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

Nicholas I Paton ,H Kalanzi,A Wapakabulo,E Chikatula,P Olal,Grace Mwimaniwa,A Sarah Walker,F Kyomuhendo,M Tibyasa,I Kunda,H Kitizo,M Mlenga,G Tumwebaze,G Bihabwa,A Nakajubi,S Kafuma,A Amone,Mary Kiconco,Namayanja Namayanja,R Namisi,P Segonga,E Buluma,M Mokaya,Ndukukire Ndukukire,F Atukunda,F Ssennono,B Chitete,James Hakim,E Lubwama,J Kyoshabire,Lucky Kabanga,M Ndigendawan,Linly Lifa,H Chimbaka,T Ssenkindu,G Mushani,Chrissie Mtali,T Mphande,Mike Moore,A Bulegyeya,S Senyonjo,J Acen,G Bekusike,B Ahimbisibwe,W Lokitala Ekiru,A Nzioka,J Bwomezi,L Lakidi,Peter Mugyenyi,P Awio,D Odoch,R Ruganda,S Kamanga,M Mulindwa,M Ngonga,I Aciro,I Senoga,J Kukundakwe,Rosemary Sikwese,S Wachira,J Achidri,K Ssegawa,M Namfukwe,O Ndhlovu,M Katuramu,Silvia Bertagnolio,S Tebbs,F Balmoi,P Ocitti Labejja,Milton Ziwoya,H Wilkes,Joep Van Oosterhout,E Ocung,Aubrey Kudzala,Symon Kaunda,M Acaku,D Mbanza,Andrew Kambugu,Cissy Kityo,M Mbidde,R Lwalanda,C Warambwa,E Agweng,D Nakiboneka,M Chamai,F Nsibuka,D Eram,S Kasuswa,C Isabirye,A Mudogo,D Kyakundi,T M Naturinda,S Kiirya,W Odong,M Kemigisa,S Chitongo,R Mbiya,G Musitwa,Jane Mallewa,O Senfuma,S Lakhi,D Kahatano,E Moriku,A Mbonye,I Nkhana,C Kapuya,S Abunyang,George Musowa,E Atuhaire,P Alipalli,E Lutalo,V Masore,M Owor Odoi,Leonard Bagenda,P Tuhirirwe,R Abiriga,J Katabaazi,S Tuhirwe,M Mudoola,H William,G Bakeinyaga,R Colebunders,F Miiro,M Fortunate,A Nshabohurira,C Komujuni,J Kipaila,A Kangewende,A Kiyingi,H Ntawiha,Immaculate Nankya,T Kayinga E Makwakwa,J Malama,Z Tamale,C Draleku,D Mulima,A Nankya,Juliet Nakku ,Sandra Mwebe ,Charles Kwobah ,A Arenas‐Pinto ,Pius Okong ,Joshua Kayiwa ,Charlie Gilks ,Joshua Matovu ,Sylvia Ojoo ,Hope Kyomugisha ,Sandra Nusinoff Lehrman ,Rose Byaruhanga ,Ruth Nhema ,Emily Ninsiima ,Elisa Rebecca Rinaldi ,Francis Kiweewa ,Chrispus Katemba ,Frank A Post ,Josephine Birungi ,Peter Okello ,Dickens Atwongyeire ,Lorna Atwine ,Lindsay Kendall ,Patricia Noonan Walsh ,James Abach ,Brian Angus ,Lydia Namuyimbwa ,James R Whittle ,Robert S Heyderman ,Sarah Walker ,Moira Spyer ,James Ditai ,S Mutsai ,Gavin Cloherty ,Michael Katwere ,Peter Mwaba ,Misheck Nkalo Phiri ,Beatrice Arach ,Michael Norton ,Nkhafwire Mkandawire ,Raymond Mwebaze ,Jane N Wanyama ,Joep J Van Oosterhout ,Marina Giuliano ,Mauro De Rosa ,Michael Tanui ,Samarjit Singh Ghuman ,Lloyd Mulenga ,Pallavi Lamba ,Abraham Siika ,Fred C Semitala ,Godfrey Pimundu ,David Baliruno ,José Ramón Arribas ,Andrew Reid ,Priscilla Cheruiyot ,Rose Nyirenda ,Peter M Mwamba ,G Tinago ,Justine Boles ,I V D Weller ,Victor Musiime ,Agnes Napyo Kasede ,Webrod Mufwambi ,Aggrey Mweemba ,Kara Wools‐Kaloustian ,Jean Van Wyk ,Neil French ,Usher Kabuga ,James F Rooney ,Philippa Easterbrook ,Dorothy Kamya ,Arlin B Rogers ,George Abongomera ,Erick Mwamba ,Ennie Chidziva ,J Tukamushaba ,Olivier Denis ,Henry Mugerwa ,Lincoln Mugarura ,Brian K Ngwatu ,Abbas Lugemwa ,Saul Kamukama ,Reuben Kiggundu ,Sam Phiri ,David Ishola ,Geoffrey Amone ,D Tumukunde ,Adrian Palfreeman ,Eva Nabulime ,R Nalumenya ,Bonnie Wandera ,Emmanuel Ndashimye ,Margaret J Thomason ,Anne Hoppé ,Peter Ssebutinde ,Emmanuel Luyirika ,Florence Nambaziira ,Mary Abwola ,Shepherd Mudzingwa ,Lyndsey Castle ,Harriet Namata ,Annette Nassali ,Paddy Mallon ,Thomas J Peto ,Godfrey Musoro ,Kunal Malik ,Hillary Alima ,Josephine Namusanje ,Crispin Moyo ,Andy Burke ,Christine Matama ,Margaret Mugenyi ,Nancy P Young ,Jennifer L Thompson ,Clement Mtika ,Winnie Namala ,Francis Ssali ,Sylvia Mulambo ,Emmanuel Kerukadho ,Wendy Snowden ,T Bafana ,Patrick Kidega ,Marco Floridia ,Angela Rweyora ,Mary Naluguza ,Jonathan Matenga ,Ali Elbireer ,Philliam Aleti ,Eva Laker ,Jonathan Nkalubo ,Ivan Mambule ,Joseph Omongin ,Hellen Musana ,Jorge Villacian

