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, Cissy Kityo, Jennifer Thompson, Immaculate Nankya, Leonard Bagenda, Anne Hoppe, James Hakim, Andrew Kambugu, Joep J. van Oosterhout, Mary Kiconco, Silvia Bertagnolio, Philippa J. Easterbrook, Peter Mugyenyi, A. Sarah Walker, E. Agweng, P. Awio, G. Bakeinyaga, C. Isabirye, U. Kabuga, S. KasuswaM. 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. Ocitti Labejja, P. Okello, P. Olal, G. Pimundu, P. Segonga, F. Ssali, Z. Tamale, D. Tumukunde, W. Namala, R. Byaruhanga, J. Kayiwa, J. Tukamushaba, S. Abunyang, D. Eram, O. Denis, R. Lwalanda, L. Mugarura, J. Namusanje, I. Nankya, E. Ndashimye, E. Nabulime, D. Mulima, O. Senfuma, 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, 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, J. Acen, J. Achidri, A. Amone, M. Chamai, J. Ditai, M. Kemigisa, M. Kiconco, C. Matama, D. Mbanza, F. Nambaziira, M. Owor Odoi, A. Rweyora, G. Tumwebaze, H. Kalanzi, J. Katabaazi, A. Kiyingi, M. Mbidde, M. Mugenyi, R. Mwebaze, P. Okong, I. Senoga, M. Abwola, D. Baliruno, J. Bwomezi, A. Kasede, M. Mudoola, R. Namisi, F. Ssennono, S. Tuhirwe, G. Abongomera, G. Amone, J. Abach, I. Aciro, B. Arach, P. Kidega, J. Omongin, E. Ocung, W. Odong, A. Philliam, 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, S. Kiirya, D. Atwongyeire, A. Nankya, C. Draleku, D. Nakiboneka, D. Odoch, L. Lakidi, R. Ruganda, R. Abiriga, M. Mulindwa, F. Balmoi, S. Kafuma, E. Moriku, J. Hakim, A. Reid, E. Chidziva, G. Musoro, C. Warambwa, G. Tinago, S. Mutsai, M. Phiri, S. Mudzingwa, T. Bafana, V. Masore, C. Moyo, R. Nhema, S. Chitongo, Robert Heyderman, Lucky Kabanga, Symon Kaunda, Aubrey Kudzala, Linly Lifa, Jane Mallewa, Mike Moore, Chrissie Mtali, George Musowa, Grace Mwimaniwa, Rosemary Sikwese, Joep van Oosterhout, Milton Ziwoya, 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, Kara Wools-Kaloustian, C. Kwobah, W. Lokitala Ekiru, M. Mokaya, A. Mudogo, A. Nzioka, A. Siika, M. Tanui, S. Wachira, K. Wools-Kaloustian, P. Alipalli, E. Chikatula, J. Kipaila, I. Kunda, S. Lakhi, J. Malama, W. Mufwambi, L. Mulenga, P. Mwaba, E. Mwamba, A. Mweemba, M. Namfukwe, E. Kerukadho, B. Ngwatu, J. Birungi, 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, M. Spyer, C. Kapuya, F. Kyomuhendo, D. Kyakundi, N. Mkandawire, S. Mulambo, S. Senyonjo, B. Angus, A. Arenas-Pinto, A. Palfreeman, F. Post, D. Ishola, J. Arribas, R. Colebunders, M. Floridia, M. Giuliano, P. Mallon, P. Walsh, M. De Rosa, E. Rinaldi, I. Weller, 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, T. Peto, N. French, J. Matenga, G. Cloherty, J. van Wyk, M. Norton, S. Lehrman, P. Lamba, K. Malik, J. Rooney, W. Snowden, J. Villacian

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)e341-e348
JournalThe Lancet HIV
Volume4
Issue number8
DOIs
StatePublished - Aug 1 2017

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Reverse Transcriptase Inhibitors
Nucleosides
Public Health
Protease Inhibitors
Therapeutics
Viral Load
HIV
Lopinavir
International Cooperation
Ritonavir
Africa South of the Sahara
Developing Countries
Biomedical Research

