A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

There are two pathways to LPV/r resistance (Mo et al. 2005): (i) an IDV-like pathway caused by mutations at positions 46, 54, and 82 (Kempf et al. 2001) and (ii) an APV-like pathway caused by mutations at positions 32, 47, 50, and 76 (Delaugerre et al. 2007; Nijhuis et al. 2007; Parkin et al. 2003; Prado et al. 2002).

Mutations at position 82 reduce susceptibility ~2-fold. Mutations at positions 54 + 82 reduce susceptibility ~10-fold. The combination of mutations at positions 46, 54, and 82 together with accessory mutations at positions 10 and 20, reduces LPV susceptibility >50-fold and reduce the virologic response to LPV/r salvage therapy (Rhee et al. 2006).

I47V and less commonly I47A are selected during LPV/r salvage therapy (Prado et al. 2002) (Parkin et al. 2003). I47A is a rare mutation which occurs in combination with V32I in which case it reduces LPV susceptibility >50-fold (Carrillo et al. 1998; Friend et al. 2004; Kagan et al. 2005). L76V is selected by and is associated with decreased LPV susceptibility (Delaugerre et al. 2007; Mueller et al. 2004; Nijhuis et al. 2007; Rhee et al. 2006).

L24I and F53L have been associated with reduced LPV susceptibility (Kempf et al. 2002). L33F is selected during LPV salvage therapy and associated with reduced LPV susceptibility and virological response (King et al. 2007; Rhee et al. 2006). T91S is an uncommon mutation that has been reported to develop when HIV-1 is cultured in the presence of increasing LPV concentrations (Carrillo et al. 1998).

The US DHHS Guidelines lists LPV/r as a preferred PI for initial HAART. Patients developing virologic failure during an initial LPV/r containing regimen, rarely develop LPV resistance suggesting that the virologic failure has been due to nonadherence (De Luca et al. 2006; Eron et al. 2006; Haubrich et al. 2007; Hicks et al. 2004; Johnson et al. 2006; Shuter et al. 2007; Walmsley et al. 2002).

LPV/r has been so potent that even in the absence of NRTIs, it has been associated with high-levels of sustained virologic suppression and the absence of emerging PI resistance(Arribas et al. 2005; Gathe et al. 2004; Norton et al. 2006). Although LPV/r monotherapy is not recommended for initial HAART, its effectiveness in this setting suggests that a regimen consisting of LPV/r plus two NRTIs is likely to be highly effective even if the NRTI component of the regimen is compromised due to failure of a previous NNRTI-based HAART regimen or to transmitted NRTI resistance.

LPV/r has been more active than SQV/r, IDV/r, ATV/r, and FPV/r in patients with virological failure who have received one or more previous PIs (Benson et al. 2002; Cohen et al. 2005; Dragsted et al. 2005; Johnson et al. 2005; Kempf et al. 2002). However, in heavily treated patients TPV/r and DRV/r have been more active, although the difference between TPV/r and LPV/r in LPV/r-naNove persons may not be statistically significant (Clotet et al. 2007; Hicks et al. 2006; Katlama et al. 2007; Madruga et al. 2007).

LPV/r has a higher genetic barrier to resistance than most PIs in that multiple PI-resistance mutations are required before the virological response to salvage therapy is compromised (Bongiovanni et al. 2003; Delaugerre et al. 2004; Kempf et al. 2002; King et al. 2007; Loutfy et al. 2004; Masquelier et al. 2002). In the PhenoSense assay reductions in susceptibility of 10-fold or lower are required before a statistically decreased virological response is observed. Levels of 60-fold or higher are required before the activity of standard doses of LPV/r are no longer sufficient to reduce viral levels by 0.5 logs (Coakely et al. 2006).