- Email: [email protected]
Antiretroviral drugs
Available online at www.sciencedirect.com
Antiretroviral drugs Erik De Clercq In October 2010, it will be exactly 25 years ago that the first antiretroviral drug, AZT (zidovudine, 30 -azido-20 ,30 dideoxythymidine), was described. It was the first of 25 antiretroviral drugs that in the past 25 years have been formally licensed for clinical use. These antiretroviral drugs fall into seven categories [nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs). The INIs (i.e. raltegravir) represent the most recent advance in the search for effective and selective anti-HIV agents. Combination of several anti-HIV drugs [often referred to as highly active antiretroviral therapy (HAART)] has drastically altered AIDS from an almost uniformly fatal disease to a chronic manageable one.
20 ,30 -dideoxycytidine (DDC), would become drugs as well] as anti-HIV agents [14], soon to be followed by stavudine (D4T, 20 ,30 -dideoxy-20 ,30 -didehydrothymidine) [3]. In fact, AZT, DDI, DDC or D4T were not the first compounds described for their anti-HIV activity; that was suramin, a compound used in the therapy of African trypanosomiasis and onchocerciasis, and that was shown in 1984 by Mitsuya et al. [15] to inhibit the in vitro infectivity of HTLV-III. However, suramin was considered too toxic for systemic (i.e. intravenous) use and therefore not further pursued for systemic treatment of AIDS.
Twenty-five antiretroviral drugs licensed Address Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium Corresponding author: De Clercq, Erik ([email protected])
Current Opinion in Pharmacology 2010, 10:507–515 This review comes from a themed issue on Anti-infectives Edited by Martin Oppermann Available online 12th May 2010 1471-4892/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2010.04.011
Introduction This year, 2010, marks the 25th anniversary of antiretroviral drug discovery and development [special issue of Antiviral Research, volume 85, issue 1, 2010] [1,2,3,4, 5,6–12]. In October 1985, Mitsuya et al. [13] described the in vitro inhibitory effect of AZT (zidovudine, 30 -azido-20 ,30 dideoxythymidine), later to become the first antiretroviral drug to be licensed for clinical use against AIDS, on the infectivity and cytopathic effect of human T-lymphotropic virus type III (HTLV-III)/lymphadenopathyassociated virus (LAV) [later renamed human immunodeficiency virus (HIV)]. Shortly thereafter, in March 1986, Mitsuya and Broder [14] described various other 20 ,30 -dideoxynucleosides [two of which, that is 20 ,30 -dideoxyinosine (DDI) and www.sciencedirect.com
The anti-HIV drug armamentarium has over a period of 25 years grown to 25 licensed drugs [16,17]; seven nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (Figure 1), didanosine (Figure 2), zalcitabine (Figure 3), stavudine (Figure 4), lamivudine (Figure 5), abacavir (Figure 6) and emtricitabine (Figure 7); one nucleotide reverse transcriptase inhibitor (NtRTI): tenofovir disoproxil fumarate (Figure 8); four non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine (Figure 9), delavirdine (Figure 10), efavirenz (Figure 11) and etravirine (Figure 12); ten protease inhibitors (PIs): saquinavir (Figure 13), ritonavir (Figure 14), indinavir (Figure 15), nelfinavir (Figure 16), amprenavir (Figure 17), lopinavir (Figure 18), atazanavir (Figure 19), fosamprenavir (Figure 20), tipranavir (Figure 21) and darunavir (Figure 22); one fusion inhibitor (FI): enfuvirtide (Figure 23); one co-receptor inhibitor (CRI): maraviroc (Figure 24) and one integrase inhibitor (INI): raltegravir (Figure 25). Not all these compounds, albeit licensed, are equally frequently used: that is zalcitabine (Figure 3), delavirdine (Figure 10), are no longer used or available. One of the (if not the) most frequently used anti-HIV drugs is tenofovir disoproxil fumarate (TDF) [18].
Forthcoming antiretroviral drugs In addition to the 25 compounds shown, there are at least three compounds that are expected to be approved soon, the NNRTI rilpivirine (Figure 26), the CRI vicriviroc (Figure 27) and the INI elvitegravir (Figure 28). The CCR5 antagonist vicriviroc shares with the other CCR5 antagonist maraviroc the same limitation, that is they are active only against the M (macrophage)-tropic HIV strains using the CCR5 co-receptor to enter the cells [they are inactive against the T (lymphocyte)-tropic Current Opinion in Pharmacology 2010, 10:507–515
508 Anti-infectives
Figure 1
Figure 4
HIV strains using the CXCR4 co-receptor to enter the cells]. Elvitegravir [19] would have the advantage over raltegravir that it could be dosed once daily at 150 mg, whereas raltegravir is currently dosed at 400 mg twice daily [17]. Rilpivirine, the next-generation NNRTI [20], may be dosed at 25 mg daily (a significant improvement compared to efavirenz, that has to be administered at 600 mg daily) [21].
