Search tips
Search criteria 


Logo of jidLink to Publisher's site
J Infect Dis. 2011 May 1; 203(9): 1204–1214.
PMCID: PMC3069732

HIV-1 Integrase Inhibitor Resistance and Its Clinical Implications


With the approval in 2007 of the first integrase inhibitor (INI), raltegravir, clinicians became better able to suppress virus replication in patients infected with human immunodeficiency virus type 1 (HIV-1) who were harboring many of the most highly drug-resistant viruses. Raltegravir also provided clinicians with additional options for first-line therapy and for the simplification of regimens in patients with stable virological suppression. Two additional INIs in advanced clinical development—elvitegravir and S/GSK1349572—may prove equally versatile. However, the INIs have a relatively low genetic barrier to resistance in that 1 or 2 mutations are capable of causing marked reductions in susceptibility to raltegravir and elvitegravir, the most well-studied INIs. This perspective reviews the genetic mechanisms of INI resistance and their implications for initial INI therapy, the treatment of antiretroviral-experienced patients, and regimen simplification.

Although the era of highly active antiretroviral (ARV) therapy began in 1996, it was not until a decade later, with the licensing of 4 new ARVs belonging to 4 ARV classes, that it became possible to fully suppress HIV-1 replication in a high proportion of the most heavily treated HIV-infected individuals. Darunavir, the protease inhibitor (PI) with the highest genetic barrier to resistance, and maraviroc, the first CCR5 inhibitor, were approved in 2006. Raltegravir (RAL; Merck Laboratories), the first integrase inhibitor (INI), was approved in 2007, and etravirine, the first non-nucleoside reverse transcriptase inhibitor (NNRTI) shown to be useful for treating patients in whom previous NNRTIs were ineffective, was approved in 2008. Of these 4 new ARVs, the development of RAL may have had the greatest effect on current ARV treatment strategies.

RAL, however, may not be unique among INIs. Two other INIs in advanced clinical development—elvitegravir (EVG; Gilead Sciences) and S/GSK1349572 (GlaxoSmithKline)—may be equally efficacious. However, resistance to RAL and EVG develops rapidly in vitro and, in the absence of other active ARVs, in vivo. Although S/GSK1349572, which is earlier in its clinical development than EVG, appears to have a higher genetic barrier to resistance than RAL or EVG, its efficacy at treating RAL-resistant viruses is incomplete. Understanding INI resistance is therefore critical to use of INIs for initial therapy, the treatment of ARV-experienced patients, and regimen simplification.


Following reverse transcription, integrase (IN) cleaves the conserved dinucleotides GT from the 3′ ends of double-stranded HIV-1 DNA, leaving 2 CA overhangs (the 3′-processing reaction). IN remains bound to each of the 3′ ends, circularizing the HIV-1 preintegration complex (PIC). IN then binds the host protein, lens epithelial-derived growth factor (LEDGF), which translocates the PIC to the nucleus, where IN catalyzes a nucleophilic attack of the viral 3′-hydroxy ends on the phosphodiester bonds of host genomic DNA (the strand-transfer reaction). Although IN catalyzes both the 3′-processing and strand-transfer reactions, only those compounds that specifically inhibit strand transfer have been effective INIs. Indeed, the development of a high-throughput screening assay for the identification of strand-transfer inhibitors that bind IN in complex with viral DNA heralded the modern era of INI development [1].

HIV-1 IN contains 288 amino acids encoded by the 3′ end of the HIV-1 pol gene. It is composed of 3 functional domains. The catalytic core domain (CCD), which encompasses amino acids 51 to 212, contains the catalytic triad D64, D116, and E152 and the viral DNA binding site. D64 and D116 coordinate the positioning of a metallic cationic cofactor (Mg++ or Mn++), which is essential for IN function. The N-terminal domain (NTD), which encompasses amino acids 1 to 50, is characterized by an HHCC zinc-binding motif. Its primary role appears to be to facilitate IN multimerization through its extensive contacts with adjacent CCD monomers. The C-terminal domain (CTD), which encompasses amino acids 213 to 288, binds host DNA nonspecifically.

