AIDS Research and Therapy | |
Antiretroviral regimens sparing agents from the nucleoside(tide) reverse transcriptase inhibitor class: a review of the recent literature | |
Amit C Achhra1  Mark A Boyd1  | |
[1] The Kirby Institute, University of New South Wales, Sydney, Australia | |
关键词: Maraviroc; Raltegravir; Dual therapy; HIV; Class-sparing; NRTI-sparing; NNRTI; NRTI; Toxicity; HAART; | |
Others : 789559 DOI : 10.1186/1742-6405-10-33 |
|
received in 2013-11-04, accepted in 2013-11-30, 发布年份 2013 | |
【 摘 要 】
The nucleoside(tide) reverse transcriptase inhibitors (NRTIs) have traditionally been an important ‘back-bone’ of an antiretroviral therapy (ART) regimen. However all agents have been associated with both short- and long-term toxicity. There have also been concerns regarding the efficacy and safety of a treatment sequencing strategy in which those with past exposure and/or resistance to one or more NRTIs are re-exposed to ‘recycled’ NRTIs in subsequent ART regimens. Newer, potent and possible safer, agents from various ART classes continue to become available. There has therefore been growing interest in evaluating NRTI-sparing regimens. In this review, we examined studies of NRTI-sparing regimens in adult HIV-positive patients with varying degrees of ART experience. We found that in treatment experienced patients currently on a failing regimen with detectable viral load, there now exists a robust evidence for the use of NRTI-sparing regimens including raltegravir with a boosted-protease inhibitor with or without a third agent. In those on a virologically suppressive regimen switching to a NRTI-sparing regimen or in those ART-naïve patients initiating an NRTI-sparing regimen, evidence is sparse and largely comes from small exploratory trials or observational studies. Overall, these studies suggest that caution needs to be exercised in carefully selecting the right candidate and agents, especially in the context of a dual-therapy regimen, to minimise the risks of virological failure. There is residual toxicity conferred by the ritonavir boost in protease-inhibitor containing NRTI-sparing regimens. Fully-powered studies are needed to explore the place of N (t)RTI-sparing regimens in the sequencing of ART. Additionally research is required to explore how to minimise the adverse effects associated with ritonavir-based pharmacoenhancement.
【 授权许可】
2013 Achhra and Boyd; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20140704184904238.pdf | 216KB | download |
【 参考文献 】
- [1]Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P, Eron JJ, Gunthard HF, Hammer SM, Reiss P, et al.: Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA 2012, 308:387-402.
- [2]World Health Organisation: Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 2013. http://www.who.int/hiv/pub/guidelines/arv2013/en/ webcite. Accessed on October 2013
- [3]European AIDS Clinical Society: European Guidelines for treatment of HIV-infected adults in Europe. Available at http://www.eacsociety.org/Guidelines.aspx webcite. Accessed on October 2013
- [4]Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf webcite. Assesed on October 2013
- [5]Calza L: Renal toxicity associated with antiretroviral therapy. HIV Clin Trials 2012, 13:189-211.
- [6]Mocroft A, Kirk O, Reiss P, De Wit S, Sedlacek D, Beniowski M, Gatell J, Phillips AN, Ledergerber B, Lundgren JD, Group ftES: Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS 2010, 24:1667-1678.
- [7]Brown TT, McComsey GA, King MS, Qaqish RB, Bernstein BM, da Silva BA: Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune Defic Syndr 2009, 51:554-561.
- [8]McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, Myers L, Melbourne K, Ha B, Sax PE: Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: aids clinical trials group A5224s, a substudy of ACTG A5202. J Infect Dis 2011, 203:1791-1801.
- [9]Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P: Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS 2012, 26:825-831.
- [10]Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG: Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS 2011, 25:1289-1298.
- [11]Worm SW, Sabin C, Weber R, Reiss P, El-Sadr W, Dabis F, De Wit S, Law M, Monforte AD, Friis-Moller N, et al.: Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis 2010, 201:318-330.
- [12]Martin A, Bloch M, Amin J, Baker D, Cooper DA, Emery S, Carr A: Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-Lamivudine: a randomized, 96-week trial. Clin Infect Dis 2009, 49:1591-1601.
- [13]Costagliola D, Lang S, Mary-Krause M, Boccara F: Abacavir and cardiovascular risk: reviewing the evidence. Curr HIV/AIDS Rep 2010, 7:127-133.
- [14]Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jagel-Guedes E, Rugina S, Kozyrev O, Cid JF, et al.: HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008, 358:568-579.
