High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients

Abstract

Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.

Antiretroviral Treatment of HIV-2 Infection: Available Drugs, Resistance Pathways, and Promising New Compounds

“…DTG, approved in 2013, has potent antiviral activity at 50 mg twice daily in various combination regimens and shows limited cross-resistance to most RAL-resistant HIV mutants [ 124 , 125 , 126 ], which is likely due to a slower dissociation rate from mutant DNA relative to RAL and EVG, and an ability to adjust its conformation in response to structural changes in the active site of IN [ 127 , 128 ]. Several studies showed that DTG is active against HIV-2 isolates from INI-naïve patients with an IC 50 range similar to that of HIV-1 [ 129 , 130 , 131 ]. Consistent with this, a recent retrospective observational study from India showed that most (86%) treatment-naive HIV-2-infected patients receiving a DTG-based regimen achieved an undetectable viral load [ 132 ].…”

“…BIC 50 mg daily is given as a fixed-dose combination with FTC and TAF for the treatment of HIV-1 infection [ 138 ]. Different cell culture studies have shown that BIC is generally active against HIV-2 group A strains with IC 50 in the nanomolar range, and also displays potent activity against group B and AB recombinant isolates [ 131 , 139 , 140 , 141 ]. Mean instantaneous inhibitory potential (IIP) value of BIC at Cmax was similar to the other INSTIs and was not significantly affected by resistance mutations, highlighting the potential of this drug to treat HIV-2 infection.…”

“…As mentioned above, mutations Y143C, Q148K/R and N155H, with or without additional mutations (i.e., E92Q, T97A, G140S), have been associated with failure to most RAL- and EVG-based regimens [ 26 , 110 , 142 , 143 , 144 , 145 , 146 ]. Three main mutational pathways confer high-level resistance to RAL and/or EVG: Y143C/G/H/R confers high-level resistance to RAL in combination with E92Q and to EVG in combination with T97A; and G140S/Q148H/K/R and E92Q/N155H confer high-level resistance to both drugs [ 14 , 131 , 145 , 146 , 147 , 148 ]. This extensive cross-resistance prevents the sequential use of RAL and EVG.…”

“…As for DTG, in reference isolate HIV-2ROD9, single or combinations of mutations E92A, E92Q, E92Q/T97A/A153G and I84V/E92Q/H157S were associated with low level resistance (2.5- to 2.6-fold) [ 145 ]. Related with this, one isolate from a patient failing a RAL-based therapy with E92Q and T97A showed intermediate resistance to DTG [ 131 ]. Also, the combination of secondary mutations R263K and E92G led to the loss of susceptibility to DTG in HIV-2-infected patients [ 120 ].…”

“…Regarding resistance to BIC, a study with HIV-2ROD9 integrase mutants has shown that G140S/Q148R and G140S/Q148H lead to 34- and 110-fold resistance to bictegravir, respectively [ 140 ]. More recently, we have shown that BIC activity was unaffected by combined mutations E92Q/T97A and E92A/Q148K that caused resistance to RAL and DTG [ 131 ]. The longer dissociation of BIC from integrase-DNA complexes may contribute to the substantial activity of this drug against HIV-2 isolates with resistance mutations to the other INSTIs [ 150 ].…”