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1. Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial

Author

Agweng, E, Awio, P, Bakeinyaga, G, Isabirye, C, Kabuga, U, Kasuswa, S, Katuramu, M, Kiweewa, F, Kyomugisha, H, Lutalo, E, 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, Senfuma, O, Bihabwa, G, Buluma, E, Elbireer, 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, Ninsiima, E, Ssenkindu, T, Mwebe, S, Atwine, L, William, H, Katemba, C, 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, Okong, P, Senoga, I, Abwola, M, Baliruno, D, Bwomezi, J, Kasede, A, Mudoola, M, Namisi, R, Ssennono, F, Tuhirwe, S, 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, 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, Ziwoya, Milton, Chitete, H Chimbaka 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, Cheruiyot, P, Kwobah, C, Ekiru, W Lokitala, Mokaya, M, Mudogo, A, Nzioka, 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, Namfukwe, M, Kerukadho, E, Ngwatu, B, Birungi, J, Boles, J, Burke, A, Castle, L, Ghuman, S, Kendall, L, Tebbs, 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, Kangewende, A, Luyirika, E, Miiro, F, Ojoo, S, Phiri, S, Wapakabulo, A, Peto, T, Matenga, J, Cloherty, G, van Wyk, J, Norton, M, Lehrman, S, Lamba, P, Malik, K, Rooney, J, Snowden, W, Villacian, J, Hakim, James G, Thompson, Jennifer, Kityo, Cissy, Hoppe, Anne, Kambugu, Andrew, van Oosterhout, Joep J, Lugemwa, Abbas, Siika, Abraham, Mwebaze, Raymond, Mweemba, Aggrey, Abongomera, George, Thomason, Margaret J, Easterbrook, Philippa, Mugyenyi, Peter, Walker, A Sarah, and Paton, Nicholas I

Published
2018
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2. 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

Author

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, 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, 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, Cheruiyot, P, 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, Kangewende, A, Luyirika, E, Miiro, F, Mwamba, P, Ojoo, S, Phiri, S, van Oosterhout, J, 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, 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, and Walker, A Sarah

Published
2017
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3. The cost‐effectiveness of prophylaxis strategies for individuals with advanced HIV starting treatment in Africa

