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Newly approved integrase inhibitors for clinical treatment of AIDS
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BIOPHA-3456; No. of Pages 5 Biomedicine & Pharmacotherapy xxx (2014) xxx–xxx
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Review
Newly approved integrase inhibitors for clinical treatment of AIDS Wan-Gang Gu * Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563003, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 21 August 2014 Accepted 21 September 2014
The current therapy for the human immunodeficiency virus (HIV) infection is a combination of anti-HIV drugs targeting multiple steps of virus replication. The drugs for the acquired immunodeficiency syndrome (AIDS) treatment include reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, co-receptor inhibitor and the newly added integrase inhibitors. Raltegravir, elvitegravir and dolutegravir are the three Food and Drug Administration (FDA) approved integrase strand transfer inhibitors for clinical treatment of HIV infection. The addition of these integrase inhibitors benefits a lot to HIV infected patients. Although it is only seven years from the first integrase inhibitor, which was approved by FDA to now, multiple drug resistant HIV strains have emerged in clinical treatment. Most of the drug resistant virus strains are against raltegravir. Some are cross-resistant to elvitegravir. Dolutegravir is effective for suppression of the current drug resistant viruses. A number of clinical trials have been performed on the three integrase inhibitors. In this study, the application of the three integrase inhibitors in clinical treatment and the findings of drug resistance to integrase inhibitors are summarized. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Integrase Inhibitor AIDS HIV Clinical treatment Drug resistance
1. Introduction Three decades have passed since the first case of HIV was reported in 1981 [1]. Scientists predicted that AIDS would be cured within 20 years shortly after the identification of the pathogen. But up to now, the only effective way for clinical treatment of HIV infected patients is still highly active antiretroviral therapy (HAART). HAART is usually a cocktail of multiple anti-HIV drugs, including reverse transcriptase inhibitors, protease inhibitors, fusion inhibitor, co-receptor antagonist and integrase inhibitors [2]. Compared with other drugs, integrase inhibitor is a new class of anti-HIV agent approved in recent years for clinical treatment of HIV infection. There are totally three integrase inhibitors [raltegravir (RAL); elvitegravir (EVG); dolutegravir (DTG)], which have been approved by FDA [3–5]. The HIV infected patients benefit a lot on the addition of integrase inhibitors to HAART. RAL has been applied for clinical treatment of AIDS since 2007 [3]. Plenty of clinical data have been achieved. For EVG and DTG, the available data are mainly originated from clinical trials since the two inhibitors were just approved in 2012 and 2013. Although integrase inhibitors enter the clinical treatment in recent years, multiple drug resistant virus strains have been discovered. Moreover, some RAL resistant
E-mail addresses: [email protected], [email protected] * Tel.: +86 15 085 592 339.
strains are cross-resistant to EVG in clinical treatment. In this study, the application of the three integrase inhibitors in clinical treatment for AIDS and the findings of drug resistance to integrase inhibitors are reviewed. 2. RAL RAL, developed by Merck & Co., Inc, also called MK0518, is the first integrase inhibitor approved by FDA in 2007 for AIDS treatment. Isentress is the brand name [6]. The approval of RAL is a milestone for integrase inhibitor development, indicating a new class of anti-HIV agents with totally different mechanism of action. RAL is an important advancement for HIV-1 treatment options. Targeting the essential strand transfer step of retroviral integration, RAL is sensitive to many drug resistant virus strains when approved [6,7]. RAL blocks the IN active site and thus inhibited integration at the strand transfer step. At the presence of RAL, the pre-integration comlex fails to bind to human DNA [8,9]. Then, the provirus which failed to integration will be repaired by normal human DNA repair mechanisms and remained inactive in cells [10]. The previously integrase strand transfer inhibitors (INSTIs) were effective with a specific b-diketo acid chemical moiety [8]. The b-diketo acid chemical moiety was substituted with naphthyrine ketones, diketones and naphthyrine carboxamides to improve the chemical stability with structure-based modifications [8]. RAL is a pyrimidine carboxamide developed on
http://dx.doi.org/10.1016/j.biopha.2014.09.013 0753-3322/ß 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Gu W-G. Newly approved integrase inhibitors for clinical treatment of AIDS. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.09.013
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Fig. 1. Chemical structures of RAL, EVG and DTG (www.wikipedia.org).
the basis of previously designed compounds [11]. The chemical name of RAL is N-[(4-fluorophenyl)methyl]-1,6-dihydro-5hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt [10]. The structure of RAL is shown in Fig. 1. There are three kinds of tablets of Isentress for treatment of HIV infected patients: film-coated tablets (400 mg), chewable tablets (100 mg scored and 25 mg) and single-use packet of 100 mg for oral suspension. The recommended dosage for adults is 400 mg film-coated tablet, twice daily (http://www.isentress. com). In HAART treatment, experienced patients infected with drug resistant HIV strains, an optimized background regimen with RAL treatment was superior to an optimized background regimen without RAL treatment [7]. RAL can be taken regardless of the meals and absorbed rapidly with a median Tmax of 4 hours in the fasting state [10]. The most reported common side effects were diarrhea (16.6%), nausea (9.9%) and headache (9.7%) in phase II/III trials with treatment-experienced persons, indicating well tolerance of RAL [10]. RAL showed efficacy, which was similar to the standard initial therapies in treatment-naive patients in phase II studies. HIV RNA was significantly lowered by the addition of RAL in treatment-experienced patients infected with drug resistant viruses in phase III clinical studies [10]. A review summarizing the basic information of RAL, such as pharmacology, pharmacokinetics, pharmacodynamics, efficacy and tolerability was provided [10]. Also, some useful information can be found in several another reviews [12–19]. 3. EVG The second strand transfer integrase inhibitor, EVG from Gilead Sciences, originally developed by Japan Tobacco, Inc was approved for AIDS treatment by FDA in 2012 [4]. Diketo acid compounds are the most effective HIV integrase inhibitors, demonstrating significant preference for inhibition of strand transfer step. A group of 4-quinolone-3-glyoxylic acids with the diketo acid functional groups were designed by Japan Tobacco, Inc based on the diketo acid motif [4]. Japan Tobacco, Inc. and Gilead Sciences signed a license agreement in 2005 which led to the clinical development of a quinolone carboxylic acid, GS-9137 (aka EVG), a strand transfer specific integrase inhibitor [20]. The chemical name of EVG is 6-[(3-chloro-2-fluorophenyl)methyl]-1-[(2S)-1-hydroxy3-methylbutan-2-yl]-7-methoxy-4-oxoquinoline-3-carboxylic acid
