digoxin and HIV-Infections

Heart failure remains a major health problem in the United States, affecting 5.8 million Americans. Its prevalence continues to rise due to the improved survival of patients. Despite advances in treatment, morbidity and mortality remain very high, with a median survival of about 5 years after the first clinical symptoms. This article describes the causes, classification, and management goals of heart failure in Stages A and B.

Topics: Adrenergic beta-Antagonists; Alcohol Drinking; Angiotensin-Converting Enzyme Inhibitors; Cardiac Pacing, Artificial; Cardiotonic Agents; Cardiotoxins; Coronary Artery Disease; Defibrillators, Implantable; Diabetic Cardiomyopathies; Digoxin; Dyslipidemias; Early Diagnosis; Endocrine System Diseases; Heart Failure; HIV Infections; Humans; Hypertension; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Risk Factors; Sedentary Behavior; Sleep Apnea Syndromes; Smoking; Tachycardia

HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation.

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Cells, Cultured; Digoxin; HIV Infections; HIV-1; Humans; Lymphocyte Activation; Virus Integration; Virus Latency

Drug-drug interactions with corticosteroids, causing Cushing's syndrome with secondary adrenal suppression, are well known in HIV patients. Corticosteroids are widely prescribed in the HIV-positive population. However, digoxin is rarely used in HIV patients; hence, digoxin toxicity due to drug-drug interaction is not widely recognised. Nevertheless, this practice might change in the future as HIV cohorts of patients are ageing, due to the successful treatment of HIV infection with combination antiretroviral therapy. We report a case of digoxin toxicity in an HIV-positive 51-year-old man, due to a combination of drug-drug interaction and renal impairment. The first case report of digoxin toxicity due to drug-drug interaction with ritonavir in an HIV-positive woman was published in 2003. To the best of our knowledge, no similar case report has since been published in the literature. This case alerts the profession to the importance of drug-drug interaction and highlights the clinical features of digoxin toxicity.

Topics: Darunavir; Digoxin; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Renal Insufficiency; Ritonavir

In inflammation and infection, cytochrome P450 (CYP) enzyme activities are down-regulated. Information on possible discrepancies in activities of CYP enzymes and drug transporters between HIV-infected patients and healthy people is limited.. We used midazolam, dextromethorphan and digoxin as in vivo phenotyping probes for CYP3A (CYP3A4/5), CYP2D6 and P-glycoprotein activities, respectively, and compared these activities between 12 healthy Caucasian volunteers and 30 treatment-naive HIV-infected patients.. Among the HIV-infected patients, the overall CYP3A activity (apparent oral midazolam clearance) was approximately 50% of the activity observed in healthy volunteers (point estimate 0.490, 90% confidence interval [CI] 0.377-0.638). The CYP2D6 activity (plasma ratio area under the curve [AUC]; AUC(dextromethorphan)/AUC(dextrorphan)) was essentially unchanged (point estimate 1.289, 90% CI 0.778-2.136). P-glycoprotein activity was slightly lower in patients (digoxin maximum concentration point estimate 1.304, 90% CI 1.034-1.644).. The overall CYP3A activity was approximately 50% lower in HIV-infected patients than in healthy volunteers. The CYP2D6 activity was highly variable, but, on average was not different between groups, whereas a marginally lower P-glycoprotein activity was observed in treatment-naive HIV-infected patients.

Topics: Adolescent; Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Case-Control Studies; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Dextromethorphan; Digoxin; Down-Regulation; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Midazolam; Middle Aged; Pyrimidinones; Ritonavir; Young Adult

Topics: Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Atrial Fibrillation; Cardiotonic Agents; Contraindications; Digoxin; Drug Interactions; Female; HIV Infections; Humans; Kidney; Middle Aged; Ritonavir

Topics: Cardiotonic Agents; Digoxin; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Female; HIV Infections; Humans; Middle Aged