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.

Keywords: HIV-2; antiretroviral activity; drug resistance; instantaneous inhibitory potential (IIP); integrase inhibitors (INIs); spiro-β-lactam BSS-730A.

Figure 1

Susceptibility of isolates from RAL-naïve patients to the four drugs. (A) Comparison of mean IC₅₀ (nM) values of all drugs; (B) Comparison of IC₅₀ fold-change; (C) Comparison of mean IC₉₀ (nM) values; (D) Comparison of IC₉₀ fold-change. One-way ANOVA with Tukey’s multiple comparisons test was used. Only p-values < 0.05 are shown. Lines indicate mean values and 95% CI.

Figure 2

Hill slope values of RAL, DTG, BIC, and BSS-730A for HIV-2 isolates. (A) Isolates from RAL-naïve patients; (B) isolates from RAL-experienced patients. Lines indicate mean values with 95% CI. One-way ANOVA with Tukey’s multiple comparisons test was used. Only p-values < 0.05 are shown.

Figure 3

IIP values of RAL (A), DTG (B), BIC (C), and BSS-730A (D) for HIV-2 isolates at different concentration ranges. The rectangle limits the range of clinical concentrations, Cmax and Cmin, determined for each INI. Cmax and Cmin have not yet been defined for BSS-730A.

Figure 4

Comparison of IIP values of RAL, DTG, BIC, and BSS-730A at Cmax (A) and Cmin (B). Lines indicate mean values with 95% CI. One-way ANOVA with Tukey’s multiple comparisons test was used. Only p-values < 0.05 are shown.

Figure 5

Comparison of IIP values of RAL (A), DTG (B), BIC (C), and BSS-730A (D) at Cmax for isolates from RAL-naïve and RAL-experienced patients. The Mann–Whitney test was used. Lines indicate mean values with 95% CI. Only p-values < 0.05 are shown.