HIV Infection
Conditions
Brief summary
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.
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.
Interventions
DRUGDolutegravir
DRUGStandard of Care
PI or non nucleoside transcriptase inhibitors
Sponsors
Institut National de la Santé Et de la Recherche Médicale, France
Program for HIV Prevention and Treatment (PHPT)
ViiV Healthcare
MRC CTU at UCL
PENTA Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Proportion With Failure (Clinical or Virological) | 96 weeks post randomisation | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Failure by 144 Weeks | 144 weeks post randomisation | Treatment failure by 144 weeks. Difference in proportion with clinical or virological failure (as defined above) |
| HIV-1 RNA <50c/ml at 96 Weeks | 96 weeks post randomisation | Proportion of children with viral load suppression \<50 c/ml at 96 weeks. |
| HIV-1 RNA <400c/mL at 96 Weeks | 96 weeks post randomisation | Proportion of children with viral load suppression \<400 c/ml at 96 weeks |
| Mean Change in CD4 Count From Baseline to Week 96 | 96 weeks post randomisation | Reporting mean change from the global baseline value across both arms. |
| Mean Change in Total Cholesterol From Baseline to Week 96 | 96 weeks post randomisation | Reporting mean change from global baseline value across both arms. |
| 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). | Incidence of serious adverse events |
| Grade 3 or Above Clinical and Laboratory 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). | Incidence of new clinical and laboratory grade 3 and 4 adverse events |
| Adverse Events Leading to ART Modification Any Grade | Randomised Phase | Incidence of adverse events (of any grade) leading to treatment modification |
| Treatment Failure by 48 Weeks | 48 weeks post randomisation | Treatment failure by 48 weeks. Difference in proportion with clinical or virological failure (as defined above) |
| 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). | Rate of clinical events : WHO 4, severe WHO 3 events and death |
| Per Protocol: Treatment Failure by 96 Weeks | 96 weeks post randomisation | Per protocol: treatment failure by 96 weeks post randomisation |
| Any Drug Class Resistance After Virologic Failure | 96 weeks post randomisation | 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. |
| NRTI Resistance After Virologic Failure | 96 weeks post randomisation | 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. |
| Health-related Quality of Life Questionnaire | 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). | 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) |
| Acceptability Questionnaire | 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). | 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) |
| NNRTI Resistance After Virologic Failure | 96 weeks post randomisation | 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. |
| PI Resistance After Virologic Failure | 96 weeks post randomisation | 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. |
| INSTI Resistance After Virologic Failure | 96 weeks post randomisation | 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. |
| Emerging Resistance to Any Drug Class After Virologic Failure | 96 weeks post randomisation | 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. |
| NRTI Emerging Resistance After Virologic Failure | 96 weeks post randomisation | 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. |
| NNRTI Emerging Resistance After Virologic Failure | 96 weeks post randomisation | 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. |
| PI Emerging Resistance After Virologic Failure | 96 weeks post randomisation | 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. |
| INSTI Emerging Resistance After Virologic Failure | 96 weeks post randomisation | 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. |
| Time to Any New or Recurrent AIDS Defining Event (WHO 4) or Severe WHO 3 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). | 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) |
| Adherence Questionnaire | 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). | 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) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Weight From Baseline | 96 weeks post randomisation | Mean change in weight from baseline to week 96 |
| Mean Change in BMI-for-age Z-score From Baseline | 96 weeks post randomisation | 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. |
Countries
Germany, Portugal, South Africa, Spain, Thailand, Uganda, United Kingdom, Zimbabwe
Participant flow
Recruitment details
Recruitment to the \>=14kg cohort took place between 20th September 2016 and 22nd June 2018 in 8 countries (Germany, Portugal, South Africa, Spain, Thailand, Uganda, United Kingdom, and Zimbabwe) across 29 centres. Recruitment to the \<14kg cohort took place between 5th July 2018 and 26th August 2019 in the African countries across 7 centres. The results published relate to the randomised phase of the study for the \>=14kg cohort and \<14kg cohort.
Pre-assignment details
\>=14kg: 819 children assessed for eligibility. 109 were ineligible: 102 failed eligibility criteria, 3 didn't return in window and 4 other reasons. Also, 3 children randomised in error: 1 not ART naïve in ODYSSEY A and 3 randomised before DTG available for weight. \<14kg: 102 children assessed for eligibility. 17 were ineligible: 14 failed eligibility criteria, 1 died before enrolment, 1 carer declined bloods and 1 ineligible due to no protocol approval at site to recruit \<14kg cohort.
Participants by arm
| Arm | Count |
|---|---|
| Dolutegravir (>=14kg Cohort) Experimental arm. DTG + 2 nucleoside transcriptase inhibitors. IMP product Dolutegravir (DTG). | 350 |
| Standard of Care (>=14kg Cohort) Active comparator arm.
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 | 357 |
| Dolutegravir (<14kg Cohort) Experimental arm. DTG + 2 nucleoside transcriptase inhibitors. IMP product Dolutegravir (DTG). | 42 |
| Standard of Care (<14kg Cohort) Active comparator arm.
