Immunologic Response to Kansui in Treated HIV+ Individuals: a Dose Escalation Study

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the safety and bioactivity of an herbal supplement called kansui, which contains several active ingredients such as ingenols that may have a role in helping clear HIV from the body. Kansui has been used in traditional Chinese medicine for centuries to treat various ailments such as for eliminating excess fluid in the abdomen or lungs, loosening phlegm from the chest, and relieving constipation. Based on preliminary in vitro data from our group, kansui extract powder is a potent activator of HIV transpcription in latently infected Jurkat cells. The investigators' hypothesis is that kansui extract powder prepared as tea will be safe and well-tolerated, elicit an in vivo immunologic response, and at the doses administered, increase HIV transcription in latently-infected cells among HIV-infected patients on suppressive antiretroviral therapy.

Detailed Description
-----------------
Millions HIV-infected individuals are now receiving life-saving antiretroviral therapy (ART). However, mortality remains high, particularly in resource-limited countries. Chronic HIV-infected individuals demonstrate evidence of persistent immune activation despite ART, which is an independent predictor of mortality in this setting. Given the current absence of an effective HIV vaccine, finding a cure for HIV will have a large impact on the long-term health of treated HIV-infected individuals. The key challenge of HIV eradication strategies is the persistence of a small pool of resting memory CD4+ T cells that harbor latent replication-competent HIV, untouched by current ART. One potential strategy to eliminate this reservoir in a shock and kill approach in which latency reactivating agents (LRAs) are used to shock the virus out of these cells in order for the host immune response, ART, and/or additional immunomodulatory agents to then kill the virus-expressing cells. The goal of the current study is to evaluate the safety and in vivo biological response to an herbal supplement used in traditional Chinese medicine (kansui) that has potent in vitro latency reactivating capabilities. Kansui is an inexpensive, readily available herbal supplement prescribed for thousands of years in traditional Chinese medicine and contains active compounds such as ingenols that have been shown to reverse latency in an animal model. A semi-synthetic form of ingenol has been shown to potently reactivate latent simian immunodeficiency virus (SIV) in rhesus macaques and is currently undergoing early drug development. Though kansui has been studied extensively in traditional Chinese medicine, this herbal supplement has never been evaluated for biologic activity in HIV disease using Western scientific research methods. This pilot clinical trial will generate preliminary results regarding the safety and in vivo biologic activity of kansui. Promising results from this study may allow future larger studies which can evaluate the efficacy of this non-pharmacologic agent in the treatment of HIV disease.

Official Title
-----------------
Immunologic Response to Euphorbia Kansui Extract Powder Prepared as Tea in HIV-infected Antiretroviral Therapy (ART)-Suppressed Individuals: a Dose Escalation Study

Conditions
-----------------
HIV, Human Immunodeficiency Virus

Intervention / Treatment
-----------------
* Drug: Euphorbia kansui extract powder prepared as tea