There are published crystal structures of the HIV-1 IN CCD plus CTD domains, the CCD plus NTD domains, the CCD bound to LEDGF, and the CCD bound to an active site inhibitor, the prototype diketo acid inhibitor 5CITEP (reviewed in [24]; see Figure 1). But the relative conformation of the CCD, NTD, and CTD domains and the tetrameric state of functional HIV-1 IN has been inferred primarily from crystallographic studies of the homologous IN of the prototype foamy virus (PFV) [5]. The applicability of the PFV IN structure to HIV-1 IN is validated by the consistency of the PFV IN structure with HIV-1 IN biochemical data and by the ability of PFV IN to co-crystallize with RAL and EVG [56].

Figure 1.
HIV-1 integrase (IN) inhibitor resistance mutations superimposed on a crystal structure of the IN central core domain bound to a prototype diketo acid inhibitor (5CITEP; PDB 1QS4) [54]. IN residues 56 to 165 are displayed in gray cartoon mode to represent ...

HIV-1 IN inhibitors are structurally diverse molecules that contain a motif for binding the essential divalent metal cations Mg++ or Mn++ and a hydrophobic region for binding within the cavity formed by integrase and the 3′ HIV-1 DNA ends containing the terminal CA dinucleotide. RAL, EVG, and S/GSK1349572 displace viral DNA in the active site and contact several active site amino acids—including those in a mobile loop extending between positions 140 and 149 [24].


The principles of INI resistance parallel those of nucleoside reverse transcriptase inhibitor (NRTI), NNRTI, and PI resistance: (1) INI resistance is caused by primary mutations that reduce INI susceptibility in combination with secondary mutations that further decrease virus susceptibility and/or compensate for the decreased fitness associated with the primary mutations; (2) there is a genetic barrier to INI resistance, defined by the number of mutations required for the loss of clinical INI activity; and (3) there is extensive but incomplete cross-resistance among the INIs.

Mutations Associated With INI Resistance

Table 1 summarizes data on 39 mutations at 26 INI positions derived from (1) in vitro passage experiments in the presence of RAL [910], EVG [79], or 572 [11]; (2) in vivo data on mutations that emerged in individuals receiving RAL [1219] or EVG [20]; and (3) in vitro susceptibility data of site-directed mutants and clinical HIV-1 isolates to RAL, EVG, and S/GSK1349572 [711, 18, 2123]. Nineteen mutations at 10 positions (T66IAK, E92QV, F121Y, Y143RCH, P145S, Q146P, S147G, Q148HRK, V151AL, and N155HS) reduce susceptibility to either RAL or EVG by 5-fold or higher. Seven of these 19 mutations (E92V, F121Y, P145S, Q146P, V151AL, and N155S), however, have not been reported in published sequences from patients receiving RAL or EVG. Twenty mutations at 16 additional positions are accessory mutations that contribute to INI resistance only in the presence of primary INI resistance mutations. G140SAC (±E138KA) and T97A are particularly important accessory mutations because of the marked contribution these mutations make to INI resistance and viral fitness in HIV-1 strains containing Q148 [2426] and Y143 [18, 21] mutations, respectively.

Table 1.
Integrase Inhibitor (INI) Resistance Mutations: Prevalence in INI-Naive and Raltegravir-Treated Individuals and Estimated Effect on Susceptibility to Raltegravir (RAL), Elvitegravir (EVG), and S/GSK1349572 (572)

With the exception of one report of transmitted INI resistance [27], fewer than .1% of INI-naive individuals harbor viruses with primary INI resistance mutations [2829]. As a corollary, naturally occurring resistance to RAL and the other INIs in advanced clinical development is currently absent. Although secondary INI resistance mutations occur in INI-naive patients, these mutations do not interfere with the virological response to RAL-containing regimens [2, 2930]. Table 1 does not show highly polymorphic mutations that have been only weakly associated with INI selective drug pressure or decreased susceptibility such as V72I, T124A, M154IL, K156N, V165I, V201I, I203M, T206S, and D232N (reviewed in [28, 31]).

