HIV Antiviral Therapies May Have Different Metabolic Signature

Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), which are a key component of combination antiretroviral therapies (ARTs), used to treat HIV and hepatitis B. In a recent study comparing TAF and TDF, TAF was associated with reduced cellular respiration in peripheral blood mononuclear cells (PBMCs). It also reduced cellular respiration both in vivo and in vitro; however, the effects of TAF should be further explored, according to the study authors.

“Our study provides a unique insight into how commonly used ART regimens differentially impact cellular bioenergetics in blood immune cells; that may contribute to alterations in immune function which are important for triggering immune cell disfunction in treated chronic HIV,” wrote study authors in an article published in Metabolism. “We found that compared to TDF, TAF induced in vitro and in vivo differential impact on several measures of cellular bioenergetics.”

TAF and TDF are antivirals that generate the active metabolite tenofovir-diphosphate (TFV-DP). NFTIs that generate more TFV-DP can be more potent at a lower dose—this is important for patients with HIV, since HIV decreases their PMBC’s mitochondrial disfunction and has downstream effects on the immune system.

Therefore, it is important to understand the mitochondrial function of PBMCs in people with HIV (PWH), which may serve as a biomarker in determining overall cellular function. Investigators aimed to evaluate the relative mitochondrial toxicity of TDF compared to TAF, while also determining mitochondrial function in PBMCs in patients with HIV.

In one of the studies designed to switch antivirals TAF and TDF in PWH already on an identical and/or similar antiviral regimen, patients with HIV-1(−) were given a comparable concentration of TAF in vitro and were then assessed for cellular oxygen consumption rate (OCR). The OCR can be used to determine mitochondrial function, with lower levels indicating worse mitochondrial function. Additionally, in a separate open labelclinical trial, investigators studied the impact of TAF compared to TDR on OCR using an in vivo assessment. They looked at patients with HIV who were switched from a from TDF-based to TAF-based ART over 9 months. The primary outcome measured was OCR.

Data showed that TAF-based ART reduced OCR more than TDF-based ART in PBMCs; however, both TAF and TDF selectively alter elements of mitochondrial energy production, study authors wrote.

The study included some limitations. First, investigators did not study metabolomics and immune disfunction in depth. Additionally, there was no detailed assessment of a PWH’s metabolic status, and the study included only younger male patients, limiting generalizability.

“A deeper understanding of the specific mechanisms mediating effects of antivirals on immune cells is crucial to allow selection of antivirals that may prevent drug-associated morbidity and immune dysfunction in treated chronic HIV infection” investigators wrote in the article.

Reference

Ritou E, Satta S, Petcherski A, et al. Blood immune cells from people with HIV on antiviral regimens that contain tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) have differential metabolic signatures. Metabolism. doi:10.1016/j.metabol.2022.155395