Clinical trial NCT02098837: Cardiovascular Risk in HIV Patients Switching From a Boosted Protease Inhibitor (PI) to Dolutegravir (DTG)
Official title: An Open Label Study Examining the Efficacy and Cardiovascular Risk of Immediate Versus Deferred Switch From a Boosted PI to Dolutegravir (DTG) in HIV Infected Patients With Stable Virological Suppression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV
Keywords: HIV
Lead sponsor: St Stephens Aids Trust
Sponsor class: OTHER
First posted: 2014-03-28
Enrollment: 415
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to investigate the benefits of switching away from a kind of drug called a boosted protease inhibitor (PI) to a new drug called dolutegravir on patients' cardiovascular health (the health of their hearts). Patients are currently taking two other anti-HIV drugs, called nucleoside reverse transcriptase inhibitors (NRTIs), with their boosted PIs; these NRTIs will not be changed throughout the study. In order to compare the boosted PI and dolutegravir more accurately, half of study participants will be switched to dolutegravir immediately, and the other half will be switched after 48 weeks of continuing on the boosted PI.

Boosted PIs are associated with increased heart and circulation risk so it is hoped that switching from a boosted PI to dolutegravir will improve the health of the patients' hearts. Dolutegravir is a drug for HIV treatment which has been approved for use in HIV patients in the US and Europe. Clinical trials using dolutegravir have found that it is effective at suppressing the HIV virus, and it is at least as effective as the other drugs.

This study will also investigate the safety (in terms of other side effects and the routine blood tests which the investigators ordinarily use to monitor patients' treatment) and monitor effectiveness, patients' viral load and CD4 counts, when patients switch treatment from a boosted PI to dolutegravir. Viral load is the amount of the HIV virus they have in their blood, and CD4 count is a measure of a type of cell that is in their immune system. We also aim to improve patients' cardiovascular health in general by providing them with information on how to live a healthy lifestyle (eg improving their diet, stopping smoking etc).

Detailed description: Study Design: Randomised, non-inferiority strategic trial over 96 weeks with early or delayed switch from an ARV regimen containing a boosted PI plus 2 NRTIs to dolutegravir (DTG) plus 2 NRTIs in patients having achieved complete virological suppression for more than 24 weeks (HIV-1 RNA \<50 c/ml). Patients will be randomised to switch at baseline or at 48 weeks.

Study visits will take place at screening, baseline, weeks 4 (immediate switch group only), 12, 24, 36, 48, 52 (deferred switch group only), 60, 72, 84 and 96, plus a follow up visit 28 days after the last dose of study medication.

Routine investigations will include viral load, CD4, haematology (including haemoglobin, white cell count and differential, platelets), biochemistry (including sodium, potassium, creatinine, albumin, glucose, ALT, ALP, total bilirubin, total cholesterol, HDL, LDL, triglycerides), quality of life questionnaires (EuroQL), urine sample (for haematuria, proteinuria, glycosuria, leukocytes, nitrate \& pregnancy test in WOCBP)

Eligibility criteria: Inclusion Criteria:

* Patient volunteers who meet all of the following criteria are eligible for this trial:

  1. Is male or female aged over 50, OR aged over 18 years with a Framingham risk score above 10%
  2. Has documented HIV-1 infection
  3. Has signed the Informed Consent Form voluntarily
  4. Is willing to comply with the protocol requirements
  5. Has been receiving an ARV regimen containing a boosted PI (darunavir, atazanavir, lopinavir, or fosamprenavir) plus 2NRTIs for \>24 weeks
  6. Has stable virological suppression (plasma HIV-RNA \<50 copies/mL for \>24 weeks)
  7. If female and of childbearing potential, is using effective birth control methods and is willing to continue practising these birth control methods during the trial and for at least 2 weeks after the last dose of study medication. Note: Non-childbearing potential is defined as either post-menopausal (12 months of spontaneous amenorrhoea and ≥45 years) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy
  8. If a heterosexually active male, he is using effective birth control methods and is willing to continue practising these birth control methods during the trial and until follow-up visit

Exclusion Criteria:

* Patients meeting 1 or more of the following criteria cannot be selected:

  1. Infected with HIV-2
  2. Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs
  3. Has acute viral hepatitis including, but not limited to, A, B, or C
  4. Has chronic hepatitis B and/or C with AST and/or ALT \>5 x ULN Note: Subjects can enter trial with chronic HBV if HBV-DNA undetectable at screen (and no detectable result in last 6 months) and with chronic HCV if not expected to require treatment during the trial period.
  5. Any investigational drug within 30 days prior to the trial drug administration
  6. History of exposure to any ARVs other than PIs or NRTIs except if switch was for tolerability/toxicity (NOTE: patients who have previously taken part in single drug trials for less than 14 days need not be excluded, or for virological failure with a genotypic resistance test without mutations
  7. Any prior evidence of primary viral resistance based on the presence of any major resistance-associated mutation to backbone NRTI
  8. History of prior virological failure,eg 2 consecutive HIV-1 RNA \>50 c/ml -at or after week 32 following first ART initiation or confirmed rebound viraemia \>200 copies/ml after having a VL of \<50 copies/ml without resistance test or with significant mutations to any other ARV regimen (NOTE: Switch for toxicity or tolerability with wild type virus does not count as virological failure)
  9. Dialysis or renal insufficiency (creatinine clearance \< 50ml/min)
  10. History of decompensated liver disease (AST or ALT≥5x the upper limit of normal (ULN) or ALT ≥ )3 x ULN and bilirubin ≥ 1.5 x ULN with \> 35% direct bilirubin.
  11. Unstable liver disease (as defined by the presence of ascities, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), know biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones))
  12. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification
  13. If female, currently pregnant or breastfeeding
  14. Opportunistic infection within 4 weeks prior to first dose of DTG
  15. Clinical decision that a switch of antiretroviral therapy should be immediate
  16. Screening blood result with any grade 3/4 toxicity according to Division of AIDS (DAIDS) grading scale, except: asymptomatic grade 3 glucose, amylase or lipid elevation or asymptomatic grade 4 triglyceride elevation (re-test allowed).
  17. Any condition (including illicit drug use or alcohol abuse) or laboratory results which, in the investigator's opinion, interfere with assessments or completion of the trial.
  18. History or presence of allergy to the study drug or their components

