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出境医 / 临床实验 / The Effect of Arsenic Trioxide on Eliminating HIV-1 Reservoir Combined With cART

The Effect of Arsenic Trioxide on Eliminating HIV-1 Reservoir Combined With cART

Study Description
Brief Summary:
To evaluate the safety and efficacy of arsenic trioxide combined with cART in eliminating latent HIV-1 reservoir, providing potential strategies for AIDS functional cure.

Condition or disease Intervention/treatment Phase
HIV/AIDS Drug: Arsenic Trioxide Phase 1

Detailed Description:
Although combined antiretroviral therapy (cART) could control human immunodeficiency virus type 1 (HIV-1) infection, the persistence of HIV-1 viral reservoir make it extremely difficult to achieving cure of AIDS. The shock and kill strategy has been extensively practiced. The latency reversing agents (LRAs) could reactivate latent HIV-1 and then the reactivated virus could be eradicated. However, no appropriate activator has been found nor manufactured. Our previous work found that the arsenic trioxide, clinically approved for treating acute promyelocytic leukemia,could efficiently reactivate latent provirus in CD4+T cells from HIV-1 patients and Simian immunodeficiency virus (SIV)-infected macaques, without significant systemic T cell activation and inflammatory responses. In this study, we are going to study the safety of and efficacy of arsenic trioxide combined with cART in 20 HIV-1 infected patients, by observing adverse events,HIV-1 reservoir, HIV-1 load, and some immune index.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The control arm includes HIV-infected patients with the therapy of Antiretroviral drugs.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Effect of Arsenic Trioxide on Eliminating HIV-1 Reservoir Combined With cART
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: Arsenic trioxide combined with cART
Receiving intravenous arsenic trioxide, 0.16mg/kg/day, no more than 10 mg per-day , two to four weeks, combined with continuous cART after attaining plasma HIV-1 suppression (plasma HIV RNA <50 cp/ml) and CD4+ cell count more than 350 cells/ul over 1 year by cART, without active HCV or HBV infection or opportunistic infections.
 Drug: Arsenic Trioxide
a arsenic class of mineral, clinically approved for treating acute promyelocytic leukemia
Other Name: Arsenic Trioxide Injectable Solution
No Intervention: Without arsenic trioxide therapy
Only receiving cART without arsenic Trioxide after attaining plasma HIV-1 suppression (plasma HIV RNA <50 cp/ml) and CD4+ cell count more than 350 cells/ul over 1 year by cART, without active HCV or HBV infection or opportunistic infections.
Outcome Measures
Primary Outcome Measures :
  1. Incidence of treatment-emergent adverse events of arsenic trioxide combined with cART [ Time Frame: 6 Months ]
    To observe the adverse events of arsenic trioxide combined with cART when treating with HIV-infected patients during the clinical trial


Secondary Outcome Measures :
  1. HIV-1 reservoir [ Time Frame: 6 Months ]
    To assay the HIV-1 viral load in the peripheral blood Mono-nuclear cells and plasma


Other Outcome Measures:
  1. HIV-specific immunity [ Time Frame: 6 Months ]
    The number of HIV-specific CD4,CD8 and their activity after receiving arsenic trioxide


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. HIV infection confirmed
  2. Receiving HAART more than 12 months.
  3. HIV viral-load < 50 copies/ml and CD4+ cell count more than 350 cells/ul.
  4. Without serious heart, lung, liver or kidney disease.
  5. Participants know about the study and sign informed consent.

Exclusion Criteria:

  1. With serious active HBV or HCV infection or opportunistic infections
  2. With serious chronic disease such as diabetes, mental illness,et al
  3. History of suffering from pancreatitis during HAART.
  4. Pregnant or breast-fed.
  5. With poor adherence.
  6. Unable to complete the follow up.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Linghua Li, Doctor 020-83710825 llheliza@126.com
Contact: Weiping Cai, Bachelor 020-83710816 gz8hcwp@126.com

