ODYSSEY (PENTA 20)

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.

Study Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Drug: Dolutegravir; Drug: Standard of Care

Detailed Description

The ODYSSEY study was an international randomised trial evaluating dolutegravir based antiretroviral therapy (ART) versus standard of care in HIV-infected children aged less than 18 years who were starting first line treatment (ODYSSEY A) or switching to second line treatment (ODYSSEY B). Participants had visits 4 weeks and 12 weeks after randomisation and every 12 weeks subsequent of that. They were followed up for a minimum of 96 weeks. The primary objective of the study was 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 were invited to consent to extended follow-up. Children's visit schedules and care were as per local clinic guidelines. Participants were followed up until July 2023 in this phase of the trial. The objectives of the extended follow-up were 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 was not available through their country's national HIV treatment programme; 2. to monitor long-term safety and effectiveness of dolutegravir versus standard of care.

• Study Type: Interventional
• Enrollment (Actual): 792
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Germany
  • Frankfurt, Germany
    • Universitata Frankfurt
  • Hamburg, Germany
    • UkE Eppendorf Hamburg
• Portugal
  • Porto, Portugal
    • Centro Materno-Infantil de Norte
• South Africa
  • Durban, South Africa
    • King Edward VIII Hospital
  • Hlabisa, South Africa
    • Africa Health Research Institute (AHRI)
  • Klerksdorp, South Africa
    • PHRU Klerksdorp
  • Parow, South Africa
    • Kid-Cru
  • Soweto, South Africa
    • PHRU
• Spain
  • Barcelona, Spain
    • Hospital San Joan de Defu
  • Madrid, Spain
    • Hospital 12 de Octubre
  • Madrid, Spain
    • Hospital La Paz
• Thailand
  • Chanthaburi, Thailand
    • Prapokklao Hospital
  • Chiang Mai, Thailand
    • Nakornping Hospital
  • Chiang Rai, Thailand
    • Chiangrai Prachanukroh Hospital
  • Khon Kaen, Thailand
    • Khon Kaen hospital
  • Maha Sarakham, Thailand
    • Mahasarakam Hospital
  • Phayao, Thailand
    • Phayao Hospital
• Uganda
  • Kampala, Uganda
    • Baylor
  • Kampala, Uganda
    • JCRC
  • Kampala, Uganda
    • MUJHU
  • Mbarara, Uganda
    • JCRC
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Heartlands Hospital
  • Leeds, United Kingdom
    • Leeds General Infirmary
  • Leicester, United Kingdom
    • Leicester Royal Infirmary
  • London, United Kingdom
    • Kings College Hospital
  • London, United Kingdom
    • Great Ormand Street Hospital
  • London, United Kingdom
    • St Mary's Hospital
• Zimbabwe
  • Harare, Zimbabwe
    • UZCRC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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)-Pharmacokinetics (PK)1 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 Nucleoside Reverse Transcriptase Inhibitor (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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DTG arm; DTG + 2 nucleoside transcriptase inhibitors	Drug: Dolutegravir; Other Names: DTG
Active Comparator: SOC arm; Standard of Care (SOC) for ODYSSEY A is defined as a PI or non nucleoside transcriptase inhibitors + 2 or 3 nucleoside transcriptase inhibitor SOC for ODYSSEY B is defined as a PI or non nucleoside transcriptase inhibitor+ 2 nucleoside transcriptase inhibitors	Drug: Standard of Care; PI or non nucleoside transcriptase inhibitors; Other Names: SOC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in Proportion With Failure (Clinical or Virological)	Treatment failure by 96 weeks. Estimated using time to the first occurrence of any of the following components: Insufficient virological response defined as < 1 log10 drop at week 24 and switch to second/third line ART for treatment failure; Viral Load (VL)>400 c/ml at or after 36 weeks confirmed by next visit; Death due to any cause; Any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events, adjudicated by the Endpoint Review Committee	96 weeks post randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV-1 RNA <50c/ml at 96 Weeks	Proportion of children with viral load suppression <50 c/ml at 96 weeks.	96 weeks post randomisation
HIV-1 RNA <400c/mL at 96 Weeks	Proportion of children with viral load suppression <400 c/ml at 96 weeks	96 weeks post randomisation
Mean Change in CD4 Count From Baseline to Week 96	Reporting mean change from the global baseline value across both arms.	96 weeks post randomisation
Mean Change in Total Cholesterol From Baseline to Week 96	Reporting mean change from global baseline value across both arms.	96 weeks post randomisation
Serious Adverse Events	Incidence of serious adverse events	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).
Grade 3 or Above Clinical and Laboratory Adverse Events	Incidence of new clinical and laboratory grade 3 and 4 adverse events	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).
Adverse Events Leading to ART Modification Any Grade	Incidence of adverse events (of any grade) leading to treatment modification	Randomised Phase
Treatment Failure by 48 Weeks	Treatment failure by 48 weeks. Difference in proportion with clinical or virological failure (as defined above)	48 weeks post randomisation
Treatment Failure by 144 Weeks	Treatment failure by 144 weeks. Difference in proportion with clinical or virological failure (as defined above)	144 weeks post randomisation
WHO 4, Severe WHO 3 Events and Death	Rate of clinical events : WHO 4, severe WHO 3 events and death	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).
Per Protocol: Treatment Failure by 96 Weeks	Per protocol: treatment failure by 96 weeks post randomisation	96 weeks post randomisation
Any Drug Class Resistance After Virologic Failure	Any drug class resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations.	96 weeks post randomisation
NRTI Resistance After Virologic Failure	NRTI resistance after virologic failure 96 weeks post randomisation. Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations.	96 weeks post randomisation
NNRTI Resistance After Virologic Failure	NNRTI resistance after virologic failure 96 weeks post randomisation. Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations.	96 weeks post randomisation