HAART: highly active antiretroviral therapy
Figure 2
Drug combination therapy, commonly termed HAART, has for some 15 years been considered as the standard treatment for patients with HIV infections, whether antiretroviral drug-naive or drug-experienced. Given the number of antiretrovirals available (see supra), the number of possible drug combinations is astronomical [16,17]. If limited to fixed-dose drug combinations, the number of double drug combinations is limited to Combivir1, Epzicom1 and Truvada1, and that of triple drug combinations to Trizivir1 and Atripla1 (Figure 29). Forthcoming would be the fixed-dose drug combinations of Truvada1 (300 mg TDF, 200 mg (-)FTC) with rilpivirine (25 mg) and the fixed-dose drug combination of Truvada1 with elvitegravir (150 mg) and GS-9350 (Cobicistat), the latter acting as metabolic enhancer (or ‘booster’) of elvitegravir, thus creating a quadruple drug combination (‘Quad pill’).
Raltegravir: validation of a new antiretroviral target, the HIV integrase Raltegravir (Isentress1) represents the ‘first-in-class’ of a totally new class of HIV antiretrovirals [22], that is Figure 5 Figure 3
Current Opinion in Pharmacology 2010, 10:507–515
www.sciencedirect.com
Antiretroviral drugs De Clercq 509
Figure 6
integrase inhibitors, which inhibit the insertion (‘integration’) of HIV-1 proviral DNA (after it has been retrotranscribed from the viral RNA genome) into the host cell genome. Raltegravir is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection in treatment-experienced adult patients with multi-drug-resistant HIV-1 strains [23]. In HIV-infected patients with limited treatment options, raltegravir plus
optimised background therapy (OBT) provided better viral suppression than OBT alone for at least 48 weeks [24]. A consistently favourable treatment response of raltegravir over placebo was demonstrated in patients that typically show a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count and low genotypic or phenotypic sensitivity score [25]. Switching from enfuvirtide to raltegravir in virologically
Figure 7
Figure 9
Figure 10 Figure 8
www.sciencedirect.com
Current Opinion in Pharmacology 2010, 10:507–515
510 Anti-infectives
Figure 11
Figure 14
suppressed HIV-1-infected patients may allow maintaining both virological (HIV-1) and immunological (CD4+ Tcell) control (at 24 weeks) [26]. At 48 weeks, raltegravir, in combination with Truvada1, would be non-inferior to efavirenz, in combination with Truvada1 [27], which
thus offers a new drug combination therapy perspective for treatment-naı¨ve patients with HIV-1 infection [28].
Figure 12
Resistance to raltegravir Resistance to INIs emerges readily through selection of one or more mutations within the HIV integrase. These mutations develop rapidly, and a single mutation is sufficient to confer resistance, suggesting that INIs do have a low genetic barrier [29]. This low threshold for HIV drug resistance excludes monotherapy, necessitating the use of Figure 15
Figure 13 Figure 16
Current Opinion in Pharmacology 2010, 10:507–515
www.sciencedirect.com
Antiretroviral drugs De Clercq 511
Figure 17
Figure 20
INIs in multi-drug salvage regimens [30]. At least four mutations (i.e. E92Q, G140S, Q148H, N155H and E157Q) can be associated with in vivo treatment failure and resistance to raltegravir [31]. For viruses harbouring the mutations Q148H and N155H, no residual antiviral activity of raltegravir seems to persist in vivo [32]. While the N155H mutation is selected early in the course of
raltegravir therapy, it is later replaced by genotypes that include Q148H/K/R [33].
Figure 18
Mutations at HIV integrase positions E92Q, G140S, Q148H and N155H, may emerge as early as one month after initiating HAART salvage regimens containing raltegravir [34]. Other mutations, that is Y143R, may be observed only after prolonged raltegravir exposure [35]. The Y143R/C mutants can be considered as delayed integrase mutations to raltegravir in vitro and in vivo [36]. Other mutations, such as Q148R and T66I, selected
Figure 21
Figure 19
Figure 22
www.sciencedirect.com
Current Opinion in Pharmacology 2010, 10:507–515
512 Anti-infectives
Figure 23
by elvitegravir, may confer reduced susceptibility to not only elvitegravir but also raltegravir [37].
