BREATHER Plus clinical trial design: A randomised non-inferiority trial evaluating the efficacy, safety and acceptability of short cycle (five days on, two days off) dolutegravir/tenofovir-based triple antiretroviral therapy (ART) compared to daily ART in virologically suppressed adolescents living with HIV aged 12 to <20 years in sub-Saharan Africa

Fredrick Katongole ; Tiyara Arumugam ; Angus Jennings ; Constantine Mutata ; Patrick Ssebunya ; Charity Wamboi ; Alexandra Green ; Mutsa Bwakura-Dangarembizi ; Cissy Kityo ; Abraham Siika ; +292 more... Moherndran Archary ; Lungile Jafta ; Stella Namukwaya ; Janet Seeley ; Henry Mugerwa ; Simon Walker ; Naomi Apoto ; Margaret J Thomason ; Deborah Ford ; Sarah L Pett ; Adeodata R Kekitiinwa ; Clinton Otieno Achida ; Dorcus Adhiambo ; Gerald Muzorah Agaba ; Gideon Ahimbisibwe ; Helen Ainscough ; George Patrick Akabwai ; Diana Louis Anena ; Juliet Ankunda ; Naomi Apoto ; Moherndran Archary ; Tiyara Arumugam ; Justus Ashaba ; Allen Asiimwe ; Juliet Ategeka ; Abigail Atwine ; Edgar Wandigali Ayesiga ; Edward Bagirigomwa ; Angella Baita ; Henry Balwa ; Alasdair Bamford ; Simangele Abigail Bengu ; Maria Aino Benita ; Sarah Bernays ; Lisanne Bevers ; Joyline Bhiri ; Raziya Bobat ; Ruth Bosire ; David Burger ; Molly Bush ; Karina Butler ; Mutsawashe Bwakura-Dangarembizi ; Precious Sphiwe Cebekhulu ; Vongai Margaret Chanaiwa ; Elizabeth Chappell ; Mary Chebet ; Cornelius Chege ; Rispher Chepkoech ; Benedister Kangogo Cheruiyot ; Salinah Cherutich ; Lynette Chibanda ; Tinashe Chidemo ; Ennie Chidziva ; Joy Chimanzi ; Shingirai Chimene ; Stuart Chitongo ; Moses Chitsamatanga ; Rufaro Chivaura ; Julie Chepchumba Choge ; Kelly Shermon Clark ; Angela Colbers ; Magda Conway ; Paul Crawley ; Jane Crawley ; Baliruno David ; Odoch Denis ; Nicholas Dhibi ; Rebecca Dodds ; Charles Draleku ; Prosper Sibonile Dube ; Wilson Lokitala Ekiru ; Deborah Ford ; Nathan Ford ; Shauna Francis ; Carlo Giaquinto ; Diana Gibb ; Shauri Kahindi Gona ; Secrecy Gondo ; Alexandra Green ; Shamiso Barbara Gwande ; Tsitsi Gwenzi ; Margaret Hook ; Tom Jacobs ; Lungile Jafta ; Beatrice K Jakait ; Angus Jennings ; Eslyne Jepkemboi ; Eunice Jepkemboi ; Edna Jepngetich ; Roselyn Kabasingo ; Rose Jacqueline Kadhuba ; Deborah Kahinju ; Hebron Kalikwani ; Crispus Katemba ; Alfed Kateta ; Fredrick Katongole ; Elizabeth Kaudha ; Jovia Kavuma ; Hilda Kaziga ; Rodney Kazooba ; Adeodata Kekitiinwa ; Teddy Kembabazi ; Mthokozisi Khuzwayo ; Nicholas Kigen ; Cecilia Kiilu ; Vincent Kipchirchir ; Hellen Jerotich Kiplagat ; Damaris Jepchumba Kiprutto ; Getruth Jerop Kiptoo ; Jairus Kipyego ; Anthony Kirabira ; Jessica Kirk ; Viola Kirui ; Richard Kipsang Kirui ; Jeremy Kirunda ; Muzamil Nsibuka Kisekka ; Cissy Kityo ; Lameck Kiyimba ; Josephine Kobusingye ; Joan Chepkurui Kotut ; Vinie Kouamou ; Priscilla Kyobutungi ; Ocitti Sunday Paul Labeja ; Faith Balmoi Labote ; Damaris Lagat ; Cleopatra Langa ; Victor Kibet Langat ; Lekku Lawrence ; Timothy Lubwama ; Muhammad Lutalo ; Ezra Lutalo ; Christopher Lwanga ; Cornelius Magut ; Imelda Mahaka ; Nathaniel Malatjie ; Bernadette Malunda ; Wendy Mapfumo ; Edson Marimo ; Lydiah Maru ; Peace Hellen Masiga ; Fathima Mather ; Farai Selina Matimba ; Allen Matubu ; Ritah Mbabazi ; Frank Mbamanya ; Faith Mbasani ; Cecilia Chebet Mengich ; Xeshelihle Mhlanga ; Jabu Mkhulise ; Innocentia Thandokuhle Mncube ; Rosie Mngqibisa ; Zethu Mnyandu ; Martha Mokeira Mokaya ; Michelle Moodley ; Nozibusiso Rejoice Mosia ; Columbus Moyo ; Alice Mudogo ; Nathalie Mudzimirema ; Shepherd Mudzingwa ; Taona Mudzviti ; Henry Mugerwa ; Hilda Mujuru ; Collins Mujyanama ; Trust Mukanganiki ; Barbara Mukanza ; Dorinda Mukura ; Disan Mulima ; Vivian Mumbiro ; Ida Mundhree ; Hazel Patricia Munyama ; Sandra Musarurwa ; Victor Musiime ; Alex V Musiime ; Godfrey Musoro ; Sharif Musumba ; Philemon Kipchirchir Mutai ; Constantine Mutata ; Khombisile Muthwa ; Shirley Mutsai ; Matthew Justus Mutuku ; Nabuuma Haawa Muweesi ; Elaine Mwandiwata ; Martha Kaimuri Mwongela ; Mariam Naabalamba ; Ronald Nabimba ; Shirat Nakabiri ; Shamim Nakabuye ; Bibian Nakigozi Nakato ; Dridah Nakiboneka ; Priscilla Nakiwala ; Cate Naluyima ; Rose Namaganda ; Miriam Namasinga ; Christine Nambi ; Rachael Kikabi Namuddu ; Brenda Efrance Namukwaya ; Stella Namukwaya ; Florence Namuli ; Josephine Namusanje ; Jamilah Namwanga ; Joan Nangiya ; Mary Nannungi ; Mangadalen Nansaigi ; Jesca Nantale ; Joan Nantege ; Barbra Nantume ; Claire Nasaazi ; Kusum Nathoo ; Rashidah Nazzinda ; Milly Ndigendawani ; Makhosonke Ndlovu ; Tshamand Fulufhelo Netshitangani ; Solomon Kimurgor Ngetich ; Pia Ngwaru ; Nothando Ngwenya ; Ruth Nhema ; Michael Njenga ; Florence Kiwunja Njulu ; Nombuso Nkosi ; Aoife Nolan ; Patricia Nahirya Ntege ; Rashina Nundlal ; Lynnet Nyakudya ; Winstone Nyandiko ; Sylvia Nylobo ; Gideon Obila ; Brian Odul ; Resty Babirye Okello ; Vincent Otieno Onyango ; Dorcas Akinyi Opot ; Millicent Orido ; Tom Oyoo Osoro ; Carol Otike ; Benson Ouma ; Evans Ochieng Ouno ; Kennedy Oyamo ; Sara Peres ; Sarah Pett ; George Pettitt ; Ntombizonta Ignatia Phewa ; Ampaire Phionah ; Misheck Phiri ; Sam Phiri ; Mowlem Pierre ; Sundrapragasen Pillay ; Clement Pillay ; Anton Pozniak ; Rayania Premoutt ; Paul Revill ; Saajida Rizvi ; Eddie Rubanga ; Baker Rubinga ; Festus Kirwa Rugut ; Diana Antonia Rutebarika ; Simona Salomone ; Violah Samoei ; Iris Jaluha Sande ; Natalie Sang ; Janet Seeley

