Monitored Antiretroviral Pause in Chronic HIV-Infected Subjects With Long-Lasting Suppressed Viremia

NCT03198325 | Completed DMC

• 1 other identifier: APACHE Study
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

Prospective, open-label, single arm, non-randomized, proof-of-concept study. Eligible patients will sign a written informed consent and will be followed-up at screening, baseline (ART interruption) and at 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption. The study visits will include: general clinical assessment, routine laboratory tests including: creatinine, phosphorus, calcium, alkaline phosphatase, AST, ALT, fasting glucose, total cholesterol, HDL- and LDL-cholesterol, triglycerides, CD4+ cell count and CD4+/CD8+ ratio. Additional 30 mL of peripheral blood will be withdrawn at study visits for further virological, and immunological investigations and for bio-banking purposes. During follow-up, the occurrence of two consecutive HIV-1 RNA values \>50 copies/mL or the occurrence of stage B or C AIDS-defining events or any serious non-AIDS clinical event at least potentially related to treatment interruption will be criteria for ART resumption. All patients with HIV-RNA\<50 copies/mL at week 48 (end of the study) will resume their baseline ART regimen. The main demographic, clinical and therapy information will be accurately recorded at the study visits in an electronic Case Report Form.

Conditions

HIV Seropositivity

Keywords

HIV-1

Outcome Measures

Primary Outcomes (1)

• Patients who will not resume antiretroviral regimen

  Cumulative proportion of patients who will not resume ART 12 months after IMAP (Monitored Antiretroviral Pause) due to the occurrence of two consecutive HIV-1 RNA values \>50 copies/mL or the occurrence of stage B or C AIDS-defining events or any serious non-AIDS clinical event at least potentially related to treatment interruption.

  12 month

Secondary Outcomes (6)

• Change in plasma viremia

  1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.

• Change in plasma HIV-DNA

  1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.

• Change in CD4+

  1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.

• Change in CD4+/CD8+ ratio

  1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.

• Change in virological biomarkers

  1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.

Study Arms (1)

Interruption of antiretroviral therapy

EXPERIMENTAL

Patients willing to stop antiretroviral therapy will stop ART.The occurrence of two consecutive HIV-1 RNA values \>50 copies/mL or the occurrence of stage B or C AIDS-defining events will be criteria for ART resumption or any serious non-AIDS clinical event at least potentially related to treatment interruption.

Other: Stop of ART

Interventions

Stop of ART OTHER

Patients willing to stop antiretroviral therapy will stop ART.The occurrence of two consecutive HIV-1 RNA values \>50 copies/mL or the occurrence of stage B or C AIDS-defining events will be criteria for ART resumption or any serious non-AIDS clinical event at least potentially related to treatment interruption.

Interruption of antiretroviral therapy

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The study will include HIV-1 infected:
• men and non-pregnant women,
• ≥18 and \<65 years-old,
• asking to stop therapy,
• with HIV-1 RNA\<50 copies/mL for ≥10 years,
• current CD4+≥500 cells/µL,
• HIV-DNA\<100 copies/106PBMCs,
• no evidence of detectable residual viremia for ≥5 years .

You may not qualify if:

• The study will exclude HIV-1 infected subjects:
• significant risk of HIV transmission during IMAP (including evidence of not adopting effective contraception methods and women who wish to be pregnant) in the opinion of the investigator,
• pregnancy and breastfeeding,
• a documented pre-ART HIV-1 RNA\<200 copies/mL,
• reactive Hepatitis B virus (HBV) surface antigen,
• positive HCV-RNA at the time of screening,
• current AIDS defining event as defined in category C of the 'Centers for disease control and prevention (CDC)' clinical classification,
• previous diagnosis of diabetes,
• a previous diagnosis of cancer or major adverse cardiac events (MACE) and currently receiving chemotherapy or immuno-modulating agents at the time of screening,
• history of HIV-related thrombocytopenia,
• active renal disease defined as a glomerular filtration rate (calculated by MDRD equation) below 50 mL/min or the presence of HIV associated nephropathy in the past medical history,
• any condition, including psychiatric or psychological disorders that might interfere with adherence to study requirements or safety of the participant,
• prior use of any HIV vaccine and/or non-established experimental therapy,
• active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

Sponsors & Collaborators

• IRCCS San Raffaele: lead

Study Sites (1)

Ospedale San Raffaele Scientific Institute

Milan, 20127, Italy

Location

Related Publications (22)

• Pau AK, George JM. Antiretroviral therapy: current drugs. Infect Dis Clin North Am. 2014 Sep;28(3):371-402. doi: 10.1016/j.idc.2014.06.001.

