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

Melanie R. Nicol; Prosperity Eneh; Rita Nakalega; Thomas Kaiser; Samuel Kabwigu; Esther Isingel; Mags Beksinska; Craig Sykes; Mary Glenn Fowler; Todd T. Brown; Christopher Staley; Flavia Kiweewa Matovu

doi:10.1093/cid/ciz443

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

Melanie R. Nicol, Prosperity Eneh, Rita Nakalega, Thomas Kaiser, Samuel Kabwigu, Esther Isingel, Mags Beksinska, Craig Sykes, Mary Glenn Fowler, Todd T. Brown, Christopher Staley, Flavia Kiweewa Matovu

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1717-1724
Number of pages	8
Journal	Clinical Infectious Diseases
Volume	70
Issue number	8
DOIs	https://doi.org/10.1093/cid/ciz443
State	Published - Apr 15 2020

Bibliographical note

Publisher Copyright:
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Keywords

DMPA
HIV
Lamivudine
Microbiome
PrEP
Tenofovir
Humans
Lamivudine/analogs & derivatives
Anti-HIV Agents/therapeutic use
Medroxyprogesterone Acetate/therapeutic use
Emtricitabine/therapeutic use
HIV Infections/drug therapy
Organophosphates
Pre-Exposure Prophylaxis
Microbiota
Female
Uganda
Dideoxynucleotides
Adenine/analogs & derivatives
Cytidine Triphosphate/analogs & derivatives
Tenofovir/therapeutic use

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/cid/ciz443

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Nicol, M. R., Eneh, P., Nakalega, R., Kaiser, T., Kabwigu, S., Isingel, E., Beksinska, M., Sykes, C., Fowler, M. G., Brown, T. T., Staley, C., & Kiweewa Matovu, F. (2020). 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, 70(8), 1717-1724. https://doi.org/10.1093/cid/ciz443

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. / Nicol, Melanie R.; Eneh, Prosperity; Nakalega, Rita et al.
In: Clinical Infectious Diseases, Vol. 70, No. 8, 15.04.2020, p. 1717-1724.

Research output: Contribution to journal › Article › peer-review

Nicol, MR, Eneh, P, Nakalega, R, Kaiser, T, Kabwigu, S, Isingel, E, Beksinska, M, Sykes, C, Fowler, MG, Brown, TT, Staley, C & Kiweewa Matovu, F 2020, '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, vol. 70, no. 8, pp. 1717-1724. https://doi.org/10.1093/cid/ciz443

Nicol MR, Eneh P, Nakalega R, Kaiser T, Kabwigu S, Isingel E et al. 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. 2020 Apr 15;70(8):1717-1724. doi: 10.1093/cid/ciz443

Nicol, Melanie R. ; Eneh, Prosperity ; Nakalega, Rita et al. / 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. In: Clinical Infectious Diseases. 2020 ; Vol. 70, No. 8. pp. 1717-1724.

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title = "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",

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.",

keywords = "DMPA, HIV, Lamivudine, Microbiome, PrEP, Tenofovir, Humans, Lamivudine/analogs & derivatives, Anti-HIV Agents/therapeutic use, Medroxyprogesterone Acetate/therapeutic use, Emtricitabine/therapeutic use, HIV Infections/drug therapy, Organophosphates, Pre-Exposure Prophylaxis, Microbiota, Female, Uganda, Dideoxynucleotides, Adenine/analogs & derivatives, Cytidine Triphosphate/analogs & derivatives, Tenofovir/therapeutic use",

author = "Nicol, {Melanie R.} and Prosperity Eneh and Rita Nakalega and Thomas Kaiser and Samuel Kabwigu and Esther Isingel and Mags Beksinska and Craig Sykes and Fowler, {Mary Glenn} and Brown, {Todd T.} and Christopher Staley and {Kiweewa Matovu}, Flavia",

year = "2020",

month = apr,

day = "15",

doi = "10.1093/cid/ciz443",

language = "English (US)",

volume = "70",

pages = "1717--1724",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "8",

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TY - JOUR

T1 - Depot medroxyprogesterone acetate and the vaginal microbiome as modifiers of tenofovir diphosphate and lamivudine triphosphate concentrations in the female genital tract of ugandan women

T2 - Implications for tenofovir disoproxil fumarate/lamivudine in preexposure prophylaxis

AU - Nicol, Melanie R.

AU - Eneh, Prosperity

AU - Nakalega, Rita

AU - Kaiser, Thomas

AU - Kabwigu, Samuel

AU - Isingel, Esther

AU - Beksinska, Mags

AU - Sykes, Craig

AU - Fowler, Mary Glenn

AU - Brown, Todd T.

AU - Staley, Christopher

AU - Kiweewa Matovu, Flavia

PY - 2020/4/15

Y1 - 2020/4/15

N2 - 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.

AB - 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.

KW - DMPA

KW - HIV

KW - Lamivudine

KW - Microbiome

KW - PrEP

KW - Tenofovir

KW - Humans

KW - Lamivudine/analogs & derivatives

KW - Anti-HIV Agents/therapeutic use

KW - Medroxyprogesterone Acetate/therapeutic use

KW - Emtricitabine/therapeutic use

KW - HIV Infections/drug therapy

KW - Organophosphates

KW - Pre-Exposure Prophylaxis

KW - Microbiota

KW - Female

KW - Uganda

KW - Dideoxynucleotides

KW - Adenine/analogs & derivatives

KW - Cytidine Triphosphate/analogs & derivatives

KW - Tenofovir/therapeutic use

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U2 - 10.1093/cid/ciz443

DO - 10.1093/cid/ciz443

M3 - Article

C2 - 31131846

AN - SCOPUS:85083537693

SN - 1058-4838

VL - 70

SP - 1717

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JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 8

ER -

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Publisher link

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