Internal and External Drivers of CD4 Recovery in People with HIV.

purpose of reviewThis review summarizes the key factors that influence CD4 recovery after antiretroviral therapy (ART) initiation in people with HIV (PWH). RECENT

findingsSeveral immunomodulatory agents have been tested in clinical trials as adjuncts to ART. While interleukin-2 and interleukin-7 produce transient CD4 increases, and agents such as recombinant human growth hormone, maraviroc, and others show modest or variable effects, most have not demonstrated clear clinical benefit. Emerging evidence underscores the need for personalized approaches, reliable biomarkers to predict CD4 recovery, and novel adjunctive therapies such as gene editing and mitochondrial-targeted interventions. Poor CD4 recovery contributes to higher rates of non-AIDS complications. We highlight clinical determinants (e.g., timing of ART initiation), biological influences (e.g., epigenetic modifications), cellular factors (e.g., mitochondrial dysfunction), and modifiable socioeconomic determinants (e.g. nutrition, substance use). Addressing factors impacting CD4 recovery is critical to improving long-term outcomes for PWH.