A TWO-PHASE randomised clinical trial has shown that low-dose hydrocortisone acutely sharpens verbal learning, memory and attention in virally suppressed women with HIV, pointing to stress-system modulation as a route to treating cognitive impairment in HIV.
Women with HIV experience high rates of trauma, chronic stress, and depression, all of which are linked to cognitive impairment. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoid receptor function, inflammation and HIV persistence have become leading candidate mechanisms, yet no intervention has directly targeted these pathways.
The placebo-controlled trial ran at Johns Hopkins University between November 2017 and July 2023. Eighty-one virally suppressed women with HIV aged 18 to 65 years, mean age 55.2 years (SD 8.0), were randomised to one of four treatment sequences. All had elevated self-reported stress, a mood or anxiety disorder, or both, alongside objective impairment in at least one cognitive domain.
Phase 1 was a double-blind crossover comparison of a single 10 mg oral dose of low-dose hydrocortisone (LDH) with placebo at 30 minutes and 4 hours.
Phase 2 compared daily 10 mg LDH with placebo over 4 weeks. Primary outcomes were verbal learning and memory (Hopkins Verbal Learning Test-Revised), working memory (Letter-Number Sequencing) and visuospatial ability.
Secondary outcomes covered attention, executive function, safety and mechanistic markers including salivary cortisol, inflammatory biomarkers, and HIV reservoirs.
The results revealed that LDH raised cortisol, peaking 75 minutes post dose (p < 0.001). At 4 hours it improved learning versus placebo (p = 0.03), while verbal delayed recall fell short of significance (p = 0.05). Attention improved at 30 minutes (p = 0.02) and 4 hours (p = 0.01). Working memory and visuospatial ability were unchanged.
In phase 2, memory improved with daily LDH but not placebo (p = 0.005), although the treatment by time interaction was not significant (p = 0.22). No biomarker tracked cognitive change.
Memory and learning impairment were common at baseline, affecting 58 (71.6%) and 41 (50.6%) participants, which supports the functional relevance of the domains that responded. LDH was well tolerated, and effect sizes sit in the range reported for other cognitive interventions.
Because peripheral biomarkers did not explain the benefit, the mechanism behind cognitive impairment in HIV remains open, and the authors position LDH as a proof-of-concept intervention rather than long-term corticosteroid treatment.
Reference
Rubin LH et al. Low-dose hydrocortisone and cognition in women with HIV: a randomized clinical trial. JAMA Netw Open. 2026;9(8):e2629185
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