A prospective randomized trial on abacavir/lamivudine plus darunavir/ritonavir or raltegravir in HIV-positive drug-naïve patients with CD4<200 cells/uL (the PRADAR study)
Autoři:
Cristina Mussini aff001; Enrica Roncaglia aff001; Vanni Borghi aff001; Stefano Rusconi aff002; Silvia Nozza aff003; Anna Maria Cattelan aff004; Daniela Segala aff005; Paolo Bonfanti aff006; Antonio Di Biagio aff007; Enrico Barchi aff008; Emanuele Focà aff009; Anna Degli Antoni aff010; Stefano Bonora aff011; Daniela Francisci aff012; Silvia Limonta aff002; Andrea Antinori aff013; Gabriella D’Ettorre aff014; Franco Maggiolo aff015
Působiště autorů:
Clinic of Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy
aff001; Clinic of Infectious Diseases, DIBIC Luigi Sacco, University of Milan, Milan, Italy
aff002; Clinic of Infectious Diseases, University Vita e Salute, San Raffaele Hospital, Milan, Italy
aff003; Clinic of Infectious Diseases, Padova Hospital, Padova, Italy
aff004; Clinic of Infectious Diseases, Sant’Anna Hospital, Ferrara, Italy
aff005; Department of Infectious Diseases, Lecco Hospital, Lecco, Italy
aff006; Clinic of Infectious Diseases, San Martino Hospital, Genova, Italy
aff007; Department of Infectious Diseases, Santa Maria Nuova Hospital, Reggio Emilia, Italy
aff008; Clinic of Infectious Diseases, University of Brescia and ASST Spedali Civili, Brescia, Italy
aff009; Clinic of Infectious Diseases, University of Parma, Parma, Italy
aff010; Clinic of Infectious Diseases, University of Torino, Torino, Italy
aff011; Clinic of Infectious Diseases, University of Perugia, Perugia, Italy
aff012; National Institute for Infectious Diseases L. Spallanzani, Rome, Italy
aff013; Clinic of Infectious Diseases, University La Sapienza, Rome, Italy
aff014; Department of Infectious Diseases, Bergamo Hospital, Bergamo, Italy
aff015
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0222650
Souhrn
Background
Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge.
Methods
Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive with CD4+ counts < 200/mm3 and a viral load (VL)<500,000 copies/mL. The primary Endpoint was the proportion of patients with undetectable viremia (VL<50 copies/mL) after 48 weeks. The planned sample size for this trial was 350 patients.
Results
In 3 years, 53 patients were screened and 46 enrolled: 22 randomized to raltegravir and 24 to darunavir/r; 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity. The snapshot analysis at 48 weeks showed a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r. Time to starting treatment was 34.5 days in raltegravir and 53 days in darunavir/r. At the as treated analysis, the median CD4 counts at 48 weeks was 297 cells/μL in raltegravir and 239 cells/μL in darunavir/r. No difference in total cholesterol, while triglycerides were higher in the darunavir/r arm. No statistical analyses were performed due to the low number of patients enrolled.
Conclusions
Late presenter patients are frequent but very difficult to enroll in clinical trials, especially in western countries. These regimens and the conditions of many patients could not allow the test and treat strategy. The rate of virologic success was higher than 65% in both arms with a median CD4 cell count >200/μL at week 48.
Trial registration
EUDRACT number: 2011-005973-21
Klíčová slova:
Viral load – HIV diagnosis and management – Cholesterol – Adverse events – Antiretrovirals – Opportunistic infections
Zdroje
1. Late presenters working group in COHERE in EuroCoord, Mocroft A, Lundgren J, Antinori A, Monforte Ad, Brännström J et al. Late presentation for HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study, 2010 to 2013. Euro Surveill. 2015;20(47).
