Acute HIV InfectionPhase 1/2NCT02475915
Efficacy of VHM After Treatment Interruption in Subjects Initiating ART During Acute HIV Infection
A Phase 1/2 study testing Vorinostat, Hydroxychloroquine and Maraviroc in people with Acute HIV Infection, run by SEARCH Research Foundation at 1 site in Thailand.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Acute HIV Infection
- What is being tested?
- Vorinostat, Hydroxychloroquine and Maraviroc
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 1 siteThailand
- Study dates
- Jan 2015to Mar 2016
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
Thailand1 site
SEARCH, the Thai Red Cross AIDS Research Centre
Bangkok, 10330
About this study
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
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.
Read the 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:
- Time to HIV RNA rebound after treatment interruption between VHM +ART versus ART only arms
- To compare the cell-associated HIV RNA (multi-spliced and unspliced) in total CD4+ T cells between the VHM +ART versus ART only arms
- To compare markers of HIV persistence (total and integrated HIV DNA and 2-LTR circles) between the VHM + ART versus ART only arms
- To compare histone acetylation (H3) between the VHM +ART versus ART only arms
- To compare adverse events both related and unrelated to the combination of vorinostat, hydroxychloroquine and maraviroc between arms
- 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:
- A higher proportion of patients with HIV RNA < 50 copies/ml following treatment interruption at the end of the study
- Longer time to HIV RNA rebound following treatment interruption
- Higher cell-associated RNA in total CD4+ T cells at the end of the VHM treatment period
- Lower reservoir size and 2 LTR circles at the end of the VHM treatment period and the end of the study
- Higher histone acetylation at the end of the VHM treatment
- Higher adverse events related to VHM
- Similar rates of acute retroviral syndrome after treatment interruption in subjects experiencing viral rebound
- Conditions
- Acute HIV Infection
- Being tested
- Vorinostat, Hydroxychloroquine, Maraviroc, Tenofovir, Emtricitabine
- Keywords
- Treatment interruption, Controlling HIV
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VorinostatDrug
Also called Zolinza
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 called Plaquenil
Hydroxychloroquine is supplied as 200mg tablets and will be administered at week 0 for 10 weeks
MaravirocDrug
Also called Selzentry
Maraviroc will be administered at 150 to 600mg/ml twice daily depending on the subject's ART regimen at week 0 for 10 weeks
TenofovirDrug
Also called Viread
NRTI. Tenofovir will be administered at 300mg 1 X day at week 0 for 10 weeks
EmtricitabineDrug
Also called Emtriva
NRTI. Emtricitabine will be administered at 200mg 1 X day at week 0 for 10 weeks
EfavirenzDrug
Also called Sustiva
NNRTI. Efavirenz will be administered at 600 mg 1 X day at week 0 for 10 weeks
DarunavirDrug
Also called Prezista
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
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Tenofovir; Drug: Emtricitabine; Drug: Efavirenz; Drug: Darunavir |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of patients with HIV RNA < 50 copies/ml following ART interruption
Measured: 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
Measured: 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
HIV expression
Measured: 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
HIV expression
Measured: 34 weeks
To compare markers of HIV persistence measured as total, integrated and 2-LTR circles HIV DNA. Measured as DNA copies/1000000 cells
HIV persistence
Measured: 34 weeks
To compare histone acetylation between the VHM + ART and ART only groups Expressed as mean fluorescence intensity
Serious Adverse Events
Measured: 10 weeks
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
Serious Adverse Events
Measured: 34 weeks
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
Acute Retroviral Syndrome
Measured: 34 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jun 2015 (estimated)
- Study startJan 2015
- Primary completionNov 2015
- Study completionMar 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Acute HIV InfectionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- SEARCH Research Foundation
- Sponsor type
- University, hospital or other
- Collaborators
- Thai Red Cross AIDS Research Centre, Cooper Human Systems
- Responsible party
- Principal investigator, Nitiya Chomchey, SEARCH Research Foundation
- Investigators
- Somchai Sriplienchan, MD, MPH, Principal investigator, SEARCH Research Foundation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02475915
- Sponsor's protocol ID
- SEARCH 019
- Status last verified
- Jun 2023
- First submitted
- 3 Jun 2015
- Last updated
- 22 Jun 2023
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
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.
PubMed 25503054Ananworanich 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.
PubMed 22479485Saez-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.
PubMed 23516360Elliott 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, Sekaly 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.
PubMed 25393648Archin 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.
PubMed 22837004Bratland 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.
PubMed 21473790Chomont 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.
PubMed 19543283Abel S, Back DJ, Vourvahis M. Maraviroc: pharmacokinetics and drug interactions. Antivir Ther. 2009;14(5):607-18.
PubMed 19704163Ananworanich J, Hirschel B. Intermittent therapy for the treatment of chronic HIV infection. AIDS. 2007 Jan 11;21(2):123-34. doi: 10.1097/01.aids.0000256414.91105.8e. No abstract available.
PubMed 17197802Paton 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.
