Objective To describe the prevalence of the L76V protease inhibitors resistance-associated mutation (PI-RAM) in relation with patients’ characteristics and protease genotypic background in HIV-1 B- and “non-B”-infected patients. Methods Frequency of the L76V mutation between 1998 and 2010 was surveyed in the laboratory database of 3 clinical centers. Major PI-RAMs were identified according to the IAS-USA list. Fisher’s and Wilcoxon tests were used to compare variables. Results Among the overall 29,643 sequences analyzed, the prevalence of L76V was 1.50%, while was 5.42% in PI-resistant viruses. Since 2008 the prevalence of L76V was higher in “non-B”-infected than in B-infected patients each year. Median time since diagnosis of HIV-1 infection and median time under antiretroviral-based regimen were both shorter in “non-B”- than in B-infected patients (8 vs 11 years, P<0.0001; and 7 vs 8 years, P = 0.004). In addition, “non-B”-infected patients had been pre-exposed to a lower number of PI (2 vs 3, P = 0.016). The L76V was also associated with a lower number of major PI-RAMs in “non-B” vs B samples (3 vs 4, P = 0.0001), and thus it was more frequent found as single major PI-RAM in “non-B” vs B subtype (10% vs 2%, P = 0.014). Conclusions We showed an impact of viral subtype on the selection of the L76V major PI-RAM with a higher prevalence in “non-B” subtypes observed since 2008. In addition, in “non-B”-infected patients this mutation appeared more rapidly and was associated with less PI-RAM.
References
[1]
Wainberg MA, Zaharatos GJ, Brenner BG (2011) Development of antiretroviral drug resistance. N Engl J Med 365: 637–646.
[2]
Ortiz R, Dejesus E, Khanlou H, Voronin E, van Lunzen J, et al. (2008) Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 22: 1389–1397.
[3]
Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, et al. (2008) Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 372: 646–655.
[4]
Delaugerre C, Flandre P, Chaix ML, Ghosn J, Raffi F, et al. (2009) Protease inhibitor resistance analysis in the MONARK trial comparing first-line lopinavir-ritonavir monotherapy to lopinavir-ritonavir plus zidovudine and lamivudine triple therapy. Antimicrob Agents Chemother 53: 2934–2939.
[5]
Nijhuis M, Wensing AM, Bierman WF, de Jong D, Kagan R, et al. (2009) Failure of treatment with first-line lopinavir boosted with ritonavir can be explained by novel resistance pathways with protease mutation 76V. J Infect Dis 200: 698–709.
[6]
Mitsuya Y, Liu TF, Rhee SY, Fessel WJ, Shafer RW (2007) Prevalence of darunavir resistance-associated mutations: patterns of occurrence and association with past treatment. J Infect Dis 196: 1177–1179.
[7]
de Mendoza C, Garrido C, Corral A, Zahonero N, Soriano V (2008) Prevalence and impact of HIV-1 protease mutation L76V on lopinavir resistance. AIDS 22: 311–313.
[8]
Charpentier C, Talla F, Nguepi E, Si-Mohamed A, Bélec L (2011) Virological failure and HIV type 1 drug resistance profiles among patients followed-up in private sector, Douala, Cameroon. AIDS Res Hum Retroviruses 27: 221–230.
[9]
Lambert-Niclot S, Flandre P, Canestri A, Peytavin G, Blanc C, et al. (2008) Factors associated with the selection of mutations conferring resistance to protease inhibitors (PIs) in PI-experienced patients displaying treatment failure on darunavir. Antimicrob Agents Chemother 52: 491–496.
[10]
Young TP, Parkin NT, Stawiski E, Pilot-Matias T, Trinh R, et al. (2010) Prevalence, mutation patterns, and effects on protease inhibitor susceptibility of the L76V mutation in HIV-1 protease. Antimicrob Agents Chemother 54: 4903–4906.
[11]
Wiesmann F, Vachta J, Ehret R, Walter H, Kaiser R, et al. (2011) The L76V mutation in HIV-1 protease is potentially associated with hypersusceptibility to protease inhibitors Atazanavir and Saquinavir: is there a clinical advantage? AIDS Res Ther 8: 7.
[12]
Tartaglia A, Saracino A, Monno L, Tinelli C, Angarano G (2009) Both a protective and a deleterious role for the L76V mutation. Antimicrob Agents Chemother 53: 1724–1725.
[13]
Johnson VA, Calvez V, Günthard HF, Paredes R, Pillay D, et al. (2011) 2011 update of the drug resistance mutations in HIV-1. Top Antivir Med 19: 156–164.
[14]
Ceccherini-Silberstein F, Erba F, Gago F, Bertoli A, Forbici F, et al. (2004) Identification of the minimal conserved structure of HIV-1 protease in the presence and absence of drug pressure. AIDS 18: F11–19.
[15]
Alteri C, Svicher V, Gori C, D’Arrigo R, Ciccozzi M, et al. (2009) Characterization of the patterns of drug-resistance mutations in newly diagnosed HIV-1 infected patients na？ve to the antiretroviral drugs. BMC Infect Dis 9: 111.
[16]
Charpentier C, Lambert-Niclot S, Larrouy L, Storto A, Landman R, et al.. (2012) Evolution of the K65R, K103N and M184V/I reverse transcriptase mutations prevalence in HIV-1-infected patients experiencing virological failure between 2005 and 2010. In: Abstract of the 19th Conference on Retroviruses and Opportunistic Infections; Seattle, WA, 2012. Abstract 726.
[17]
Champenois K, Baras A, Choisy P, Ajana F, Melliez H, et al. (2011) Lopinavir/ritonavir resistance in patients infected with HIV-1: two divergent resistance pathways? J Med Virol 83: 1677–1681.
[18]
Deshpande A, Jauvin V, Magnin N, Pinson P, Faure M, et al. (2007) Resistance mutations in subtype C HIV type 1 isolates from Indian patients of Mumbai receiving NRTIs plus NNRTIs and experiencing a treatment failure: resistance to AR. AIDS Res Hum Retroviruses 23: 335–340.
[19]
Brenner B, Turner D, Oliveira M, Moisi D, Detorio M, et al. (2003) A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors. AIDS 17: F1–5.
[20]
Ma？ga AI, Malet I, Soulie C, Derache A, Koita V, et al. (2009) Genetic barriers for integrase inhibitor drug resistance in HIV type-1 B and CRF02_AG subtypes. Antivir Ther 14: 123–129.
[21]
Mammano F, Petit C, Clavel F (1998) Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients. J Virol 72: 7632–7637.
[22]
Dam E, Quercia R, Glass B, Descamps D, Launay O, et al. (2009) Gag mutations strongly contribute to HIV-1 resistance to protease inhibitors in highly drug- experienced patients besides compensating for fitness loss. PLoS Pathog 5: e1000345.
[23]
Nijhuis M, van Maarseveen NM, Lastere S, Schipper P, Coakley E, et al. (2007) A novel substrate-based HIV-1 protease inhibitor drug resistance mechanism. PLoS Med 4: e36.
[24]
Ghosn J, Delaugerre C, Flandre P, Galimand J, Cohen-Codar I, et al. (2011) Polymorphism in Gag gene cleavage sites of HIV-1 non-B subtype and virological outcome of a first-line lopinavir/ritonavir single drug regimen. PLoS One 6: e24798.
