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

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.

Inclusion Criteria:

1. Confirmed HIV-1 infection in adults aged 18 years or older.

2. 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.

3. 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.

4. Two CD4+ T cell counts >350 cells/μl in the six months prior to screening.

Exclusion Criteria:

1. Pre-ART viral load <2000 copies/ml (HIV controllers)

2. 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.

3. Recent hospitalization in the last 90 days.

4. Recent infection in the last 90 days requiring systemic antibiotics.

5. Recent vaccination within the last 8 weeks prior to study scree or any study blood
draw.

6. 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.

7. 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

8. Any renal disease (eGFR < 90 ml/min) or acute nephritis.

9. Screening hemoglobin below 12.5 g/dL.

10. Screening TSH consistent with hypothyroidism.

11. Significant myocardial disease (current myocarditis or reduced left ventricular
ejection fraction below the lower limit of normal) or diagnosed coronary artery
disease.

12. Significant respiratory disease requiring oxygen.

13. Diabetes or current hypothyroidism.

14. 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.

15. Exposure to any immunomodulatory drug (including maraviroc) in the16 weeks prior to
study.

16. Prior or current use of experiment agents used with the intent to perturb the HIV-1
viral reservoir.

17. History of seizures, psychosis, abnormal electroencephalogram or brain damage with
significant persisting neurological deficit

18. Positive test for tuberculosis by either skin test (PPD) or blood interferon-gamma
release assay (QuantiFERON).

19. Significant substance use, which in the opinion of the investigator(s), is likely to
interfere with the conduct of the study.