Table 2 shows the most common patterns of INI resistance mutations in published HIV-1 IN sequences from individuals receiving RAL [32]. Among 192 viral isolates from 105 RAL-treated individuals, 121 viruses contained mutations belonging to one of the 3 most commonly reported RAL-resistance mutation pathways: (1) Q148HRK ± G140SA (n = 58), (2) N155H ± E92Q (n = 38), and (3) Y143CR ± T97A (n = 25). The remaining 71 viruses from 44 individuals included 50 viruses without primary INI resistance mutations, 18 viruses with mutations belonging to more than one of the 3 most common mutational pathways, and 3 with primary mutations not belonging to any of the 3 common mutational pathways. Despite the fact that one mutation such as Y143R, Q148HKR, or N155H is often sufficient to reduce RAL susceptibility more than 10-fold—particularly in site-directed mutagenesis experiments—most RAL-resistant viruses obtained from RAL-treated patients have 2 or more RAL resistance mutations.

Table 2.
Phenotypic Susceptibility Data Associated With the Most Common INI Resistance Mutation Patterns Present in 192 Virus Isolates From 105 Patients

Most published INI susceptibility data have been produced by Monogram’s PhenoSense assay, Virco’s Antivirogram assay, and various permutations of HeLa-CD4+ reporter gene assays. Although these assays frequently yield divergent results, the relative reductions in susceptibility associated with different mutation patterns is consistent among the different assays.

Q148 is a critical part of the IN active site believed to interact with the terminal adenosine and preterminal cytosine of the reactive viral DNA strand. Q148HRK decreases susceptibility to each of the INIs but also markedly decreases IN function. The replication defect associated with Q148HKR, however, is largely reversed by mutations at position 140 and, to a lesser extent, at position 138 [21, 24]. In clinical isolates, viruses with Q148 plus G140 mutations have >150-fold reduced susceptibility to RAL and EVG and up to 10- to 20-fold reduced susceptibility to S/GSK1349572 particularly when a third INI resistance mutation is also present (Table 2).

The second-most common pathway to RAL resistance includes N155H. N155H lies at the base of the catalytic site, where it may form a hydrogen bond with the active site residue E152 and directly interfere with IN metal binding [2]. N155H reduces susceptibility to RAL and EVG but not S/GSK1349572. N155H alone decreases replication capacity less than that of viruses with Q148 mutations alone. The addition of E92Q to N155H further decreases RAL and EVG susceptibility but does not rescue viral fitness [21]. Therefore, viruses with N155H ± E92Q are often outcompeted by viruses with G140 + Q148 mutations [21, 24].

Y143RC is the third-most common pathway to RAL resistance. When RAL binds IN, it induces a stacking interaction with Y143 [5, 34]. Substitution of Y with C or R removes this favorable interaction. S/GSK1349572 and EVG do not appear to contact Y143, and viral susceptibility to these INIs is not affected by Y143 mutations (Table 2). T97A markedly increases Y143RC-mediated RAL resistance [18, 21]. Y143H usually occurs as part of an electrophoretic mixture and may represent a transition between Y and R (TAC/T [Y] => CAC/T [H] => CGC/T [R]).

The Genetic Barrier to INI Resistance

The genetic barrier to INI resistance is lower than that of the PIs and most NRTIs. First, INI resistance is usually selected more rapidly during in vitro passage experiments with INIs than with most NRTIs and PIs [710]. Second, virological failure on an INI-containing regimen often occurs within the first several months of therapy and is often accompanied by INI resistance mutations [12, 19, 35]. In Merck Protocol 005, 35 of 38 subjects with virological failure developed RAL-resistant viruses [35], and in the BENCHMRK trials 64 of 94 with virological failure who underwent genotypic resistance testing had RAL-resistant viruses [12]. Likewise, a high proportion of subjects who developed virological failure while receiving EVG in the phase II trial GS-153-105 developed EVG-resistant viruses [2]. Third, the substitution of RAL for lopinavir/ritonavir (LPV/r) in the SWITCHMRK trial in patients with stably suppressed HIV-1 infection was associated with an increased risk of virological rebound [36]. Fourth, although RAL resistance mutations have been associated with decreased replication capacity [2526], no clinical benefit has been observed from continuing RAL in patients with high-level RAL resistance [37], presumably because most primary RAL resistance mutations occur in combination with accessory compensatory mutations [2426].

