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

Katongole, F; Arumugam, T; Jennings, A; Mutata, C; Ssebunya, P; Wamboi, C; Green, A; Bwakura-Dangarembizi, M; Kityo, C; Siika, A; +292 more...Archary, M; Jafta, L; Namukwaya, S; Seeley, J; Mugerwa, H; Walker, S; Apoto, N; Thomason, MJ; Ford, D; Pett, SL; Kekitiinwa, AR; Achida, CO; Adhiambo, D; Agaba, GM; Ahimbisibwe, G; Ainscough, H; Akabwai, GP; Anena, DL; Ankunda, J; Apoto, N; Archary, M; Arumugam, T; Ashaba, J; Asiimwe, A; Ategeka, J; Atwine, A; Ayesiga, EW; Bagirigomwa, E; Baita, A; Balwa, H; Bamford, A; Bengu, SA; Benita, MA; Bernays, S; Bevers, L; Bhiri, J; Bobat, R; Bosire, R; Burger, D; Bush, M; Butler, K; Bwakura-Dangarembizi, M; Cebekhulu, PS; Chanaiwa, VM; Chappell, E; Chebet, M; Chege, C; Chepkoech, R; Cheruiyot, BK; Cherutich, S; Chibanda, L; Chidemo, T; Chidziva, E; Chimanzi, J; Chimene, S; Chitongo, S; Chitsamatanga, M; Chivaura, R; Choge, JC; Clark, KS; Colbers, A; Conway, M; Crawley, P; Crawley, J; David, B; Denis, O; Dhibi, N; Dodds, R; Draleku, C; Dube, PS; Ekiru, WL; Ford, D; Ford, N; Francis, S; Giaquinto, C; Gibb, D; Gona, SK; Gondo, S; Green, A; Gwande, SB; Gwenzi, T; Hook, M; Jacobs, T; Jafta, L; Jakait, BK; Jennings, A; Jepkemboi, E; Jepkemboi, E; Jepngetich, E; Kabasingo, R; Kadhuba, RJ; Kahinju, D; Kalikwani, H; Katemba, C; Kateta, A; Katongole, F; Kaudha, E; Kavuma, J; Kaziga, H; Kazooba, R; Kekitiinwa, A; Kembabazi, T; Khuzwayo, M; Kigen, N; Kiilu, C; Kipchirchir, V; Kiplagat, HJ; Kiprutto, DJ; Kiptoo, GJ; Kipyego, J; Kirabira, A; Kirk, J; Kirui, V; Kirui, RK; Kirunda, J; Kisekka, MN; Kityo, C; Kiyimba, L; Kobusingye, J; Kotut, JC; Kouamou, V; Kyobutungi, P; Labeja, OSP; Labote, FB; Lagat, D; Langa, C; Langat, VK; Lawrence, L; Lubwama, T; Lutalo, M; Lutalo, E; Lwanga, C; Magut, C; Mahaka, I; Malatjie, N; Malunda, B; Mapfumo, W; Marimo, E; Maru, L; Masiga, PH; Mather, F; Matimba, FS; Matubu, A; Mbabazi, R; Mbamanya, F; Mbasani, F; Mengich, CC; Mhlanga, X; Mkhulise, J; Mncube, IT; Mngqibisa, R; Mnyandu, Z; Mokaya, MM; Moodley, M; Mosia, NR; Moyo, C; Mudogo, A; Mudzimirema, N; Mudzingwa, S; Mudzviti, T; Mugerwa, H; Mujuru, H; Mujyanama, C; Mukanganiki, T; Mukanza, B; Mukura, D; Mulima, D; Mumbiro, V; Mundhree, I; Munyama, HP; Musarurwa, S; Musiime, V; Musiime, AV; Musoro, G; Musumba, S; Mutai, PK; Mutata, C; Muthwa, K; Mutsai, S; Mutuku, MJ; Muweesi, NH; Mwandiwata, E; Mwongela, MK; Naabalamba, M; Nabimba, R; Nakabiri, S; Nakabuye, S; Nakato, BN; Nakiboneka, D; Nakiwala, P; Naluyima, C; Namaganda, R; Namasinga, M; Nambi, C; Namuddu, RK; Namukwaya, BE; Namukwaya, S; Namuli, F; Namusanje, J; Namwanga, J; Nangiya, J; Nannungi, M; Nansaigi, M; Nantale, J; Nantege, J; Nantume, B; Nasaazi, C; Nathoo, K; Nazzinda, R; Ndigendawani, M; Ndlovu, M; Netshitangani, TF; Ngetich, SK; Ngwaru, P; Ngwenya, N; Nhema, R; Njenga, M; Njulu, FK; Nkosi, N; Nolan, A; Ntege, PN; Nundlal, R; Nyakudya, L; Nyandiko, W; Nylobo, S; Obila, G; Odul, B; Okello, RB; Onyango, VO; Opot, DA; Orido, M; Osoro, TO; Otike, C; Ouma, B; Ouno, EO; Oyamo, K; Peres, S; Pett, S; Pettitt, G; Phewa, NI; Phionah, A; Phiri, M; Phiri, S; Pierre, M; Pillay, S; Pillay, C; Pozniak, A; Premoutt, R; Revill, P; Rizvi, S; Rubanga, E; Rubinga, B; Rugut, FK; Rutebarika, DA; Salomone, S; Samoei, V; Sande, IJ; Sang, N; Seeley, J

; Seunanden, T; Shabalala, P; Shali, AM; Shibemba, M; Shickle, J; Siika, A; Simatwa, S; Singh, S; Sithole, S; South, A; Ssebunya, P; Sum, A; Sweeney, H; Tarus, T; Thiebaut, R; Thomason, M; Tikabibamu, J; Tomu, M; Tonui, R; Townsend, S; Tshuma, M; Tukamuhebwa, S; Van Looy, N; Vincent, D; Violari, A; Walker, S; Wambui, C; Wandera, C; Wanjiru, SN; Watiri, CM; Weza, S; White, E; Williams, ED and (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.