Background: Data informing the use of boosted-protease inhibitor monotherapy as second-line treatment are limited. There are also no randomized trials addressing treatment options after failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimens.

Methods: HIV-infected subjects ≥18 years, with HIV-RNA≥1,000 copies/mL while using NNRTI+2NRTIs, and naïve to PI were randomized to LPV/r 400/100 mg twice daily (mono-LPV/r) or tenofovir once daily +lamivudine twice daily +LPV/r 400/100 mg twice daily (TDF/3TC/LPV/r) at 9 sites in Thailand. The primary outcome was time-weighted area under curve (TWAUC) change in HIV-RNA over 48 weeks. A priori hypothesis was that the LPV monotherapy arm would be considered non-inferior if the upper 95% confidence limit in TWAUC mean difference was ≤0.5 log(10) copies/mL.

Results: The intention-to-treat population comprised 195 patients (mono-LPV/r n =98 and TDF/3TC/LPV/r n =97); male 58%, baseline mean (SD) age of 38 (7) years, CD4 count of 204 (135) cells/mm(3), and HIV-RNA of 4.1 (0.6) log(10) copies/mL. The majority had HIV-1 recombinant CRF01_AE infection, and thymidine analog mutation (TAM)-2 mutations were 3 times more common than TAM-1. At 48 weeks, the difference in TWAUC HIV-RNA between arms was 0.15 (95% CI -0.04 to 0.33) log(10) copies/mL, consistent with our definition of non-inferiority. However, the proportion with HIV-RNA<50 copies/mL was significantly lower in the mono-LPV/r arm: 61% vs. 83% (ITT, p<0.01). Baseline HIV-RNA≥5 log(10) copies/mL (p<0.001) and mono-LPV/r use (p=0.003) were predictors of virologic failure. Baseline genotypic sensitivity scores ≥2 and TAM-2 were associated with better virologic control in subjects treated with the TDF-containing regimen.

Conclusion: In PI-naïve patients failing NNRTI-based first-line HAART, mono-LPV/r had a significantly lower proportion of patients with HIV-RNA<50 copies/mL compared to the TDF/3TC/LPV/r treatment. Thus, mono-LPV/r should not be recommended as a second-line option.