The genetic barrier to INI resistance, however, may not be as low as that of lamivudine, emtricitabine, or the NNRTIs nevirapine and efavirenz. In contrast to the NNRTIs, RAL has been highly effective at treating ARV-experienced individuals with few therapeutic options. In the BENCHMRK trials, RAL-containing regimens often produced complete virological suppression despite the absence of other highly active ARVs [12]. In addition, most patients with low-level virological rebound while receiving RAL do not develop INI resistance mutations. For example, none of the 14 subjects in the ANRS 139 TRIO trial with virological rebound developed INI resistance mutations [30] (Table 3). It has also been extremely difficult to select for S/GSK1349572 resistance in vitro, suggesting that this INI has a higher genetic barrier to resistance than RAL or EVG [11].

Table 3.
Integrase Inhibitor Clinical Trials and Associated Drug Resistance Data

INI Cross-Resistance

The 2 most commonly occurring RAL-associated mutation pathways—Q148HRK + G140SAC and N155H ± E92Q—both cause high-level EVG resistance. In contrast, the third RAL-associated mutation pathway, Y143CR ± T97A, does not confer EVG cross-resistance. Similarly, the common EVG-associated resistance mutations T66I [89] and S147G [2, 7] do not confer RAL cross-resistance. S/GSK1349572 is fully active in vitro against viruses with N155H ± E92Q or Y143CR ± T97A. However, susceptibility to S/GSK1349572 is reduced by about 10- to 20-fold by mutations at positions Q148HRK ± G140SAC ± E138KA [11, 33].


RAL was first approved because of its effectiveness in the treatment of 3- and 4-class experienced HIV-infected individuals. It was subsequently approved for first-line therapy because of the noninferiority of tenofovir (TDF) + emtricitabine (FTC) + RAL compared with the standard-of-care first-line regimen TDF + FTC + efavirenz (EFV). RAL has since found a third role as a well-tolerated substitute for enfuvirtide or ritonavir-boosted PIs in patients with stable virological suppression (“regimen simplification”).

The novel stage at which INIs block HIV-1 replication has prompted intensification studies designed to eradicate HIV-1 from long-lived cellular reservoirs or to eliminate low-level residual viremia that emanates from this reservoir. These studies have shown that RAL intensification does not appear to reduce the size of the latent virus reservoir or eliminate low-level residual viremia [5052]. One study has shown that in some patients the latent HIV-1 reservoir is replenished by ongoing low-level replication because telltale episomal viral forms accumulate in some patients receiving RAL intensification [53].

Initial ARV Therapy

Table 3 summarizes published clinical trials in which INIs were used for initial ARV therapy [3839, 4144]. In the phase III STARTMRK trials, RAL + TDF/FTC twice daily was as effective as the standard-of-care regimen (EFV + TDF/FTC once daily) [39]. As a result, published guidelines have recommended RAL + TDF/FTC as a preferred first-line regimen.

In a viral dynamic substudy of the phase II trial Protocol 004 [38], RAL-containing treatment was shown to accelerate the decline in plasma HIV-1 RNA levels relative to EFV-containing treatment. The accelerated decline in virus levels appears to result from INI-induced prevention of the release and production of virions from cells with unintegrated forms of HIV-1 DNA. This accelerated decline, however, has not been shown to provide a unique clinical benefit presumably because the longer period of detectable viremia in patients not receiving INIs is caused by virions produced from unintegrated viral DNA that are unable to infect new cells in the presence of active reverse transcriptase or protease inhibition.

In an interim 48-week analysis of the phase IIb trial comparing 48 subjects receiving EVG + cobicistat (an investigational pharmacokinetic enhancer) + TDF/FTC with 23 subjects receiving EFV + TDF/FTC, the EVG- and EFV-containing arms demonstrated similar virological efficacy [41]. In a dose-ranging 24-week phase II study of S/GSK1349572, at least 90% of subjects receiving each of the 3 S/GSK1349572 dosages had plasma HIV-1 RNA levels below 50 copies/mL [42].