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 | 43 |
| Total | 792 |
Baseline characteristics
| Characteristic | Dolutegravir (>=14kg Cohort) | Dolutegravir (<14kg Cohort) | Standard of Care (<14kg Cohort) | Total | Standard of Care (>=14kg Cohort) |
|---|---|---|---|---|---|
| Age, Continuous | 12.2 years | 1.3 years | 1.5 years | 11.4 years | 12.1 years |
| Age, Customized 12-<18 years | 182 Participants | 0 Participants | 0 Participants | 364 Participants | 182 Participants |
| Age, Customized 1-<2 years | 0 Participants | 22 Participants | 22 Participants | 44 Participants | 0 Participants |
| Age, Customized 2-<6 years | 15 Participants | 4 Participants | 5 Participants | 35 Participants | 11 Participants |
| Age, Customized 6-<12 years | 153 Participants | 0 Participants | 0 Participants | 317 Participants | 164 Participants |
| Age, Customized <6 months | 0 Participants | 11 Participants | 8 Participants | 19 Participants | 0 Participants |
| Age, Customized 6 months-<1 year | 0 Participants | 5 Participants | 8 Participants | 13 Participants | 0 Participants |
| BMI-for-age z-score >=0 | 92 Participants | 13 Participants | 17 Participants | 221 Participants | 99 Participants |
| BMI-for-age z-score -2-<0 | 216 Participants | 20 Participants | 14 Participants | 469 Participants | 219 Participants |
| BMI-for-age z-score <-3 | 22 Participants | 3 Participants | 6 Participants | 42 Participants | 11 Participants |
| BMI-for-age z-score -3-<-2 | 20 Participants | 6 Participants | 6 Participants | 60 Participants | 28 Participants |
| BMI-for-age z-score missing | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| BMI-for-age z-score | -0.6 z-score | -1.1 z-score | -0.7 z-score | -0.6 z-score | -0.6 z-score |
| CD4 <200 cells/mm^3 | 88 Participants | 3 Participants | 4 Participants | 165 Participants | 70 Participants |
| CD4 200 to <500 cells/mm^3 | 118 Participants | 2 Participants | 3 Participants | 237 Participants | 114 Participants |
| CD4 >=500 cells/mm^3 | 144 Participants | 36 Participants | 33 Participants | 386 Participants | 173 Participants |
| CD4 Missing | 0 Participants | 1 Participants | 3 Participants | 4 Participants | 0 Participants |
| CD4 | 444 cells/mm^3 | 1639 cells/mm^3 | 1221 cells/mm^3 | 494 cells/mm^3 | 486 cells/mm^3 |
| CD4% <15% | 121 Participants | 7 Participants | 11 Participants | 247 Participants | 108 Participants |
| CD4% 15-<30% | 152 Participants | 22 Participants | 18 Participants | 339 Participants | 147 Participants |
| CD4% >=30% | 77 Participants | 12 Participants | 11 Participants | 202 Participants | 102 Participants |
| CD4% Missing | 0 Participants | 1 Participants | 3 Participants | 4 Participants | 0 Participants |
| CD4% | 20 % | 24 % | 23 % | 21 % | 22 % |
| History of WHO Staging Stage 1-2 | 253 Participants | 31 Participants | 25 Participants | 574 Participants | 265 Participants |
| History of WHO Staging Stage 3 | 69 Participants | 6 Participants | 8 Participants | 143 Participants | 60 Participants |
| History of WHO Staging Stage 4 | 28 Participants | 5 Participants | 10 Participants | 75 Participants | 32 Participants |
| Log 10 Viral load copies/mL | 4.5 copies/mL | 5.2 copies/mL | 5.4 copies/mL | 4.5 copies/mL | 4.4 copies/mL |
| ODYSSEY A/B ODYSSEY A (starting first-line ART) | 154 Participants | 35 Participants | 37 Participants | 383 Participants | 157 Participants |
| ODYSSEY A/B ODYSSEY B (Switching to second-line ART) | 196 Participants | 7 Participants | 6 Participants | 409 Participants | 200 Participants |
| Race/Ethnicity, Customized Asian | 28 Participants | 0 Participants | 0 Participants | 60 Participants | 32 Participants |
| Race/Ethnicity, Customized Black African | 310 Participants | 41 Participants | 42 Participants | 706 Participants | 313 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 1 Participants | 1 Participants | 20 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 0 Participants | 0 Participants | 6 Participants | 1 Participants |
| Region of Enrollment Europe | 12 Participants | 0 Participants | 0 Participants | 25 Participants | 13 Participants |
| Region of Enrollment South Africa | 61 Participants | 8 Participants | 12 Participants | 164 Participants | 83 Participants |
| Region of Enrollment Thailand | 28 Participants | 0 Participants | 0 Participants | 61 Participants | 33 Participants |
| Region of Enrollment Uganda | 170 Participants | 22 Participants | 21 Participants | 374 Participants | 161 Participants |
| Region of Enrollment Zimbabwe | 79 Participants | 12 Participants | 10 Participants | 168 Participants | 67 Participants |
| Sex: Female, Male Female | 174 Participants | 26 Participants | 18 Participants | 389 Participants | 171 Participants |
| Sex: Female, Male Male | 176 Participants | 16 Participants | 25 Participants | 403 Participants | 186 Participants |
| Viral Load copies/mL <10,000 | 93 Participants | 4 Participants | 7 Participants | 227 Participants | 123 Participants |
| Viral Load copies/mL >=100,000 | 98 Participants | 25 Participants | 26 Participants | 224 Participants | 75 Participants |
| Viral Load copies/mL 10,000-<100,000 | 159 Participants | 13 Participants | 5 Participants | 335 Participants | 158 Participants |
| Viral Load copies/mL Missing | 0 Participants | 0 Participants | 5 Participants | 6 Participants | 1 Participants |
| Weight 10-<14kg | 0 Participants | 11 Participants | 11 Participants | 22 Participants | 0 Participants |
| Weight 14-<20kg | 39 Participants | 0 Participants | 0 Participants | 82 Participants | 43 Participants |
| Weight 20-<25kg | 71 Participants | 0 Participants | 0 Participants | 135 Participants | 64 Participants |
| Weight 25-<30kg | 58 Participants | 0 Participants | 0 Participants | 117 Participants | 59 Participants |
| Weight 30-<35kg | 38 Participants | 0 Participants | 0 Participants | 89 Participants | 51 Participants |
| Weight 35-<40kg | 29 Participants | 0 Participants | 0 Participants | 61 Participants | 32 Participants |
| Weight >=40kg | 115 Participants | 0 Participants | 0 Participants | 223 Participants | 108 Participants |
| Weight 6-<10kg | 0 Participants | 20 Participants | 20 Participants | 40 Participants | 0 Participants |
| Weight <6kg | 0 Participants | 11 Participants | 12 Participants | 23 Participants | 0 Participants |
| Weight | 30.4 kilogram(s) | 8.1 kilogram(s) | 8.2 kilogram(s) | 28.7 kilogram(s) | 31.0 kilogram(s) |
| Weight-for-age z-score >=0 | 14 Participants | 3 Participants | 3 Participants | 39 Participants | 19 Participants |
| Weight-for-age z-score -2-<0 | 78 Participants | 18 Participants | 21 Participants | 200 Participants | 83 Participants |
| Weight-for-age z-score <-3 | 4 Participants | 14 Participants | 13 Participants | 35 Participants | 4 Participants |
| Weight-for-age z-score -3-<-2 | 20 Participants | 7 Participants | 6 Participants | 45 Participants | 12 Participants |
| Weight-for-age z-score missing | 234 Participants | 0 Participants | 0 Participants | 473 Participants | 239 Participants |
| Weight-for-age z-score | -1.2 z-score | -2.1 z-score | -1.8 z-score | -1.2 z-score | -0.9 z-score |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 350 | 3 / 357 | 2 / 42 | 4 / 43 | 2 / 154 | 2 / 157 | 0 / 196 | 1 / 200 |
| other Total, other adverse events | 0 / 350 | 0 / 357 | 0 / 42 | 0 / 43 | 0 / 154 | 0 / 157 | 0 / 196 | 0 / 200 |
| serious Total, serious adverse events | 35 / 350 | 40 / 357 | 11 / 42 | 11 / 43 | 23 / 154 | 27 / 157 | 12 / 196 | 13 / 200 |
Outcome results
Primary
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
Time frame: 96 weeks post randomisation
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dolutegravir (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Severe WHO 3 | 0 Participants |
| Dolutegravir (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Confirmed VL>=400 copies/mL | 40 Participants |
| Dolutegravir (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | WHO 4 | 7 Participants |
| Dolutegravir (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Death | 0 Participants |
| Dolutegravir (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Insufficient virological response | 0 Participants |
| Standard of Care (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | WHO 4 | 5 Participants |
| Standard of Care (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Confirmed VL>=400 copies/mL | 64 Participants |
| Standard of Care (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Insufficient virological response | 3 Participants |