ASJC Scopus subject areas

  • Epidemiology
  • Immunology
  • Infectious Diseases
  • Virology

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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. / Paton, Nicholas I.; Kityo, Cissy; Thompson, Jennifer; Nankya, Immaculate; Bagenda, Leonard; Hoppe, Anne; Hakim, James; Kambugu, Andrew; van Oosterhout, Joep J.; Kiconco, Mary; Bertagnolio, Silvia; Easterbrook, Philippa J.; Mugyenyi, Peter; Walker, A. Sarah; Agweng, E.; Awio, P.; Bakeinyaga, G.; Isabirye, C.; Kabuga, U.; Kasuswa, S.; Katuramu, M.; Kityo, C.; Kiweewa, F.; Kyomugisha, H.; Lutalo, E.; Mugyenyi, P.; Mulima, D.; Musana, H.; Musitwa, G.; Musiime, V.; Ndigendawan, M.; Namata, H.; Nkalubo, J.; Labejja, P. Ocitti; Okello, P.; Olal, P.; Pimundu, G.; Segonga, P.; Ssali, F.; Tamale, Z.; Tumukunde, D.; Namala, W.; Byaruhanga, R.; Kayiwa, J.; Tukamushaba, J.; Abunyang, S.; Eram, D.; Denis, O.; Lwalanda, R.; Mugarura, L.; Namusanje, J.; Nankya, I.; Ndashimye, E.; Nabulime, E.; Mulima, D.; Senfuma, O.; Bihabwa, G.; Buluma, E.; Easterbrook, P.; Elbireer, A.; Kambugu, A.; Kamya, D.; Katwere, M.; Kiggundu, R.; Komujuni, C.; Laker, E.; Lubwama, E.; Mambule, I.; Matovu, J.; Nakajubi, A.; Nakku, J.; Nalumenya, R.; Namuyimbwa, L.; Semitala, F.; Wandera, B.; Wanyama, J.; Mugerwa, H.; Lugemwa, A.; Ninsiima, E.; Ssenkindu, T.; Mwebe, S.; Atwine, L.; William, H.; Katemba, C.; Abunyang, S.; Acaku, M.; Ssebutinde, P.; Kitizo, H.; Kukundakwe, J.; Naluguza, M.; Ssegawa, K.; Namayanja; Nsibuka, F.; Tuhirirwe, P.; Fortunate, M.; Acen, J.; Achidri, J.; Amone, A.; Chamai, M.; Ditai, J.; Kemigisa, M.; Kiconco, M.; Matama, C.; Mbanza, D.; Nambaziira, F.; Odoi, M. Owor; Rweyora, A.; Tumwebaze, G.; Kalanzi, H.; Katabaazi, J.; Kiyingi, A.; Mbidde, M.; Mugenyi, M.; Mwebaze, R.; Okong, P.; Senoga, I.; Abwola, M.; Baliruno, D.; Bwomezi, J.; Kasede, A.; Mudoola, M.; Namisi, R.; Ssennono, F.; Tuhirwe, S.; Abongomera, G.; Amone, G.; Abach, J.; Aciro, I.; Arach, B.; Kidega, P.; Omongin, J.; Ocung, E.; Odong, W.; Philliam, A.; Alima, H.; Ahimbisibwe, B.; Atuhaire