Tripterygium Wilfordii Hook F (TwHF) Treatment for Immune Non-responders With HIV-1 Infection

Study Overview
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Brief Summary
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HIV-1 infection is characterized by progressive depletion of CD4+ T cells that eventually leads to clinically significant immunodeficiency. A chronic generalized immune activation is now being recognized to be the main driving force for T cell depletion, loss of anti-HIV-1 immunity and disease progression during chronic HIV-1 infection. However, it is still unknown whether reducing immune activation will restore CD4 T cell counts and leading to immune reconstitution in chronic HIV infection. Tripterygium Wilfordii Hook F (TwHF) has been demonstrated to decrease immune activation of the host, and can suppress inflammation in human diseases. Here, the investigators propose a hypothesis that TwHF can reduce immune over-activation which subsequently leads to the restoration of CD4 T-cell counts and immune reconstitution in HIV-infected immune non-responders.

Detailed Description
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Although HIV-1 infection is characterized by progressive depletion of CD4+ T cells that eventually leads to clinically significant immunodeficiency, a chronic generalized immune activation is now being recognized to be the main driving force for T cell depletion, loss of anti-HIV-1 immunity and disease progression during chronic HIV-1 infection. In particular, this immune activation has been identified as a disease determinant independent of viral load or cell death in HIV-1 infection. A series of clinical evidences have indicated that activated CD8 T cells may attack body cells infected with viruses. Because of this, CD4 cells infected with HIV are frequently destroyed by CD8 cells. In traditional Chinese medicine, extracts of the roots of the medicinal vine Tripterygium wilfordii Hook F (TwHF) (known in China as lei gong teng or thunder god vine) have shown therapeutic promise in treating autoimmune and inflammatory conditions as well as cancer. In this extracts, three diterpenoids-triptolide, tripdiolide, and triptonide-are the most abundant and account for the immunosuppressive and anti-inflammatory effects observed in both in vitro and in vivo studies. Recently, different extracts of TwHF have been used in Chinese allopathic medicine for the treatment of autoimmune and inflammatory diseases, and small controlled trials reported good responses with TwHF extracts in patients with cadaveric kidney transplants and Crohn disease. In particular, a multicenter, double-blind, active comparator trial of a standardized TwHF extract in patients with active rheumatoid arthritis has shown a 20% improvement in American College of Rheumatology criteria in patients with TwHF than with sulfasalazine. Thus, TwHF may reduce inflammatory responses and promote tissue recovery in human diseases. The purpose of this study is to learn whether and how well TwHF reduces the level of activation of CD8 cells in people infected with HIV. The decreased activation of CD8 cells may lead to a more CD4 T cell restoration and immune reconstitution in HIV infection. This study will also look at how well TwHF is tolerated and its safety in HIV- infected patients. Participants in this study will be randomly assigned to one of two treatment arms: Arm A: Participants will receive 48 weeks of TwHF treatment. Arm B: Participants will receive 48 weeks of placebo Study treatment will be given 20 mg, three times per day for a full 48 weeks. After treatment has started, participants will be asked to come to the clinic on Weeks 4, 8, 12, 16, 24, 36, and 48. At each visit participants will receive enough study treatment to last until the next visit. Each visit will last between 2 and 3 hours. At most visits participants will have a physical exam, answer questions about any medications they are taking and how they are feeling, and have blood drawn for safety to assess CD4/CD8 cell counts and viral load. Some additional blood will also be stored for immunology testing. At some visits participants will be asked questions about their medication and medical history, have pupils dilated, have a hearing test, and have an electrocardiogram (EKG). Some visits will require participants to arrive fasting. Pregnancy tests may also be conducted if the participant is able to become pregnant or if pregnancy is suspected.