In the NRTI-sparing PROGRESS trial, RAL 400 mg BID + LPV/r 400/100 mg BID produced virological responses similar to the standard-of-care regimen TDF/FTC + LPV/r 400/100 mg BID [44] (Table 3). Four subjects in the RAL-containing arm met the protocol-defined criteria for virological failure and genotypic resistance testing, and one had INI resistance. In the 24-week NRTI-sparing SPARTAN trial, open-label RAL 400 mg BID + atazanavir (ATV) 300 mg BID in 63 patients was similar in efficacy to the standard-of-care arm (ATV/r + TDF/FTC) [43]. However, among the 11 RAL recipients with virological failure, 5 developed RAL resistance, suggesting that despite the clinical efficacy of RAL + ATV, the regimen may be associated with a higher risk of INI resistance at the time of virological failure. The clinical trial was halted because of the frequent occurrence of INI resistance and hyperbilirubinemia [43].

Regimen Simplification

One controlled comparative trial [45] and multiple open-label pilot studies have shown that patients with stable virological suppression on an enfuvirtide-containing regimen can substitute RAL for enfuvirtide without risking virological rebound. The substitution of RAL for a boosted PI, however, has not been uniformly successful. In the large randomized double-blinded controlled SWITCHMRK trial, RAL regimen simplification was less efficacious than continued LPV/r: 84% of 353 RAL recipients versus 91% of 354 suppressed subjects continuing LPV/r maintained a plasma HIV-1 RNA level of fewer than 50 copies/mL by week 24 [36]. Moreover, 8 of the 11 RAL recipients with virological failure developed RAL resistance. In contrast, in the phase IV open-label SPIRAL trial, RAL substitution was at least as efficacious as the boosted PI arm: 89% versus 87% of subjects, respectively, maintained plasma HIV-1 RNA levels of fewer than 50 copies/mL over the 48-week study period [46].

The higher risk of virological failure associated with RAL in the SWITCHMRK compared with the SPIRAL trial is consistent with the observation that failure in SWITCHMRK was associated with previous NRTI failure, so LPV/r was more effective than RAL in the context of a compromised background regimen. In contrast, in the SPIRAL trial about one-half of the subjects in the comparator arm received ATV/r and fosamprenavir/r, PIs with a lower genetic barrier to resistance than LPV/r. Subjects in the SPIRAL trial also had a longer baseline history of virological suppression (≥6 months versus ≥3 months) than those in the SWITCHMRK trial, placing the SPIRAL trial participants at a lower risk of virological failure.

ARV-Experienced Patients

The phase III randomized double-blind controlled BENCHMRK trial demonstrated the efficacy of RAL for highly ARV-experienced patients (Table 3). The phase II GS-183-105 trial compared several different ritonavir-boosted EVG (EVG/r) dosages with an optimized ritonavir-boosted PI-containing regimen. In GS-183-105, the superiority of EVG/r relative to the comparator arm was less than that in the BENCHMRK trials because in GS-183-105, EVG/r was compared with a boosted PI and an optimized background regimen. In contrast, in the BENCHMRK trials, RAL was compared solely with an optimized background regimen. A double-blinded phase III study directly comparing the safety and efficacy of EVG/r with RAL has been fully enrolled (NCT00708162).

Although the treatment of highly ARV-experienced patients with ARV regimens containing RAL or EVG has been successful in the majority of patients in these trials, virological failure and INI resistance occurred in a large proportion of subjects whose optimized background regimen contained no additional active ARVs. The successful use of RAL for treating highly ARV-experienced patients in clinical practice has also been high, particularly when it is part of a regimen containing one or more recently approved ARVs such as darunavir, maraviroc, or etravirine [49].

