Efficacy of VHM After Treatment Interruption in Subjects Initiating ART During Acute HIV Infection - Full Text View

Purpose

This study is a two-arm prospective 1:1 randomised controlled trial comparing the proportion of patients between:

Group 1: vorinostat/hydroxychloroquine/maraviroc (VHM) co-administered with anti-retroviral therapy (ART) Group 2: ART only who are able to maintain HIV RNA < 50 copies/ml following treatment interruption. Subjects will be recruited from RV254/SEARCH 010, an acute HIV infection cohort conducted by the Thai Red Cross AIDS Research Centre in Bangkok, Thailand. The study will run for a minimum of 34 weeks from screening.

Condition	Intervention	Phase
Acute HIV Infection	Drug: Vorinostat Drug: Hydroxychloroquine Drug: Maraviroc Drug: Tenofovir Drug: Emtricitabine Drug: Efavirenz Drug: Darunavir	Phase 1 Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Randomized Study to Compare the Efficacy of Vorinostat/Hydroxychloroquine/Maraviroc (VHM) in Controlling HIV After Treatment Interruption in Subjects Who Initiated ART During Acute HIV Infection

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS

U.S. FDA Resources

Further study details as provided by Prof.Praphan Phanuphak, MD, PhD, South East Asia Research Collaboration with Hawaii:

Primary Outcome Measures:

Proportion of patients with HIV RNA < 50 copies/ml following ART interruption [ Time Frame: 24 weeks ]

Secondary Outcome Measures:

Time to HIV RNA rebound after treatment interruption between VHM +ART versus ART only arms defined as > 1000 HIV-1 RNA copies/ml on two consecutive plasma samples [ Time Frame: 24 weeks ]
To compare the cell-associated spliced HIV RNA in total CD4+ T cells between the VHM+ ART and ART only arms. Measured as copies multi-spliced RNA/1000000 cells [ Time Frame: 34 weeks ]
HIV expression
To compare the cell-associated unspliced HIV RNA in total CD4+ T cells between the VHM+ ART and ART only arms. Measured as copies unspliced RNA/1000000 18S [ Time Frame: 34 weeks ]
HIV expression
To compare markers of HIV persistence measured as total, integrated and 2-LTR circles HIV DNA. Measured as DNA copies/1000000 cells [ Time Frame: 34 weeks ]
HIV persistence
To compare histone acetylation between the VHM + ART and ART only groups Expressed as mean fluorescence intensity [ Time Frame: 10 weeks ]
Serious Adverse Events
To compare adverse events both related and unrelated to the combination of hydroxychloroquine and maraviroc between arms graded according to NCI Common Terminology for Adverse Events [ Time Frame: 34 weeks ]
Serious Adverse Events
The occurrence and severity of acute retroviral syndrome between arms following treatment interruption using a combination of at least 3 clinical symptoms such as fever, lymphadenopathy and pharyngitis [ Time Frame: 34 weeks ]
Acute Retroviral Syndrome


