Efficacy of VHM After Treatment Interruption in Subjects Initiating ART During Acute HIV Infection

NCT02475915 | Completed Phase 1 DMC

• 1 other identifier: SEARCH 019
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute HIV Infection

Keywords

Treatment interruption; Controlling HIV

Outcome Measures

Primary Outcomes (1)

• Proportion of patients with HIV RNA < 50 copies/ml following ART interruption

  24 weeks

Secondary Outcomes (7)

• 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

  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

  34 weeks

• 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

  34 weeks

• To compare markers of HIV persistence measured as total, integrated and 2-LTR circles HIV DNA. Measured as DNA copies/1000000 cells

  34 weeks

• To compare histone acetylation between the VHM + ART and ART only groups Expressed as mean fluorescence intensity

  10 weeks

Study Arms (2)

ART + VHM

EXPERIMENTAL

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; Drug: Hydroxychloroquine; Drug: Maraviroc; Drug: Tenofovir; Drug: Emtricitabine; Drug: Efavirenz; Drug: Darunavir

ART alone

ACTIVE COMPARATOR

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; Drug: Emtricitabine; Drug: Efavirenz; Drug: Darunavir

Interventions

Vorinostat DRUG

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.

Also known as: Zolinza

ART + VHM

Hydroxychloroquine DRUG

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

Also known as: Plaquenil

ART + VHM

Maraviroc DRUG

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

Also known as: Selzentry

ART + VHM

Tenofovir DRUG

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

Also known as: Viread

ART + VHM; ART alone

Emtricitabine DRUG

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

Also known as: Emtriva

ART + VHM; ART alone

Efavirenz DRUG

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

Also known as: Sustiva

ART + VHM; ART alone

Darunavir DRUG

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

Also known as: Prezista

ART + VHM; ART alone

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• SEARCH Research Foundation: lead
• The Thai Red Cross AIDS Research Centre: collaborator
• Cooper Human Systems: collaborator

Study Sites (1)

SEARCH, the Thai Red Cross AIDS Research Centre

Bangkok, 10330, Thailand

Location

Related Publications (15)

• 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.

  PMID: 25503054 BACKGROUND

• 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.

  PMID: 22479485 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.

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• 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.

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• 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, Sekaly 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.

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MeSH Terms

Interventions

Vorinostat; Hydroxychloroquine; Maraviroc; Tenofovir; Emtricitabine; efavirenz; Darunavir

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Organophosphonates; Organophosphorus Compounds; Adenine; Purines; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Sulfonamides; Carbamates; Acids, Acyclic; Sulfones; Sulfur Compounds; Furans

Study Officials

• Somchai Sriplienchan, MD, MPH

  SEARCH Research Foundation

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.Praphan Phanuphak, MD, PhD

Study Record Dates

• First Submitted: June 3, 2015
• First Posted: June 19, 2015
• Study Start: January 1, 2015
• Primary Completion: November 1, 2015
• Study Completion: March 1, 2016
• Last Updated: June 22, 2023

Record last verified: 2023-06

Locations

TH (1)