In the absence of human serum, the mean 50% effective concentration (EC 50 ) values of lopinavir against five different HIV-1 subtype B laboratory strains in lymphoblastic cell lines ranged from 10-27 nM (0.006-0.017 µg/mL, 1 µg/mL = 1.6 µM), and ranged from 4-11 nM (0.003-0.007 µg/mL) against several HIV-1 subtype B clinical isolates in peripheral blood lymphocytes (n = 6). In the presence of 50% human serum, the mean EC 50 values of lopinavir against these five HIV-1 laboratory strains ranged from 65-289 nM (0.04-0.18 µg/mL), representing a 7 to 11-fold attenuation. The EC 50 values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg/mL).
HIV-1 isolates with reduced susceptibility to lopinavir have been selected in cell culture. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in cell culture.
In a study of 653 antiretroviral treatment-naïve patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNA >400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No specific amino acid substitutions could be associated with resistance to KALETRA in the virus from 37 evaluable KALETRA-treated patients. The selection of resistance to KALETRA in antiretroviral treatment-naïve pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).
Resistance to KALETRA has been noted to emerge in patients treated with other protease inhibitors prior to KALETRA therapy. In studies of 227 antiretroviral treatment-naïve and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (>400 copies/mL) viral RNA following treatment with KALETRA for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. All four of these patients had previously received treatment with at least one protease inhibitor and had at least 4 substitutions associated with protease inhibitor resistance immediately prior to KALETRA therapy. Following viral rebound, isolates from these patients all contained additional substitutions, some of which are recognized to be associated with protease inhibitor resistance.
Varying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. The antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined (Table 18).
|Susceptibility reduced by >4 fold||Susceptibility reduced to LPV|
|Indinavir (n=16)||5.7 fold|
|Nelfinavir (n=13)||<4 fold|
|Ritonavir (n=3)||8.32 fold|
|Saquinavir (n=4)||<4 fold|
The clinical relevance of reduced susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to KALETRA therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.
Virologic response to KALETRA has been shown to be affected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 19 shows the 48-week virologic response (HIV-1 RNA <400 copies/mL) according to the number of the above protease inhibitor resistance-associated substitutions at baseline in studies 888 and 765 [see Clinical Studies ( 14.2) and ( 14.3)] and study 957 (see below). Once daily administration of KALETRA for adult patients with three or more of the above substitutions is not recommended.
|Number of protease inhibitor substitutions at baseline 1||Study 888 (Single protease inhibitor-experienced 2 , NNRTI-naïve) n=130||Study 765 (Single protease inhibitor-experienced 3 , NNRTI-naïve) n=56||Study 957 (Multiple protease inhibitor-experienced 4 , NNRTI-naïve) n=50|
|0-2||76/103 (74%)||34/45 (76%)||19/20 (95%)|
|3-5||13/26 (50%)||8/11 (73%)||18/26 (69%)|
|6 or more||0/1 (0%)||N/A||1/4 (25%)|
|1 Substitutions considered in the analysis included L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. 2 43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir. 3 41% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir. 4 86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.|
Virologic response to KALETRA therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-naïve patients with HIV-1 RNA >1,000 copies/mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of KALETRA in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC 50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC 50 value. Fifty-five percent (31/56) of these baseline isolates displayed >4-fold reduced susceptibility to lopinavir. These 31 isolates had a median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 20.
|Lopinavir susceptibility 2 at baseline||HIV-1 RNA <400 copies/mL (%)||HIV-1 RNA <50 copies/mL (%)|
|< 10 fold||25/27 (93%)||22/27 (81%)|
|> 10 and < 40 fold||11/15 (73%)||9/15 (60%)|
|≥ 40 fold||2/8 (25%)||2/8 (25%)|
|1 Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic. 2 Fold change in susceptibility from wild type.|
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