2. Calmy A, Ford N, Meintjes G. The Persistent Challenge of Advanced HIV Disease and AIDS in the Era of Antiretroviral Therapy. Clin Infect Dis. 2018 Mar 4;66(suppl_2):S103–SS105. doi: 10.1093/cid/cix1138 29514231
3. van Opstal SEM, van der Zwan JS, Wagener MN, Been SK, Miedema HS, Roelofs PDDM et al. Late Presentation of HIV Infection in the Netherlands: Reasons for Late Diagnoses and Impact on Vocational Functioning. AIDS Behav. 2018 Aug;22(8):2593–2603. doi: 10.1007/s10461-018-2082-9 29550940
4. Sierra-Madero J, Villasis-Keever A, Mendez P, Mosqueda-Gómez JL, Torres-Escobar I, Gutiérrez-Escolano F et al. Prospective, randomized, open label trial of efavirenz vs lopinavir/ritonavir in HIV+ treatment-naive subjects with CD4+<200 cells/mm3 in Mexico. J Acquir Immune Defic Syndr 2010;53:582–8. doi: 10.1097/QAI.0b013e3181cae4a1 20090545
5. Miró JM, Manzardo C, Pich J, Domingo P, Ferrer E, Arribas JR et al for the Advanz Study Group. Immune reconstitution in severely immunosuppressed antiretroviral-naive HIV type 1-infected patients using a nonnucleoside reverse transcriptase inhibitor-based or a boosted protease inhibitor-based antiretroviral regimen: three-year results (The Advanz Trial): a randomized, controlled trial. AIDS Res Hum Retroviruses. 2010;26:747–57. doi: 10.1089/aid.2009.0105 20624069
6. Miro JM, Manzardo C, Ferrer E, Loncà M, Guardo AC, Podzamczer D et al for the Advanz-3 Study Group. Immune Reconstitution in Severely Immunosuppressed Antiretroviral-Naive HIV-1-Infected Patients Starting Efavirenz, Lopinavir-Ritonavir, or Atazanavir-Ritonavir Plus Tenofovir/Emtricitabine: Final 48-Week Results (The Advanz-3 Trial). J Acquir Immune Defic Syndr. 2015;69:206–15. doi: 10.1097/QAI.0000000000000567 25831464
7. Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575. doi: 10.1371/journal.pone.0005575 19440326
8. Havlir DV, Kendall MA, Ive P, Kumwenda J, Swindells S, Qasba SS et al.Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011 Oct 20;365(16):1482–91. doi: 10.1056/NEJMoa1013607 22010914
9. Török ME, Yen NT, Chau TT, Mai NT, Phu NH, Mai PP et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)—associated tuberculous meningitis. Clin Infect Dis. 2011 Jun;52(11):1374–83. doi: 10.1093/cid/cir230 21596680
10. Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014 Jun 26;370(26):2487–98. doi: 10.1056/NEJMoa1312884 24963568
11. Eshun-Wilson I, Okwen MP, Richardson M, Bicanic T. Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis. Cochrane Database Syst Rev. 2018 Jul 24;7
12. Lévy Y, Lelièvre JD, Assoumou L, Aznar E, Pulido F, Tambussi G et al. for the OPTIMAL trial team. Optimized Phase III Trial of Immuno-stimulation with Maraviroc, a CCR5 antagonist, combined with Anti Retroviral Therapy (cART) in advanced, Late diagnosed HIV-1 infected patients with an AIDS-defining event and/or CD4 counts < 200 cells/mm3. OPTIMAL trial. Presented at International AIDS Society Conference, July 23–26 2017, Paris, France Abstract MOAB0102.
