PMID- 28600625
OWN - NLM
STAT- MEDLINE
DCOM- 20180612
LR  - 20191008
IS  - 2190-3948 (Electronic)
IS  - 2190-393X (Print)
IS  - 2190-393X (Linking)
VI  - 7
IP  - 6
DP  - 2017 Dec
TI  - An intravaginal ring that releases three antiviral agents and a contraceptive 
      blocks SHIV-RT infection, reduces HSV-2 shedding, and suppresses hormonal cycling 
      in rhesus macaques.
PG  - 840-858
LID - 10.1007/s13346-017-0389-0 [doi]
AB  - Women globally need access to multipurpose prevention technologies (MPTs) that 
      prevent human immunodeficiency virus (HIV), sexually transmitted infections that 
      increase HIV acquisition/transmission risk, and unintended pregnancy. Seeking an 
      MPT with activity against HIV, herpes simplex virus-2 (HSV-2), and human 
      papillomavirus (HPV), we developed a prototype intravaginal ring (IVR), the MZCL 
      IVR, which released the antiviral agents MIV-150, zinc acetate, and carrageenan 
      (MZC for short) and the contraceptive levonorgestrel (LNG). Previously, we showed 
      that an MZC gel has potent activity against immunodeficiency viruses, HSV-2, and 
      HPV and that the MZCL (MZC with LNG) IVR releases all four components in macaques 
      in vivo at levels associated with efficacy. Vaginal fluid from treated macaques 
      has in vitro activity against HIV, HSV-2, and HPV. Herein, we assessed the 
      ability of the MZCL IVR to protect macaques against repeated co-challenge with 
      HSV-2 and SHIV-RT (simian immunodeficiency virus [SIV] containing the reverse 
      transcriptase gene from HIV) and prevent hormonal cycling. We evaluated in vivo 
      drug release in co-challenged macaques by measuring drug levels in blood and 
      vaginal fluid and residual drug levels in used IVRs. The MZCL IVR significantly 
      prevented SHIV-RT infection, reduced HSV-2 vaginal shedding, and prevented 
      cycling. No non-nucleoside HIV reverse transcriptase inhibitor (NNRTI)-resistant 
      SHIV was detected in macaques that became infected after continuous exposure to 
      MZC from the IVR. Macaques wearing the MZCL IVR also had carrageenan levels in 
      vaginal fluid expected to protect from HPV (extrapolated from mice) and LNG 
      levels in blood associated with contraceptive efficacy. The MZCL IVR is a 
      promising MPT candidate that warrants further development.
FAU - Derby, Nina
AU  - Derby N
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA. 
      nderby@popcouncil.org.
FAU - Aravantinou, Meropi
AU  - Aravantinou M
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Kenney, Jessica
AU  - Kenney J
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Ugaonkar, Shweta R
AU  - Ugaonkar SR
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Wesenberg, Asa
AU  - Wesenberg A
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Wilk, Jolanta
AU  - Wilk J
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Kizima, Larisa
AU  - Kizima L
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Rodriguez, Aixa
AU  - Rodriguez A
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Zhang, Shimin
AU  - Zhang S
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Mizenina, Olga
AU  - Mizenina O
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Levendosky, Keith
AU  - Levendosky K
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Cooney, Michael L
AU  - Cooney ML
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Seidor, Samantha
AU  - Seidor S
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Gettie, Agegnehu
AU  - Gettie A
AD  - Aaron Diamond AIDS Research Center, 455 First Avenue, 7th Floor, New York, NY, 
      10016, USA.
FAU - Grasperge, Brooke
AU  - Grasperge B
AD  - Tulane Primate Research Center, 18703 Three Rivers Road, Covington, LA, 
      70433-8915, USA.
FAU - Blanchard, James
AU  - Blanchard J
AD  - Tulane Primate Research Center, 18703 Three Rivers Road, Covington, LA, 
      70433-8915, USA.
FAU - Piatak, Michael Jr
AU  - Piatak M Jr
AD  - AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick 
      National Laboratory for Cancer Research, Frederick, MD, 21702-1201, USA.