PI Resistance After Virologic Failure	PI resistance after virologic failure 96 weeks post randomisation. Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations.	96 weeks post randomisation
INSTI Resistance After Virologic Failure	INSTI resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations.	96 weeks post randomisation
Emerging Resistance to Any Drug Class After Virologic Failure	Emerging resistance to any drug class after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations. >=14kg cohort: among participants with virologic failure and exposure to the drug class, percentage of participants with emerging resistance was estimated under an assumption of the same proportion of new resistance in participants with an available baseline resistance test and those without. <14kg cohort: percentage reported for participants with whom resistance test was available post-failure and at baseline, and exposed to drug-class during trial.	96 weeks post randomisation
NRTI Emerging Resistance After Virologic Failure	NRTI emerging resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations. >=14kg cohort: among participants with virologic failure and exposure to the drug class, percentage of participants with emerging resistance was estimated under an assumption of the same proportion of new resistance in participants with an available baseline resistance test and those without. <14kg cohort: percentage reported for participants with whom a resistance test was available post-failure and at baseline, and exposed to drug-class during trial.	96 weeks post randomisation
NNRTI Emerging Resistance After Virologic Failure	NNRTI emerging resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations. >=14kg cohort: among participants with virologic failure and exposure to the drug class, percentage of participants with emerging resistance was estimated under an assumption of the same proportion of new resistance in participants with an available baseline resistance test and those without. <14kg cohort: percentage reported for participants with whom a resistance test was available post-failure and at baseline, and exposed to drug-class during trial.	96 weeks post randomisation
PI Emerging Resistance After Virologic Failure	PI emerging resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations. >=14kg cohort: among participants with virologic failure and exposure to the drug class, percentage of participants with emerging resistance was estimated under an assumption of the same proportion of new resistance in participants with an available baseline resistance test and those without. <14kg cohort: percentage reported for participants with whom a resistance test was available post-failure and at baseline, and exposed to drug-class during trial.	96 weeks post randomisation
INSTI Emerging Resistance After Virologic Failure	INSTI emerging resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations. >=14kg cohort: among participants with virologic failure and exposure to the drug class, percentage of participants with emerging resistance was estimated under an assumption of the same proportion of new resistance in participants with an available baseline resistance test and those without. <14kg cohort: percentage reported for participants with whom a resistance test was available post-failure and at baseline, and exposed to drug-class during trial. The integrase gene was not sequenced for the standard of care arm.	96 weeks post randomisation
Time to Any New or Recurrent AIDS Defining Event (WHO 4) or Severe WHO 3 Events	Time to any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events adjudicated by the Endpoint Review Committee. Reported in >=14kg and <14kg papers. >=14kg cohort paper (https://www.nejm.org/doi/full/10.1056/NEJMoa2108793) <14kg cohort paper (https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(22)00163-1/fulltext)	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).
Adherence Questionnaire	The proportion of adherence questionnaires where the participant/carer reports missing a dose within the last week will be compared between randomised groups. Reported in >=14kg and <14kg papers. >=14kg cohort paper (https://www.nejm.org/doi/full/10.1056/NEJMoa2108793) <14kg cohort paper (https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(22)00163-1/fulltext)	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).
Health-related Quality of Life Questionnaire	Adapted from the Euro Quality of Life Questionnaire (Qol)-5D questionnaire The EQ5D-3L (3-level version of EQ-5D) questionnaire contains five questions about the participants' quality of life: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each question has three dimensions: no problems, some problems, and extreme problems. This analysis reports whether the participant reports any problems (some or extreme). Percentages are of participants completing at least one EQ5D-3L questionnaire during follow-up. Reported in >=14kg cohort paper (https://www.nejm.org/doi/full/10.1056/NEJMoa2108793)	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).
Acceptability Questionnaire	Number of participants reported to have problems with size, taste or swallowing of the medicines as assessed by Acceptability questionnaire Reported in >=14kg and <14kg papers. >=14kg cohort paper (https://www.nejm.org/doi/full/10.1056/NEJMoa2108793) <14kg cohort paper (https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(22)00163-1/fulltext)	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Weight From Baseline	Mean change in weight from baseline to week 96	96 weeks post randomisation
Mean Change in BMI-for-age Z-score From Baseline	Mean change in BMI-for-age from baseline to week 96. Reporting mean change from the global baseline value across both arms. z-scores (standard scores) are the number of standard deviations the observed data is above or below the population (z-score of 0 represents the population median). Positive z-scores represent the standard deviations above the median and negative z-scores represent the standard deviations below the median. BMI-for-age Z scores indicate: <-3SD severe thinness; <-2SD thinness; -2 to 1SD healthy weight; >1SD overweight; >2SD obese.	96 weeks post randomisation

