Quashie, Peter K.a,b; Mesplède, Thibaulta; Wainberg, Mark A.a,b,c
As the only virally encoded enzyme necessary for integration, and one that is present in its active form in infectious HIV particles, integrase was an early choice for HIV drug development . However, despite several promising leads, it was not until the approval of raltegravir (RAL) for clinical use by the U.S. Food and Drug Administration (FDA) in 2007  that an integrase inhibitor (INI) was added to the HIV antiretroviral (ARV) armamentarium. Another INI, elvitegravir (EVG), has also now completed phase III development by Gilead Sciences. A coformulation of cobicistat (COBI)-boosted EVG, tenofovir disoproxil fumarate (TDF), and emtricitabine (FTC), known as the ‘QUAD’ pill, has also now been approved for use in treatment-naive patients [3▪]. Another promising drug, dolutegravir (DTG), is now undergoing phase III clinical testing by ViiV Healthcare, coformulated with lamivudine (3TC) and abacavir (ABC), and should be approved for first-line therapy in 2013 . These three drugs belong to a class of INIs termed integrase strand transfer inhibitors (INSTIs) because of their preferential targeting of the strand transfer step of integration . The development of INIs has been discussed in more detail elsewhere . Recent crystal structure evidence has shown that RAL, EVG, and DTG all bind in the active site of the integrase–vDNA complex with similar coordination of the two divalent metal cofactors (Mg2+ or Mn2+) [7,8] (Fig. 1).
MAJOR INTEGRASE STRAND TRANSFER INHIBITOR DRUG RESISTANCE PATHWAYS
Primary INSTI resistance mutations, as reported for other ARV drugs, result in the loss of integrase activity and viral replicative capacity, whereas secondary DRMs usually increase replicative capacity, drug resistance, or both . Given that the two INSTIs that have been used extensively in the clinic are RAL and EVG, only DRMs for these two drugs have been well studied, and mutations at positions 143, 148, and 155 seem to be the most clinically relevant (Table 1[8,11–16,17▪,18,19▪,20–23]). As more clinical and in-vitro data have been made available, it has become clear that each of these primary resistance mutations occurs independently of each other [12,24,25▪▪,26–28] except in rare cases. Most reports point to these mutations as not being present prior to the initiation of therapy [12,24,25▪▪,26–28]. There are, however, rare reports of transmitted drug resistance involving INSTI DRMs under conditions in which viral replication fitness is not compromised [26,29▪–31▪].
DYNAMISM OF DRUG RESISTANCE MUTATIONS
The evolution of DRMs during selections with RAL and during therapy has been elucidated with the advent of new-generation sequencing methods [24,25▪▪,26,27,32,33]. In a comprehensive study to better define primary resistance variations in patients during continued RAL therapy, characterization of 200 RAL-resistant viruses was carried out. These specimens were derived from patients in the SCOPE cohort, RAL BENCHMRK phase III studies, as well as from patient samples submitted to the Monogram Clinical Reference Library for routine INI testing, with clonal analysis performed for select patient virus isolates [25▪▪]. They found that variants with Y143R or Q148H/R tended to have larger susceptibility fold changes than N155H containing viruses in line with previous studies [12,24,26,32–35]. There were also temporal shifts in subpopulation proportions of N155H, Y143R, and Q148H DRMs within the same patient. By using molecular clones from different patients, isolated at different time-points, they showed that N155H, under continued RAL therapy, is gradually replaced with Y143R or Q148HR, and that the pathway that eventually becomes the predominant species is determined by a specific amino acid substitution at residue 148 as well as by a secondary mutation in addition to Y143R [25▪▪]. In one patient, N155H was the first mutation to appear at week 8, and was then supplanted by the Y143R mutation that first appeared at week 16 and remained the dominant species at week 24; the maximum fold change measured in this patient was 54. Another patient had all three primary mutations present as subpopulations at week 11 (11% E92Q/Y143R; 21% wt; 21% E92Q/N155H; 56% G140S/Q148R), despite the fact that none of these mutations was detected at baseline. Y143R was present in all clones by week 28 (5% Y143R/E92Q; 5% Y143R; 90% Y143R/T97A). The fold change in this patient was greater than 150 at week 11 and remained high with only slight decreases in replicative capacity compared to baseline. In another patient harboring all three primary mutations at week 11 (5% N155H; 23% Q148H/G140S), the N155H mutation was lost by week 16 (15% Y143R; 85% Q148H/G140S) with Q148H/G140S being present in all viruses by week 24. Thus, the 148 pathway dominated when the mutation was Q148H/G140S and the Y143 pathway became dominant in a mixture of N155H and Y143R mutations in these three patients. In an individual in whom a mixture of all three primary mutations was present, the dominance of the 148 pathway was offset only when Y143R occurred in combination with E92Q [25▪▪].