Primary outcomes:
measure: Virological suppression
timeFrame: 48 weeks
measure: Total cholesterol
timeFrame: 48 weeks
Secondary outcomes:
measure: Virological Suppression
timeFrame: 24 - 96 weeks
measure: CD4 count from baseline
timeFrame: 24 - 96 weeks
measure: Baseline in total cholesterol
timeFrame: 24 - 96 weeks
measure: Change from baseline to lipid values
timeFrame: 24 - 96 weeks
measure: Safety
timeFrame: 24 - 96 weeks
measure: Changes in markers of inflammation
timeFrame: 48 - 96 weeks
measure: Tolerability
timeFrame: 24 - 96 weeks
measure: Changes in markers of coagulation
timeFrame: 48 - 96 weeks
measure: Changes in markers of endothelial dysfunction
timeFrame: 48 - 96 weeks
measure: Change to arterial stiffness augmentation index at weeks 48 and 96
timeFrame: 48 - 96 weeks
measure: Change to average thickness of common carotid artery walls at weeks 48 and 96
timeFrame: 48 - 96 weeks
Other outcomes:
Locations:
city: Antwerp
country: Belgium
facility: Insititute Of Tropical Medicine Antwerp
city: Brussels
country: Belgium
facility: CHU Saint-Pierre
city: Gent
country: Belgium
facility: Universitaire Ziekenhuis Gent
city: Lyon
country: France
facility: Hopital de la Croix Rousse
city: Nantes
country: France
facility: Service des Maladies Infectieuses et Tropicales du CHU de NANTES
city: Paris
country: France
facility: Hopital Saint Louis
city: Paris
country: France
facility: Pitié-Salpêtrière Hospital
city: Paris
country: France
facility: Hospital Bichat Claude-Bernard
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der Goethe-Universität Frankfurt
city: Hamburg
country: Germany
facility: ICH Infektiologisches Centrum Hamburg
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Firenze
country: Italy
facility: Santa Maria Annunziata di Firenze
city: Milan
country: Italy
facility: San Paolo Hospital
city: Milan
country: Italy
facility: Azienda Ospedaliera - Polo Universitario 'Luigi Sacco'
city: Modena
country: Italy
facility: Universitaria di Modena
city: Alicante
country: Spain
facility: Universitario Alicante
city: Alicante
country: Spain
facility: Hospital General Universitario de Elche
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Barcelona
country: Spain
facility: Universitari de Bellvitge
city: Barcelona
country: Spain
facility: IrsiCaixa
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Brighton
country: United Kingdom
facility: Elton John Centre
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: London
country: United Kingdom
facility: Bart's Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: St Thomas Hospital
city: London
country: United Kingdom
facility: Chelsea & Westminster Hospital
city: London
country: United Kingdom
facility: St Mary's Hospital
city: London
country: United Kingdom
facility: Mortimer Market Centre
Study officials:
affiliation: Spanish healthcare system
name: Jose Gatell, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Saumoy M, Sanchez-Quesada JL, Assoumou L, Gatell JM, Gonzalez-Cordon A, Guaraldi G, Domingo P, Giacomelli A, Connault J, Katlama C, Masia M, Ordonez-Llanos J, Pozniak A, Martinez E, Podzamczer D. Atherogenicity of low-density lipoproteins after switching from a protease inhibitor to dolutegravir: a substudy of the NEAT022 study. J Antimicrob Chemother. 2022 Jun 29;77(7):1980-1988. doi: 10.1093/jac/dkac117.
citation: Gatell JM, Assoumou L, Moyle G, Waters L, Johnson M, Domingo P, Fox J, Martinez E, Stellbrink HJ, Guaraldi G, Masia M, Gompels M, De Wit S, Florence E, Esser S, Raffi F, Stephan C, Rockstroh J, Giacomelli A, Vera J, Bernardino JI, Winston A, Saumoy M, Gras J, Katlama C, Pozniak AL; European Network for AIDS Treatment 022 (NEAT022) Study Group. Immediate Versus Deferred Switching From a Boosted Protease Inhibitor-based Regimen to a Dolutegravir-based Regimen in Virologically Suppressed Patients With High Cardiovascular Risk or Age >/=50 Years: Final 96-Week Results of the NEAT022 Study. Clin Infect Dis. 2019 Feb 1;68(4):597-606. doi: 10.1093/cid/ciy505.