Background: Kaletra is a co-formulation of lopinavir (LPV) and ritonavir (r). At the LPV/r clinical dose of 400/100 mg BID, the mean LPV inhibitory quotient (IQ = trough conc/protein binding-corrected wild type (wt)-HIV IC₅₀) is >75-fold, while the IQ for RTV is less than 0.3.  In phase II/III clinical studies in 470 ARV-naïve subjects on LPV/r plus d4T/3TC, no resistance to LPV/r has been noted to date, even in subjects whose viral replication was not completely suppressed. Although rebound of wild-type virus has been observed in patients receiving HAART, the virtual absence of resistance in this population is intriguing. In this study, we explore the theoretical mechanisms for the observed phenomena.

Methods: Since viral replication is rapid and has low fidelity, we assume that wild-type and first mutants preexist at baseline in ARV-naïve subjects. Assuming similar fitness, the selective advantage (selection pressure) of first mutants over wt viruses is defined as the difference in residual viral replication between the competing strains. Residual viral replication was calculated using a simple Emax-type response relationship. The difference in percentage of residual viral replication was simulated for 3 model drugs to which a single mutation produced the following change in susceptibility, compared to wt virus: A: 3-fold; B: 10-fold; C: 100-fold. Based on in vitro data, LPV is approximated by model drug A.

Results: The difference in percentage of residual viral replication between mutants and wild type viruses for various levels of drug concentrations achieved by the 3 model drugs are shown below:

 

Drug concentration achieved	Drug A IC50mu=3X	Drug B IC50mu=10X	Drug C IC50mu=100X
1/100 of IC50,wt	0.7%	0.7%	1.0%
IC50,wt	25.0%	40.9%	49.0%
IC50,mu	25.0%	40.9%	49.0%
IC90,wt	15.0%	42.6%	81.7%
IC90,mu	6.4%	8.9%	9.9%
75X of IC50,wt	2.5%	10.4%	55.8%

 

 

Maximum selective advantage was determined to be at drug concentrations between the two IC₅₀ values. The extent of selective advantage was found to be a function of the difference between the two IC₅₀ values (~27%, 50%, and 82% for model drugs A, B, and C, respectively).  For drugs achieving low plasma concentrations relative to IC₅₀, this model predicts that a long t_1/2 can produce a lengthy period of selective advantage for mutants over wt virus, particularly during periods of inconsistent adherence.

Conclusions: Theoretical simulations suggest that the lack of development of resistant virus in ARV-naïve subjects receiving LPV/r 400/100 mg BID might be attributed to its high plasma concentrations and relatively small changes in IC₅₀ values between the initial mutants and wt viruses. The rapid decline in LPV plasma concentrations following missed doses, primarily due to declining ritonavir concentrations, may also contribute to the low incidence of LPV resistance in vivo.