An earlier study analyzed resistance in 23 patients who began a salvage therapy containing RAL. Despite an absence of the 143, 148, and 155 mutations at baseline (frequency <1%), the Y143R, Q148H, and N155H mutations appeared at virological failure under RAL therapy with increased resistance and viral fitness . The presence of secondary resistance mutations such as T97A, V151I, and G163R, despite being detected at very low levels, did not have any effect on the development of resistant variants at failure , suggesting that patterns of resistance development did not appear to be significantly affected by baseline mutations , though other baseline mutations in integrase and other proteins such as protease and reverse transcriptase may have an effect on levels of susceptibility even for variants with identical resistance profiles [28,33,36].
Treatment of patients with EVG has the potential to select for EVG resistance mutations, many with demonstrated cross-resistance to RAL [33,37–39]. Both the 148 and 155 resistance pathways cause a high fold change for EVG [6,12,28,33,39,40]. Mutations at position 143 do not affect the susceptibility of EVG , but EVG is associated with additional primary mutations at position 66 in conjunction with mutations that select for high resistance (fold changes >150) (Table 2[8,11–16,17▪,18,19▪,20–23]) . Additionally, the RAL secondary mutation E92Q is a primary resistance mutation for EVG [33,37,41]. In 10 patients, treated with EVG over 2 weeks, primary resistance mutations selected were T66A/K, E92Q, Q148R, and N155H . After 48 weeks of treatment, there was more resistance mutational diversity in the EVG-treated patients, with the most common double DRM combinations being G140CS/Q148HKR, E138AK/Q148HKR, S147G/Q148HKR, and E92Q/N155H, with a triple DRM combination E138K/S147G/Q148R being present in three patients. Despite having sequenced multiple clones at multiple time-points in the EVG-treated patients, primary DRMs were not detected at baseline. Moreover, the DRMs E138AK, G140C/S, and S147G were never identified alone and combinations of N155H/S together with S147G or G140C/S were not seen . In the RAL-treated arm, the most common combinations identified were G140S/Q148H, sometimes in conjunction with E138A or Y143C .
DTG has not yet been shown to select for resistance mutations in clinical trials [4,42▪,43], and appears to have a very high genetic barrier for the development of resistance. Cell culture work has, however, selected potential DRMs for DTG; the mutations T124A, S153Y, T124A/S153Y, and L101Y/T124A/S153Y were observed on passage with DTG up to day 112 [17▪] without, however, resulting in a large fold change for this drug [17▪,35]. Additionally, recent passage of DTG in multiple subtype B, CRF02_AG, and C viruses selected the moderate DTG DRM R263K in five of six subtype B viruses, and in one of two CRF02_AG viruses, but not in subtype C viruses [19▪]. Instead, the G118R mutation, which had previously been selected in a subtype-C virus with an INSTI termed MK-2048  and in a RAL-treated patient with a CRF02_AG virus , was also selected in one of two CRF02_AG and one of two subtype C viruses, while a H51Y mutation was selected in three of four non-B subtypes [19▪]. Other studies have started with RAL-resistant viruses and attempted to select additional resistance mutations using DTG [45,46]; to date, DTG has been shown to be efficacious against all primary RAL and EVG DRMs, with only reduced susceptibility (10 < fold changes < 20) toward viruses harboring the G140S plus Q148H/R/K mutations, regardless of whether additional mutations were present [45,46,47▪▪]. The clinical use of twice-daily DTG with other drugs may be able to suppress viruses containing RAL and EVG mutations .