, E.; Atukunda, F.; Bekusike, G.; Bulegyeya, A.; Kahatano, D.; Kamukama, S.; Kyoshabire, J.; Nassali, A.; Mbonye, A.; Naturinda, T. M.; Ndukukire; Nshabohurira, A.; Ntawiha, H.; Rogers, A.; Tibyasa, M.; Kiirya, S.; Atwongyeire, D.; Nankya, A.; Draleku, C.; Nakiboneka, D.; Odoch, D.; Lakidi, L.; Ruganda, R.; Abiriga, R.; Mulindwa, M.; Balmoi, F.; Kafuma, S.; Moriku, E.; Hakim, J.; Reid, A.; Chidziva, E.; Musoro, G.; Warambwa, C.; Tinago, G.; Mutsai, S.; Phiri, M.; Mudzingwa, S.; Bafana, T.; Masore, V.; Moyo, C.; Nhema, R.; Chitongo, S.; Heyderman, Robert; Kabanga, Lucky; Kaunda, Symon; Kudzala, Aubrey; Lifa, Linly; Mallewa, Jane; Moore, Mike; Mtali, Chrissie; Musowa, George; Mwimaniwa, Grace; Sikwese, Rosemary; van Oosterhout, Joep; Ziwoya, Milton; Chimbaka, H.; Chitete, B.; Kamanga, S.; Makwakwa, T. Kayinga E.; Mbiya, R.; Mlenga, M.; Mphande, T.; Mtika, C.; Mushani, G.; Ndhlovu, O.; Ngonga, M.; Nkhana, I.; Nyirenda, R.; Wools-Kaloustian, Kara; Kwobah, C.; Ekiru, W. Lokitala; Mokaya, M.; Mudogo, A.; Nzioka, A.; Siika, A.; Tanui, M.; Wachira, S.; Wools-Kaloustian, K.; Alipalli, P.; Chikatula, E.; Kipaila, J.; Kunda, I.; Lakhi, S.; Malama, J.; Mufwambi, W.; Mulenga, L.; Mwaba, P.; Mwamba, E.; Mweemba, A.; Namfukwe, M.; Kerukadho, E.; Ngwatu, B.; Birungi, J.; Paton, N.; Boles, J.; Burke, A.; Castle, L.; Ghuman, S.; Kendall, L.; Hoppe, A.; Tebbs, S.; Thomason, M.; Thompson, J.; Walker, S.; Whittle, J.; Wilkes, H.; Young, N.; Spyer, M.; Kapuya, C.; Kyomuhendo, F.; Kyakundi, D.; Mkandawire, N.; Mulambo, S.; Senyonjo, S.; Angus, B.; Arenas-Pinto, A.; Palfreeman, A.; Post, F.; Ishola, D.; Arribas, J.; Colebunders, R.; Floridia, M.; Giuliano, M.; Mallon, P.; Walsh, P.; De Rosa, M.; Rinaldi, E.; Weller, I.; Gilks, C.; Hakim, J.; Kangewende, A.; Lakhi, S.; Luyirika, E.; Miiro, F.; Mwamba, P.; Mugyenyi, P.; Ojoo, S.; Paton, N.; Phiri, S.; van Oosterhout, J.; Siika, A.; Walker, S.; Wapakabulo, A.; Peto, T.; French, N.; Matenga, J.; Cloherty, G.; van Wyk, J.; Norton, M.; Lehrman, S.; Lamba, P.; Malik, K.; Rooney, J.; Snowden, W.; Villacian, J.