PubMed 22820788Piconi 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.
PubMed 21576701Prince 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.
PubMed 19509172Beliakova-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.
PubMed 23221426Lewin 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. No abstract available.
PubMed 23769215Katlama 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.
PubMed 23541541
Study at a glance
From the registry record, last updated by the sponsor on 22 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02475915
- Acronym / sponsor ID
- SEARCH 019
- Conditions
- Acute HIV Infection
- Keywords
- Treatment interruption, Controlling HIV
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- SEARCH Research FoundationUniversity, hospital or other
- Collaborators
- Thai Red Cross AIDS Research Centre, Cooper Human Systems
- Study start
- Jan 2015
- Primary completion
- Nov 2015 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 19 Jun 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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:
- Time to HIV RNA rebound after treatment interruption between VHM +ART versus ART only arms
- To compare the cell-associated HIV RNA (multi-spliced and unspliced) in total CD4+ T cells between the VHM +ART versus ART only arms
- To compare markers of HIV persistence (total and integrated HIV DNA and 2-LTR circles) between the VHM + ART versus ART only arms
- To compare histone acetylation (H3) between the VHM +ART versus ART only arms
- To compare adverse events both related and unrelated to the combination of vorinostat, hydroxychloroquine and maraviroc between arms
- 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:
- A higher proportion of patients with HIV RNA < 50 copies/ml following treatment interruption at the end of the study
- Longer time to HIV RNA rebound following treatment interruption
- Higher cell-associated RNA in total CD4+ T cells at the end of the VHM treatment period
- Lower reservoir size and 2 LTR circles at the end of the VHM treatment period and the end of the study
- Higher histone acetylation at the end of the VHM treatment
- Higher adverse events related to VHM
- Similar rates of acute retroviral syndrome after treatment interruption in subjects experiencing viral rebound
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ART + VHM | Experimental | Drug: Vorinostat, Drug: Hydroxychloroquine, Drug: Maraviroc, Drug: Tenofovir, Drug: Emtricitabine, Drug: Efavirenz, Drug: DarunavirGroup 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. |
| ART alone | Active comparator | Drug: Tenofovir, Drug: Emtricitabine, Drug: Efavirenz, Drug: DarunavirGroup 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. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VorinostatAlso: ZolinzaVorinostat (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. | Drug | ART + VHM |
| HydroxychloroquineAlso: PlaquenilHydroxychloroquine is supplied as 200mg tablets and will be administered at week 0 for 10 weeks | Drug | ART + VHM |
| MaravirocAlso: SelzentryMaraviroc will be administered at 150 to 600mg/ml twice daily depending on the subject's ART regimen at week 0 for 10 weeks | Drug | ART + VHM |
| TenofovirAlso: VireadNRTI. Tenofovir will be administered at 300mg 1 X day at week 0 for 10 weeks | Drug | ART + VHM, ART alone |
| EmtricitabineAlso: EmtrivaNRTI. Emtricitabine will be administered at 200mg 1 X day at week 0 for 10 weeks | Drug | ART + VHM, ART alone |
| EfavirenzAlso: SustivaNNRTI. Efavirenz will be administered at 600 mg 1 X day at week 0 for 10 weeks | Drug | ART + VHM, ART alone |
| DarunavirAlso: PrezistaProtease 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 | Drug | ART + VHM, ART alone |
Primary outcome
Proportion of patients with HIV RNA < 50 copies/ml following ART interruption
Time frame: 24 weeks
7 secondary outcomes
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
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
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
To compare histone acetylation between the VHM + ART and ART only groups Expressed as mean fluorescence intensity
Time frame: 10 weeks
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
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jun 2023.
- Background: PubMed 25503054Schuetz 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.
- Background: PubMed 22479485Ananworanich 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.
- Background: PubMed 23516360Saez-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.
- Background: PubMed 25393648Elliott 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, Sekaly 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.
- Background: PubMed 22837004Archin 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.
- Background: PubMed 21473790Bratland 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.
- Background: PubMed 19543283Chomont 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.
- Background: PubMed 19704163Abel S, Back DJ, Vourvahis M. Maraviroc: pharmacokinetics and drug interactions. Antivir Ther. 2009;14(5):607-18.
- Background: PubMed 17197802Ananworanich J, Hirschel B. Intermittent therapy for the treatment of chronic HIV infection. AIDS. 2007 Jan 11;21(2):123-34. doi: 10.1097/01.aids.0000256414.91105.8e. No abstract available.
- Background: PubMed 22820788Paton 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.
- Background: PubMed 21576701Piconi 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.
- Background: PubMed 19509172Prince 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Somchai Sriplienchan, MD, MPH principal investigator
SEARCH Research Foundation
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Vorinostat, Hydroxychloroquine and Maraviroc in people with Acute HIV Infection, run by SEARCH Research Foundation at 1 site in Thailand.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Thailand. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of patients with HIV RNA < 50 copies/ml following ART interruption (time frame: 24 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02475915, which also lists 15 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jun 2023.