Antiretroviral drug combinations When anti-HIV drug combinations (‘cocktails’) are envisaged, especially containing the new antiretroviral drugs, raltegravir (or elvitegravir), maraviroc (or vicriviroc), etravirine (or rilpivirine), darunavir (or tipranavir) [38], it deserves due attention to investigate, beforehand, any possible interactions between these antiretrovirals [39]. Figure 24
Current Opinion in Pharmacology 2010, 10:507–515
We know now that there is no significant drug interaction between raltegravir and tenofovir [40] or raltegravir and tipranavir (boosted by ritonavir) [41]. Thus, raltegravir may be considered an effective ingredient of future drug combinations (cocktails) including those containing raltegravir, etravirine and (ritonavir-boosted) darunavir [42,43]. The latter drug combination cocktails have proven to be highly effective and well-tolerated antiretroviral drug salvage regimens in patients infected with multidrug-resistant HIV infections. Figure 25
www.sciencedirect.com
Antiretroviral drugs De Clercq 513
Figure 26
Figure 28
Figure 27
Conclusion/perspectives The combined use of antiretrovirals (now best known under its acronym HAART) has changed the landscape of HIV disease from an almost uniformly fatal disease to a chronic manageable one [11]. This is one more myth to the many others that have been dispelled [44]. AIDS is no longer an untreatable or incurable disease (in my opinion, it never was; but the public perception was often different). We now have at our disposal, strong anti-HIV agents, which should eventually allow us to win the battle against AIDS. There are still some hurdles to cross: costs, lifelong adherence to therapy and long-term consequences thereof [45], but these are relatively minor
Figure 29
www.sciencedirect.com
Current Opinion in Pharmacology 2010, 10:507–515
514 Anti-infectives
hurdles compared to those we crossed already. But, one major objective remains: how could we ever prevent the disease from further spreading. With the virus vaccine being abeyant, the chemoprophylaxis may be the only soulage, and that is where the final hope is to ever stop this dreadful disease.
Acknowledgement This paper is an ‘homage’ to the dedicated (editorial) devotion of Mrs. Christiane Callebaut.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest
1.
Broder S: The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antiviral Res 2010, 85:1-18. An historical perspective on the start of antiretroviral therapy. 2.
De Clercq E: In search of a selective therapy of viral infections. Antiviral Res 2010, 85:19-24.
3.
Martin JC, Hitchcock MJM, De Clercq E, Prusoff WH: Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: a brief history of stavudine (D4T) and its comparison with other dideoxynucleosides. Antiviral Res 2010, 85:34-38.
4.
Cihlar T, Ray AS: Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res 2010, 85:39-58. A comprehensive review on the current state of the art of NRTIs (nucleos(t)ide reverse transcriptase inhibitors).
5.
Wensing AM, van Maarseveen NM, Nijhuis M: Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance. Antiviral Res 2010, 85:59-74. The most recent (global) review on PIs (protease inhibitors). 6.
7.
de Be´thune MP: Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989–2009). Antiviral Res 2010, 85:75-90. Tilton JC, Doms RW: Entry inhibitors in the treatment of HIV-1 infection. Antiviral Res 2010, 85:91-100.
8.
McColl DJ, Chen X: Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy. Antiviral Res 2010, 85:101-118.
9.
Adamson CS, Freed EO: Novel approaches to inhibiting HIV-1 replication. Antiviral Res 2010, 85:119-141.
10. Dickinson L, Khoo S, Back D: Pharmacokinetics and drug-drug interactions of antiretrovirals: an update. Antiviral Res 2010, 85:176-189. 11. Hawkins T: Understanding and managing the adverse effects of antiretroviral therapy. Antiviral Res 2010, 85:201-209. 12. Mene´ndez-Arias L: Molecular basis of human immunodeficiency virus drug resistance: an update. Antiviral Res 2010, 85:210-231. 13. Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S: 30 -Azido-30 deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA 1985, 82:7096-7100. 14. Mitsuya H, Broder S: Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/ lymphadenopathy-associated virus (HTLV-III/LAV) by 20 ,30 -dideoxynucleosides. Proc Natl Acad Sci USA 1986, 83:1911-1915. Current Opinion in Pharmacology 2010, 10:507–515
