Project: BREATHER Plus: A randomised open-label 3-arm, 96-week trial evaluating the efficacy, safety and acceptability of weekends off dolutegravir-based antiretroviral therapy (ART) and monthly long-acting injectable ART compared to daily dolutegravir-based ART in virologically suppressed HIV-infected children and adolescents in sub-Saharan Africa
| Acronym | BREATHER Plus (Reference Number: RIA2017MC-2005) |
| Duration | 01/01/2020 - 31/12/2024 |
| Project Topic | Over 2 million adolescents aged 10-19 years are living with HIV, with the majority in sub-Saharan Africa (SSA). Current recommendations are life-long, daily oral antiretroviral therapy (ART). However, it is clear that there is a need for novel ART strategies to improve quality-of-life, engagement in care and treatment adherence for the large numbers of perinatally HIV-infected children entering adolescence, and for adolescents newly-infected through sexual transmission. Young people expressed a strong preference for weekends off (2 days-off) compared to daily ART in the BREATHER trial (BREaks in Adolescent and child THerapy using Efavirenz and two nRtis] PENTA-16) which showed this approach was non-inferior and safe with 12-weekly viral load monitoring over nearly 4 years’ follow-up. Adult participants reported high levels of satisfaction with monthly long-acting injectable ART in the LATTE-2 study and Phase III studies are ongoing. The objective of this proposal is to evaluate innovative and contemporary ART strategies in HIV-infected adolescents to provide choice for young people facing life-long treatment. This will either be achieved by conducting one 3-arm randomised, open-label trial recruiting 690 adolescents aged 12 to <20 years or two 2-arm randomised, open-label trials recruiting 460 adolescents in each. Regardless of the design, all participants will be virologically suppressed on current daily ART in South Africa, Zimbabwe, Kenya and Uganda and followed for 96 weeks. BREATHER Plus will assess two different ART reduction strategies challenging the need for daily oral ART: first, through a weekends-off approach (building on BREATHER) using dolutegravir-based ART, which is beginning roll-out in SSA as first-line ART; and second, using monthly nucleoside-reverse transcriptase-inhibitor (NRTI)-sparing long-acting injectable ART. Both strategies will be compared to daily oral dolutegravir-based ART. Study drugs are to be provided by Cipla Ltd; in addition, oral cabotegravir and rilpivirine and the the long-acting injectables formulations of these antiretroviral drugs may be provided by Viiv Healthcare, and Janssen Pharmaceutical Company (a subsidiary of Johnson & Johnson). Importantly for generalisability to low- and middle-income settings, the trial will be conducted in settings where annual standard-of-care viral load monitoring is recommended by the World Health Organization; the trial has specific guidance for pregnancy and tuberculosis management. The trial(s) is (are) powered to demonstrate noninferior virological suppression over 96 weeks (margin 10%) for dolutegravir-based weekends-off and long-acting injectable ART independently versus continuous therapy and aims to show benefits in reduced toxicities and/or improved acceptability and quality-of-life. Cost-effectiveness of strategies will be evaluated. BREATHER Plus directly addresses the EDCTP call through exploration of alternative treatment strategies to meet the specific needs of HIV-infected adolescents in SSA, and improve their long-term health, by adaptation of ART using weekends-off, and using novel drugs (long-acting injectable ART), in real-life settings where annual viral load monitoring is current standard-of-care. |
| Network | EDCTP2 |
| Call | Clinical trials and operational research studies to optimise the use of products for poverty-related diseases in mothers, newborns, children and/or adolescents |
Project partner
| Number | Name | Role | Country |
|---|---|---|---|
| 1 | Baylor College of Medicine Children’s Foundation Uganda Limited | Coordinator | Uganda |
| 3 | Enhancing Care Foundation NPC | Partner | South Africa |
| 4 | Fondazione PENTA ONLUS | Partner | Italy |
| 5 | Joint Clinical Research Center Limited | Partner | Uganda |
| 6 | KwaZulu-Natal Research Institute for TB-HIV | Partner | South Africa |
| 7 | London School of Hygiene and Tropical Medicine | Partner | United Kingdom |
| 8 | Makerere University | Partner | Uganda |
| 9 | Moi University | Partner | Kenya |
| 10 | Stichting Katholieke Universiteit- Radboudumc | Partner | Netherlands |
| 11 | University College London | Partner | United Kingdom |
| 13 | University of York | Partner | United Kingdom |
| 14 | University of Zimbabwe | Partner | Zimbawe |