doi:10.1016/s2352-3018(17)30065-6

Abstract

SummaryBackgroundCross-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.MethodsWe 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).FindingsBaseline 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).InterpretationGenotypic 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.FundingEuropean 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.

Highlights

More than 17 million people receive antiretroviral therapy (ART) for HIV infection, mainly delivered with the WHOrecommended public health approach, characterised by use of standardised sequential regimens.[1,2] Standardised first-line and second-line regimens both include nucleoside reverse-transcriptase inhibitors (NRTIs), combined with a non-NRTI (NNRTI) in first-line and a boosted protease inhibitor in second-line therapy.[3]
We found two cohort studies done in sub-Saharan Africa (243 and 101 participants, follow-up 12 months) and one in Asia (105 participants, follow-up 12 months) and analyses of the NRTI plus protease inhibitor arm in two randomised controlled trials (254 participants, follow-up 48 weeks; 270 participants, follow-up 96 weeks)
Our analysis shows that a regimen containing NRTIs with no or limited predicted activity achieved viral load suppression in a high proportion of patients, which was sustained throughout longer-term follow-up

Summary

Introduction

More than 17 million people receive antiretroviral therapy (ART) for HIV infection, mainly delivered with the WHOrecommended public health approach, characterised by use of standardised sequential regimens.[1,2] Standardised first-line and second-line regimens both include nucleoside reverse-transcriptase inhibitors (NRTIs), combined with a non-NRTI (NNRTI) in first-line and a boosted protease inhibitor in second-line therapy.[3]. Evidence before this study We searched PubMed with no start date or language restrictions for articles published until Aug 1, 2016, with the terms “second-line therapy”, “protease inhibitors”, “resistance testing”, and the individual drug names, and we reviewed relevant HIV conference abstracts. This search identified studies that examined the association between nucleoside reverse-transcriptase inhibitor (NRTI) resistance and virological outcomes for NRTI plus protease inhibitor second-line therapy after failure on a first-line non-NRTI (NNRTI)-containing regimen. These studies either reported no association or an inverse association between predicted activity of prescribed NRTIs and viral load suppression

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