Author

Walker, Simon M., Cox, Edward, Revill, Paul, Musiime, Victor, Bwakura?Dangarembizi, Mutsa, Mallewa, Jane, Cheruiyot, Priscilla, Maitland, Kathryn, Ford, Nathan, Gibb, Diana M., Walker, A Sarah, Soares, Marta, Mugyenyi, P, Kityo, C, Musiime, V, Wavamunno, P, Nambi, E, Ocitti, P, Ndigendawani, M, Kabahenda, S, Kemigisa, M, Acen, J, Olebo, D, Mpamize, G, Amone, A, Okweny, D, Mbonye, A, Nambaziira, F, Rweyora, A, Kangah, M, Kabaswahili, V, Abach, J, Abongomera, G, Omongin, J, Aciro, I, Philliam, A, Arach, B, Ocung, E, Amone, G, Miles, P, Adong, C, Tumsuiime, C, Kidega, P, Otto, B, Apio, F, Baleeta, K, Mukuye, A, Abwola, M, Ssennono, F, Baliruno, D, Tuhirwe, S, Namisi, R, Kigongo, F, Kikyonkyo, D, Mushahara, F, Tusiime, J, Musiime, A, Nankya, A, Atwongyeire, D, Sirikye, S, Mula, S, Noowe, N, Lugemwa, A, Kasozi, M, Mwebe, S, Atwine, L, Senkindu, T, Natuhurira, T, Katemba, C, Ninsiima, E, Acaku, M, Kyomuhangi, J, Ankunda, R, Tukwasibwe, D, Ayesiga, L, Hakim, J, Nathoo, K, Bwakura?Dangarembizi, M, Reid, A, Chidziva, E, Mhute, T, Tinago, Gc, Bhiri, J, Mudzingwa, S, Phiri, M, Steamer, J, Nhema, R, Warambwa, C, Musoro, G, Mutsai, S, Nemasango, B, Moyo, C, Chitongo, S, Rashirai, K, Vhembo, S, Mlambo, B, Nkomani, S, Ndemera, B, Willard, M, Berejena, C, Musodza, Y, Matiza, P, Mudenge, B, Guti, V, Etyang, A, Agutu, C, Berkley, J, Maitland, K, Njuguna, P, Mwaringa, S, Etyang, T, Awuondo, K, Wale, S, Shangala, J, Kithunga, J, Mwarumba, S, Maitha, S Said, Mutai, R, Lewa, M Lozi, Mwambingu, G, Mwanzu, A, Kalama, C, Latham, H, Shikuku, J, Fondo, A, Njogu, A, Khadenge, C, Mwakisha, B, Siika, A, Wools?Kaloustian, K, Nyandiko, W, Cheruiyot, P, Sudoi, A, Wachira, S, Meli, B, Karoney, M, Nzioka, A, Tanui, M, Mokaya, M, Ekiru, W, Mboya, C, Mwimali, D, Mengich, C, Choge, J, Injera, W, Njenga, K, Cherutich, S, Orido, M Anyango, Lwande, G Omondi, Rutto, P, Mudogo, A, Kutto, I, Shali, A, Jaika, L, Jerotich, H, Pierre, M, Mallewa, J, Kaunda, S, Van Oosterhout, J, O'Hare, B, Heydermann, R, Gonzalez, C, Dzabala, N, Kelly, C, Denis, B, Selemani, G, Mipando, L Nyondo, Chirwa, E, Banda, P, Mvula, L, Msuku, H, Ziwoya, M, Manda, Y, Nicholas, S, Masesa, C, Mwalukomo, T, Makhaza, L, Sheha, I, Bwanali, J, Limbuni, M, Gibb, D, Thomason, M, Walker, As, Pett, S, Szubert, A, Griffiths, A, Wilkes, H, Rajapakse, C, Spyer, M, Prendergast, A, Klein, N, Rauchenberger, M, Van Looy, N, Little, E, Fairbrother, K, Cowan, F, Seeley, J, Bernays, S, Kawuma, R, Mupambireyi, Z, Kyomuhendo, F, Nakalanzi, S, Peshu, J, Ndaa, S, Chabuka, J, Mkandawire, N, Matandika, L, Kapuya, C, Weller, I, Malianga, E, Mwansambo, C, Miiro, F, Elyanu, P, Bukusi, E, Katabira, E, Mugurungi, O, Peto, T, Musoke, P, Matenga, J, Phiri, S, Lyall, H, Johnston, V, Fitzgerald, F, Post, F, Ssali, F, Arenas?Pinto, A, Turkova, A, and Bamford, A

Subjects
Cost benefit analysis, Practice guidelines (Medicine) -- Evaluation, HIV infection -- Diagnosis -- Care and treatment, Cost benefit analysis, Health
Abstract

: Introduction: Many HIV‐positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced‐prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4 Methods: The REALITY trial enrolled from June 2013 to April 2015. A decision‐analytic model was developed to estimate the cost‐effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard‐prophylaxis, enhanced‐prophylaxis, standard‐prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced‐prophylaxis (CrAg‐positive) or standard‐prophylaxis (CrAg‐negative), the second to enhanced‐prophylaxis (CrAg‐positive) or enhanced‐prophylaxis without fluconazole (CrAg‐negative) and the third to standard‐prophylaxis with fluconazole (CrAg‐positive) or without fluconazole (CrAg‐negative). The model estimated costs, life‐years and quality‐adjusted life‐years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. Results: Enhanced‐prophylaxis was cost‐effective at cost‐effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost‐effectiveness ratio (ICER) of US$157 per QALY in the CD4 Conclusions: The REALITY enhanced‐prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost‐effective. Efforts should continue to ensure that components are accessed at lowest available prices., Introduction In low‐ and middle‐income settings, more than a third of HIV‐positive individuals starting antiretroviral therapy (ART) present with advanced disease (CD4 ≤ 200 cells/mm[sup.3]); over half of these have [...]