13. Kityo C, Szubert AJ, Siika A, Heyderman R, Bwakura-Dangarembizi M, Lugemwa A et al. Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial. PLoS Med. 2018 Dec 4;15(12):e1002706. doi: 10.1371/journal.pmed.1002706 30513108
14. Slama L, Landman R, Assoumou L, Benalycherif A, Samri A, Joly V et al. Efficacy and safety of once-daily ritonavir-boosted atazanavir or darunavir in combination with a dual nucleos(t)ide analogue backbone in HIV-1-infected combined ART (cART)-naive patients with severe immunosuppression: a 48 week, non-comparative, randomized, multicentre trial (IMEA 040 DATA trial). J Antimicrob Chemother. 2016;71:2252–61. doi: 10.1093/jac/dkw103 27068399
15. Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS 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. doi: 10.1016/S0140-6736(09)60918-1 19647866
16. Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461–71. doi: 10.7326/M14-1084 25285539
17. Sax PE, Tierney C, Collier AC, Daar ES, Mollan K, Budhathoki C et al for the AIDS Clinical Trials Group Study A5202 Team. Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results. J Infect Dis 2011;204(8):1191–1201. doi: 10.1093/infdis/jir505 21917892
18. Supplemento del Notiziario dell’Iss (Volume 31—Numero 9, Supplemento 1–2017)–Aggiornamento delle nuove diagnosi di infezione da Hiv e dei casi di Aids in Italia al 31 dicembre 2017” available from http://www.salute.gov.it/imgs/C_17_notizie_3557_listaFile_itemName_0_file.pdf
19. Gallant J, Lazzarin A, Mills A, Orkin C, Podzamczer D, Tebas P et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet 2017;390(10107):2063–2072. doi: 10.1016/S0140-6736(17)32299-7 28867497
20. Young B, Vanig T, DeJesus E, Hawkins T, St Clair M, Yau L et al for the Shield Study Team. A Pilot Study of Abacavir/Lamivudine and Raltegravir in Antiretroviral-Naïve HIV-1–Infected Patients: 48-Week Results of the SHIELD Trial. HIV Clin Trials 2010;11(5):260–269. doi: 10.1310/hct1105-260 21126956
21. Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C et al for the SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013;381(9868):735–43 doi: 10.1016/S0140-6736(12)61853-4 23306000
22. Raffi F, Babiker AG, Richert L, Molina JM, George EC, Antinori A et al for the NEAT001/ANRS143 Study Group. Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet 2014;384:1942–51. doi: 10.1016/S0140-6736(14)61170-3 25103176
23. Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE et al for the GEMINI Study Team. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet 2019;393:143–155. doi: 10.1016/S0140-6736(18)32462-0 30420123
24. Clotet B, Feinberg J, van Lunzen J, Khuong-Josses MA, Antinori A, Dumitru I et al for the ING114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014 Jun 28;383(9936):2222–31. doi: 10.1016/S0140-6736(14)60084-2 24698485
25. INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med 2015 Aug 27;373(9):795–807. doi: 10.1056/NEJMoa1506816 26192873
26. Rosen S, Maskew M, Fox MP, Nyoni C, Mongwenyana C, Malete G et al. Initiating Antiretroviral Therapy for HIV at a Patient's First Clinic Visit: The RapIT Randomized Controlled Trial. PLoS Med. 2016 May 10;13(5):e1002015. doi: 10.1371/journal.pmed.1002015 27163694
27. Ford N, Migone C, Calmy A, Kerschberger B, Kanters S, Nsanzimana S et al.. Benefits and risks of rapid initiation of antiretroviral therapy. AIDS 2018 Jan 2;32(1):17–23. doi: 10.1097/QAD.0000000000001671 29112073
28. The Late Presenter Treatment Optimisation Study (LAPTOP) ClinicalTrials.gov Identifier: NCT03696160
29. Young J, Smith C, Teira R, Reiss P, Jarrín Vera I, Crane H et al for the Antiretroviral Therapy Cohort Collaboration (ART-CC). Antiretroviral pill count and clinical outcomes in treatment- naıve patients with HIV infection. HIV Med 2018, 19, 132–142 doi: 10.1111/hiv.12562 29110395
30. Serrano-Villar S, Zhou Y, Rodgers AJ, Moreno S. Different impact of raltegravir versus efavirenz on CD4/CD8 ratio recovery in HIV-infected patients. J Antimicrob Chemother 2017 Jan;72(1):235–239 doi: 10.1093/jac/dkw375 27655859
Článok vyšiel v časopise
PLOS One
2019 Číslo 9
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- Nejasný stín na plicích – kazuistika
- Masturbační chování žen v ČR − dotazníková studie
- Je Fuchsova endotelová dystrofie rohovky neurodegenerativní onemocnění?
- Fixní kombinace paracetamol/kodein nabízí synergické analgetické účinky
Najčítanejšie v tomto čísle
- Graviola (Annona muricata) attenuates behavioural alterations and testicular oxidative stress induced by streptozotocin in diabetic rats
- CH(II), a cerebroprotein hydrolysate, exhibits potential neuro-protective effect on Alzheimer’s disease
- Comparison between Aptima Assays (Hologic) and the Allplex STI Essential Assay (Seegene) for the diagnosis of Sexually transmitted infections
- Assessment of glucose-6-phosphate dehydrogenase activity using CareStart G6PD rapid diagnostic test and associated genetic variants in Plasmodium vivax malaria endemic setting in Mauritania