Empirical treatment with valganciclovir in infants living with HIV and hospitalised with severe pneumonia in Africa: a multicentre, open-label, factorial, randomised, controlled, superiority trial.

Mortality among infants with severe HIV-associated pneumonia remains high. This trial (EMPIRICAL) tested whether empirical valganciclovir treatment for cytomegalovirus improves survival in infants in Africa. This multicentre, open-label, group-sequential designed, 2 × 2 factorial, randomised, controlled, superiority trial was conducted in 19 hospitals across Côte d'Ivoire, Malawi, Mozambique, Uganda, Zambia, and Zimbabwe. Infants aged 28-365 days admitted with severe HIV-associated pneumonia were centrally and individually randomly assigned (1:1:1:1) using a secure web-based system stratified by site and severity to receive standard of care (SOC) comprising treatment for bacterial (WHO-recommended antibiotics) and Pneumocystis jirovecii (cotrimoxazole and steroids) pneumonia, SOC plus 15 days of oral valganciclovir (16 mg/kg per 12 h), or SOC plus 6 months of tuberculosis treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol for 2 months, plus isoniazid and rifampicin for 4 subsequent months), or both interventions combined. The primary endpoint was all-cause mortality, assessed at day 15 and over 1-year follow-up in the intention-to-treat population. In this Article, we report results for the valganciclovir comparison groups. The trial is registered with ClinicalTrials.gov, NCT03915366 and is complete. From March 15, 2020, to Jan 31, 2024, 563 participants were enrolled; 558 were included in the analyses, with 276 allocated to valganciclovir groups (140 valganciclovir; 136 valganciclovir plus tuberculosis treatment) and 282 to groups without valganciclovir (142 SOC; 140 tuberculosis treatment). The median patient age was 4·4 months (IQR 3·2-7·4), and 274 (49%) were female. There was no evidence of interaction between valganciclovir and tuberculosis treatment (adjusted hazard ratio 1·19 [95% CI 0·73-1·95], heterogeneity p=0·48). At day 15, 64 (23%) of 276 participants in the valganciclovir group and 76 (27%) of 282 in groups without valganciclovir died (rate ratio 0·81 [95% CI 0·61-1·08], p=0·15). 24 (9%) of 276 participants and 13 (5%) of 282, respectively, were lost to follow-up. After 12 months, 119 (43%) of 276 participants in the valganciclovir groups and 134 (48%) of 282 in the groups without valganciclovir died (0·88 [95% CI 0·74-1·05] p=0·15). In a time-varying effects model, at day 15, the adjusted hazard ratio of death was 0·60 (95% CI 0·41-0·87, p=0·0063), and their hazard of death over 1 year was 0·79 (0·62-1·01; p=0·068), or 0·76 (0·58-1·00; p=0·0500) when excluding deaths within 48 h of treatment. Severe adverse events during follow-up were not more common in the valganciclovir treatment groups (odds ratio 0·64 [95% CI 0·35-1·16]). Empirical valganciclovir treatment appeared to be associated with a lower hazard of death in infants with severe HIV-associated pneumonia than SOC alone or SOC plus empirical tuberculosis treatment, and there was little evidence of associated harms. European and Developing Countries Clinical Trials Partnership.