Chidamide in Combination With ART for Reactivation of the Latent HIV-1 Reservoir

Efficacy of the Histone Deacetylase Inhibitor Chidamide in Combination With Antiretroviral Therapy for Reactivation of the Latent HIV-1 Reservoir:a Randomized Controlled Clinical Trial

HIV replication can be effectively suppressed and acquired immunodeficiency syndrome(AIDS) can be prevented with highly active antiretroviral therapy (HAART). However, HIV-infected people must remain on treatment continuously to avoid viral rebound and progression to AIDS. HIV persistence is thought to stem primarily from the presence of integrated copies of the proviral genome within long-lived cells. Because active viral gene expression causes cell death due to viral cytopathic effects and the immune response, long-lived cells likely harbor transcriptionally silent, latent provirus. HIV-1 persistence in long-lived cellular reservoirs remains a major barrier to a cure. HDACi have the potential to activate ("Kick") these latently infected cells. This will make the HIV infected cells visible to the immune system; the immune response and antiretrovirals(ARVs) will be able to attack and eliminate ("Kill") the infected cells. This study is subsequent to our NCT02513901. The purpose of this study is to verify the efficacy of multi-dose Chidamide in combination with antiretroviral therapy in HIV-infected adults with suppressed viral load in a randomized controlled clinical trial.

Study Overview

• Status: Unknown
• Conditions: Chronic HIV Infections
• Intervention / Treatment: Drug: ART plus Chidamide; Drug: ART plus Placebo

Detailed Description

Sixty participants will be recruited and stratified by their CD4 cell count(30 for <500 cells/μL and 30 for ≥500 cells/μL). Each layer was 1:1 randomly divided into Chidamide group or Placebo-controlled group.Chidamide and Placebo will be administrated 10mg each time, twice a week, interval not less than 3 days. Chidamide and Placebo intervention will last 12 consecutive weeks. All participants will keep their antiretroviral therapy during this study.

This study will last for 96 weeks, involving 16 study visits(Screening, Week 0, 2, 4, 8, 12, 14, 16, 20, 24, 36, 48, 60, 72, 84, 96) for every participant. At the screening visit, participants will give a medical history and will undergo a physical exam; blood samples will be collected. If participants agree, their blood samples may be stored for future research.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• China
  • Guangxi
    • Nanning, Guangxi, China
      • The First Affiliated Hospital of Guangxi Medical University
  • Shaanxi
    • Xi'an, Shaanxi, China, 710038
      • Department of Infectious Diseases, Tangdu Hospital, The Fourth Military Medical University
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Zhejiang University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Documented HIV-1 infection
• Currently receiving cART and having received cART for a minimum of 24 months, HIV-1 plasma RNA <20 copies/mL for at least 1.5 year (excluding viral load blips)
• CD4 T cell count >350 cells/mm3
• Able, willing to give written informed consent and to adhere to therapy and to comply with time requirements for study visits and evaluations
• Adequate vascular access for leukapheresis

Exclusion Criteria:

• Acute HIV-1 infection
• Received blood transfusions or hematopoetic growth factors within 3 months receipt of compounds with HDAC inhibitor-like activity, such as valproic acid within the last 1 month. Potential participants may enroll after a 30-day washout period.
• Any significant acute medical illness in the past 8 weeks
• Any evidence of an active AIDS-defining opportunistic infection
• Hepatitis B or C infection as indicated by the presence of Hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA (HCV-RNA) in blood

• Patient has the following laboratory values within 3 weeks before starting the investigational drug

  1. Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN)
  2. Serum total bilirubin ≥1.5 ULN
  3. Serum creatinine levels ≥1.5 x ULN, or calculated creatinine clearance ≤60 ml/min
  4. Platelet count ≤100 x109/L
  5. Absolute neutrophil count ≤1.5x109/L
  6. Serum potassium, magnesium, phosphorus outside normal limits
  7. Total calcium (corrected for serum albumin) or ionized calcium ≤lower normal limits
• A personal history of clinically significant cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for Torsades de pointes (e.g. heart failure)
• History of malignancy or transplantation, including skin cancers or Kaposi sarcoma
• History of diabetes mellitus
• Known hypersensitivity to the components of chidamide or its analogues
• Pregnancy or breast feeding, or expecting to father children within the projected duration of the study
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chidamide; Chidamide will be administrated 10mg each time, twice a week, interval not less than 3 days for 12 weeks.	Drug: ART plus Chidamide; Chidamide will be administrated 10mg each time, twice a week, interval not less than 3 days for 12 weeks.Antiretroviral therapy will be kept during entire study.
Placebo Comparator: Placebo-controlled; Placebo with the same taste and appearance like Chidamide will be administrated 10mg each time, twice a week, interval not less than 3 days for 12 weeks.	Drug: ART plus Placebo; Placebo will be administrated 10mg each time, twice a week, interval not less than 3 days for 12 weeks.Antiretroviral therapy will be kept during entire study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in HIV transcription measured as cell associated HIV-1 RNA (copies per 10E6 PBMCs)	Measured on week 0, 2, 4, 8, 12, 14, 16, 24
Change in HIV production measured as plasma HIV RNA (by Roche COMBAS TaqMan HIV-1 Test version 2.0)	Measured on week 0, 2, 4, 8, 12, 14, 16, 24, 36, 48, 60, 72, 84, 96
Change in HIV-1 reservoir size measured in PBMCs by Total HIV-1 DNA(copies per 10E6 PBMCs)	Measured on week 0, 2, 4, 8, 12, 14, 16, 24, 36, 48, 60, 72, 84, 96

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability evaluation as measured by adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR), serious unexpected adverse reactions (SUSAR)	Measured through 96 weeks
Cell surface markers of immune activation and immune checkpoints and so on	Measured on week 0, 2, 4, 8, 12, 14, 16, 24, 36, 48, 60, 72, 84, 96
Plasma inflammatory biomarkers	Measured on week 0, 4, 8, 12, 16, 24, 48, 72, 96

Collaborators and Investigators

• Sponsor: Tang-Du Hospital
• Collaborators: Zhejiang University; Chipscreen Biosciences, Ltd.; First Affiliated Hospital of Guangxi Medical University

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2016
• Primary Completion (Anticipated): August 1, 2018
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: September 6, 2016
• First Submitted That Met QC Criteria: September 11, 2016
• First Posted (Estimate): September 15, 2016

Study Record Updates

• Last Update Posted (Actual): April 26, 2018
• Last Update Submitted That Met QC Criteria: April 24, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Antiretroviral Therapy; Chidamide; Histone Deacetylase Inhibitor; HIV-1 Reservoir; Chronic HIV infections; HIV Eradication
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: 2016TD-Chidamide RCT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We do not have data share plan because of participants' privacy.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No