Dolutegravir in Real Life in Lesotho (DO-REAL)

Observational Assessment of the Nation-wide Roll-out of Dolutegravir in Lesotho

DO-REAL is an observational cohort study assessing the large-scale roll-out of the antiretroviral drug dolutegravir (DTG) in Lesotho.

DTG has been shown to have low side-effects and superior treatment outcomes for people living with HIV-1 when compared to other antiretroviral drugs currently in use in low-income countries. The use of DTG in first-line antiretroviral therapy (ART) regimens was recommended by the World Health Organisation in 2018 and adopted by the Ministry of Health in Lesotho in 2019. While DTG-based ART regimens have led to promising health outcomes in high-income and clinical trial settings, certain concerns remain regarding the risk of ART-experienced patients transitioning to a DTG-based ART regimen being placed on a functional monotherapy (increasing the otherwise low risk of viral resistance to DTG) as well as side-effects including psychological symptoms and weight gain.

Thus, the DO-REAL study intends to address these concerns and provide data on health outcomes of HIV patients on DTG in a "real-life" high-prevalence setting.

Study Overview

• Status: Completed
• Conditions: HIV-1-infection
• Intervention / Treatment: Drug: Dolutegravir

Detailed Description

SUMMARY: DO-REAL is an observational cohort study assessing the large-scale roll-out of the antiretroviral drug dolutegravir (DTG) in Lesotho.

BACKGROUND: DTG is a second-generation integrase strand transfer inhibitor with low side-effects and superior treatment outcomes for people living with HIV-1 when compared to other antiretroviral drugs currently in use in low-income countries. Though some cases have been described, HIV-1 resistance to DTG is rare in clinical settings when DTG is used as part of a combination therapy. The use of DTG in first-line antiretroviral therapy (ART) regimens was recommended by the World Health Organisation in 2018 and was adopted by the Ministry of Health in Lesotho in 2019. DTG now forms part of the recommended first-line therapy for many ART-naïve patients in Lesotho. In addition, many patients on a non-DTG-based first-line ART regimen will be transitioned to a DTG-based regimen.

OBJECTIVES: Despite the positive health outcomes observed in patients receiving DTG-based ART in high-income countries and in clinical trial settings, there is little data on virologic outcomes of patients on DTG during large-scale implementation in low- and lower middle-income countries. Concerns remain regarding the risk that some patients transitioning to a DTG-based regimen will be placed on a functional monotherapy. Furthermore, there are concerns as to psychological side-effects and observed weight gain. This observational study aims to assess the virologic outcomes (viral suppression rates as well as potential drug resistance) as well as side-effects of people living with HIV-1 and transitioning to a DTG-based ART regimen in Lesotho.

DO-REAL has two major objectives:

• To assess virologic outcomes after the programmatic shift to DTG-based regimens.
• To assess psychological and somatic wellbeing in patients before and after the programmatic shift to DTG-based regimens.

METHODS: DO-REAL is a cohort study enrolling people living with HIV who are initiating or are eligible (according to national guidelines and the local implementation thereof) to initiate a DTG-based antiretroviral therapy (ART) regimen. The study will take place at three hospitals in two districts (Butha-Buthe, Mokhotlong) in Lesotho, and aims to enrol over 2000 participants. Viral loads will be measured on the day of initiating a DTG-based regimen (or on the day this was offered), as well as four, 12 and 24 months thereafter. In a post-hoc analysis, samples will be tested for drug resistance in samples where the viral load permits (approx. ≥100 c/mL). A subset of participants will complete screenings for depression, general health, and HIV-related symptoms.

• Study Type: Observational
• Enrollment (Actual): 1433

Contacts and Locations

Study Locations

• Lesotho
  • Butha-Buthe, Lesotho
    • Butha-Buthe Government Hospital
  • Butha-Buthe, Lesotho
    • Seboche Mission Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Participants will be enrolled at two government hospitals and one missionary hospital in two districts (Butha-Buthe and Mokhotlong) in Lesotho.

Description

Inclusion Criteria:

• HIV-1-positive
• Initiating or eligible to initiate (offered to initiate) a DTG-based ART regimen
• Informed written consent (and assent, if applicable) provided

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HIV-1-positive individuals; HIV-1-positive individuals eligible to receive a DTG-based ART regimen at enrolment.	Drug: Dolutegravir; Eligibility to receive DTG-based ART at enrolment (i.e., initiation or offer to initiate DTG-based ART)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virologic outcomes after programmatic transition to DTG-containing regimens	Viral load	4 months after initiation of a DTG-containing regimen
Quality of life screening score (change from baseline)	12-Item Short Form Health Survey (SF-12; 12-item index in which questions are scored and weighted into 2 subscales, physical health and mental health; scores can range from 0-100 with higher scores indicating higher physical or mental health)	Change between time of initiation of a DTG-containing ART regimen and 4 months thereafter
Depression screening score (change from baseline)	Patient Health Questionnaire-9 (PHQ-9; 9-item index with each item scored 0-3, providing a 0-27 severity score with a higher score indicating higher severity)	Change between time of initiation of a DTG-containing ART regimen and 4 months thereafter
HIV symptom screening score (change from baseline)	Modified HIV Symptom Index (21-item index with each item scored 0-4, providing a 0-84 severity score with a higher score indicating higher severity)	Change between time of initiation of a DTG-containing ART regimen and 4 months thereafter