In: The Lancet HIV, Vol. 4, No. 8, 01.08.2017, p. e341-e348.

Research output: Contribution to journalArticle

Paton, NI, Kityo, C, Thompson, J, Nankya, I, Bagenda, L, Hoppe, A, Hakim, J, Kambugu, A, van Oosterhout, JJ, Kiconco, M, Bertagnolio, S, Easterbrook, PJ, Mugyenyi, P, Walker, AS, Agweng, E, Awio, P, Bakeinyaga, G, Isabirye, C, Kabuga, U, Kasuswa, S, Katuramu, M, Kityo, C, Kiweewa, F, Kyomugisha, H, Lutalo, E, Mugyenyi, P, Mulima, D, Musana, H, Musitwa, G, Musiime, V, Ndigendawan, M, Namata, H, Nkalubo, J, Labejja, PO, Okello, P, Olal, P, Pimundu, G, Segonga, P, Ssali, F, Tamale, Z, Tumukunde, D, Namala, W, Byaruhanga, R, Kayiwa, J, Tukamushaba, J, Abunyang, S, Eram, D, Denis, O, Lwalanda, R, Mugarura, L, Namusanje, J, Nankya, I, Ndashimye, E, Nabulime, E, Mulima, D, Senfuma, O, Bihabwa, G, Buluma, E, Easterbrook, P, Elbireer, A, Kambugu, A, Kamya, D, Katwere, M, Kiggundu, R, Komujuni, C, Laker, E, Lubwama, E, Mambule, I, Matovu, J, Nakajubi, A, Nakku, J, Nalumenya, R, Namuyimbwa, L, Semitala, F, Wandera, B, Wanyama, J, Mugerwa, H, Lugemwa, A, Ninsiima, E, Ssenkindu, T, Mwebe, S, Atwine, L, William, H, Katemba, C, Abunyang, S, Acaku, M, Ssebutinde, P, Kitizo, H, Kukundakwe, J, Naluguza, M, Ssegawa, K, Namayanja, Nsibuka, F, Tuhirirwe, P, Fortunate, M, Acen, J, Achidri, J, Amone, A, Chamai, M, Ditai, J, Kemigisa, M, Kiconco, M, Matama, C, Mbanza, D, Nambaziira, F, Odoi, MO, Rweyora, A, Tumwebaze, G, Kalanzi, H, Katabaazi, J, Kiyingi, A, Mbidde, M, Mugenyi, M, Mwebaze, R, Okong, P, Senoga, I, Abwola, M, Baliruno, D, Bwomezi, J, Kasede, A, Mudoola, M, Namisi, R, Ssennono, F, Tuhirwe, S, Abongomera, G, Amone, G, Abach, J, Aciro, I, Arach, B, Kidega, P, Omongin, J, Ocung, E, Odong, W, Philliam, A, Alima, H, Ahimbisibwe, B, Atuhaire, E, Atukunda, F, Bekusike, G, Bulegyeya, A, Kahatano, D, Kamukama, S, Kyoshabire, J, Nassali, A, Mbonye, A, Naturinda, TM, Ndukukire, Nshabohurira, A, Ntawiha, H, Rogers, A, Tibyasa, M, Kiirya, S, Atwongyeire, D, Nankya, A, Draleku, C, Nakiboneka, D, Odoch, D, Lakidi, L, Ruganda, R, Abiriga, R, Mulindwa, M, Balmoi, F, Kafuma, S, Moriku, E, Hakim, J, Reid, A, Chidziva, E, Musoro, G, Warambwa, C, Tinago, G, Mutsai, S, Phiri, M, Mudzingwa, S, Bafana, T, Masore, V, Moyo, C, Nhema, R, Chitongo, S, Heyderman, R, Kabanga, L, Kaunda, S, Kudzala, A, Lifa, L, Mallewa, J, Moore, M, Mtali, C, Musowa, G, Mwimaniwa, G, Sikwese, R, van Oosterhout, J, Ziwoya, M, Chimbaka, H, Chitete, B, Kamanga, S, Makwakwa, TKE, Mbiya, R, Mlenga, M, Mphande, T, Mtika, C, Mushani, G, Ndhlovu, O, Ngonga, M, Nkhana, I, Nyirenda, R, Wools-Kaloustian, K, Kwobah, C, Ekiru, WL, Mokaya, M, Mudogo, A, Nzioka, A, Siika, A, Tanui, M, Wachira, S, Wools-Kaloustian, K, Alipalli, P, Chikatula, E, Kipaila, J, Kunda, I, Lakhi, S, Malama, J, Mufwambi, W, Mulenga, L, Mwaba, P, Mwamba, E, Mweemba, A, Namfukwe, M, Kerukadho, E, Ngwatu, B, Birungi, J, Paton, N, Boles, J, Burke, A, Castle, L, Ghuman, S, Kendall, L, Hoppe, A, Tebbs, S, Thomason, M, Thompson, J, Walker, S, Whittle, J, Wilkes, H, Young, N, Spyer, M, Kapuya, C, Kyomuhendo, F, Kyakundi, D, Mkandawire, N, Mulambo, S, Senyonjo, S, Angus, B, Arenas-Pinto, A, Palfreeman, A, Post, F, Ishola, D, Arribas, J, Colebunders, R, Floridia, M, Giuliano, M, Mallon, P, Walsh, P, De Rosa, M, Rinaldi, E, Weller, I, Gilks, C, Hakim, J, Kangewende, A, Lakhi, S, Luyirika, E, Miiro, F, Mwamba, P, Mugyenyi, P, Ojoo, S, Paton, N, Phiri, S, van Oosterhout, J, Siika, A, Walker, S, Wapakabulo, A, Peto, T, French, N, Matenga, J, Cloherty, G, van Wyk, J, Norton, M, Lehrman, S, Lamba, P, Malik, K, Rooney, J, Snowden, W & Villacian, J 2017, '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, vol. 4, no. 8, pp. e341-e348. https://doi.org/10.1016/S2352-3018(17)30065-6
