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). Randomisation and Treatment: Eligible participants will be randomised via REDCap to one of the two treatment arms. Study medication will be dispensed within 24 hours of randomisation, and dosing will be supervised by nursing or study staff during hospitalisation. Follow-up Visits: Participants will be followed daily while in hospital, then weekly to week 4, and at weeks 8 and 12 post-randomisation. At each visit, clinical status, medication adherence, vital signs, and laboratory parameters will be reviewed. CMV viral load will be measured at baseline, days 14 and 28, and weeks 8 and 12. Blood counts, creatinine, and liver enzymes will be checked at multiple time points. Safety Monitoring: Adverse events of special interest (AESIs) include severe neutropenia, anaemia, thrombocytopenia, renal dysfunction, and hepatotoxicity. Participants experiencing grade ≥ 3 events will be promptly evaluated; study medication will be discontinued if no alternative cause is identified. Pharmacokinetic (PK) Sampling: Sparse PK samples will be collected at 2-3 hours post-dose on days 4, 7, 14, and 28 from all randomised participants. Intensive PK sampling will be performed in the sub-study cohort. Plasma samples will be analysed at the Infectious Diseases Institute laboratory in Uganda. Immunology Sub-study: Blood samples at baseline and selected follow-up points will be used for cytokine and interferon-gamma analyses to characterise immune response to CMV antigen. Withdrawal and Replacement Participants discontinuing study drug will continue scheduled follow-up unless consent is withdrawn. Data collected prior to withdrawal will be retained; participants withdrawing before 4 weeks may be replaced. Outcome Measures Primary Outcome: Composite of safety events (adverse events of special interest, re-hospitalisation, or death) up to 8 weeks after randomisation. Secondary Outcomes: Safety: same composite endpoint up to 12 weeks. Hospital length of stay post-randomisation. Serious adverse events through week 12. Mortality: survival time and all-cause mortality at 4 and 12 weeks. Efficacy: Median reduction in CMV viral load (log₁₀ IU/mL) from baseline to day 28 and week 12. Proportion of participants with undetectable CMV viral load at weeks 2, 4, 8, and 12. Tolerability: proportion of participants discontinuing study medication early. Resistance: presence of UL97 kinase or UL54 DNA polymerase gene mutations at week 4. HIV treatment response: proportion achieving HIV RNA \< 50 copies/mL at 12 weeks. Pharmacokinetic parameters of valganciclovir. Immunologic markers of cytokine response. Statistical Considerations The study is powered to detect a 20 percent difference in the primary efficacy endpoint-median reduction in CMV viral load-between treatment arms with 90 percent power and a two-sided α of 0.05. Allowing for attrition, 130 randomised participants (65 per arm) will be enrolled. Analyses will follow the intention-to-treat principle. Primary efficacy comparisons will use the geometric mean ratio of log₁₀ CMV viral load with 95 percent confidence intervals. Safety analyses will summarise adverse events by frequency and grade with absolute risk differences between arms. Missing data will be addressed using multiple imputation when appropriate. PK data will be analysed using both non-compartmental and mixed-effects modelling to explore exposure-response relationships. Safety Monitoring and Reporting All adverse events, serious adverse events (SAEs), and AESIs will be recorded in eCRFs. SAEs deemed related to study intervention and unexpected for the patient population will be reported promptly to the relevant institutional review boards (IRBs) and national regulatory authorities according to local requirements. An independent Data Safety and Monitoring Committee (DSMC) will review unblinded safety and efficacy data periodically. The DSMC will include independent clinicians from Uganda and South Africa, the trial statistician, and a chairperson. Recommendations from the DSMC will guide the Trial Management Group on continuation or modification of the study. Data Management Data will be collected electronically using a secure REDCap platform with built-in range and consistency checks. Paper worksheets may be used temporarily if electronic capture is unavailable. The Clinical HIV Research Unit in Johannesburg will maintain the de-identified database on a secure server with restricted access. Quality-control procedures include regular data audits, query resolution, and compliance with Good Clinical Data Management Practice. Participant confidentiality will be preserved using coded identifiers; no personally identifying data will leave the site. Ethical and Regulatory Oversight The trial will be conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice (GCP), and all applicable national and institutional regulations. Ethical approval will be obtained from the University of the Witwatersrand Human Research Ethics Committee, the Uganda National Council for Science and Technology, and the London School of Hygiene and Tropical Medicine Research Ethics Committee. Written informed consent will be obtained from all participants or their authorised representatives. Consent procedures will be conducted in participants' preferred languages, with accommodations for literacy and comprehension. All participants will be informed that participation is voluntary and that withdrawal will not affect their medical care. Participant confidentiality will be maintained through coded data, secure storage, and controlled access. Clinical information will be released only to authorised entities such as the sponsor, IRBs, and regulatory authorities for monitoring and auditing purposes. Study Governance The Wits Health Consortium serves as the trial sponsor. Principal Investigators include Dr Mohammed Rassool (South Africa) and Dr Laura Nsangi (Uganda), with oversight by an international team of co-investigators from the London School of Hygiene and Tropical Medicine, the Infectious Diseases Institute (Uganda), St George's University of London, and the University of Minnesota. A Trial Management Group (TMG) composed of investigators and the study statistician will meet regularly to monitor trial progress, review data, and approve protocol amendments and publications. An independent Trial Advisory Committee (TAC) of senior external academics will review progress approximately every six months and advise the TMG. All investigators have completed Human Subjects Protection Training and have declared no conflicts of interest. Personnel are indemnified by their employing institutions. Funding is provided by the United Kingdom Medical Research Council. Expected Impact The NIRVANA trial addresses a major gap in the management of advanced HIV disease in resource-limited settings. CMV viraemia is common and strongly associated with early mortality, yet there is no evidence-based therapeutic strategy to address it. By establishing whether valganciclovir safely reduces CMV viral load and by defining its pharmacokinetics and tolerability in this population, NIRVANA will provide the essential foundation for a definitive Phase 3 trial powered to detect mortality benefit. If successful, the findings could lead to a low-cost, implementable intervention to reduce deaths among people with advanced HIV disease worldwide.