HIV
Conditions
Keywords
HIV, Spironolactone, HIV Cure, XPB, Block and Lock
Brief summary
This is a prospective, interventional, exploratory clinical study designed to evaluate the pharmacokinetics, safety, and biological effects of spironolactone on the degradation of the XPB (ERCC3) protein and its potential impact on the HIV reservoir. Spironolactone is an FDA-approved mineralocorticoid receptor antagonist that has recently been shown in preclinical studies to induce rapid and reversible proteolytic degradation of XPB, a key subunit of the transcription factor IIH (TFIIH) complex, which is essential for cellular transcription, DNA repair, and viral replication. The study will enroll adult participants, including both HIV-negative individuals and people living with HIV receiving suppressive antiretroviral therapy with undetectable plasma viral load. Participants will receive oral spironolactone with stepwise dose escalation according to individual tolerability, followed by a post-treatment follow-up period. Primary assessments include evaluation of XPB protein degradation in CD4+ T cells and characterization of the pharmacokinetic profile of spironolactone and its active metabolites. In participants living with HIV, secondary assessments include quantitative and functional measurements of the HIV reservoir. Safety will be monitored throughout the study through clinical evaluations, laboratory testing, and electrocardiographic assessments. This study aims to generate initial clinical evidence supporting the repositioning of spironolactone as a potential component of HIV cure strategies, particularly within a "block-and-lock" approach targeting sustained viral transcriptional silencing.
Detailed description
Detailed Description This study is an exploratory, interventional clinical investigation designed to characterize the biological and pharmacokinetic effects of spironolactone in adult participants, with a particular focus on its ability to induce proteolytic degradation of the XPB (ERCC3) protein and its potential implications for HIV persistence. Scientific Rationale The transcription factor IIH (TFIIH) complex plays a central role in RNA polymerase II-mediated transcription initiation and nucleotide excision repair. XPB (ERCC3), an ATP-dependent 3'-5' DNA helicase and a core subunit of TFIIH, is essential for DNA unwinding during transcription and is also required for efficient replication of several viruses, including HIV. Preclinical studies have demonstrated that spironolactone and its active metabolites induce rapid, reversible proteasomal degradation of XPB without causing generalized cytotoxicity or impairing cellular viability. In models of HIV infection, depletion of XPB has been shown to inhibit Tat-dependent viral transcription, suppress viral replication, and prevent reactivation of latent proviruses in CD4+ T cells. These findings suggest that pharmacological targeting of XPB may represent a novel host-directed strategy to suppress HIV transcription and stabilize viral latency, consistent with a "block-and-lock" approach to HIV cure research. However, the clinical reproducibility of XPB degradation and its relationship with systemic drug exposure in humans remain insufficiently characterized. Study Design Participants will receive oral spironolactone administered once daily using a stepwise dose-escalation strategy based on individual tolerability. The intervention period will be followed by a post-treatment observation phase to assess reversibility of biological effects and safety parameters. Dose adjustments, temporary interruptions, or discontinuation of the study drug will be permitted according to predefined safety criteria. The study includes both HIV-negative individuals and people living with HIV receiving suppressive antiretroviral therapy with sustained plasma viral suppression. This design allows evaluation of XPB degradation in the absence of viral infection as well as assessment of downstream effects on viral persistence in individuals living with HIV. Pharmacokinetic and Pharmacodynamic Assessments Systemic exposure to spironolactone and its major metabolites, including canrenone and thiomethylated derivatives, will be quantified using validated liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters will be derived to characterize drug absorption, metabolism, and elimination during dose escalation and steady-state conditions. Pharmacodynamic effects will be assessed by measuring XPB protein levels in isolated CD4+ T cells obtained from peripheral blood samples. XPB degradation profiles will be correlated with circulating concentrations of spironolactone and its metabolites to explore exposure-response relationships. Evaluation of HIV Reservoir In participants living with HIV, the impact of spironolactone exposure on viral persistence will be evaluated using complementary molecular and functional assays. These include quantification of cell-associated HIV DNA and RNA as markers of infected cell frequency and transcriptional activity, as well as functional assessment of replication-competent virus using viral outgrowth methodologies. These analyses aim to determine whether XPB degradation is associated with modulation of the size or transcriptional activity of the latent HIV reservoir. Safety Monitoring Safety assessments will include regular clinical evaluations, vital signs, laboratory testing with particular attention to electrolyte balance, renal and hepatic function, and electrocardiographic monitoring. Adverse events will be graded and managed according to predefined criteria, and participant safety will be continuously reviewed throughout the study. Exploratory Objectives Exploratory analyses will examine relationships between drug exposure, XPB degradation, and virological parameters, as well as the reversibility of observed biological effects following treatment discontinuation. The results of this study are intended to inform the design of subsequent clinical investigations evaluating spironolactone or related compounds as host-directed agents within HIV cure strategies.
