By: Craig W. Hendrix, MD., The Johns Hopkins University School of Medicine, Baltimore, MD
HIV is very common among transgender women, indicating a special population that would greatly benefit from pre-exposure prophylaxis (PrEP) with oral tenofovir and emtricitabine (sold by the brand name Truvada®). However, transgender women are not well represented in most large PrEP clinical trials and there are very few pharmacokinetic studies (where drug concentrations are measured over time) in transgender women. In addition, many transgender women also benefit from taking estrogens with or without anti-androgens as gender-affirming hormone therapy (GAHT). However, several surveys of transgender women taking GAHT indicate a high degree of unwillingness to take PrEP due to concerns that PrEP may impact their hormone regimens. Given the established benefits from both PrEP and GAHT, their likely use together, and the reluctance of many transgender women to take PrEP, it is essential to understand the potential for interactions between these drugs. Better understanding could provide reassurance to transgender women and clinicians that PrEP and GAHT could be prescribed together without risk of reducing the effectiveness or increasing side effects of either regimen.
Previously, laboratory and animal studies suggested that estrogens might either increase or decrease the concentrations of PrEP drugs, depending on which specific tests were used and in which tissues. Naturally high concentrations of estrogen in pregnant women are associated with reduced concentrations of many drugs that are processed by the kidneys, including PrEP drugs. There is no laboratory or clinical evidence to suggest that PrEP drugs have any effect on estrogen concentrations, but this has not been previously studied directly in clinical trials. Given the concern among transgender women that PrEP might adversely affect GAHT, and conflicting laboratory data that estrogen might affect PrEP drug concentrations, we and others set out to study drug-drug interactions between PrEP and GAHT in transgender women.
We performed a small, open label study of daily oral PrEP drug concentrations in blood and rectal tissue in eight HIV-negative transgender women (TGW) consistently taking GAHT and eight cisgender men. Research participants took daily oral PrEP for one week under direct observation in the research clinic to assure 100% adherence. After the last dose, blood and rectal tissue were collected to measure PrEP drug concentrations. We also measured estrogen and testosterone in the blood. We reported study results at the HIVR4P (HIV Research for Prevention) meeting in Madrid in October 2018.
The two primary outcome measures were differences in PrEP drug concentrations between transgender women and cisgender men, and changes in estrogen concentrations before and after PrEP in transgender women. To assess the impact of GAHT on PrEP, we calculated the total drug concentration in blood over 24 hours, also known as the area under the concentration versus time curve for 24 hours (AUC24), and we measured the drug concentration 24 hours after the last PrEP dose was taken, also known as the trough concentration. After one week of daily PrEP dosing, tenofovir and emtricitabine AUC24 and trough in the blood plasma of TGW were lower by 20% to 27% when compared to cisgender men. The other research team at the Thai Red Cross/HIVNAT also showed a slightly lower 12-18% reduction in tenofovir blood concentrations when an estrogen/cyproterone regimen was added to PrEP alone (presented at the Paris IAS 2017 meeting). Seeking a biologic explanation for these results, we found that kidney function (creatinine clearance and glomerular filtration rate) was substantially higher in the transgender women. These measures were also strongly and inversely correlated with plasma AUC and trough concentrations for both drugs—meaning that the higher the clearance, the lower the PrEP drug concentrations.
To work, both of the medicines included in Truvada® must be activated by enzymes in the body’s cells by the addition of phosphates to become tenofovir diphosphate and emtricitabine triphosphate. Because we believe the location of drug action for these medicines used as PrEP in transgender women is primarily in the rectal tissue cells, we measured these activated forms of the medicines in rectal tissue as well as blood. The differences in concentration of both active drugs inside certain white blood cells, known as peripheral blood mononuclear cells (PBMC), showed similar lower concentrations like that seen in the blood plasma. Unlike the plasma, however, these were not statistically significant and could have occurred by chance alone. In rectal tissue cells, the differences in active drug concentration were 62% to 68% lower in TGW compared to cisgender men, however, as in the PBMC, these were not statistically significant. Measuring drugs in tissue cells is highly variable and the small differences seen in plasma are hard to detect. Thus, we cannot say with confidence that the differences in activated drug in PBMC and rectal tissue cells are real. However, PBMC concentrations are highly related to blood plasma concentrations based on other studies, and we saw no evidence of changes in the body to explain a loss of this relationship. These facts provide a good reason to do larger studies to determine with confidence whether or not these changes in active PrEP drug concentration truly occur when PrEP is taken together with GAHT.
We saw no effect of Truvada® on estrogen or testosterone in our study. However, not all transgender study participants were on the same GAHT regimen, which introduced a lot of variability, making it harder to pick up small differences. Better evidence to prove there is no effect of PrEP on GAHT comes from the Thai Red Cross/HIVNAT study (mentioned earlier) in which all transgender women were on the same GAHT regimen of estrogen/cyproterone, in which PrEP drugs had no impact on estrogen concentrations. Their rigorous study design allowed the investigators to confidently detect smaller differences in drug concentrations than we could. Taken together, these studies provide good evidence that GAHT is not affected by oral PrEP. Because cyproterone is not available in the US and its specific role in the changes seen in PrEP drug concentrations was not directly assessed, we believe additional studies are needed.
The magnitude of the decreases in the 2 PrEP medicines in transgender women on GAHT are similar to the effects of regularly missing 1-2 doses each week. This decrease probably still provides high concentrations of protection with a daily dosing regimen – even if the rectal tissue cell concentrations are real and consistent with every other day dosing. However, PrEP drug concentrations in combination with GAHT and an on demand oral PrEP regimen, such as the regimen used in the Ipergay trial (the so-called 2-1-1 regimen), may fall below protective concentrations. Therefore, it would be wise to only recommend daily dosing of oral PrEP using Truvada® in transgender women, as in cisgender women, until other studies are completed. More importantly, there is reassurance across these two studies that PrEP drugs do not affect GAHT drug concentrations. Larger and more carefully controlled PrEP-GAHT interaction studies are needed to establish whether the differences in PBMC and rectal tissue are real, so that we could better understand the role of the different anti-androgen drugs such as spironolactone or Lupron in the GAHT regimens, and to provide more definitive guidance to clinicians who prescribe GAHT to transgender women who wish to take Truvada® as PrEP and GAHT together.
Dr. Craig Hendrix is the Wellcome Professor and Director in the Division of Clinical Pharmacology in the Departments of Medicine and Pharmacology and Molecular Sciences at Johns Hopkins University School of Medicine.