Structured Treatment Interruptions and Low Doses of IL-2 in Patients with Primary HIV Infection. Inflammatory, Virological and Immunological Outcomes

Omar Sued, Juan Ambrosioni, David Nicolás, Christian Manzardo, Fernando Agüero, Xavier Claramonte, Montserrat Plana, Montserrat Tuset, Tomás Pumarola, Teresa Gallart, José María Gatell, José María Miró, Omar Sued, Juan Ambrosioni, David Nicolás, Christian Manzardo, Fernando Agüero, Xavier Claramonte, Montserrat Plana, Montserrat Tuset, Tomás Pumarola, Teresa Gallart, José María Gatell, José María Miró

Abstract

Background: Interventions during primary HIV infection (PHI) can modify the clinical course during the chronic phase. The long-term effect of structured treatment interruptions (STI) followed by low doses of interleukin-2 (IL-2) in treated PHI patients is unknown.

Methods: Twelve PHI patients with viral load (VL) <20 copies/mL, CD4 cells >500 cells/mm3, and CD4/CD8 ratio >1, on antiretroviral therapy (ART) initiated within the first 90 days of infection and continued for at least 12 months were included. They underwent four STI and were then allocated (week 0 of the study) to ART alone or ART plus low doses of IL-2. ART was stopped once VL <20 copies/mL ('final stop'). Primary endpoints were VL<3000 copies/mL and CD4 cells >500 cells/mm3 at 48 weeks; secondary endpoints were immune activation, inflammatory markers until 48 weeks and the time before resuming ART (CD4 <350 cells/mm3 or AIDS) after 'final stop', compared between groups.

Results: Ten out of 12 patients were males, median age was 35 years and the main risk was men-who-have-sex-with-men. Only one out of 12 patients (in the STI group) maintained VL<3000 copies/mL and CD4 cells >500 cells/mm3 without ART at 48 weeks. All other virological and immunological parameters were comparable between groups at week 0, 'final stop' and week 48. However, the proportion of CD8-CD38+ cells, tumor necrosis factor and srIL-2 were higher in the IL-2 group at 'final stop' and week 24. All these differences vanished during follow-up. At 5 years after the final stop 3 out of 6 patients in the IL-2 group and 6 out of 6 patients in the STI group have resumed ART (P = 0.19).

Conclusions: STI and IL-2 failed to achieve virological control after ART interruption. STI were not deleterious in long-term follow-up, an important issue for eradication and functional cure trials.

Trial registration: ClinicalTrials.gov NCT02300623.

Conflict of interest statement

Competing Interests: For this study, the authors have received funding from a commercial source (Chiron Pharmaceuticals) but this does not alter adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Flow diagram of the trial.
Fig 1. Flow diagram of the trial.
Fig 2. Design of the study.
Fig 2. Design of the study.
Footnote: (a) Eligible individuals were patients treated within 90 days of HIV exposure on stable ART for at least 12 months. Patients had to show good virological and immunological responses (at least 2 viral load 1). All individuals started four structured treatment interruption cycles (b) of 8 week each (off-ART), followed by four cycles (c) of treatment (on-ART). After the last treatment interruption (week 0) 6 patients started self-administrated IL-2 at a dose of 750,000 UI/m2 daily for 6 months (d). Treatment was interrupted in both arms when patients reached viral load <20 copies/mL (e). Analyses were performed at 24 and 48 weeks and after a long term follow-up period (9 years). During this period (f) treatment was restarted in patients whose CD4 cell count dropped below 350 cell/mm3.
Fig 3. A) Plasma HIV Viral Load…
Fig 3. A) Plasma HIV Viral Load evolution after 4th STI cycle. B) CD4+ T cell evolution after 4th STI cycle. Footnote: The period of IL-2 administration is shown in grey.
The filled points represent periods on ART. Empty points are determinations without ART.
Fig 4. Proportion of patients not receiving…
Fig 4. Proportion of patients not receiving ART after the final stop.