Published
2020
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4. Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial

Author

Kityo, C, Szubert, AJ, Siika, A, Heyderman, R, Bwakura-Dangarembizi, M, Lugemwa, A, Mwaringa, S, Griffiths, A, Nkanya, I, Kabahenda, S, Wachira, S, Musoro, G, Rajapakse, C, Etyang, T, Abach, J, Spyer, MJ, Wavamunno, P, Nyondo-Mipando, L, Chidziva, E, Nathoo, K, Klein, N, Hakim, J, Gibb, DM, Walker, AS, Pett, SL, Mugyenyi, P, Musiime, V, Nambi, E, Ocitti, P, Ndigendawani, M, Kemigisa, M, Acen, J, Olebo, D, Mpamize, G, Amone, A, Okweny, D, Mbonye, A, Nambaziira, F, Rweyora, A, Kangah, M, Kabaswahili, V, Abongomera, G, Omongin, J, Aciro, I, Philliam, A, Arach, B, Ocung, E, Amone, G, Miles, P, Adong, C, Tumsuiime, C, Kidega, P, Otto, B, Apio, F, Baleeta, K, Mukuye, A, Abwola, M, Ssennono, F, Baliruno, D, Tuhirwe, S, Namisi, R, Kigongo, F, Kikyonkyo, D, Mushahara, F, Tusiime, J, Musiime, A, Nankya, A, Atwongyeire, D, Sirikye, S, Mula, S, Noowe, N, Kasozi, M, Mwebe, S, Atwine, L, Senkindu, T, Natuhurira, T, Katemba, C, Ninsiima, E, Acaku, M, Kyomuhangi, J, Ankunda, R, Tukwasibwe, D, Ayesiga, L, Reid, A, Mhute, T, Tinago, GC, Bhiri, J, Mudzingwa, S, Phiri, M, Steamer, J, Nhema, R, Warambwa, C, Mutsai, S, Nemasango, B, Moyo, C, Chitongo, S, Rashirai, K, Vhembo, S, Mlambo, B, Nkomani, S, Ndemera, B, Willard, M, Berejena, C, Musodza, Y, Matiza, P, Mudenge, B, Guti, V, Etyang, A, Agutu, C, Berkley, J, Maitland, K, Njuguna, P, Awuondo, K, Wale, S, Shangala, J, Kithunga, J, Mwarumba, S, Maitha, SS, Mutai, R, Lewa, ML, Mwambingu, G, Mwanzu, A, Kalama, C, Latham, H, Shikuku, J, Fondo, A, Njogu, A, Khadenge, C, Mwakisha, B, Wools-Kaloustian, K, Nyandiko, W, Cheruiyot, P, Sudoi, A, Meli, B, Karoney, M, Nzioka, A, Tanui, M, Mokaya, M, Ekiru, W, Mboya, C, Mwimali, D, Mengich, C, Choge, J, Injera, W, Njenga, K, Cherutich, S, Orido, MA, Lwande, GO, Rutto, P, Mudogo, A, Kutto, I, Shali, A, Jaika, L, Jerotich, H, Pierre, M, Mallewa, J, Kaunda, S, Van Oosterhout, J, O'Hare, B, Heydermann, R, Gonzalez, C, Dzabala, N, Kelly, C, Denis, B, Selemani, G, Mipando, LN, Chirwa, E, Banda, P, Mvula, L, Msuku, H, Ziwoya, M, Manda, Y, Nicholas, S, Masesa, C, Mwalukomo, T, Makhaza, L, Sheha, I, Bwanali, J, Limbuni, M, and DiFDMRCWellcome Trust

Subjects
Adult, Male, Zimbabwe, Malawi, Adolescent, Anti-HIV Agents, BIOMARKERS, CHILDREN, HIV Infections, Drug Administration Schedule, Health Services Accessibility, IMMUNE RECONSTITUTION, EFAVIRENZ, Young Adult, Medicine, General & Internal, General & Internal Medicine, Raltegravir Potassium, INFECTION, Humans, Uganda, Child, 11 Medical and Health Sciences, RESTORATION, IMMUNODEFICIENCY, Science & Technology, MORTALITY, ADULTS, SOUTH-AFRICA, Kenya, Anti-Retroviral Agents, Child, Preschool, Africa, Disease Progression, Female, Life Sciences & Biomedicine, REALITY trial team, Follow-Up Studies
Abstract

Background In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events. Methods and findings In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76–1.28], p = 0.91); in serious (aHR = 0.99 [0.81–1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71–1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63–1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76–1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes. Conclusions Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals. Trial registration ClinicalTrials.gov NCT01825031.

