In vivo clinical and preclinical studies using interventional study designs allow direct testing of novel hypotheses generated in the lab.
DISulfiram for COVID-19 (DISCO) trial (Phase 2 Trial)
The identification of a safe, effective treatment for individuals with early symptomatic COVID-19 that prevents progression to more severe disease would have immediate public health implications. A hallmark of severe COVID-19 disease is immune system dysregulation called "cytokine storm." Multiple studies have reported that patients with severe disease demonstrate elevated levels of pro-inflammatory cytokines early in disease, such as interleukin (IL)-6. Recent data suggests multiple mechanisms by which disulfiram, an FDA-approved drug for the treatment of alcohol dependence disorder with a good safety profile and easy dosing schedule, may act on COVID-19 both as a direct antiviral as well as an indirect anti-inflammatory agent (e.g., via inhibition of the NLRP3 inflammasome and cytokine production). We have previously shown that disulfiram, given at high doses (2000 mg/day), is well-tolerated in HIV-infected individuals. Disulfiram has a short half-life ~7.5 hours with >90% of drug eliminated within 3 days post-dose, allowing quick reversal of any potential adverse effects. For the DISCO trial (https://clinicaltrials.gov/ct2/show/NCT04485130), recent COVID-19+ individuals will be randomized (2:1) to receive either oral disulfiram (1000 mg/day or 2000 mg/day) for 5 consecutive days or placebo to assess the effects of the drug on COVID-19 symptom severity, SARS-CoV-2 viral shedding, and inflammation.
UCSF Immediate ART During Acute HIV Study (Phase IV Trial)
Given the potential individual and public health benefits of immediate antiretroviral therapy (ART) initiation, HIV+ individuals as now being treated as early as possible. The potential for future HIV cure is likely to be greater in these individuals, since the size of the HIV “reservoir” (cells in which HIV persist despite effective ART) is smaller with very early viral suppression. In collaboration with our HIV/AIDS Clinic at the San Francisco General Hospital and the city of San Francisco’s aggressive campaign to identify and immediately treat early HIV+ individuals, we have enrolled over 40 early HIV+ (<90 days of infection) individuals into an ongoing phase IV study providing immediate ART and long-term longitudinal follow-up (https://clinicaltrials.gov/ct2/show/NCT02656511). Biospecimens collected as part of this study will then be leveraged for performing translational experiments that may provide direct insights into the pathophysiology of the earliest stages of acute HIV and the predictors and virologic/immunologic characteristics of a functional cure.
Immunologic Response and Safety of Euphorbia Kansui: A Phase I Clinical Trial
This unique proof-of-concept clinical trial will test the hypothesis that kansui, an herbal supplement commonly used in traditional Chinese medicine, is safe and well tolerated. The experiments of this study will extend in vitro data demonstrating that kansui extract can reactivate virus from latently infected Jurkat cells to a clinical study evaluating the tolerability and biologic effect of kansui in treated HIV-infected human participants. In collaboration with Dr. Adam Spivak at the University of Utah, will test whether kansui extract prepared as tea, given as a single or 3 daily doses will be safe and well tolerated and induce T cell activation and reactivate latent HIV in a phase I randomized, placebo-controlled crossover trial (https://clinicaltrials.gov/ct2/show/NCT02531295).
Short-Term and Long-Term Methamphetamine Exposure on Residual HIV Transcription and Inflammation
The most commonly used illicit stimulant in HIV-infected individuals is methamphetamine (MA), and prior studies demonstrate strong evidence that MA promotes increased HIV transcription as well as immune dysregulation. A challenge in achieving worldwide HIV eradication is targeting specific vulnerable populations who are most likely to benefit from an HIV cure. These individuals may possess poor immune responses as a result of residual viral replication due to suboptimal ART adherence and/or direct immune dysfunction from illicit substance use. Preclinical findings suggest that HIV+ individuals who use MA may experience greater immune dysfunction and face additional challenges for future HIV eradication. This study will enroll HIV+ ART-suppressed individuals with active MA use to participant in a longitudinal cohort study providing lymph node samples as well as enroll HIV+ ART-suppressed individuals with a prior history of non-dependent MA use to enroll in an interventional trial administering FDA-approved oral MA (Desoxyn®) in an inpatient setting (https://clinicaltrials.gov/ct2/show/NCT03825536). Results from this study will identify novel targets for reversing HIV latency, reducing inflammation, and personalizing future therapeutic strategies specific to the population of HIV+ ART-suppressed individuals who use MA.
