Neuropsychiatric adverse events in tenofovir disoproxil fumarate- and tenofovir alafenamide-based HIV therapy and prophylaxis: a systematic review and meta-analysis.

Tenofovir is integral to antiretroviral therapy (ART) and preexposure prophylaxis (PrEP) for HIV, but its neuropsychiatric adverse events (NPAEs) have not been systematically investigated. This systematic review aims to characterize common NPAEs during tenofovir-based ART and PrEP and to assess tenofovir's specific role in their emergence. Four literature databases and three trial registries were searched up to December 31, 2023, for randomized controlled trials reporting NPAEs in treatment-naïve adults receiving tenofovir-based ART or PrEP. Meta-analyses compared tenofovir (with/without emtricitabine) to placebo and tenofovir alafenamide- to tenofovir disoproxil fumarate-based regimens. Sixty-nine trials (62 on ART, 7 on PrEP) with 29 340 patients on tenofovir-based therapies revealed headache, dizziness, insomnia, and depression as common NPAEs, especially in HIV studies. Meta-analyses of tenofovir (with/without emtricitabine) versus placebo only indicated an increased risk of dizziness (OR 1.32; CI 1.09-1.59; P = 0.004). Comparisons between tenofovir alafenamide and disoproxil fumarate did not reveal significant differences in NPAE risks, although sensitivity analyses suggested a higher risk of headache with tenofovir alafenamide in HIV studies (OR 1.24; CI 1.01-1.52; P = 0.04). Common NPAEs in tenofovir-based HIV multi-drug regimens highlight the need to screen HIV patients for neuropsychiatric complications. The lack of effect of tenofovir compared to placebo for most analyzable NPAEs suggests that tenofovir itself is mostly safe regarding NPAEs. However, a possible increase in dizziness risk with tenofovir, and a potential rise in headache risk with tenofovir alafenamide- compared to tenofovir disoproxil fumarate-based regimens in HIV therapy, merit further investigation.