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Background & rationale

A pragmatic randomised controlled strategy trial of three second-line treatment options for use in public health rollout programme settings: The Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial.

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Background & rationale

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  1. A pragmatic randomised controlled strategy trial of three second-line treatment options for use in public health rollout programme settings: The Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial N. Paton, C. Kityo, A. Hoppe, J. Hakim,J. van Oosterhout, A. Siika, P. Mwaba, A. Kambugu, P. Easterbrook, J. Boles, S. Walker, P. Mugyenyi for the EARNEST Trial Group

  2. Background & rationale • 6 million on ART in sub-Saharan Africa, using public health approach: • standardised regimens for 1st and 2nd line • clinical + CD4 monitoring (no/limited VL; no resistance testing) • Standardised 2nd-line: PI/r + 2NRTI • “moderate quality evidence” (WHO, 2013 guidelines) • Does (compromised) efficacy of 2NRTIs outweigh toxicity? • Hypotheses 1) PI/r + RAL superior efficacy (↓ toxicity? ↑cost) 2) PI/r mono. non-inferior efficacy (↓toxicity ↓complexity ↓cost ) • Aims • compare these 3 options for 2nd-line therapy • A pragmatic trial that replicates typical public health approach settings

  3. Trial design (1) HIV positive adolescents / adults (n=1200)1st line NNRTI-based regimen >12m; > 90% adherence last 1mFailure by WHO (2010) clinical, CD4 (VL-confirmed) or VL criteria RANDOMIZE PI + RAL (12 wkinduction) PI + 2-3 NRTIs (NRTIs according to local standard of care) PI + RAL PI (Monotherapy) FOLLOW-UP FOR 144 WEEKS • Primary outcome at week 96: • Good HIV disease control –defined as all of: • Alive and no new WHO4 events from 0-96 weeks AND • CD4 cell count > 250 cells/mm3 at 96 weeks AND • VL<10,000 c/ml OR >10,000 c/ml without PI res. mutations at 96 weeks

  4. Trial design (2) • Monitoring • Clinical and CD4 (every 12-16 weeks) • VL: annual visits; batched analysis in central lab (JCRC Kampala, Abbott m2000rt assay); blinded with DMC review • Resistance: annual visits (all samples with VL>1000 c/ml); batched analysis in central lab (Janssen Diagnostics); blinded with DMC review

  5. Trial design (3) Sample size: 1200 (400 per arm) PI/RAL vs PI/NRTI: 87% power to detect 10% superiority of PI/RAL [predicted response 75% in PI/NRTI; 10% LTFU; 2-sided α=0.025] PI mono vsPI/NRTI 80% power to exclude >10% inferior response in PI mono arm [predicted response, LTFU as above; 1-sided α=0.025] Analysis • ITT for all comparisons • Primary endpoint: absolute risk difference • Multiple imputation for missing CD4, VL, genotypes at w96

  6. Sites and recruitment 14 Sites: Uganda Zimbabwe Malawi Kenya Zambia April 2010 - April 2011: 1277 patients randomised

  7. Baseline characteristics (at randomisation / switch to second-line) Note: n(%) or median (IQR)

  8. Treatment and follow-up TREATMENT NRTI regimen prescribed: • TDF+3/FTC 70% • TDF/3TC/ZDV 9% (Malawi national guidelines) • ddI+ABC 12% ZDV+3TC 4% Other 4% LPV/r used throughout in >99% Regimen consistent with randomised strategy at w96: >97% Complete adherence (0 missed pills/last 1m): 88% of visits FOLLOW UP Protocol-mandated visits attended: > 95% Withdrawal / lost to follow up before w96: 1.3%

  9. Primary endpoint at 96 weeks • Good disease control: PI/NRTI: 60% PI/RAL: 64% PI mono+: 56% • Risk diff (95% CI): PI/RAL – PI/NRTI: +4.2% (-2.4%,+10.8%; P=0.21) • Risk diff (95% CI): PImono+ – PI/NRTI: -4.1% (-10.8%, +2.6%; P=0.23) P<0.0001 P=0.08 Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96

