Clinical Trials

MainTitle

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

This study has been completed
Sponsor
South East Asia Research Collaboration with Hawaii

Collaborator
The Thai Red Cross AIDS Research Centre
Cooper Human Systems

Information provided by (Responsible Party)
Prof.Praphan Phanuphak, MD, PhD, South East Asia Research Collaboration with Hawaii

ClinicalTrials.gov Identifier
NCT02475915

First received: June 3, 2015
Last updated: March 29, 2016
Last Verified: March 2016
History of Changes
Purpose

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: None (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

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

Detailed Description:

Study site:
This will be a single-center proof-of-concept study in which recruitment and follow-up of volunteers will be done at the Thai Red Cross AIDS Research Centre (TRC-ARC).
Subject Population:
Subjects aged 18-60 years old, who initiated ART during acute HIV infection and have maintained viral suppression (HIV RNA < 50 copies/ml) for at least 28 weeks prior will be asked to enroll in the study. The subjects must have CD4 ≥ 450 cells/µl, and EKG and laboratory values within acceptable ranges.
Sample Size:
Fifteen subjects will be enrolled randomized 2:1 to VHM + ART (N=10) versus ART (N=5) only.
Study Design An exploratory, open label, randomized study of vorinostat/hydroxychloroquine/maraviroc (VHM) + ART versus ART only.
Study Drug Vorinostat will be administered at 400mg orally every 24h for 3 cycles, each of 14 days with an interim rest-period of 14 days between each cycle over a period of 10 weeks. Hydroxychloroquine (HCQ) will be administered at a dose of 200mg 2X/daily during the course of vorinostat administration for 10 weeks. Maraviroc will be administered at 600 mg 2X/daily on the same schedule as HCQ. This dose of maraviroc is based on its concomitant use with efavirenz. Dosing will be adjusted as appropriate should the subject be on an integrase inhibitor or a protease inhibitor instead of efavirenz due to intolerance to the drug or primary non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance. Any standard ART regimen may be used. However, it is expected that the majority of subjects will be on 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTI) [emtricitabine (FTC) and tenofovir (TDF) and 1 NNRTI [efavirenz (EFV)]. ART will be administered at the following doses: FTC, 200mg 1X/day or 3TC, 300mg 1X/day; TDF, 300mg 1X/day and EFV, 600mg 1X/day.
In subjects on NNRTI-based therapy, the NNRTI will be interrupted at week 8 and the rest of the regimens will be interrupted at week 10. In order to prevent NNRTI resistance, protease inhibitor replacement therapy with darunavir (900 mg 1X/day with ritonavir 100 mg 1X/day) will be given between weeks 8 and 10 and maraviroc will be reduced from 1200mg/day to 300mg/day.
Study Duration on Protocol:
A minimum of 34 weeks from treatment initiation. Subjects must have been on ART for a minimum of 42 weeks prior to study entry. Note that some subjects may be enrolled from RV254/SEARCH010 who have already fulfilled the minimum 42-week ART requirement. The VHM treatment will occur over 10 weeks and the follow-up period will be 24 weeks.
Study Design and Methodology:
The study design is a two-arm, open label randomized study. Subjects will be recruited from RV254/SEARCH 010. RV254/SEARCH 010 is an acute HIV infection cohort conducted by the Thai Red Cross AIDS Research Centre in Bangkok, Thailand. Subjects will be followed twice daily for the first 24h following the first treatment administration and then at weeks 1, 2, 4, 5, 6, 8 and 10 and weekly thereafter to week 22, and every 2 weeks thereafter until week 34. Phlebotomy will be performed for clinical hematology, CD4, HIV RNA, ALT, creatinine and lipids and those in the VHM arm will also receive an EKG and eye examination at screening and/or enrollment. Subjects will be monitored weekly following treatment interruption for the following 12 weeks for viral load and every two weeks to week 34 to ensure that there is no viral rebound, defined as 2 consecutive viral load measurements of >1000 copies/ml. ART will be re-initiated and CD4 counts measured in the event of viral rebound.
A smaller proviral reservoir and less diverse viral population occur in early HIV infection relative to chronic infection. Preliminary data from the RV254/SEARCH 010 study indicate that T cell immunity is better preserved in subjects treated with ART during early HIV infection relative to chronic HIV infection.
The investigators hypothesize that subjects treated with ART during early HIV infection and further treated with multiple cycles of the histone deacetylase inhibitor (HDACi), vorinostat, in combination with hydroxychloroquine and maraviroc will lead to activation of the latent reservoir and reduce virus infection of new targets. Furthermore, as subjects were treated with ART early in HIV infection, the T cell response will be capable of eliminating virus activated by the HDACi and result in a reduction of the viral reservoir.
Primary Objective:
To compare the proportion of patients between VHM co-administered withART versus ART only arms who are able to maintain HIV RNA < 50 copies/ml following treatment interruption.

SECONDARY OBJECTIVES

    :
    1. Time to HIV RNA rebound after treatment interruption between VHM +ART versus ART only arms
    2. To compare the cell-associated HIV RNA (multi-spliced and unspliced) in total CD4+ T cells between the VHM +ART versus ART only arms
    3. To compare markers of HIV persistence (total and integrated HIV DNA and 2-LTR circles) between the VHM + ART versus ART only arms
    4. To compare histone acetylation (H3) between the VHM +ART versus ART only arms
    5. To compare adverse events both related and unrelated to the combination of vorinostat, hydroxychloroquine and maraviroc between arms
    6. To compare the occurrence and severity of acute retroviral syndrome between arms following treatment interruption

    Hypotheses: Compared to the ART only arm, the VHM +ART arm will have:
  1. A higher proportion of patients with HIV RNA < 50 copies/ml following treatment interruption at the end of the study
  2. Longer time to HIV RNA rebound following treatment interruption
  3. Higher cell-associated RNA in total CD4+ T cells at the end of the VHM treatment period
  4. Lower reservoir size and 2 LTR circles at the end of the VHM treatment period and the end of the study
  5. Higher histone acetylation at the end of the VHM treatment
  6. Higher adverse events related to VHM
  7. Similar rates of acute retroviral syndrome after treatment interruption in subjects
experiencing viral rebound

Eligibility

Eligibility

Ages Eligible for Study: 18 Years to 60 Years  
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

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

More Information


Responsible Party: Prof.Praphan Phanuphak, MD, PhD, 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    
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
Tenofovir
Emtricitabine
Efavirenz
Darunavir
Maraviroc
Hydroxychloroquine
HIV Protease Inhibitors
Vorinostat
Protease Inhibitors

ClinicalTrials.gov processed this data on October 17, 2019
This information is provided by ClinicalTrials.gov.