A Phase 2b Trial of valganciclovir for the treatment of CMV viraemia for hospitalised adults with advanced HIV disease.

Despite the widespread roll-out of antiretroviral therapy (ART), 30-40% of people living with HIV (PWH) still present to care with advanced HIV disease (AHD), defined as CD4 < 200 cells/mm3 or WHO stage 3 or 4 disease. Approximately one-quarter of adults in sub-Saharan Africa start ART with CD4 counts < 100 cells/mm3 and have an estimated 10% mortality during the first 6 months; among patients with AHD requiring admission to hospital, in-hospital mortality is 25% or higher. The World Health Organization has highlighted AHD as a priority research area. Up to 50% of people living with AHD have detectable cytomegalovirus (CMV) in their blood; CMV viraemia (CMVV) has consistently been associated with increased mortality, but it is not known if this represents a causal link, or an association confounded by advanced immunosuppression and reactivation. Direct and indirect pathological effects of CMVV have long been suspected but the potential benefit of anti-CMV therapy has not been tested in randomised studies amongst hospitalised adults with AHD. Recent studies have shown that the novel anti-CMV drug letermovir reduces mortality in patients with haematological malignancy. Letermovir is prohibitively expensive and not widely available in countries where the majority of PWH live. Valganciclovir is an oral anti-CMV agent indicated for prophylaxis and treatment of CMV disease, including in AHD where there is extensive clinical experience of safety and effectiveness in patients with CMV end-organ disease including colitis and retinitis. Importantly, valganciclovir is the most affordable anti-CMV drug in low resource settings and therefore - if demonstrated to be efficacious and safe - is a feasible option for treatment of AHD-associated CMVV. We hypothesise that, in patients with AHD and CMVV, valganciclovir provided with ART will be safe, will result in a significant reduction in CMV viral load, and will lead to reduced mortality. To test these hypotheses, we will conduct a multi-site phase 2b placebo-controlled, randomised trial to evaluate safety and virological efficacy, and to gather preliminary data on the impact on mortality risk of valganciclovir in hospitalised adults with AHD and CMVV. One hundred and thirty patients with CMV viral load > 500 copies/mL will be randomised to valganciclovir 900mg daily for 28 days, or matched placebo on a background of standard care for AHD, including ART initiated in line with WHO guidance. The primary efficacy outcome is virologic response, measured by area under the time versus viral concentration curve (AUC) at 4 weeks. The primary safety outcome is grade 3 or higher treatment emergent adverse events. Secondary outcomes include all-cause mortality through 12 weeks, grade 3 or higher adverse events of special interest (cytopaemias), CMV viral load and HIV viral load measured at 12-weeks, and valganciclovir pharmacokinetics. The study will be performed by a group of experienced trialists in South Africa and Uganda, where case numbers and existing infrastructure support feasibility. If valganciclovir is demonstrated to be safe and efficacious in this context, this will provide strong justification for a phase 3 placebo-controlled randomised trial powered to definitively test whether valganciclovir has an impact on mortality. This phase 2b RCT will generate novel, important safety and efficacy data, and further develop research capacity at these two sites for a subsequent planned phase 3 RCT. A successful phase 3 study would directly influence WHO treatment recommendations as well as international and national treatment guidelines.