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virologic status at programmatic transition to DTG-containing regimens	Viral load (post-hoc analysis)	On day of initiation of a DTG-containing regimen
Viral drug resistance at programmatic transition to DTG-containing regimens	HIV-1 drug resistance (assessed by Sanger sequencing) in the case of an unsuppressed viral load (post-hoc analysis)	On day of initiation of a DTG-containing ART regimen
Weight (change from baseline)	Change from time of enrolment; median and interquartile range; in kg	On day of initiation of a DTG-containing ART regimen and 4, 12 and 24 months thereafter
Reasons for discontinuation of a DTG-containing regimen	Reasons for discontinuing a DTG-containing regimen as noted in medical records, where applicable	Up to 24 months after enrolment
Long-term virologic outcomes after programmatic transition to DTG-containing regimens	Viral load	12 and 24 months after initiation of a DTG-containing regimen
Viral drug resistance after programmatic transition to DTG-containing regimens	HIV-1 drug resistance (assessed by Sanger sequencing) in the case of an unsuppressed viral load	4, 12 and 24 months after initiation of a DTG-containing regimen

Collaborators and Investigators

• Sponsor: Swiss Tropical & Public Health Institute
• Collaborators: University of Basel; Ministry of Health, Lesotho; District Health Management Team of Butha-Buthe, Lesotho; SolidarMed; District Health Management Team of Mokhotlong, Lesotho
• Investigators: Study Director: Josephine Muhairwe, MD, MPH, SolidarMed Lesotho; Principal Investigator: Jennifer A Brown, MSc, MAS D&C, Swiss Tropical & Public Health Institute; Study Chair: Niklaus D Labhardt, MD, MIH, Swiss Tropical & Public Health Institute; Study Director: Thomas Klimkait, PhD, University of Basel

Publications and helpful links

General Publications

• Brown JA, Nsakala BL, Mokhele K, Rakuoane I, Muhairwe J, Urda L, Amstutz A, Tschumi N, Klimkait T, Labhardt ND. Viral suppression after transition from nonnucleoside reverse transcriptase inhibitor- to dolutegravir-based antiretroviral therapy: A prospective cohort study in Lesotho (DO-REAL study). HIV Med. 2022 Mar;23(3):287-293. doi: 10.1111/hiv.13189. Epub 2021 Oct 10.
• Brown JA, Nsakala BL, Mokhele K, Rakuoane I, Muhairwe J, Glass TR, Amstutz A, Tschumi N, Belus JM, Klimkait T, Labhardt ND. Dolutegravir in real life: Self-reported mental and physical health outcomes after transitioning from efavirenz- to dolutegravir-based antiretroviral therapy in a prospective cohort study in Lesotho. HIV Med. 2023 Feb;24(2):153-162. doi: 10.1111/hiv.13352. Epub 2022 Jun 22.

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2020
• Primary Completion (Actual): May 19, 2021
• Study Completion (Actual): May 20, 2021

Study Registration Dates

• First Submitted: November 14, 2019
• First Submitted That Met QC Criteria: January 22, 2020
• First Posted (Actual): January 23, 2020

Study Record Updates

• Last Update Posted (Actual): May 23, 2023
• Last Update Submitted That Met QC Criteria: May 19, 2023
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: HIV-1; AIDS; Lesotho; sub-Saharan Africa; dolutegravir; antiretroviral therapy
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Dolutegravir
• Other Study ID Numbers: P001-19-1.2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Pseudonymized dataset for the published manuscripts "Viral suppression after transition from nonnucleoside reverse transcriptase inhibitor- to dolutegravir-based antiretroviral therapy: A prospective cohort study in Lesotho (DO-REAL study)" and "Dolutegravir in Real Life: self-reported mental and physical health outcomes after transitioning from efavirenz- to dolutegravir-based antiretroviral therapy in a prospective cohort study in Lesotho" are publicly available on Zenodo:

https://zenodo.org/record/5948369 https://zenodo.org/record/6654462

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: 10.5281/zenodo.6654462
   Information comments:

   Dataset relating to:

   Brown JA, Nsakala BL, Mokhele K, et al. Dolutegravir in real life: Self-reported mental and physical health outcomes after transitioning from efavirenz- to dolutegravir-based antiretroviral therapy in a prospective cohort study in Lesotho. HIV Med. Published online June 22, 2022. doi:10.1111/hiv.13352

2. Individual Participant Data Set
   Information comments:

   Dataset relating to:

   Brown JA, Nsakala BL, Mokhele K, et al. Viral suppression after transition from nonnucleoside reverse transcriptase inhibitor- to dolutegravir-based antiretroviral therapy: A prospective cohort study in Lesotho (DO-REAL study). HIV Med. 2022;23(3):287-293. doi:10.1111/hiv.13189

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No