PMID- 28982161
OWN - NLM
STAT- MEDLINE
DCOM- 20171031
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 10
DP  - 2017
TI  - Novel multipurpose pod-intravaginal ring for the prevention of HIV, HSV, and
      unintended pregnancy: Pharmacokinetic evaluation in a macaque model.
PG  - e0185946
LID - 10.1371/journal.pone.0185946 [doi]
AB  - Globally, women bear an uneven burden for sexual HIV acquisition. Results from
      two clinical trials evaluating intravaginal rings (IVRs) delivering the
      antiretroviral agent dapivirine have shown that protection from HIV infection can
      be achieved with this modality, but high adherence is essential. Multipurpose
      prevention technologies (MPTs) can potentially increase product adherence by
      offering protection against multiple vaginally transmitted infections and
      unintended pregnancy. Here we describe a coitally independent, long-acting
      pod-IVR MPT that could potentially prevent HIV and HSV infection as well as
      unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir
      alafenamide hemifumarate (TAF2) to prevent HIV, acyclovir (ACV) to prevent HSV,
      and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved
      hormonal contraceptives, were evaluated in pigtailed macaques (N = 6) over 35
      days. Pod IVRs were exchanged at 14 days with the only modification being lower
      ENG release rates in the second IVR. Plasma progesterone was monitored weekly to 
      determine the effect of ENG/EE on menstrual cycle. The mean in vivo release rates
      (mg d-1) for the two formulations over 30 days ranged as follows: TAF2 0.35-0.40;
      ACV 0.56-0.70; EE 0.03-0.08; ENG (high releasing) 0.63; and ENG (low releasing)
      0.05. Mean peak progesterone levels were 4.4 +/- 1.8 ng mL-1 prior to IVR
      insertion and 0.075 +/- 0.064 ng mL-1 for 5 weeks after insertion, suggesting
      that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF2
      and ACV release rates and resulting vaginal tissue drug concentrations (medians: 
      TFV, 2.4 ng mg-1; ACV, 0.2 ng mg-1) may be sufficient to protect against HIV and 
      HSV infection, respectively. This proof of principle study demonstrates that
      MPT-pod IVRs could serve as a potent biomedical prevention tool to protect
      women's sexual and reproductive health and may increase adherence to HIV PrEP
      even among younger high-risk populations.
FAU - Smith, James M
AU  - Smith JM
AD  - Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS,
      Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and
      Prevention, Atlanta, Georgia, United States of America.
FAU - Moss, John A
AU  - Moss JA
AD  - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California,
      United States of America.
FAU - Srinivasan, Priya
AU  - Srinivasan P
AD  - Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS,
      Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and
      Prevention, Atlanta, Georgia, United States of America.
FAU - Butkyavichene, Irina
AU  - Butkyavichene I
AD  - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California,
      United States of America.
FAU - Gunawardana, Manjula
AU  - Gunawardana M
AD  - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California,
      United States of America.
FAU - Fanter, Rob
AU  - Fanter R
AD  - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California,
      United States of America.
FAU - Miller, Christine S
AU  - Miller CS
AD  - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California,
      United States of America.
FAU - Sanchez, Debbie
AU  - Sanchez D
AD  - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California,
      United States of America.
FAU - Yang, Flora
AU  - Yang F
AD  - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California,
      United States of America.
FAU - Ellis, Shanon
AU  - Ellis S
AD  - Libra Management Group, Decatur, Georgia, United States of America.
FAU - Zhang, Jining
AU  - Zhang J
AD  - Libra Management Group, Decatur, Georgia, United States of America.
FAU - Marzinke, Mark A
AU  - Marzinke MA
AD  - Department of Medicine, Johns Hopkins University, Osler, Baltimore, Maryland,
      United States of America.
AD  - Department of Pathology, Johns Hopkins University, Sheikh Zayed Tower, Baltimore,
      Maryland, United States of America.
FAU - Hendrix, Craig W
AU  - Hendrix CW
AD  - Department of Medicine, Johns Hopkins University, Osler, Baltimore, Maryland,
      United States of America.
FAU - Kapoor, Amita
AU  - Kapoor A
AD  - Wisconsin National Primate Research Center, University of Wisconsin-Madison,
      Capitol Court, Madison, Wisconsin, United States of America.
FAU - Baum, Marc M
AU  - Baum MM
AUID- ORCID: http://orcid.org/0000-0003-1558-5649
AD  - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California,
      United States of America.
LA  - eng
PT  - Journal Article
DEP - 20171005
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antiviral Agents)
SB  - IM
MH  - Administration, Intravaginal
MH  - Animals
MH  - Antiviral Agents/*administration & dosage/pharmacokinetics
MH  - *Contraceptive Devices, Female
MH  - Female
MH  - HIV Infections/*prevention & control
MH  - Herpes Genitalis/*prevention & control
MH  - Humans
MH  - Macaca nemestrina
MH  - Pregnancy
MH  - *Pregnancy, Unplanned
PMC - PMC5628903
EDAT- 2017/10/06 06:00
MHDA- 2017/11/01 06:00
CRDT- 2017/10/06 06:00
PHST- 2017/07/19 00:00 [received]
PHST- 2017/09/21 00:00 [accepted]
PHST- 2017/10/06 06:00 [entrez]
PHST- 2017/10/06 06:00 [pubmed]
PHST- 2017/11/01 06:00 [medline]
AID - 10.1371/journal.pone.0185946 [doi]
AID - PONE-D-17-27119 [pii]
PST - epublish
SO  - PLoS One. 2017 Oct 5;12(10):e0185946. doi: 10.1371/journal.pone.0185946.
      eCollection 2017.