Background: Phenotypic and genotypic correlates of antiviral response (AR) derived from clinical investigation characterize an antiretroviral’s (ART) ability to inhibit HIV. The VIKING-3 and VIKING-4 (V3/4) studies examined DTG 50mg twice-daily in patients with resistance to multiple ART’s, including integrase inhibitors (INI). Baseline Integrase (IN) genotypes and phenotypes were assessed to identify correlates to AR.
Methods: In both studies DTG 50mg BID was given through Day 8 as functional monotherapy followed by optimization of background regimen. V3 data only was used for deriving correlates to AR. Day 8 categories for AR as change from Baseline in HIV-1 RNA were pre-defined as Full (>1.0 log10), Intermediate (0.5-1.0 log10) or No response (<0.5 log10). IN resistance tests were performed by Monogram BioSciences. Baseline DTG fold change (FC) phenotypic cut-offs for Day 8 AR were examined using non-linear logistic regression modeling. For IN genotypic correlates, incidence of resistance-associated mutations and co-incidence of mutation pairs at Baseline were examined. Multivariate logistic regression analyses of genotypic data were performed to identify Baseline IN mutations impacting Day 8 AR. Derived IN resistance correlates were tested on Week 24 and Week 48 AR (ITT-E, %<50 c/mL, ‘Snapshot’) using combined V3/4 AR data (N=213).
Results: At Day 8, no definite DTG FC cut-offs for No AR and Full AR were identified due to limited numbers of non-responders and few viruses with high DTG FC. A high correlation between mutations at position G140 and Q148 was confirmed (P <0.001). Three Baseline IN resistance mutation groups were identified as predictors of Day 8 AR which remained associated with response at Weeks 24 and 48 in V3: No Q148 (includes Y143, N155, T66, E92 and virus with only historic IN primary mutations), Q148+1 and Q148+2 (of one or two or more of specific secondary mutations G140A/C/S, L74I, or E138A/K/T). Integrated V3/4 Week 24 AR rates by these derived mutation groups were 78%, 52%, and 24%, respectively; a similar AR pattern was seen at Week 48 with 70%, 48%, and 28%(ITT-E, % <50c/mL by Snapshot).
Conclusions: The three derived baseline IN genotypic groups (No Q148 mutations, Q148 +1, and Q148 +2) were good predictors for DTG responses through Week 48, and thus provide guidance for the clinical use of DTG in patients with INI-resistant virus. Response rates were maintained between Week 24 and 48 for all three IN genotypic groups.