Enrollment:	15
Study Start Date:	January 2015
Study Completion Date:	March 2016
Primary Completion Date:	November 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: ART + VHM Group 1: Combination Antiretroviral Therapy prescribed at week 0 for a period of 10 weeks. Likely consisting of two NRTI such as tenofovir and emtricitabine and an NNRTI, such as efavirenz. For subjects on NNRTI therapy, a protease inhibitor, such as darunavir will be substituted for the NNRTI 2 weeks prior to treatment interruption. Plus: 3 X 14-day cycles of vorinostat administered at weeks 0, 4 and 8; hydroxychloroquine and maraviroc prescribed at week 0 for a period of 10 weeks.	Drug: Vorinostat Vorinostat (suberoylanilide hydroxamic acid) inhibits histone deacetylases class I and II. Vorinostat is supplied as 100mg capsules and will be administered at 400mg/ day in 2 week cycles beginning at week 0 for 10 weeks - 42 doses. Other Name: Zolinza Drug: Hydroxychloroquine Hydroxychloroquine is supplied as 200mg tablets and will be administered at week 0 for 10 weeks Other Name: Plaquenil Drug: Maraviroc Maraviroc will be administered at 150 to 600mg/ml twice daily depending on the subject's ART regimen at week 0 for 10 weeks Other Name: Selzentry Drug: Tenofovir NRTI. Tenofovir will be administered at 300mg 1 X day at week 0 for 10 weeks Other Name: Viread Drug: Emtricitabine NRTI. Emtricitabine will be administered at 200mg 1 X day at week 0 for 10 weeks Other Name: Emtriva Drug: Efavirenz NNRTI. Efavirenz will be administered at 600 mg 1 X day at week 0 for 10 weeks Other Name: Sustiva Drug: Darunavir Protease Inhibitor. Darunavir will be administered at a dose of 900mg 1 X day for subjects on NNRTI based ART beginning at week 8 until week 10 Other Name: Prezista
Active Comparator: ART alone Group 2: Combination Antiretroviral Therapy prescribed at week 0 for a period of 10 weeks. Likely consisting of two NRTI such as tenofovir and emtricitabine and either an NNRTI, such as efavirenz. For subjects on NNRTI therapy, a protease inhibitor, such as darunavir will be substituted for the NNRTI 2 weeks prior to treatment interruption.	Drug: Tenofovir NRTI. Tenofovir will be administered at 300mg 1 X day at week 0 for 10 weeks Other Name: Viread Drug: Emtricitabine NRTI. Emtricitabine will be administered at 200mg 1 X day at week 0 for 10 weeks Other Name: Emtriva Drug: Efavirenz NNRTI. Efavirenz will be administered at 600 mg 1 X day at week 0 for 10 weeks Other Name: Sustiva Drug: Darunavir Protease Inhibitor. Darunavir will be administered at a dose of 900mg 1 X day for subjects on NNRTI based ART beginning at week 8 until week 10 Other Name: Prezista

Arms

Assigned Interventions

Experimental: ART + VHM

Group 1: Combination Antiretroviral Therapy prescribed at week 0 for a period of 10 weeks. Likely consisting of two NRTI such as tenofovir and emtricitabine and an NNRTI, such as efavirenz. For subjects on NNRTI therapy, a protease inhibitor, such as darunavir will be substituted for the NNRTI 2 weeks prior to treatment interruption.

Plus: 3 X 14-day cycles of vorinostat administered at weeks 0, 4 and 8; hydroxychloroquine and maraviroc prescribed at week 0 for a period of 10 weeks.

Drug: Vorinostat

Vorinostat (suberoylanilide hydroxamic acid) inhibits histone deacetylases class I and II. Vorinostat is supplied as 100mg capsules and will be administered at 400mg/ day in 2 week cycles beginning at week 0 for 10 weeks - 42 doses.

Other Name: Zolinza

Drug: Hydroxychloroquine

Hydroxychloroquine is supplied as 200mg tablets and will be administered at week 0 for 10 weeks

Other Name: Plaquenil

Drug: Maraviroc

Maraviroc will be administered at 150 to 600mg/ml twice daily depending on the subject's ART regimen at week 0 for 10 weeks

Other Name: Selzentry

Drug: Tenofovir

NRTI. Tenofovir will be administered at 300mg 1 X day at week 0 for 10 weeks

Other Name: Viread

Drug: Emtricitabine

NRTI. Emtricitabine will be administered at 200mg 1 X day at week 0 for 10 weeks

Other Name: Emtriva

Drug: Efavirenz

NNRTI. Efavirenz will be administered at 600 mg 1 X day at week 0 for 10 weeks

Other Name: Sustiva

Drug: Darunavir

Protease Inhibitor. Darunavir will be administered at a dose of 900mg 1 X day for subjects on NNRTI based ART beginning at week 8 until week 10

Other Name: Prezista

Active Comparator: ART alone

Group 2: Combination Antiretroviral Therapy prescribed at week 0 for a period of 10 weeks. Likely consisting of two NRTI such as tenofovir and emtricitabine and either an NNRTI, such as efavirenz. For subjects on NNRTI therapy, a protease inhibitor, such as darunavir will be substituted for the NNRTI 2 weeks prior to treatment interruption.