Interventions
Oral spironolactone starting at 50 mg once daily with weekly 50 mg increments up to 400 mg/day as tolerated; dosing schedule per protocol.
Sponsors
University of Sao Paulo General Hospital
The Scripps Research Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Adults aged 18 to 60 years. * Able and willing to provide written informed consent. * For HIV-negative cohort: documented HIV-negative test result at screening. * For HIV-positive cohort: * documented HIV-1 infection; * on stable antiretroviral therapy (ART); .plasma HIV-1 RNA below the limit of detection at screening.
Exclusion criteria
* Pregnancy or breastfeeding. * Known hypersensitivity or contraindication to spironolactone. * Clinically significant baseline electrolyte abnormalities, including hyperkalemia, or conditions that increase the risk of hyperkalemia. * Clinically significant renal dysfunction or hepatic dysfunction that, in the investigator's judgment, increases risk with spironolactone. * History of clinically significant cardiac arrhythmias or screening electrocardiogram findings that contraindicate spironolactone in the investigator's judgment. * Use of aspirin (acetylsalicylic acid) on a continuous basis or recent use prior to screening, or planned use during the study. * Current use of medications or supplements that increase potassium levels or otherwise substantially increase the risk of hyperkalemia, or inability/unwillingness to avoid high-potassium supplements and products during the intervention period. * Use of non-steroidal anti-inflammatory drugs (NSAIDs) or systemic corticosteroids that cannot be discontinued for the duration of study drug administration. * Any condition that, in the investigator's judgment, would interfere with study participation, study procedures, or participant safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| XPB Protein Degradation in CD4+ T Cells | Baseline through up to 4 weeks of spironolactone treatment. | Change in XPB (ERCC3) protein levels in peripheral blood CD4+ T cells following oral administration of spironolactone, assessed by immunoblotting and expressed as relative protein abundance compared with baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration (Cmax) of Spironolactone and Canrenone | Baseline to Week 4 of spironolactone treatment. | Maximum observed plasma concentration (Cmax) of spironolactone and its major active metabolite canrenone, measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). |
| Area Under the Plasma Concentration-Time Curve (AUC) of Spironolactone and Canrenone | Baseline to Week 4 of spironolactone treatment. | Area under the plasma concentration-time curve (AUC) of spironolactone and its major active metabolite canrenone, determined using LC-MS/MS. |
| Elimination Half-Life (t½) of Spironolactone and Canrenone | Baseline to Week 4 of spironolactone treatment. | Terminal elimination half-life (t½) of spironolactone and its major active metabolite canrenone, calculated from plasma concentration-time data obtained by LC-MS/MS. |
| Correlation Between Spironolactone/Canrenone Plasma Concentrations and XPB (ERCC3) Protein Degradation | Baseline to Week 4 of spironolactone treatment. | Association between plasma concentrations of spironolactone and canrenone (ng/mL, measured by LC-MS/MS) and XPB (ERCC3) protein abundance in peripheral blood CD4+ T cells (relative abundance vs baseline, assessed by immunoblotting/Western blot). |
| Cell-Associated HIV-1 DNA Levels in CD4+ T Cells | Baseline to Week 4 of spironolactone treatment. | Change in cell-associated HIV-1 DNA levels in peripheral blood CD4+ T cells, quantified by digital droplet PCR (ddPCR) and expressed as copies per 10⁶ CD4+ T cells, as a measure of the frequency of infected cells in participants living with HIV. |
| Cell-Associated HIV-1 RNA Levels in CD4+ T Cells | Baseline to Week 4 of spironolactone treatment. | Change in cell-associated HIV-1 RNA levels in peripheral blood CD4+ T cells, quantified by digital droplet PCR (ddPCR) and expressed as copies per 10⁶ CD4+ T cells, as a measure of HIV transcriptional activity in participants living with HIV. |
| Replication-Competent HIV Reservoir (QVOA) | Baseline to Week 4 of spironolactone treatment. | Change in the frequency of replication-competent HIV in peripheral blood CD4+ T cells from participants living with HIV, measured by quantitative viral outgrowth assay (QVOA) and expressed as infectious units per million CD4+ T cells (IUPM). |
| Safety and Tolerability of Spironolactone | Baseline through study completion (up to 8 weeks). | Incidence, severity, and relationship to study drug of adverse events, laboratory abnormalities (including serum potassium and renal function), and clinically significant changes in vital signs and electrocardiographic parameters during spironolactone treatment and post-treatment follow-up. |
Countries
Brazil
Contacts
PRINCIPAL_INVESTIGATOREsper G. Kallas, PhD
University of Sao Paulo
Outcome results
None listed