[4]. The chemical structure of EVG is shown in Fig. 1. Stribild is a tablet containing150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate for oral use. The recommended dosage is one tablet once daily with food for treatment of HIV infection (https://www.stribild.com/). Two long terminal repeat DNA segments accumulated in the intracellular region as the evidence of strand transfer reaction inhibition by EVG, resulting in non-productive integration [21,22]. A 10-day monotherapy study was performed in patients with HIV infection, demonstrating that EVG 800 mg/day, 200, 400 and 800 mg twice daily and 50 mg boosted with ritonavir 100 mg/day provided a maximum mean change of viral load from baseline [23,24]. EVG is metabolized mainly with cytochrome P450 (CYP3A) enzymes as well as minor pathways, such as primary or secondary glucuronidation [25]. The drug interactions between zidovudine, didanosine, stavudine, abacavir, etravirine and ritonavir-boosted elvitegravir were studied. The results showed that these drugs can be co-administered regardless of dose adjustment [25–27]. Studies of EVG vs. optimized background therapy in treatment-experienced patient showed that 125 mg dose of EVG led to superior time-weighted change at 16, 24 and 48 weeks in log10 viral RNA [28,29]. A study with treatment-naive patients for randomized active control approach of elvitegravir/cobicistat/ emtricitabine/tenofovir disoproxil fumarate vs efavirenz/emtricitabine/tenofovir disoproxil fumarate showed that 90 and 83% of patients achieved a virus load lower than 50 copies/mL at 24 and 48 weeks, respectively. Psychiatric side effects in the elvitegravir/ cobicistat/emtricitabine/tenofovir disoproxil fumarate arm were less common than that of the efavirenz/emtricitabine/tenofovir disoproxil fumarate arm [30]. Reviews summarizing the pharmacodynamics, pharmacokinetics, metabolism and clinical efficacy were available [4,22,25] A review of use of EVG in adult patients with HIV-1 infection was provided [31]. 4. DTG DTG (S/GSK1349572) is the first approved second generation integrase strand transfer inhibitor. Tivicay is the brand name. The chemical name of DTG is (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,12,12a-tetrahydro2H-pyrido[5,6]pyrazino[2,6-b][1,3]oxazine-9-carboxamide. The chemical structure of DTG is shown in Fig. 1. DTG was approved by FDA for treatment-naive and treatment-experienced persons with HIV infection in August 2013 as the third guideline-preferred agents targeting integrase strand transfer step for the administration of treatment-naive patients with HIV infection. DTG is used clinically in tablets for oral use. Fifty milligrams once daily is recommended for treating naive patients or treatment-experienced but INSTI naive patients. Fifty milligrams twice daily is recommended for treatment-naive patients or treatment-experienced but INSTI naive patients when co-administered with potent UGT1A (UDP-glucuronosyltransferase)/CYP3A inducers: tipranavir/ritonavir, fosamprenavir/ritonavir, efavirenz or rifampin (GlaxoSmithKline instruction). More information can be found on website of Tivicay (http://www.tivicay.com/). The efficacy and safety of DTG for both treatment-naive and treatment-experienced persons with HIV infection have been proved in phase III studies [32]. DTG was well tolerated except for Grade I adverse events at a low rate [33]. Other studies provided support for the assessment of once daily 50 mg dolutegravir in phase III trials [34]. 5. Drug resistance Drug resistance is always a serious problem to clinical treatment of HIV infection. The high mutation rate of viral RNA is
Please cite this article in press as: Gu W-G. Newly approved integrase inhibitors for clinical treatment of AIDS. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.09.013
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the main reason account for emerging of drug resistant HIV strains. Patients who had exhausted most current anti-HIV drug options benefit a lot when RAL was added to an optimized therapy based on the resistance profile. Although the substitution rate of IN amino acids was just 0.06% per year during long period anti-HIV treatment, some substitutions were associated with drug resistance to multiple IN inhibitors [35]. A report from the joint Antimicrobial Agents and Chemotherapy (ICAAC)/ Infectious Diseases Society of America (IDSA) meeting in 2008 summarized the early drug resistance and action mechanism to RAL [36]. Studies have identified that N155H and Q148R (H)(K) in integrase can reduce the susceptibility to RAL. N155H and Q148R(H)(K) mutations were observed to occur independently in clonal analysis. These two mutations also reduced the replication capacity of HIV [37,38]. RAL failure is most associated with mutations via two genetic pathways (N155H, G140S/A or Q148K/R/H) [39,40]. N155H was selected early in the evolution process of RAL resistance in patients and was later replaced by genotype that containging Q148HKR [41]. N155H mutation in HIV-2 integrase also showed high RAL resistance and impaired virus replication capacity [42]. Resistance profile of RAL to patients infected with HIV-2 has been studied [43]. No residual anti-virus activity of RAL was persisted in patients when strains harbouring one of the two major resistance mutations emerged [44]. Previous studies showed that the mutations of integrase gene were mainly involving position 148 or 155 in cases with virological failure in RAL treatment. In the study with 17 patients with RAL treatment and displayed virological failure, Q148R, T66A, E92Q, G140S, Q148H and N155H mutations were detected. Mutations in viral DNA were detected in all the tested patients. Resistance mutations to RAL could be archived in peripheral blood mononuclear cells (PBMCs) in early stage [45]. The development of drug resistance to RAL was evaluated in two identical trials with patients in whom anti-HIV therapy had failed as infected with triple-class drug resistance virus [46]. After 48 weeks, 23% of the patients (105 of 462) receiving RAL had virologic failure. Genotyping results showed that known integrase mutations associated to RAL phenotypic resistance were detected in 64 patients (68%). Seventy-five percent of the patients showed two or more mutations associated with resistance [46]. Study with a novel resistance selection protocol discovered that Q148R, E92Q, and T66I were primary resistance mutations to both RAL and EVG. The mutations were highlighted in the integrase catalytic sites [47]. In the patients with RAL resistance, integrase G140S mutation rescued catalytic defect due to the mutation of Q148H [48]. Evidence shows that some RAL resistance mutations in integrase are reversible in the presence and after withdraw of the RAL treatment [49]. E157Q mutation was rapidly achieved in a short-term low level replication in a RAL containing treatment [50]. Although RAL resistant virus strains have emerged in clinical treatment, when in combination with ETR, and DRV, RAL containing regimen is highly effective and well tolerated to multidrug-resistant virus [12,51,52]. A lot of additional RAL resistant mutations were discovered in baseline genotypes. Resistance mutations developed dependent on virus subtype and exposure period on RAL if HIV was not suppressed optimally [53]. The current integrase related mutations are mainly associated with RAL and occasionally with EVG. Some EVG resistance features were reviewed [54,55]. The EVG resistance profile was reported to be similar to RAL [4]. But EVG produced rapid virologic suppression to resistant HIV-1 with well tolerance in phase II study [28]. DTG shows significant antiviral activity against RAL and EVG resistant HIV-1 strains [56]. None of the 1222 antiretroviral naive patients received DTG treatment developed resistance against DTG in a recent study [57].