- [15]Hosseinipour MC, van Oosterhout JJ, Weigel R, Phiri S, Kamwendo D, Parkin N, Fiscus SA, Nelson JA, Eron JJ, Kumwenda J: The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy. AIDS 2009, 23:1127-1134.
- [16]Eron JJ, Young B, Cooper DA, Youle M, DeJesus E, Andrade-Villanueva J, Workman C, Zajdenverg R, Fätkenheuer G, Berger DS, et al.: Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet 2010, 375:396-407.
- [17]Martinez E, Arnaiz JA, Podzamczer D, Dalmau D, Ribera E, Domingo P, Knobel H, Riera M, Pedrol E, Force L, et al.: Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med 2003, 349:1036-1046.
- [18]Boyd MA, Kumarasamy N, Moore CL, Nwizu C, Losso MH, Mohapi L, Martin A, Kerr S, Sohn AH, Teppler H, et al.: Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet 2013, 381:2091-2099.
- [19]Paton N, Kityo C, Hoppe A, Hakim J, van Oosterhout J, Siika A, Mwaba P, Kambugu A, Easterbrook , Boles J, Walker S, Mugyenyi P, EARNEST Trial Group: A pragmatic randomised controlled strategy trial of three second-line treatment options for use in public health rollout programme settings: the Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial [Abstract WELBB02]. In 7th International AIDS Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur,Malaysia; June-July 2013.
- [20]Tashima K, OPTIONS Study group: Omitting NRTI from ARV regimens is not inferior to adding NRTI in treatment-experienced HIV+ subjects failing a protease inhibitor regimen: the ACTG OPTIONS study [Abstract 153LB]. In 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, Georgia (USA); March 2013.
- [21]Imaz A, Llibre JM, Mora M, Mateo G, Camacho A, Blanco JR, Curran A, Santos JR, Caballero E, Bravo I, et al.: Efficacy and safety of nucleoside reverse transcriptase inhibitor-sparing salvage therapy for multidrug-resistant HIV-1 infection based on new-class and new-generation antiretrovirals [Erratum appears in]. J Antimicrob Chemother 2011, 66(9):2194.
- [22]Nozza S, Galli L, Bigoloni A, Nicola G, Pogliaghi M, Cossarini F, Salpietro S, Galli A, Della Torre L, Tambussi G, et al.: Durability and safety of a novel salvage therapy in R5-tropic HIV-infected patients: maraviroc, raltegravir, etravirine. J Acquir Immune Defic Syndr 2011, 56:e113-e115.
- [23]Florence E, De Wit S, Castagna A, Ribera E, Hill A, Vanaken H, van Delft Y, Marks S: HIV RNA suppression rates after 24 weeks of treatment with etravirine, darunavir/ritonavir and raltegravir in the etravirine early access programme. Int J STD AIDS 2010, 21:224-225.
- [24]Ruane P, Brinson C, Kumar P, De Jesus E, Ryan R, Cho M, Anderson D: Intelence aNd pRezista Once A Day Study (INROADS): A Multicenter, Single-Arm, Open-Label Study of Once Daily Combination of Etravirine (ETR) and Darunavir/Ritonavir (DRV/r) as Dual Therapy in Early Treatment-Experienced Subjects (Abstract WEPE515). In 7th International AIDS Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, Malaysia; June-July 2013.
- [25]Hoy J, Martin A, Moore C, Mallon P, Emery S, Belloso W, Phanuphak P, Ferret S, Cooper D, Boyd M, SECOND LINE study team: Changes in bone mineral density over 48 weeks among participants randomised to either lopinavir/ritonavir (LPV/r) + 2-3N(t)RTI or LPV/r + raltegravir as second-line therapy: a sub-study of the SECONDLINE trial. In 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, Malaysia; June-July 2013.
- [26]Ward DJ, O'Neil DJ: Nucleoside-sparing antiretroviral regimens in clinical practice. [Abstract H-659]. In the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Denver USA; Sept. 2013.
- [27]Calin R, Valantin M, Simon A, Paris L, Tubiana R, Schneider L, Stitou H, Delanoe C, Wirden M, Agher R, Katlama C: Raltegravir/etravirine dual therapy as a virologically safe treatment option in suppressed HIV-1-infected patients without previous NNRTI failure. In 7th International AIDS Society Conference on HIV Pathogenesis Treatment and Prevention. Kuala Lumpur, Malaysia; June-July 2013.