Paton, Nicholas I. ; Kityo, Cissy ; Thompson, Jennifer ; Nankya, Immaculate ; Bagenda, Leonard ; Hoppe, Anne ; Hakim, James ; Kambugu, Andrew ; van Oosterhout, Joep J. ; Kiconco, Mary ; Bertagnolio, Silvia ; Easterbrook, Philippa J. ; Mugyenyi, Peter ; Walker, A. Sarah ; Agweng, E. ; Awio, P. ; Bakeinyaga, G. ; Isabirye, C. ; Kabuga, U. ; Kasuswa, S. ; Katuramu, M. ; Kityo, C. ; Kiweewa, F. ; Kyomugisha, H. ; Lutalo, E. ; Mugyenyi, P. ; Mulima, D. ; Musana, H. ; Musitwa, G. ; Musiime, V. ; Ndigendawan, M. ; Namata, H. ; Nkalubo, J. ; Labejja, P. Ocitti ; Okello, P. ; Olal, P. ; Pimundu, G. ; Segonga, P. ; Ssali, F. ; Tamale, Z. ; Tumukunde, D. ; Namala, W. ; Byaruhanga, R. ; Kayiwa, J. ; Tukamushaba, J. ; Abunyang, S. ; Eram, D. ; Denis, O. ; Lwalanda, R. ; Mugarura, L. ; Namusanje, J. ; Nankya, I. ; Ndashimye, E. ; Nabulime, E. ; Mulima, D. ; Senfuma, O. ; Bihabwa, G. ; Buluma, E. ; Easterbrook, P. ; Elbireer, A. ; Kambugu, A. ; Kamya, D. ; Katwere, M. ; Kiggundu, R. ; Komujuni, C. ; Laker, E. ; Lubwama, E. ; Mambule, I. ; Matovu, J. ; Nakajubi, A. ; Nakku, J. ; Nalumenya, R. ; Namuyimbwa, L. ; Semitala, F. ; Wandera, B. ; Wanyama, J. ; Mugerwa, H. ; Lugemwa, A. ; Ninsiima, E. ; Ssenkindu, T. ; Mwebe, S. ; Atwine, L. ; William, H. ; Katemba, C. ; Abunyang, S. ; Acaku, M. ; Ssebutinde, P. ; Kitizo, H. ; Kukundakwe, J. ; Naluguza, M. ; Ssegawa, K. ; Namayanja ; Nsibuka, F. ; Tuhirirwe, P. ; Fortunate, M. ; Acen, J. ; Achidri, J. ; Amone, A. ; Chamai, M. ; Ditai, J. ; Kemigisa, M. ; Kiconco, M. ; Matama, C. ; Mbanza, D. ; Nambaziira, F. ; Odoi, M. Owor ; Rweyora, A. ; Tumwebaze, G. ; Kalanzi, H. ; Katabaazi, J. ; Kiyingi, A. ; Mbidde, M. ; Mugenyi, M. ; Mwebaze, R. ; Okong, P. ; Senoga, I. ; Abwola, M. ; Baliruno, D. ; Bwomezi, J. ; Kasede, A. ; Mudoola, M. ; Namisi, R. ; Ssennono, F. ; Tuhirwe, S. ; Abongomera, G. ; Amone, G. ; Abach, J. ; Aciro, I. ; Arach, B. ; Kidega, P. ; Omongin, J. ; Ocung, E. ; Odong, W. ; Philliam, A. ; Alima, H. ; Ahimbisibwe, B. ; Atuhaire, E. ; Atukunda, F. ; Bekusike, G. ; Bulegyeya, A. ; Kahatano, D. ; Kamukama, S. ; Kyoshabire, J. ; Nassali, A. ; Mbonye, A. ; Naturinda, T. M. ; Ndukukire ; Nshabohurira, A. ; Ntawiha, H. ; Rogers, A. ; Tibyasa, M. ; Kiirya, S. ; Atwongyeire, D. ; Nankya, A. ; Draleku, C. ; Nakiboneka, D. ; Odoch, D. ; Lakidi, L. ; Ruganda, R. ; Abiriga, R. ; Mulindwa, M. ; Balmoi, F. ; Kafuma, S. ; Moriku, E. ; Hakim, J. ; Reid, A. ; Chidziva, E. ; Musoro, G. ; Warambwa, C. ; Tinago, G. ; Mutsai, S. ; Phiri, M. ; Mudzingwa, S. ; Bafana, T. ; Masore, V. ; Moyo, C. ; Nhema, R. ; Chitongo, S. ; Heyderman, Robert ; Kabanga, Lucky ; Kaunda, Symon ; Kudzala, Aubrey ; Lifa, Linly ; Mallewa, Jane ; Moore, Mike ; Mtali, Chrissie ; Musowa, George ; Mwimaniwa, Grace ; Sikwese, Rosemary ; van