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6. Discussion The discovery of strand transfer inhibitors, like most cases in findings, was not a plain sailing. The early studies to inhibit the integrase activity were focused on ribozymes and small molecules which can bind to viral DNA [58]. RAL was finally approved by FDA after a long period of development. RAL, EVG and DTG are the presently approved three intergrase strand transfer inhibitors for treatment of HIV infected patients as guideline-preferred agents as members of antiviral regimen for treatment of naive persons [29]. RAL and EVG were both applied in conjunction with a PI/r in treatment-experienced persons, demonstrating that RAL had the similar performance with EVG [59]. Raltegravir is usually dosed twice/day. Elvitegravir is dosed once/day because the consideration of drug–drug interactions with a potent CYP3A4 inhibitor, pharmacokinetic booster cobicistat [32]. Raltegravir and elvitegravir have cross-resistance and low genetic barrier to resistance. As a novel generation of strand transfer inhibitor administrated once/day, DTG can be co-formulated with other agents in a single tablet regimen since no pharmacokinetic booster is existing. Compared with RAL and EVG, DTG possesses a higher resistance genetic barrier [32]. As the second-generation integrase strand transfer inhibitor, DTG shows distinct advantages than RAL and EVG. DTG can be dosed once daily for treatment-naive patients. DTG containing regimens showed either non-inferiority or superiority to multiple regimens containing existing first line agents, such as RAL, efavirenz and darunavir/ritonavir in phase III clinical trials [60]. Also, DGT seems to be effective for RAL/EVG treated patients. This means DGT is sensitive to RAL/EVG resistant virus strains [56,61]. A 48-week study with once daily DTG versus RAL in treatment-naive adults with HIV infection was performed. After 48 weeks, 88% participants achieved a viral RNA value less than 50 copies/mL in the DGT group compared with 85% in the RAL group [62]. Participants from the two groups have similar adverse effects such as nausea (14% in DGT group vs 13% in RAL group), headache (2% vs 12%), nasopharyngitis (11% vs 12%) and diarrhea (11% in each group) [62]. No treatment-emergent resistance was observed in participants with virological failure on DTG. But 6% of the patients with virological failure with RAL treatment appeared integrase treatment-emergent resistance [62–64]. The addition of RAL, EVG and DTG to clinical treatment of AIDS is a great progress for HAART therapy although drug resistant virus strains have emerged. The management of anti-HIV agents in clinical treatment is a key problem for control of drug resistance [65]. As a target for anti-HIV research, multiple steps of integrase activity are available for integrase inhibitor development. Although the three approved inhibitors are integrase strand transfer inhibitors, drug development targeting 30 -terminal processing was studied [66]. Integrase is discovered to interact with multiple host factors in the process of integration. The protein–protein interaction (PPI) between integrase and host factor is promising target for integrase inhibitor design. Lens epithelium-derived growth factor (LEDGF)/p75 is the first host factor to be considered for integrase inhibitor development. The inhibitors targeting integrase LEDGF/p75 binding site (LEDGINs) are in development [67,68]. Drug developments through chemical synthesis and virtual screening have also been performed targeting IN-LEDGF/p75 interaction [5,69,70]. Some studies focus on development of new integrase inhibitor effective in suppressing drug resistant virus strains. A series of newly synthesized compounds (1,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides, 1,4-dihydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine3-carboxamides, and 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides) exhibited nanomolar EC50 values against IN in cell assays. Several new compounds showed greater anti-HIV efficacy compared to RAL when tested against IN mutants (G118R,
Please cite this article in press as: Gu W-G. Newly approved integrase inhibitors for clinical treatment of AIDS. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.09.013
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Y143R, G140S/Q148H, N155H, and E138K/Q148K) [71]. All these studies contribute new benefits to the class and will provide new options for the clinical treatment of HIV infected patients in the future. Disclosure of interest The author declares that he has no conflicts of interest concerning this article. Acknowledgements This work was partially supported by the National Natural Science Foundation of China (81360503), the United Foundation of Guizhou (Qiankehe J LKZ[2013]21), the Incubation Project for 2011 Collaborative Innovation Center for Tuberculosis Prevention and Cure in Guizhou Province and the seed grant from Zunyi Medical University for newly recruited talents to Dr. Wan-Gang Gu. References [1] Gayle JA, Selik RM, Chu SY. Surveillance for AIDS and HIV infection among black and Hispanic children and women of childbearing age 1981–1989. MMWR Surveill Summ 1990;39:23–30. [2] McCutchan JA, Wu JW, Robertson K, Koletar SL, Ellis RJ, Cohn S, et al. HIV suppression by HAART preserves cognitive function in advanced, immunereconstituted AIDS patients. AIDS 2007;21:1109–17. [3] Evering TH, Markowitz M, Raltegravir. (MK-0518): an integrase inhibitor for the treatment of HIV-1. Drugs Today 2007;43:865–77. [4] Wills T, Vega V. Elvitegravir: a once-daily inhibitor of HIV-1 integrase. Expert Opin Investig Drugs 2012;21:395–401. [5] Shah BM, Schafer JJ, Desimone Jr JA. Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV. Pharmacotherapy 2013;34:506–20. [6] Anker M, Corales RB, Raltegravir. (MK-0518): a novel integrase inhibitor for the treatment of HIV infection. Expert Opin Investig Drugs 2008;17:97–103. [7] Hicks C, Gulick RM. Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis 2009;48:931–9. [8] Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS 2006;20:489–501. [9] Hazuda DJ, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler JA, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000;287:646–50. [10] Cocohoba J, Dong BJ. Raltegravir: the first HIV integrase inhibitor. Clin Ther 2008;30:1747–65. [11] Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, et al. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 2008;51:5843– 55. [12] Imaz A, del Saz SV, Ribas MA, Curran A, Caballero E, Falco V, et al. Raltegravir, etravirine, and ritonavir-boosted darunavir: a safe and successful rescue regimen for multidrug-resistant HIV-1 infection. J Acquir Immune Defic Syndr 2009;52:382–6. [13] Hughes CA, Robinson L, Tseng A, MacArthur RD. New antiretroviral drugs: a review of the efficacy, safety, pharmacokinetics, and resistance profile of tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir. Expert Opin Pharmacother 2009;10:2445–66. [14] Croxtall JD, Keam SJ. Raltegravir: a review of its use in the management of HIV infection in treatment-experienced patients. Drugs 2009;69:1059–75. [15] Cossarini F, Castagna A, Lazzarin A. Raltegravir in treatment naive patients. Eur J Med Res 2009;14(Suppl. 3):22–9. [16] Briz V, Garrido C, Poveda E, Morello J, Barreiro P, de Mendoza C, et al. Raltegravir and etravirine are active against HIV type 1 group O. AIDS Res Hum Retroviruses 2009;25:225–7. [17] Sayana S, Khanlou H. Raltegravir: the first in a new class of integrase inhibitors for the treatment of HIV. Expert Rev Anti Infect Ther 2008;6:419–26. [18] Cahn P, Sued O. Raltegravir: a new antiretroviral class for salvage therapy. Lancet 2007;369:1235–6. [19] Schafer JJ, Squires KE. Integrase inhibitors: a novel class of antiretroviral agents. Ann Pharmacother 2009;44:145–56. [20] Serrao E, Odde S, Ramkumar K, Neamati N, Raltegravir. elvitegravir, and metoogravir: the birth of ‘‘me-too’’ HIV-1 integrase inhibitors. Retrovirology 2009;6:25. [21] Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet 2011;50:229–44. [22] Shimura K, Kodama EN. Elvitegravir: a new HIV integrase inhibitor. Antivir Chem Chemother 2009;20:79–85.