Locations
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China, Guangdong
Guangzhou 8th People's Hospital Recruiting
Guangzhou, Guangdong, China, 510060
Contact: Linghua LI, PhD    020-83710825    llheliza@126.com   
Contact: C         
Sponsors and Collaborators
Guangzhou 8th People's Hospital
Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences
Investigators
Layout table for investigator information
Study Chair: Weiping Cai, Bachelor Guangzhou 8th People's Hospital
Tracking Information
First Submitted Date  ICMJE June 7, 2019
First Posted Date  ICMJE June 10, 2019
Last Update Posted Date June 10, 2019
Actual Study Start Date  ICMJE April 1, 2019
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 7, 2019) 		Incidence of treatment-emergent adverse events of arsenic trioxide combined with cART [ Time Frame: 6 Months ]
To observe the adverse events of arsenic trioxide combined with cART when treating with HIV-infected patients during the clinical trial
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2019) 		HIV-1 reservoir [ Time Frame: 6 Months ]
To assay the HIV-1 viral load in the peripheral blood Mono-nuclear cells and plasma
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 7, 2019) 		HIV-specific immunity [ Time Frame: 6 Months ]
The number of HIV-specific CD4,CD8 and their activity after receiving arsenic trioxide
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE The Effect of Arsenic Trioxide on Eliminating HIV-1 Reservoir Combined With cART
Official Title  ICMJE The Effect of Arsenic Trioxide on Eliminating HIV-1 Reservoir Combined With cART
Brief Summary To evaluate the safety and efficacy of arsenic trioxide combined with cART in eliminating latent HIV-1 reservoir, providing potential strategies for AIDS functional cure.
Detailed Description Although combined antiretroviral therapy (cART) could control human immunodeficiency virus type 1 (HIV-1) infection, the persistence of HIV-1 viral reservoir make it extremely difficult to achieving cure of AIDS. The shock and kill strategy has been extensively practiced. The latency reversing agents (LRAs) could reactivate latent HIV-1 and then the reactivated virus could be eradicated. However, no appropriate activator has been found nor manufactured. Our previous work found that the arsenic trioxide, clinically approved for treating acute promyelocytic leukemia,could efficiently reactivate latent provirus in CD4+T cells from HIV-1 patients and Simian immunodeficiency virus (SIV)-infected macaques, without significant systemic T cell activation and inflammatory responses. In this study, we are going to study the safety of and efficacy of arsenic trioxide combined with cART in 20 HIV-1 infected patients, by observing adverse events,HIV-1 reservoir, HIV-1 load, and some immune index.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
The control arm includes HIV-infected patients with the therapy of Antiretroviral drugs.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HIV/AIDS
Intervention  ICMJE Drug: Arsenic Trioxide
a arsenic class of mineral, clinically approved for treating acute promyelocytic leukemia
Other Name: Arsenic Trioxide Injectable Solution
Study Arms  ICMJE
  • Experimental: Arsenic trioxide combined with cART
    Receiving intravenous arsenic trioxide, 0.16mg/kg/day, no more than 10 mg per-day , two to four weeks, combined with continuous cART after attaining plasma HIV-1 suppression (plasma HIV RNA <50 cp/ml) and CD4+ cell count more than 350 cells/ul over 1 year by cART, without active HCV or HBV infection or opportunistic infections.
    Intervention: Drug: Arsenic Trioxide
  • No Intervention: Without arsenic trioxide therapy
    Only receiving cART without arsenic Trioxide after attaining plasma HIV-1 suppression (plasma HIV RNA <50 cp/ml) and CD4+ cell count more than 350 cells/ul over 1 year by cART, without active HCV or HBV infection or opportunistic infections.
Publications *
  • Liu C, Ma X, Liu B, Chen C, Zhang H. HIV-1 functional cure: will the dream come true? BMC Med. 2015 Nov 20;13:284. doi: 10.1186/s12916-015-0517-y. Review.
  • Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8869-73.
  • Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G, Lai J, McHugh HL, Hao H, Zhang H, Margolick JB, Gurer C, Murphy AJ, Valenzuela DM, Yancopoulos GD, Deeks SG, Strowig T, Kumar P, Siliciano JD, Salzberg SL, Flavell RA, Shan L, Siliciano RF. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015 Jan 15;517(7534):381-5. doi: 10.1038/nature14053. Epub 2015 Jan 7.