The VIKING trial is a phase II single-arm study of S/GSK1349572 QD administered to subjects with RAL-resistant viruses in whom a previous RAL-containing regimen had been unsuccessful [33]. For the first 10 days of the trial, S/GSK1349572 was given as functional monotherapy (ie, in combination with existing ARVs for those subjects who had already discontinued RAL or as replacement for RAL for those subjects still receiving it). In the 18 subjects with viruses having mutations in the N155 or Y143 mutational pathways, the mean RNA decrease was 1.8 logs by day 11. In contrast, the virological response was poorer in patients with viruses having Q148 pathway mutations. Although 3 of 5 subjects with Q148H + G140S had an RNA decrease ≥.7 logs by day 11 (the primary end point), none of 4 subjects with a Q148 mutation plus 2 or more additional mutations at positions 74, 138, and 140 had an RNA decrease ≥.7 logs. Whether or not the 10- to 20-fold decreased susceptibility to S/GSK1349572 associated with a Q148 mutation plus one or more mutations can be overcome with a higher S/GSK1349572 dosage (50 mg twice daily) is being evaluated in a second cohort of this trial (NCT00950859;

There have been no studies of RAL or EVG in patients infected with viruses containing INI resistance mutations or having a history of previous INI therapy. Therefore, there are no clinically validated genotypic susceptibility scores or phenotypic cutoffs yet for these INIs. However, treatment with RAL is unlikely to be effective at treating viruses containing one of the major RAL resistance mutations such as Y143CR, Q148HRK, and N155H. Likewise, treatment with EVG is unlikely to be effective at treating viruses containing one of the major EVG resistance mutations such as T66IAK, E92Q, S147G, Q148HRK, and N155H.


The potency and tolerability of RAL have made it an important option for first-line therapy, the treatment of highly ARV-experienced patients, and regimen simplification. RAL’s relatively low genetic barrier to resistance, coupled with the high level of cross-resistance within the INI class, calls for clinicians to be familiar with the studies that define RAL’s optimal use. The investigational INIs EVG and S/GSK1349572 are also being studied for first-line therapy and the treatment of highly ARV-experienced patients. If these INIs are approved and prove to be as well tolerated as RAL, they are also likely to be used for regimen simplification. S/GSK1349572 may also prove useful at treating a significant subset of patients who have RAL-resistant viruses.

This study was supported by NIH grants AI46148 and AI068581. J.-L.B. was supported in part by the Spanish Infectious Diseases Society.