[23] Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, et al. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol 2008;82:764–74. [24] DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr 2006;43:1–5. [25] Klibanov OM, Elvitegravir. an oral HIV integrase inhibitor, for the potential treatment of HIV infection. Curr Opin Investig Drugs 2009;10:190–200. [26] Ramanathan S, Kakuda TN, Mack R, West S, Kearney BP. Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine. Antivir Ther 2008;13:1011–7. [27] Mathias AA, Hinkle J, Shen G, Enejosa J, Piliero PJ, Sekar V, et al. Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir. J Acquir Immune Defic Syndr 2008;49:156–62. [28] Zolopa AR, Berger DS, Lampiris H, Zhong L, Chuck SL, Enejosa JV, 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. [29] Grant P, Zolopa A. Integrase inhibitors: a clinical review of raltegravir and elvitegravir. J HIV Ther 2008;13:36–9. [30] Cohen C, Elion R, Ruane P, Shamblaw D, DeJesus E, Rashbaum B, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/ cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/ emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS 2011;25:F7–12. [31] Deeks ED, Elvitegravir:. A review of its use in adults with HIV-1 infection. Drugs 2014. [32] Shah BM, Schafer JJ, Desimone Jr JA, Dolutegravir:. A new integrase strand transfer inhibitor for the treatment of HIV. Pharmacotherapy 2013. [33] Weller S, Borland J, Chen S, Johnson M, Savina P, Wynne B, et al. Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment. Eur J Clin Pharmacol 2013;70:29–35. [34] van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, 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 2011;12:111–8. [35] Buzon MJ, Marfil S, Puertas MC, Garcia E, Clotet B, Ruiz L, et al. Raltegravir susceptibility and fitness progression of HIV type-1 integrase in patients on long-term antiretroviral therapy. Antivir Ther 2008;13:881–93. [36] Albrecht H. Report from the 2008 joint ICAAC/IDSA meeting. More on raltegravir: resistance and mechanisms of action. AIDS Clin Care 2008;20:97–8. [37] Fransen S, Gupta S, Danovich R, Hazuda D, Miller M, Witmer M, et al. Loss of raltegravir susceptibility by human immunodeficiency virus type 1 is conferred via multiple nonoverlapping genetic pathways. J Virol 2009;83:11440–6. [38] Fransen S, Karmochkine M, Huang W, Weiss L, Petropoulos CJ, Charpentier C. Longitudinal analysis of raltegravir susceptibility and integrase replication capacity of human immunodeficiency virus type 1 during virologic failure. Antimicrob Agents Chemother 2009;53:4522–4. [39] Malet I, Delelis O, Soulie C, Wirden M, Tchertanov L, Mottaz P, et al. Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV1-infected patients. J Antimicrob Chemother 2009;63:795–804. [40] Mouscadet JF, Arora R, Andre J, Lambry JC, Delelis O, Malet I, et al. IN alternative molecular recognition of DNA induced by raltegravir resistance mutations. J Mol Recognit 2009;22:480–94. [41] Quercia R, Dam E, Perez-Bercoff D, Clavel F. Selective-advantage profile of human immunodeficiency virus type 1 integrase mutants explains in vivo evolution of raltegravir resistance genotypes. J Virol 2009;83:10245–9. [42] Salgado M, Toro C, Simon A, Garrido C, Blanco F, Soriano V, et al. Mutation N155H in HIV-2 integrase confers high phenotypic resistance to raltegravir and impairs replication capacity. J Clin Virol 2009;46:173–5. [43] Xu L, Anderson J, Garrett N, Ferns B, Wildfire A, Cook P, et al. Dynamics of raltegravir resistance profile in an HIV type 2-infected patient. AIDS Res Hum Retroviruses 2009;25:843–7. [44] Wirden M, Simon A, Schneider L, Tubiana R, Malet I, Ait-Mohand H, 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. [45] Charpentier C, Karmochkine M, Laureillard D, Tisserand P, Belec L, Weiss L, et al. Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy. HIV Med 2008;9:765–70. [46] Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, et al. resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008;359:355–65. [47] Goethals O, Clayton R, Van Ginderen M, Vereycken I, Wagemans E, Geluykens P, 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. [48] Delelis O, Malet I, Na L, Tchertanov L, Calvez V, Marcelin AG, 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. [49] Ferns RB, Kirk S, Bennett J, Cook PM, Williams I, Edwards S, et al. The dynamics of appearance and disappearance of HIV-1 integrase mutations during and after withdrawal of raltegravir therapy. AIDS 2009;23:2159–64.
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BIOPHA-3456; No. of Pages 5 W.-G. Gu / Biomedicine & Pharmacotherapy xxx (2014) xxx–xxx [50] Ghosn J, Mazet AA, Avettand-Fenoel V, Peytavin G, Wirden M, Delfraissy JF, et al. Rapid selection and archiving of mutation E157Q in HIV-1 DNA during short-term low-level replication on a raltegravir-containing regimen. J Antimicrob Chemother 2009;64:433–4. [51] Thuret I, Chaix ML, Tamalet C, Reliquet V, Firtion G, Tricoire J, et al. etravirine and r-darunavir combination in adolescents with multidrug-resistant virus. AIDS 2009;23:2364–6. [52] Yazdanpanah Y, Fagard C, Descamps D, Taburet AM, Colin C, Roquebert B, 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. [53] Sichtig N, Sierra S, Kaiser R, Daumer M, Reuter S, Schulter E, et al. Evolution of raltegravir resistance during therapy. J Antimicrob Chemother 2009;64:25– 32. [54] Bourgeois A, Womack S, Newsom D, Caldwell D. A review of rilpivirine and elvitegravir resistance features and implications for treatment sequencing. HIV Clin 2012;24:12–5. [55] Hurt CB, Sebastian J, Hicks CB, Eron JJ. Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States 2009–2012. Clin Infect Dis 2013;58:423–31. [56] Hightower KE, Wang R, Deanda F, Johns BA, Weaver K, Shen Y, 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;55:4552–9. [57] Oliveira M, Mesplede T, Quashie PK, Moisi D, Wainberg MA. Resistance mutations against dolutegravir in HIV integrase impair the emergence of resistance against reverse transcriptase inhibitors. AIDS 2014;28:813–9. [58] Bouziane M, Cherny DI, Mouscadet JF, Auclair C. Alternate strand DNA triple helix-mediated inhibition of HIV-1 U5 long terminal repeat integration in vitro. J Biol Chem 1996;271:10359–64. [59] Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu YP, et al. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis 2011;12:27–35.
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[60] Rathbun RC, Lockhart SM, Miller MM, Liedtke MD. Dolutegravir a secondgeneration integrase inhibitor for the treatment of HIV-1 infection. Ann Pharmacother 2013;48:395–403. [61] Wu G, Abraham T, Saad N. Dolutegravir for the treatment of adult patients with HIV-1 infection. Expert Rev Anti Infect Ther 2014;12:535–44. [62] Waters LJ, Barber TJ. Dolutegravir for treatment of HIV: SPRING forwards? Lancet 2013;381:705–6. [63] Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2013;13:927– 35. [64] Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013;369:1807–18. [65] Mesplede T, Quashie PK, Zanichelli V, Wainberg MA. Integrase strand transfer inhibitors in the management of HIV-positive individuals. Ann Med 2014;46:123–9. [66] Fenwick C, Amad M, Bailey MD, BethellF R., Bos M, Bonneau P, et al. Preclinical profile of BI 224436, a novel HIV-1 non-catalytic site integrase inhibitor. Antimicrob Agents Chemother 2014;58:3233–44. [67] Karmon SL, Markowitz M. Next-generation integrase inhibitors: where to after raltegravir? Drugs 2013;73:213–28. [68] Demeulemeester J, Chaltin P, Marchand A, De Maeyer M, Debyser Z, Christ F. LEDGINs, non-catalytic site inhibitors of HIV-1 integrase: a patent review (2006–2014). Expert Opin Ther Pathol 2014;24:609–32. [69] Xue W, Liu H, Yao X. Molecular modeling study on the allosteric inhibition mechanism of HIV-1 integrase by LEDGF/p75 binding site inhibitors. PLoS One 2014;9:e90799. [70] Reddy KK, Singh P, Singh SK. Blocking the interaction between HIV-1 integrase and human LEDGF/p75: mutational studies, virtual screening and molecular dynamics simulations. Mol Biosyst 2014;10:526–36. [71] Zhao XZ, Smith SJ, Metifiot M, Johnson BC, Marchand C, Pommier Y, et al. Bicyclic 1-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide-containing HIV-1 integrase inhibitors having high antiviral potency against cells harboring raltegravir-resistant integrase mutants. J Med Chem 2014;57:1573–82.