  PMID: 25151562 BACKGROUND

• Strategies for Management of Antiretroviral Therapy (SMART) Study Group; El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, Arduino RC, Babiker A, Burman W, Clumeck N, Cohen CJ, Cohn D, Cooper D, Darbyshire J, Emery S, Fatkenheuer G, Gazzard B, Grund B, Hoy J, Klingman K, Losso M, Markowitz N, Neuhaus J, Phillips A, Rappoport C. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006 Nov 30;355(22):2283-96. doi: 10.1056/NEJMoa062360.

  PMID: 17135583 BACKGROUND

• Strategies for Management of Antiretroviral Therapy (SMART) Study Group; Emery S, Neuhaus JA, Phillips AN, Babiker A, Cohen CJ, Gatell JM, Girard PM, Grund B, Law M, Losso MH, Palfreeman A, Wood R. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. 2008 Apr 15;197(8):1133-44. doi: 10.1086/586713.

  PMID: 18476292 BACKGROUND

• Skiest DJ, Krambrink A, Su Z, Robertson KR, Margolis DM; A5170 Study Team. Improved measures of quality of life, lipid profile, and lipoatrophy after treatment interruption in HIV-infected patients with immune preservation: results of ACTG 5170. J Acquir Immune Defic Syndr. 2008 Dec 1;49(4):377-83. doi: 10.1097/QAI.0b013e31818cde21.

  PMID: 18931631 BACKGROUND

• Strategies for Management of Antiretroviral Therapy (SMART) Study Group; Lundgren JD, Babiker A, El-Sadr W, Emery S, Grund B, Neaton JD, Neuhaus J, Phillips AN. Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ Cell counts and HIV RNA levels during follow-up. J Infect Dis. 2008 Apr 15;197(8):1145-55. doi: 10.1086/529523.

  PMID: 18476293 BACKGROUND

• Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, Potard V, Versmisse P, Melard A, Prazuck T, Descours B, Guergnon J, Viard JP, Boufassa F, Lambotte O, Goujard C, Meyer L, Costagliola D, Venet A, Pancino G, Autran B, Rouzioux C; ANRS VISCONTI Study Group. 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 Mar;9(3):e1003211. doi: 10.1371/journal.ppat.1003211. Epub 2013 Mar 14.

  PMID: 23516360 BACKGROUND

• Williams JP, Hurst J, Stohr W, Robinson N, Brown H, Fisher M, Kinloch S, Cooper D, Schechter M, Tambussi G, Fidler S, Carrington M, Babiker A, Weber J, Koelsch KK, Kelleher AD, Phillips RE, Frater J; SPARTACTrial Investigators. HIV-1 DNA predicts disease progression and post-treatment virological control. Elife. 2014 Sep 12;3:e03821. doi: 10.7554/eLife.03821.

  PMID: 25217531 BACKGROUND

• Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, Lai J, Blankson JN, Siliciano JD, Siliciano RF. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell. 2013 Oct 24;155(3):540-51. doi: 10.1016/j.cell.2013.09.020. Epub 2013 Oct 24.

  PMID: 24243014 BACKGROUND

• Hurst J, Hoffmann M, Pace M, Williams JP, Thornhill J, Hamlyn E, Meyerowitz J, Willberg C, Koelsch KK, Robinson N, Brown H, Fisher M, Kinloch S, Cooper DA, Schechter M, Tambussi G, Fidler S, Babiker A, Weber J, Kelleher AD, Phillips RE, Frater J. Immunological biomarkers predict HIV-1 viral rebound after treatment interruption. Nat Commun. 2015 Oct 9;6:8495. doi: 10.1038/ncomms9495.

  PMID: 26449164 BACKGROUND

• Lee SA, Bacchetti P, Chomont N, Fromentin R, Lewin SR, O'Doherty U, Palmer S, Richman DD, Siliciano JD, Yukl SA, Deeks SG, Burbelo PD. Anti-HIV Antibody Responses and the HIV Reservoir Size during Antiretroviral Therapy. PLoS One. 2016 Aug 2;11(8):e0160192. doi: 10.1371/journal.pone.0160192. eCollection 2016.

  PMID: 27483366 BACKGROUND

• Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, Kovacs C, Gange SJ, Siliciano RF. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003 Jun;9(6):727-8. doi: 10.1038/nm880. Epub 2003 May 18.

  PMID: 12754504 BACKGROUND

• Burbelo PD, Lebovitz EE, Notkins AL. Luciferase immunoprecipitation systems for measuring antibodies in autoimmune and infectious diseases. Transl Res. 2015 Feb;165(2):325-35. doi: 10.1016/j.trsl.2014.08.006. Epub 2014 Sep 1.

  PMID: 25241936 BACKGROUND

• Assoumou L, Weiss L, Piketty C, Burgard M, Melard A, Girard PM, Rouzioux C, Costagliola D; ANRS 116 SALTO study group. A low HIV-DNA level in peripheral blood mononuclear cells at antiretroviral treatment interruption predicts a higher probability of maintaining viral control. AIDS. 2015 Sep 24;29(15):2003-7. doi: 10.1097/QAD.0000000000000734.