| Standard of Care (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Death | 2 Participants |
| Standard of Care (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Severe WHO 3 | 1 Participants |
| Dolutegravir (<14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Confirmed VL>=400 copies/mL | 9 Participants |
| Dolutegravir (<14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Insufficient virological response | 0 Participants |
| Dolutegravir (<14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Severe WHO 3 | 0 Participants |
| Dolutegravir (<14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | WHO 4 | 1 Participants |
| Dolutegravir (<14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Death | 2 Participants |
| Standard of Care (<14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Confirmed VL>=400 copies/mL | 16 Participants |
| Standard of Care (<14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Severe WHO 3 | 0 Participants |
| Standard of Care (<14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | WHO 4 | 1 Participants |
| Standard of Care (<14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Death | 4 Participants |
| Standard of Care (<14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Insufficient virological response | 0 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Confirmed VL>=400 copies/mL | 10 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Insufficient virological response | 0 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Severe WHO 3 | 0 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | WHO 4 | 5 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Death | 0 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Death | 1 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Severe WHO 3 | 0 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Insufficient virological response | 2 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | WHO 4 | 5 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Confirmed VL>=400 copies/mL | 26 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Confirmed VL>=400 copies/mL | 30 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | WHO 4 | 2 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Severe WHO 3 | 0 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Insufficient virological response | 0 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Death | 0 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Confirmed VL>=400 copies/mL | 38 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Insufficient virological response | 1 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | WHO 4 | 0 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Death | 1 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Difference in Proportion With Failure (Clinical or Virological) | Severe WHO 3 | 1 Participants |
Comparison: Statistical Analysis Title: Primary: Diff in adj. KM estimates (\>=14kg)~Number of subjects included in analysis: 707~Analysis specification: Pre-specifiedp-value: =0.00495% CI: [-0.14, -0.03]Bootstrap method
Comparison: Statistical Analysis Title: Diff in adj. KM estimates (Frequentist \<14kg)~Number of subjects included in analysis: 85~Analysis Specification: Pre-specifiedp-value: =0.05795% CI: [-0.36, 0.02]Bootstrap method
Comparison: Statistical Analysis Title: Primary: diff in adj. KM estimates (Bayesian \<14kg)~Number of subjects included in analysis: 85~Analysis Specification: Pre-specifiedp-value: 0.0295% CI: [-0.19, -0.02]Bootstrap method
Comparison: Statistical Analysis Title: Diff in adj. KM estimates (ODYSSEY A\>=14kg)~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: 0.00395% CI: [-0.21, -0.04]Bootstrap method
Comparison: Statistical Analysis Title: Diff in adj. KM estimates (ODYSSEY B \>=14kg)~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: 0.2295% CI: [-0.12, 0.03]Bootstrap method
Secondary
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)
Time frame: 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).
Secondary
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)
Time frame: 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).
Secondary
Adverse Events Leading to ART Modification Any Grade
Incidence of adverse events (of any grade) leading to treatment modification
Time frame: Randomised Phase
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | Adverse Events Leading to ART Modification Any Grade | 5 participants with events |
| Standard of Care (>=14kg Cohort) | Adverse Events Leading to ART Modification Any Grade | 17 participants with events |
| Dolutegravir (<14kg Cohort) | Adverse Events Leading to ART Modification Any Grade | 0 participants with events |
| Standard of Care (<14kg Cohort) | Adverse Events Leading to ART Modification Any Grade | 2 participants with events |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Adverse Events Leading to ART Modification Any Grade | 3 participants with events |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Adverse Events Leading to ART Modification Any Grade | 8 participants with events |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Adverse Events Leading to ART Modification Any Grade | 2 participants with events |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Adverse Events Leading to ART Modification Any Grade | 9 participants with events |
Comparison: Statistical Analysis Title: Adjusted time to first event (\>=14kg)~Number of subjects included in analysis: 707~Analysis Specification: Pre-specifiedp-value: =0.0195% CI: [0.11, 0.77]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (ODYSSEY A \>=14kg)~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: =0.1395% CI: [0.09, 1.33]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (ODYSSEY B \>=14kg)~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: 0.05595% CI: [0.05, 1.03]Regression, Cox
Secondary
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.
Time frame: 96 weeks post randomisation
Population: Shown are the numbers of participants with resistance after virologic failure, among those with virologic failure by week 96 who had a post-treatment failure resistance test available for the drug class.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | Any Drug Class Resistance After Virologic Failure | 0 Participants |
| Standard of Care (>=14kg Cohort) | Any Drug Class Resistance After Virologic Failure | 28 Participants |
| Dolutegravir (<14kg Cohort) | Any Drug Class Resistance After Virologic Failure | 23 Participants |
| Standard of Care (<14kg Cohort) | Any Drug Class Resistance After Virologic Failure | 36 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Any Drug Class Resistance After Virologic Failure | 6 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Any Drug Class Resistance After Virologic Failure | 12 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Any Drug Class Resistance After Virologic Failure | 2 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Any Drug Class Resistance After Virologic Failure | 3 Participants |
Secondary
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.
Time frame: 96 weeks post randomisation
Population: Dolutegravir - ODYSSEY A (\>=14kg cohort): 0 participants had resistance to INSTI post failure Standard of Care - ODYSSEY B (\<14kg Cohort) - 0 participants with virological failure and any gene sequenced at baseline and post-failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care (>=14kg Cohort) | Emerging Resistance to Any Drug Class After Virologic Failure | 97 percentage of participants |
| Dolutegravir (<14kg Cohort) | Emerging Resistance to Any Drug Class After Virologic Failure | 22 percentage of participants |
| Standard of Care (<14kg Cohort) | Emerging Resistance to Any Drug Class After Virologic Failure | 19 percentage of participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Emerging Resistance to Any Drug Class After Virologic Failure | 0 percentage of participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Emerging Resistance to Any Drug Class After Virologic Failure | 100 percentage of participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Emerging Resistance to Any Drug Class After Virologic Failure | 50 percentage of participants |
Secondary
Grade 3 or Above Clinical and Laboratory Adverse Events
Incidence of new clinical and laboratory grade 3 and 4 adverse events
Time frame: 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).
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | Grade 3 or Above Clinical and Laboratory Adverse Events | 73 participants with events |
| Standard of Care (>=14kg Cohort) | Grade 3 or Above Clinical and Laboratory Adverse Events | 86 participants with events |
| Dolutegravir (<14kg Cohort) | Grade 3 or Above Clinical and Laboratory Adverse Events | 19 participants with events |
| Standard of Care (<14kg Cohort) | Grade 3 or Above Clinical and Laboratory Adverse Events | 21 participants with events |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Grade 3 or Above Clinical and Laboratory Adverse Events | 48 participants with events |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Grade 3 or Above Clinical and Laboratory Adverse Events | 43 participants with events |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Grade 3 or Above Clinical and Laboratory Adverse Events | 25 participants with events |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Grade 3 or Above Clinical and Laboratory Adverse Events | 43 participants with events |
Comparison: Statistical Analysis Title: Adjusted time to first event (\>=14kg)~Number of subjects included in analysis: 707~Analysis Specification: Pre-specifiedp-value: =0.2495% CI: [0.61, 1.13]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (\<14kg)~Number of subjects included in analysis: 85~Analysis Specification: Pre-specifiedp-value: =0.8395% CI: [0.5, 1.74]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (ODYSSEY A \>=14kg)~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: =0.5795% CI: [0.75, 1.7]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (ODYSSEY B \>=14kg)~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: =0.0195% CI: [0.33, 0.88]Regression, Cox
Secondary
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)
Time frame: 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).
Secondary
HIV-1 RNA <400c/mL at 96 Weeks
Proportion of children with viral load suppression \<400 c/ml at 96 weeks
Time frame: 96 weeks post randomisation
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | HIV-1 RNA <400c/mL at 96 Weeks | 299 Participants |
| Standard of Care (>=14kg Cohort) | HIV-1 RNA <400c/mL at 96 Weeks | 285 Participants |
| Dolutegravir (<14kg Cohort) | HIV-1 RNA <400c/mL at 96 Weeks | 33 Participants |
| Standard of Care (<14kg Cohort) | HIV-1 RNA <400c/mL at 96 Weeks | 26 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | HIV-1 RNA <400c/mL at 96 Weeks | 129 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | HIV-1 RNA <400c/mL at 96 Weeks | 124 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | HIV-1 RNA <400c/mL at 96 Weeks | 170 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | HIV-1 RNA <400c/mL at 96 Weeks | 161 Participants |
Comparison: Statistical Analysis Title: Adjusted Difference (\>=14kg)~Number of subjects included in analysis: 670~Analysis Specification: Pre-specifiedp-value: =0.225695% CI: [-2, 8]Regression, Logistic
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY A \>=14kg)~Number of subjects included in analysis: 286~Analysis Specification: Pre-specifiedp-value: =0.953695% CI: [-8, 7]Regression, Logistic
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY B \>=14kg)~Number of subjects included in analysis: 384~Analysis Specification: Pre-specifiedp-value: =0.110495% CI: [-1, 12]Regression, Logistic
p-value: 0.03895% CI: [2, 37]Regression, Logistic
Secondary
HIV-1 RNA <50c/ml at 96 Weeks
Proportion of children with viral load suppression \<50 c/ml at 96 weeks.
Time frame: 96 weeks post randomisation
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | HIV-1 RNA <50c/ml at 96 Weeks | 270 Participants |
| Standard of Care (>=14kg Cohort) | HIV-1 RNA <50c/ml at 96 Weeks | 252 Participants |
| Dolutegravir (<14kg Cohort) | HIV-1 RNA <50c/ml at 96 Weeks | 27 Participants |
| Standard of Care (<14kg Cohort) | HIV-1 RNA <50c/ml at 96 Weeks | 19 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | HIV-1 RNA <50c/ml at 96 Weeks | 117 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | HIV-1 RNA <50c/ml at 96 Weeks | 113 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | HIV-1 RNA <50c/ml at 96 Weeks | 153 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | HIV-1 RNA <50c/ml at 96 Weeks | 139 Participants |
Comparison: Statistical Analysis Title: Adjusted Difference (\>=14kg)~Number of subjects included in analysis: 665~Analysis Specification: Pre-specifiedp-value: =0.137795% CI: [-1, 11]Regression, Logistic
Comparison: Statistical Analysis Title: Adjusted difference (ODYSSEY A \>=14kg)~Number of subjects included in analysis: 286~Analysis Specification: Pre-specifiedp-value: =0.889595% CI: [-10, 8]Regression, Logistic
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY B \>=14kg)~Number of subjects included in analysis: 381~Analysis Specification: Pre-specifiedp-value: =0.043595% CI: [0.4, 17]Regression, Logistic
p-value: 0.02195% CI: [6, 47]Regression, Logistic
Secondary
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.
Time frame: 96 weeks post randomisation
Population: Emergent drug resistance estimated only in participants exposed to drug class during trial (SOC arm not exposed to INSTI drug class).~Dolutegravir - ODYSSEY A (\>=14kg cohort) - 0 participants had resistance post failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care (>=14kg Cohort) | INSTI Emerging Resistance After Virologic Failure | 18 percentage of participants |
| Dolutegravir (<14kg Cohort) | INSTI Emerging Resistance After Virologic Failure | 0 percentage of participants |
| Standard of Care (<14kg Cohort) | INSTI Emerging Resistance After Virologic Failure | 50 percentage of participants |
Secondary
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.
Time frame: 96 weeks post randomisation
Population: Shown are the numbers of participants with resistance after virologic failure, among those with virologic failure by week 96 who had a post-treatment failure resistance test available for the drug class. The integrase gene was not sequenced for standard of care arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | INSTI Resistance After Virologic Failure | 0 Participants |
| Standard of Care (>=14kg Cohort) | INSTI Resistance After Virologic Failure | 4 Participants |
| Dolutegravir (<14kg Cohort) | INSTI Resistance After Virologic Failure | 0 Participants |
| Standard of Care (<14kg Cohort) | INSTI Resistance After Virologic Failure | 1 Participants |
Secondary
Mean Change in CD4 Count From Baseline to Week 96
Reporting mean change from the global baseline value across both arms.
