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.

BACKGROUND: 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.

METHODS: 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.

FINDINGS: 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]).

INTERPRETATION: 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.

FUNDING: European and Developing Countries Clinical Trials Partnership.