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

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

References

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
2. Raugi DN, Smith RA, Gottlieb GS, University of Washington-Dakar HIV-2 Study Group. Four amino acid changes in HIV-2 protease confer class-wide sensitivity to protease inhibitors. J Virol. 2015;90:1062-1069.
3. Witvrouw M, Pannecouque C, Switzer WM, Folks TM, De Clercq E, Heneine W. Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and postexposure prophylaxis. Antivir Ther. 2004;9:57-65.
4. Borrego P, Calado R, Marcelino JM, et al. Baseline susceptibility of primary HIV-2 to entry inhibitors. Antivir Ther. 2012;17:565-570.
5. Desbois D, Roquebert B, Peytavin G, et al. In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors. Antimicrob Agents Chemother. 2008;52:1545-1548.
6. Smith RA, Raugi DN, Kiviat NB, et al. Phenotypic susceptibility of HIV-2 to raltegravir: integrase mutations Q148R and N155H confer raltegravir resistance. AIDS. 2011;25:2235-2241.
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.