15. Mitsuya H, Popovic M, Yarchoan R, Matsushita S, Gallo RC, Broder S: Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III. Science 1984, 226:172-174. 16. De Clercq E: Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int J Antimicrob Agents 2009, 33:307-320. 17. De Clercq E: The history of antiretrovirals: key discoveries over the past 25 years. Rev Med Virol 2009, 19:287-299. 18. De Clercq E: Tenofovir disoproxil fumarate (TDF): discovery and clinical development. In Antiviral Drugs: Biology, Chemistry, Clinic. Edited by Kazmierski WM. John Wiley Sons Inc., Hoboken, NJ; 2010:in press. 19. Shimura K, Kodama EN: Elvitegravir: a new HIV integrase inhibitor. Antiviral Chem Chemother 2009, 20:79-85. 20. Azijn H, Tirry I, Vingerhoets J, de Be´thune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT: TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother 2010, 54:718-727. The most recent account on what to expect from rilpivirine, the forthcoming NNRTI (non-nucleoside reverse transcriptase inhibitor). 21. De Clercq E: From TIBO to rilpivirine: the chronicle of the discovery of the ideal non-nucleoside reverse transcriptase inhibitor (NNRTI). In Antiviral Drug Strategies. Edited by De Clercq E. Wiley-VCH Verlag, Weinheim, Germany; 2010:in press. 22. Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, Fiore F, Gardelli C, Gonzalez Paz O, Hazuda DJ et al.: Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 2008, 51:5843-5855. 23. Croxtall JD, Keam SJ: Raltegravir: a review of its use in the management of HIV infection in treatment-experienced patients. Drugs 2009, 69:1059-1075. 24. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Gatell JM, Rockstroh JK et al.: Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008, 359:339-354. 25. Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Kumar PN, Eron JE et al.: Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008, 359:355-365. 26. Grant PM, Palmer S, Bendavid E, Talbot A, Slamowitz DC, Cain P, Kobayashi SS, Balamane M, Zolopa AR: Switch from enfuvirtide to raltegravir in virologically suppressed HIV-1 infected patients: effects on level of residual viremia and quality of life. J Clin Virol 2009, 46:305-308. 27. Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, Zhao J, Xu X, Williams-Diaz A, Rodgers AJ 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. 28. De Clercq E: A new drug combination therapy for treatmentnaı¨ve patients with HIV-1 infection, consisting of Raltegravir, emtricitabine and tenofovir disoproxil fumarate. Expert Opin Pharmacother 2009, 10:2935-2937. 29. Marcelin AG, Ceccherini-Silberstein F, Perno CF, Calvez V: Resistance to novel drug classes. Curr Opin HIV AIDS 2009, 4:531-537. 30. Koelsch KK, Cooper DA: Integrase inhibitors in salvage therapy regimens for HIV-1 infection. Curr Opin HIV AIDS 2009, 4:518-523. 31. Malet I, Delelis O, Valantin MA, Montes B, Soulie C, Wirden M, Tchertanov L, Peytavin G, Reynes J, Mouscadet JF et al.: Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother 2008, 52:1351-1358. www.sciencedirect.com
Antiretroviral drugs De Clercq 515
32. Wirden M, Simon A, Schneider L, Tubiana R, Malet I, AitMohand H, Peytavin G, Katlama C, Calvez V, Marcelin AG: Raltegravir has no residual antiviral activity in vivo against HIV-1 with resistance-associated mutations to this drug. J Antimicrob Chemother 2009, 64:1087-1090. 33. Quercia R, Dam E, Perez-Bercoff D, Clavel F: Selectiveadvantage profile of human immunodeficiency virus type 1 integrase mutants explains in vivo evolution of raltegravir resistance genotypes. J Virol 2009, 83:10245-10249. 34. 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, 82:116-122. Integrase inhibitors (INIs): (still not) the ‘holy grail’ for future antiretroviral therapy?. 35. Sichtig N, Sierra S, Kaiser R, Da¨umer M, Reuter S, Schu¨lter E, Altmann A, Fa¨tkenheuer G, Dittmer U, Pfister H, Esser S: Evolution of raltegravir resistance during therapy. J Antimicrob Chemother 2009, 64:25-32. 36. Delelis O, Thierry S, Subra F, Simon F, Malet I, Alloui C, Sayon S, Calvez V, Deprez E, Marcelin AG 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.
39. Brown KC, Paul S, Kashuba AD: Drug interactions with new and investigational antiretrovirals. Clin Pharmacokinet 2009, 48:211-241. 40. Wenning LA, Friedman EJ, Kost JT, Breidinger SA, Stek JE, Lasseter KC, Gottesdiener KM, Chen J, Teppler H, Wagner JA et al.: Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrob Agents Chemother 2008, 52:3253-3258. 41. Hanley WD, Wenning LA, Moreau A, Kost JT, Mangin E, Shamp T, Stone JA, Gottesdiener KM, Wagner JA, Iwamoto M: Effect of tipranavir-ritonavir on pharmacokinetics of raltegravir. Antimicrob Agents Chemother 2009, 53:2752-2755. 42. Imaz A, del Saz SV, Ribas MA, Curran A, Caballero E, Falco´ V, Crespo M, Ocan˜a I, Diaz M, de Gopegui ER 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, 52:382-386. 43. Thuret I, Chaix ML, Tamalet C, Reliquet V, Firtion G, Tricoire J, Rabaud C, Frange P, Aumaıˆtre H, Blanche S: Raltegravir, etravirine and r-darunavir combination in adolescents with multidrug-resistant virus. AIDS 2009, 23:2364-2366.
37. Goethals O, Clayton R, Van Ginderen M, Vereycken I, Wagemans E, Geluykens P, Dockx K, Strijbos R, Smits V, Vos A et al.: Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol 2008, 82:10366-10374.
44. Piot P, Kazatchkine M, Dybul M, Lob-Levyt J: AIDS: lessons learnt and myths dispelled. Lancet 2009, 374:260-263. Where do we stand with the combat against AIDS, almost 30 years after the disease was identified?
38. 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, 10:2445-2466.
45. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ: The challenge of finding a cure for HIV infection. Science 2009, 323:1304-1307. AIDS is not curable, but it is a manageable disease, even if treatment is lifelong.
www.sciencedirect.com
Current Opinion in Pharmacology 2010, 10:507–515
Antiretroviral drugs Erik De Clercq In October 2010, it will be exactly 25 years ago that the first antiretroviral drug, AZT (zidovudine, 30 -azido-20 ,30 dideoxythymidine), was described. It was the first of 25 antiretroviral drugs that in the past 25 years have been formally licensed for clinical use. These antiretroviral drugs fall into seven categories [nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs). The INIs (i.e. raltegravir) represent the most recent advance in the search for effective and selective anti-HIV agents. Combination of several anti-HIV drugs [often referred to as highly active antiretroviral therapy (HAART)] has drastically altered AIDS from an almost uniformly fatal disease to a chronic manageable one.
20 ,30 -dideoxycytidine (DDC), would become drugs as well] as anti-HIV agents [14], soon to be followed by stavudine (D4T, 20 ,30 -dideoxy-20 ,30 -didehydrothymidine) [3]. In fact, AZT, DDI, DDC or D4T were not the first compounds described for their anti-HIV activity; that was suramin, a compound used in the therapy of African trypanosomiasis and onchocerciasis, and that was shown in 1984 by Mitsuya et al. [15] to inhibit the in vitro infectivity of HTLV-III. However, suramin was considered too toxic for systemic (i.e. intravenous) use and therefore not further pursued for systemic treatment of AIDS.
Twenty-five antiretroviral drugs licensed Address Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium Corresponding author: De Clercq, Erik ([email protected])
Current Opinion in Pharmacology 2010, 10:507–515 This review comes from a themed issue on Anti-infectives Edited by Martin Oppermann Available online 12th May 2010 1471-4892/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2010.04.011
Introduction This year, 2010, marks the 25th anniversary of antiretroviral drug discovery and development [special issue of Antiviral Research, volume 85, issue 1, 2010] [1,2,3,4, 5,6–12]. In October 1985, Mitsuya et al. [13] described the in vitro inhibitory effect of AZT (zidovudine, 30 -azido-20 ,30 dideoxythymidine), later to become the first antiretroviral drug to be licensed for clinical use against AIDS, on the infectivity and cytopathic effect of human T-lymphotropic virus type III (HTLV-III)/lymphadenopathyassociated virus (LAV) [later renamed human immunodeficiency virus (HIV)]. Shortly thereafter, in March 1986, Mitsuya and Broder [14] described various other 20 ,30 -dideoxynucleosides [two of which, that is 20 ,30 -dideoxyinosine (DDI) and www.sciencedirect.com
The anti-HIV drug armamentarium has over a period of 25 years grown to 25 licensed drugs [16,17]; seven nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (Figure 1), didanosine (Figure 2), zalcitabine (Figure 3), stavudine (Figure 4), lamivudine (Figure 5), abacavir (Figure 6) and emtricitabine (Figure 7); one nucleotide reverse transcriptase inhibitor (NtRTI): tenofovir disoproxil fumarate (Figure 8); four non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine (Figure 9), delavirdine (Figure 10), efavirenz (Figure 11) and etravirine (Figure 12); ten protease inhibitors (PIs): saquinavir (Figure 13), ritonavir (Figure 14), indinavir (Figure 15), nelfinavir (Figure 16), amprenavir (Figure 17), lopinavir (Figure 18), atazanavir (Figure 19), fosamprenavir (Figure 20), tipranavir (Figure 21) and darunavir (Figure 22); one fusion inhibitor (FI): enfuvirtide (Figure 23); one co-receptor inhibitor (CRI): maraviroc (Figure 24) and one integrase inhibitor (INI): raltegravir (Figure 25). Not all these compounds, albeit licensed, are equally frequently used: that is zalcitabine (Figure 3), delavirdine (Figure 10), are no longer used or available. One of the (if not the) most frequently used anti-HIV drugs is tenofovir disoproxil fumarate (TDF) [18].
Forthcoming antiretroviral drugs In addition to the 25 compounds shown, there are at least three compounds that are expected to be approved soon, the NNRTI rilpivirine (Figure 26), the CRI vicriviroc (Figure 27) and the INI elvitegravir (Figure 28). The CCR5 antagonist vicriviroc shares with the other CCR5 antagonist maraviroc the same limitation, that is they are active only against the M (macrophage)-tropic HIV strains using the CCR5 co-receptor to enter the cells [they are inactive against the T (lymphocyte)-tropic Current Opinion in Pharmacology 2010, 10:507–515
508 Anti-infectives
Figure 1
Figure 4
HIV strains using the CXCR4 co-receptor to enter the cells]. Elvitegravir [19] would have the advantage over raltegravir that it could be dosed once daily at 150 mg, whereas raltegravir is currently dosed at 400 mg twice daily [17]. Rilpivirine, the next-generation NNRTI [20], may be dosed at 25 mg daily (a significant improvement compared to efavirenz, that has to be administered at 600 mg daily) [21].
