Two studies were presented at the recent virtual Conference on Retroviruses and Opportunistic Infections (CROI) looking at the interaction between gender-affirming hormone therapy (GAHT) and HIV pre-exposure prophylaxis (PrEP), both conducted by Dr Jenna Yager and colleagues at the University of Colorado, provided reassurance that levels of GAHT are not significantly lower in young transgender men and women once they start taking PrEP. Looking at the effect of GAHT on PrEP levels, although intracellular levels of the PrEP drugs tenofovir disoproxil fumarate and emtricitabine were lower in trans women than in trans men, they were still well within the range of levels seen in similar studies of directly observed PrEP conducted in cisgender people.
In both studies, young trans people aged 16-24 (average age 20) who had been on GAHT for at least a month – half of them women taking oestrogen and half of them men taking testosterone – then started taking directly observed daily oral PrEP using tenofovir/emtricitabine. The first study focused on hormone levels. In the second, PrEP levels were compared between the women and men in the study, and were also compared with PrEP levels in studies that established typical PrEP levels in cisgender people (an example is HPTN 066). GAHT was not discontinued during either study.
The same 24 trans men and 26 trans women took part in both studies, except that hormone levels could not be measured in one female participant, so the first study has data on 25 trans women.
In the first study, while the levels of estradiol (the metabolite of oestrogen) and testosterone were both slightly lower after PrEP was started, the difference in levels was not statistically significant and would not have any clinical effect. Estradiol levels were collected at baseline (before PrEP) and after 2-3 weeks on PrEP.
There were no significant differences in hormone levels after starting PrEP in either gender. Various measures of hormone levels were taken but the Cmax or peak levels were perhaps of most interest as they were compared with existing guidelines issued by the US Endocrine Society.
The Cmax of estradiol in the women was 334 picograms per millilitre (pg/ml) off PrEP and 284 pg/ml on it. This 15% difference was not statistically significant. The levels were actually slightly higher than the guideline levels of 100-200 pg/ml issued by the Endocrine Society. In the men, the Cmax levels of testosterone were 813 nanograms/ml (ng/ml) before PrEP and 739 ng/ml on it, a 10% difference and also not significant. This was well within the Endocrine Society’s recommended levels of 300-1000 ng/ml.
In the second study, after participants started PrEP, levels of the PrEP drugs tenofovir and emtricitabine were initially taken at random times during the first 2-3 weeks, just to get an idea of the range of levels and how they built up in cells. They were then taken four hours after dosing and then 24 hours after dosing (just before the next pill).
Levels were measured as intracellular levels of tenofovir and emtricitabine in lymphocytes circulating in the blood – so called peripheral blood mononuclear cells or PBMCs.
Among the women, 12 were taking their GAHT as intramuscular injections and 14 were taking oral pills. Eighteen (69%) were also taking the testosterone blocker spironolactone. Among the men, 12 were taking intramuscular testosterone injections and 12 subcutaneous ones.
Kidney function, as measured by creatinine clearance, was on average 136 ml/min (with a lowest value 102 ml/min) in the trans women and on average 117 ml/min (lowest value 69 ml/min) in the men.
Kidney function and route of administration are worth mentioning as they turned out to be important, at least in the trans women.
The intracellular levels of tenofovir were 34% higher in the men than the women, and the emtricitabine levels 56% higher. This difference was statistically significant (p = 0.0485 for tenofovir and p = 0.0032 for emtricitabine) but it stopped being significant for tenofovir once the rate of elimination via the kidneys was taken into account (p = 0.15).
The absolute values for tenofovir were 75 femtomols per million cells (fmols/106 cells) in men and 56 fmols/106 cells in women. Historical controls in cisgender participants show typical levels to range from 36 to 71 fmols/106 cells, so these average levels were reassuringly normal.
Emtricitabine levels were 6.2 fmols/106 cells in men and 4.3 fmols/106 cells in women, with levels in cisgender historical controls ranging from 2.2 to 5.3 fmols/106 cells, so again high enough, or possibly even on the high side in men.
However, tenofovir values fell below the historical control levels in eight women (minimum value, 15 fmols/106 cells). This is where the method of administration of hormones becomes relevant.
Tenofovir and emtricitabine levels were both 42% lower in women who took their oestrogen via a weekly or fortnightly intramuscular injection than in women who took oral pills. For both drugs, these differences were statistically significant (p = 0.0134 and 0.0012).
All but one of the eight lowest tenofovir values were in women who took their oestrogen as an intramuscular injection. With the exception of this one outlier (who had the lowest tenofovir levels of all), tenofovir levels in the remaining 13 women who took oral oestrogen were either within the historical control levels, or even somewhat higher. In contrast, only five of the 12 women who took intramuscular oestrogen had levels above the lower limit of the historical controls.
The PrEP drug levels were not affected by mode of hormone administration in men.
Whether any of this has clinical significance is unknown. Dr Yager commented that the differences seen in intracellular drug levels were not reflected in plasma levels, where there was no difference between men and women. She added that it was too early to turn the findings on mode of administration into any kind of recommendation.
“We are not able to extrapolate the findings by route of hormone administration," she told aidsmap.com. "Since this was an exploratory analysis, these findings are hypothesis-generating and something that should be studied further.”
She also commented that to be surer about the significance of the evidence, drug levels would have to be measured in tissue from mucous membranes. A study to do this is being planned in Thailand.
Yager JL et al. Exogenous hormone pharmacokinetics in transgender adolescents receiving oral TDF/FTC. Conference on Retroviruses and Opportunistic Infections, abstract 366, 2021.
Yager JL et al. TFV-DP and FTC-TP in PBMC among transgender adolescents receiving daily TDF/FTC. Conference on Retroviruses and Opportunistic Infections, abstract 367, 2021.