +ribarivin [36]. In the age of DAAs, new models are being developed to meet the challenge associated with these new agents [37][38][39].…”