Effect of hormonal contraception on tenofovir levels unclear
After a detailed study of the pharmacokinetics of oral tenofovir in women using various contraceptive methods, researchers were unable to determine whether hormonal contraception lowers tenofovir concentrations.
An analysis of secondary data from the Microbicide Trials Network phase 2 MTN-001 trial — designed to evaluate adherence to oral and vaginal formulations of the antiretroviral drug tenofovir to prevent HIV transmission — was presented by lead researcher Jenell Coleman, MD, MPH, assistant professor of gynecology and obstetrics and of medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland, here at the AIDS 2012: XIX International AIDS Conference.
Tenofovir alone or in combination with emtricitabine as preexposure prophylaxis against HIV has yielded various results in terms of risk reduction for infection. The mixed results could be due to behavioral differences (such as adherence or sexual or partnership characteristics) or, as Dr. Coleman and colleagues hypothesized, they could be due to sex or hormonal differences.
Estrogen and progesterone have positive and negative effects on various cellular transporters that cause the uptake or efflux of tenofovir from cells.
The researchers evaluated the effects of hormonal contraception on tenofovir pharmacokinetics. They enrolled 138 healthy, HIV-negative, sexually active women in South Africa, the United States, and Uganda who were using effective forms of birth control.
For contraception, 40 women (29%) used nonhormonal methods (intrauterine device, sterilization), 59 (42.8%) used injectable hormones, and 39 (28.2%) used oral contraceptives.
The women took a single daily oral dose of tenofovir for 6 weeks. Two pharmacokinetic analyses were done: a noncompartmental analysis (NCA) that involved just the American women, and a pharmacokinetic mixed-effect analysis that involved the African and American women.
NCA is highly dependent on total drug exposure (estimated using the area under the concentration curve [AUC]), which in turn is highly dependent on the blood-sampling frequency. Sampling was much more frequent after drug dosing in the NCA cohort.
The NCA cohort was about half white and half black, whereas the mixed-effect cohort was 57% black and 35% white. The NCA cohort was heavier than the mixed-effect cohort by about 4 kg.
In the NCA cohort, 47.1% used nonhormonal contraception, 11.4% used injectable hormones, and 41.4% used oral contraceptives; in the mixed-effect cohort, the rates were 36.0%, 28.0%, and 35.0%, respectively. Creatinine clearance rates were similar in the 2 cohorts, and were normal.
There was no difference in the predose concentrations of tenofovir among the different forms of contraception.
Dr. Coleman reported tenofovir concentrations at 0 to 8 hours for the NCA cohort. "All contraceptive types appear to be similar; however, the injectables showed decreased tenofovir levels across all time points," she said.
Across the board, oral contraceptives led to the lowest intracellular concentrations of tenofovir in peripheral blood mononuclear cells (PBMCs), she noted.
However, the injectable hormones were associated with decreased tenofovir maximum concentrations (Cmax) and AUC. There were no statistically significant predose differences in intracellular concentrations in PBMCs, although oral contraceptives led to a slightly lower Cmax and predose AUC.
When all 138 women were analyzed together, "injectables appeared to decrease both serum tenofovir levels and diphosphate intracellular concentrations," Dr. Coleman reported.
Predose intracellular levels were approximately 23 fmol/10⁶ cells with nonhormonal methods, approximately 17 fmol/10⁶ cells with injectable hormones, and between 17 and 23 fmol/10⁶ cells with oral contraceptives.
For the mixed-effect cohort (100 African women with 473 measured concentrations), older age was associated with less clearance of tenofovir, higher body weight increased the volume of distribution, and race was associated with a parameter (C0) that took into account predose concentration.
In the mixed-effect cohort, "the effect of injectables on clearance was evident," Dr. Coleman said. "However, it was not significant once it was placed into the multivariable model."
She explained that in the NCA cohort, "there were significant differences between injectables, [oral contraception], and nonhormonal contraception." With the injectables, there were statistically significant decreases in Cmax, AUC, and the predose concentration.
Oral contraception was associated with decreases in Cmax and AUC in PBMCs.
In the mixed-effect cohort, injectable hormones were not a significant covariate in tenofovir serum clearance. There was a higher clearance rate in the NCA cohort, but that was highly influenced by 2 women who had very high clearance levels.
Dr. Coleman noted that although the data are provocative, it is not possible to draw any "definitive conclusions about whether or not hormonal contraception lowers tenofovir concentrations." Furthermore, the effective concentration of tenofovir for HIV prophylaxis is not known, so the effect of the hormonal contraceptives on prevention is unclear.
The MTN-001 trial was not designed to address the questions investigated in this secondary analysis, which is a limitation of the study. Also, it did not control for age, which is highly correlated with injectable hormone use, and the specific composition of the oral contraceptives and injectable hormones was not known, she noted.
Session moderator Heather Jaspan, MD, PhD, senior scientist at Seattle BioMed in Washington, and senior lecturer at the University of Cape Town, South Africa, told Medscape Medical News that the results of this study do not give any clinical guidance, but it is definitely worth pursuing the relation between hormonal contraception and tenofovir levels.
Dr. Jaspan pointed out that it is important to look at the way hormone levels and inflammation relate to drug levels. "It's probably most important to look in the female genital tract or in the rectum, where the drugs are actually working, and not necessarily in the blood...in cervical-vaginal lavages, for example," she said. "At least the data give us insights into what factors we should be looking at in future studies," she noted.
The study was funded by the US National Institutes of Health, and Gilead provided the tenofovir. Dr. Coleman and Dr. Jaspan have disclosed no relevant financial relationships.
By Daniel M. Keller, PhD
AIDS 2012: XIX International AIDS Conference: Presentation FRLBC03 – Late Breaker. Presented July 27, 2012.
Source: Medscape Today