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

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)

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