- [28]Katlama C, Assoumou L, Valantin M, Duvivier C, Soulie C, Chablais L, Pialoux G, Mercie P, Peytavin G, Marcelin A: Maraviroc plus Raltegravir dual Therapy in Aviremic HIV infected Patients with Lipodystrophy: results from the ROCnRAL ANRS 157 Study. In 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA; March 2013.
- [29]Cotte L, Durant J, Brochier C, André P, Cottalorda J, Pradat P, Vanhems P, Dellamonica P: Safety and efficacy of a Maraviroc-Raltegravir combination following a 6 month induction phase with Maraviroc-Raltegravir-Tenofovir-Emtricitabine in naïve HIV-1 infected patients with CCR5 Virus:interim analysis of the No Nuc No Boost study [Abstract WEPE511]. In 7th International AIDS Society Conference on HIV Pathogenesis Treatment and Prevention. Kuala Lumpur, Malaysia; June-July 2013.
- [30]Burgos J, Crespo M, Falco V, Curran A, Navarro J, Imaz A, Domingo P, Podzamczer D, Mateo MG, Villar S, et al.: Simplification to dual antiretroviral therapy including a ritonavir-boosted protease inhibitor in treatment-experienced HIV-1-infected patients. J Antimicrob Chemother 2012, 67:2479-2486.
- [31]Ofotokun I, Sheth AN, Sanford SE, Easley KA, Shenvi N, White K, Eaton ME, Del Rio C, Lennox JL: A switch in therapy to a reverse transcriptase inhibitor sparing combination of lopinavir/ritonavir and raltegravir in virologically suppressed HIV-infected patients: a pilot randomized trial to assess efficacy and safety profile: the KITE study. AIDS Res Hum Retroviruses 2012, 28:1196-1206.
- [32]Carey D, Pett SL, Bloch M, Wand H, MacRae K, Beileiter K, Ray JE, Boyd MA, Emery S, Cooper DA: A randomized study of pharmacokinetics, efficacy, and safety of 2 raltegravir plus atazanavir strategies in ART-treated adults. J Acquir Immune Defic Syndr 2012, 60:143-149.
- [33]Allavena C, Mounoury O, Rodallec A, Reliquet V, Billaud E, Raffi F: Efficacy and safety of an NRTI-sparing dual regimen of raltegravir and ritonavir-boosted protease inhibitor in a triple antiretroviral class-experienced population. HIV Clin Trials 2009, 10:337-340.
- [34]Fischl MA, Collier AC, Mukherjee AL, Feinberg JE, Demeter LM, Tebas P, Giuliano M, Dehlinger M, Garren K, Brizz B, Bassett R: Randomized open-label trial of two simplified, class-sparing regimens following a first suppressive three or four-drug regimen. AIDS 2007, 21:325-333.
- [35]Cordery DV, Hesse K, Amin J, Cooper DA: Raltegravir and unboosted atazanavir dual therapy in virologically suppressed antiretroviral treatment-experienced HIV patients. Antivir Ther 2010, 15:1035-1038.
- [36]Monteiro P, Perez I, Laguno M, Martinez-Rebollar M, Gonzalez-Cordon A, Lonca M, Mallolas J, Blanco JL, Gatell JM, Martinez E: Dual therapy with etravirine plus raltegravir for virologically suppressed HIV-infected patients: a pilot study. J Antimicrob Chemother 2013. Epub ahead of print] doi:10.1093/jac/dkt406
- [37]Bierman WF, van Agtmael MA, Nijhuis M, Danner SA, Boucher CA: HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS 2009, 23:279-291.
- [38]Arribas JR, Doroana M, Turner D, Vandekerckhove L, Streinu-Cercel A: Boosted protease inhibitor monotherapy in HIV-infected adults: outputs from a pan-European expert panel meeting. AIDS Res Ther 2013, 10:3. BioMed Central Full Text
- [39]Arribas JR, Delgado R, Arranz A, Munoz R, Portilla J, Pasquau J, Perez-Elias MJ, Iribarren JA, Rubio R, Ocampo A, et al.: Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis. J Acquir Immune Defic Syndr 2009, 51:147-152.
- [40]Clumeck N, Rieger A, Banhegyi D, Schmidt W, Hill A, Van Delft Y, Moecklinghoff C, Arribas J: 96 week results from the MONET trial: a randomized comparison of darunavir/ritonavir with versus without nucleoside analogues, for patients with HIV RNA <50 copies/mL at baseline. J Antimicrob Chemother 2011, 66:1878-1885.