Oosterhout, Joep ; Ziwoya, Milton ; Chimbaka, H. ; Chitete, B. ; Kamanga, S. ; Makwakwa, T. Kayinga E. ; Mbiya, R. ; Mlenga, M. ; Mphande, T. ; Mtika, C. ; Mushani, G. ; Ndhlovu, O. ; Ngonga, M. ; Nkhana, I. ; Nyirenda, R. ; Wools-Kaloustian, Kara ; Kwobah, C. ; Ekiru, W. Lokitala ; Mokaya, M. ; Mudogo, A. ; Nzioka, A. ; Siika, A. ; Tanui, M. ; Wachira, S. ; Wools-Kaloustian, K. ; Alipalli, P. ; Chikatula, E. ; Kipaila, J. ; Kunda, I. ; Lakhi, S. ; Malama, J. ; Mufwambi, W. ; Mulenga, L. ; Mwaba, P. ; Mwamba, E. ; Mweemba, A. ; Namfukwe, M. ; Kerukadho, E. ; Ngwatu, B. ; Birungi, J. ; Paton, N. ; Boles, J. ; Burke, A. ; Castle, L. ; Ghuman, S. ; Kendall, L. ; Hoppe, A. ; Tebbs, S. ; Thomason, M. ; Thompson, J. ; Walker, S. ; Whittle, J. ; Wilkes, H. ; Young, N. ; Spyer, M. ; Kapuya, C. ; Kyomuhendo, F. ; Kyakundi, D. ; Mkandawire, N. ; Mulambo, S. ; Senyonjo, S. ; Angus, B. ; Arenas-Pinto, A. ; Palfreeman, A. ; Post, F. ; Ishola, D. ; Arribas, J. ; Colebunders, R. ; Floridia, M. ; Giuliano, M. ; Mallon, P. ; Walsh, P. ; De Rosa, M. ; Rinaldi, E. ; Weller, I. ; Gilks, C. ; Hakim, J. ; Kangewende, A. ; Lakhi, S. ; Luyirika, E. ; Miiro, F. ; Mwamba, P. ; Mugyenyi, P. ; Ojoo, S. ; Paton, N. ; Phiri, S. ; van Oosterhout, J. ; Siika, A. ; Walker, S. ; Wapakabulo, A. ; Peto, T. ; French, N. ; Matenga, J. ; Cloherty, G. ; van Wyk, J. ; Norton, M. ; Lehrman, S. ; Lamba, P. ; Malik, K. ; Rooney, J. ; Snowden, W. ; Villacian, J. / 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. In: The Lancet HIV. 2017 ; Vol. 4, No. 8. pp. e341-e348.
@article{eebca811fc7f439d98292dee36b44553,
title = "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",
abstract = "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.",
author = "Paton, {Nicholas I.} and Cissy Kityo and Jennifer Thompson and Immaculate Nankya and Leonard Bagenda and Anne Hoppe and James Hakim and Andrew Kambugu and {van Oosterhout}, {Joep J.} and Mary Kiconco and Silvia Bertagnolio and Easterbrook, {Philippa J.} and Peter Mugyenyi and Walker, {A. Sarah} and E. Agweng and P. Awio and G. Bakeinyaga and C. Isabirye and U. Kabuga and S. Kasuswa and M. Katuramu and C. Kityo and F. Kiweewa and H. Kyomugisha and E. Lutalo and P. Mugyenyi and D. Mulima and H. Musana and G. Musitwa and V. Musiime and M. Ndigendawan and H. Namata and J. Nkalubo and Labejja, {P. Ocitti} and P. Okello and P. Olal and G. Pimundu and P. Segonga and F. Ssali and Z. Tamale and D. Tumukunde and W. Namala and R. Byaruhanga and J. Kayiwa and J. Tukamushaba and S. Abunyang and D. Eram and O. Denis and R. Lwalanda and L. Mugarura and J. Namusanje and I. Nankya and E. Ndashimye and E. Nabulime and D. Mulima and O. Senfuma and G. Bihabwa and E. Buluma and P. Easterbrook and A. Elbireer and A. Kambugu and D. Kamya and M. Katwere and R. Kiggundu and C. Komujuni and E. Laker and E. Lubwama and I. Mambule and J. Matovu and A. Nakajubi and J. Nakku and R. Nalumenya and L. Namuyimbwa and F. Semitala and B. Wandera and J. Wanyama and H. Mugerwa and A. Lugemwa and E. Ninsiima and T. Ssenkindu and S. Mwebe and L. Atwine and H. William and C. Katemba and S. Abunyang and M. Acaku and P. Ssebutinde and H. Kitizo and J. Kukundakwe and M. Naluguza and K. Ssegawa and Namayanja and F. Nsibuka and P. Tuhirirwe and