  PMID: 26355572 BACKGROUND

• Calin R, Hamimi C, Lambert-Niclot S, Carcelain G, Bellet J, Assoumou L, Tubiana R, Calvez V, Dudoit Y, Costagliola D, Autran B, Katlama C; ULTRASTOP Study Group. Treatment interruption in chronically HIV-infected patients with an ultralow HIV reservoir. AIDS. 2016 Mar 13;30(5):761-9. doi: 10.1097/QAD.0000000000000987.

  PMID: 26730568 BACKGROUND

• Cuzin L, Pugliese P, Saune K, Allavena C, Ghosn J, Cottalorda J, Rodallec A, Chaix ML, Fafi-Kremer S, Soulie C, Ouka M, Charpentier C, Bocket L, Mirand A, Guiguet M; Dat'AIDS study group. Levels of intracellular HIV-DNA in patients with suppressive antiretroviral therapy. AIDS. 2015 Aug 24;29(13):1665-71. doi: 10.1097/QAD.0000000000000723.

  PMID: 26372277 BACKGROUND

• Zheng L, Bosch RJ, Chan ES, Read S, Kearney M, Margolis DM, Mellors JW, Eron JJ, Gandhi RT; DS Clinical Trials Group (ACTG) A5244 Team. Predictors of residual viraemia in patients on long-term suppressive antiretroviral therapy. Antivir Ther. 2013;18(1):39-43. doi: 10.3851/IMP2323. Epub 2012 Aug 22.

  PMID: 22914318 BACKGROUND

• Maggiolo F, Callegaro A, Cologni G, Bernardini C, Velenti D, Gregis G, Quinzan G, Soavi L, Iannotti N, Malfatto E, Leone S. Ultrasensitive assessment of residual low-level HIV viremia in HAART-treated patients and risk of virological failure. J Acquir Immune Defic Syndr. 2012 Aug 15;60(5):473-82. doi: 10.1097/QAI.0b013e3182567a57.

  PMID: 22481602 BACKGROUND

• Gianotti N, Canducci F, Galli L, Cossarini F, Salpietro S, Poli A, Nozza S, Spagnuolo V, Clementi M, Sampaolo M, Ceresola ER, Racca S, Lazzarin A, Castagna A. HIV DNA loads, plasma residual viraemia and risk of virological rebound in heavily treated, virologically suppressed HIV-infected patients. Clin Microbiol Infect. 2015 Jan;21(1):103.e7-103.e10. doi: 10.1016/j.cmi.2014.08.004. Epub 2014 Oct 13.

  PMID: 25636935 BACKGROUND

• Li JZ, Etemad B, Ahmed H, Aga E, Bosch RJ, Mellors JW, Kuritzkes DR, Lederman MM, Para M, Gandhi RT. The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption. AIDS. 2016 Jan 28;30(3):343-53. doi: 10.1097/QAD.0000000000000953.

  PMID: 26588174 BACKGROUND

• Tedaldi E, Peters L, Neuhaus J, Puoti M, Rockstroh J, Klein MB, Dore GJ, Mocroft A, Soriano V, Clotet B, Lundgren JD; SMART Study Group and International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). Opportunistic disease and mortality in patients coinfected with hepatitis B or C virus in the strategic management of antiretroviral therapy (SMART) study. Clin Infect Dis. 2008 Dec 1;47(11):1468-75. doi: 10.1086/593102.

  PMID: 18959492 BACKGROUND

• Monroe AK, Chander G, Moore RD. Control of medical comorbidities in individuals with HIV. J Acquir Immune Defic Syndr. 2011 Dec 15;58(5):458-62. doi: 10.1097/QAI.0b013e31823801c4.

  PMID: 22083037 BACKGROUND

• Mastrangelo A, Burbelo PD, Galli L, Poli A, Alteri C, Scutari R, Muccini C, Spagnuolo V, Caccia R, Turrini F, Bigoloni A, Galli A, Castagna A, Cinque P. Anti-HIV antibodies are representative of the latent reservoir but do not correlate with viral control in people with long-lasting virological suppression undergoing analytical treatment interruption (APACHE study). J Antimicrob Chemother. 2021 May 12;76(6):1646-1648. doi: 10.1093/jac/dkab060. No abstract available.

  PMID: 33693943 DERIVED

MeSH Terms

Conditions

HIV Seropositivity

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 21, 2017
• First Posted: June 26, 2017
• Study Start: July 27, 2016
• Primary Completion: December 1, 2017
• Study Completion: April 1, 2018
• Last Updated: February 9, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share

Locations

IT (1)