- [41]Mills A, Mildvan D, Podzamczer D, Fatkenheuer G, Leal M, Than S, Valluri SR, Craig C, McFadyen L, Vourvahis M, et al.: Maraviroc once-daily nucleoside analog-sparing regimen in treatment-naive patients: randomized, open-label pilot study. J Acquir Immune Defic Syndr 2013, 62:164-170.
- [42]Reynes J, Trinh R, Pulido F, Soto-Malave R, Gathe J, Qaqish R, Tian M, Fredrick L, Podsadecki T, Norton M, Nilius A: Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive subjects: 96-week results of the PROGRESS study. AIDS Res Hum Retroviruses 2013, 29:256-265.
- [43]Taiwo B, Swindells S, Berzins B, Acosta E, Ryscavage P, Lalezari J, Castro J, Adeyemi O, Yip B, Rathert M, Kuritzkes D, Eron J, MIDAS Study Team: Week 48 results of the Maraviroc Plus Darunavir/ritonavir Study (MIDAS) for treatment-naive patients infected with R5-tropic HIV-1 [Abstract TUPE099]. In 19th International AIDS Conference. Washington, DC (USA); July 2012.
- [44]Bedimo R, Drechsler H, Turner D, Moore T, Ghormley J, Jain M, Petersen T, Santos M, Farukhi I, Cutrell J: RADAR study: Raltegravir combined with 656 boosted Darunavir has similar safety and antiviral efficacy as tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naïve patients [Abstract MOPE214]. In 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Rome (Italy); July 2011.
- [45]Taiwo B, Zheng L, Gallien S, Matining RM, Kuritzkes DR, Wilson CC, Berzins BI, Acosta EP, Bastow B, Kim PS, et al.: Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262). AIDS 2011, 25:2113-2122.
- [46]Riddler SA, Haubrich R, DiRienzo AG, Peeples L, Powderly WG, Klingman KL, Garren KW, George T, Rooney JF, Brizz B, et al.: Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008, 358:2095-2106.
- [47]Kozal MJ, Lupo S, DeJesus E, Molina JM, McDonald C, Raffi F, Benetucci J, Mancini M, Yang R, Wirtz V, et al.: A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naive HIV-infected patients: SPARTAN study results. HIV Clin Trials 2012, 13:119-130.
- [48]Taiwo B, Acosta EP, Ryscavage P, Berzins B, Lu D, Lalezari J, Castro J, Adeyemi O, Kuritzkes DR, Eron JJ, et al.: Virologic response, early HIV-1 decay, and maraviroc pharmacokinetics with the nucleos(t)ide-free regimen of maraviroc plus darunavir/ritonavir in a pilot study. J Acquir Immune Defic Syndr 2013, 64:167-173.
- [49]The GARDEL Study Team: Dual therapy with Lopinavir/ Ritonavir (LPV/r) and Lamivudine (3TC) is non-inferior to standard triple drug therapy in Naïve HIV-1 infected subjects: 48-week results of the GARDEL Study [Abstract LBPS7/6]. In 14th European AIDS Conference. Brussels (Belgium); Sept. 2013.
- [50]Hill A, Sawyer W, Gazzard B: Effects of first-line use of nucleoside analogues, efavirenz, and ritonavir-boosted protease inhibitors on lipid levels. HIV Clin Trials 2009, 10:1-12.
- [51]Achhra AC, Amin J, Hoy J, Tanuma J, Sirisanthana T, Nolan D, Merati T, Giles M: Differences in lipid measurements by antiretroviral regimen exposure in cohorts from Asia and australia. AIDS Res Treat 2012, 2012:246280.
- [52]Sax P: MODERN Study Stopped: An NRTI-Sparing, Two-Drug Initial Regimen Disappoints Again. Available at http://blogs.jwatch.org/hiv-id-observations/index.php/modern-study-stopped-an-nrti-sparing-two-drug-initial-regimen-disappoints-again/2013/10/14/ webcite. Accessed on 30 October 2013
- [53]Achhra AC, Boyd M, Law MG, Matthews G, Kelleher AD, Cooper DA: Sequencing antiretroviral therapy to maximize patient safety: could we move away from Ritonavir, Abacavir, Tenofovir, and Efavirenz(RATE) - agents that concern prescribers and patients? A feasibility study and Call for a trial [Abstract: PE8/6]. In 14th European AIDS Conference. Brussels (Belgium); Sept. 2013.
- [54]Gazzard B, Duvivier C, Zagler C, Castagna A, Hill A, van Delft Y, Marks S: Phase 2 double-blind, randomized trial of etravirine versus efavirenz in treatment-naive patients: 48-week results. AIDS 2011, 25:2249-2258.