FACTORS AFFECTING THE DEVELOPMENT OF RESISTANCE
As with other ARV DRMs, the primary driving force for the occurrence of integrase DRMs is the high error rate of the HIV reverse transcriptase enzyme , that leads to a diverse pool of reverse transcribed DNA and multiple virus subpopulations. In the presence of nonsuppressive INSTI-containing therapy, mutants that have partial resistance to the INSTI being used will out-compete the susceptible wild-type viruses. If, as in the case of N155H viruses, the initially selected mutants have low fitness, they may gradually develop additional mutations that increase fitness and resistance or become replaced by more resistant and fit viruses. There does not appear to be any known effect of baseline polymorphisms on the development of resistance pathways, and multiple studies have shown that INSTI resistance development is stochastic. Despite the fact that N155H is usually the first detected primary DRM in cases of INSTI resistance, its maintenance and replacement by other resistant viruses depends entirely on relative resistance/fitness ratios between the resistant viruses that are present and more fit viruses that gradually become dominant during long-term therapy. This underscores the importance of suppressing viral replication as a means of restricting viral subpopulations. Another driving force behind INSTI resistance is the amount of INSTI that may be bound to integrase at any given time. DTG binds to wild-type integrase significantly longer than either RAL (∼9×) or EVG (∼27×), and this may underscore its ability to resist the development of resistance as well as to retain activity against viruses that are resistant to RAL and EVG [48▪▪]. The long residence time of DTG in an integrase-bound state may also reduce the effect of another driving force of resistance, that is, adherence. This is because DTG binds longer to the protein (t1/2 = 72 h) [48▪▪] and remains bound to intracellular integrase long after it is no longer detectable in the plasma. This may provide continued inhibition, even in the case of low adherence to drugs, limiting the emergence of resistance phenotypes [4,43,48▪▪]. Another factor that may play a role in resistance is variability among viral subtypes [33,36,49]. There is an increasing body of literature to suggest that wild-type HIV proteins of various subtypes are similar in activity and drug susceptibility. This notwithstanding, some DRMs may result in different levels of susceptibility to different INSTIs in different subtypes [19▪,33,36,44,49]. This subject will need to be carefully monitored as INSTIs become more integrated into standard antiretroviral therapy.
REGIMEN SIMPLIFICATION AND ITS EFFECTS ON THE DEVELOPMENT OF RESISTANCE
The results of recent clinical trials involving the three INSTIs, RAL , EVG [3▪], and DTG [42▪], have recently been reported. The idea behind these trials is to increase drug adherence and suppress viral replication. In the case of these INSTI trials, the complete regimen consists of only a single once-daily pill (DTG and EVG) or a twice-daily INSTI (RAL). Though not strictly a simplification trial, the RAL ANRS 139 TRIO trial employed a twice-daily regimen of RAL plus ETV plus DRV/RTV plus optimum background therapy (OBT) (multiple pills) in treatment-experienced HIV-positive individuals (n = 103) harboring multi-DRMs with a mean plasma viral load (vRNA) greater than 1000 copies/ml , but who were naïve to the study drugs. Eighty-seven percent of participants received an OBT of nucleoside reverse transcriptase inhibitors (NRTIs) (n = 86) and enfuvitide (T20) (n = 12); by week 96, 78% were receiving OBT. Week 48 data showed that 86% of all participants achieved virologic suppression (vRNA <50 copies/ml) with a mean CD4+ cell count increase of 108 cells/ml. One hundred patients opted to stay on therapy with follow-up till week 96. The results showed high-level viral suppression (88%) after 96 weeks and no detectable RAL primary resistance mutations ; OBT did not appear to have a significant effect on treatment success . The ‘QUAD’ trials [3▪,51–53] have established that the combination of EVG plus COBI plus EFV plus FTC was noninferior to Atripla (EFV plus TDF plus FTC). In the phase III NCT01095796 trial, 700 treatment-naïve patients were randomized and treated with EVG plus COBI plus FTC plus TDF (n = 348) or EFV plus TDF plus FTC (n = 352) [3▪]. By week 48, 88 and 84% of participants in the respective arms had viral suppression with low levels of DRM. Of the 14 patients (4%) in the EVG arm who qualified for resistance testing (sufficient HIV-1 vRNA), 8 had DRMs with 7 of 8 (<2%) harboring the E92Q mutation [3▪]. The T66I, Q148R, and N155H mutations were also detected at less than 1% prevalence. In recently announced results of the SINGLE  and SPRING [42▪] trials, which have DTG as part of a single once-daily pill (DTG plus 3TC plus ABC) compared, respectively, with Atripla or twice-daily RAL plus OBT, DTG was shown to be noninferior to RAL and superior to Atripla , and did not identify any primary INI resistance mutations in DTG-treated patients. Taken together, this may mean that the previously reported high prevalence of INI-resistance mutations  may be partially because of poor adherence and that a simplified properly optimized regimen may stem the appearance of DRMs.