HAART: highly active antiretroviral therapy
Figure 2
Drug combination therapy, commonly termed HAART, has for some 15 years been considered as the standard treatment for patients with HIV infections, whether antiretroviral drug-naive or drug-experienced. Given the number of antiretrovirals available (see supra), the number of possible drug combinations is astronomical [16,17]. If limited to fixed-dose drug combinations, the number of double drug combinations is limited to Combivir1, Epzicom1 and Truvada1, and that of triple drug combinations to Trizivir1 and Atripla1 (Figure 29). Forthcoming would be the fixed-dose drug combinations of Truvada1 (300 mg TDF, 200 mg (-)FTC) with rilpivirine (25 mg) and the fixed-dose drug combination of Truvada1 with elvitegravir (150 mg) and GS-9350 (Cobicistat), the latter acting as metabolic enhancer (or ‘booster’) of elvitegravir, thus creating a quadruple drug combination (‘Quad pill’).
Raltegravir: validation of a new antiretroviral target, the HIV integrase Raltegravir (Isentress1) represents the ‘first-in-class’ of a totally new class of HIV antiretrovirals [22], that is Figure 5 Figure 3
Current Opinion in Pharmacology 2010, 10:507–515
www.sciencedirect.com
Antiretroviral drugs De Clercq 509
Figure 6
integrase inhibitors, which inhibit the insertion (‘integration’) of HIV-1 proviral DNA (after it has been retrotranscribed from the viral RNA genome) into the host cell genome. Raltegravir is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection in treatment-experienced adult patients with multi-drug-resistant HIV-1 strains [23]. In HIV-infected patients with limited treatment options, raltegravir plus
optimised background therapy (OBT) provided better viral suppression than OBT alone for at least 48 weeks [24]. A consistently favourable treatment response of raltegravir over placebo was demonstrated in patients that typically show a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count and low genotypic or phenotypic sensitivity score [25]. Switching from enfuvirtide to raltegravir in virologically
Figure 7
Figure 9
Figure 10 Figure 8
www.sciencedirect.com
Current Opinion in Pharmacology 2010, 10:507–515
510 Anti-infectives
Figure 11
Figure 14
suppressed HIV-1-infected patients may allow maintaining both virological (HIV-1) and immunological (CD4+ Tcell) control (at 24 weeks) [26]. At 48 weeks, raltegravir, in combination with Truvada1, would be non-inferior to efavirenz, in combination with Truvada1 [27], which
thus offers a new drug combination therapy perspective for treatment-naı¨ve patients with HIV-1 infection [28].
Figure 12
Resistance to raltegravir Resistance to INIs emerges readily through selection of one or more mutations within the HIV integrase. These mutations develop rapidly, and a single mutation is sufficient to confer resistance, suggesting that INIs do have a low genetic barrier [29]. This low threshold for HIV drug resistance excludes monotherapy, necessitating the use of Figure 15
Figure 13 Figure 16
Current Opinion in Pharmacology 2010, 10:507–515
www.sciencedirect.com
Antiretroviral drugs De Clercq 511
Figure 17
Figure 20
INIs in multi-drug salvage regimens [30]. At least four mutations (i.e. E92Q, G140S, Q148H, N155H and E157Q) can be associated with in vivo treatment failure and resistance to raltegravir [31]. For viruses harbouring the mutations Q148H and N155H, no residual antiviral activity of raltegravir seems to persist in vivo [32]. While the N155H mutation is selected early in the course of
raltegravir therapy, it is later replaced by genotypes that include Q148H/K/R [33].
Figure 18
Mutations at HIV integrase positions E92Q, G140S, Q148H and N155H, may emerge as early as one month after initiating HAART salvage regimens containing raltegravir [34]. Other mutations, that is Y143R, may be observed only after prolonged raltegravir exposure [35]. The Y143R/C mutants can be considered as delayed integrase mutations to raltegravir in vitro and in vivo [36]. Other mutations, such as Q148R and T66I, selected
Figure 21
Figure 19
Figure 22
www.sciencedirect.com
Current Opinion in Pharmacology 2010, 10:507–515
512 Anti-infectives
Figure 23
by elvitegravir, may confer reduced susceptibility to not only elvitegravir but also raltegravir [37].
