Relative Mitochondrial Toxicity of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil Fumarate (TDF)
Status:
Recruiting
Trial end date:
2022-07-01
Target enrollment:
Participant gender:
Summary
Increased comorbidities such as cardiovascular disease (CVD), are emerging problems in HIV
infection but the mechanisms are unclear. Understanding how antiretrovirals can minimize
morbidity in treated HIV infection is a research priority. Nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs) are included in all HIV treatment regimens. Tenofovir (TFV)
disoproxil fumarate (TDF) has been associated with an increased risk of nephrotoxicity and
bone disease compared with other NRTIs. Tenofovir alafenamide (TAF) is an oral prodrug of
TFV, but is more stable in plasma as compared with TDF and lower plasma levels of TFV are
thought to lead to the favorable safety profile of TAF. Mitochondrial dysfunction has a key
role in HIV pathogenesis and may be the common denominator that drives pathogenesis of
several comorbidities. Despite the better safety profile of newer (such as TDF) compared to
older NRTIs, there are concerns for the potential for longer term toxicity of NRTIs since the
exact cellular effects of NRTIs remain unclear. It is unknown whether a four-fold increase in
intracellular drug levels seen in peripheral blood mononuclear cells (PBMCs) with TAF may
increase toxicity in mitochondria. Better understanding of these effects could provide
insights into mechanisms of HIV pathogenesis and selection of NRTIs that improve morbidity in
chronic HIV infection.
Hypothesis: Despite higher intracellular levels, TAF has minimal mitochondrial toxicity
compared to TDF in vivo. This research will explore the relative mitochondrial toxicity of
newer NRTIs (TAF, TDF) as a possible mechanism for differential NTRI-related toxicities.
These data will allow selection of NRTIs that may improve morbidity in chronic treated HIV
infection. Towards this aim, the investigators will use a robust experimental approach to
study NRTI-related mitochondrial dysfunction using novel methods, human cell lines and PBMC.
Our specific aims are: Aim 1: To evaluate the relative in vitro effects of TAF and TDF
compared to an older NRTI (ddC) on 5 independent measures of mitochondrial function in the
human cell line HepG2 and PBMC. Aim 2: To explore in vivo whether there is increased
mitochondrial dysfunction with the use of TAF vs. TDF in chronic treated HIV infection. The
investigators anticipate that the proposed experimental approach will set the basis for
future large scale studies to directly compare subtle potential mitochondrial toxicities of
newer NRTIs in large HIV cohorts.