  • McCoy LE, Weiss RA. Neutralizing antibodies to HIV-1 induced by immunization. J Exp Med. 2013 Feb 11;210(2):209-23. doi: 10.1084/jem.20121827. Review.
  • Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, Lysenko ES, Bosch RJ, Lai J, Chioma S, Emad F, Abdel-Mohsen M, Hoh R, Hecht F, Hunt P, Somsouk M, Wong J, Johnston R, Siliciano RF, Richman DD, O'Doherty U, Palmer S, Deeks SG, Siliciano JD. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog. 2013 Feb;9(2):e1003174. doi: 10.1371/journal.ppat.1003174. Epub 2013 Feb 14.
  • Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009 Feb 12;360(7):692-8. doi: 10.1056/NEJMoa0802905.
  • Leong YA, Atnerkar A, Yu D. Human Immunodeficiency Virus Playing Hide-and-Seek: Understanding the T(FH) Cell Reservoir and Proposing Strategies to Overcome the Follicle Sanctuary. Front Immunol. 2017 May 31;8:622. doi: 10.3389/fimmu.2017.00622. eCollection 2017. Review.
  • Fellmann C, Gowen BG, Lin PC, Doudna JA, Corn JE. Cornerstones of CRISPR-Cas in drug discovery and therapy. Nat Rev Drug Discov. 2017 Feb;16(2):89-100. doi: 10.1038/nrd.2016.238. Epub 2016 Dec 23. Review.
  • 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. Epub 2003 May 18.
  • Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997 Nov 14;278(5341):1295-300.
  • Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, Lloyd AL, Nowak MA, Fauci AS. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13193-7.
  • Wong JK, Hezareh M, Günthard HF, Havlir DV, Ignacio CC, Spina CA, Richman DD. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997 Nov 14;278(5341):1291-5.
  • Donahue DA, Wainberg MA. Cellular and molecular mechanisms involved in the establishment of HIV-1 latency. Retrovirology. 2013 Feb 1;10:11. doi: 10.1186/1742-4690-10-11. Review.
  • Goulder PJ, Watkins DI. HIV and SIV CTL escape: implications for vaccine design. Nat Rev Immunol. 2004 Aug;4(8):630-40. Review.
  • Goonetilleke N, Liu MK, Salazar-Gonzalez JF, Ferrari G, Giorgi E, Ganusov VV, Keele BF, Learn GH, Turnbull EL, Salazar MG, Weinhold KJ, Moore S; CHAVI Clinical Core B, Letvin N, Haynes BF, Cohen MS, Hraber P, Bhattacharya T, Borrow P, Perelson AS, Hahn BH, Shaw GM, Korber BT, McMichael AJ. The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med. 2009 Jun 8;206(6):1253-72. doi: 10.1084/jem.20090365. Epub 2009 Jun 1.
  • Qiao L, Li Y, Xiong G, Liu X, He S, Tong X, Wu S, Hu H, Wang R, Hu H, Chen L, Zhang L, Wu J, Dai F, Lu C, Xiang Z. Effects of altered catecholamine metabolism on pigmentation and physical properties of sclerotized regions in the silkworm melanism mutant. PLoS One. 2012;7(8):e42968. doi: 10.1371/journal.pone.0042968. Epub 2012 Aug 24.
  • Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. doi: 10.1182/blood-2016-09-736686. Epub 2016 Dec 21.
  • Wang P, Qu X, Wang X, Liu L, Zhu X, Zeng H, Zhu H. As2O3 synergistically reactivate latent HIV-1 by induction of NF-κB. Antiviral Res. 2013 Dec;100(3):688-97.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 7, 2019) 		20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. HIV infection confirmed
  2. Receiving HAART more than 12 months.
  3. HIV viral-load < 50 copies/ml and CD4+ cell count more than 350 cells/ul.
  4. Without serious heart, lung, liver or kidney disease.
  5. Participants know about the study and sign informed consent.

Exclusion Criteria:

  1. With serious active HBV or HCV infection or opportunistic infections
  2. With serious chronic disease such as diabetes, mental illness,et al
  3. History of suffering from pancreatitis during HAART.
  4. Pregnant or breast-fed.
  5. With poor adherence.
  6. Unable to complete the follow up.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Linghua Li, Doctor 020-83710825 llheliza@126.com
Contact: Weiping Cai, Bachelor 020-83710816 gz8hcwp@126.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03980665
Other Study ID Numbers  ICMJE 20170812V1
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Linghua LI, Guangzhou 8th People's Hospital
Study Sponsor  ICMJE Guangzhou 8th People's Hospital
Collaborators  ICMJE Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences
Investigators  ICMJE
Study Chair: Weiping Cai, Bachelor Guangzhou 8th People's Hospital
PRS Account Guangzhou 8th People's Hospital
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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