References

    1. Kaufmann GR, Zaunders JJ, Cunningham P, Kelleher AD, Grey P, Smith D, et al. Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection. AIDS 2000; 14(17):2643–2651.
    1. Zaunders JJ, Cunningham PH, Kelleher AD, Kaufmann GR, Jaramillo AB, Wright R, et al. Potent antiretroviral therapy of primary human immunodeficiency virus type 1 (HIV-1) infection: partial normalization of T lymphocyte subsets and limited reduction of HIV-1 DNA despite clearance of plasma viremia. J Infect Dis 1999; 180(2):320–329.
    1. Yerly S, Perneger TV, Vora S, Hirschel B, Perrin L. Decay of cell-associated HIV-1 DNA correlates with residual replication in patients treated during acute HIV-1 infection. AIDS 2000; 14(18):2805–2812.
    1. Hocqueloux L, Avettand-Fenoel V, Jacquot S, Prazuck T, Legac E, Melard A, et al. Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T cell counts. J Antimicrob Chemother 2013.
    1. Altfeld M, Rosenberg ES, Shankarappa R, Mukherjee JS, Hecht FM, Eldridge RL, et al. Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. J Exp Med 2001; 193(2):169–180.
    1. Oxenius A, Price DA, Easterbrook PJ, O'Callaghan CA, Kelleher AD, Whelan JA, et al. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A 2000; 97(7):3382–3387.
    1. Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, et al. Immune control of HIV-1 after early treatment of acute infection. Nature 2000; 407(6803):523–526.
    1. Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997; 278(5342):1447–1450.
    1. Ambrosioni J, Calmy A, Hirschel B. HIV treatment for prevention. J Int AIDS Soc 2011; 14:28 10.1186/1758-2652-14-28
    1. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365(6):493–505. 10.1056/NEJMoa1105243
    1. Plana M, Garcia F, Gallart T, Miro JM, Gatell JM. Lack of T-cell proliferative response to HIV-1 antigens after 1 year of highly active antiretroviral treatment in early HIV-1 disease. Immunology Study Group of Spanish EARTH-1 Study. Lancet 1998; 352(9135):1194–1195.
    1. Shasha D, Walker BD. Lessons to be Learned from Natural Control of. Front Immunol 2013; 4:162 10.3389/fimmu.2013.00162
    1. Zaunders J, van BD. Innate and Adaptive Immunity in Long-Term Non-Progression in HIV Disease. Front Immunol 2013; 4:95 10.3389/fimmu.2013.00095
    1. Lisziewicz J, Rosenberg E, Lieberman J, Jessen H, Lopalco L, Siliciano R, et al. Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 1999; 340(21):1683–1684.
    1. Ortiz GM, Nixon DF, Trkola A, Binley J, Jin X, Bonhoeffer S, et al. HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest 1999; 104(6):R13–R18.
    1. Fagard C, Oxenius A, Gunthard H, Garcia F, Le BM, Mestre G, et al. A prospective trial of structured treatment interruptions in human immunodeficiency virus infection. Arch Intern Med 2003; 163(10):1220–1226.
    1. Jacobson JM, Pat BR, Spritzler J, Saag MS, Eron JJ Jr, Coombs RW, et al. Evidence that intermittent structured treatment interruption, but not immunization with ALVAC-HIV vCP1452, promotes host control of HIV replication: the results of AIDS Clinical Trials Group 5068. J Infect Dis 2006; 194(5):623–632.
    1. Papasavvas E, Kostman JR, Mounzer K, Grant RM, Gross R, Gallo C, et al. Randomized, controlled trial of therapy interruption in chronic HIV-1 infection. PLoS Med 2004; 1(3):e64
    1. Lori F, Lewis MG, Xu J, Varga G, Zinn DE Jr, Crabbs C, et al. Control of SIV rebound through structured treatment interruptions during early infection. Science 2000; 290(5496):1591–1593.
    1. Allen TM, Kelleher AD, Zaunders J, Walker BD. STI and beyond: the prospects of boosting anti-HIV immune responses. Trends Immunol 2002; 23(9):456–460.
    1. Autran B, Carcelain G. AIDS. Boosting immunity to HIV—can the virus help? Science 2000; 290(5493):946–949.