Official Title
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Phase 1/2 Study of Tripterygium Wilfordii Hook F (TwHF) Treatment for Evaluation the Efficacy and Safety in Immune Non-responders With HIV-1 Infection

Conditions
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Human Immunodeficiency Virus

Intervention / Treatment
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* Drug: TwHF
* Drug: placebo treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV infected antiretroviral therapy (ART) for at least 24 months prior to study entry and continue within the 12 months after study entry CD4 count less than or equal to 250 cells/mm3 continuously before entry and at screening, obtained within 30 days prior to study entry Viral load less than or equal to 400 copies/mL obtained within 30 days prior to study entry Certain specified laboratory values obtained within 30 days prior to study entry. More information on this criterion can be found in the study protocol. Documentation that pre-entry specimen for the primary immune activation endpoint responses has been obtained No history of CDC category C AIDS-related opportunistic infections Karnofsky performance score greater than or equal to 70 within 30 days prior to study entry Ability and willingness to provide informed consent Exclusion Criteria: Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry Renal insufficiency, defined as serum creatinine greater than 1.5 mg/L, within 30 days prior to study entry History of retinal disease History of neoplasm other than localized squamous cell carcinoma of the skin History of cardiac conduction abnormality or cardiomyopathy. More information on this criterion can be found in the study protocol.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TwHF, lifestyle counseling<br>Participants will receive TwHF (20mg each time, 3 times per day, for 48 weeks) from Day 0 through the Week 48 study visit. | Drug: TwHF<br>* Taken oral, three times per day, at a dose of 20 mg/time for 48 weeks.<br>* Other names: treatment;|
| Placebo Comparator: placebo, Lifestyle<br>Participants will receive placebo treatment (20mg each time, three times per day for 48 weeks) from Day 0 through the Week 48 study visit. | Drug: placebo treatment<br>* Taken oral, three times per day, at a dose of 20 mg/time for 48 weeks.<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the total CD4 T cell counts compared with CD4 T cell counts at baseline |  | At Baseline and at week 4, 8, 12, 24, 36 and 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the CD38 expression on CD8 T cells |  | At Baseline and at week 4, 8, 12, 24, 36 and 48 | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability |  | at baseline and up to week 48 | 
| plasma RNA copies/mL |  | At Entry and at week 12 , 24 and 48 | 
| the ratio of CD4 and CD8 T cells |  | At baseline and at week 4, 8, 12, 24, 36 and 48 | 
| the total cell counts of peripheral CD3 T cells |  | At baseline and at week 4, 8, 12, 24, 36 and 48 | 
| the total cell counts of peripheral CD45RA+CCR7+ naive T cells |  | At baseline and at week 4, 8, 12, 24, 36 and 48 | 
| the cytokine levels of IL-1b in the plasma |  | At entry and at week 12, 24 and 48 | 
| the IL-2-producing T-cell number under stimulation with HIV Gag peptide pool |  | At entry and at week 12, 24 and 48 | 
| the HLA-DR expression on CD8 T cells |  | At Baseline and at week 4, 8, 12, 24, 36 and 48 | 
| the total cell number of peripheral CD8 T cells |  | At baseline and at week 4, 8, 12, 24, 36 and 48 | 
| the total cell counts of peripheral CD45RA+CCR7- central memory T cells |  | At baseline and at week 4, 8, 12, 24, 36 and 48 | 
| the total cell counts of peripheral CD45RA-CCR7- effector memory T cells |  | At baseline and at week 4, 8, 12, 24, 36 and 48 | 
| the cytokine levels of IL-6 in the plasma |  | At entry and at week 12, 24 and 48 | 
| the cytokine levels of TNF-a in the plasma |  | At entry and at week 12, 24 and 48 | 
| the levels of total IgG in the plasma |  | At entry and at week 12, 24 and 48 | 
| the cytokine levels of IFNa in the plasma |  | At entry and at week 12, 24 and 48 | 
| the IFN-g-producing T-cell number under stimulation with HIV Gag peptide pool |  | At entry and at week 12, 24 and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tripterygium wilfordii Hook F (TwHF), HIV, CD4, immune over-activation