Metabolic Effects of Preexposure Prophylaxis With Coformulated Tenofovir Disoproxil Fumarate and Emtricitabine

Background. Tenofovir disoproxil fumarate (TDF) is commonly used in antiretroviral treatment (ART) and preexposure prophylaxis regimens. We evaluated the relationship of prenatal TDF use and growth outcomes among Kenyan HIV-exposed uninfected (HEU) infants.Materials and Methods.We included PCR-confirmed HEU infants enrolled in a cross-sectional survey of mother-infant pairs conducted between July and December 2013 in Kenya. Maternal ART regimen during pregnancy was determined by self-report and clinic records. Six-week and 9-monthz-scores for weight-for-age (WAZ), weight-for-length (WLZ), length-for-age (LAZ), and head circumference-for-age (HCAZ) were compared among HEU infants with and without TDF exposure usingt-tests and multivariate linear regression models.Results.Among 277 mothers who received ART during pregnancy, 63% initiated ART before pregnancy, of which 89 (32%) used TDF. No differences in birth weight (3.0 kg versus 3.1 kg,p=0.21) or gestational age (38 weeks versus 38 weeks,p=0.16) were detected between TDF-exposed and TDF-unexposed infants. At 6 weeks, unadjusted mean WAZ was lower among TDF-exposed infants (−0.8 versus −0.4,p=0.03), with a trend towards association in adjusted analyses (p=0.06). There were no associations between prenatal TDF use and WLZ, LAZ, and HCAZ in 6-week or 9-month infant cohorts.Conclusion.Maternal TDF use did not adversely affect infant growth compared to other regimens.

Download Full-text

Changes in Kidney Function Associated With Daily Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Preexposure Prophylaxis Use in the United States Demonstration Project

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0000000000001566 ◽

2018 ◽

Vol 77 (2) ◽

pp. 193-198 ◽

Cited By ~ 16

Author(s):

Eric C. Tang ◽

Eric Vittinghoff ◽

Peter L. Anderson ◽

Stephanie E. Cohen ◽

Susanne Doblecki-Lewis ◽

...

Keyword(s):

United States ◽

Kidney Function ◽

Tenofovir Disoproxil Fumarate ◽

The United States ◽

Demonstration Project ◽

Preexposure Prophylaxis

Download Full-text

Depot Medroxyprogesterone Acetate and the Vaginal Microbiome as Modifiers of Tenofovir Diphosphate and Lamivudine Triphosphate Concentrations in the Female Genital Tract of Ugandan Women: Implications for Tenofovir Disoproxil Fumarate/Lamivudine in Preexposure Prophylaxis

Clinical Infectious Diseases ◽

10.1093/cid/ciz443 ◽

2019 ◽

Vol 70 (8) ◽

pp. 1717-1724 ◽

Cited By ~ 4

Author(s):

Melanie R Nicol ◽

Prosperity Eneh ◽

Rita Nakalega ◽

Thomas Kaiser ◽

Samuel Kabwigu ◽

...

Keyword(s):

Medroxyprogesterone Acetate ◽

Tenofovir Disoproxil Fumarate ◽

Genital Tract ◽

Female Genital Tract ◽

Depot Medroxyprogesterone Acetate ◽

Preexposure Prophylaxis ◽

Increased Risk ◽

Vaginal Swabs ◽

Tenofovir Diphosphate ◽

Female Genital

Abstract Background Effective concentrations of antiretrovirals in the female genital tract (FGT) are critical for suppression of viral shedding or effective preexposure prophylaxis. The disposition of tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) in the FGT have been previously described. Despite widespread use, however, lamivudine triphosphate (3TC-TP) exposure in the FGT is unknown. Depot medroxyprogesterone acetate (DMPA) and vaginal dysbiosis have been implicated in increased risk of human immunodeficiency virus (HIV) acquisition, but whether they alter TFV-DP or 3TC-TP exposure, and therefore compromise prevention efficacy, is unknown. Methods Fifty premenopausal women living with HIV in Kampala, Uganda, and receiving daily tenofovir disoproxil fumarate/lamivudine were recruited. Ectocervical biopsies were obtained for quantification of TFV-DP and 3TC-TP using liquid chromatography–mass spectrometry. 16S ribosomal RNA gene sequencing was performed on DNA extracted from vaginal swabs. Wilcoxon rank-sum was used to test for differences between contraceptive groups. Results 3TC-TP concentrations were on average 17-fold greater than TFV-DP concentrations in cervical tissues. TFV-DP concentrations in cervical biopsies were 76% greater in DMPA users compared with women using nonhormonal contraception (n = 23 per group). Abundance of Lactobacillus in vaginal swabs was correlated with 3TC-TP concentrations in cervical tissues. Conclusions We found that TFV-DP concentrations were significantly greater in DMPA users compared with women using nonhormonal contraception, suggesting that prevention efficacy is unlikely to be compromised by DMPA use. Similar to reports of FTC-TP, 3TC-TP exposure was significantly greater than TFV-DP in cervical tissue and was correlated with abundance of Lactobacillus. These data support lamivudine as an option for preexposure prophylaxis. Clinical Trials Registration NCT03377608.