Drug: Tenofovir

NRTI. Tenofovir will be administered at 300mg 1 X day at week 0 for 10 weeks

Other Name: Viread

Drug: Emtricitabine

NRTI. Emtricitabine will be administered at 200mg 1 X day at week 0 for 10 weeks

Other Name: Emtriva

Drug: Efavirenz

NNRTI. Efavirenz will be administered at 600 mg 1 X day at week 0 for 10 weeks

Other Name: Sustiva

Drug: Darunavir

Protease Inhibitor. Darunavir will be administered at a dose of 900mg 1 X day for subjects on NNRTI based ART beginning at week 8 until week 10

Other Name: Prezista

Show Detailed Description

Eligibility


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

Criteria

Inclusion Criteria:

HIV-1 infected adults 18-60 years
Initiated ART during acute HIV infection period, defined serologically as up to a positive but incomplete profile by Western blot and has been on ART for at least 42 weeks
HIV RNA <50 copies/ml within the past 7 months (28 weeks)
CD4 cell count ≥ 450 cells/μl on at least 2 occasions during the past 6 months
Informed consent

Exclusion Criteria:

Any significant medical illness in the past 12 weeks
Any evidence of AIDS-defining opportunistic infection
Current or gastrointestinal disease that may impact absorption of the study drug
ALT or AST >3X upper limit of normal
Hemoglobin, white blood cell counts or platelets ≥ grade 2 by US NIH DAIDS grading system
History of diabetes or fasting glucose >126mg/dl
Documented hepatitis B infection as indicated by the presence of HBsAG
History of clinically significant cardiac disease or clinically significant EKG abnormalities
History of retinal disease
History of malignancy
Females who are pregnant or with a positive urine pregnancy test during screening or women of child bearing potential who are unwilling to use an acceptable method of contraception to avoid pregnancy for 4 weeks before, during the study and 4 weeks after the study

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02475915

Locations


Thailand
SEARCH, the Thai Red Cross AIDS Research Centre
Bangkok, Thailand, 10330

Sponsors and Collaborators

South East Asia Research Collaboration with Hawaii

The Thai Red Cross AIDS Research Centre

Cooper Human Systems

Investigators


Principal Investigator:	Praphan - Phanuphak, MD, PhD	The Thai Red Cross AIDS Research Centre

More Information

Publications:

Schuetz A, Deleage C, Sereti I, Rerknimitr R, Phanuphak N, Phuang-Ngern Y, Estes JD, Sandler NG, Sukhumvittaya S, Marovich M, Jongrakthaitae S, Akapirat S, Fletscher JL, Kroon E, Dewar R, Trichavaroj R, Chomchey N, Douek DC, O Connell RJ, Ngauy V, Robb ML, Phanuphak P, Michael NL, Excler JL, Kim JH, de Souza MS, Ananworanich J; RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups. Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLoS Pathog. 2014 Dec 11;10(12):e1004543. doi: 10.1371/journal.ppat.1004543. eCollection 2014 Dec.

Ananworanich J, Schuetz A, Vandergeeten C, Sereti I, de Souza M, Rerknimitr R, Dewar R, Marovich M, van Griensven F, Sekaly R, Pinyakorn S, Phanuphak N, Trichavaroj R, Rutvisuttinunt W, Chomchey N, Paris R, Peel S, Valcour V, Maldarelli F, Chomont N, Michael N, Phanuphak P, Kim JH; RV254/SEARCH 010 Study Group. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS One. 2012;7(3):e33948. doi: 10.1371/journal.pone.0033948. Epub 2012 Mar 30.

Sáez-Cirión 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.

Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, Smith MZ, Spelman T, McMahon J, Velayudham P, Brown G, Roney J, Watson J, Prince MH, Hoy JF, Chomont N, Fromentin R, Procopio FA, Zeidan J, Palmer S, Odevall L, Johnstone RW, Martin BP, Sinclair E, Deeks SG, Hazuda DJ, Cameron PU, Sékaly RP, Lewin SR. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014 Nov 13;10(10):e1004473. doi: 10.1371/journal.ppat.1004473. eCollection 2014 Oct.

Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5. doi: 10.1038/nature11286. Erratum in: Nature. 2012 Sep 20;489(7416):460.

Bratland A, Dueland S, Hollywood D, Flatmark K, Ree AH. Gastrointestinal toxicity of vorinostat: reanalysis of phase 1 study results with emphasis on dose-volume effects of pelvic radiotherapy. Radiat Oncol. 2011 Apr 8;6:33. doi: 10.1186/1748-717X-6-33.

Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel MR, Ghattas G, Brenchley JM, Schacker TW, Hill BJ, Douek DC, Routy JP, Haddad EK, Sékaly RP. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009 Aug;15(8):893-900. doi: 10.1038/nm.1972. Epub 2009 Jun 21.

Abel S, Back DJ, Vourvahis M. Maraviroc: pharmacokinetics and drug interactions. Antivir Ther. 2009;14(5):607-18. Review.

Ananworanich J, Hirschel B. Intermittent therapy for the treatment of chronic HIV infection. AIDS. 2007 Jan 11;21(2):123-34. Review.

Paton NI, Goodall RL, Dunn DT, Franzen S, Collaco-Moraes Y, Gazzard BG, Williams IG, Fisher MJ, Winston A, Fox J, Orkin C, Herieka EA, Ainsworth JG, Post FA, Wansbrough-Jones M, Kelleher P; Hydroxychloroquine Trial Team. Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: a randomized controlled trial. JAMA. 2012 Jul 25;308(4):353-61. doi: 10.1001/jama.2012.6936.

Piconi S, Parisotto S, Rizzardini G, Passerini S, Terzi R, Argenteri B, Meraviglia P, Capetti A, Biasin M, Trabattoni D, Clerici M. Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders. Blood. 2011 Sep 22;118(12):3263-72. doi: 10.1182/blood-2011-01-329060. Epub 2011 May 16.

Prince HM, Bishton MJ, Harrison SJ. Clinical studies of histone deacetylase inhibitors. Clin Cancer Res. 2009 Jun 15;15(12):3958-69. doi: 10.1158/1078-0432.CCR-08-2785. Epub 2009 Jun 9. Review.

Beliakova-Bethell N, Zhang JX, Singhania A, Lee V, Terry VH, Richman DD, Spina CA, Woelk CH. Suberoylanilide hydroxamic acid induces limited changes in the transcriptome of primary CD4(+) T cells. AIDS. 2013 Jan 2;27(1):29-37. doi: 10.1097/QAD.0b013e32835b3e26.

Lewin SR. A cure for HIV: where we've been, and where we're headed. Lancet. 2013 Jun 15;381(9883):2057-8. doi: 10.1016/S0140-6736(13)61180-0.

Katlama C, Deeks SG, Autran B, Martinez-Picado J, van Lunzen J, Rouzioux C, Miller M, Vella S, Schmitz JE, Ahlers J, Richman DD, Sekaly RP. Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet. 2013 Jun 15;381(9883):2109-17. doi: 10.1016/S0140-6736(13)60104-X. Epub 2013 Mar 29. Review.


Responsible Party:	Prof.Praphan Phanuphak, MD, PhD, South East Asia Research Collaboration with Hawaii
ClinicalTrials.gov Identifier:	NCT02475915 History of Changes
Other Study ID Numbers:	SEARCH 019
Study First Received:	June 3, 2015
Last Updated:	March 29, 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Keywords provided by Prof.Praphan Phanuphak, MD, PhD, South East Asia Research Collaboration with Hawaii:


Treatment interruption Controlling HIV

Additional relevant MeSH terms:


Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Slow Virus Diseases Tenofovir Efavirenz	Emtricitabine Darunavir Maraviroc Hydroxychloroquine Vorinostat HIV Protease Inhibitors Protease Inhibitors Antiviral Agents Anti-Infective Agents Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-Retroviral Agents Anti-HIV Agents

ClinicalTrials.gov processed this record on July 17, 2017