Time frame: 96 weeks post randomisation
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dolutegravir (>=14kg Cohort) | Mean Change in CD4 Count From Baseline to Week 96 | 265 cells/mm^3 | Standard Error 17 |
| Standard of Care (>=14kg Cohort) | Mean Change in CD4 Count From Baseline to Week 96 | 230 cells/mm^3 | Standard Error 17 |
| Dolutegravir (<14kg Cohort) | Mean Change in CD4 Count From Baseline to Week 96 | 72 cells/mm^3 | Standard Error 116 |
| Standard of Care (<14kg Cohort) | Mean Change in CD4 Count From Baseline to Week 96 | 51 cells/mm^3 | Standard Error 118 |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Mean Change in CD4 Count From Baseline to Week 96 | 311 cells/mm^3 | Standard Error 23 |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Mean Change in CD4 Count From Baseline to Week 96 | 267 cells/mm^3 | Standard Error 24 |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Mean Change in CD4 Count From Baseline to Week 96 | 228 cells/mm^3 | Standard Error 24 |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Mean Change in CD4 Count From Baseline to Week 96 | 202 cells/mm^3 | Standard Error 24 |
Comparison: Statistical Analysis Title: Adjusted Difference (\>=14kg)~Statistical analysis description: Linear regression of CD4 at week 96, adjusted for randomised arm, baseline CD4 and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 707~Analysis Specification: Pre-specifiedp-value: =0.14495% CI: [-12, 82]Regression, Linear
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY A \>=14kg)~Statistical analysis description: Linear regression of CD4 at week 96, adjusting for randomised arm, baseline CD4 and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: 0.18595% CI: [-21, 109]Regression, Linear
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY B \>=14kg)~Statistical analysis description: Linear regression of CD4 at week 96, adjusting for randomised arm, baseline CD4 and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: =0.42795% CI: [-39, 93]Regression, Linear
p-value: 0.8695% CI: [-308, 368]Regression, Linear
Secondary
Mean Change in Total Cholesterol From Baseline to Week 96
Reporting mean change from global baseline value across both arms.
Time frame: 96 weeks post randomisation
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dolutegravir (>=14kg Cohort) | Mean Change in Total Cholesterol From Baseline to Week 96 | -5.0 mg/dl | Standard Error 1.5 |
| Standard of Care (>=14kg Cohort) | Mean Change in Total Cholesterol From Baseline to Week 96 | 9.9 mg/dl | Standard Error 1.5 |
| Dolutegravir (<14kg Cohort) | Mean Change in Total Cholesterol From Baseline to Week 96 | 4.5 mg/dl | Standard Error 5.6 |
| Standard of Care (<14kg Cohort) | Mean Change in Total Cholesterol From Baseline to Week 96 | 29.6 mg/dl | Standard Error 5.9 |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Mean Change in Total Cholesterol From Baseline to Week 96 | 2.1 mg/dl | Standard Error 2.3 |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Mean Change in Total Cholesterol From Baseline to Week 96 | 19.6 mg/dl | Standard Error 2.3 |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Mean Change in Total Cholesterol From Baseline to Week 96 | -10.5 mg/dl | Standard Error 1.8 |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Mean Change in Total Cholesterol From Baseline to Week 96 | 2.8 mg/dl | Standard Error 1.8 |
Comparison: Statistical Analysis Title: Adjusted Difference (\>=14kg)~Statistical analysis description: Linear regression of total cholesterol at week 96, adjusting for randomised arm, baseline total cholesterol and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 707~Analysis Specification: Pre-specifiedp-value: <0.00195% CI: [-19, -11.1]Regression, Linear
Comparison: Statistical Analysis Title: Adjusted Difference (\<14kg)~Statistical analysis description: Linear regression of total cholesterol at week 96, adjusting for randomised arm, baseline total cholesterol and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 85~Analysis Specification: Pre-specifiedp-value: =0.003295% CI: [-40.3, -8.5]Regression, Linear
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY A \>=14kg)~Statistical analysis description: Linear regression of total cholesterol at week 96, adjusting for randomised arm, baseline total cholesterol and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: <0.00195% CI: [-23.9, -11.1]Regression, Linear
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY B \>=14kg)~Statistical analysis description: Linear regression of total cholesterol at week 96, adjusting for randomised arm, baseline total cholesterol and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: <0.00195% CI: [-18.5, -8.4]Regression, Linear
Secondary
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.
Time frame: 96 weeks post randomisation
Population: Emergent drug resistance estimated only in participants exposed to drug class during trial (DTG arm not exposed to NNRTI class).~Standard of Care - ODYSSEY A (\<14kg Cohort) and Standard of Care - ODYSSEY B (\<14kg Cohort) - 0 participants with virological failure, exposed to drug-class, and gene sequenced at baseline and post-failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | NNRTI Emerging Resistance After Virologic Failure | 88 percentage of participants |
| Standard of Care (>=14kg Cohort) | NNRTI Emerging Resistance After Virologic Failure | 100 percentage of participants |
Secondary
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.
Time frame: 96 weeks post randomisation
Population: Shown are the numbers of participants with resistance after virologic failure, among those with virologic failure by week 96 who had a post-treatment failure resistance test available for the drug class.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | NNRTI Resistance After Virologic Failure | 0 Participants |
| Standard of Care (>=14kg Cohort) | NNRTI Resistance After Virologic Failure | 27 Participants |
| Dolutegravir (<14kg Cohort) | NNRTI Resistance After Virologic Failure | 22 Participants |
| Standard of Care (<14kg Cohort) | NNRTI Resistance After Virologic Failure | 36 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | NNRTI Resistance After Virologic Failure | 6 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | NNRTI Resistance After Virologic Failure | 11 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | NNRTI Resistance After Virologic Failure | 2 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | NNRTI Resistance After Virologic Failure | 3 Participants |
Secondary
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.
Time frame: 96 weeks post randomisation
Population: Dolutegravir - ODYSSEY A (\>=14kg cohort) - 0 participants had resistance post failure.~Dolutegravir - ODYSSEY A (\<14kg Cohort) and Standard of Care - ODYSSEY B (\<14kg Cohort) - 0 participants with virological failure, exposed to drug-class, and gene sequenced at baseline and post-failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care (>=14kg Cohort) | NRTI Emerging Resistance After Virologic Failure | 62 percentage of participants |
| Dolutegravir (<14kg Cohort) | NRTI Emerging Resistance After Virologic Failure | 8 percentage of participants |
| Standard of Care (<14kg Cohort) | NRTI Emerging Resistance After Virologic Failure | 10 percentage of participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | NRTI Emerging Resistance After Virologic Failure | 100 percentage of participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | NRTI Emerging Resistance After Virologic Failure | 100 percentage of participants |
Secondary
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.
Time frame: 96 weeks post randomisation
Population: Shown are the numbers of participants with resistance after virologic failure, among those with virologic failure by week 96 who had a post-treatment failure resistance test available for the drug class.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | NRTI Resistance After Virologic Failure | 0 Participants |
| Standard of Care (>=14kg Cohort) | NRTI Resistance After Virologic Failure | 18 Participants |
| Dolutegravir (<14kg Cohort) | NRTI Resistance After Virologic Failure | 21 Participants |
| Standard of Care (<14kg Cohort) | NRTI Resistance After Virologic Failure | 31 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | NRTI Resistance After Virologic Failure | 1 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | NRTI Resistance After Virologic Failure | 10 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | NRTI Resistance After Virologic Failure | 1 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | NRTI Resistance After Virologic Failure | 3 Participants |
Secondary
Per Protocol: Treatment Failure by 96 Weeks
Per protocol: treatment failure by 96 weeks post randomisation
Time frame: 96 weeks post randomisation
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | Per Protocol: Treatment Failure by 96 Weeks | 44 Participants |
| Standard of Care (>=14kg Cohort) | Per Protocol: Treatment Failure by 96 Weeks | 62 Participants |
| Dolutegravir (<14kg Cohort) | Per Protocol: Treatment Failure by 96 Weeks | 12 Participants |
| Standard of Care (<14kg Cohort) | Per Protocol: Treatment Failure by 96 Weeks | 20 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Per Protocol: Treatment Failure by 96 Weeks | 13 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Per Protocol: Treatment Failure by 96 Weeks | 28 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Per Protocol: Treatment Failure by 96 Weeks | 31 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Per Protocol: Treatment Failure by 96 Weeks | 34 Participants |
Comparison: Statistical Analysis Title: Diff in adj. KM estimates (\>=14kg)~Statistical analysis description: Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 96 weeks after randomisation.~Number of subjects included in analysis: 677~Analysis Specification: Pre-specifiedp-value: =0.01595% CI: [-0.12, -0.01]Bootstrap method
Comparison: Statistical Analysis Title: Adjusted difference (frequentist \<14kg)~Statistical analysis description: Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 96 weeks after randomisation.~Number of subjects included in analysis: 85~Analysis Specification: Pre-specifiedp-value: =0.07595% CI: [-0.362, 0.029]Bootstrap method
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY A \>=14kg)~Statistical analysis description: Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 96 weeks after randomisation.~Number of subjects included in analysis: 295~Analysis Specification: Pre-specifiedp-value: =0.00495% CI: [-0.21, -0.036]Bootstrap method
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY B \>=14kg)~Statistical analysis description: Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 96 weeks after randomisation.~Number of subjects included in analysis: 382~Analysis Specification: Pre-specifiedp-value: =0.54795% CI: [-0.096, 0.056]Bootstrap method
Secondary
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.
Time frame: 96 weeks post randomisation
Population: Emergent drug resistance estimated only in participants exposed to drug class during trial (DTG arm not exposed to PI class).~Standard of Care - ODYSSEY A (\>=14kg cohort) - 0 participants had resistance post failure.~Standard of Care - ODYSSEY B (\<14kg Cohort) - 0 participants with virological failure, exposed to drug-class, and gene sequenced at baseline and post-failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care (>=14kg Cohort) | PI Emerging Resistance After Virologic Failure | 5 percentage of participants |
| Dolutegravir (<14kg Cohort) | PI Emerging Resistance After Virologic Failure | 100 percentage of participants |
Secondary
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.
Time frame: 96 weeks post randomisation
Population: Shown are the numbers of participants with resistance after virologic failure, among those with virologic failure by week 96 who had a post-treatment failure resistance test available for the drug class.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | PI Resistance After Virologic Failure | 0 Participants |
| Standard of Care (>=14kg Cohort) | PI Resistance After Virologic Failure | 0 Participants |
| Dolutegravir (<14kg Cohort) | PI Resistance After Virologic Failure | 2 Participants |
| Standard of Care (<14kg Cohort) | PI Resistance After Virologic Failure | 3 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | PI Resistance After Virologic Failure | 0 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | PI Resistance After Virologic Failure | 2 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | PI Resistance After Virologic Failure | 0 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | PI Resistance After Virologic Failure | 0 Participants |
Secondary
Serious Adverse Events
Incidence of serious adverse events
Time frame: 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).
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | Serious Adverse Events | 35 participants with events |
| Standard of Care (>=14kg Cohort) | Serious Adverse Events | 40 participants with events |
| Dolutegravir (<14kg Cohort) | Serious Adverse Events | 11 participants with events |
| Standard of Care (<14kg Cohort) | Serious Adverse Events | 11 participants with events |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Serious Adverse Events | 23 participants with events |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Serious Adverse Events | 27 participants with events |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Serious Adverse Events | 12 participants with events |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Serious Adverse Events | 13 participants with events |
Comparison: Statistical Analysis Title: Adjusted time to first event (\>=14kg)~Number of subjects included in analysis: 707~Analysis Specification: Pre-specifiedp-value: =0.5395% CI: [0.55, 1.36]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (\<14kg)~Number of subjects included in analysis: 85~Analysis Specification: Pre-specifiedp-value: =0.8695% CI: [0.47, 2.49]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (ODYSSEY A \>=14kg)~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: =0.5295% CI: [0.48, 1.46]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (ODYSSEY B \>=14kg)~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: =0.8695% CI: [0.42, 2.04]Regression, Cox
Secondary
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)
Time frame: 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).
Secondary
Treatment Failure by 144 Weeks
Treatment failure by 144 weeks. Difference in proportion with clinical or virological failure (as defined above)
Time frame: 144 weeks post randomisation
Population: Note: analysis could not be performed in \<14kg cohort due to shorter follow-up
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dolutegravir (>=14kg Cohort) | Treatment Failure by 144 Weeks | Death | 0 Participants |
| Dolutegravir (>=14kg Cohort) | Treatment Failure by 144 Weeks | Severe WHO stage 3 | 0 Participants |
| Dolutegravir (>=14kg Cohort) | Treatment Failure by 144 Weeks | Confirmed viral load>400c/mL | 48 Participants |
| Dolutegravir (>=14kg Cohort) | Treatment Failure by 144 Weeks | WHO stage 4 | 8 Participants |
| Dolutegravir (>=14kg Cohort) | Treatment Failure by 144 Weeks | Insufficient virologic response | 0 Participants |
| Standard of Care (>=14kg Cohort) | Treatment Failure by 144 Weeks | Severe WHO stage 3 | 1 Participants |
| Standard of Care (>=14kg Cohort) | Treatment Failure by 144 Weeks | WHO stage 4 | 5 Participants |
| Standard of Care (>=14kg Cohort) | Treatment Failure by 144 Weeks | Death | 2 Participants |
| Standard of Care (>=14kg Cohort) | Treatment Failure by 144 Weeks | Confirmed viral load>400c/mL | 76 Participants |
| Standard of Care (>=14kg Cohort) | Treatment Failure by 144 Weeks | Insufficient virologic response | 3 Participants |
| Dolutegravir (<14kg Cohort) | Treatment Failure by 144 Weeks | Insufficient virologic response | 0 Participants |
| Dolutegravir (<14kg Cohort) | Treatment Failure by 144 Weeks | Severe WHO stage 3 | 0 Participants |
| Dolutegravir (<14kg Cohort) | Treatment Failure by 144 Weeks | WHO stage 4 | 6 Participants |
| Dolutegravir (<14kg Cohort) | Treatment Failure by 144 Weeks | Death | 0 Participants |
| Dolutegravir (<14kg Cohort) | Treatment Failure by 144 Weeks | Confirmed viral load>400c/mL | 13 Participants |
| Standard of Care (<14kg Cohort) | Treatment Failure by 144 Weeks | Insufficient virologic response | 2 Participants |
| Standard of Care (<14kg Cohort) | Treatment Failure by 144 Weeks | Death | 1 Participants |
| Standard of Care (<14kg Cohort) | Treatment Failure by 144 Weeks | Severe WHO stage 3 | 0 Participants |
| Standard of Care (<14kg Cohort) | Treatment Failure by 144 Weeks | Confirmed viral load>400c/mL | 28 Participants |
| Standard of Care (<14kg Cohort) | Treatment Failure by 144 Weeks | WHO stage 4 | 5 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 144 Weeks | WHO stage 4 | 2 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 144 Weeks | Insufficient virologic response | 0 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 144 Weeks | Severe WHO stage 3 | 0 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 144 Weeks | Confirmed viral load>400c/mL | 35 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 144 Weeks | Death | 0 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 144 Weeks | Confirmed viral load>400c/mL | 48 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 144 Weeks | WHO stage 4 | 0 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 144 Weeks | Insufficient virologic response | 1 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 144 Weeks | Death | 1 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 144 Weeks | Severe WHO stage 3 | 1 Participants |
Comparison: Statistical Analysis Title: Diff in adj. KM estimates (\>=14kg)~Statistical analysis description: Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 144 weeks after randomisation.~Number of subjects included in analysis: 707~Analysis Specification: Pre-specifiedp-value: =0.00395% CI: [-0.16, -0.04]Bootstrap method
Comparison: Statistical Analysis Title: Diff in adj. KM estimates (ODYSSEY A \>=14kg)~Statistical analysis description: Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 144 weeks after randomisation.~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: =0.00995% CI: [-0.21, -0.03]Bootstrap method
Comparison: Statistical Analysis Title: Diff in adj. KM estimates (ODYSSEY B \>=14kg)~Statistical analysis description: Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 144 weeks after randomisation.~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: =0.07995% CI: [-0.16, 0.01]Bootstrap method
Secondary
Treatment Failure by 48 Weeks
Treatment failure by 48 weeks. Difference in proportion with clinical or virological failure (as defined above)
Time frame: 48 weeks post randomisation
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dolutegravir (>=14kg Cohort) | Treatment Failure by 48 Weeks | WHO stage 4 | 7 Participants |
| Dolutegravir (>=14kg Cohort) | Treatment Failure by 48 Weeks | Death | 0 Participants |
| Dolutegravir (>=14kg Cohort) | Treatment Failure by 48 Weeks | Severe WHO stage 3 | 0 Participants |
| Dolutegravir (>=14kg Cohort) | Treatment Failure by 48 Weeks | Insufficient virologic response | 0 Participants |
| Dolutegravir (>=14kg Cohort) | Treatment Failure by 48 Weeks | Confirmed viral load >400c/ml | 13 Participants |
| Standard of Care (>=14kg Cohort) | Treatment Failure by 48 Weeks | Insufficient virologic response | 3 Participants |
| Standard of Care (>=14kg Cohort) | Treatment Failure by 48 Weeks | Confirmed viral load >400c/ml | 31 Participants |
| Standard of Care (>=14kg Cohort) | Treatment Failure by 48 Weeks | Death | 2 Participants |
| Standard of Care (>=14kg Cohort) | Treatment Failure by 48 Weeks | WHO stage 4 | 5 Participants |
| Standard of Care (>=14kg Cohort) | Treatment Failure by 48 Weeks | Severe WHO stage 3 | 1 Participants |
| Dolutegravir (<14kg Cohort) | Treatment Failure by 48 Weeks | Death | 2 Participants |
| Dolutegravir (<14kg Cohort) | Treatment Failure by 48 Weeks | Severe WHO stage 3 | 0 Participants |
| Dolutegravir (<14kg Cohort) | Treatment Failure by 48 Weeks | Insufficient virologic response | 0 Participants |
| Dolutegravir (<14kg Cohort) | Treatment Failure by 48 Weeks | WHO stage 4 | 1 Participants |
| Dolutegravir (<14kg Cohort) | Treatment Failure by 48 Weeks | Confirmed viral load >400c/ml | 4 Participants |
| Standard of Care (<14kg Cohort) | Treatment Failure by 48 Weeks | Confirmed viral load >400c/ml | 11 Participants |
| Standard of Care (<14kg Cohort) | Treatment Failure by 48 Weeks | Death | 3 Participants |
| Standard of Care (<14kg Cohort) | Treatment Failure by 48 Weeks | Severe WHO stage 3 | 0 Participants |
| Standard of Care (<14kg Cohort) | Treatment Failure by 48 Weeks | Insufficient virologic response | 0 Participants |
| Standard of Care (<14kg Cohort) | Treatment Failure by 48 Weeks | WHO stage 4 | 1 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 48 Weeks | Severe WHO stage 3 | 0 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 48 Weeks | WHO stage 4 | 5 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 48 Weeks | Insufficient virologic response | 0 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 48 Weeks | Death | 0 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 48 Weeks | Confirmed viral load >400c/ml | 4 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 48 Weeks | Confirmed viral load >400c/ml | 12 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 48 Weeks | Insufficient virologic response | 2 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 48 Weeks | Severe WHO stage 3 | 0 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 48 Weeks | WHO stage 4 | 5 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Treatment Failure by 48 Weeks | Death | 1 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Treatment Failure by 48 Weeks | Severe WHO stage 3 | 0 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Treatment Failure by 48 Weeks | Insufficient virologic response | 0 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Treatment Failure by 48 Weeks | Death | 0 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Treatment Failure by 48 Weeks | WHO stage 4 | 2 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Treatment Failure by 48 Weeks | Confirmed viral load >400c/ml | 9 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Treatment Failure by 48 Weeks | Severe WHO stage 3 | 1 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Treatment Failure by 48 Weeks | Confirmed viral load >400c/ml | 19 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Treatment Failure by 48 Weeks | Death | 1 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Treatment Failure by 48 Weeks | Insufficient virologic response | 1 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Treatment Failure by 48 Weeks | WHO stage 4 | 0 Participants |
Comparison: Statistical Analysis Title: Diff in adj. KM estimates (\>=14kg)~Statistical analysis description: Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 48 weeks after randomisation.~Number of subjects included in analysis: 707~Analysis Specification: Pre-specifiedp-value: =0.00395% CI: [-0.1, -0.02]Bootstrap method
Comparison: Statistical Analysis Title: Diff in adj. KM estimates (ODYSSEY A \>=14kg)~Statistical analysis description: Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 48 weeks after randomisation.~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: =0.03595% CI: [-0.13, -0.01]Bootstrap method
Comparison: Statistical Analysis Title: Diff in adj. KM estimates (ODYSSEY B \>=14kg)~Statistical analysis description: Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 48 weeks after randomisation.~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: =0.03995% CI: [-0.11, -0.004]Bootstrap method
p-value: 0.05795% CI: [-0.36, 0.02]Other [Bootstrap method]
Secondary
WHO 4, Severe WHO 3 Events and Death
Rate of clinical events : WHO 4, severe WHO 3 events and death
Time frame: 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).
