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AVT-080205-Ait-Khaled Antiviral Therapy 8:111-120 HIV-1 reverse transcriptase and protease resistance mutations selected during 16–72 weeks of therapy in isolates from antiretroviral therapy-experienced patients receiving abacavir/efavirenz/amprenavir in the CNA2007 study Mounir Ait-Khaled1*, Abdelrahim Rakik2, Philip Griffin2, Chris Stone2, Naomi Richards3, Deborah Thomas4, Judith Falloon5 and Margaret Tisdale2 for the CNA2007 international study team 1GlaxoSmithKline, HIV Clinical Development and Medical Affairs Europe, Greenford, UK 2GlaxoSmithKline, International Clinical Virology, Stevenage, UK 3GlaxoSmithKline, Statistics, Greenford, UK 4GlaxSmithKline, North American Medical Affairs, Research Triangle Park, NC, USA 5National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., USA *Corresponding author: Tel: +44 208 966 2703; Fax: +44 208 966 4514; E-mail: [email protected] Objective: To determine HIV-1 reverse transcriptase (RT) TAMs were observed, new L74V or I mutations developed and protease (PRO) mutations selected in isolates from in 39 and 16% of isolates, respectively, however, new antiretroviral therapy (ART)-experienced patients receiving M184V mutations were only detected in isolates from two an efavirenz/abacavir/amprenavir salvage regimen. patients, one of whom had added lamivudine + didano- Methods: Open-label, single arm of abacavir, 300 mg sine. M184V was common at baseline (55%) and twice daily, amprenavir, 1200 mg twice daily and maintained in 22/27 (81%) isolates (five of these 22 efavirenz, 600 mg once daily, in ART-experienced added lamivudine or didanosine, or both). The PRO muta- patients of which 42% were non-nucleoside reverse tran- tions selected were in accordance with the distinct scriptase inhibitor-naive. The virology population resistance profile of amprenavir compared with other examined consisted of all patients who took at least 16 protease inhibitors. Mutations D30N, G48V, N88D/S, weeks of study drugs (n=74). Plasma population L90M and I54V were de-selected, and mutations I50V, I or sequencing was carried out at baseline and last time V to 54M/L, I84V, M46I/L, L33F, I47V as well mutations at point at which patients were still taking the three study position 10 were observed in 20/49 (41%) isolates. drugs ± other ART. The median follow-up was 48 weeks Conclusion: Prior NNRTI and NRTI therapy influences the (range week 16–72). pathway of resistance to efavirenz. In this study, the Results: Baseline (n=73) and on-therapy (n=49) genotypes prevalence of mutations selected by efavirenz were were obtained. By 48 weeks, 51% of isolates had ≥3 non- different from those described in less ART-experienced nucleoside reverse transcriptase inhibitor (NNRTI) patients. Baseline Y181C was associated with the devel- mutations. NNRTI mutations selected on therapy were opment of mutations at position 190, but not L100I or K103N (51%), substitutions at position 190 (17/49, 35%): K103N. In this patient population, abacavir with G to A (n=11) / S (n=4) / E (n=1) and T (n=1); L100I (37%) efavirenz preferentially selected for L74V but not for and V108I (20%) mutations. P225H was not observed in thymidine analogue mutations. M184V was rarely this study. L100I and G190A/S/E/T mutations were rarely selected and was maintained in only 77% of patients detected in the same viral population and baseline Y181C who did not add lamivudine or didanosine. Finally, favoured the G190 mutations (OR=8.9, P<0.001), rather amprenavir-specific mutations were selected in the back- than the L100I. The NRTI mutations selected were in accor- ground of other primary protease inhibitor mutations, dance with abacavir known resistance profile, no new confirming the distinct resistance profile of amprenavir. Introduction Abacavir (ABC, Ziagen), a nucleoside inhibitor of combination with other antiretroviral (ART) agents HIV-1, is converted by cellular enzymes to 2′ [4]. Resistance to ABC is relatively slow to develop in deoxyguanosine triphosphate and effectively inhibits vitro and in vivo, requiring multiple mutations (at HIV-1 reverse transcriptase (RT) [1–3]. ABC effec- codons K65R, L74V, Y115F and/or M184V) before tively suppresses HIV-1 replication when used in sensitivity is significantly reduced [1–3]. Antiviral ©2003 International Medical Press 1359-6535/02/$17.00 111 M Ait-Khaled et al. activity of ABC against HIV-1 isolates resistant to ical rebound, 40% had viruses with three linked lamivudine (3TC) and zidovudine (ZDV) has been NNRTI mutations [11]. In these studies, the pattern of demonstrated in vivo in ART-experienced patients who NNRTI mutations was not influenced by the dose of added ABC to a background regimen [5]. The retro- EFV or the drugs combined with EFV (indinavir vs spective analysis of the pooled data from studies where 3TC/ZDV) [11]. ABC was added as a sole agent to background thera- Amprenavir (APV, Agenerase), is a potent and pies has shown that baseline vRNA and genotypic selective protease