FAU - Lifson, Jeffrey D
AU  - Lifson JD
AD  - AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick 
      National Laboratory for Cancer Research, Frederick, MD, 21702-1201, USA.
FAU - Fernandez-Romero, Jose
AU  - Fernandez-Romero J
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
AD  - Science Department, Borough of Manhattan Community College, The City University 
      of New York, 199 Chambers Street, New York, NY, 10007, USA.
FAU - Zydowsky, Thomas M
AU  - Zydowsky TM
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
FAU - Robbiani, Melissa
AU  - Robbiani M
AD  - Population Council, 1230 York Avenue, New York, NY, 10065, USA.
LA  - eng
GR  - P51 OD011092/OD/NIH HHS/United States
GR  - PEPFAR/PEPFAR/
GR  - P51 OD011104/OD/NIH HHS/United States
GR  - R21 AI098645/AI/NIAID NIH HHS/United States
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Drug Deliv Transl Res
JT  - Drug delivery and translational research
JID - 101540061
RN  - 0 (Antiviral Agents)
RN  - 0 (Contraceptive Agents, Female)
RN  - 0 (MIV 150)
RN  - 0 (Pyridines)
RN  - 0 (Vaginal Creams, Foams, and Jellies)
RN  - 8W8T17847W (Urea)
RN  - 9000-07-1 (Carrageenan)
RN  - FM5526K07A (Zinc Acetate)
SB  - IM
MH  - Alphapapillomavirus/drug effects/physiology
MH  - Animals
MH  - Antiviral Agents/*administration & dosage/pharmacology
MH  - Carrageenan/administration & dosage/pharmacology
MH  - Contraceptive Agents, Female/*administration & dosage/pharmacology
MH  - Contraceptive Devices, Female
MH  - Disease Models, Animal
MH  - Drug Therapy, Combination/methods
MH  - Female
MH  - Herpes Simplex/prevention & control
MH  - Herpesvirus 2, Human/drug effects/physiology
MH  - Humans
MH  - Macaca mulatta
MH  - Menstrual Cycle
MH  - Pyridines/administration & dosage/pharmacology
MH  - Simian Acquired Immunodeficiency Syndrome/*prevention & control
MH  - Urea/administration & dosage/analogs & derivatives/pharmacology
MH  - Vaginal Creams, Foams, and Jellies/*administration & dosage/pharmacology
MH  - Virus Shedding/*drug effects
MH  - Zinc Acetate/administration & dosage/pharmacology
PMC - PMC5656733
OTO - NOTNLM
OT  - *Contraception
OT  - *HIV
OT  - *HPV
OT  - *HSV-2
OT  - *Intravaginal ring
OT  - *Multipurpose prevention technology
COIS- All the experiments published in this manuscript comply with the current laws of 
      the country in which they were performed. All institutional and national 
      guidelines for the care and use of laboratory animals were followed. CONFLICTS OF 
      INTEREST: Author Nina Derby, author Shweta R. Ugaonkar, author Jessica Kenney, 
      author Meropi Aravantinou, author Asa Wesenberg, author Jolanta Wilk, author 
      Larisa Kizima, author Aixa Rodriguez, author Shimin Zhang, author Olga Mizenina, 
      author Keith Levendosky, author Michael L. Cooney, author Samantha Seidor, author 
      Agegnehu Gettie, author Brooke Grasperge, author James Blanchard, author Jeffrey 
      D. Lifson, author Jose Fernandez-Romero, author Thomas M. Zydowsky, and author 
      Melissa Robbiani declare that they have no conflict of interest.
EDAT- 2017/06/11 06:00
MHDA- 2018/06/13 06:00
PMCR- 2017/06/09
CRDT- 2017/06/11 06:00
PHST- 2017/06/11 06:00 [pubmed]
PHST- 2018/06/13 06:00 [medline]
PHST- 2017/06/11 06:00 [entrez]
PHST- 2017/06/09 00:00 [pmc-release]
AID - 10.1007/s13346-017-0389-0 [pii]
AID - 389 [pii]
AID - 10.1007/s13346-017-0389-0 [doi]
PST - ppublish
SO  - Drug Deliv Transl Res. 2017 Dec;7(6):840-858. doi: 10.1007/s13346-017-0389-0.