M. Fortunate and J. Acen and J. Achidri and A. Amone and M. Chamai and J. Ditai and M. Kemigisa and M. Kiconco and C. Matama and D. Mbanza and F. Nambaziira and Odoi, {M. Owor} and A. Rweyora and G. Tumwebaze and H. Kalanzi and J. Katabaazi and A. Kiyingi and M. Mbidde and M. Mugenyi and R. Mwebaze and P. Okong and I. Senoga and M. Abwola and D. Baliruno and J. Bwomezi and A. Kasede and M. Mudoola and R. Namisi and F. Ssennono and S. Tuhirwe and G. Abongomera and G. Amone and J. Abach and I. Aciro and B. Arach and P. Kidega and J. Omongin and E. Ocung and W. Odong and A. Philliam and H. Alima and B. Ahimbisibwe and E. Atuhaire and F. Atukunda and G. Bekusike and A. Bulegyeya and D. Kahatano and S. Kamukama and J. Kyoshabire and A. Nassali and A. Mbonye and Naturinda, {T. M.} and Ndukukire and A. Nshabohurira and H. Ntawiha and A. Rogers and M. Tibyasa and S. Kiirya and D. Atwongyeire and A. Nankya and C. Draleku and D. Nakiboneka and D. Odoch and L. Lakidi and R. Ruganda and R. Abiriga and M. Mulindwa and F. Balmoi and S. Kafuma and E. Moriku and J. Hakim and A. Reid and E. Chidziva and G. Musoro and C. Warambwa and G. Tinago and S. Mutsai and M. Phiri and S. Mudzingwa and T. Bafana and V. Masore and C. Moyo and R. Nhema and S. Chitongo and Robert Heyderman and Lucky Kabanga and Symon Kaunda and Aubrey Kudzala and Linly Lifa and Jane Mallewa and Mike Moore and Chrissie Mtali and George Musowa and Grace Mwimaniwa and Rosemary Sikwese and {van Oosterhout}, Joep and Milton Ziwoya and H. Chimbaka and B. Chitete and S. Kamanga and Makwakwa, {T. Kayinga E.} and R. Mbiya and M. Mlenga and T. Mphande and C. Mtika and G. Mushani and O. Ndhlovu and M. Ngonga and I. Nkhana and R. Nyirenda and Kara Wools-Kaloustian and C. Kwobah and Ekiru, {W. Lokitala} and M. Mokaya and A. Mudogo and A. Nzioka and A. Siika and M. Tanui and S. Wachira and K. Wools-Kaloustian and P. Alipalli and E. Chikatula and J. Kipaila and I. Kunda and S. Lakhi and J. Malama and W. Mufwambi and L. Mulenga and P. Mwaba and E. Mwamba and A. Mweemba and M. Namfukwe and E. Kerukadho and B. Ngwatu and J. Birungi and N. Paton and J. Boles and A. Burke and L. Castle and S. Ghuman and L. Kendall and A. Hoppe and S. Tebbs and M. Thomason and J. Thompson and S. Walker and J. Whittle and H. Wilkes and N. Young and M. Spyer and C. Kapuya and F. Kyomuhendo and D. Kyakundi and N. Mkandawire and S. Mulambo and S. Senyonjo and B. Angus and A. Arenas-Pinto and A. Palfreeman and F. Post and D. Ishola and J. Arribas and R. Colebunders and M. Floridia and M. Giuliano and P. Mallon and P. Walsh and {De Rosa}, M. and E. Rinaldi and I. Weller and C. Gilks and J. Hakim and A. Kangewende and S. Lakhi and E. Luyirika and F. Miiro and P. Mwamba and P. Mugyenyi and S. Ojoo and N. Paton and S. Phiri and {van Oosterhout}, J. and A. Siika and S. Walker and A. Wapakabulo and T. Peto and N. French and J. Matenga and G. Cloherty and {van Wyk}, J. and M. Norton and S. Lehrman and P. Lamba and K. Malik and J. Rooney and W. Snowden and J. Villacian",
year = "2017",
month = "8",
day = "1",
doi = "10.1016/S2352-3018(17)30065-6",
language = "English (US)",
volume = "4",
pages = "e341--e348",
journal = "The Lancet HIV",
issn = "2352-3018",
publisher = "Elsevier Limited",
number = "8",