INSTIs are ARV drugs that contribute positively to patient health and promise to become even more important in the future. New genotyping methods have confirmed the appearance of DRMs in patients failing therapy, underlining the importance of effective treatment. In this regard, single-pill regimens will positively contribute to viral suppression. If new drug combinations are tolerated by patients, the excellent tolerability of INSTIs will lead to a scenario in which combinations of INSTIs with non-nucleoside reverse transcriptase inhibitors (NNRTIs) and NRTIs will become more commonplace.
The authors thank the Canadian Institutes of Health Research (CIHR), the Canadian Foundation for AIDS Research (CANFAR), and ISTP Canada for support. P.K.Q. is a recipient of a CAHR/CIHR Doctoral Scholarship. T.M. is the recipient of the BMS/CTN Postdoctoral Fellowship.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 100–101).
1. Hirsch MS. Chemotherapy of human immunodeficiency virus infections: current practice and future prospects. J Infect Dis 1990; 161:845–857.
2. FDA notifications. FDA approves raltegravir for HIV-1 treatment-naive patients. AIDS Alert 2009; 24:106–107.
3▪. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012; 379:2439–2448.
The 48-week results of EVG ‘QUAD’ trials.
4. Katlama C, Murphy R. Dolutegravir for the treatment of HIV. Expert Opin Investig Drugs 2012; 21:523–530.
5. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000; 287:646–650.
6. Quashie PK, Sloan RD, Wainberg MA. Novel therapeutic strategies targeting HIV integrase. BMC Med 2012; 10:34–45.
7. Hare S, Vos AM, Clayton RF, et al. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci USA 2010; 107:20057–20062.
8. Hare S, Smith SJ, Metifiot M, et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol 2011; 80:565–572.
9. The PyMOL Molecular Graphics System, Version 1.3. Schrödinger, LLC.
10. Shafer RW. Rationale and uses of a public HIV drug-resistance database. J Infect Dis 2006; 194 (Suppl. 1):S51–S58.
11. Bar-Magen T, Sloan RD, Donahue DA, et al. Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor. J Virol 2010; 84:9210–9216.
12. Blanco JL, Varghese V, Rhee SY, et al. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis 2011; 203:1204–1214.
13. Dicker IB, Terry B, Lin Z, et al. Biochemical analysis of HIV-1 integrase variants resistant to strand transfer inhibitors. J Biol Chem 2008; 283:23599–23609.
14. Goethals O, Clayton R, Van Ginderen M, et al. Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol 2008; 82:10366–10374.
15. Goethals O, Van Ginderen M, Vos A, et al. Resistance to raltegravir highlights integrase mutations at codon 148 in conferring cross-resistance to a second-generation HIV-1 integrase inhibitor. Antiviral Res 2011; 91:167–176.
16. Hazuda DJ. Resistance to inhibitors of the human immunodeficiency virus type 1 integration. Braz J Infect Dis 2010; 14:513–518.
