A post-mortem analysis of tenofovir, lamivudine, efavirenz and fluconazole penetration in female genital tissues

Author:

Wang Fan1,Namuju Olivie C2,Pastick Katelyn A34ORCID,Abdusalaamu Kizito2,Mishra Usha1,Collins Lindsey1,Boulware David R3ORCID,Lukande Robert5,Meya David B35,Nicol Melanie R1ORCID

Affiliation:

1. Department of Experimental and Clinical Pharmacology, University of Minnesota , Minneapolis, MN , USA

2. Infectious Disease Institute , Kampala , Uganda

3. Department of Medicine, University of Minnesota , Minneapolis, MN , USA

4. Massachusetts General Hospital , Boston, MA , USA

5. Makerere University , Kampala , Uganda

Abstract

Abstract Background Optimal penetration of anti-infectives in the female genital tract (FGT) is paramount in the treatment and prevention of infectious diseases. While exposure of anti-infectives in lower FGT tissues (e.g. cervix, vagina) has been described, little data exist on upper genital tissues (e.g. ovary, uterus). Methods Autopsies were performed and post-mortem tissues were collected within 24 h of death for female participants with advanced HIV in Uganda (n = 27). Tenofovir, lamivudine, efavirenz and fluconazole concentrations were measured using LC-MS/MS in plasma, ovarian, uterine, cervical and vaginal tissues. Tissue penetration was calculated as tissue-to-plasma concentration ratios (TPRs). Results TPRs of tenofovir, lamivudine and fluconazole were highest in vaginal tissue (medians 1.86, 1.83 and 0.94, respectively), while the TPR of efavirenz was highest in ovarian tissue (median 0.65). With cervix as a reference compartment, vaginal TPRs were significantly higher than cervical for all four drugs; TPRs of efavirenz in uterine and ovarian compartments were also significantly higher than cervical. Most of the post-mortem FGT samples had a TPR of greater than 1 for tenofovir and lamivudine, while less than 50% had a TPR of greater than 1 for both efavirenz and fluconazole. Conclusions Penetration of anti-infectives was not homogeneous among the FGT compartments. Approximately 70% of FGT tissues had a TPR of greater than 1 for tenofovir and lamivudine, favouring the prevention of local HIV replication and transmission in the FGT.

Funder

National Institute of Neurologic Diseases and Stroke

National Institute of Allergy and Infectious Diseases

University of Minnesota

NIH

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology,Microbiology (medical)

Reference25 articles.

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3. Immunologic, virologic, and pharmacologic characterization of the female upper genital tract in HIV-infected women;Rahangdale;J Acquir Immune Defic Syndr,2015

4. Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis;Dumond;AIDS,2007

5. Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission;Patterson;Sci Transl Med,2011

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