Tenofovir Achieves High Levels in the Genital tract of Men & Women and Reduces HIV RNA in Genital Tract of Men & Women
Reported by Jules Levin
"A Pharmacologic Basis for the Use of Tenofovir in Pre- and Post-Exposure Prophylaxis: Intra and Extracellular Genital Tract Pharmacokinetics and Pharmacodynamics from First Dose to Steady State in HIV-1 Infected Men and Women"
M Vourvahis1, H Tappouni1, K Patterson1, Y Chen1, NL Rezk1, S Fiscus1, BP Kearney2, JF Rooney2, M Cohen1, ADM Kashuba1
1University of North Carolina, Chapel Hill, NC, 2Gilead Sciences, Inc, Foster City, CA
Tenofovir rapidly achieves high extracellular and intracellular concentrations in the genital tract of men & women. Tenofovir monotherapy significantly reduced HIV RNA by -1.1 log copies/ml in men & -1.0 log copies/ml in women in the genital tract over 14 days.
From Day 1 to steady-state, TFV exposures were high in the GT (genital tract) of men (EC and IC) and women (EC)
- Extracellular TFV GT:B (blood) concentration ratios in men at C24h on Day 1 and steady-state were 4.4 ± 5.1 and 5.1 ± 6.8, respectively
- Extracellular TFV GT:B concentration ratios in women at C24h on Day 1 and
steady-state were 9.7 ± 15.2 and 8.8 ± 12.1, respectively
- Extracellular TFV GT:B AUC0-24h ratios in women on Day 1 and steady-state
were 4.2 ± 3.9 and 2.5 ± 3.1, respectively
- Intracellular TFV-DP GT:B concentration ratios in men at C24h on Day 1 and
Day 7 were 3.1 ± 5.4 and 7.0 ± 14.8, respectively
- Mean IC blood mononuclear cell concentration was 255 ± 384 fmol/106 cells
- Mean IC GT mononuclear cell concentration was 772 ± 1592 fmol/106 cells
- Intracellular concentrations of TFV-DP could not be detected in the GT of all women and some men due to low cell yields (< 106 cells/sample)
Tenofovir monotherapy significantly reduced HIV-1 RNA in men by 1.1 ± 0.4
log10 copies/mL in Blood and 1.0 ± 0.5 log10 copies/mL in Genital Tract over 14 days (p < 0.05).
In the 1 woman on tenofovir monotherapy, HIV-1 RNA decreased by
0.8 log10 copies/mL in both Blood and Genital Tract.
The rapid achievement of high extracellular and intracellular tenofovir
concentrations in the genital tract of men and women is encouraging and supports further study of tenofovir in pre- and post-exposure prophylaxis trials.
Background: Tenofovir (TFV) is effective in preventing HIV transmission in animal models, and is being investigated for pre-exposure prophylaxis in a number of populations. However, no comprehensive data exist describing TFV exposure in the genital tract (GT). This is the first study to measure TFV extracellular (EC) and intracellular (IC) diphosphate (TFV-DP) concentrations
(CONC) in the GT of men (M) and women (W) from Day 1 to steady-state (SS).
Methods: A non-blinded pharmacokinetic study was performed in HIV-1 infected subjects (9Men/13Women). A subset (8Men/1Women) underwent 14d of monotherapy to assess TFV effects on GT HIV-1 RNA. For M, paired blood (B) and GT samples were obtained 24h post-dose on D1, 3, 5, and 7. At SS (≥14 days), 10 B and 5 GT samples were obtained over 24h. For W, 6 paired B and GT samples were obtained over 24h on D1 and at SS. IC CONC were measured in mononuclear cells (MC) isolated from blood, semen, and cervical cytobrush samples using percoll and/or Dynabeads. GT EC CONC were measured in B plasma, seminal plasma, or directly aspirated cervicovaginal fluid. CONC were measured by validated LC/MS/MS and LC/UV assays. B and GT HIV-1 RNA were measured by Roche Amplicor HIV-1 Monitor UltraSensitive and Nucli-Sens HIV-1 kits. Data were analyzed using noncompartmental PK and nonparametric statistical methods. Data are presented as mean (SD).