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Review
Newly approved integrase inhibitors for clinical treatment of AIDS Wan-Gang Gu * Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563003, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 21 August 2014 Accepted 21 September 2014
The current therapy for the human immunodeficiency virus (HIV) infection is a combination of anti-HIV drugs targeting multiple steps of virus replication. The drugs for the acquired immunodeficiency syndrome (AIDS) treatment include reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, co-receptor inhibitor and the newly added integrase inhibitors. Raltegravir, elvitegravir and dolutegravir are the three Food and Drug Administration (FDA) approved integrase strand transfer inhibitors for clinical treatment of HIV infection. The addition of these integrase inhibitors benefits a lot to HIV infected patients. Although it is only seven years from the first integrase inhibitor, which was approved by FDA to now, multiple drug resistant HIV strains have emerged in clinical treatment. Most of the drug resistant virus strains are against raltegravir. Some are cross-resistant to elvitegravir. Dolutegravir is effective for suppression of the current drug resistant viruses. A number of clinical trials have been performed on the three integrase inhibitors. In this study, the application of the three integrase inhibitors in clinical treatment and the findings of drug resistance to integrase inhibitors are summarized. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Integrase Inhibitor AIDS HIV Clinical treatment Drug resistance
1. Introduction Three decades have passed since the first case of HIV was reported in 1981 [1]. Scientists predicted that AIDS would be cured within 20 years shortly after the identification of the pathogen. But up to now, the only effective way for clinical treatment of HIV infected patients is still highly active antiretroviral therapy (HAART). HAART is usually a cocktail of multiple anti-HIV drugs, including reverse transcriptase inhibitors, protease inhibitors, fusion inhibitor, co-receptor antagonist and integrase inhibitors [2]. Compared with other drugs, integrase inhibitor is a new class of anti-HIV agent approved in recent years for clinical treatment of HIV infection. There are totally three integrase inhibitors [raltegravir (RAL); elvitegravir (EVG); dolutegravir (DTG)], which have been approved by FDA [3–5]. The HIV infected patients benefit a lot on the addition of integrase inhibitors to HAART. RAL has been applied for clinical treatment of AIDS since 2007 [3]. Plenty of clinical data have been achieved. For EVG and DTG, the available data are mainly originated from clinical trials since the two inhibitors were just approved in 2012 and 2013. Although integrase inhibitors enter the clinical treatment in recent years, multiple drug resistant virus strains have been discovered. Moreover, some RAL resistant
E-mail addresses: [email protected], [email protected] * Tel.: +86 15 085 592 339.
strains are cross-resistant to EVG in clinical treatment. In this study, the application of the three integrase inhibitors in clinical treatment for AIDS and the findings of drug resistance to integrase inhibitors are reviewed. 2. RAL RAL, developed by Merck & Co., Inc, also called MK0518, is the first integrase inhibitor approved by FDA in 2007 for AIDS treatment. Isentress is the brand name [6]. The approval of RAL is a milestone for integrase inhibitor development, indicating a new class of anti-HIV agents with totally different mechanism of action. RAL is an important advancement for HIV-1 treatment options. Targeting the essential strand transfer step of retroviral integration, RAL is sensitive to many drug resistant virus strains when approved [6,7]. RAL blocks the IN active site and thus inhibited integration at the strand transfer step. At the presence of RAL, the pre-integration comlex fails to bind to human DNA [8,9]. Then, the provirus which failed to integration will be repaired by normal human DNA repair mechanisms and remained inactive in cells [10]. The previously integrase strand transfer inhibitors (INSTIs) were effective with a specific b-diketo acid chemical moiety [8]. The b-diketo acid chemical moiety was substituted with naphthyrine ketones, diketones and naphthyrine carboxamides to improve the chemical stability with structure-based modifications [8]. RAL is a pyrimidine carboxamide developed on
http://dx.doi.org/10.1016/j.biopha.2014.09.013 0753-3322/ß 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Gu W-G. Newly approved integrase inhibitors for clinical treatment of AIDS. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.09.013
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Fig. 1. Chemical structures of RAL, EVG and DTG (www.wikipedia.org).
the basis of previously designed compounds [11]. The chemical name of RAL is N-[(4-fluorophenyl)methyl]-1,6-dihydro-5hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt [10]. The structure of RAL is shown in Fig. 1. There are three kinds of tablets of Isentress for treatment of HIV infected patients: film-coated tablets (400 mg), chewable tablets (100 mg scored and 25 mg) and single-use packet of 100 mg for oral suspension. The recommended dosage for adults is 400 mg film-coated tablet, twice daily (http://www.isentress. com). In HAART treatment, experienced patients infected with drug resistant HIV strains, an optimized background regimen with RAL treatment was superior to an optimized background regimen without RAL treatment [7]. RAL can be taken regardless of the meals and absorbed rapidly with a median Tmax of 4 hours in the fasting state [10]. The most reported common side effects were diarrhea (16.6%), nausea (9.9%) and headache (9.7%) in phase II/III trials with treatment-experienced persons, indicating well tolerance of RAL [10]. RAL showed efficacy, which was similar to the standard initial therapies in treatment-naive patients in phase II studies. HIV RNA was significantly lowered by the addition of RAL in treatment-experienced patients infected with drug resistant viruses in phase III clinical studies [10]. A review summarizing the basic information of RAL, such as pharmacology, pharmacokinetics, pharmacodynamics, efficacy and tolerability was provided [10]. Also, some useful information can be found in several another reviews [12–19]. 3. EVG The second strand transfer integrase inhibitor, EVG from Gilead Sciences, originally developed by Japan Tobacco, Inc was approved for AIDS treatment by FDA in 2012 [4]. Diketo acid compounds are the most effective HIV integrase inhibitors, demonstrating significant preference for inhibition of strand transfer step. A group of 4-quinolone-3-glyoxylic acids with the diketo acid functional groups were designed by Japan Tobacco, Inc based on the diketo acid motif [4]. Japan Tobacco, Inc. and Gilead Sciences signed a license agreement in 2005 which led to the clinical development of a quinolone carboxylic acid, GS-9137 (aka EVG), a strand transfer specific integrase inhibitor [20]. The chemical name of EVG is 6-[(3-chloro-2-fluorophenyl)methyl]-1-[(2S)-1-hydroxy3-methylbutan-2-yl]-7-methoxy-4-oxoquinoline-3-carboxylic acid