Published
2018

5. Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial

Author

Mallewa, J, Szubert, A, Mugyenyi, P, Chidziva, E, Thomason, M, Chepkorir, P, Abongomera, G, Baleeta, K, Etyang, A, Warambwa, C, Melly, B, Mudzingwa, S, Kelly, C, Agutu, C, Wilkes, H, Nkomani, S, Musiime, V, Lugemwa, A, Pett, S, Bwakura-Dangarembizi, M, Prendergast, A, Gibb, D, Walker, A, Berkley, J, and team, REALITY trial

Abstract

BACKGROUND: In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing ready-to-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only. METHODS: We did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks' of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5-12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] 0·7). Through 48 weeks, adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight, BMI, and MUAC than the no-RUSF group (p=0·004, 0·004, and 0·03, respectively). The most common type of serious adverse event was specific infections, occurring in 90 (10%) of 897 participants assigned RUSF and 87 (10%) of 908 assigned no-RUSF. By week 48, 205 participants had serious adverse events in both groups (p=0·81), and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group (p=0·45). INTERPRETATION: In severely immunocompromised HIV-infected individuals, providing RUSF universally at ART initiation, compared with providing RUTF to severely malnourished individuals only, improved short-term weight gain but not mortality. A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present. FUNDING: Joint Global Health Trials Scheme (UK Medical Research Council, UK Department for International Development, and Wellcome Trust).

Published
2018

6. Late Presentation with HIV in Africa: Phenotypes, Risk, and Risk Stratification in the REALITY Trial

Author

Siika, A, McCabe, L, Bwakura-Dangarembizi, M, Kityo, C, Mallewa, J, Berkley, J, Maitland, K, Griffiths, A, Baleeta, K, Mudzingwa, S, Abach, J, Nathoo, K, Thomason, MJ, Prendergast, AJ, Walker, AS, Gibb, DM, Mugyenyi, P, Musiime, V, Wavamunno, P, Nambi, E, Ocitti, P, Ndigendawani, M, Kemigisa, M, Acen, J, Olebo, D, Mpamize, G, Amone, A, Okweny, D, Mbonye, A, Nambaziira, F, Rweyora, A, Kangah, M, Kabaswahili, V, Abongomera, G, Omongin, J, Aciro, I, Philliam, A, Arach, B, Ocung, E, Amone, G, Miles, P, Adong, C, Tumsuiime, C, Kidega, P, Otto, B, Apio, F, Mukuye, A, Abwola, M, Ssennono, F, Baliruno, D, Tuhirwe, S, Namisi, R, Kigongo, F, Kikyonkyo, D, Mushahara, F, Tusiime, J, Musiime, A, Nankya, A, Atwongyeire, D, Sirikye, S, Mula, S, Noowe, N, Lugemwa, A, Kasozi, M, Mwebe, S, Atwine, L, Senkindu, T, Natuhurira, T, Katemba, C, Ninsiima, E, Acaku, M, Kyomuhangi, J, Ankunda, R, Tukwasibwe, D, Ayesiga, L, Hakim, J, Reid, A, Chidziva, E, Mhute, T, Tinago, GC, Bhiri, J, Phiri, M, Steamer, J, Nhema, R, Warambwa, C, Musoro, G, Mutsai, S, Nemasango, B, Moyo, C, Chitongo, S, Rashirai, K, Vhembo, S, Mlambo, B, Global Health, Graduate School, APH - Personalized Medicine, APH - Quality of Care, AII - Infectious diseases, University of St Andrews. School of Medicine, University of St Andrews. Infection and Global Health Division, and DiFDMRCWellcome Trust