1. Espeseth AS, Felock P, Wolfe A, et al. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc Natl Acad Sci U S A. 2000;97:11244–9. [PubMed]
2. McColl DJ, Chen X. Strand transfer inhibitors of HIV-1 integrase: bringing in a new era of antiretroviral therapy. Antivir Res. 2010;85:101–18. [PubMed]
3. Mouscadet JF, Delelis O, Marcelin AG, Tchertanov L. Resistance to HIV-1 integrase inhibitors: a structural perspective. Drug Resist Updat. 2010;13:139–50. [PubMed]
4. Metifiot M, Marchand C, Maddali K, Pommier Y. Resistance to integrase inhibitors. Viruses. 2010;2:1347–66. [PMC free article] [PubMed]
5. Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature. 2010;464:232–6. [PMC free article] [PubMed]
6. Alian A, Griner SL, Chiang V, et al. Catalytically-active complex of HIV-1 integrase with a viral DNA substrate binds anti-integrase drugs. Proc Natl Acad Sci U S A. 2009;106:8192–7. [PubMed]
7. Shimura K, Kodama E, Sakagami Y, et al. Broad anti-retroviral activity and resistance profile of a novel human immunodeficiency virus integrase inhibitor, elvitegravir (JTK-303/GS-9137) J Virol. 2007;82:764–74. [PMC free article] [PubMed]
8. 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;82:10366–74. [PMC free article] [PubMed]
9. Kobayashi M, Nakahara K, Seki T, et al. Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants. Antivir Res. 2008;80:213–22. [PubMed]
10. 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;402:338–46. [PubMed]
11. Kobayashi M, Yoshinaga T, Seki T, et al. In vitro virology of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011;55:813–21. [PMC free article] [PubMed]
12. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med. 2008;359:355–65. [PubMed]
13. Malet I, Delelis O, Valantin MA, et al. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother. 2008;52:1351–8. [PMC free article] [PubMed]
14. Sichtig N, Sierra S, Kaiser R, et al. Evolution of raltegravir resistance during therapy. J Antimicrob Chemother. 2009;64:25–32. [PubMed]
15. Wittkop L, Breilh D, Da Silva D, et al. Virological and immunological response in HIV-1-infected patients with multiple treatment failures receiving raltegravir and optimized background therapy, ANRS CO3 Aquitaine Cohort. J Antimicrob Chemother. 2009;63:1251–5. [PMC free article] [PubMed]
16. Canducci F, Sampaolo M, Marinozzi MC, et al. Dynamic patterns of human immunodeficiency virus type 1 integrase gene evolution in patients failing raltegravir-based salvage therapies. AIDS. 2009;23:455–60. [PubMed]
17. Baldanti F, Paolucci S, Gulminetti R, Brandolini M, Barbarini G, Maserati R. Early emergence of raltegravir resistance mutations in patients receiving HAART salvage regimens. J Med Virol. 2010;82:116–22. [PubMed]
18. Reuman EC, Bachmann MH, Varghese V, Fessel WJ, Shafer RW. Panel of prototypical raltegravir-resistant infectious molecular clones in a novel integrase-deleted cloning vector. Antimicrob Agents Chemother. 2010;54:934–6. [PMC free article] [PubMed]
19. Hatano H, Lampiris H, Fransen S, et al. Evolution of integrase resistance during failure of integrase inhibitor-based antiretroviral therapy. J Acquir Immune Defic Syndr. 2010;54:389–93. [PMC free article] [PubMed]
20. Zolopa AR, Berger DS, Lampiris H, et al. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. J Infect Dis. 2010;201:814–22. [PubMed]
21. Fransen S, Gupta S, Danovich R, et al. Loss of raltegravir susceptibility of HIV-1 is conferred by multiple non-overlapping genetic pathways. J Virol. 2009;83:11440–6. [PMC free article] [PubMed]
22. Jones GS, Yu F, Zeynalzadegan A, et al. Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother. 2009;53:1194–203. [PMC free article] [PubMed]
23. da Silva D, Van Wesenbeeck L, Breilh D, et al. HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. J Antimicrob Chemother. 2010;65:1262–9. [PubMed]
24. Delelis O, Malet I, Na L, et al. The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation. Nucleic Acids Res. 2009;37:1193–201. [PMC free article] [PubMed]
25. Fransen S, Karmochkine M, Huang W, Weiss L, Petropoulos CJ, Charpentier C. Longitudinal analysis of raltegravir susceptibility and integrase replication capacity of HIV-1 during virologic failure. Antimicrob Agents Chemother. 2009;53:4522–4. [PMC free article] [PubMed]
26. Hu Z, Kuritzkes DR. Effect of raltegravir resistance mutations in HIV-1 integrase on viral fitness. J Acquir Immune Defic Syndr. 2010;55:148–55. [PMC free article] [PubMed]
27. Fransen S, Young B, Frantzell A, et al. Control of viral replication following transmission of HIV-1 exhibiting resistance to reverse transcriptase, protease, and integrase inhibitors [abstract 56] Antivir Ther. 2010;15(Suppl 2):A67.
28. Ceccherini-Silberstein F, Malet I, D’Arrigo R, Antinori A, Marcelin AG, Perno CF. Characterization and structural analysis of HIV-1 integrase conservation. AIDS Rev. 2009;11:17–29. [PubMed]
