PMID- 28650381
OWN - NLM
STAT- MEDLINE
DCOM- 20180508
LR  - 20220129
IS  - 1473-5571 (Electronic)
IS  - 0269-9370 (Print)
IS  - 0269-9370 (Linking)
VI  - 31
IP  - 14
DP  - 2017 Sep 10
TI  - Potential for immune-driven viral polymorphisms to compromise 
      antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection.
PG  - 1935-1943
LID - 10.1097/QAD.0000000000001575 [doi]
AB  - OBJECTIVE: Long-acting rilpivirine is a candidate for preexposure prophylaxis 
      (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance 
      mutations at reverse transcriptase codon 138 (E138X) occur naturally in a 
      minority of HIV-1-infected persons; in particular those expressing human 
      leukocyte antigen (HLA)-B18 where reverse transcriptase-E138X arises as an immune 
      escape mutation. We investigate the global prevalence, B18-linkage and 
      replicative cost of reverse transcriptase-E138X and its regional implications for 
      rilpivirine PrEP. METHODS: We analyzed linked reverse transcriptase-E138X/HLA 
      data from 7772 antiretroviral-naive patients from 16 cohorts spanning five 
      continents and five HIV-1 subtypes, alongside unlinked global reverse 
      transcriptase-E138X and HLA frequencies from public databases. E138X-containing 
      HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation 
      stability following transmission. RESULTS: Reverse transcriptase-E138X variants, 
      where the most common were rilpivirine resistance-associated mutations E138A/G/K, 
      were significantly enriched in HLA-B18-positive individuals globally 
      (P = 3.5 x 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X 
      and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA 
      genotypes (Spearman's R = 0.75; P = 7.6 x 10) and in unlinked HIV/HLA data from 
      43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse 
      transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic 
      regions (e.g. sub-Saharan Africa, Southeastern Europe) where B18 is more common. 
      This, along with the observation that reverse transcriptase-E138X variants do not 
      confer in-vitro replicative costs, supports their persistence, and ongoing 
      accumulation in circulation over time. CONCLUSIONS: Results illustrate the 
      potential for a natural immune-driven HIV-1 polymorphism to compromise 
      antiretroviral-based prevention, particularly in key epidemic regions. Regional 
      reverse transcriptase-E138X surveillance should be undertaken before use of 
      rilpivirine PrEP.
FAU - Gatanaga, Hiroyuki
AU  - Gatanaga H
AD  - aAIDS Clinical Center, National Center for Global Health and Medicine, Tokyo 
      bCenter for AIDS Research, Kumamoto University, Kumamoto, Japan cFaculty of 
      Health Sciences, Simon Fraser University, Burnaby dBritish Columbia Centre for 
      Excellence in HIV/AIDS, Vancouver, British Columbia, Canada eDepartment of 
      Paediatrics, University of Oxford, Oxford, UK fCentre for Research in Infectious 
      Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico 
      gInfectious Diseases Clinic, Roosevelt Hospital, Guatemala City, Guatemala 
      hNational Hospital of Tropical Diseases, Dong Da District, Hanoi, Vietnam iHIV 
      National Laboratory, Honduran Ministry of Health jHospital Escuela Universitario, 
      Tegucigalpa, Honduras kGorgas Memorial Institute for Health Studies, Panama City, 
      Panama lHospital Metropolitano Vivian Pellas, Managua, Nicaragua mMinistry of 
      Health, Belmopan, Belize nUniversity of California San Francisco, San Francisco, 
      California oCancer and Inflammation Program, Leidos Biomedical Research, Inc., 
      Frederick National Laboratory, Frederick, Maryland pRagon Institute of 
      Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard 
      University, Cambridge, Massachusetts, USA qMurdoch University, Perth, Australia 
      rVanderbilt University, Nashville, Tennessee, USA sDepartment of Pathology and 
      Laboratory Medicine, Western University, London, Ontario, Canada.