    1. Gandhi RT, Walker BD. Promises and pitfalls in the reconstitution of immunity in patients who have HIV-1 infection. Curr Opin Immunol 2002; 14(4):487–494.
    1. Kaufmann DE, Lichterfeld M, Altfeld M, Addo MM, Johnston MN, Lee PK, et al. Limited durability of viral control following treated acute HIV infection. PLoS Med 2004; 1(2):e36
    1. Hocqueloux L, Prazuck T, Avettand-Fenoel V, Lafeuillade A, Cardon B, Viard JP, et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS 2010; 24(10):1598–1601.
    1. Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog 2013; 9(3):e1003211 10.1371/journal.ppat.1003211
    1. Smith KA. Interleukin-2: inception, impact, and implications. Science 1988; 240(4856):1169–1176.
    1. Jacobson EL, Pilaro F, Smith KA. Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity. Proc Natl Acad Sci U S A 1996; 93(19):10405–10410.
    1. Jacobson EL, Pilaro F, Smith KA. Interleukin-2 infusions in HIV-infected patients. N Engl J Med 1997; 336(17):1260–1261.
    1. Smith KA. Low-dose daily interleukin-2 immunotherapy: accelerating immune restoration and expanding HIV-specific T-cell immunity without toxicity. AIDS 2001; 15 Suppl 2:S28–S35.
    1. El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355(22):2283–2296.
    1. Goujard C, Emilie D, Roussillon C, Godot V, Rouzioux C, Venet A, et al. Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial. AIDS 2012; 26(15):1895–1905.
    1. Schockmel GA, Balavoine JF, Yerly S, Perrin L. Use of highly sensitive assays for the evaluation of post-exposure HIV prophylaxis. AIDS 1998; 12(13):1726–1727.
    1. Alos L, Navarrete P, Morente V, Garcia F, Garrido M, Plana M, et al. Immunoarchitecture of lymphoid tissue in HIV-infection during antiretroviral therapy correlates with viral persistence. Mod Pathol 2005; 18(1):127–136.
    1. REGA HIV-1 Subtyping Tool—Version 2.0 Available: . Accessed: May 2008.
    1. Goujard C, Girault I, Rouzioux C, Lecuroux C, Deveau C, Chaix ML, et al. HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy. Antivir Ther 2012; 17(6):1001–1009. 10.3851/IMP2273
    1. Le T, Wright EJ, Smith DM, He W, Catano G, Okulicz JF, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med 2013; 368(3):218–230. 10.1056/NEJMoa1110187
    1. Ambrosioni J, Junier T, Delhumeau C, Calmy A, Hirschel B, Zdobnov E, et al. Impact of highly active antiretroviral therapy on the molecular epidemiology of newly diagnosed HIV infections. AIDS 2012; 26(16):2079–2086. 10.1097/QAD.0b013e32835805b6
    1. Brenner BG, Roger M, Moisi DD, Oliveira M, Hardy I, Turgel R, et al. Transmission networks of drug resistance acquired in primary/early stage HIV infection. AIDS 2008; 22(18):2509–2515. 10.1097/QAD.0b013e3283121c90
    1. Grijsen M, Koster G, van VM, van KM, Kootstra G, Steingrover R, et al. Temporary antiretroviral treatment during primary HIV-1 infection has a positive impact on health-related quality of life: data from the Primo-SHM cohort study. HIV Med 2012; 13(10):630–635. 10.1111/j.1468-1293.2012.01020.x
    1. Cutrell J, Bedimo R. Non-AIDS-defining cancers among HIV-infected patients. Curr HIV/AIDS Rep 2013; 10(3):207–216. 10.1007/s11904-013-0166-8
    1. Abrams D, Levy Y, Losso MH, Babiker A, Collins G, Cooper DA, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med 2009; 361(16):1548–1559. 10.1056/NEJMoa0903175
    1. Grijsen ML, Steingrover R, Wit FW, Jurriaans S, Verbon A, Brinkman K, et al. No treatment versus 24 or 60 weeks of antiretroviral treatment during primary HIV infection: the randomized Primo-SHM trial. PLoS Med 2012; 9(3):e1001196 10.1371/journal.pmed.1001196
    1. Fidler S, Porter K, Ewings F, Frater J, Ramjee G, Cooper D, et al. Short-course antiretroviral therapy in primary HIV infection. N Engl J Med 2013; 368(3):207–217. 10.1056/NEJMoa1110039

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