PMID- 26986803 OWN - NLM STAT- MEDLINE DCOM- 20161227 LR - 20210606 IS - 2046-4924 (Electronic) IS - 1366-5278 (Print) IS - 1366-5278 (Linking) VI - 20 IP - 21 DP - 2016 Mar TI - 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. PG - 1-158 LID - 10.3310/hta20210 [doi] AB - 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. DESIGN: Open-label, parallel-group, randomised controlled trial. SETTING: Forty-three HIV clinical centres in the UK NHS. PARTICIPANTS: HIV-positive adults taking standard combination ART with a suppressed VL for >/= 6 months. INTERVENTIONS: 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. MAIN OUTCOME MEASURES: 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. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04857074. FUNDING: 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. FAU - Paton, Nicholas I AU - Paton NI AD - Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK. AD - Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. FAU - Stohr, Wolfgang AU - Stohr W AD - Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK. FAU - Oddershede, Lars AU - Oddershede L AD - Danish Centre for Healthcare Improvements, Faculty of Social Sciences and Faculty of Health Sciences, Aalborg University, Aalborg, Denmark. FAU - Arenas-Pinto, Alejandro AU - Arenas-Pinto A AD - Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK. FAU - Walker, Simon AU - Walker S AD - Centre for Health Economics, University of York, York, UK. FAU - Sculpher, Mark AU - Sculpher M AD - Centre for Health Economics, University of York, York, UK. FAU - Dunn, David T AU - Dunn DT AD - Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK. LA - eng SI - ISRCTN/ISRCTN04857074 GR - 06/403/501/DH_/Department of Health/United Kingdom GR - 06/403/90/DH_/Department of Health/United Kingdom GR - HTA/06/403/501/DH_/Department of Health/United Kingdom GR - MC_UU_12023/23/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - Health Technol Assess JT - Health technology assessment (Winchester, England) JID - 9706284 RN - 0 (Anti-Retroviral Agents) RN - 0 (HIV Protease Inhibitors) RN - O3J8G9O825 (Ritonavir) SB - IM CIN - Evid Based Med. 2016 Oct;21(5):184. PMID: 27565944 MH - Adult MH - Anti-Retroviral Agents/adverse effects/*therapeutic use MH - CD4 Lymphocyte Count MH - Drug Resistance, Viral MH - Drug Therapy, Combination MH - HIV/drug effects/isolation & purification MH - HIV Infections/*drug therapy/virology MH - HIV Protease Inhibitors/adverse effects/*therapeutic use MH - Humans MH - Male MH - Middle Aged MH - Quality of Life MH - Ritonavir/adverse effects/*therapeutic use MH - Treatment Outcome MH - United Kingdom MH - Viral Load PMC - PMC4819204 EDAT- 2016/03/18 06:00 MHDA- 2016/12/28 06:00 PMCR- 2016/04/04 CRDT- 2016/03/18 06:00 PHST- 2016/03/18 06:00 [entrez] PHST- 2016/03/18 06:00 [pubmed] PHST- 2016/12/28 06:00 [medline] PHST- 2016/04/04 00:00 [pmc-release] AID - 10.3310/hta20210 [doi] PST - ppublish SO - Health Technol Assess. 2016 Mar;20(21):1-158. doi: 10.3310/hta20210.