The effect of depot medroxyprogesterone acetate on tenofovir alafenamide in rhesus macaques

Abstract

Prevention of HIV infection and unintended pregnancies are public health priorities. In sub-Saharan Africa, where HIV prevalence is highest, depot medroxyprogesterone acetate (DMPA) is widely used as contraception. Therefore, understanding potential interactions between DMPA and antiretrovirals is critical. Here, we use a macaque model to investigate the effect of DMPA on the pharmacology of the antiretroviral tenofovir alafenamide (TAF). Female rhesus macaques received 30 mg of DMPA (n = 9) or were untreated (n = 9). Macaques received a human equivalent dose of TAF (1.5 mg/kg) orally by gavage. Tenofovir (TFV) and TFV-diphosphate (TFV-DP) were measured in blood, secretions, and tissues over 72 h. The median area under the curve (AUC 0–72h ) values for TFV-DP in peripheral blood mononuclear cells were similar in DMPA-treated (6991 fmol*h/10 6 cells) and untreated controls (5256 fmol*h/10 6 cells) (P = 0.174). Rectal tissue TFV-DP concentrations from DMPA+ animals [median: 20.23 fmol/mg of tissue (range: 4.94–107.95)] were higher than the DMPA− group [median: below the limit of quantification (BLOQ-11.92)], (P = 0.019). TFV-DP was not detectable in vaginal tissue from either group. A high-dose DMPA treatment in macaques was associated with increased rectal TFV-DP levels, indicating a potential tissue-specific drug-drug interaction. The lack of detectable TFV-DP in the vaginal tissue warrants further investigation of PrEP efficacy with single-agent TAF products. DMPA did not affect systemic TAF metabolism, with similar PBMC TFV-DP in both groups, suggesting that DMPA use should not alter the antiviral activity of TAF.

Pharmacokinetic Study of Islatravir and Etonogestrel Implants in Macaques

“…ISL-TP competes with the natural nucleotide dATP for incorporation by reverse transcriptase, and some studies suggest that hormonal contraceptives can alter nucleotide metabolism [ 39 , 40 , 41 ]. To determine whether ENG affected nucleotide metabolism and possibly competition between ISL-TP and dATP, we compared ratios between ISL-TP and dATP among ISL-98 mg-implanted animals before and after ENG-33 mg implantation.…”

“…As dATP and ISL-TP compete for the active site of reverse transcriptase, a higher ratio of ISL-TP:dATP indicates a higher likelihood of ISL-TP incorporation and viral inhibition. Other studies have noted compartment-specific effects of hormonal treatments on nucleotides, both endogenous and antiretrovirals [ 39 , 40 , 41 ]. Further studies are needed to define the vaginal PrEP efficacy of ISL and possible modulations of activity in the presence of ENG or other hormonal contraceptives.…”

Consensus recommendations for use of long‐acting antiretroviral medications in the treatment and prevention of HIV‐1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy, Canadian HIV and Viral Hepatitis Pharmacists Network, European AIDS Clinical Society, and Society of Infectious Diseases Pharmacists

“…Early work on MPTs to prevent HIV-1 and pregnancy via administration of ARVs and hormonal contraceptive agents as subcutaneous injections, implants, and intravaginal rings is promising. [197][198][199][200] Future LA ARV formulations should focus on pairing with other MPTs.…”

Cell and Tissue Specific Metabolism of Nucleoside and Nucleotide Drugs: Case Studies and Implications for Precision Medicine

“…As such, understanding the effects that contraceptives may have on TFV phosphorylation is also an important area of study. In a macaque study, it was shown that depot medroxyprogesterone acetate (DMPA) use resulted in increased rectal concentrations of TFV-DP after an oral dose of TAF (Daly et al, 2021). There were no differences in PBMC TFV-DP concentrations, and vaginal tissue levels were undetectable in both groups.…”