inhibitor (PI) of HIV-1 and HIV-2, profiles were independent predictors of virological which is approved for use in children and adults response to ABC [5]. Patients harbouring viruses with infected with HIV [16]. The key signature amino acid ≥3 nucleoside reverse transcriptase inhibitor (NRTI)- substitution associated with APV resistance that was associated mutations have a reduced likelihood of identified from in vitro and subsequent clinical studies maximal response to <400 copies/ml, however, ≥4 was isoleucine to valine at position 50 (I50V) in HIV NRTI-associated mutations were required for protease. Four pathways of APV resistance have been decreased likelihood of any antiviral response (that is, identified in the clinic that involve key protease substi- <400 copies/ml or at least 0.5 log decrease in plasma tutions; either I50V, V32I+I47V, I54L/M or I84V, HIV-1 RNA at week 4) [5]. which may be accompanied by one or more accessory In vivo, initial virological rebound in previously mutations (M46I/L, L33F, L10F) [17]. In subjects ART-naive patients on ABC with 3TC and ZDV has failing APV as their first PI, pathway selection appears been shown to be associated with the M184V mutation to be partly dependent on APV plasma levels, with the [6,7]. In some viruses, M184V is followed by the I50V and I84V pathways associated with the highest subsequent accumulation of thymidine analogue muta- levels of resistance being more frequent at higher tions (TAMs: M41L, D67N, K70R, L210W, T215F/Y concentrations of APV [18]. However, the I50V mutant and K219Q/E) or further ABC-specific mutations has a marked reduction on viral fitness, and gag (L74V, Y115F) [6,7]. The median time for detection of cleavage site mutations at positions P1′ and P5′ of p1/p6 the second mutation after M184V was 24 weeks [7]. are linked to the I50V and improve viral fitness [19]. Efavirenz (EFV) is a non-nucleoside reverse tran- In this study we report the type and pattern of HIV- scriptase inhibitor (NNRTI) that has been used as a 1 RT mutations selected by EFV, ABC and APV in component of highly active antiretroviral therapy heavily ART-experienced patients with detectable HIV- (HAART) [8]. A variety of mutations in HIV-1 RT 1 RNA while receiving ABC/EFV/APV ± other ART have been associated with resistance to NNRTIs. (CNA2007). In this cohort (per protocol population), These mutations cluster around the NNRTI binding durable antiviral activity to <400 copies/ml occurred in pocket and occur at positions 98, 100, 101, 103, 106, only 32% (24/74) of patients [15]. Response was asso- 108, 138, 179, 181, 188, 189, 190, 225, 227 and 236 ciated with lower baseline viral load and baseline [9]. Mutations compensatory to the G190E crippling susceptibility to a greater number of the three study substitution, namely V75I and L74V/I, have been drugs [15]. observed upon in vitro passage experiments [10], but the G190E and consequently V75I or L74V/I were Methods rarely seen in vivo after EFV [11] or nevirapine [12] treatment. The in vivo resistance profile of EFV has Study design been characterized by clonal sequencing of isolates CNA2007 was a Phase II, open-label, single-arm, from patients with virological failures during EFV multicentre study to evaluate the safety and antiviral Phase II studies (DMP 266-003 -004 and -005) [11]. activity of combination therapy with ABC, APV and In these studies of previously NNRTI-naive patients EFV in patients with screening vRNA levels of ≥500 with a limited nucleoside inhibitors experience, the copies/ml despite at least 20 weeks treatment with at most common mutations selected by EFV were the least one of the four licensed PIs. There were no restric- K103N (>90% of patients), the V108I and P225H tions on CD4 cell count for entry. Patients must have (~40%), both mainly in combination with the K103N, been receiving combination therapy including indi- and G190S (~10%). The K103N, as well as all navir, ritonavir, saquinavir and/or nelfinavir at primary NNRTI mutations, has been shown to cause screening and up to study entry and must have been clinical cross resistance to the entire class [13–15]. receiving the same PI therapy during the most recent Other double mutants, observed in approximately 12 weeks. All patients were required to stop all back- 10% of EFV treatment failures included L100I- ground antiretroviral agents at study entry. All were K103N and K101Q-K103N. By week 14 naive to study medications, which were then investiga- post-virological rebound, 50% of patients had double tional drugs. Patients were permitted to add antiviral NNRTI-mutant viruses and by week 44 post-virolog- agents after week 16 [15]. 112 ©2003 International Medical Press Abacavir, efavirenz salvage therapy and on-therapy genotypes Patient population the association between L74V or L74V/I with any on- A hundred and one individuals with HIV-1 infection therapy mutation. All P-values reported are two-sided enrolled in the study and 99 started therapy.
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