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Spironolactone and XPB-1 Integrity in the TFIIH Complex

Enrolling By InvitationNA

Sponsor: University of Sao Paulo General Hospital

Conditions: HIV

Interventions: Spironolactone (drug)

Countries: Brazil

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.

Eligibility overview

Sex: ALL

Age: 18 Years to 60 Years

Healthy volunteers: Yes

Study type: INTERVENTIONAL

Eligibility criteria

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.

Locations (1)

São Paulo, São Paulo, Brazil