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Emerging patterns and implications of HIV-1 integrase inhibitor resistance

Geretti, Anna Mariaa; Armenia, Danieleb; Ceccherini-Silberstein, Francescab

Current Opinion in Infectious Diseases: December 2012 - Volume 25 - Issue 6 - p 677–686
doi: 10.1097/QCO.0b013e32835a1de7
ANTIMICROBIAL AGENTS: Edited by Monica A. Slavin, Simon L. Croft and Deenan Pillay

Purpose of review This review highlights recent data on the pathways of resistance that impact the clinical activity of first-generation and second-generation integrase inhibitors.

Recent findings Raltegravir (RAL) and elvitegravir (EVG) are highly efficacious in first-line antiretroviral therapy, with small numbers of virological failures observed in clinical trials. Durable activity in treatment-experienced patients requires a fully supportive background regimen. RAL and EVG show a low-to-moderate genetic barrier to resistance and extensive cross-resistance, which preclude their sequential use. Resistance to dolutegravir (DTG) is not selected as readily in vitro and has not emerged in studies of treatment-naïve patients to date. Both in vitro and in vivo, DTG retains activity against several RAL and EVG resistant strains, but susceptibility is variably impaired by multiple mutations within the G148 pathway, which are common after RAL or EVG failure. Cross-resistance can be partially overcome by doubling DTG dosing to twice daily, but durability of responses remains dependent on a supportive background regimen. There is variability in the integrase gene of circulating HIV strains, which does not appear to reduce drug activity, although it may influence the emergence and evolution of integrase resistance. Transmission of integrase resistance remains rare but surveillance is required.

Summary Integrase inhibitors provide a potent option for the treatment of HIV infection. Drug resistance remains a challenge, which may be partially overcome by the introduction of second-generation compounds. Prompt management of RAL and EVG failure is required to prevent the accumulation of multiple resistance mutations that reduce DTG susceptibility.

aInstitute of Infection and Global Health, University of Liverpool, Liverpool, UK

bDepartment of Experimental Medicine and Surgery, University of Rome Tor Vergata, Italy

Correspondence to Professor Anna Maria Geretti, MD, PhD, FRCPath, Institute of Infection and Global Health, University of Liverpool, Liverpool L69 3BX, UK. Tel: +44 151 794 2000; e-mail:

© 2012 Lippincott Williams & Wilkins, Inc.