Download Full-text

Inhibitory Effects of Probenecid on Pharmacokinetics of Tenofovir Disoproxil Fumarate and Emtricitabine for On‐Demand HIV Preexposure Prophylaxis

Clinical Pharmacology & Therapeutics ◽

10.1002/cpt.1714 ◽

2019 ◽

Vol 107 (5) ◽

pp. 1200-1208 ◽

Cited By ~ 1

Author(s):

Stephanie N. Liu ◽

Brandon T. Gufford ◽

Jessica Bo Li Lu ◽

Lane R. Bushman ◽

Peter L. Anderson ◽

...

Keyword(s):

Tenofovir Disoproxil Fumarate ◽

Inhibitory Effects ◽

On Demand ◽

Preexposure Prophylaxis

Download Full-text

Vaginally Delivered Tenofovir Disoproxil Fumarate Provides Greater Protection than Tenofovir against Genital Herpes in a Murine Model of Efficacy and Safety

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01818-13 ◽

2013 ◽

Vol 58 (2) ◽

pp. 1153-1160 ◽

Cited By ~ 19

Author(s):

Briana Nixon ◽

Thomas Jandl ◽

Ryan S. Teller ◽

Ekaterina Taneva ◽

Yanhua Wang ◽

...

Keyword(s):

Genital Herpes ◽

Murine Model ◽

Tenofovir Disoproxil Fumarate ◽

Mitochondrial Gene ◽

High Dose ◽

Significant Protection ◽

Preexposure Prophylaxis ◽

Before And After ◽

Simplex Virus ◽

Herpes Simplex Virus 2

ABSTRACTIncreased susceptibility to genital herpes in medroxyprogesterone-treated mice may provide a surrogate of increased HIV risk and a preclinical biomarker of topical preexposure prophylaxis safety. We evaluated tenofovir disoproxil fumarate (TDF) in this murine model because an intravaginal ring eluting this drug is being advanced into clinical trials. To avoid the complications of surgically inserting a ring, hydroxyethylcellulose (HEC)-stable formulations of TDF were prepared. One week of twice-daily 0.3% TDF gel was well tolerated and did not result in any increase in HSV-2 susceptibility but protected mice from herpes simplex virus 2 (HSV-2) disease compared to mice treated with the HEC placebo gel. No significant increase in inflammatory cytokines or chemokines in vaginal washes or change in cytokine, chemokine, or mitochondrial gene expression in RNA extracted from genital tract tissue was detected. To further evaluate efficacy, mice were treated with gel once daily beginning 12 h prior to high-dose HSV-2 challenge or 2 h before and after viral challenge (BAT24 dosing). The 0.3% TDF gel provided significant protection compared to the HEC gel following either daily (in 9/10 versus 1/10 mice,P< 0.01) or BAT24 (in 14/20 versus 4/20 mice,P< 0.01) dosing. In contrast, 1% tenofovir (TFV) gel protected only 4/10 mice treated with either regimen. Significant protection was also observed with daily 0.03% TDF compared to HEC. Protection was associated with greater murine cellular permeability of radiolabeled TDF than of TFV. Together, these findings suggest that TDF is safe, may provide substantially greater protection against HSV than TFV, and support the further clinical development of a TDF ring.

Download Full-text

Is Emtricitabine-Tenofovir Disoproxil Fumarate Pre-exposure Prophylaxis for the Prevention of Human Immunodeficiency Virus Infection Safer Than Aspirin?

