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

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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Acute HIV Infection

Intervention / Treatment
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* Drug: Vorinostat
* Drug: Hydroxychloroquine
* Drug: Maraviroc
* Drug: Tenofovir
* Drug: Emtricitabine
* Drug: Efavirenz
* Drug: Darunavir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ART + VHM<br>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<br>* 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.<br>* Other names: Zolinza;Drug: Hydroxychloroquine<br>* Hydroxychloroquine is supplied as 200mg tablets and will be administered at week 0 for 10 weeks<br>* Other names: Plaquenil;Drug: Maraviroc<br>* Maraviroc will be administered at 150 to 600mg/ml twice daily depending on the subject's ART regimen at week 0 for 10 weeks<br>* Other names: Selzentry;Drug: Tenofovir<br>* NRTI. Tenofovir will be administered at 300mg 1 X day at week 0 for 10 weeks<br>* Other names: Viread;Drug: Emtricitabine<br>* NRTI. Emtricitabine will be administered at 200mg 1 X day at week 0 for 10 weeks<br>* Other names: Emtriva;Drug: Efavirenz<br>* NNRTI. Efavirenz will be administered at 600 mg 1 X day at week 0 for 10 weeks<br>* Other names: Sustiva;Drug: Darunavir<br>* 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<br>* Other names: Prezista;|
| Active Comparator: ART alone<br>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<br>* NRTI. Tenofovir will be administered at 300mg 1 X day at week 0 for 10 weeks<br>* Other names: Viread;Drug: Emtricitabine<br>* NRTI. Emtricitabine will be administered at 200mg 1 X day at week 0 for 10 weeks<br>* Other names: Emtriva;Drug: Efavirenz<br>* NNRTI. Efavirenz will be administered at 600 mg 1 X day at week 0 for 10 weeks<br>* Other names: Sustiva;Drug: Darunavir<br>* 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<br>* Other names: Prezista;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with HIV RNA < 50 copies/ml following ART interruption |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | HIV expression | 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 | 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 | 34 weeks | 
| To compare histone acetylation between the VHM + ART and ART only groups Expressed as mean fluorescence intensity | Serious Adverse Events | 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 | 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 | 34 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment interruption, Controlling HIV