Antiretroviral drug combinations When anti-HIV drug combinations (‘cocktails’) are envisaged, especially containing the new antiretroviral drugs, raltegravir (or elvitegravir), maraviroc (or vicriviroc), etravirine (or rilpivirine), darunavir (or tipranavir) [38], it deserves due attention to investigate, beforehand, any possible interactions between these antiretrovirals [39]. Figure 24
Current Opinion in Pharmacology 2010, 10:507–515
We know now that there is no significant drug interaction between raltegravir and tenofovir [40] or raltegravir and tipranavir (boosted by ritonavir) [41]. Thus, raltegravir may be considered an effective ingredient of future drug combinations (cocktails) including those containing raltegravir, etravirine and (ritonavir-boosted) darunavir [42,43]. The latter drug combination cocktails have proven to be highly effective and well-tolerated antiretroviral drug salvage regimens in patients infected with multidrug-resistant HIV infections. Figure 25
www.sciencedirect.com
Antiretroviral drugs De Clercq 513
Figure 26
Figure 28
Figure 27
Conclusion/perspectives The combined use of antiretrovirals (now best known under its acronym HAART) has changed the landscape of HIV disease from an almost uniformly fatal disease to a chronic manageable one [11]. This is one more myth to the many others that have been dispelled [44]. AIDS is no longer an untreatable or incurable disease (in my opinion, it never was; but the public perception was often different). We now have at our disposal, strong anti-HIV agents, which should eventually allow us to win the battle against AIDS. There are still some hurdles to cross: costs, lifelong adherence to therapy and long-term consequences thereof [45], but these are relatively minor
Figure 29
www.sciencedirect.com
Current Opinion in Pharmacology 2010, 10:507–515
514 Anti-infectives
hurdles compared to those we crossed already. But, one major objective remains: how could we ever prevent the disease from further spreading. With the virus vaccine being abeyant, the chemoprophylaxis may be the only soulage, and that is where the final hope is to ever stop this dreadful disease.
Acknowledgement This paper is an ‘homage’ to the dedicated (editorial) devotion of Mrs. Christiane Callebaut.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest
1.
Broder S: The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antiviral Res 2010, 85:1-18. An historical perspective on the start of antiretroviral therapy. 2.
De Clercq E: In search of a selective therapy of viral infections. Antiviral Res 2010, 85:19-24.
3.
Martin JC, Hitchcock MJM, De Clercq E, Prusoff WH: Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: a brief history of stavudine (D4T) and its comparison with other dideoxynucleosides. Antiviral Res 2010, 85:34-38.
4.
Cihlar T, Ray AS: Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res 2010, 85:39-58. A comprehensive review on the current state of the art of NRTIs (nucleos(t)ide reverse transcriptase inhibitors).
5.
Wensing AM, van Maarseveen NM, Nijhuis M: Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance. Antiviral Res 2010, 85:59-74. The most recent (global) review on PIs (protease inhibitors). 6.
7.
de Be´thune MP: Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989–2009). Antiviral Res 2010, 85:75-90. Tilton JC, Doms RW: Entry inhibitors in the treatment of HIV-1 infection. Antiviral Res 2010, 85:91-100.
8.
McColl DJ, Chen X: Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy. Antiviral Res 2010, 85:101-118.
9.
Adamson CS, Freed EO: Novel approaches to inhibiting HIV-1 replication. Antiviral Res 2010, 85:119-141.
10. Dickinson L, Khoo S, Back D: Pharmacokinetics and drug-drug interactions of antiretrovirals: an update. Antiviral Res 2010, 85:176-189. 11. Hawkins T: Understanding and managing the adverse effects of antiretroviral therapy. Antiviral Res 2010, 85:201-209. 12. Mene´ndez-Arias L: Molecular basis of human immunodeficiency virus drug resistance: an update. Antiviral Res 2010, 85:210-231. 13. Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S: 30 -Azido-30 deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA 1985, 82:7096-7100. 14. Mitsuya H, Broder S: Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/ lymphadenopathy-associated virus (HTLV-III/LAV) by 20 ,30 -dideoxynucleosides. Proc Natl Acad Sci USA 1986, 83:1911-1915. Current Opinion in Pharmacology 2010, 10:507–515
