Shambhu G Aralaguppe [1], Ujjwal Neogi [1], Kamalendra Singh [1,2], Leonard C. Rogers [2], Duncan T Njenda [1], Bo Hejdeman [3], Anders Sönnerborg [1]
Affiliates: [1] Karolinska Institutet, Huddinge, Stockholm, Sweden. [2] University of Missouri, Columbia, Missouri, USA. [3] South Hospital, Stockholm, Sweden.

Background
To determine the antiretroviral activity of first- and second generation integrase strand transfer inhibitors (INSTIs) against different subtypes as well as primary and acquired drug resistance mutations (DRM) in a patient-cohort infected with diverse subtypes. Biochemical and virological drug sensitivity analysis using patient derived HIV-1 genes and a cross-sectional/longitudinal clinical study.

Methods
Assays for inhibition of 3′-end processing (IC50-3P), strand transfer (IC50S) 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
INSTIs inhibited 3’-end processing at a lower efficiency than strand transfer. Raltegravir had higher IC50S than the other INSTIs for all subtypes, but comparable potency for non-B subtypes and HIV-1B. Elvitegravir had relatively higher IC50S for non-B subtypes. For the second generation INSTIs, the non-B subtypes showed lower or comparable IC50S to that of 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 first-generation INSTIs. No subtype specific clustering was identified. One patient had a primary DRMs (0.3%, 1/270), but 17 (6.3%) patients had one major accessory DRM of which 12 were E157Q.

Conclusion
The equal or higher potency in non-B subtypes of all three second-generation INSTIs 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.