Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection

Jessica Radzio-Basu; Olivia Council; Mian-Er Cong; Susan Ruone; Alicia Newton; Xierong Wei; James Mitchell; Shanon Ellis; Christos J Petropoulos; Wei Huang; William Spreen; Walid Heneine; J Gerardo García-Lerma

doi:10.1038/s41467-019-10047-w

Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection

Nat Commun. 2019 May 1;10(1):2005. doi: 10.1038/s41467-019-10047-w.

Affiliations

¹ Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA, 30329, USA.
² Monogram Biosciences, 345 Oyster Point Blvd, San Francisco, CA, 94080, USA.
³ ViiV Healthcare, Research Triangle Park, NC, 27709, USA.
⁴ Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA, 30329, USA. [email protected].

Abstract

A long-acting injectable formulation of the HIV integrase inhibitor cabotegravir (CAB-LA) is currently in clinical development for PrEP. Although the long plasma half-life of CAB-LA is an important attribute for PrEP, it also raises concerns about drug resistance emergence if someone becomes infected with HIV, or if PrEP is initiated during undiagnosed acute infection. Here we use a macaque model of SHIV infection to model risks of drug resistance to CAB-LA PrEP. Six macaques infected with SHIV received CAB-LA before seroconversion. We show integrase mutations G118R, E92G/Q, or G140R in plasma from 3/6 macaques as early as day 57, and identify G118R and E92Q in viruses from vaginal and rectal fluids. G118R and G140R confer > 800-fold resistance to CAB and cross-resistance to all licensed integrase inhibitors. Our results emphasize the need for appropriate HIV testing strategies before and possibly shortly after initiating CAB LA PrEP to exclude acute infection.

Publication types

Research Support, U.S. Gov't, P.H.S.

MeSH terms

Acute Disease
Animals
Disease Models, Animal
Drug Resistance, Viral / drug effects
Drug Resistance, Viral / genetics*
Female
HEK293 Cells
HIV Infections / blood
HIV Infections / immunology
HIV Infections / prevention & control*
HIV Infections / virology
HIV Integrase / genetics
HIV Integrase Inhibitors / blood
HIV Integrase Inhibitors / pharmacology*
HIV Integrase Inhibitors / therapeutic use
HIV-1 / drug effects
HIV-1 / genetics
Half-Life
Humans
Macaca
Male
Pre-Exposure Prophylaxis / methods*
Pyridones / blood
Pyridones / pharmacology*
Pyridones / therapeutic use
Seroconversion
Simian Acquired Immunodeficiency Syndrome / blood
Simian Acquired Immunodeficiency Syndrome / immunology
Simian Acquired Immunodeficiency Syndrome / prevention & control*
Simian Acquired Immunodeficiency Syndrome / virology
Simian Immunodeficiency Virus / drug effects
Simian Immunodeficiency Virus / genetics
Simian Immunodeficiency Virus / immunology
Time Factors

Substances

HIV Integrase Inhibitors
Pyridones
HIV Integrase
cabotegravir