; Tamlyn Seunanden ; Popi Shabalala ; Amina Msuo Shali ; Mercy Shibemba ; Jemima Shickle ; Abraham Siika ; Sophia Simatwa ; Sheleika Singh ; Sidney Sithole ; Annabelle South ; Patrick Ssebunya ; Andy Sum ; Hannah Sweeney ; Teri Tarus ; Rodolphe Thiebaut ; Margaret Thomason ; Judith Tikabibamu ; Musunga Tomu ; Ronald Tonui ; Stephen Townsend ; Maureen Tshuma ; Susan Tukamuhebwa ; Nadine Van Looy ; Deka Vincent ; Avy Violari ; Simon Walker ; Charity Wambui ; Centurio Wandera ; Scholastica Njeri Wanjiru ; Caroline Maina Watiri ; Sibusisiwe Weza ; Ellen White ; Eram David Williams ; (2025) BREATHER Plus clinical trial design: A randomised non-inferiority trial evaluating the efficacy, safety and acceptability of short cycle (five days on, two days off) dolutegravir/tenofovir-based triple antiretroviral therapy (ART) compared to daily ART in virologically suppressed adolescents living with HIV aged 12 to <20 years in sub-Saharan Africa. Contemporary clinical trials, 155. p. 107963. ISSN 1551-7144 DOI: 10.1016/j.cct.2025.107963

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<h4>Background</h4>Novel strategies to improve ART adherence, retention in care and quality of life among adolescents living with HIV (ALHIV) are needed. Short-Cycle Therapy (SCT) with 4/5 sequential days on ART, 2/3 days off ART per week has shown non-inferior virological outcomes and high acceptability, but most data are in adults and are very limited for dolutegravir (DTG)-based SCT.<h4>Methods</h4>BREATHER Plus is an ongoing 96-week non-inferiority randomised trial evaluating efficacy, safety and acceptability of SCT (5 sequential days on, 2 days off at the weekend) with DTG/tenofovir (TNV)-based triple ART versus continuous (daily) therapy (CT) in ALHIV. Participants are aged 12 to <20 years in Kenya/South Africa/Uganda/Zimbabwe, virologically suppressed (Viral Load (VL) <50copies/mL) for ≥12 months at enrollment, with no prior treatment failure. Randomisation is 1:1 to SCT versus CT. VL monitoring for clinical management is 6-12 monthly aligning with standard-of-care. The primary outcome is confirmed virological rebound ≥50 copies/mL by 96 weeks. The trial employs the Smooth Away From Expected (SAFE) non-inferiority frontier, where the non-inferiority margin depends on the observed event risk in the CT arm. Secondary outcomes include HIV resistance, toxicities, patient-reported outcomes and cost-effectiveness. Enrolment of 470 participants completed in June 2023.<h4>Discussion</h4>BREATHER Plus is the first randomised trial specifically evaluating DTG/TNV-triple based SCT. Rapid roll-out of DTG and a pragmatic approach to VL monitoring mean results will be generalisable to ALHIV across sub-Saharan Africa. If SCT provides non-inferior virological suppression to CT, it may offer choice for ALHIV on how they take their ART.