17▪. Kobayashi M, Yoshinaga T, Seki T, et al. In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother 2011; 55:813–821.
Comprehensive in-vitro characterization of DTG and its activity against EVG and RAL resistant viruses.
18. Metifiot M, Vandegraaff N, Maddali K, et al. Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS 2011; 25:1175–1178.
19▪. Quashie PK, Mesplede T, Han YS, et al. Characterization of the R263K mutation in HIV-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir. J Virol 2012; 86:2696–2705.
The first report of a possible DTG resistance mutation.
20. Van Wesenbeeck L, Rondelez E, Feyaerts M, et al. Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical isolates. Antimicrob Agents Chemother 2011; 55:321–325.
21. Shafer RW. Rationale and uses of a public HIV drug-resistance database. J Infect Dis 2006; 194 (Suppl. 1):S51–58.
22. Seki T, Kobayashi M, Wakasa-Morimoto C, et al. S/GSK1349572 is a potent next generation HIV integrase inhibitor and demonstrates a superior resistance profile substantiated with 60 integrase mutant molecular clones. In: 17th CROI Conference on Retroviruses and Opportunistic Infections; February 27–March 2, 2010; San Francisco, CA; 2010.
23. Jones G, Ledford R, Yu F, et al. In vitro resistance profile of HIV-1 mutants selected by the HIV-1 integrase inhibitor, GS-9137 (JTK-303). In: 14th Conference on Retroviruses and Opportunistic Infections; February 25–28, 2007; Los Angeles, CA; 2007.
24. Fransen S, Gupta S, Danovich R, et al. Loss of raltegravir susceptibility by human immunodeficiency virus type 1 is conferred via multiple nonoverlapping genetic pathways. J Virol 2009; 83:11440–11446.
25▪▪. Fransen S, Gupta S, Frantzell A, et al. Substitutions at amino acid positions 143, 148, and 155 of HIV-1 integrase define distinct genetic barriers to raltegravir resistance in vivo. J Virol 2012; 86:7249–7255.
A longitudinal analysis of viral subpopulation under continued therapy showing superiority of Y143 and Q148 pathways relative to N155.
26. Codoner FM, Pou C, Thielen A, et al. Dynamic escape of preexisting raltegravir-resistant HIV-1 from raltegravir selection pressure. Antiviral Res 2010; 88:281–286.
27. Armenia D, Vandenbroucke I, Fabeni L, et al. Study of genotypic and phenotypic HIV-1 dynamics of integrase mutations during raltegravir treatment: a refined analysis by ultra-deep 454 pyrosequencing. J Infect Dis 2012; 205:557–567.
28. Winters MA, Lloyd RM Jr, Shafer RW, et al. Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations. PLoS One 2012; 7:e40514.
29▪. Young B, Fransen S, Greenberg KS, et al. Transmission of integrase strand-transfer inhibitor multidrug-resistant HIV-1: case report and response to raltegravir-containing antiretroviral therapy. Antivir Ther 2011; 16:253–256.
One example of transmission of INSTI resistance.
30▪. Boyd SD, Maldarelli F, Sereti I, et al. Transmitted raltegravir resistance in an HIV-1 CRF_AG-infected patient. Antivir Ther 2011; 16:257–261.
Reported transmission of INSTI resistance.
31▪. Hurt CB. Transmitted resistance to HIV integrase strand-transfer inhibitors: right on schedule. Antivir Ther 2011; 16:137–140.
Transmission of an INSTI-resistant HIV strain.
32. Fransen S, Karmochkine M, Huang W, et al. Longitudinal analysis of raltegravir susceptibility and integrase replication capacity of human immunodeficiency virus type 1 during virologic failure. Antimicrob Agents Chemother 2009; 53:4522–4524.
