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Ex vivo antiretroviral potency of newer integrase strand transfer inhibitors cabotegravir and bictegravir in HIV-1 non-B subtypes.

Ex vivo antiretroviral potency of newer integrase strand transfer inhibitors cabotegravir and bictegravir in HIV-1 non-B subtypes.
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Neogi U, Singh K, Aralaguppe SG, Rogers LC, Njenda DT, Sarafianos SG, Hejdeman B, Sönnerborg A,


Neogi U, Singh K, Aralaguppe SG, Rogers LC, Njenda DT, Sarafianos SG, Hejdeman B, Sönnerborg A, (click to view)

Neogi U, Singh K, Aralaguppe SG, Rogers LC, Njenda DT, Sarafianos SG, Hejdeman B, Sönnerborg A,

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AIDS (London, England) 2017 12 12() doi 10.1097/QAD.0000000000001726

Abstract
OBJECTIVE
To determine the antiretroviral activity of the integrase strand transfer inhibitors (INSTIs), raltegravir, elvitegravir, dolutegravir, cabotegravir and bictegravir, against different subtypes as well as primary and acquired drug resistance mutations (DRM) in a patient-cohort infected with diverse subtypes.

DESIGN
Biochemical and virological drug sensitivity analysis using patient derived HIV-1 genes and cross-sectional/longitudinal clinical study.

METHODS
Assays for inhibition of 3′-end processing (IC50-3P), strand transfer (IC50-ST) and drug sensitivity (DSA) for five INSTIs were done using patient-derived integrase or gag-pol genes from subtypes A1, B, C, 01_AE and 02_AG. Integrase from INSTI-naïve (n = 270) and experienced (n = 96) patients were sequenced.

RESULTS
Raltegravir had higher IC50-ST than the other INSTIs for all subtypes. Elvitegravir had higher IC50-ST for HIV-1C (p < 0.05) and 02_AG (p < 0.05) than HIV-1B. Dolutegravir showed lower IC50-ST in HIV-1C than HIV-1B (p = 0.003). In CAB, the non-B subtypes showed lower IC50-ST (p < 0.05) than HIV-1B. In BIC, lower IC50-ST in 01_AE (p = 0.017) and 02_AG (p = 0.045) than HIV-1B. In DSA, EC50 for dolutegravir [median (IQR) 2.14 (1.3 to 2.56)], cabotegravir [1.68 (1.34 to 2.55)], and bictegravir [1.07 (0.22 to 2.53)] were lower than raltegravir and elvitegravir. One patient had a primary DRMs (0.3%, 1/270), but 17 (6.3%) had one major accessory DRM of which 12 were E157Q. CONCLUSION
The equal or higher potency in non-B subtypes of dolutegravir, cabotegravir and bictegravir compared to raltegravir and elvitegravir confirms their suitability for use in countries dominated by non-B subtypes. Any impact of the high prevalence of major accessory mutations, especially E157Q, requires long-term follow-up studies.

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