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.
OBJECTIVE
To determine HIV-1 reverse transcriptase (RT) and protease (PRO) mutations selected in isolates from antiretroviral therapy (ART)-experienced patients receiving an efavirenz/abacavir/amprenavir salvage regimen.


METHODS
Open-label, single arm of abacavir, 300 mg twice daily, amprenavir, 1200 mg twice daily and efavirenz, 600 mg once daily, in ART-experienced patients of which 42% were non-nucleoside reverse transcriptase inhibitor-naive. The virology population examined consisted of all patients who took at least 16 weeks of study drugs (n=74). Plasma population sequencing was carried out at baseline and last time point at which patients were still taking the three study drugs + other ART. The median follow-up was 48 weeks (range week 16-72).


RESULTS
Baseline (n=73) and on-therapy (n=49) genotypes were obtained. By 48 weeks, 51% of isolates had > or = 3 non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations. NNRTI mutations selected on therapy were K103N (51%), substitutions at position 190 (17/49, 35%): G to A (n=11) / S (n=4) / E (n=1) and T (n=1); L100I (37%) and V1081 (20%) mutations. P225H was not observed in this study. L100I and G190A/S/E/T mutations were rarely detected in the same viral population and baseline Y181C favoured the G190 mutations (OR=8.9, P<0.001), rather than the L100I. The NRTI mutations selected were in accordance with abacavir known resistance profile, no new TAMs were observed, new L74V or I mutations developed in 39 and 16% of isolates, respectively, however, new M184V mutations were only detected in isolates from two patients, one of whom had added lamivudine + didanosine. M184V was common at baseline (55%) and maintained in 22/27 (81%) isolates (five of these 22 added lamivudine or didanosine, or both). The PRO mutations selected were in accordance with the distinct resistance profile of amprenavir compared with other protease inhibitors. Mutations D30N, G48V, N88D/S, L90M and 154V were de-selected, and mutations I50V, I or V to 54M/L, I84V, M46I/L, L33F, I47V as well mutations at position 10 were observed in 20/49 (41%) isolates.


CONCLUSIONS
Prior NNRTI and NRTI therapy influences the pathway of resistance to efavirenz. In this study, the prevalence of mutations selected by efavirenz were different from those described in less ART-experienced patients. Baseline Y181C was associated with the development of mutations at position 190, but not L100I or K103N. In this patient population, abacavir with efavirenz preferentially selected for L74V but not for thymidine analogue mutations. M184V was rarely selected and was maintained in only 77% of patients who did not add lamivudine or didanosine. Finally, amprenavir-specific mutations were selected in the background of other primary protease inhibitor mutations, confirming the distinct resistance profile of amprenavir.
Ait-Khaled
Mounir
M
GlaxoSmithKline, HIV Clinical Development and Medical Affairs Europe, Greenford, UK. mak75231@gsk.com
Rakik
Abdelrahim
A
Griffin
Philip
P
Stone
Chris
C
Richards
Naomi
N
Thomas
Deborah
D
Falloon
Judith
J
Tisdale
Margaret
M
D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines; D002219:Carbamates; D015331:Cohort Studies; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005663:Furans; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010078:Oxazines / Q000627:therapeutic use; D016879:Salvage Therapy; D013449:Sulfonamides / Q000627:therapeutic use; D000099227:Abacavir
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D002219:Carbamates; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D005663:Furans; D016333:HIV Protease; D054303:HIV Reverse Transcriptase; D010078:Oxazines; D013449:Sulfonamides; D000099227:Abacavir; C095108:amprenavir; C098320:efavirenz