33. Mesplede T, Quashie PK, Wainberg MA. Resistance to HIV integrase inhibitors. Curr Opin HIV AIDS 2012; 7:401–408.
34. Briz V, Poveda E, Soriano V. HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother 2006; 57ss:619–627.
35. Seki T KM, Wakasa-Morimoto C, Yoshinaga T, et al. No impact of HIV integrase polymorphisms at position 101 and 124 on in vitro resistance isolation with dolutegravir (DTG, S/GSK1349572), a potent next generation HIV integrase inhibitor. In: 6th IAS Conference on HIV Pathogenesis Treatment and Prevention; 17–20 July 2011; Rome, Italy; 2011. Poster TUP092.
36. Bar-Magen T, Donahue DA, McDonough EI, Wainberg MA. HIV-1 subtype B and C integrase enzymes exhibit differential patterns of resistance to integrase inhibitors in biochemical assays. AIDS 2010; 24:2171–2179.
37. Margot NA, Hluhanich RM, Jones GS, et al. In vitro resistance selections using elvitegravir, raltegravir, and two metabolites of elvitegravir M1 and M4. Antiviral Res 2012; 93:288–296.
38. Desimmie BA, Schrijvers R, Debyser Z. Elvitegravir: a once daily alternative to raltegravir. Lancet Infect Dis 2012; 12:3–5.
39. Goethals O, Vos A, Van Ginderen M, et al. Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles. Virology 2010; 402:338–346.
40. Jones G, Ledford R, Yu F, et al. Resistance profile of HIV-1 mutants in vitro selected by the HIV-1 integrase inhibitor, GS-9137 (JTK-303). In: 14th Conference on retroviruses and opportunistic infections; February 25–28, 2007; Los Angeles, CA; 2007.
41. Mbisa JL, Martin SA, Cane PA. Patterns of resistance development with integrase inhibitors in HIV. Infect Drug Resist 2011; 4:65–76.
42▪. Van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 2012; 12:111–118.
The 48-week SPRING results.
43. Boyd M. Dolutegravir – a promising antiretroviral in development. Lancet Infect Dis 2012; 12:90–91.
44. Malet I, Fourati S, Charpentier C, et al. The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. J Antimicrob Chemother 2011; 66:2827–2830.
45. Canducci F, Ceresola ER, Boeri E, et al. Cross-resistance profile of the novel integrase inhibitor dolutegravir (S/GSK1349572) using clonal viral variants selected in patients failing raltegravir. J Infect Dis 2011; 204:1811–1815.
46. Garrido C, Soriano V, Geretti AM, et al. Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients – impact of HIV subtypes and prior raltegravir experience. Antiviral Res 2011; 90:164–167.
47▪▪. Underwood MR, Johns BA, Sato A, et al. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr 2012; 61:297–301.
Activity of DTG against RAL-resistant viruses derived from treated patients.
48▪▪. Hightower KE, Wang R, Deanda F, et al. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase–DNA complexes. Antimicrob Agents Chemother 2011; 55:4552–4559.
Correlation between INSTI dissociation rate from integrase–DNA complex and resistance.
49. Brenner BG, Lowe M, Moisi D, et al. Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors. J Med Virol 2011; 83:751–759.
50. Fagard C, Colin C, Charpentier C, et al. Long-term efficacy and safety of raltegravir, etravirine, and darunavir/ritonavir in treatment-experienced patients: week 96 results from the ANRS 139 TRIO trial. J Acquir Immune Defic Syndr 2012; 59:489–493.
51. Elion R, Gathe J, Rashburn B, et al. The single-tablet regimen elvitegravir/cobicstat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF; ‘QUAD’) maintains a high rate of virologic supression, and cobicstat (COBI) is an effective pharmacoenhancer through 48 weeks. In: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; 12–15 October 2010; Boston, MA; 2010.
52. Anonymous. Single-tablet Quad regimen achieves high rate of virologic suppression. AIDS Patient Care STDS 2010; 24:197.
53. Marchand C. The elvitegravir Quad pill: the first once-daily dual-target anti-HIV tablet. Expert Opin Investig Drugs 2012; 21:901–904.
54. Crunkhorn S. Trial watch: HIV integrase inhibitor-based regimen beats market leader. Nat Rev Drug Discov 2012; 11:664.
© 2013 Lippincott Williams & Wilkins, Inc.