Background: Hyper-susceptibility (HS) to HIV-1 Protease Inhibitors (PIs) has been reported by several groups. The clinical significance of this phenomenon is unclear.

Methods: ESS40006 was designed to compare 2 regimens of Amprenavir (APV)/Ritonavir (RTV) (600/100 vs 900/100 twice daily) in subjects failing their current ART regimen. NNRTI-naïve subjects were also started on efavirenz, abacavir, and one additional NRTI, based on baseline susceptibility (abacavir £ 5-fold-change from control, all others ≤ 4, PhenoSense). NNRTI-experienced subjects received tenofovir in place of efavirenz. Multiple logistic regression analysis was used to assess the effect of HS to APV and to identify predictors of virologic response at week 24 (< 200 c/mL). Baseline (BL) APV-fold change (FC) was used as a continuous variable and APV HS was defined as < 0.66 FC based on sample distribution.

Results: Eighty-seven percent (87%; 27/31) of NNRTI-naïve subjects achieved undetectable viral load (< 200 c/mL) by wk 24 (ITT Observed analysis), while 65% (39/60) of NNRTI-experienced subjects, achieved < 200 c/mL (ITT Obs.). Modeling was not done for the EFV cohort because only 4 of 31 subjects did not become undetectable by wk 24. For the TDF cohort, HS to APV (Odds Ratio [OR]: 7.24, p = 0.015), APV FC (OR: 0.31, p = 0.018), and BL HIV-1 RNA (OR: 0.35, p = 0.022) each separately predicted virologic response. The number of prior PIs used approached significance (p = 0.062). When the significant covariates were studied in the same model using stepwise selection, APV HS and BL HIV-1 RNA remained significant. Due to study design there was little variability in susceptibility scores, however, genotypic susceptibility scores (GSS, updated from IAS), phenotypic susceptibility scores (PSS, using different clinical cut-offs), number of mutations (total or by class), number of prior NRTIs, duration of prior ART, CDC classification, baseline CD4 count and APV treatment group (600/100 or 900/100) were not predictive of response.

Conclusions: APV/RTV-based therapy is effective in subjects failing prior ART selected by baseline susceptibility. For NNRTI- experienced subjects, HS to APV, lower APV FC, and a lower baseline viral load were associated with an increased odds of achieving undetectability at 24 wks.