Subjects
0301 basic medicine, Male, Human immunodeficiency virus (HIV), HIV Infections, R Medicine (General), medicine.disease_cause, Late presentation, 0302 clinical medicine, Risk Factors, Antiretroviral Therapy, Highly Active, Health care, 030212 general & internal medicine, Child, health care economics and organizations, immunosuppression, Age Factors, 11 Medical And Health Sciences, 3. Good health, Phenotype, Infectious Diseases, Child, Preschool, Risk stratification, Female, Adult, Microbiology (medical), Adolescent, Anti-HIV Agents, 030106 microbiology, NDAS, Library science, Microbiology, Risk Assessment, 03 medical and health sciences, Immunocompromised Host, SDG 3 - Good Health and Well-being, medicine, Humans, Advanced HIV Disease, Mortality, Africa South of the Sahara, AIDS-Related Opportunistic Infections, business.industry, HIV, 06 Biological Sciences, Supplementary food, Antiretroviral therapy, mortality, R1, CD4 Lymphocyte Count, Clinical trials unit, Africa, Self care, business, Immunosuppression
Abstract

REALITY was funded by the Joint Global Health Trials Scheme (JGHTS) of the UK Department for International Development, the Wellcome Trust, and Medical Research Council (MRC) (grant number G1100693). Additional funding support was provided by the PENTA Foundation and core support to the MRC Clinical Trials Unit at University College London (grant numbers MC_UU_12023/23 and MC_UU_12023/26). Cipla Ltd, Gilead Sciences, ViiV Healthcare/GlaxoSmithKline, and Merck Sharp & Dohme donated drugs for REALITY, and ready-to-use supplementary food was purchased from Valid International. A. J. P. is funded by the Wellcome Trust (grant number 108065/Z/15/Z). J. A. B. is funded by the JGHTS (grant number MR/M007367/1). The Malawi-Liverpool–Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine (grant number 101113/Z/13/Z) and the Kenya Medical Research Institute (KEMRI)/Wellcome Trust Research Programme, Kilifi (grant number 203077/Z/16/Z) are supported by strategic awards from the Wellcome Trust, United Kingdom. Permission to publish was granted by the Director of KEMRI. This supplement was supported by funds from the Bill & Melinda Gates Foundation. Background. Severely immunocompromised human immunodefciency virus (HIV)-infected individuals have high mortality shortly afer starting antiretroviral therapy (ART). We investigated predictors of early mortality and "late presenter" phenotypes. Methods. Te Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children =5 years of age with CD4 counts .1). Results. Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P

