title: The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial: a randomised controlled trial of a protease inhibitor monotherapy strategy for long-term management of human immunodeficiency virus infection.
abstract: BACKGROUND
  Standard-of-care antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection uses a combination of drugs, until now considered essential to minimise treatment failure and development of drug resistance. Protease inhibitors (PIs) are potent with a high genetic barrier to resistance and have the potential for use as monotherapy after viral load (VL) suppression achieved on combination therapy. However, longer-term resistance and toxicity risks are uncertain.
  
  
  OBJECTIVE
  To compare the effectiveness, toxicity profile and cost-effectiveness of PI monotherapy with those of standard-of-care triple therapy in a pragmatic long-term clinical trial.
  
  
  METHODS
  Open-label, parallel-group, randomised controlled trial.
  
  
  METHODS
  Forty-three HIV clinical centres in the UK NHS.
  
  
  METHODS
  HIV-positive adults taking standard combination ART with a suppressed VL for ≥ 6 months.
  
  
  METHODS
  Patients were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected ritonavir-boosted PI monotherapy (PI-mono), with prompt return to combination therapy in the event of VL rebound.
  
  
  METHODS
  The primary outcome was reduction of future drug options, defined as new intermediate-/high-level resistance to one or more drugs to which the patient's virus was considered to be sensitive at trial entry (non-inferiority comparison, 10% margin). Secondary outcomes included confirmed virological rebound, serious drug- or disease-related complications, total grade 3 or 4 adverse events (AEs), neurocognitive function change, cluster of differentiation 4 (CD4) cell count change, change in health-related quality of life, cardiovascular risk change, health-care costs and health economic analysis.
  
  
  RESULTS
  In total, 587 participants were randomised (77% male, 68% white) to OT (n = 291) or PI-mono (n = 296) and followed for a median of 44 months, of whom 2.7% withdrew/were lost to follow-up. One or more episodes of confirmed VL rebound were observed in eight patients (Kaplan-Meier estimate 3.2%) in the OT group and 95 patients (35.0%) in the PI-mono group [absolute risk difference 31.8%, 95% confidence interval (CI) 24.6% to 39.0%; p < 0.001]. PI-mono patients who changed to ART after VL rebound all resuppressed (median 3.5 weeks). The proportions with loss of a future drug option at 3 years were 0.7% in the OT group and 2.1% in the PI-mono group (difference 1.4%, (95% CI -0.4% to 3.4%); non-inferiority demonstrated). There were no significant differences in serious disease complications between groups or in the frequency of grade 3 or 4 clinical AEs (16.8% OT group vs. 22% PI-mono group; absolute risk difference 5.1%, 95% CI -1.3% to 11.5%; p = 0.12). Overall, the PI-mono strategy was shown to be cost-effective compared with OT under most scenarios explored. PI-mono was cost saving because of the large savings in ART drug costs while being no less effective in terms of quality-adjusted life-years in the within-trial analysis and only marginally less effective when extrapolated to lifetime outcomes.
  
  
  CONCLUSIONS
  PI monotherapy, with prompt reintroduction of combination therapy for VL rebound, was non-inferior to combination therapy in preserving future treatment options and is an acceptable and cost-effective alternative for long-term management of HIV infection.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN04857074.
  
  
  BACKGROUND
  This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 21. See the NIHR Journals Library website for further project information.
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK.|Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Paton
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stöhr
authors.affiliation: Danish Centre for Healthcare Improvements, Faculty of Social Sciences and Faculty of Health Sciences, Aalborg University, Aalborg, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Oddershede
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Arenas-Pinto
authors.affiliation: Centre for Health Economics, University of York, York, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Walker
authors.affiliation: Centre for Health Economics, University of York, York, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Sculpher
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Dunn
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D006678:HIV / Q000187:drug effects / Q000302:isolation & purification; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D019438:Ritonavir / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D006113:United Kingdom; D019562:Viral Load
chemical_list: D044966:Anti-Retroviral Agents; D017320:HIV Protease Inhibitors; D019438:Ritonavir