[4]. The chemical structure of EVG is shown in Fig. 1. Stribild is a tablet containing150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate for oral use. The recommended dosage is one tablet once daily with food for treatment of HIV infection (https://www.stribild.com/). Two long terminal repeat DNA segments accumulated in the intracellular region as the evidence of strand transfer reaction inhibition by EVG, resulting in non-productive integration [21,22]. A 10-day monotherapy study was performed in patients with HIV infection, demonstrating that EVG 800 mg/day, 200, 400 and 800 mg twice daily and 50 mg boosted with ritonavir 100 mg/day provided a maximum mean change of viral load from baseline [23,24]. EVG is metabolized mainly with cytochrome P450 (CYP3A) enzymes as well as minor pathways, such as primary or secondary glucuronidation [25]. The drug interactions between zidovudine, didanosine, stavudine, abacavir, etravirine and ritonavir-boosted elvitegravir were studied. The results showed that these drugs can be co-administered regardless of dose adjustment [25–27]. Studies of EVG vs. optimized background therapy in treatment-experienced patient showed that 125 mg dose of EVG led to superior time-weighted change at 16, 24 and 48 weeks in log10 viral RNA [28,29]. A study with treatment-naive patients for randomized active control approach of elvitegravir/cobicistat/ emtricitabine/tenofovir disoproxil fumarate vs efavirenz/emtricitabine/tenofovir disoproxil fumarate showed that 90 and 83% of patients achieved a virus load lower than 50 copies/mL at 24 and 48 weeks, respectively. Psychiatric side effects in the elvitegravir/ cobicistat/emtricitabine/tenofovir disoproxil fumarate arm were less common than that of the efavirenz/emtricitabine/tenofovir disoproxil fumarate arm [30]. Reviews summarizing the pharmacodynamics, pharmacokinetics, metabolism and clinical efficacy were available [4,22,25] A review of use of EVG in adult patients with HIV-1 infection was provided [31]. 4. DTG DTG (S/GSK1349572) is the first approved second generation integrase strand transfer inhibitor. Tivicay is the brand name. The chemical name of DTG is (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,12,12a-tetrahydro2H-pyrido[5,6]pyrazino[2,6-b][1,3]oxazine-9-carboxamide. The chemical structure of DTG is shown in Fig. 1. DTG was approved by FDA for treatment-naive and treatment-experienced persons with HIV infection in August 2013 as the third guideline-preferred agents targeting integrase strand transfer step for the administration of treatment-naive patients with HIV infection. DTG is used clinically in tablets for oral use. Fifty milligrams once daily is recommended for treating naive patients or treatment-experienced but INSTI naive patients. Fifty milligrams twice daily is recommended for treatment-naive patients or treatment-experienced but INSTI naive patients when co-administered with potent UGT1A (UDP-glucuronosyltransferase)/CYP3A inducers: tipranavir/ritonavir, fosamprenavir/ritonavir, efavirenz or rifampin (GlaxoSmithKline instruction). More information can be found on website of Tivicay (http://www.tivicay.com/). The efficacy and safety of DTG for both treatment-naive and treatment-experienced persons with HIV infection have been proved in phase III studies [32]. DTG was well tolerated except for Grade I adverse events at a low rate [33]. Other studies provided support for the assessment of once daily 50 mg dolutegravir in phase III trials [34]. 5. Drug resistance Drug resistance is always a serious problem to clinical treatment of HIV infection. The high mutation rate of viral RNA is
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the main reason account for emerging of drug resistant HIV strains. Patients who had exhausted most current anti-HIV drug options benefit a lot when RAL was added to an optimized therapy based on the resistance profile. Although the substitution rate of IN amino acids was just 0.06% per year during long period anti-HIV treatment, some substitutions were associated with drug resistance to multiple IN inhibitors [35]. A report from the joint Antimicrobial Agents and Chemotherapy (ICAAC)/ Infectious Diseases Society of America (IDSA) meeting in 2008 summarized the early drug resistance and action mechanism to RAL [36]. Studies have identified that N155H and Q148R (H)(K) in integrase can reduce the susceptibility to RAL. N155H and Q148R(H)(K) mutations were observed to occur independently in clonal analysis. These two mutations also reduced the replication capacity of HIV [37,38]. RAL failure is most associated with mutations via two genetic pathways (N155H, G140S/A or Q148K/R/H) [39,40]. N155H was selected early in the evolution process of RAL resistance in patients and was later replaced by genotype that containging Q148HKR [41]. N155H mutation in HIV-2 integrase also showed high RAL resistance and impaired virus replication capacity [42]. Resistance profile of RAL to patients infected with HIV-2 has been studied [43]. No residual anti-virus activity of RAL was persisted in patients when strains harbouring one of the two major resistance mutations emerged [44]. Previous studies showed that the mutations of integrase gene were mainly involving position 148 or 155 in cases with virological failure in RAL treatment. In the study with 17 patients with RAL treatment and displayed virological failure, Q148R, T66A, E92Q, G140S, Q148H and N155H mutations were detected. Mutations in viral DNA were detected in all the tested patients. Resistance mutations to RAL could be archived in peripheral blood mononuclear cells (PBMCs) in early stage [45]. The development of drug resistance to RAL was evaluated in two identical trials with patients in whom anti-HIV therapy had failed as infected with triple-class drug resistance virus [46]. After 48 weeks, 23% of the patients (105 of 462) receiving RAL had virologic failure. Genotyping results showed that known integrase mutations associated to RAL phenotypic resistance were detected in 64 patients (68%). Seventy-five percent of the patients showed two or more mutations associated with resistance [46]. Study with a novel resistance selection protocol discovered that Q148R, E92Q, and T66I were primary resistance mutations to both RAL and EVG. The mutations were highlighted in the integrase catalytic sites [47]. In the patients with RAL resistance, integrase G140S mutation rescued catalytic defect due to the mutation of Q148H [48]. Evidence shows that some RAL resistance mutations in integrase are reversible in the presence and after withdraw of the RAL treatment [49]. E157Q mutation was rapidly achieved in a short-term low level replication in a RAL containing treatment [50]. Although RAL resistant virus strains have emerged in clinical treatment, when in combination with ETR, and DRV, RAL containing regimen is highly effective and well tolerated to multidrug-resistant virus [12,51,52]. A lot of additional RAL resistant mutations were discovered in baseline genotypes. Resistance mutations developed dependent on virus subtype and exposure period on RAL if HIV was not suppressed optimally [53]. The current integrase related mutations are mainly associated with RAL and occasionally with EVG. Some EVG resistance features were reviewed [54,55]. The EVG resistance profile was reported to be similar to RAL [4]. But EVG produced rapid virologic suppression to resistant HIV-1 with well tolerance in phase II study [28]. DTG shows significant antiviral activity against RAL and EVG resistant HIV-1 strains [56]. None of the 1222 antiretroviral naive patients received DTG treatment developed resistance against DTG in a recent study [57].
