Genotype-Informed Versus Empiric Management of VirEmia

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.

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