Interpretation of Genotype and Pharmacokinetics for Resistance to Fosamprenavir-Ritonavir-Based Regimens in Antiretroviral-Experienced Patients

Abstract

In this study, named the Zephir study (Telzir-pharmacokinetics), 121 antiretroviral-experienced human immunodeficiency virus (HIV) patients failing on highly active antiretroviral therapy (HAART) were included in a prospective cohort and received a fosamprenavir-ritonavir (700 mg/100 mg twice a day)-based regimen. The impact of baseline HIV type 1 (HIV-1) mutations, pharmacokinetic (PK) parameters, and genotype inhibitory quotient (GIQ) on the virological response at week 12 (W12) was assessed. HIV reverse transcriptase and protease were sequenced at W0. The response at W12 was defined as <2.3 log 10 HIV-1 RNA copies/ml or a virus load decrease of >1 log 10 copies/ml. W4 amprenavir PK were determined by high-performance liquid chromatography. Patients had a median of nine previous treatments over 8 years. Median W0 values were as follows: 295 CD4 ؉ /l, 4.4 log 10 HIV-1 RNA copies/ml, and 6 protease-and 5 nucleotide reverse transcription inhibitor-related mutations. Respective values for minimum concentration of drug in serum (C min ) and area under the concentration-time curve (AUC) from 0 to 24 h were 1,400 ng/ml and 35 mg ⅐ h/ml. At W12, 52% of the patients were successes, with a median decrease of ؊0.7 log 10 HIV-1 RNA copies/ml. The Zephir mutation score included 12 IAS protease mutations associated with poorer virological response: L10I/F/R/V, L33F, M36I, M46I/L, I54L/M/T/V, I62V, L63P, A71I/L/V/T, G73A/C/F/T, V82A/F/S/T, I84V, L90M, and polymorphism mutations I13V, L19I, K55R, and L89M. Comparing <4 versus >4 mutations, HIV-1 RNA decreases were ؊2.3 log 10 copies/ml versus ؊0.1 log 10 copies/ml (P < 10 ؊4 ) with 93% versus 19% successes (P < 10 ؊4 ), respectively. This score predicted W12 failure with 94% sensitivity, versus 31% for the ANRS 2005 algorithm. C min (<1,600 ng/ml), AUC (<40 mg ⅐ h/ml), and GIQ (<300) values were associated with failure (all P values were <10 ؊4 ). The need to test genotype-based algorithms using different patient databases before their implementation in clinical practice is highlighted. Specific mutations, PK and GIQ, provide relevant information for monitoring fosamprenavir-ritonavir-based HAART.Pharmacokinetic (PK) parameters and virological characteristics have been associated with virological responses to highly active antiretroviral therapy (HAART) (2,9,13,19,20,28,29,30,39). The human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) fosamprenavir (FPV)-an amprenavir (APV) prodrug-is rapidly hydrolyzed during absorption into its APV parent form by cellular phosphatases in the gut epithelium (Lexiva [prescribing information]; GlaxoSmithKline, Research Triangle Park, NC). APV undergoes CYP450-based catabolism in the gastrointestinal tract and liver and has been shown to inhibit and induce different isoforms of this system (6, 15). Coadministration of ritonavir, a potent CYP450 inhibitor, decreases APV elimination (34), resulting in clinically significant increases of APV exposure (10, 14, 33); plasma APV levels are similarly boosted when ritonavir is coadminis...

Amide hydrogen exchange in HIV–1 subtype B and C proteases – insights into reduced drug susceptibility and dimer stability

“…The M36I mutation is the only polymorphic mutation in the C-SA protease that is associated with drug resistance to most of the FDAapproved PIs in combination with ritonavir [41]. This mutation is associated with virological failure or a reduced virological response to atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, saquinavir and tipranavir in combination with ritonavir [42][43][44][45][46][47][48][49]. Mutations at residue position 89 are associated with virological failure to darunavir and tipranavir in combination with ritonavir [44,50], and mutations at resi- In the subtype B protease (A) (PDB ID: 2PC0 [13]), M36 appears to provide anchorage for E35, and stabilizes the salt bridge between E35 and R57.…”

“…Polymorphic sites of the subtype B protease (PDB ID: 2PC0) [13] and the C-SA protease (PDB ID: 3U71) [37]. The flexible flaps of the protease (residues at positions [46][47][48][49][50][51][52][53][54] are coloured cyan. The fulcrum region (residues at positions 10-23), hinge region (residues at positions 35-42 and 57-61) and cantilever region (residues at positions 62-78) are implicated in flap opening.…”

Frequency and diversity of human immunodeficiency virus type 1 mutations associated with antiretroviral resistance among patients from Southern Brazil failing highly active antiretroviral therapy (HAART)

“…The most frequent, L90M and others including G48V (9.0%) and I84V (7.1%) are contraindications to the use of saquinavir associated with ritonavir (SQV/r) (32)(33)(34). The mutations I84V (7.1%), V32I (4.0%), I47V (1.6%), and I54L (0.8%), are contraindications to the use of fosamprenavir associated with ritonavir (FSP/r) (35)(36)(37). The number of licensed PI antiretroviral drug class has expanded and the number of mutations associated with PI resistance is higher when compared with other antiretroviral drug classes.…”

Genotypic Resistance Analysis of the Virological Response to Fosamprenavir-Ritonavir in Protease Inhibitor-Experienced Patients in CONTEXT and TRIAD Clinical Trials

“…The protease mutations selected in vitro or in vivo in the presence of amprenavir (I50V, V32I plus I47V, I54LM/M, and I84V) (13) are rarely selected in patients treated by first-line FPV-containing regimens, particularly when boosted with ritonavir (RTV) (12,22). In PIexperienced patients, few data are available concerning the prediction of virological response to FPV/r by genotypic resistance analysis (2,17,20). Recently, the ANRS proposed a genotypic interpretation algorithm for FPV/r including a genotypic score (L10F/I/V, L33F, M36I, I54L/M/V/A/T/S, I62V, V82A/F/C/G, I84V, and L90M) and the presence or absence of the mutations I50V or V32I plus I47V/A as an independent predictor of virological response in 73 PI-experienced patients (17).…”