Baseline viral load, not sex, accounts for differences in early virologic response timing under direct-acting antiviral therapy: a mechanistic simulation using published kinetic parameters

Abstract Background. Early virologic response milestones inherited from the interferon era — rapid virologic response at week 4, early virologic response at week 12 — remain in use as descriptive categories under direct-acting antiviral therapy. Cohort reports occasionally describe women reaching undetectable HCV RNA earlier than men, an observation variously attributed to assay detection limits or to a sex-specific antiviral or immunological mechanism. Whether either explanation is required has not been tested against the standard kinetic model. Objective. To determine (i) whether undetectability by week 4 is predicted by the standard biphasic HCV kinetic model at typical baseline viral load, and (ii) whether an apparent sex difference in response timing can be reproduced without invoking any sex-specific parameter. Methods. We simulated the standard target-cell-limited biphasic HCV kinetic model 1,2 over 12 weeks of therapy, using rate constants from the published parameter-estimation literature: infected-cell loss rate δ = 0.14/day, viral clearance rate c = 22.3/day, infection rate β = 5 × 10⁻⁸ mL/day/virion, production coefficient p = 8.18, and target-cell death rate d = 0.01/day 3 . Two experiments were performed. First, time to undetectable HCV RNA (< 15 IU/mL) was computed at three treatment efficacies (ε = 0.95, 0.99, 0.999) from a typical baseline of 10^6.5 IU/mL. Second, treatment efficacy was held fixed at ε = 0.99 and baseline viral load alone was varied by one log₁₀ (10^5.5 versus 10^6.5 IU/mL), with all kinetic parameters identical between arms. No patient data were used. Results. At a baseline of 10^6.5 IU/mL, time to undetectability was 10.0 weeks at ε = 0.95, 7.9 weeks at ε = 0.99, and 5.5 weeks at ε = 0.999. None of the three reached the week-4 threshold. Varying only baseline viral load by one log₁₀ at fixed efficacy produced undetectability at week 5.5 versus week 7.9 — a difference of approximately 2.4 weeks (17 days) generated entirely by starting concentration, with δ, c, and ε identical between arms. Conclusions. Undetectability by week 4 is not predicted by the standard kinetic model at typical baseline viral load and literature-derived rate constants, which argues against using week-4 response as a population-wide expectation under DAA therapy. A reported sex difference in response timing of roughly two to three weeks is fully accounted for by a one-log₁₀ difference in baseline viral load propagating through sex-invariant clearance kinetics, and requires neither an assay artefact nor a sex-specific biological mechanism. We give the quantitative prediction against which cohort data can test this directly.