Tolerability of Lopinavir Versus Dolutegravir for Children and Adolescents Living With HIV

Study Overview
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Brief Summary
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Dolutegravir-based antiretroviral therapy is set to be increasingly replace ritonavir-boosted lopinavir-based regimens for the treatment of paediatric HIV. This prospective cohort study aims to compare tolerability, adverse effects, and virological outcomes between the two regimen types using a before-after design. The study is conducted in Lesotho, southern Africa, and includes children and adolescents transitioning from ritonavir-boosted lopinavir-based to dolutegravir-based antiretroviral therapy. It aims to provide detailed information on treatment tolerability and to inform paediatric treatment programmes.

Detailed Description
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Dolutegravir, an antiretroviral drug to treat HIV, has recently been rolled out on a large scale across much of Africa. With paediatric formulations becoming increasingly available, dolutegravir is set to replace ritonavir-boosted lopinavir as the core agent in paediatric treatment regimens in many countries. While both drugs are well-studied and highly effective, they reportedly differ with regards to their tolerability at least in adults, with ritonavir-boosted lopinavir typically associated with gastrointestinal adverse effects and dolutegravir mostly associated with neuropsychiatric adverse effects including insomnia. Resistance patterns also differ between these two treatment options. However, studies focusing specifically on the tolerability of and adverse effects associated with either drug in children and adolescents are scarce. This prospective cohort study aims to i) compare treatment satisfaction, health-related quality of life, tolerability, and symptoms or side-effects associated with either drug option, ii) specifically compare sleep outcomes quantified through actigraphy with either drug option, and iii) provide observational evidence on virological outcomes in a resource-limited setting using a before-after design. The study is conducted at several sites in Lesotho, southern Africa. It enrols children and adolescents <18 years of age who are taking ritonavir-boosted lopinavir-based therapy at enrolment and routinely due to transition to dolutegravir-based therapy as per the national roll-out plan. On the day of transitioning to dolutegravir as well as four weeks thereafter, participants will complete questionnaires on treatment satisfaction, gastrointestinal symptoms, depressive symptoms, and sleep habits. A subset of participants fulfilling additional inclusion criteria will additionally use actigraphy sensors to monitor sleep duration and sleep fragmentation; these individuals will have study visits two weeks before transition to dolutegravir to initiate actigraphy, at transition, as well as two and four weeks after transition, with questionnaires at all but the pre-transition visit and actigraphy (target: at least seven nights with high-quality data) between all visits. For all participants, medical records will be assessed and additional clinical and sociodemographic data collected. A viral load test will be done on the day of transitioning to dolutegravir, and subsequent routine viral load test results (every six months as per national guidelines) will be assessed. Dried blood spots will be taken at all visits, barring the pre-transition visit for those with actigraphy. This study aims to inform the continued roll-out of dolutegravir replacing ritonavir-boosted lopinavir in paediatric antiretroviral therapy regimens, notably assessing the suitability of a one-size-fits-all approach and providing detailed information on tolerability and adverse effects of either regimen.

Official Title
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Tolerability of Lopinavir Versus Dolutegravir for Children and Adolescents Living With HIV (LoDoCA): a Prospective Cohort Study

Conditions
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HIV

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - general: Currently taking ritonavir-boosted lopinavir-containing antiretroviral therapy Eligible for dolutegravir-based antiretroviral therapy as per national roll-out/guidelines Age < 18 years Informed consent (as per consenting procedures) Exclusion Criteria - general: No transition to dolutegravir-based antiretroviral therapy foreseen Already enrolled in another study judged as non-compatible by the Principal Investigator or Local Principal Investigator Inclusion Criteria - actigraphy: Enrolled into main cohort Age ≥6 and <18 years Taking ritonavir-boosted lopinavir-containing antiretroviral therapy for at least 12 weeks Last viral load <50 copies/mL and taken within <36 weeks and while taking ritonavir-boosted lopinavir-containing antiretroviral therapy Willingness to wear an actimetry sensor every night for at least 7 nights (daytime wearing optional) Patient and/or caregiver judged to be able to fulfil requirements (wearing actimetry sensor; filling in sleep diary) by study team member conducting screening Stated ability to attend all study visits Informed consent (as per consenting procedures) Exclusion Criteria - actigraphy: Intention to transfer out of the study site (and not into a different study site) within 6 weeks No actimetry sensor available

