Pharmacokinetics and pharmacodynamics of valganciclovir in infants with severe HIV-associated pneumonia in Africa: a sub-study of the EMPIRICAL randomised controlled trial

Background Cytomegalovirus (CMV) is a major unrecognised cause of morbidity and mortality in infants living with HIV. Valganciclovir, an oral prodrug of ganciclovir, treats CMV in immunocompromised patients, but pharmacokinetic data in infants living with HIV are lacking. This study evaluated exploratory valganciclovir pharmacokinetic and pharmacodynamic outcomes in infants with severe HIV-associated pneumonia. Methods As part of the EMPIRICAL clinical trial (ClinicalTrials.gov: NCT03915366, recruitment closed), infants living with HIV aged 1–12 months received valganciclovir 16 mg/kg twice daily. Pharmacokinetic sampling occurred on day 3 after enrolment at 2- and 5 h post-morning dose. Plasma CMV viral load was measured on days 0 and 15. The area-under–the-curve for ganciclovir over a 12-h interval (AUC 0–12 h ) was estimated using a limited sampling equation. Geometric mean AUC 0–12 h and the proportion of participants within the adult AUC 0–12 h target range (40–60 h mg/L) were calculated. Associations of ganciclovir AUC 0–12 h with covariates and log-change in plasma CMV viraemia were evaluated using linear regression. Infants were enrolled in this study between August 2020 and August 2022. Findings Of 98 participants, 87 had evaluable pharmacokinetic profiles. Geometric mean AUC 0–12h (%CV) was 38.5 (54.8) h·mg/L. Only 35% achieved the adult AUC 0–12 h target; 47% were below, and 18% above it. Reduced renal function was the only covariate associated with higher ganciclovir AUC 0–12 h . Ganciclovir AUC 0–12 h did not correlate with plasma CMV viral load reduction. Interpretation Approximately two-thirds of infants was not within adult pharmacokinetic targets at 16 mg/kg/dose of valganciclovir. However, ganciclovir exposure was not predictive for virologic response or toxicity, suggesting lower exposures did not affect treatment efficacy in the EMPIRICAL trial. Funding This project is funded by the European and Developing Countries Clinical Trials Partnership (EDCTP2) program supported by the European Union (RIA2017MC-2013).