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Transmitted Resistance to All Integrase Inhibitors: A Rare Event, or the Tip of the Iceberg?

The first documented case of primary resistance to all integrase strand transfer inhibitors (INSTIs) in an ART-naive woman raises questions about universal screening for INSTI resistance.

Researchers present the case of a 42-year-old woman who had a negativeHIV test in August 2016 and was diagnosed with HIV infection in May 2018. She denied any history of antiretroviral therapy (ART), including pre- or postexposure prophylaxis.

A pretreatment genotype, including integrase sequencing, was obtained and showed three major INSTI mutations: E138A, G140S, and Q148H. These were also demonstrated on a repeat genotype. Subsequent genotypic sequencing of the presumed source patient, an HIV-infected sexual partner, revealed the same integrase mutations, confirming that this almost certainly represented transmitted integrase resistance. The source patient’s treatment history included raltegravir and dolutegravir.

INSTIs are now a component of every recommended initial regimen for ART-naive patients, per U.S. Department of Health and Human Services and International Antiviral Society -USA Panel guidelines.

This report leads us to ask once again if integrase resistance testing should be performed universally at HIV diagnosis. Despite this concerning case, the jury is still out, and the answer may depend on whether the initial regimen contains first- or second-generation INSTIs.

The first-generation agents, raltegravir and elvitegravir, have a lower barrier to resistance; multiple mutations to these agents can lead to cross-resistance to the second-generation agents, dolutegravir and bictegravir, as likely happened in the source patient.

Whether this mutational pattern would have led to virologic failure on a bictegravir- or dolutegravir-containing regimen is unknown, but a first-generation INSTI regimen would have been significantly compromised.

Modeling data (Clin Infect Dis 2017; 65:1274) suggest that baseline integrase resistance testing is not cost-effective and leads to worse clinical outcomes when the initial regimen contains a second-generation INSTI, but slightly better outcomes when a first-generation agent is selected. Continued monitoring of transmitted INSTI resistance is necessary and will help inform future recommendations.
EDITOR DISCLOSURES AT TIME OF PUBLICATIONDisclosures for Wendy S. Armstrong, MD at time of publicationNothing to disclose
CITATION(S):McGee KS et al. Canary in the coal mine? Transmitted mutations conferring resistance to all integrase strand transfer inhibitors in a treatment-naive patient. Open Forum Infect Dis 2018 Nov 8; 5:ofy294. (