Collaborators and Investigators

• Sponsor: PENTA Foundation
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; ViiV Healthcare; MRC CTU at UCL; Program for HIV Prevention and Treatment (PHPT)
• Investigators: Principal Investigator: Diana Gibb, Medical Research Council Clinical Trials Unit at UCL

Publications and helpful links

General Publications

• Turkova A, Waalewijn H, Chan MK, Bollen PDJ, Bwakura-Dangarembizi MF, Kekitiinwa AR, Cotton MF, Lugemwa A, Variava E, Ahimbisibwe GM, Srirompotong U, Mumbiro V, Amuge P, Zuidewind P, Ali S, Kityo CM, Archary M, Ferrand RA, Violari A, Gibb DM, Burger DM, Ford D, Colbers A; ODYSSEY Trial Team. Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial. Lancet HIV. 2022 Sep;9(9):e627-e637. doi: 10.1016/S2352-3018(22)00160-6. Epub 2022 Jul 19.
• Singh RP, Adkison KK, Baker M, Parasrampuria R, Wolstenholme A, Davies M, Sewell N, Brothers C, Buchanan AM. Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children. Pediatr Infect Dis J. 2022 Mar 1;41(3):230-237. doi: 10.1097/INF.0000000000003366.
• Moore CL, Turkova A, Mujuru H, Kekitiinwa A, Lugemwa A, Kityo CM, Barlow-Mosha LN, Cressey TR, Violari A, Variava E, Cotton MF, Archary M, Compagnucci A, Puthanakit T, Behuhuma O, Saiotadi Y, Hakim J, Amuge P, Atwine L, Musiime V, Burger DM, Shakeshaft C, Giaquinto C, Rojo P, Gibb DM, Ford D; ODYSSEY Trial Team. ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing. BMC Infect Dis. 2021 Jan 4;21(1):5. doi: 10.1186/s12879-020-05672-6.
• Bollen PDJ, Moore CL, Mujuru HA, Makumbi S, Kekitiinwa AR, Kaudha E, Parker A, Musoro G, Nanduudu A, Lugemwa A, Amuge P, Hakim JG, Rojo P, Giaquinto C, Colbers A, Gibb DM, Ford D, Turkova A, Burger DM; ODYSSEY trial team. Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial. Lancet HIV. 2020 Aug;7(8):e533-e544. doi: 10.1016/S2352-3018(20)30189-2.
• Turkova A, White E, Mujuru HA, Kekitiinwa AR, Kityo CM, Violari A, Lugemwa A, Cressey TR, Musoke P, Variava E, Cotton MF, Archary M, Puthanakit T, Behuhuma O, Kobbe R, Welch SB, Bwakura-Dangarembizi M, Amuge P, Kaudha E, Barlow-Mosha L, Makumbi S, Ramsagar N, Ngampiyaskul C, Musoro G, Atwine L, Liberty A, Musiime V, Bbuye D, Ahimbisibwe GM, Chalermpantmetagul S, Ali S, Sarfati T, Wynne B, Shakeshaft C, Colbers A, Klein N, Bernays S, Saidi Y, Coelho A, Grossele T, Compagnucci A, Giaquinto C, Rojo P, Ford D, Gibb DM; ODYSSEY Trial Team. Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children. N Engl J Med. 2021 Dec 30;385(27):2531-2543. doi: 10.1056/NEJMoa2108793.
• Amuge P, Lugemwa A, Wynne B, Mujuru HA, Violari A, Kityo CM, Archary M, Variava E, White E, Turner RM, Shakeshaft C, Ali S, Nathoo KJ, Atwine L, Liberty A, Bbuye D, Kaudha E, Mngqibisa R, Mosala M, Mumbiro V, Nanduudu A, Ankunda R, Maseko L, Kekitiinwa AR, Giaquinto C, Rojo P, Gibb DM, Turkova A, Ford D; ODYSSEY Trial Team. Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial. Lancet HIV. 2022 Sep;9(9):e638-e648. doi: 10.1016/S2352-3018(22)00163-1.

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2016
• Primary Completion (Actual): March 2, 2021
• Study Completion (Actual): December 7, 2023

Study Registration Dates

• First Submitted: September 30, 2014
• First Submitted That Met QC Criteria: October 7, 2014
• First Posted (Estimated): October 8, 2014

Study Record Updates

• Last Update Posted (Actual): July 29, 2025
• Last Update Submitted That Met QC Criteria: July 9, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Immune System Diseases; RNA Virus Infections; Virus Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Infections; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Dolutegravir
• Other Study ID Numbers: ODYSSEY (PENTA 20); 2014-002632-14 (EudraCT Number)