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6. Discussion The discovery of strand transfer inhibitors, like most cases in findings, was not a plain sailing. The early studies to inhibit the integrase activity were focused on ribozymes and small molecules which can bind to viral DNA [58]. RAL was finally approved by FDA after a long period of development. RAL, EVG and DTG are the presently approved three intergrase strand transfer inhibitors for treatment of HIV infected patients as guideline-preferred agents as members of antiviral regimen for treatment of naive persons [29]. RAL and EVG were both applied in conjunction with a PI/r in treatment-experienced persons, demonstrating that RAL had the similar performance with EVG [59]. Raltegravir is usually dosed twice/day. Elvitegravir is dosed once/day because the consideration of drug–drug interactions with a potent CYP3A4 inhibitor, pharmacokinetic booster cobicistat [32]. Raltegravir and elvitegravir have cross-resistance and low genetic barrier to resistance. As a novel generation of strand transfer inhibitor administrated once/day, DTG can be co-formulated with other agents in a single tablet regimen since no pharmacokinetic booster is existing. Compared with RAL and EVG, DTG possesses a higher resistance genetic barrier [32]. As the second-generation integrase strand transfer inhibitor, DTG shows distinct advantages than RAL and EVG. DTG can be dosed once daily for treatment-naive patients. DTG containing regimens showed either non-inferiority or superiority to multiple regimens containing existing first line agents, such as RAL, efavirenz and darunavir/ritonavir in phase III clinical trials [60]. Also, DGT seems to be effective for RAL/EVG treated patients. This means DGT is sensitive to RAL/EVG resistant virus strains [56,61]. A 48-week study with once daily DTG versus RAL in treatment-naive adults with HIV infection was performed. After 48 weeks, 88% participants achieved a viral RNA value less than 50 copies/mL in the DGT group compared with 85% in the RAL group [62]. Participants from the two groups have similar adverse effects such as nausea (14% in DGT group vs 13% in RAL group), headache (2% vs 12%), nasopharyngitis (11% vs 12%) and diarrhea (11% in each group) [62]. No treatment-emergent resistance was observed in participants with virological failure on DTG. But 6% of the patients with virological failure with RAL treatment appeared integrase treatment-emergent resistance [62–64]. The addition of RAL, EVG and DTG to clinical treatment of AIDS is a great progress for HAART therapy although drug resistant virus strains have emerged. The management of anti-HIV agents in clinical treatment is a key problem for control of drug resistance [65]. As a target for anti-HIV research, multiple steps of integrase activity are available for integrase inhibitor development. Although the three approved inhibitors are integrase strand transfer inhibitors, drug development targeting 30 -terminal processing was studied [66]. Integrase is discovered to interact with multiple host factors in the process of integration. The protein–protein interaction (PPI) between integrase and host factor is promising target for integrase inhibitor design. Lens epithelium-derived growth factor (LEDGF)/p75 is the first host factor to be considered for integrase inhibitor development. The inhibitors targeting integrase LEDGF/p75 binding site (LEDGINs) are in development [67,68]. Drug developments through chemical synthesis and virtual screening have also been performed targeting IN-LEDGF/p75 interaction [5,69,70]. Some studies focus on development of new integrase inhibitor effective in suppressing drug resistant virus strains. A series of newly synthesized compounds (1,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides, 1,4-dihydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine3-carboxamides, and 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides) exhibited nanomolar EC50 values against IN in cell assays. Several new compounds showed greater anti-HIV efficacy compared to RAL when tested against IN mutants (G118R,
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Y143R, G140S/Q148H, N155H, and E138K/Q148K) [71]. All these studies contribute new benefits to the class and will provide new options for the clinical treatment of HIV infected patients in the future. Disclosure of interest The author declares that he has no conflicts of interest concerning this article. Acknowledgements This work was partially supported by the National Natural Science Foundation of China (81360503), the United Foundation of Guizhou (Qiankehe J LKZ[2013]21), the Incubation Project for 2011 Collaborative Innovation Center for Tuberculosis Prevention and Cure in Guizhou Province and the seed grant from Zunyi Medical University for newly recruited talents to Dr. Wan-Gang Gu. References [1] Gayle JA, Selik RM, Chu SY. Surveillance for AIDS and HIV infection among black and Hispanic children and women of childbearing age 1981–1989. MMWR Surveill Summ 1990;39:23–30. [2] McCutchan JA, Wu JW, Robertson K, Koletar SL, Ellis RJ, Cohn S, et al. HIV suppression by HAART preserves cognitive function in advanced, immunereconstituted AIDS patients. AIDS 2007;21:1109–17. [3] Evering TH, Markowitz M, Raltegravir. (MK-0518): an integrase inhibitor for the treatment of HIV-1. Drugs Today 2007;43:865–77. [4] Wills T, Vega V. Elvitegravir: a once-daily inhibitor of HIV-1 integrase. Expert Opin Investig Drugs 2012;21:395–401. [5] Shah BM, Schafer JJ, Desimone Jr JA. Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV. Pharmacotherapy 2013;34:506–20. [6] Anker M, Corales RB, Raltegravir. (MK-0518): a novel integrase inhibitor for the treatment of HIV infection. Expert Opin Investig Drugs 2008;17:97–103. [7] Hicks C, Gulick RM. Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis 2009;48:931–9. [8] Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS 2006;20:489–501. [9] Hazuda DJ, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler JA, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000;287:646–50. [10] Cocohoba J, Dong BJ. Raltegravir: the first HIV integrase inhibitor. Clin Ther 2008;30:1747–65. [11] Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, et al. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 2008;51:5843– 55. [12] Imaz A, del Saz SV, Ribas MA, Curran A, Caballero E, Falco V, et al. Raltegravir, etravirine, and ritonavir-boosted darunavir: a safe and successful rescue regimen for multidrug-resistant HIV-1 infection. J Acquir Immune Defic Syndr 2009;52:382–6. [13] Hughes CA, Robinson L, Tseng A, MacArthur RD. New antiretroviral drugs: a review of the efficacy, safety, pharmacokinetics, and resistance profile of tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir. Expert Opin Pharmacother 2009;10:2445–66. [14] Croxtall JD, Keam SJ. Raltegravir: a review of its use in the management of HIV infection in treatment-experienced patients. Drugs 2009;69:1059–75. [15] Cossarini F, Castagna A, Lazzarin A. Raltegravir in treatment naive patients. Eur J Med Res 2009;14(Suppl. 3):22–9. [16] Briz V, Garrido C, Poveda E, Morello J, Barreiro P, de Mendoza C, et al. Raltegravir and etravirine are active against HIV type 1 group O. AIDS Res Hum Retroviruses 2009;25:225–7. [17] Sayana S, Khanlou H. Raltegravir: the first in a new class of integrase inhibitors for the treatment of HIV. Expert Rev Anti Infect Ther 2008;6:419–26. [18] Cahn P, Sued O. Raltegravir: a new antiretroviral class for salvage therapy. Lancet 2007;369:1235–6. [19] Schafer JJ, Squires KE. Integrase inhibitors: a novel class of antiretroviral agents. Ann Pharmacother 2009;44:145–56. [20] Serrao E, Odde S, Ramkumar K, Neamati N, Raltegravir. elvitegravir, and metoogravir: the birth of ‘‘me-too’’ HIV-1 integrase inhibitors. Retrovirology 2009;6:25. [21] Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet 2011;50:229–44. [22] Shimura K, Kodama EN. Elvitegravir: a new HIV integrase inhibitor. Antivir Chem Chemother 2009;20:79–85.
