Valganciclovir for cytomegalovirus viraemia in advanced HIV disease: a phase 2b randomized placebo-controlled trial of valganciclovir for cytomegalovirus viraemia in adults and adolescents with advanced HIV disease.

Mortality among adults hospitalized with advanced HIV disease (AHD; CD4 <200 cells μl-1 or a WHO stage 3 or 4 disease) is >20%; there is an urgent need to evaluate strategies to reduce mortality within this extremely high-risk group. Approximately 50% of adults with CD4 counts <100 cells μl-1 have detectable cytomegalovirus (CMV) viraemia, and high-level CMV viraemia is associated with greater than double the hazard of death in this population. Despite this, there are no current treatment guidelines to inform treatment of CMV viraemia without end-organ disease in the context of AHD. The NIRVANA study is a double-blinded, placebo-controlled, multi-centre phase 2b trial to evaluate efficacy and safety of valganciclovir for patients with AHD and CMV viraemia. We will enrol 150 hospitalized adults and adolescents (aged ≥15 years) with CD4 <100 cells μl-1, and CMV viraemia >500 IU ml-1 from two hospitals in Uganda and South Africa. Participants will be randomized 1 : 1 to either valganciclovir 900 mg orally or matched placebo for 28 days. Safety monitoring and CMV viral load testing will occur weekly until week 4, and thereafter at week 8 and at study termination at week 12. The primary endpoint is a composite of adverse events of special interest, re-hospitalization or death within 8 weeks. Secondary endpoints include median reduction in CMV viral load at day 28 and week 12, proportion with CMV below the limit of detection at weeks 2, 4, 8 and 12, mortality, grade ≥3 adverse events and serious adverse events, duration of hospitalization, tolerability, HIV treatment response, proportion with ganciclovir resistance and valganciclovir pharmacokinetics. Data from the NIRVANA phase 2 trial including valganciclovir pharmacokinetic data will be used to inform design of a multi-site phase 3 randomized controlled trial powered for survival to investigate whether valganciclovir reduces mortality among hospitalized adults with AHD-associated CMV viraemia.This article is part of the discussion meeting issue 'The indirect effects of cytomegalovirus infection: mechanisms and consequences'.