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)

English version

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
doi: 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:

Adverse events – Antiretrovirals – HIV diagnosis and management – Cholesterol – Viral load – 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

A prospective randomized trial on abacavir/lamivudine plus darunavir/ritonavir or raltegravir in HIV-positive drug-naïve patients with CD4&lt;200 cells/uL (the PRADAR study)

Souhrn

Background

Methods

Results

Conclusions

Trial registration

Klíčová slova:

Zdroje

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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)