At 24h, IC TFV-DP GT:B ratios in M for D1 and 7 were 3.1±5.4 and 7.0±14.8, respectively. TFV-DP could not be detected in the GT of all Women and some Mendue to low cell yields (< 106 cells/sample). TFV exposures were significantly greater (p<0.05) in GT than B at both D1 and SS in M and W. Over 14 days in M, HIV-1 RNA decreased by 1.1±0.5 log10 copies/mL in B and 1.0±0.4 log10 copies/mL in GT (p<0.05). In the 1 W on TFV monotherapy, HIV-1 RNA decreased by 0.8 log10 copies/mL in both B and GT.
Conclusions: From Day 1 to Steady State, TFV exposures were high in the GT of Men (EC and IC) and Women (EC). These EC and IC GT exposures are the highest (relative to B) amongst other ARVs reported to date. TDF monotherapy significantly reduced both Blood and GT HIV-1 RNA over 14 days. The rapid achievement of high EC and IC CONC in the GT of Men and Women is encouraging, and supports further study of TDF in pre- and post-exposure prophylaxis trials.
The male and female genital tract may be a reservoir for HIV-1 replication1-3
--Resistant HIV-1 isolates have also been recovered from the male and
female genital tract4
Sexual transmission of HIV-1 is dependent on the viral load in the genital tract5
--Resistant HIV-1 isolates can be spread from HIV-infected sexual partners
via infectious genital tract secretions6
--Evolution of HIV-1 resistant variants in blood and the genital tract may be
Antiretroviral drug concentrations in the genital tract of males and females
may influence viral replication and the development of drug resistant virus
--Antiretrovirals that reduce viral shedding in the genital tract may decrease
the sexual transmission of HIV-18,9
--Sub-optimal concentrations of antiretrovirals in the genital tract may exert a
selective pressure on HIV-1 variants4
--Penetration of NRTIs into the genital tract are superior to PIs10
Tenofovir is effective in preventing HIV transmission in animal models11,12,13
though recent data has shown mixed results14
Pre-exposure prophylaxis is currently being studied in the United States,
Ghana, Thailand, and Botswana
No comprehensive data exist describing tenofovir exposure in the genital tract
This is the first study to measure extra- and intra-cellular concentrations of
tenofovir in the genital tract from Day 1 to steady-state
-- HIV-1 infected men and women with HIV-1 RNA > 200 copies/mL
-- Not currently taking any ARV medications OR on a stable ARV regimen without plans for altering baseline regimen for one month
-- Pregnant or lactating women, history of hysterectomy, active genital infection or dysfunctional uterine bleeding or renal impairment (Clcr < 60 mL/min)
14 days of TDF monotherapy (N=9; 8M, 1F)
>20 days of TDF added to stable ARV regimen (N=13; 1M, 12F)
MEN (N=9; n=8 monotherapy, n=1 intensification)
-- 4 outpatient visits
BP & GT at 24h post-dose on D1, 3, 5, and 7
1 intensive inpatient steady-state PK visit (D14)
--BP at t = 0, 1, 2, 3, 4, 5, 6, 8, 12 and 24h
GT sample at t = 0, 12h
-- as above, with additional BP and GT PK samples
at t=2, 4, 12, and 24h post-dose
WOMEN (N=13; n=1 monotherapy, n=12 combination therapy)
-- 2 intensive inpatient PK visits (D1 and ≥D14) for all subjects
BP at t = 0, 2, 4, 6, 12 and 24h
GT sample at t = 0, 2, 4, 6, 12 and 24h
Age: median 40 yrs for men; 35 yrs for women
HIV RNA (c/ml): men - 40,800; women - 51,000
CD4: median 181 for men; 313 for women.
Figure 1. HIV-1 RNA response to TDF monotherapy in blood plasma and genital tract for men (solid lines) and one woman (dotted line). Median (IQR) values are plotted.
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