}

TY - JOUR

T1 - Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach

T2 - an observational analysis within the randomised, open-label, EARNEST trial

AU - Paton, Nicholas I.

AU - Kityo, Cissy

AU - Thompson, Jennifer

AU - Nankya, Immaculate

AU - Bagenda, Leonard

AU - Hoppe, Anne

AU - Hakim, James

AU - Kambugu, Andrew

AU - van Oosterhout, Joep J.

AU - Kiconco, Mary

AU - Bertagnolio, Silvia

AU - Easterbrook, Philippa J.

AU - Mugyenyi, Peter

AU - Walker, A. Sarah

AU - Agweng, E.

AU - Awio, P.

AU - Bakeinyaga, G.

AU - Isabirye, C.

AU - Kabuga, U.

AU - Kasuswa, S.

AU - Katuramu, M.

AU - Kityo, C.

AU - Kiweewa, F.

AU - Kyomugisha, H.

AU - Lutalo, E.

AU - Mugyenyi, P.

AU - Mulima, D.

AU - Musana, H.

AU - Musitwa, G.

AU - Musiime, V.

AU - Ndigendawan, M.

AU - Namata, H.

AU - Nkalubo, J.

AU - Labejja, P. Ocitti

AU - Okello, P.

AU - Olal, P.

AU - Pimundu, G.

AU - Segonga, P.

AU - Ssali, F.

AU - Tamale, Z.

AU - Tumukunde, D.

AU - Namala, W.

AU - Byaruhanga, R.

AU - Kayiwa, J.

AU - Tukamushaba, J.

AU - Abunyang, S.

AU - Eram, D.

AU - Denis, O.

AU - Lwalanda, R.

AU - Mugarura, L.

AU - Namusanje, J.

AU - Nankya, I.

AU - Ndashimye, E.

AU - Nabulime, E.

AU - Mulima, D.

AU - Senfuma, O.

AU - Bihabwa, G.

AU - Buluma, E.

AU - Easterbrook, P.

AU - Elbireer, A.

AU - Kambugu, A.

AU - Kamya, D.

AU - Katwere, M.

AU - Kiggundu, R.

AU - Komujuni, C.

AU - Laker, E.

AU - Lubwama, E.

AU - Mambule, I.

AU - Matovu, J.

AU - Nakajubi, A.

AU - Nakku, J.

AU - Nalumenya, R.

AU - Namuyimbwa, L.

AU - Semitala, F.

AU - Wandera, B.

AU - Wanyama, J.

AU - Mugerwa, H.

AU - Lugemwa, A.

AU - Ninsiima, E.

AU - Ssenkindu, T.

AU - Mwebe, S.

AU - Atwine, L.

AU - William, H.

AU - Katemba, C.

AU - Abunyang, S.

AU - Acaku, M.

AU - Ssebutinde, P.

AU - Kitizo, H.

AU - Kukundakwe, J.

AU - Naluguza, M.

AU - Ssegawa, K.

AU - Namayanja,

AU - Nsibuka, F.

AU - Tuhirirwe, P.

AU - Fortunate, M.

AU - Acen, J.

AU - Achidri, J.

AU - Amone, A.

AU - Chamai, M.

AU - Ditai, J.

AU - Kemigisa, M.

AU - Kiconco, M.

AU - Matama, C.

AU - Mbanza, D.

AU - Nambaziira, F.

AU - Odoi, M. Owor

AU - Rweyora, A.

AU - Tumwebaze, G.

AU - Kalanzi, H.

AU - Katabaazi, J.

AU - Kiyingi, A.

AU - Mbidde, M.

AU - Mugenyi, M.

AU - Mwebaze, R.

AU - Okong, P.

AU - Senoga, I.

AU - Abwola, M.

AU - Baliruno, D.

AU - Bwomezi, J.

AU - Kasede, A.

AU - Mudoola, M.

AU - Namisi, R.

AU - Ssennono, F.

AU - Tuhirwe, S.

AU - Abongomera, G.

AU - Amone, G.

AU - Abach, J.

AU - Aciro, I.

AU - Arach, B.

AU - Kidega, P.

AU - Omongin, J.

AU - Ocung, E.

AU - Odong, W.

AU - Philliam, A.

AU - Alima, H.

AU - Ahimbisibwe, B.

AU - Atuhaire, E.

AU - Atukunda, F.

AU - Bekusike, G.

AU - Bulegyeya, A.

AU - Kahatano, D.

AU - Kamukama, S.

AU - Kyoshabire, J.

AU - Nassali, A.

AU - Mbonye, A.

AU - Naturinda, T. M.

AU - Ndukukire,

AU - Nshabohurira, A.

AU - Ntawiha, H.

AU - Rogers, A.

AU - Tibyasa, M.

AU - Kiirya, S.

AU - Atwongyeire, D.

AU - Nankya, A.

AU - Draleku, C.

AU - Nakiboneka, D.

AU - Odoch, D.

AU - Lakidi, L.

AU - Ruganda, R.

AU - Abiriga, R.

AU - Mulindwa, M.

AU - Balmoi, F.

AU - Kafuma, S.

AU - Moriku, E.

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PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

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U2 - 10.1016/S2352-3018(17)30065-6

DO - 10.1016/S2352-3018(17)30065-6

M3 - Article

C2 - 28495562

AN - SCOPUS:85019020889

VL - 4

SP - e341-e348

JO - The Lancet HIV

JF - The Lancet HIV

SN - 2352-3018

IS - 8

ER -