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No actigraphy<br>Participants will receive viral load testing at transition from LPV/r-based to DTG-based ART, and subsequent routine viral load data will be analysed. Questionnaires will be filled in and dried blood spots collected at transition and at four weeks. Medical history as well as clinical and socio-demographic data will be collected. | |
| With actigraphy<br>Participants will receive viral load testing at transition from LPV/r-based to DTG-based ART, and subsequent routine viral load data will be analysed. Baseline actigraphy data will be collected for two weeks prior to transition (actigraphy period 1), and for four weeks after transition (actigraphy period 2 from 0-2 weeks after transition; actigraphy period 3 from 2-4 weeks after transition). Sleep diaries will be filled in during all actigraphy periods. Questionnaires will be filled in and dried blood spots taken at transition as well as two and four weeks after transition. Medical history as well as clinical and socio-demographic data will be collected. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sleep duration during monitoring period 3 (2-4 weeks post-transition) versus monitoring period 1 (0-2 weeks pre-transition) | Sleep will be monitored using actigraphy sensors for a subset of participants. There will be three sleep monitoring periods: 0-2 weeks before transition from ritonavir-boosted lopinavir- to dolutegravir-based antiretroviral therapy (period 1), 0-2 weeks after transition, and 2-4 weeks after transition). We will conduct a before-after analysis. | [2-4 weeks post-transition] vs [0-2 weeks pre-transition] | 
| Change in treatment satisfaction, assessed using the HIV Treatment Satisfaction Questionnaire (HIVTSQ) change version (HIVTSQ-c) | 10-item scale with each item scored from -3 to +3 (overall range -30 to +30), with higher scores indicating increases in treatment satisfaction | 4 weeks post-transition | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral suppression rate among those with virological data | Proportion of participants with a viral load <50 copies/mL among all participants with virological data | 6 months, 12 months, and 24 months after transition | 
| Engagement in care with viral suppression | Proportion of participants with a viral load <50 copies/mL among all participants | 6 months, 12 months, and 24 months after transition | 
| Sleep duration during monitoring period 2 (0-2 weeks post-transition) versus monitoring period 1 (0-2 weeks pre-transition) | Sleep will be monitored using actigraphy sensors for a subset of participants. There will be three sleep monitoring periods: 0-2 weeks before transition from ritonavir-boosted lopinavir- to dolutegravir-based antiretroviral therapy (period 1), 0-2 weeks after transition, and 2-4 weeks after transition). We will conduct a before-after analysis. | [0-2 weeks post-transition] vs [0-2 weeks pre-transition] | 
| Sleep fragmentation | Sleep will be monitored using actigraphy sensors for a subset of participants. There will be three sleep monitoring periods: 0-2 weeks before transition from ritonavir-boosted lopinavir- to dolutegravir-based antiretroviral therapy (period 1), 0-2 weeks after transition, and 2-4 weeks after transition). We will conduct a before-after analysis. | [2-4 weeks post-transition] vs [0-2 weeks pre-transition], and [0-2 weeks post-transition] vs [0-2 weeks pre-transition] | 
| Treatment satisfaction after vs before transition, assessed using the HIVTSQ status version (HIVTSQ-s) | 10-item scale with each item scored from 0 to 6 (overall range 0 to 60), with higher scores indicating higher treatment satisfaction. Two time points compared in a before-after analysis. | 4 weeks post-transition vs at transition | 
| Gastrointestinal symptoms after vs before transition, assessed using the Gastrointestinal Symptom Rating Scale adapted for protease inhibitors (GSRS-PI) | 13-item scale with each item scored from 1 to 6, with higher scores indicating greater discomfort. Two time points compared in a before-after analysis. | 4 weeks post-transition vs at transition | 
| Depressive symptoms after vs before transition, assessed using the Center for Epidemiological Studies Depression Scale for Children (CES-DC) | 20-item scale with each item scored from 0 to 3 (overall range 0 to 60), with higher scores indicating higher depressive symptoms. Two time points compared in a before-after analysis. | 4 weeks post-transition vs at transition | 
| Sleep outcomes after vs before transition, assessed using the Child Sleep Habits Questionnaire (CSHQ) or Adolescent Sleep Habits Questionnaire (ASHQ) | 33-item scale (2 items used in two subscales) with each item scored from 1 to 3, with higher scores indicating more sleep problems. Two time points compared in a before-after analysis. | 4 weeks post-transition vs at transition | 
| Health-related quality of life after vs before transition, assessed using the KINDL questionnaire | 24-item scale with each item scored from 1 to five, with higher scores indicating higher health-related quality of life | 4 weeks post-transition vs at transition | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dolutegravir, lopinavir, children, adolescents, paediatric, adverse effects, tolerability, treatment satisfaction, insomnia, sleep, gastrointestinal, depression, human immunodeficiency virus, cohort