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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 258

Contacts and Locations

Study Locations

• Lesotho
  • Maseru, Lesotho
    • Baylor Center of Excellence Maseru

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Children and adolescents living with HIV, receiving treatment, and transitioning from ritonavir-boosted lopinavir-based to dolutegravir-based antiretroviral therapy in the context of the national rollout of dolutegravir.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
No actigraphy; 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; 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?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with drug resistance among participants with viraemia while taking dolutegravir	Classified Stanford HIV drug resistance database (susceptible, potential low-level resistance, low-level resistance, intermediate resistance, high-level resistance) referring to each drug in the current ART regimen	until 24 months after transition
Impact of drug resistance at time of transition on subsequent viral suppression	Assessment whether resistance at transition predicts subsequent routinely assessed viral load outcomes	until 24 months after transition

Collaborators and Investigators

• Sponsor: Swiss Tropical & Public Health Institute
• Collaborators: University of Zurich; University Hospital, Basel, Switzerland; University of Basel; Baylor International Pediatric AIDS Initiative; Lesotho Ministry of Health; Baylor College of Medicine Children's Foundation Lesotho
• Investigators: Principal Investigator: Jennifer Brown, PhD, University of Basel; Principal Investigator: Akash Devendra, MBChB, Baylor International Paediatric AIDS Initiative

Study record dates

Study Major Dates

• Study Start (Actual): July 11, 2022
• Primary Completion (Actual): September 20, 2023
• Study Completion (Actual): September 20, 2023

Study Registration Dates

• First Submitted: June 11, 2022
• First Submitted That Met QC Criteria: June 15, 2022
• First Posted (Actual): June 22, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 10, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: tolerability; sleep; depression; children; insomnia; adolescents; cohort; adverse effects; dolutegravir; gastrointestinal; lopinavir; paediatric; treatment satisfaction; human immunodeficiency virus
• Other Study ID Numbers: P001-22-1.0; ID37-2022 (Other Identifier: National Health Research Ethics Committee (Lesotho)); H-51472 (Other Identifier: Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals); 3ZX1422 (Other Grant/Funding Number: University of Basel Research Fund)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data will be shared in a data repository upon publication of results.