Cardiovascular Risk in HIV Patients Switching From a Boosted Protease Inhibitor (PI) to Dolutegravir (DTG)

Study Overview
=================
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)

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

Conditions
-----------------
HIV

Intervention / Treatment
-----------------
* Drug: Dolutegravir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient volunteers who meet all of the following criteria are eligible for this trial: Is male or female aged over 50, OR aged over 18 years with a Framingham risk score above 10% Has documented HIV-1 infection Has signed the Informed Consent Form voluntarily Is willing to comply with the protocol requirements Has been receiving an ARV regimen containing a boosted PI (darunavir, atazanavir, lopinavir, or fosamprenavir) plus 2NRTIs for >24 weeks Has stable virological suppression (plasma HIV-RNA <50 copies/mL for >24 weeks) 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 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: Infected with HIV-2 Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs Has acute viral hepatitis including, but not limited to, A, B, or C 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. Any investigational drug within 30 days prior to the trial drug administration 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 Any prior evidence of primary viral resistance based on the presence of any major resistance-associated mutation to backbone NRTI 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) Dialysis or renal insufficiency (creatinine clearance < 50ml/min) 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. 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)) Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification If female, currently pregnant or breastfeeding Opportunistic infection within 4 weeks prior to first dose of DTG Clinical decision that a switch of antiretroviral therapy should be immediate 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). 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. History or presence of allergy to the study drug or their components

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Immediate switch<br>Patients will be randomised to switch from a boosted PI to dolutegravir at baseline. | Drug: Dolutegravir<br>* Dolutegravir 50mg once daily<br>* Other names: Tivicay;|
| Active Comparator: Deferred switch<br>Patients will be randomised to switch from a boosted PI to dolutegravir after 48 weeks. | Drug: Dolutegravir<br>* Dolutegravir 50mg once daily<br>* Other names: Tivicay;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological suppression | Maintenance of virological suppression (ie HIV-1 RNA <50 c/ml) after 48 weeks | 48 weeks | 
| Total cholesterol | Change from baseline in total cholesterol at week 48 | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological Suppression | Maintenance of virological suppression (ie HIV-1 RNA <50 c/ml) at week 24 and 96 | 24 - 96 weeks | 
| CD4 count from baseline | Change in CD4 count from baseline to week 24, 48 and 96 | 24 - 96 weeks | 
| Baseline in total cholesterol | Change from baseline in total cholesterol at weeks 24 and 96 | 24 - 96 weeks | 
| Change from baseline to lipid values | Change from baseline to lipid values (LDL, HDL, triglycerides and TC:HDL ratio) and Framingham and DAD scores at weeks 24, 48 and 96 | 24 - 96 weeks | 
| Safety | Safety (clinical and laboratory adverse events) at weeks 24, 48 and 96 | 24 - 96 weeks | 
| Changes in markers of inflammation | Changes in markers of inflammation at baseline, week 48 and week 96 | 48 - 96 weeks | 
| Tolerability | Tolerability (EuroQoL questionnaire) at weeks 24, 48 and 96 | 24 - 96 weeks | 
| Changes in markers of coagulation | Changes in markers of coagulation at baseline, week 48 and week 96 | 48 - 96 weeks | 
| Changes in markers of endothelial dysfunction | Changes in markers of endothelial dysfunction at baseline, week 48 and week 96 | 48 - 96 weeks | 
| Change to arterial stiffness augmentation index at weeks 48 and 96 | Change from baseline to arterial stiffness augmentation index at weeks 48 and 96 | 48 - 96 weeks | 
| Change to average thickness of common carotid artery walls at weeks 48 and 96 | Change from baseline to average thickness of common carotid artery walls at weeks 48 and 96 | 48 - 96 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV