Clinical trial NCT04233242: Genotype-Informed Versus Empiric Management of VirEmia
Official title: Genotype-Informed Versus Empiric Management of VirEmia (GIVE MOVE) in HIV-Infected Children and Adolescents on Antiretroviral Therapy: An Open-Label Randomised Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV-1-infection
Keywords: HIV-1
acquired immunodeficiency syndrome
drug resistance
treatment failure
child
adolescent
Lesotho
Tanzania
Lead sponsor: Swiss Tropical & Public Health Institute
Sponsor class: OTHER
Collaborators: name: University Hospital, Basel, Switzerland
name: University of Basel
name: SolidarMed, Partnerships for Health
name: Seboche Mission Hospital
name: Ifakara Health Institute
name: Baylor College of Medicine Children's Foundation
First posted: 2020-01-18
Enrollment: 286
Sex: ALL
Minimum age (years): 6
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-centre, open-label, parallel-group (1:1 allocation), superiority randomised clinical trial
Primary purpose: DIAGNOSTIC

Brief summary: HIV infection can be effectively controlled with antiretroviral therapy (ART). However, children and adolescents living with HIV and receiving ART suffer high rates of treatment failure, predominantly caused by suboptimal adherence to therapy and/or viral drug resistance. While high-income countries routinely use genotypic resistance testing (GRT) to determine which drug combinations are likely to be effective, this diagnostic tool is relatively costly and labour-intensive and is not routinely available in most resource-limited settings.

GIVE MOVE is a multi-country (Lesotho, Tanzania) randomised clinical trial assessing if rapid GRT after detecting an unsuppressed viral load improves the clinical management and thus health outcomes for children and adolescents living with HIV. Children and adolescents with an unsuppressed viral load despite ART are enrolled and randomly allocated to a control or an intervention arm (50% of participants in each arm). The control arm receives care according to the current standard of care, consisting of three sessions of enhanced adherence counselling at monthly intervals, followed by a second viral load test. Onward treatment is informed by the outcome of this viral load test alongside empirical guidelines and clinical judgement. The intervention arm receives GRT and GRT-informed onward therapy. Participants in the intervention arm also receive three sessions of enhanced adherence counselling, which is informed by GRT results (i.e., if no drug resistance is detected, there is a high chance of suboptimal adherence to ART and this can be directly addressed).

This trial will assess if the rapid provision of GRT improves participants' health outcomes at 9 months after enrolment. A nested study will assess the cost and cost-effectiveness of GRT. Thus, this trial will provide evidence on whether the provision of GRT for children and adolescents with HIV should be prioritised in resource-limited settings.

Detailed description: Background and rationale:

Children and adolescents living with HIV and receiving antiretroviral therapy (ART) suffer high rates of treatment failure, predominantly caused by suboptimal adherence to therapy and/or viral drug resistance. While high-income countries routinely use genotypic resistance testing (GRT) to select an optimal ART regimen, this diagnostic tool is not routinely available in many resource-limited settings.

Objective:

The GIVE MOVE trial assesses if rapid GRT after detection of an unsuppressed viral load in children and adolescents on ART improves health outcomes when compared to the current standard of care. Furthermore, a nested study will assess the cost-effectiveness of this intervention. Combined, these results will provide evidence on whether GRT should be prioritised for children and adolescents with HIV.

Study design:

GIVE MOVE is a multi-centre (several centres in 2 countries, Lesotho and Tanzania), parallel-group (1:1 allocation), open-label randomised clinical trial. Children and adolescents living with HIV with a viral load ≥400 c/mL are enrolled.

The control group is managed as per the current standard of care that follows the World Health Organization guidelines, i.e. three sessions of enhanced adherence counselling at monthly intervals, followed by a second viral load test and viral load-informed onward treatment.

In the intervention arm, participants receive GRT, a GRT-informed treatment recommendation by a GRT Expert Committee, and GRT-informed onward therapy, selecting the best locally available drugs according to the drug resistance profile.

The GIVE MOVE trial will compare clinical outcomes (mortality, morbidity, viral suppression; see the Primary Outcome section for the composite primary endpoint) at nine months. Assuming that 20% vs 35% reach the primary endpoint in the intervention vs control arm, and at a significance level of 5%, 276 participants (138 per arm) are required to reach 80% power.

In addition to clinical outcomes, the trial intends to assess the cost and cost-effectiveness of the intervention. The GIVE MOVE trial aims at informing future clinical guidelines on the management of paediatric HIV.

Eligibility criteria: Inclusion Criteria:

* In care in a study site
* Age ≥6 months and \<19 years
* Latest HIV viral load result ≥400 c/mL
* On an unchanged ART regimen for ≥6 months
* Phlebotomy for latest viral load test \<4 months before screening
* Consent given

Exclusion Criteria:

* Indication for treatment switch according to WHO guidelines at screening
* 1st enhanced adherence counselling (EAC) session initiated \>2 weeks prior to screening
* Intention to transfer out of the study site (and not into a different study site) within 3 months after randomisation
* Already enrolled in another study if judged as non-compatible by the (Local) Principal Investigator
* Pregnant or breastfeeding at screening (no exclusion based on pregnancy or breastfeeding after enrolment)
* Acute illness requiring hospitalisation at screening (no exclusion based on hospitalisation after enrolment)
* Received a resistance test in the last 12 months

Primary outcomes:
measure: Composite primary endpoint
timeFrame: At 9 months follow-up visit (window: 32-44 weeks)
Secondary outcomes:
measure: Proportion with death due to any cause
timeFrame: Within 36 weeks after baseline
measure: Proportion with HIV- or ART-related hospital admission of ≥24 hours duration
timeFrame: Within 36 weeks after baseline
measure: Proportion with new clinical WHO stage IV event(s) (with some exclusions)
timeFrame: Within 36 weeks after baseline
measure: Proportion without documentation of a suppressed viral load
timeFrame: At 9 months follow-up visit (window: 32-44 weeks)
measure: Proportion lost to follow-up
timeFrame: At 9 months follow-up visit (window: 32-44 weeks)
measure: Proportion with observed virologic failure
timeFrame: At 9 months follow-up visit (window: 32-44 weeks)
measure: Composite endpoint
timeFrame: 6 months (window: 20-28 weeks) after the decision on onward treatment
Other outcomes:
measure: Time to viral suppression
timeFrame: 3- (window: 10-14 weeks), 6- (window: 20-28 weeks), and 9-month (window: 32-44 weeks) study visit
measure: Proportion with drug regimen switches in the absence of major drug resistance mutations and/or non-switches in the presence of major drug resistance mutations
timeFrame: Baseline and 9-month (window: 32-44 weeks) study visit
measure: Proportion with new drug resistance mutations emerged within the study period
timeFrame: Change from baseline to 9-month (window: 32-44 weeks) study visit
Locations:
city: Seboche
country: Lesotho
facility: Seboche Mission Hospital
state: Butha-Buthe
city: Hlotse
country: Lesotho
facility: Baylor Clinic Leribe
state: Leribe
city: Butha-Buthe
country: Lesotho
facility: Baylor Clinic Butha-Buthe
city: Maseru
country: Lesotho
facility: Baylor Clinic Maseru
city: Mohale's Hoek
country: Lesotho
facility: Baylor Clinic Mohale's Hoek
city: Mokhotlong
country: Lesotho
facility: Baylor Clinic Mokhotlong
city: Ifakara
country: Tanzania
facility: One-Stop Clinic and Chronic Diseases Clinic (CDCI) at St Francis Referral Hospital
state: Morogoro
city: Dar Es Salaam
country: Tanzania
facility: Mbagala Rangi Tatu Hospital
city: Dar es Salaam
country: Tanzania
facility: Temeke Regional Referral Hospital
city: Dar Es Salaam
country: Tanzania
facility: Upendano Dispensary
Study officials:
affiliation: Swiss Tropical & Public Health Institute
name: Niklaus D Labhardt, MD, MIH
role: STUDY_CHAIR
affiliation: Swiss Tropical & Public Health Institute
name: Jennifer A Brown, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Basel
name: Thomas Klimkait, PhD
role: STUDY_DIRECTOR
affiliation: SolidarMed, Partnerships for Health
name: Josephine Muhairwe, MD, MPH
role: STUDY_DIRECTOR
affiliation: Baylor College of Medicine Children's Foundation Lesotho
name: Buntshi P Kayembe, MD
role: STUDY_DIRECTOR
affiliation: Baylor College of Medicine Children's Foundation Lesotho
name: Mosa M Hlasoa, MD
role: STUDY_DIRECTOR
affiliation: SolidarMed, Partnerships for Health
name: Isaac Ringera, MPH, RN
role: STUDY_DIRECTOR
affiliation: Swiss Tropical & Public Health Institute
name: Maja Weisser, MD
role: STUDY_DIRECTOR
affiliation: Ifakara Health Institute
name: Ezekiel Luoga, MD
role: STUDY_DIRECTOR
affiliation: Swiss Tropical & Public Health Institute
name: Tracy R Glass, PhD
role: STUDY_DIRECTOR
References:
citation: Brown JA, Ringera I, Luoga E, Cheleboi M, Kimera N, Muhairwe J, Kayembe BP, Molapo Hlasoa M, Kabundi L, Yav CWD, Mothobi B, Thahane L, Amstutz A, Bachmann N, Mollel GJ, Bresser M, Glass TR, Paris DH, Klimkait T, Weisser M, Labhardt ND. Genotype-Informed Versus Empiric Management Of VirEmia (GIVE MOVE): study protocol of an open-label randomised clinical trial in children and adolescents living with HIV in Lesotho and Tanzania. BMC Infect Dis. 2020 Oct 19;20(1):773. doi: 10.1186/s12879-020-05491-9.
citation: Brown JA, Ringera IK, Luoga E, Bresser M, Mothobi B, Kabundi L, Ilunga M, Mokhele K, Isaac AB, Tsoaeli N, Mbaya T, Simba B, Mayogu K, Mabula E, Cheleboi M, Molatelle M, Kimera N, Mollel GJ, Sando D, Tschumi N, Amstutz A, Thahane L, Hlasoa MM, Kayembe BP, Muhairwe J, Klimkait T, Glass TR, Weisser M, Labhardt ND. Resistance-informed versus empirical management of viraemia in children and adolescents with HIV in Lesotho and Tanzania (GIVE MOVE trial): a multisite, open-label randomised controlled trial. Lancet Glob Health. 2024 Aug;12(8):e1312-e1322. doi: 10.1016/S2214-109X(24)00183-9.