Efavirenz to Dolutegravir Switch in Patients With CNS Toxicity

A Phase IV Open-label, Multi-centre, Randomised, Dual-arm, Pilot Study to Assess the Feasibility of Switching Individuals Receiving Efavirenz With Continuing Central Nervous System (CNS) Toxicity, to Dolutegravir

This is a phase IV, open label, multicentre trial that will be taking place at 4 sites in the United Kingdom (UK). Efavirenz which is taken in combination with Kivexa® or as part of the combination pill, Atripla® is a recommended firstline regimen for the treatment of Human Immunodeficiency Virus-1 (HIV- 1) infection. Treatment against the HIV virus is also referred to as antiretroviral therapy.

Toxicity is the most common reason for modification of firstline therapy. Central Nervous System (CNS) side effects such as difficulty with sleeping & bad dreams are common side effect of Efavirenz based therapy and is one of the most frequent reasons for switching or discontinuing highly active antiretroviral therapy.

Dolutegravir is within a novel class of antiretroviral agents licensed in the UK for the treatment of HIV. In combination with Truvada®, it showed fewer side effects when compared to Efavirenz in other clinical studies, where patients were starting HIV treatment for the first time, or switching from other agents.

The purpose of the study is to investigate the benefits of switching away from Eefavirenz (in combination with Kivexa® or as part of the combination pill, Atripla®) to Dolutegravir in patients with CNS side effects (such as difficulty with sleeping, bad dreams etc).

The main aim of this study is to investigate the benefits of switching from Efavirenz (taken in combination with Kivexa®or as part of the combination pill, Atripla®) in patients with Central Nervous System (CNS) side effects (such as difficulty with sleeping, bad dreams etc). The study aims to investigate the effect of switching Efavirenz to Dolutegravir while continuing Truvada (tenofovir plus emtricitabine, two constituents of Atripla) or Kivexa. Dolutegravir will be the only new component of the combination.

In addition to the aims stated above, the study also aims:

To investigate whether switching to dolutegravir based combination Antiretroviral Therapy (cART) is associated with resolution of CNS toxicity (determined by CNS questionnaire) at 12 weeks post switch To investigate continued virological suppression at levels of <400 and <50 copies/ml in individuals switching to dolutegravircontaining cART at 4 and 12 weeks post switch To investigate changes in cluster of differentiation 4+ (CD4+) cell count in individuals switching to dolutegravircontaining cART over 12 weeks post switch To investigate the safety (laboratory and non CNS adverse events) of switching to dolutegravir based cART over 12 weeks post switch To investigate changes in quality of life in individuals switching to dolutegravir based cART as assessed by Quality of life (EuroQOL) questionnaires over 12 weeks post switch To investigate the impact of switching to dolutegravir based CART on anxiety and depression (as determined by Hospital Anxiety and Depression Score (HADS) over 12 weeks post switch To investigate changes in quality of sleep in individuals switching to dolutegravir based cART as per standardized sleep questionnaire at 4 and 12 weeks post switch To assess the impact of switching to dolutegravir based cART on adherence by standard questionnaire over 12 weeks post switch To investigate changes in neuropsychiatric function in individuals switching to dolutegravir based cART by CogState battery and Instrumental Activities of Daily Life (IADL) questionnaire over 12 weeks post switch To investigate changes in fasting cholesterol and triglycerides in individuals switching to dolutegravir based cART over 12 weekspost switch To investigate Efavirenz (EFV) plasma decay and its impact on Dolutegravir (DTG) concentrations following the switch (Maximum Concentration (Cmax), Minimum Concentration (Cmin), Area Under the concentration-time Curve (AUC) at weeks 1, 2 and 3 post switch) To investigate the association between genetic polymorphisms in drug disposition genes and drug exposure To assess changes in the levels of tryptophan, kynurenine, kynurenine/tryptophan ratio, neopterin, tumour necrosis factorα and interferonγ in plasma following treatment switch from efavirenz to dolutegravir.

To investigate the relationship between the immune activation biomarkers and the kynurenine/tryptophan ratio at baseline and post switch.

To investigate the relationship between the kynurenine/tryptophan ratio and measures of CNS toxicity and neurocognitive impairment at baseline and postswitch.

Inclusion Criteria:

• Is male or female aged 18 years or older
• Has HIV-1 infection documented in their medical notes
• Has signed the Informed Consent Form voluntarily
• Is willing to comply with the protocol requirements
• Is currently on an antiretroviral regimen comprising at least three licensed antiretroviral agents one of which is EFV, for at least 12 weeks
• No previous exposure to integrase inhibitors
• Has an HIV-plasma viral load at screening <400 copies/mL (single re-test allowed)
• Has a CD4 cell count at screening >50 cells/mm3
• Estimated glomerular filtration rate (MDRD) >50 ml/min.
• Has symptomatic CNS related toxicity associated with EFV at least Grade 2 by ACTG criteria
• If female and of childbearing potential, is using effective birth control methods (as agreed by the investigator) and is willing to continue practising these birth control methods during the trial and for at least 30 days after the end of the trial.

Exclusion Criteria:

• Infected with HIV-2
• Using any concomitant therapy disallowed as per SPC for the study drugs
• Has acute viral hepatitis including, but not limited to, A, B, or C
• Subjects positive for Hepatitis B at screening (+HBsAg), or anticipated need for Hepatitis C virus (HCV) therapy during the study
• Alanine aminotransferase (ALT) greater than or equal to 5 times the upper limit of normal (ULN), OR ALT greater than or equal to 3xULN and bilirubin greater than or equal to 1.5xULN (with >35% direct bilirubin)
• Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• Any investigational drug within 30 days prior to the trial drug administration
• Has received dolutegravir in the past
• Any clinical evidence of baseline resistance mutations
• History or presence of allergy to DTG or excipients (D-Mannitol, Microcystalline Cellulose, Povidone, Croscarmellose Sodium, Sodium Stearyl Fumarate, Talc, white film coat)
• Subjects with moderate to severe hepatic impairment (Class B or greater) as determined by Child-Pugh classification
• Moderate or severe renal impairment (creatinine clearance < 50ml/min by Cockroft-Gault method)
• If female, she is pregnant or breastfeeding
• 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 drug/alcohol abuse) or laboratory results which, in the investigator's opinion, interfere with assessments or completion of the trial.