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dolutegravir (>=14kg Cohort) | WHO 4, Severe WHO 3 Events and Death | 8 Participants |
| Standard of Care (>=14kg Cohort) | WHO 4, Severe WHO 3 Events and Death | 8 Participants |
| Dolutegravir (<14kg Cohort) | WHO 4, Severe WHO 3 Events and Death | 3 Participants |
| Standard of Care (<14kg Cohort) | WHO 4, Severe WHO 3 Events and Death | 6 Participants |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | WHO 4, Severe WHO 3 Events and Death | 6 Participants |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | WHO 4, Severe WHO 3 Events and Death | 6 Participants |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | WHO 4, Severe WHO 3 Events and Death | 2 Participants |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | WHO 4, Severe WHO 3 Events and Death | 2 Participants |
Comparison: Statistical Analysis Title: Adjusted time to first event (\>=14kg)~Number of subjects included in analysis: 707~Analysis Specification: Pre-specifiedp-value: =0.99395% CI: [0.38, 2.68]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (\<14kg)~Number of subjects included in analysis: 85~Analysis Specification: Pre-specifiedp-value: =0.3395% CI: [0.13, 2]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (ODYSSEY A \>=14kg)~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: =0.99195% CI: [0.32, 3.12]Regression, Cox
Comparison: Statistical Analysis Title: Adjusted time to first event (ODYSSEY B \>=14kg)~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: =0.99795% CI: [0.14, 7.13]Regression, Cox
Other Pre-specified
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.
Time frame: 96 weeks post randomisation
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dolutegravir (>=14kg Cohort) | Mean Change in BMI-for-age Z-score From Baseline | 0.24 Z-score | Standard Error 0.04 |
| Standard of Care (>=14kg Cohort) | Mean Change in BMI-for-age Z-score From Baseline | 0.11 Z-score | Standard Error 0.04 |
| Dolutegravir (<14kg Cohort) | Mean Change in BMI-for-age Z-score From Baseline | 1.1 Z-score | Standard Error 0.3 |
| Standard of Care (<14kg Cohort) | Mean Change in BMI-for-age Z-score From Baseline | 1.5 Z-score | Standard Error 0.3 |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Mean Change in BMI-for-age Z-score From Baseline | 0.36 Z-score | Standard Error 0.07 |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Mean Change in BMI-for-age Z-score From Baseline | 0.20 Z-score | Standard Error 0.07 |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Mean Change in BMI-for-age Z-score From Baseline | 0.14 Z-score | Standard Error 0.05 |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Mean Change in BMI-for-age Z-score From Baseline | 0.04 Z-score | Standard Error 0.05 |
p-value: 0.595% CI: [-1.1, 0.5]Regression, Linear
Comparison: Statistical Analysis Title: Adjusted Difference (\>=14kg)~Statistical analysis description: Linear regression of BMI-for-age at week 96, adjusting for randomised arm, baseline BMI-for-age and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 707~Analysis Specification: Pre-specifiedp-value: =0.03695% CI: [0.01, 0.25]Regression, Linear
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY A \>=14kg)~Statistical analysis description: Linear regression of BMI-for-age at week 96, adjusting for randomised arm, baseline BMI-for-age and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: =0.09295% CI: [-0.03, 0.36]Regression, Linear
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY B \>=14kg)~Statistical analysis description: Linear regression of BMI-for-age at week 96, adjusting for randomised arm, baseline BMI-for-age and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: =0.17695% CI: [-0.05, 0.25]Regression, Linear
Other Pre-specified
Mean Change in Weight From Baseline
Mean change in weight from baseline to week 96
Time frame: 96 weeks post randomisation
Population: Results not presented by ODYSSEY A and B in \<14kg cohort due to due ODYSSEY B having too few participants (n=13).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dolutegravir (>=14kg Cohort) | Mean Change in Weight From Baseline | 7.1 kg | Standard Error 0.3 |
| Standard of Care (>=14kg Cohort) | Mean Change in Weight From Baseline | 6.1 kg | Standard Error 0.3 |
| Dolutegravir (<14kg Cohort) | Mean Change in Weight From Baseline | 5.0 kg | Standard Error 0.2 |
| Standard of Care (<14kg Cohort) | Mean Change in Weight From Baseline | 5.1 kg | Standard Error 0.2 |
| Dolutegravir - ODYSSEY A (>=14kg Cohort) | Mean Change in Weight From Baseline | 7.8 kg | Standard Error 0.4 |
| Standard of Care - ODYSSEY A (>=14kg Cohort) | Mean Change in Weight From Baseline | 6.5 kg | Standard Error 0.4 |
| Dolutegravir - ODYSSEY B (>=14kg Cohort) | Mean Change in Weight From Baseline | 6.7 kg | Standard Error 0.3 |
| Standard of Care - ODYSSEY B (>=14kg Cohort) | Mean Change in Weight From Baseline | 5.9 kg | Standard Error 0.3 |
Comparison: Statistical Analysis Title: Adjusted Difference (\>=14kg)~Number of subjects included in analysis: 707~Analysis Specification: Pre-specifiedp-value: =0.00495% CI: [0.3, 1.7]Regression, Linear
Comparison: Statistical Analysis Title: Adjusted Difference (ODYSSEY A \>=14kg)~Statistical analysis description: Linear regression of weight at week 96, adjusting for randomised arm, baseline weight and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 311~Analysis Specification: Pre-specifiedp-value: =0.02495% CI: [0.2, 2.5]Regression, Linear
Comparison: Statistical Analysis Title: Adjusting Difference (ODYSSEY B \>=14kg)~Statistical analysis description: Linear regression of weight at week 96, adjusting for randomised arm, baseline weight and stratification factors. Presenting mean difference between arms.~Number of subjects included in analysis: 396~Analysis Specification: Pre-specifiedp-value: =0.07595% CI: [-0.1, 1.6]Regression, Linear
p-value: 0.6795% CI: [-0.8, 0.5]Regression, Linear