29. Varghese V, Liu TF, Rhee SY, et al. HIV-1 integrase sequence variability in antiretroviral naive patients and in triple-class experienced patients subsequently treated with raltegravir. AIDS Res Hum Retroviruses. 2010;26:1323–6. [PMC free article] [PubMed]
30. Charpentier C, Roquebert B, Colin C, et al. Resistance analyses in highly experienced patients failing raltegravir, etravirine and darunavir/ritonavir regimen. AIDS. 2010;24:2651–6. [PubMed]
31. Rhee SY, Liu TF, Kiuchi M, et al. Natural variation of HIV-1 group M integrase: implications for a new class of antiretroviral inhibitors. Retrovirology. 2008;5:74. [PMC free article] [PubMed]
32. Rhee SY, Gonzales MJ, Kantor R, Betts BJ, Ravela J, Shafer RW. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res. 2003;31:298–303. [PMC free article] [PubMed]
33. Eron J, Livrozet J, Mortal P, et al. 10th International Congress on Drug Therapy in HIV Infection, Glasgow, Scotland, November 7–11, 2010. Activity of integrase inhibitor S/GSK9572 in subjects with HIV exhibiting raltegravir resistance: week 24 results of VIKING study (ING112961) [abstract O50]
34. Delelis O, Thierry S, Subra F, et al. Impact of Y143 HIV-1 integrase mutations on resistance to raltegravir in vitro and in vivo. Antimicrob Agents Chemother. 2010;54:491–501. [PMC free article] [PubMed]
35. Gatell JM, Katlama C, Grinsztejn B, et al. Long-term efficacy and safety of the HIV integrase inhibitor raltegravir in patients with limited treatment options in a phase II study. J Acquir Immune Defic Syndr. 2010;53:456–63. [PubMed]
36. Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010;375:396–407. [PubMed]
37. Wirden M, Simon A, Schneider L, et al. Raltegravir has no residual antiviral activity in vivo against HIV-1 with resistance-associated mutations to this drug. J Antimicrob Chemother. 2009;64:1087–90. [PubMed]
38. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006;43:509–15. [PubMed]
39. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374:796–806. [PubMed]
40. Lennox JL, Dejesus E, Berger DS, et al. Raltegravir versus efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J Acquir Immune Defic Syndr. 2010;55:39–48. [PubMed]
41. Elion R, Gathe J, Rashburn B, et al. 50th International Conference on Antimicrobial Agents and Chemotherapy. 2010. The single-tablet regimen elvitegravir/cobicstat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF; “QUAD”) maintains a high rate of virologic suppression, and cobicstat (COBI) is an effective pharmacoenhancer through 48 weeks.
42. Rockstroh J, Felizarta F, Maggiolo F, et al. 10th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland: Once-daily S/GSK1349572 combination therapy in antiretroviral-naive adults: rapid and potent 24-week antiviral responses in SPRING-1 (ING112276) [abstract O434] November 7–11, 2010.
43. Kozal M, Lupo S, DeJesus E, et al. 18th International AIDS Conference. Vienna, Austria: The SPARTAN study: a pilot study to assess the safety and efficacy of an investigational NRTI- and RTV-sparing regimen of atazanavir (ATV) experimental dose of 300 mg BID plus raltegravir (RAL) 400 mg BID in treatment-naive HIV-infected subjects [abstract THLBB204] July 18–23, 2010.
44. Reynes J, Lawal A, Pulido F, et al. 18th International AIDS Conference. Vienna, Austria: Lopinavir/ritonavir (LPV/r) combined with raltegravir (RAL) demonstrated similar efficacy and safety as LPV/r combined with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive HIV-1-infected subjects: PROGRESS 48 week results [abstract] July 18–23, 2010.
45. De Castro N, Braun J, Charreau I, et al. Switch from enfuvirtide to raltegravir in virologically suppressed multidrug-resistant HIV-1-infected patients: a randomized open-label trial. Clin Infect Dis. 2009;49:1259–67. [PubMed]
46. Martinez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS. 2010;24:1697–707. [PubMed]
47. Vispo E, Barreiro P, Maida I, et al. Simplification from protease inhibitors to once- or twice-daily raltegravir: the ODIS trial. HIV Clin Trials. 2010;11:197–204. [PubMed]
48. Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007;369:1261–69. [PubMed]
49. Yazdanpanah Y, Fagard C, Descamps D, et al. High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO trial. Clin Infect Dis. 2009;49:1441–9. [PubMed]
50. McMahon D, Jones J, Wiegand A, et al. Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy. Clin Infect Dis. 2010;50:912–9. [PMC free article] [PubMed]
51. Gandhi RT, Zheng L, Bosch RJ, et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLOS Med. 2010;7:e1000321. [PMC free article] [PubMed]
52. Yukl SA, Shergill AK, McQuaid K, et al. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS. 2010;24:2451–60. [PMC free article] [PubMed]
53. Buzon MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. 2010;16:460–5. [PubMed]
54. Goldgur Y, Craigie R, Cohen GH, et al. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: a platform for antiviral drug design. Proc Natl Acad Sci U S A. 1999;96:13040–3. [PubMed]

Articles from The Journal of Infectious Diseases are provided here courtesy of Oxford University Press