Mitochondrial disorders after 12 months of HIV-1 preexposure prophylaxis based on tenofovir disoproxil fumarate plus emtricitabine in healthy adults.

Abstract

Background: New nucleos(t)ide reverse transcriptase inhibitors are considerably less toxic than their predecessors, but they may not be entirely devoid of toxicity. However, their effect in healthy adults remains unknown. We aimed to analyze the impact of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC)-based preexposure prophylaxis (PrEP) on mitochondria of subjects at high risk of HIV-1 infection.

Methods: This is an observational, prospective study of 59 healthy adults enrolled in the PrEP program at Virgen del Rocio University Hospital. Mitochondrial DNA and common deletion 4977 were measured using digital droplet PCR. Mitochondrial density, membrane potential, oxidative stress, metabolic profile, and morphology were assessed by flow cytometry, real-time cellular bioenergetics measurements, and transmission electron microscope, respectively, at baseline and after 12 months. Values were compared by the Wilcoxon test, and correlations between variables were assessed using the Spearman rank correlation coefficient (ρ).

Results: Our results showed that after 12 months, TDF/FTC induced a mitochondrial oxidative stress increase in myeloid and lymphoid populations. Mitochondrial density decreased in CD8+ T cells and NK cells, while mitochondrial membrane potential augmented in all lymphoid populations. Cell bioenergetic health was compromised, evidenced by reduced oxygen consumption rate, declined ATP production, and impaired response capacity to an energetic demand. Changes in mitochondrial shape, membrane integrity, cristae structure, size, and distribution throughout the cytoplasm were also observed. All participants experienced alterations in one or more measured parameters.

Conclusions: TDF/FTC-based PrEP induces mitochondrial toxicity in healthy subjects after 12 months of treatment, negatively affecting mitochondrial function and morphology.