ValgaNciclovIR for CMV Viraemia in AdvaNced HIV diseAse

Scientific Background and Rationale

Despite the widespread availability of antiretroviral therapy (ART), approximately 30 percent of adults with HIV continue to present to care with AHD, defined as a CD4 count \< 200 cells/μL or a World Health Organization (WHO) stage 3 or 4 disease. In sub-Saharan Africa, mortality among hospitalised adults with AHD remains unacceptably high, typically exceeding 20 percent within weeks of admission. There is an urgent need for interventions that reduce early mortality in this extremely vulnerable population.

Cytomegalovirus is a ubiquitous herpesvirus that remains latent after primary infection but can reactivate when immunity is impaired. In individuals with AHD, CMV reactivation is common: up to 50 percent of those with CD4 counts \< 100 cells/μL have detectable CMV DNA in plasma. CMV viraemia, even without end-organ disease, is associated with increased risk of death and opportunistic infections. However, no guidelines currently recommend antiviral therapy for CMV viraemia in this setting. International HIV guidelines emphasise early ART initiation, yet early mortality remains high irrespective of ART timing.

Valganciclovir, the oral prodrug of ganciclovir, is widely available, affordable, and effective against CMV. It has a well-characterised safety profile, though it can cause dose-related bone-marrow suppression. Observational and mechanistic studies suggest that CMV may contribute directly and indirectly to immune dysfunction, inflammation, and mortality among people with advanced HIV disease. If pre-emptive suppression of CMV replication reduces viraemia and improves outcomes, it could represent a feasible strategy to lower mortality in low-resource settings.

The NIRVANA trial will therefore assess whether valganciclovir is a safe and effective therapy for CMV viraemia in AHD. Pharmacokinetic data in this population are scarce; this study will also describe drug exposure and relationships with viral suppression and toxicity. The findings will inform the design of a larger Phase 3 trial powered to evaluate survival benefit.

Study Objectives and Hypothesis

Primary Objective:

To determine whether valganciclovir safely reduces CMV viral load compared with placebo among hospitalised adults with advanced HIV disease and CMV viraemia.

Secondary Objectives:

To assess the effect of valganciclovir on all-cause mortality and re-hospitalisation up to 12 weeks.

To characterise the pharmacokinetics of valganciclovir in this population. To evaluate tolerability and adverse-event rates. To explore immune responses, including cytokine profiles and interferon-gamma release to CMV antigen.

To describe HIV viral suppression at week 12 stratified by ART status. To examine emergence of ganciclovir resistance mutations at week 4.

Hypothesis:

Valganciclovir 900 mg once daily for 4 weeks, started at hospital admission, will significantly reduce CMV viral load compared with placebo and will be a safe therapeutic option for AHD-associated CMV viraemia.

Study Design

This is a multicentre, double-blind, parallel-group, randomised, placebo-controlled Phase 2b trial with a nested open-label pharmacokinetic sub-study. Participants meeting eligibility criteria will be randomised 1:1 to receive valganciclovir or placebo, stratified by site and baseline CMV viral load (\> 1000 IU/mL). Randomisation will be implemented through a central, web-based REDCap system using computer-generated blocks to maintain allocation concealment. Study tablets for both arms are identical in appearance, packaging, and dosing schedule. Participants and all site staff involved in patient management and outcome assessment will remain blinded to allocation.

An additional non-randomised sub-study of 20 participants receiving valganciclovir will provide intensive pharmacokinetic sampling before the main randomised trial begins.

The study duration per participant is 12 weeks, including 4 weeks of study treatment and 8 weeks of post-treatment follow-up. The overall trial is expected to last approximately 24 months.

Intervention and Comparator

Experimental Arm:

Valganciclovir 900 mg once daily, taken orally for 28 days, beginning on the day of randomisation. Participants with creatinine clearance 40-60 mL/min will receive 450 mg daily.

Control Arm:

Matching placebo tablets, identical in size, colour, and packaging, administered once daily for 28 days.

All participants will continue to receive \*\*standard of care (SOC)\*\* for advanced HIV disease according to national or local guidelines, which may include:

Diagnosis and treatment of opportunistic infections Antiretroviral therapy (ART) initiation or re-initiation Tuberculosis preventive therapy Cotrimoxazole prophylaxis Cryptococcal antigen screening and pre-emptive antifungal therapy if positive

ART initiation will follow WHO and national recommendations, typically within 2-3 weeks of hospital admission, except for participants with cryptococcal or tuberculous meningitis, who will defer ART for 4-8 weeks.

Study Population and Setting

Study Sites:

Helen Joseph Hospital, Johannesburg, South Africa Mulago National Referral Hospital, Kampala, Uganda

Target Population:

Hospitalised adults and adolescents (≥ 15 years) with advanced HIV disease and detectable CMV viraemia.

Inclusion Criteria:

Age ≥ 15 years Confirmed HIV infection CD4 count ≤ 100 cells/µL Plasma CMV viral load \> 500 IU/mL Ability to provide informed consent (or via legal surrogate if incapacitated)

Exclusion Criteria:

Clinical suspicion or diagnosis of CMV end-organ disease (including CMV retinitis) Pregnancy or breastfeeding Haematologic contraindications (absolute neutrophil count \< 1.0 × 10⁹/L, haemoglobin \< 8 g/dL, platelets \< 100 × 10⁹/L) Estimated creatinine clearance \< 40 mL/min or alanine aminotransferase \> 3× upper limit of normal Current high-dose acyclovir use or concurrent myelosuppressive therapy (e.g., amphotericin B deoxycholate, linezolid) Allergy or prior adverse reaction to valganciclovir Inability to swallow tablets or expected inability to complete follow-up Moribund condition likely to result in death within 48 hours

Study Procedures and Follow-up

Screening and Consent:

All hospital admissions will be screened for HIV and CD4 count per routine care. Eligible individuals with AHD will be approached for study participation. Informed consent will be obtained in the participant's preferred language. For those lacking decision-making capacity, proxy consent from a legally authorised representative will be permitted, with re-consent sought if the participant regains capacity.

Baseline Assessments:

Demographics, clinical history, physical examination, ART status, concomitant medications, and baseline laboratory tests (haematology, renal and liver function, HIV viral load, CD4 count, CMV viral load) will be recorded in electronic case-report forms (eCRFs).