A Randomised Trial of Dolutegravir (DTG)-Based Antiretroviral Therapy vs. Standard of Care (SOC) in Children With HIV Infection Starting First-line or Switching to Second-line ART

A new anti-HIV medicine (Dolutegravir) combined with 2 currently used anti-HIV medicines is non-inferior to the standard combination of medicines used in terms of efficacy and better in terms of toxicity.

The ODYSSEY study is an ongoing international randomised trial evaluating dolutegravir based antiretroviral therapy versus standard of care in HIV-infected children aged less than 18 years who are starting first line treatment (ODYSSEY A) or switching to second line treatment (ODYSSEY B). Participants have visits 4 weeks and 12 weeks after randomisation and every 12 weeks subsequent of that. They are followed up for a minimum of 96 weeks. The primary objective of the study is to assess the difference in virological or clinical failure by 96 weeks between children receiving a DTG-based regimen and those on standard of care.

At the end of study visit for the randomised phase, children and carers will be invited to consent to extended follow-up. Children's visit schedules and care will be as per local clinic guidelines. Participants will be followed up until May 2023 in this phase of the trial. The objectives of the extended follow-up are two-fold: 1. to provide safety data for ViiV Healthcare for participants who, in the opinion of the treating physician, continue to derive benefit from dolutegravir and receive dolutegravir from ViiV Healthcare where it is not available through their country's national HIV treatment programme; 2. to monitor long-term safety and effectiveness of dolutegravir versus standard of care.

Eligibility Criteria:
Inclusion Criteria:

ALL PATIENTS:

* Children ≥28 days and \<18 years weighing ≥3kg with confirmed HIV-1 infection
* Parents/carers and children, where applicable, give informed written consent
* Girls aged 12 years or older who have reached menses must have a negative pregnancy test at screening and be willing to adhere to effective methods of contraception if sexually active
* Children with co-infections who need to start ART can be enrolled into ODYSSEY according to local/national guidelines
* Parents/carers and children, where applicable, willing to adhere to a minimum of 96 weeks' follow-up

  * Children weighing 3 to \<14kg must be eligible and willing to participate in the Weight band (WB)-PK1 substudy unless direct enrolment for the child's weight band has opened following the WB-PK1 substudy and/or dosing information has become available from the IMPAACT P1093 DTG dose-finding study.

ADDITIONAL CRITERIA FOR ODYSSEY A:

• Planning to start first-line ART

ADDITIONAL CRITERIA FOR ODYSSEY B:

* Planning to start second-line ART defined as either: (i) switch of at least 2 ART drugs due to treatment failure; or (ii) switch of only the third agent due to treatment failure where drug sensitivity tests show no mutations conferring NRTI resistance
* Treated with only one previous ART regimen. Single drug substitutions for toxicity, simplification, changes in national guidelines or drug availability are allowed
* At least one NRTI with predicted preserved activity available for a background regimen
* In settings where resistance tests are routinely available, at least one new active NRTI from tenofovir disoproxil fumarate, abacavir or zidovudine should have preserved activity based on cumulative results of resistance tests
* In settings where resistance tests are not routinely available, children who are due to switch according to national guidelines should have at least one new NRTI predicted to be available from tenofovir disoproxil fumarate, abacavir or zidovudine
* Viral load ≥ 500 c/ml at screening visit

Exclusion Criteria:

* History or presence of known allergy or contraindications to dolutegravir
* History or presence of known allergy or contraindications to proposed available NRTI backbone or proposed available SOC third agent.
* Alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal, OR ALT ≥3x upper limit of normal and bilirubin ≥2x upper limit of normal
* Patients with severe hepatic impairment or unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
* Anticipated need for Hepatitis C virus (HCV) therapy during the study
* Pregnancy or breastfeeding
* Evidence of lack of susceptibility to integrase inhibitors or more than a 2-week exposure to antiretrovirals of this class