title: Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations.
abstract: BACKGROUND
  There are contradictory reports regarding the effects of protease inhibitors on the ECG measures of QT and PR interval durations. The effect of interrupting use of protease inhibitors on QT and PR progression is also unknown.
  
  
  METHODS
  This analysis included 3719 participants from the Strategies for Management of Antiretroviral Therapy (SMART) study, of whom 1879 were randomized to receive intermittent antiretroviral therapy (ART) (drug conservation group), whereas the rest received these drugs continuously (viral suppression group). Linear regression analysis was used to compare four ritonavir-boosted protease inhibitor (protease inhibitor/r) regimens [saquinavir (SQV/r), lopinavir (LPV/r), atazanavir (ATV/r), and other protease inhibitor/r], and nonboosted protease inhibitor regimens with nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens for Bazett's (QTcB) and Fredericia's (QTcF) heart rate corrected QT and PR. Changes in QTcB, QTcF, and PR after 12 and 24 months of randomization were compared in the drug conservation group and viral suppression group.
  
  
  RESULTS
  Average levels of QTcB, QTcF, and PR duration at entry were 415, 406, and 158 ms. At study entry, 49% of participants were taking an NNRTI (no protease inhibitor)-based regimen and 31% were prescribed a boosted protease inhibitor, the most common being LPV/r. After adjustment for baseline factors, QTcB and QTcF levels did not vary by boosted protease inhibitor group (P = 0.26 and P = 0.34, respectively). For those given any of the boosted protease inhibitors, QTcB was 1.5 ms lower than the NNRTI group (P = 0.04). Both boosted and nonboosted protease inhibitor-containing regimens were significantly associated (P < 0.01 for each) with longer PR intervals compared to the NNRTI group. After adjustment, the difference between boosted protease inhibitors and the NNRTI group was 5.11 ms (P < 0.01); for nonboosted protease inhibitors, this difference was 3.00 ms (P < 0.01). Following ART interruption, PR duration declined for both the boosted and nonboosted protease inhibitor groups and compared to the viral suppression group, significant changes in PR interval were observed 24 months after ART interruption of boosted protease inhibitors (P < 0.01).
  
  
  CONCLUSIONS
  Different protease inhibitor-based regimens have a similar, minimal effect on QT compared to NNRTI-based regimens. All protease inhibitor-based regimens (boosted and nonboosted) were associated with prolongation of PR, and interruption of protease inhibitor regimens reduced the prolonged PR duration. Further research is needed to confirm the findings of this study and assess the clinical relevance of the differences.
authors.affiliation: Epidemiological Cardiology Research Center, Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston Salem, North Carolina 27104, USA. esoliman@wfubmc.edu
authors.forename: Elsayed Z
authors.initials: EZ
authors.lastname: Soliman
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
authors.forename: Mollie P
authors.initials: MP
authors.lastname: Roediger
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Duprez
authors.forename: Zelalem
authors.initials: Z
authors.lastname: Temesgen
authors.forename: Markus
authors.initials: M
authors.lastname: Bickel
authors.forename: Judith C
authors.initials: JC
authors.lastname: Shlay
authors.forename: Charurut
authors.initials: C
authors.lastname: Somboonwit
authors.forename: Peter
authors.initials: P
authors.lastname: Reiss
authors.forename: James H
authors.initials: JH
authors.lastname: Stein
authors.forename: James D
authors.initials: JD
authors.lastname: Neaton
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015716:Electrocardiography, Ambulatory / Q000379:methods; D005260:Female; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D011480:Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D044966:Anti-Retroviral Agents; D011480:Protease Inhibitors