FAU - Brumme, Zabrina L
AU  - Brumme ZL
FAU - Adland, Emily
AU  - Adland E
FAU - Reyes-Teran, Gustavo
AU  - Reyes-Teran G
FAU - Avila-Rios, Santiago
AU  - Avila-Rios S
FAU - Mejia-Villatoro, Carlos R
AU  - Mejia-Villatoro CR
FAU - Hayashida, Tsunefusa
AU  - Hayashida T
FAU - Chikata, Takayuki
AU  - Chikata T
FAU - Van Tran, Giang
AU  - Van Tran G
FAU - Van Nguyen, Kinh
AU  - Van Nguyen K
FAU - Meza, Rita I
AU  - Meza RI
FAU - Palou, Elsa Y
AU  - Palou EY
FAU - Valenzuela-Ponce, Humberto
AU  - Valenzuela-Ponce H
FAU - Pascale, Juan M
AU  - Pascale JM
FAU - Porras-Cortes, Guillermo
AU  - Porras-Cortes G
FAU - Manzanero, Marvin
AU  - Manzanero M
FAU - Lee, Guinevere Q
AU  - Lee GQ
FAU - Martin, Jeffrey N
AU  - Martin JN
FAU - Carrington, Mary N
AU  - Carrington MN
FAU - John, Mina
AU  - John M
FAU - Mallal, Simon
AU  - Mallal S
FAU - Poon, Art F Y
AU  - Poon AFY
FAU - Goulder, Philip
AU  - Goulder P
FAU - Takiguchi, Masafumi
AU  - Takiguchi M
FAU - Oka, Shinichi
AU  - Oka S
CN  - International HIV Adaptation Collaborative
LA  - eng
GR  - Z01 BC010791/ImNIH/Intramural NIH HHS/United States
GR  - UM1 CA181255/CA/NCI NIH HHS/United States
GR  - Z01 BC010792/ImNIH/Intramural NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
GR  - R01 MH054907/MH/NIMH NIH HHS/United States
GR  - MR/L006588/1/MRC_/Medical Research Council/United Kingdom
GR  - WT104748MA/WT_/Wellcome Trust/United Kingdom
GR  - P30 AI027763/AI/NIAID NIH HHS/United States
GR  - PJT-148621/CIHR/Canada
GR  - R01 AI046995/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - AIDS
JT  - AIDS (London, England)
JID - 8710219
RN  - 0 (Anti-Retroviral Agents)
RN  - 0 (HLA-B18 Antigen)
RN  - EC 2.7.7.49 (HIV Reverse Transcriptase)
RN  - FI96A8X663 (Rilpivirine)
SB  - IM
MH  - Anti-Retroviral Agents/*pharmacology
MH  - *Drug Resistance, Viral
MH  - Global Health
MH  - HIV Infections/*prevention & control/virology
MH  - HIV Reverse Transcriptase/genetics
MH  - HIV-1/enzymology/genetics/*immunology
MH  - HLA-B18 Antigen/genetics
MH  - Humans
MH  - *Immune Evasion
MH  - *Mutation, Missense
MH  - Polymorphism, Genetic
MH  - *Pre-Exposure Prophylaxis
MH  - Rilpivirine/pharmacology
PMC - PMC8171589
MID - NIHMS1697909
COIS- Conflicts of interest There are no conflicts of interest.
EDAT- 2017/06/27 06:00
MHDA- 2018/05/09 06:00
PMCR- 2021/06/02
CRDT- 2017/06/27 06:00
PHST- 2017/06/27 06:00 [pubmed]
PHST- 2018/05/09 06:00 [medline]
PHST- 2017/06/27 06:00 [entrez]
PHST- 2021/06/02 00:00 [pmc-release]
AID - 10.1097/QAD.0000000000001575 [doi]
PST - ppublish
SO  - AIDS. 2017 Sep 10;31(14):1935-1943. doi: 10.1097/QAD.0000000000001575.