[23] Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, et al. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol 2008;82:764–74. [24] DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr 2006;43:1–5. [25] Klibanov OM, Elvitegravir. an oral HIV integrase inhibitor, for the potential treatment of HIV infection. Curr Opin Investig Drugs 2009;10:190–200. [26] Ramanathan S, Kakuda TN, Mack R, West S, Kearney BP. Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine. Antivir Ther 2008;13:1011–7. [27] Mathias AA, Hinkle J, Shen G, Enejosa J, Piliero PJ, Sekar V, et al. Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir. J Acquir Immune Defic Syndr 2008;49:156–62. [28] Zolopa AR, Berger DS, Lampiris H, Zhong L, Chuck SL, Enejosa JV, 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. [29] Grant P, Zolopa A. Integrase inhibitors: a clinical review of raltegravir and elvitegravir. J HIV Ther 2008;13:36–9. [30] Cohen C, Elion R, Ruane P, Shamblaw D, DeJesus E, Rashbaum B, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/ cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/ emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS 2011;25:F7–12. [31] Deeks ED, Elvitegravir:. A review of its use in adults with HIV-1 infection. Drugs 2014. [32] Shah BM, Schafer JJ, Desimone Jr JA, Dolutegravir:. A new integrase strand transfer inhibitor for the treatment of HIV. Pharmacotherapy 2013. [33] Weller S, Borland J, Chen S, Johnson M, Savina P, Wynne B, et al. Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment. Eur J Clin Pharmacol 2013;70:29–35. [34] van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, 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 2011;12:111–8. [35] Buzon MJ, Marfil S, Puertas MC, Garcia E, Clotet B, Ruiz L, et al. Raltegravir susceptibility and fitness progression of HIV type-1 integrase in patients on long-term antiretroviral therapy. Antivir Ther 2008;13:881–93. [36] Albrecht H. Report from the 2008 joint ICAAC/IDSA meeting. More on raltegravir: resistance and mechanisms of action. AIDS Clin Care 2008;20:97–8. [37] Fransen S, Gupta S, Danovich R, Hazuda D, Miller M, Witmer M, et al. Loss of raltegravir susceptibility by human immunodeficiency virus type 1 is conferred via multiple nonoverlapping genetic pathways. J Virol 2009;83:11440–6. [38] Fransen S, Karmochkine M, Huang W, Weiss L, Petropoulos CJ, Charpentier C. Longitudinal analysis of raltegravir susceptibility and integrase replication capacity of human immunodeficiency virus type 1 during virologic failure. Antimicrob Agents Chemother 2009;53:4522–4. [39] Malet I, Delelis O, Soulie C, Wirden M, Tchertanov L, Mottaz P, et al. Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV1-infected patients. J Antimicrob Chemother 2009;63:795–804. [40] Mouscadet JF, Arora R, Andre J, Lambry JC, Delelis O, Malet I, et al. IN alternative molecular recognition of DNA induced by raltegravir resistance mutations. J Mol Recognit 2009;22:480–94. [41] Quercia R, Dam E, Perez-Bercoff D, Clavel F. Selective-advantage profile of human immunodeficiency virus type 1 integrase mutants explains in vivo evolution of raltegravir resistance genotypes. J Virol 2009;83:10245–9. [42] Salgado M, Toro C, Simon A, Garrido C, Blanco F, Soriano V, et al. Mutation N155H in HIV-2 integrase confers high phenotypic resistance to raltegravir and impairs replication capacity. J Clin Virol 2009;46:173–5. [43] Xu L, Anderson J, Garrett N, Ferns B, Wildfire A, Cook P, et al. Dynamics of raltegravir resistance profile in an HIV type 2-infected patient. AIDS Res Hum Retroviruses 2009;25:843–7. [44] Wirden M, Simon A, Schneider L, Tubiana R, Malet I, Ait-Mohand H, 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. [45] Charpentier C, Karmochkine M, Laureillard D, Tisserand P, Belec L, Weiss L, et al. Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy. HIV Med 2008;9:765–70. [46] Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, et al. resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008;359:355–65. [47] Goethals O, Clayton R, Van Ginderen M, Vereycken I, Wagemans E, Geluykens P, 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. [48] Delelis O, Malet I, Na L, Tchertanov L, Calvez V, Marcelin AG, 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. [49] Ferns RB, Kirk S, Bennett J, Cook PM, Williams I, Edwards S, et al. The dynamics of appearance and disappearance of HIV-1 integrase mutations during and after withdrawal of raltegravir therapy. AIDS 2009;23:2159–64.
Please cite this article in press as: Gu W-G. Newly approved integrase inhibitors for clinical treatment of AIDS. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.09.013
G Model
BIOPHA-3456; No. of Pages 5 W.-G. Gu / Biomedicine & Pharmacotherapy xxx (2014) xxx–xxx [50] Ghosn J, Mazet AA, Avettand-Fenoel V, Peytavin G, Wirden M, Delfraissy JF, et al. Rapid selection and archiving of mutation E157Q in HIV-1 DNA during short-term low-level replication on a raltegravir-containing regimen. J Antimicrob Chemother 2009;64:433–4. [51] Thuret I, Chaix ML, Tamalet C, Reliquet V, Firtion G, Tricoire J, et al. etravirine and r-darunavir combination in adolescents with multidrug-resistant virus. AIDS 2009;23:2364–6. [52] Yazdanpanah Y, Fagard C, Descamps D, Taburet AM, Colin C, Roquebert B, 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. [53] Sichtig N, Sierra S, Kaiser R, Daumer M, Reuter S, Schulter E, et al. Evolution of raltegravir resistance during therapy. J Antimicrob Chemother 2009;64:25– 32. [54] Bourgeois A, Womack S, Newsom D, Caldwell D. A review of rilpivirine and elvitegravir resistance features and implications for treatment sequencing. HIV Clin 2012;24:12–5. [55] Hurt CB, Sebastian J, Hicks CB, Eron JJ. Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States 2009–2012. Clin Infect Dis 2013;58:423–31. [56] Hightower KE, Wang R, Deanda F, Johns BA, Weaver K, Shen Y, 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;55:4552–9. [57] Oliveira M, Mesplede T, Quashie PK, Moisi D, Wainberg MA. Resistance mutations against dolutegravir in HIV integrase impair the emergence of resistance against reverse transcriptase inhibitors. AIDS 2014;28:813–9. [58] Bouziane M, Cherny DI, Mouscadet JF, Auclair C. Alternate strand DNA triple helix-mediated inhibition of HIV-1 U5 long terminal repeat integration in vitro. J Biol Chem 1996;271:10359–64. [59] Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu YP, et al. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis 2011;12:27–35.
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[60] Rathbun RC, Lockhart SM, Miller MM, Liedtke MD. Dolutegravir a secondgeneration integrase inhibitor for the treatment of HIV-1 infection. Ann Pharmacother 2013;48:395–403. [61] Wu G, Abraham T, Saad N. Dolutegravir for the treatment of adult patients with HIV-1 infection. Expert Rev Anti Infect Ther 2014;12:535–44. [62] Waters LJ, Barber TJ. Dolutegravir for treatment of HIV: SPRING forwards? Lancet 2013;381:705–6. [63] Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2013;13:927– 35. [64] Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013;369:1807–18. [65] Mesplede T, Quashie PK, Zanichelli V, Wainberg MA. Integrase strand transfer inhibitors in the management of HIV-positive individuals. Ann Med 2014;46:123–9. [66] Fenwick C, Amad M, Bailey MD, BethellF R., Bos M, Bonneau P, et al. Preclinical profile of BI 224436, a novel HIV-1 non-catalytic site integrase inhibitor. Antimicrob Agents Chemother 2014;58:3233–44. [67] Karmon SL, Markowitz M. Next-generation integrase inhibitors: where to after raltegravir? Drugs 2013;73:213–28. [68] Demeulemeester J, Chaltin P, Marchand A, De Maeyer M, Debyser Z, Christ F. LEDGINs, non-catalytic site inhibitors of HIV-1 integrase: a patent review (2006–2014). Expert Opin Ther Pathol 2014;24:609–32. [69] Xue W, Liu H, Yao X. Molecular modeling study on the allosteric inhibition mechanism of HIV-1 integrase by LEDGF/p75 binding site inhibitors. PLoS One 2014;9:e90799. [70] Reddy KK, Singh P, Singh SK. Blocking the interaction between HIV-1 integrase and human LEDGF/p75: mutational studies, virtual screening and molecular dynamics simulations. Mol Biosyst 2014;10:526–36. [71] Zhao XZ, Smith SJ, Metifiot M, Johnson BC, Marchand C, Pommier Y, et al. Bicyclic 1-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide-containing HIV-1 integrase inhibitors having high antiviral potency against cells harboring raltegravir-resistant integrase mutants. J Med Chem 2014;57:1573–82.
Please cite this article in press as: Gu W-G. Newly approved integrase inhibitors for clinical treatment of AIDS. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.09.013