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

HIV Seropositivity Clinical Trial

— APACHE  

Official title:

Monitored Antiretroviral Pause in Chronic HIV-Infected Subjects With Long-Lasting Suppressed Viremia (APACHE Study)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03198325
• Other study ID #: APACHE Study
• Status: Completed
• Phase: N/A
• Start date: July 27, 2016
• Est. completion date: April 2018

Study information

• Verified date: February 2024
• Source: IRCCS San Raffaele
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 Additional 30 mL of peripheral blood will be withdrawn at study visits for further virological, and immunological investigations and for bio-banking purposes.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.

Description:

The aim of this proof-of-concept study on adult (>18 and <65 years old), chronically HIV-1 infected individuals with undetectable viremia for ≥10 years, undetectable HIV-DNA, CD4+≥500 cells/µL and no evidence of detectable residual viremia for ≥5 years is to evaluate the frequency of spontaneous control of virus replication after ART pausing for up to 12 months and to identify the virological and immunological markers associated with spontaneous control of viral replication. 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 clinical assessment (study visit) will include: the evaluation of CDC stage, height, weight, systolic and diastolic blood pressure and smoking status, 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, urine analysis]. Additional 30 mL of peripheral blood will be withdrawn at study visits and stored in a biobank for further investigations. 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 will be criteria for ART resumption or any serious non-AIDS clinical event at least potentially related to treatment interruption. 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 (eCRF).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: April 2018
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

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 . Exclusion Criteria:

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.

Related Conditions & MeSH terms

• HIV Seropositivity
• Viremia

Intervention

Other:
• Stop of ART
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.

Locations

Country	Name	City	State
Italy	Ospedale San Raffaele Scientific Institute	Milan

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS San Raffaele

Country where clinical trial is conducted

Italy, 

References & Publications (21)

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. — View Citation

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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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: AIDS. 2016 Sep 10;30(14):2259. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Change in plasma viremia	Change in plasma viremia	1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.
Secondary	Change in plasma HIV-DNA	Change in plasma HIV-DNA	1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.
Secondary	Change in CD4+	Change in CD4+	1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.
Secondary	Change in CD4+/CD8+ ratio	Change in CD4+/CD8+ ratio	1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.
Secondary	Change in virological biomarkers	Change in virological biomarkers prior to ART interruption and/or at ART resumption	1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.
Secondary	Change in immunological biomarkers	Change in immunological biomarkers prior to ART interruption and/or at ART resumption	1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption.