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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial
The Lancet HIV, Volume 4, No. 8, Year 2017
Notification
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Description
Background Cross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV. Methods We did an observational analysis of additional data from a published open-label, randomised trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 adults or adolescents infected with HIV in whom first-line ART had failed (assessed by WHO criteria with virological confirmation) were randomly assigned to a boosted protease inhibitor (standardised to ritonavir-boosted lopinavir) with two to three NRTIs (clinician-selected, without resistance testing); or with raltegravir; or alone as protease inhibitor monotherapy (discontinued after week 96). We tested genotypic resistance on stored baseline samples in patients in the protease inhibitor and NRTI group and calculated the predicted activity of prescribed second-line NRTIs. We measured viral load in stored samples for all patients obtained every 12–16 weeks. This trial is registered with Controlled-Trials.com (number ISRCTN 37737787) and ClinicalTrials.gov (number NCT00988039). Findings Baseline genotypes were available in 391 (92%) of 426 patients in the protease inhibitor and NRTI group. 176 (89%) of 198 patients prescribed a protease inhibitor with no predicted-active NRTIs had viral suppression (viral load <400 copies per mL) at week 144, compared with 312 (81%) of 383 patients in the protease inhibitor and raltegravir group at week 144 (p=0·02) and 233 (61%) of 280 patients in the protease inhibitor monotherapy group at week 96 (p<0·0001). Compared with results with no active NRTIs, 95 (85%) of 112 patients with one predicted-active NRTI had viral suppression (p=0·3) and 20 (77%) of 26 patients with two or three active NRTIs had viral suppression (p=0·08). Over all follow-up, greater predicted NRTI activity was associated with worse viral load suppression (global p=0·0004). Interpretation Genotypic resistance testing might not accurately predict NRTI activity in protease inhibitor-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs. Funding European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Institito de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, WHO, Merck. © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC5555436/bin/mmc1.pdf
Authors & Co-Authors
Paton, Nicholas I.J.
Singapore, Singapore City
National University of Singapore
United Kingdom, London
University College London
Kityo, Cissy Mutuluuza
Uganda, Kampala
Joint Clinical Research Center Uganda
Thompson, Jennifer A.
United Kingdom, London
University College London
Nankya, Immaculate L.
Uganda, Kampala
Joint Clinical Research Center Uganda
Bagenda, Leonard
Uganda, Kampala
Joint Clinical Research Center Uganda
Hoppe, Anne
United Kingdom, London
University College London
Hakim, James Gita
Zimbabwe, Harare
University of Zimbabwe
Kambugu, Andrew Ddungu
Uganda, Kampala
Makerere University
van Oosterhout, Joep J.G.
Malawi, Blantyre
Kamuzu University of Health Sciences
Canada, Toronto
Dignitas International
Kiconco, Mary
Uganda, Kampala
Jcrc
Bertagnolio, Silvia
Switzerland, Geneva
Organisation Mondiale de la Santé
Easterbrook, Philippa Jane
Uganda, Kampala
Makerere University
Switzerland, Geneva
Organisation Mondiale de la Santé
Mugyenyi, Peter N.
Uganda, Kampala
Joint Clinical Research Center Uganda
Walker, A. Sarah
United Kingdom, London
University College London
Agweng, E.
Unknown Affiliation
Awio, Peter
Unknown Affiliation
Bakeinyaga, G. T.
Unknown Affiliation
Isabirye, C.
Unknown Affiliation
Kabuga, Usher
Unknown Affiliation
Kasuswa, S.
Unknown Affiliation
Katuramu, M.
Unknown Affiliation
Kiweewa, Francis
Unknown Affiliation
Kyomugisha, Hope
Unknown Affiliation
Lutalo, Ezra
Unknown Affiliation
Mulima, Disan
Unknown Affiliation
Musana, Hellen Wambongo
Unknown Affiliation
Musitwa, G.
Unknown Affiliation
Musiime, Victor
Unknown Affiliation
Ndigendawan, M.
Unknown Affiliation
Namata, Harriet
Unknown Affiliation
Nkalubo, J.
Unknown Affiliation
Labejja, P. Ocitti
Unknown Affiliation
Okello, Peter
Unknown Affiliation
Olal, Patrick
Unknown Affiliation
Pimundu, Godfrey
Unknown Affiliation
Segonga, P.
Unknown Affiliation
Ssali, Francis N.
Unknown Affiliation
Tamale, Z.
Unknown Affiliation
Tumukunde, Dinah
Unknown Affiliation
Namala, Winnie S.
Unknown Affiliation
Byaruhanga, Rose
Unknown Affiliation
Kayiwa, Joshua
Unknown Affiliation
Tukamushaba, J.
Unknown Affiliation
Abunyang, S.
Unknown Affiliation
Eram, David
Unknown Affiliation
Denis, O.
Unknown Affiliation
Lwalanda, R.
Unknown Affiliation
Mugarura, Lincoln
Unknown Affiliation
Namusanje, Josephine
Unknown Affiliation
Ndashimye, Emmanuel
Unknown Affiliation
Nabulime, Eva
Unknown Affiliation
Senfuma, Oscar
Unknown Affiliation
Bihabwa, G.
Unknown Affiliation
Buluma, E.
Unknown Affiliation
Easterbrook, P.
Unknown Affiliation
Elbireer, Ali M.
Unknown Affiliation
Kamya, Deus
Unknown Affiliation
Katwere, Michael
Unknown Affiliation
Kiggundu, Reuben K.
Unknown Affiliation
Komujuni, C.
Unknown Affiliation
Laker, Eva Agnes Odongpiny
Unknown Affiliation
Lubwama, E.
Unknown Affiliation
Mambule, Ivan Kiggundu
Unknown Affiliation
Matovu, Joshua
Unknown Affiliation
Nakajubi, A.
Unknown Affiliation
Nakku, Juliet E.M.
Unknown Affiliation
Nalumenya, Ruth
Unknown Affiliation
Namuyimbwa, Lydia
Unknown Affiliation
Semitala, Fred Collins
Unknown Affiliation
Wandera, Bonnie
Unknown Affiliation
Wanyama, Jane Namukasa
Unknown Affiliation
Mugerwa, Henry
Unknown Affiliation
Lugemwa, Abbas
Unknown Affiliation
Ninsiima, Emily
Unknown Affiliation
Ssenkindu, T.
Unknown Affiliation
Mwebe, Sandra Z.
Unknown Affiliation
Atwine, Lorna
Unknown Affiliation
William, Henry
Unknown Affiliation
Katemba, Chrispus
Unknown Affiliation
Acaku, Moses
Unknown Affiliation
Ssebutinde, Peter
Unknown Affiliation
Kitizo, H.
Unknown Affiliation
Kukundakwe, J.
Unknown Affiliation
Naluguza, Mary
Unknown Affiliation
Ssegawa, K.
Unknown Affiliation
Namayanja,
Unknown Affiliation
Nsibuka, F.
Unknown Affiliation
Tuhirirwe, P.
Unknown Affiliation
Fortunate, M.
Unknown Affiliation
Acen, Juliet
Unknown Affiliation
Achidri, J.
Unknown Affiliation
Amone, Alexander
Unknown Affiliation
Chamai, Martin
Unknown Affiliation
Ditai, James
Unknown Affiliation
Kemigisa, Mable
Unknown Affiliation
Matama, Christine
Unknown Affiliation
Mbanza, D.
Unknown Affiliation
Nambaziira, Florence
Unknown Affiliation
Odoi, M. Owor
Unknown Affiliation
Rweyora, Angela K.
Unknown Affiliation
Mugenyi, Margaret
Unknown Affiliation
Mwebaze, Raymond Mbayo
Unknown Affiliation
Okong, P.
Unknown Affiliation
Senoga, Ismail
Unknown Affiliation
Abwola, Mary C.
Unknown Affiliation
Baliruno, David
Unknown Affiliation
Bwomezi, J.
Unknown Affiliation
Napyo, Agnes
Unknown Affiliation
Mudoola, Macreen
Unknown Affiliation
Namisi, Ronald
Unknown Affiliation
Ssennono, Fred
Unknown Affiliation
Tuhirwe, Stephen
Unknown Affiliation
Abongomera, George
Unknown Affiliation
Amone, Geoffrey
Unknown Affiliation
Abach, James
Unknown Affiliation
Aciro, Irene Claren
Unknown Affiliation
Arach, Beatrice
Unknown Affiliation
Kidega, Patrick
Unknown Affiliation
Omongin, Joseph
Unknown Affiliation
Ocung, Emmanuel
Unknown Affiliation
Odong, Willy Agings
Unknown Affiliation
Philliam, Aleti
Unknown Affiliation
Alima, Hillary
Unknown Affiliation
Mbonye, Andrew
Unknown Affiliation
Atwongyeire, Dickens
Unknown Affiliation
Nankya, Agnes
Unknown Affiliation
Nakiboneka-Ssenabulya, Deborah L.
Unknown Affiliation
Odoch, Denis
Unknown Affiliation
Lakidi, Luke
Unknown Affiliation
Mulindwa, M.
Unknown Affiliation
Reid, Andrew
Unknown Affiliation
Chidziva, Ennie
Unknown Affiliation
Musoro, Godfrey
Unknown Affiliation
Warambwa, Colin
Unknown Affiliation
Tinago, Gloria C.
Unknown Affiliation
Mutsai, Shirley
Unknown Affiliation
Phiri, Misheck Nkalo
Unknown Affiliation
Mudzingwa, Shepherd
Unknown Affiliation
Bafana, Themelihle
Unknown Affiliation
Masore, V.
Unknown Affiliation
Moyo, Columbus
Unknown Affiliation
Nhema, Ruth
Unknown Affiliation
Chitongo, Stuart
Unknown Affiliation
Heyderman, Robert Simon
Unknown Affiliation
Kabanga, Lucky
Unknown Affiliation
Kaunda, Symon
Unknown Affiliation
Kudzala, Aubrey G.
Unknown Affiliation
Mallewa, Jane E.
Unknown Affiliation
Moore, Mike J.
Unknown Affiliation
Mwimaniwa, Grace
Unknown Affiliation
Sikwese, Rosemary
Unknown Affiliation
Mlenga, Maurice
Unknown Affiliation
Nyirenda, Rose Kolola
Unknown Affiliation
Cheruiyot, Priscilla Chepkorir
Unknown Affiliation
Kwobah, Charles Meja
Unknown Affiliation
Mokaya, Martha Mokeira Bisieri
Unknown Affiliation
Siika, Abraham Mosigisi
Unknown Affiliation
Wachira, Simon
Unknown Affiliation
Wools-Kaloustian, Kara K.
Unknown Affiliation
Lakhi, Shabir
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Mufwambi, Webrod
Unknown Affiliation
Mulenga, Lloyd Berdad
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Mwaba, Peter B.
Unknown Affiliation
Mwamba, Erick
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Mweemba, Aggrey
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Namfukwe, Mebelo
Unknown Affiliation
Kerukadho, Emmanuel
Unknown Affiliation
Ngwatu, Brian Kermu
Unknown Affiliation
Birungi, Josephine
Unknown Affiliation
Boles, Justine
Unknown Affiliation
Burke, Andrew
Unknown Affiliation
Kendall, Lindsay K.
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Thomason, Margaret J.
Unknown Affiliation
Walker, Sarah A.S.
Unknown Affiliation
Wilkes, Helen C.
Unknown Affiliation
Young, N.
Unknown Affiliation
Spyer, Moira J.
Unknown Affiliation
Kyomuhendo, Flavia
Unknown Affiliation
Mkandawire, Nkhafwire
Unknown Affiliation
Mulambo, Sylvia
Unknown Affiliation
Angus, Brian John
Unknown Affiliation
Arenas-Pinto, Alejandro
Unknown Affiliation
Palfreeman, Adrian J.
Unknown Affiliation
Post, Frank A.
Unknown Affiliation
Ishola, David A.
Unknown Affiliation
Arribas, Jose R.
Unknown Affiliation
Colebunders, Robert Leon
Unknown Affiliation
Floridia, Marco
Unknown Affiliation
Giuliano, Marina
Unknown Affiliation
Mallon, Patrick W.G.
Unknown Affiliation
Weller, Ian V.D.
Unknown Affiliation
Gilks, Charles F.
Unknown Affiliation
Luyirika, Emmanuel B.K.
Unknown Affiliation
Miiro, F.
Unknown Affiliation
Mwamba, Pike
Unknown Affiliation
Ojoo, Sylvia A.
Unknown Affiliation
Phiri, Sam John Peter
Unknown Affiliation
Peto, Timothy E.A.
Unknown Affiliation
Matenga, Jonathan Arthur
Unknown Affiliation
Cloherty, Gavin A.
Unknown Affiliation
van Wyk, Jean P.H.
Unknown Affiliation
Norton, Michael R.
Unknown Affiliation
Lehrman, Sandra Nusinoff
Unknown Affiliation
Rooney, James F.
Unknown Affiliation
Snowden, Wendy B.
Unknown Affiliation
Statistics
Citations: 68
Authors: 205
Affiliations: 9
Identifiers
Doi:
10.1016/S2352-3018(17)30065-6
ISSN:
23523018
Research Areas
Health System And Policy
Infectious Diseases
Study Design
Cohort Study