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed HIV-1 infection in adults aged 18 years or older. Continuous therapy with a DHHS recommended/alternative combination ART for least 36 months (at least 3 agents) at study entry with no regimen changes in the preceding 24 weeks. Maintenance of undetectable plasma HIV-1 RNA (<40 copies/ml) for at least 36 months. Episodes of single HIV plasma RNA 50-500 copies.ml will not exclude participation if subsequent HIV plasma RNA is <40 copies/ml. Two CD4+ T cell counts >350 cells/μl in the six months prior to screening. Exclusion Criteria: Pre-ART viral load <2000 copies/ml (HIV controllers) Based on prior history and/or virologic testing, no alternative ART regimens are available in the event that the current ART regimen is compromised as a result of this study. Recent hospitalization in the last 90 days. Recent infection in the last 90 days requiring systemic antibiotics. Recent vaccination within the last 8 weeks prior to study scree or any study blood draw. Any known history of liver-related diseases including but not limited to: hepatic cirrhosis of decompensated chronic liver diseases; clinically active hepatitis B or C infection as evidenced by clinical jaundice or Grade 2 or higher liver function test abnormalities; any hepatic impairment, regardless of the graded liver function test abnormalities. Any known history of gastrointestinal diseases including but not limited to: history of diarrheal illness requiring the use of anti-motility agents including inflammatory bowel disease, chronic diarrhea not otherwise specified; history of gastrointestinal bleeding with hemoglobin below 12.5 g/dL; history of gastric or duodenal ulcers; inflammatory gastrointestinal disease such as Crohn's disease or ulcerative colitis Any renal disease (eGFR < 90 ml/min) or acute nephritis. Screening hemoglobin below 12.5 g/dL. Screening TSH consistent with hypothyroidism. Significant myocardial disease (current myocarditis or reduced left ventricular ejection fraction below the lower limit of normal) or diagnosed coronary artery disease. Significant respiratory disease requiring oxygen. Diabetes or current hypothyroidism. Participants of reproductive potential or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test at screening. All participants of childbearing potential must agree to use a double-barrier method of contraception throughout the study period and up to 90 days after the last dose of kansui. Exposure to any immunomodulatory drug (including maraviroc) in the16 weeks prior to study. Prior or current use of experiment agents used with the intent to perturb the HIV-1 viral reservoir. History of seizures, psychosis, abnormal electroencephalogram or brain damage with significant persisting neurological deficit Positive test for tuberculosis by either skin test (PPD) or blood interferon-gamma release assay (QuantiFERON). Significant substance use, which in the opinion of the investigator(s), is likely to interfere with the conduct of the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Kansui 1g per day x 1 day<br>Study participants will be given 1 g of Euphorbia kansui extract powder prepared as tea for a total of 1 daily dose. | Drug: Euphorbia kansui extract powder prepared as tea<br>* 1 g of Euphorbia kansui extract powder, measured and reconstituted in 4 fluid ounces of boiled water allowed to cool and administered as tea, taken by mouth daily<br>* Other names: Kansui;|
| Experimental: Kansui 1g per day x 2 days<br>Study participants will be given 1 g of Euphorbia kansui extract powder prepared as tea for a total of 2 consecutive daily doses. | Drug: Euphorbia kansui extract powder prepared as tea<br>* 1 g of Euphorbia kansui extract powder, measured and reconstituted in 4 fluid ounces of boiled water allowed to cool and administered as tea, taken by mouth daily<br>* Other names: Kansui;|
| Experimental: Kansui 1g per day x 3 days<br>Study participants will be given 1 g of Euphorbia kansui extract powder prepared as tea for a total of 3 consecutive daily doses. | Drug: Euphorbia kansui extract powder prepared as tea<br>* 1 g of Euphorbia kansui extract powder, measured and reconstituted in 4 fluid ounces of boiled water allowed to cool and administered as tea, taken by mouth daily<br>* Other names: Kansui;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Euphorbia kansui extract powder prepared as tea assessed by the number of grade 2 or higher severity adverse events or drug-related laboratory abnormalities that exceed a frequency of 5% | The number of grade 2 or higher severity adverse events (AEs) or drug-related laboratory abnormalities that exceed a frequency of 5% over a 31 day study period. | 31 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early T cell immune activation (%CD69+ CD4+ and CD8+ T cells) | The change in early immune activation levels (as measured by the %CD69+ CD4+ and CD8+ T cells) over a 31 day study period. | 31 days | 
| T cell immune activation (%CD38+HLA-DR+ CD4+ and CD8+ T cells) | The change in immune activation levels (as measured by the %CD38+HLADR+ CD4+ and CD8+ T cells) over a 31 day study period. | 31 days | 
| HIV reservoir size (cell-associated HIV RNA) | The change in HIV reservoir size (as measured by cell-associated HIV RNA levels) over a 31 day study period. | 31 days | 
| HIV reservoir size (plasma HIV RNA) | The change in HIV reservoir size (as measured by ultra-sensitive plasma HIV RNA levels) over a 31 day study period. | 31 days |