A New Pathway of HIV-2 Integrase Strand-Transfer Inhibitor Resistance

Role of Highly-Active Antiretroviral Therapy
Role of Highly-Active Antiretroviral Therapy
A new integrase inhibitors resistance pathway in HIV-2 infected patients has been identified rendering isolates that are highly resistant.

A new integrase inhibitors resistance pathway has been identified in people infected with HIV-2, rendering isolates that are highly resistant to raltegravir and elvitegravir and moderately resistant to dolutegravir and cabotegravir, according to a study published in Clinical Infectious Diseases.1

Few therapeutic options exist for treating HIV-2 because of its natural resistance to non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, and some protease inhibitors.2-5 Thus, the integrase strand-transfer inhibitors (INSTI) are crucial for the treatment of HIV-2 infections. In vitro phenotypic assays have demonstrated 50% inhibitory concentrations (IC50) against HIV-2 clinical isolates that are similar in range to those of HIV-1 isolates.5-7 

Researchers sought to determine the susceptibility of integrase-mutated and wild-type HIV-2 isolates to 5 different INSTIs that are currently on the market or are in development: raltegravir, elvitegravir, dolutegravir, cabotegravir, and bictegravir.1 The study investigators found that wild-type viruses were susceptible to the 5 INSTIs, with bictegravir having a lower IC50 than the other INSTIs. In addition, a new INSTI resistance pathway was identified, with a 5 amino-acids insertion at codon 231 of HIV-2 integrase, rendering isolates highly resistant to raltegravir and elvitegravir and moderately resistant to dolutegravir and cabotegravir. For bictegravir, 2 isolates remained susceptible and 2 had a slight increase in IC50. As a result, clinicians should closely follow patients who are started on an INSTI-based regimen.    

The study authors concluded, “Our results confirm the potency of integrase inhibitors on wild-type integrase HIV-2 clinical isolates. In addition, we identified a new INSTI resistance pathway, 231INS, selected in highly antiretroviral-experienced patients with multi-resistant HIV-2 viruses.”1

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  1. Le Hingrat Q, Collin G, Lê M, et al, ANRS CO5 HIV-2 Cohort. A new mechanism of resistance of HIV-2 to integrase inhibitors: a 5 amino-acids insertion in the integrase C-terminal domain [published online November 1, 2018]. Clin Infect Dis. doi: 10.1093/cid/ciy940
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  7. Smith RA, Raugi DN, Pan C, et al. In vitro activity of dolutegravir against wild-type and integrase inhibitor-resistant HIV-2. Retrovirology. 2015;12:10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328052/. Accessed March 30, 2018.