Open Forum Infectious Diseases ◽

10.1093/ofid/ofv221 ◽

2016 ◽

Vol 3 (1) ◽

Cited By ~ 7

Author(s):

Noah Kojima ◽

Jeffrey D. Klausner

Keyword(s):

Human Immunodeficiency Virus ◽

Gastrointestinal Bleeding ◽

Hiv Infection ◽

Tenofovir Disoproxil Fumarate ◽

African Women ◽

Health Study ◽

Heterosexual Couples ◽

Preexposure Prophylaxis ◽

Immunodeficiency Virus ◽

Exposure Prophylaxis

Abstract Background. The safety and effectiveness studies of emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for human immunodeficiency virus (HIV) infection pre-exposure prophylaxis (PrEP) in men and women showed that daily use reduced the risk of HIV acquisition, but there still may concerns about safety. Methods. A narrative review was done in September 2015 comparing the 5 major studies on PrEP for HIV infection—Preexposure Prophylaxis Initiative (N = 2499; 3324 person-years), Partners Preexposure Prophylaxis (N = 4747; 7830 person-years), TDF2 (N = 1219; 1563 person-years), Preexposure Prophylaxis Trial for HIV Prevention among African Women (N = 2056; 1407 person-years), and Vaginal and Oral Interventions to Control the Epidemic (N = 4969; 5509 person-years)—and the 2 major studies on aspirin safety—Physicians' Health Study (N = 22 071; over 110 000 person-years) and the Women's Health Study (N = 39 876; approximately 400 000 person-years). The numbers needed to harm (NNH) were calculated for FTC-TDF for HIV infection PrEP and aspirin. Results. The NNH for FTC-TDF in men who have sex with men and transgender women was 114 for nausea and 96 for unintentional weight loss; in heterosexual couples, the NNH was 68 for moderate decreased absolute neutrophil count. For aspirin, the NNH was 909 for major gastrointestinal bleeding, 123 for any gastrointestinal bleeding, and 15 for any bleeding problems in men. In women, the NNH for easy bruising was 10. Conclusions. We conclude that FTC-TDF for PrEP for HIV infection favorably compares with aspirin in terms of user safety. Although long-term studies are needed, providers should feel reassured about the safety of short- and medium-term PrEP for HIV infection with FTC-TDF.

Download Full-text

Differential Mechanisms of Tenofovir and Tenofovir Disoproxil Fumarate Cellular Transport and Implications for Topical Preexposure Prophylaxis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02793-15 ◽

2015 ◽

Vol 60 (3) ◽

pp. 1667-1675 ◽

Cited By ~ 19

Author(s):

Ekaterina Taneva ◽

Kerry Crooker ◽

Sung Hyun Park ◽

Jonathan T. Su ◽

Adina Ott ◽

...

Keyword(s):

T Cells ◽

Tenofovir Disoproxil Fumarate ◽

High Performance ◽

Drug Transport ◽

Organic Anion ◽

Cellular Transport ◽

Nonlinear Kinetics ◽

Anion Transporters ◽

Preexposure Prophylaxis ◽

Simplex Virus

Intravaginal rings releasing tenofovir (TFV) or its prodrug, tenofovir disoproxil fumarate (TDF), are being evaluated for HIV and herpes simplex virus (HSV) prevention. The current studies were designed to determine the mechanisms of drug accumulation in human vaginal and immune cells. The exposure of vaginal epithelial or T cells to equimolar concentrations of radiolabeled TDF resulted in over 10-fold higher intracellular drug levels than exposure to TFV. Permeability studies demonstrated that TDF, but not TFV, entered cells by passive diffusion. TDF uptake was energy independent but its accumulation followed nonlinear kinetics, and excess unlabeled TDF inhibited radiolabeled TDF uptake in competition studies. The carboxylesterase inhibitor bis-nitrophenyl phosphate reduced TDF uptake, suggesting saturability of intracellular carboxylesterases. In contrast, although TFV uptake was energy dependent, no competition between unlabeled and radiolabeled TFV was observed, and the previously identified transporters, organic anion transporters (OATs) 1 and 3, were not expressed in human vaginal or T cells. The intracellular accumulation of TFV was reduced by the addition of endocytosis inhibitors, and this resulted in the loss of TFV antiviral activity. Kinetics of drug transport and metabolism were monitored by quantifying the parent drugs and their metabolites by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Results were consistent with the identified mechanisms of transport, and the exposure of vaginal epithelial cells to equimolar concentrations of TDF compared to TFV resulted in ∼40-fold higher levels of the active metabolite, tenofovir diphosphate. Together, these findings indicate that substantially lower concentrations of TDF than TFV are needed to protect cells from HIV and HSV-2.

Download Full-text