15. Mitsuya H, Popovic M, Yarchoan R, Matsushita S, Gallo RC, Broder S: Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III. Science 1984, 226:172-174. 16. De Clercq E: Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int J Antimicrob Agents 2009, 33:307-320. 17. De Clercq E: The history of antiretrovirals: key discoveries over the past 25 years. Rev Med Virol 2009, 19:287-299. 18. De Clercq E: Tenofovir disoproxil fumarate (TDF): discovery and clinical development. In Antiviral Drugs: Biology, Chemistry, Clinic. Edited by Kazmierski WM. John Wiley Sons Inc., Hoboken, NJ; 2010:in press. 19. Shimura K, Kodama EN: Elvitegravir: a new HIV integrase inhibitor. Antiviral Chem Chemother 2009, 20:79-85. 20. Azijn H, Tirry I, Vingerhoets J, de Be´thune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT: TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother 2010, 54:718-727. The most recent account on what to expect from rilpivirine, the forthcoming NNRTI (non-nucleoside reverse transcriptase inhibitor). 21. De Clercq E: From TIBO to rilpivirine: the chronicle of the discovery of the ideal non-nucleoside reverse transcriptase inhibitor (NNRTI). In Antiviral Drug Strategies. Edited by De Clercq E. Wiley-VCH Verlag, Weinheim, Germany; 2010:in press. 22. Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, Fiore F, Gardelli C, Gonzalez Paz O, Hazuda DJ et al.: Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 2008, 51:5843-5855. 23. Croxtall JD, Keam SJ: Raltegravir: a review of its use in the management of HIV infection in treatment-experienced patients. Drugs 2009, 69:1059-1075. 24. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Gatell JM, Rockstroh JK et al.: Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008, 359:339-354. 25. Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Kumar PN, Eron JE et al.: Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008, 359:355-365. 26. Grant PM, Palmer S, Bendavid E, Talbot A, Slamowitz DC, Cain P, Kobayashi SS, Balamane M, Zolopa AR: Switch from enfuvirtide to raltegravir in virologically suppressed HIV-1 infected patients: effects on level of residual viremia and quality of life. J Clin Virol 2009, 46:305-308. 27. Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, Zhao J, Xu X, Williams-Diaz A, Rodgers AJ 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. 28. De Clercq E: A new drug combination therapy for treatmentnaı¨ve patients with HIV-1 infection, consisting of Raltegravir, emtricitabine and tenofovir disoproxil fumarate. Expert Opin Pharmacother 2009, 10:2935-2937. 29. Marcelin AG, Ceccherini-Silberstein F, Perno CF, Calvez V: Resistance to novel drug classes. Curr Opin HIV AIDS 2009, 4:531-537. 30. Koelsch KK, Cooper DA: Integrase inhibitors in salvage therapy regimens for HIV-1 infection. Curr Opin HIV AIDS 2009, 4:518-523. 31. Malet I, Delelis O, Valantin MA, Montes B, Soulie C, Wirden M, Tchertanov L, Peytavin G, Reynes J, Mouscadet JF et al.: Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother 2008, 52:1351-1358. www.sciencedirect.com
Antiretroviral drugs De Clercq 515
32. Wirden M, Simon A, Schneider L, Tubiana R, Malet I, AitMohand H, Peytavin G, Katlama C, Calvez V, Marcelin AG: Raltegravir has no residual antiviral activity in vivo against HIV-1 with resistance-associated mutations to this drug. J Antimicrob Chemother 2009, 64:1087-1090. 33. Quercia R, Dam E, Perez-Bercoff D, Clavel F: Selectiveadvantage profile of human immunodeficiency virus type 1 integrase mutants explains in vivo evolution of raltegravir resistance genotypes. J Virol 2009, 83:10245-10249. 34. 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, 82:116-122. Integrase inhibitors (INIs): (still not) the ‘holy grail’ for future antiretroviral therapy?. 35. Sichtig N, Sierra S, Kaiser R, Da¨umer M, Reuter S, Schu¨lter E, Altmann A, Fa¨tkenheuer G, Dittmer U, Pfister H, Esser S: Evolution of raltegravir resistance during therapy. J Antimicrob Chemother 2009, 64:25-32. 36. Delelis O, Thierry S, Subra F, Simon F, Malet I, Alloui C, Sayon S, Calvez V, Deprez E, Marcelin AG 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.
39. Brown KC, Paul S, Kashuba AD: Drug interactions with new and investigational antiretrovirals. Clin Pharmacokinet 2009, 48:211-241. 40. Wenning LA, Friedman EJ, Kost JT, Breidinger SA, Stek JE, Lasseter KC, Gottesdiener KM, Chen J, Teppler H, Wagner JA et al.: Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrob Agents Chemother 2008, 52:3253-3258. 41. Hanley WD, Wenning LA, Moreau A, Kost JT, Mangin E, Shamp T, Stone JA, Gottesdiener KM, Wagner JA, Iwamoto M: Effect of tipranavir-ritonavir on pharmacokinetics of raltegravir. Antimicrob Agents Chemother 2009, 53:2752-2755. 42. Imaz A, del Saz SV, Ribas MA, Curran A, Caballero E, Falco´ V, Crespo M, Ocan˜a I, Diaz M, de Gopegui ER 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, 52:382-386. 43. Thuret I, Chaix ML, Tamalet C, Reliquet V, Firtion G, Tricoire J, Rabaud C, Frange P, Aumaıˆtre H, Blanche S: Raltegravir, etravirine and r-darunavir combination in adolescents with multidrug-resistant virus. AIDS 2009, 23:2364-2366.
37. Goethals O, Clayton R, Van Ginderen M, Vereycken I, Wagemans E, Geluykens P, Dockx K, Strijbos R, Smits V, Vos A et al.: Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol 2008, 82:10366-10374.
44. Piot P, Kazatchkine M, Dybul M, Lob-Levyt J: AIDS: lessons learnt and myths dispelled. Lancet 2009, 374:260-263. Where do we stand with the combat against AIDS, almost 30 years after the disease was identified?
38. 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, 10:2445-2466.
45. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ: The challenge of finding a cure for HIV infection. Science 2009, 323:1304-1307. AIDS is not curable, but it is a manageable disease, even if treatment is lifelong.
www.sciencedirect.com
Current Opinion in Pharmacology 2010, 10:507–515