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Introduction
Pneumonia remains the main cause of death in children in the postnatal period. Although underdiagnosed, tuberculosis is also a common cause of death, particularly in children with HIV infection. In 2022, according to UNAIDS, 1.5 million children under 15 years of age were living with HIV worldwide, mainly in Sub-Saharan Africa, and the global number of child deaths is 110,000 to 120,000 per year. Of those, 40,000 deaths could be attributable to tuberculosis (TB), despite early initiation of antiretroviral treatment (ART) [1, 2].
The current World Health Organization (WHO) guidelines include a standard of care (SoC) intervention to treat pneumonia in children living with HIV (CLHIV) caused by Pneumocystis jirovecii, Streptococcus pneumoniae, and Haemophilus influenzae b [3]. This intervention has insufficiently decreased mortality, allegedly due to other important causes of death, such as cytomegalovirus (CMV) and TB. Both are still underdiagnosed and undertreated in this population [4] due to the barriers and difficulties in diagnosis. The current SoC includes microbiological testing for TB in those children with suspected TB. However, even with this approach, a significant number of TB patients remain undiagnosed or late diagnosed. According to the WHO, improving access to oral systemic treatment with valganciclovir to treat CMV pneumonia is an explicit priority in children according to the 2017 Advanced HIV Disease Guidelines [5].
Systematic empirical treatment for CMV and TB may be lifesaving for infants living with HIV. Systematic empirical treatment for TB in severely immunosuppressed HIV-infected patients without evidence of active TB disease is an open question that has been assessed in a randomized trial in adults, but currently, there are no similar studies focused on infants [6]. Although synergistic deleterious effects of CMV and TB coinfection have been reported, the impact of these coinfections is poorly understood in children [7, 8, 9–10].
The ongoing EMPIRICAL trial is an international phase II-III multicenter, open-label randomized factorial clinical trial. This trial is funded by EDCTP (Grant number: RIA2017MC- 2013 EMPIRICAL). This trial is being conducted in six African countries, Ivory Coast, Malawi, Mozambique, Uganda, Zambia, and Zimbabwe, in collaboration with research organizations from Spain, France, the UK, Italy, and The Netherlands. Participants in the trial were randomized to four different arms in a 1:1:1:1 fashion (SoC, TB-Treatment + SoC, Valganciclovir...
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