  10. VL suppression at 96 weeks

  11. VL suppression at 96 weeks PI/RAL vs PI/NRTI P=0.36 P=0.87 P=0.97 P=0.88

  12. VL suppression at 96 weeks PI/RAL vs PI/NRTI P=0.36 P=0.87 P=0.97 P=0.88 PImono+ vs PI/NRTI P=0.002 P<0.0001 P<0.0001 P<0.0001

  13. Resistance at 96 weeks (predicted in whole population) X X * Note: assuming susceptible if VL<1000 c/ml at week 96; and using inverse probability weighting for VL>1000 c/ml with missing genotype at week 96 based on those with observed genotypes *One patient in RAL/PI with intermediate/high level resistance to TDF had moved to 3TC TDF ALV at week 4 due to rash

  14. Mean CD4 through 96 weeks PI/RAL vs PI/NRTI w96 P=0.05 Global P=0.05 PImono+ vs PI/NRTI w96 P=0.99 Global P=0.19 400 RAL/bPI NRTI/PI bPImono+ 300 Mean absolute CD4 (95% CI) 200 100 0 12 24 36 48 64 80 96 Weeks from randomisation (switch to second-line)

  15. Grade 3/4 adverse events 1.00 HR(PI/RAL: PI/NRTI)=1.08 (0.81,1.43) HR(PImono: PI/NRTI)=1.09 (0.82,1.45) global p=0.54 0.75 PImono+ Probability of remaining grade 3/4 adverse event-free 0.50 PI/RAL PI/NRTI 0.25 0.00 0 24 48 72 96 Weeks from randomisation

  16. Conclusions • PI/NRTI had excellent clinical outcome (90% WHO4 event-free survival) and VL suppression (86% < 400c/ml) at 96 weeks, even in advanced 1st-line failure (and without using resistance testing or VL monitoring) • PI/NRTI regimen should be made more widely available for 2nd line therapy in public health approach • PI/RAL was not superior to PI/NRTI; borderline CD4 advantage – 144w follow-up will assess clinical benefit and cost-effectiveness • PI monotherapy is inferior to PI/NRTI: lower VL suppression, more resistance. PI mono unsuitable for public health approach. • New/recycled NRTIs retain substantial virologicalactivity in 2nd line with little added toxicity

  17. Acknowledgments Uganda: JCRC Kampala (African trial co-ordinating centre; 231) E Agweng, P Awio, G Bakeinyaga, C Isabirye, U Kabuga, S Kasuswa, M Katuramu, C Kityo, F Kiweewa, H Kyomugisha, E Lutalo, P Mugyenyi, D Mulima, H Musana, G Musitwa, V Musiime, M Ndigendawan, H Namata, J Nkalubo, P OcittiLabejja, P Okello, P Olal, G Pimundu, P Segonga, F Ssali, Z Tamale, D Tumukunde, W Namala, R Byaruhanga, J Kayiwa, J Tukamushaba. IDI, Kampala (216):G Bihabwa, E Buluma, P Easterbrook, A Elbireer, A Kambugu, D Kamya, M Katwere, R Kiggundu, C Komujuni, E Laker, E Lubwama,  I Mambule, J Matovu, A Nakajubi, J Nakku, R Nalumenya, L Namuyimbwa, F Semitala, B Wandera, J Wanyama; JCRC, Mbarara(97): H Mugerwa, A Lugemwa, E Ninsiima, T Ssenkindu, S Mwebe, L Atwine, H William, C Katemba, S Abunyang, M Acaku, P Ssebutinde, H Kitizo, J Kukundakwe, M Naluguza, K Ssegawa, Namayanja, F Nsibuka, P Tuhirirwe, M Fortunate; JCRC Fort Portal (66): J Acen, J Achidri, A Amone, M. Chamai, J Ditai, M Kemigisa, M Kiconco, C Matama, D Mbanza, F Nambaziira, M OworOdoi, A Rweyora, G. Tumwebaze. San Raphael of St Francis Hospital, Nsambya(48):H Kalanzi, J Katabaazi , A Kiyingi, M Mbidde, M. Mugenyi, R Mwebaze, P Okong, I Senoga. JCRC Mbale(47): M Abwola, D Baliruno, J Bwomezi, A Kasede, M Mudoola, R Namisi, F Ssennono, S Tuhirwe. JCRC Gulu(43):G Abongomera, G Amone, J Abach, I Aciro, B Arach, P Kidega, J Omongin, E Ocung, W Odong, A Philliam. JCRC Kabale(33):H Alima, B Ahimbisibwe, E Atuhaire, F Atukunda, G Bekusike, A Bulegyeya, D. Kahatano, S Kamukama, J Kyoshabire, A Nassali, A Mbonye, T M Naturinda, Ndukukire, A Nshabohurira, H. Ntawiha, A Rogers, M Tibyasa;JCRC Kakira(31): S. Kiirya, D. Atwongeire, A. Nankya, C. Draleku, D. Nakiboneka, D. Odoch, L. Lakidi, R. Ruganda, R. Abiriga, M. Mulindwa, F. Balmoi, S. Kafuma, E. Moriku Zimbabwe:University of Zimbabwe Clinical Research Centre, Harare (265): J Hakim, A Reid, E Chidziva, G Musoro, C Warambwa, G Tinago, S Mutsai, MPhiri, S Mudzingwa, T Bafana, V Masore, C Moyo, R Nhema, S Chitongo Malawi:College of Medicine, University of Malawi, Blanytre(92): Rob Heyderman, Lucky Kabanga, Symon Kaunda, Aubrey Kudzala, LinlyLifa, Jane Mallewa, Mike Moore, Chrissie Mtali, George Musowa, Grace Mwimaniwa, Rosemary Sikwese, Joep van Oosterhout, Milton Ziwoya. MzuzuCentral Hospital, Mzuzu(19):H Chimbaka. B Chitete, S Kamanga, T Kayinga E Makwakwa, R Mbiya, M Mlenga, T Mphande, C Mtika, G Mushani, O Ndhlovu, M Ngonga, I Nkhana, R Nyirenda Kenya: MoiTeaching and Referral Hospital (52):P Cheruiyot, C Kwobah, W LokitalaEkiru, M Mokaya, A Mudogo, A Nzioka, A Siika, M Tanui, S Wachira, K Wools-Kaloustian Zambia:University Teaching Hospital(37):P Alipalli, E Chikatula, J Kipaila, I Kunda, S Lakhi, J Malama, W Mufwambi, L Mulenga, P Mwaba, E Mwamba, A Mweemba, M Namfukwe The Aids Support Organisation (TASO), Uganda: E Kerukadho, B Ngwatu, J Birungi MRC Clinical Trials Unit: N Paton, J Boles, A Burke, L Castle, S Ghuman, L Kendall, A Hoppe, S Tebbs, M Thomason, J Thompson, S Walker, J Whittle, H Wilkes, N Young Monitors: C Kapuya, F Kyomuhendo, D Kyakundi, N Mkandawire, S Mulambo, S Senyonjo Clinical Expert Review Committee: B Angus, A Arenas-Pinto, A Palfreeman, F Post, D Ishola European Collaborators: J Arribas, B Colebunders, M Floridia, M Giuliano, P Mallon, P Walsh, M De Rosa, E Rinaldi Trial Steering Committee: I Weller (Chair), C Gilks, J Hakim, A Kangewende, S Lakhi, E Luyirika, F Miiro, P Mwamba, P Mugyenyi, S Ojoo, N Paton, S Phiri, J van Oosterhout, A Siika, S Walker, A Wapakabulo, Data Monitoring Committee: T Peto (Chair), N French, J Matenga Pharmaceutical companies : J van Wyk, M Norton, S Lehrman, P Lamba, K Malik, J Rooney, W Snowden, J Villacian, G Cloherty Funding and in-kind support: Funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) with contributions from the Medical Research Council, UK, Institito de Salud Carlos III, Spain, Irish Aid, Ireland, Swedish International Development Cooperation Agency (SIDA), Sweden, InstitutoSuperiore di Sanita (ISS), Italy and Merck, USA. Substantive in-kind contributions were made by the Medical Research Council Clinical Trials Unit, UK, CINECA, Bologna, Italy, Janssen Diagnostics, Mechelen, Belgium; GSK, UK; Abbott Laboratories, USA. Trial medication was donated by AbbVie, Merck, Pfizer, GSK and Gilead

  18. Participants We thank all the participants in the EARNEST trial www. earnesttrial.com

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