Published
2018

7. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial

Author

DART Trial Team, Mugyenyi, P, Walker, AS, Hakim, J, Munderi, P, Gibb, DM, Kityo, C, Reid, A, Grosskurth, H, Darbyshire, JH, Ssali, F, Bray, D, Katabira, E, Babiker, AG, Gilks, CF, Kabuye, G, Nsibambi, D, Kasirye, R, Zalwango, E, Nakazibwe, M, Kikaire, B, Nassuna, G, Massa, R, Fadhiru, K, Namyalo, M, Zalwango, A, Generous, L, Khauka, P, Rutikarayo, N, Nakahima, W, Mugisha, A, Todd, J, Levin, J, Muyingo, S, Ruberantwari, A, Kaleebu, P, Yirrell, D, Ndembi, N, Lyagoba, F, Hughes, P, Aber, M, Lara, A Medina, Foster, S, Amurwon, J, Wakholi, B Nyanzi, Whitworth, J, Wangati, K, Amuron, B, Kajungu, D, Nakiyingi, J, Omony, W, Tumukunde, D, Otim, T, Kabanda, J, Musana, H, Akao, J, Kyomugisha, H, Byamukama, A, Sabiiti, J, Komugyena, J, Wavamunno, P, Mukiibi, S, Drasiku, A, Byaruhanga, R, Labeja, O, Katundu, P, Tugume, S, Awio, P, Namazzi, A, Bakeinyaga, GT, Katabira, H, Abaine, D, Tukamushaba, J, Anywar, W, Ojiambo, W, Angweng, E, Murungi, S, Haguma, W, Atwiine, S, Kigozi, J, Namale, L, Mukose, A, Mulindwa, G, Atwiine, D, Muhwezi, A, Nimwesiga, E, Barungi, G, Takubwa, J, Mwebesa, D, Kagina, G, Mulindwa, M, Ahimbisibwe, F, Mwesigwa, P, Akuma, S, Zawedde, C, Nyiraguhirwa, D, Tumusiime, C, Bagaya, L, Namara, W, Karungi, J, Kankunda, R, Enzama, R, Latif, A, Robertson, V, Chidziva, E, Bulaya-Tembo, R, Musoro, G, Taziwa, F, Chimbetete, C, Chakonza, L, Mawora, A, Muvirimi, C, Tinago, G, Svovanapasis, P, Simango, M, Chirema, O, Machingura, J, Mutsai, S, Phiri, M, Bafana, T, Chirara, M, Muchabaiwa, L, Muzambi, M, Mutowo, J, Chivhunga, T, Chigwedere, E, Pascoe, M, Warambwa, C, Zengeza, E, Mapinge, F, Makota, S, Jamu, A, Ngorima, N, Chirairo, H, Chitsungo, S, Chimanzi, J, Maweni, C, Warara, R, Matongo, M, Mudzingwa, S, Jangano, M, Moyo, K, Vere, L, Mdege, N, Machingura, I, Ronald, A, Kambungu, A, Lutwama, F, Mambule, I, Nanfuka, A, Walusimbi, J, Nabankema, E, Nalumenya, R, Namuli, T, Kulume, R, Namata, I, Nyachwo, L, Florence, A, Kusiima, A, Lubwama, E, Nairuba, R, Oketta, F, Buluma, E, Waita, R, Ojiambo, H, Sadik, F, Wanyama, J, Nabongo, P, Oyugi, J, Sematala, F, Muganzi, A, Twijukye, C, Byakwaga, H, Ochai, R, Muhweezi, D, Coutinho, A, Etukoit, B, Gilks, C, Boocock, K, Puddephatt, C, Grundy, C, Bohannon, J, Winogron, D, Burke, A, Babiker, A, Wilkes, H, Rauchenberger, M, Sheehan, S, Spencer-Drake, C, Taylor, K, Spyer, M, Ferrier, A, Naidoo, B, Dunn, D, Goodall, R, Peto, L, Nanfuka, R, Mufuka-Kapuya, C, Pillay, D, McCormick, A, Weller, I, Bahendeka, S, Bassett, M, Wapakhabulo, A Chogo, Gazzard, B, Mapuchere, C, Mugurungi, O, Burke, C, Jones, S, Newland, C, Pearce, G, Rahim, S, Rooney, J, Smith, M, Snowden, W, Steens, J-M, Breckenridge, A, McLaren, A, Hill, C, Matenga, J, Pozniak, A, Serwadda, D, Peto, T, Palfreeman, A, and Borok, M

Subjects
Male, Neutrophils, HIV Infections, law.invention, Hemoglobins, Randomized controlled trial, law, Medicine, Urea, HIV-Associated Lipodystrophy Syndrome, Hazard ratio, Lamivudine, Anemia, General Medicine, Middle Aged, Viral Load, Anti-Retroviral Agents, Creatinine, Disease Progression, RNA, Viral, Female, Drug Monitoring, Zidovudine, medicine.drug, Glomerular Filtration Rate, Adult, medicine.medical_specialty, Neutropenia, Adolescent, Organophosphonates, Acquired immunodeficiency syndrome (AIDS), Internal medicine, Fast track — Articles, Humans, Nevirapine, Adverse effect, Tenofovir, Aged, Intention-to-treat analysis, business.industry, Adenine, medicine.disease, Dideoxynucleosides, CD4 Lymphocyte Count, Clinical trial, Clinical research, Immunology, Africa, HIV-1, business
Abstract

BACKGROUND: HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. METHODS: In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. FINDINGS: Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). INTERPRETATION: ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

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8. Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial.

Author

Mallewa J, Szubert AJ, Mugyenyi P, Chidziva E, Thomason MJ, Chepkorir P, Abongomera G, Baleeta K, Etyang A, Warambwa C, Melly B, Mudzingwa S, Kelly C, Agutu C, Wilkes H, Nkomani S, Musiime V, Lugemwa A, Pett SL, Bwakura-Dangarembizi M, Prendergast AJ, Gibb DM, Walker AS, and Berkley JA

Subjects
Adolescent, Adult, Africa South of the Sahara, Aged, Anti-Infective Agents administration & dosage, Arachis, Body Mass Index, Body Weight, Child, Child, Preschool, Female, Humans, Male, Micronutrients administration & dosage, Middle Aged, Raltegravir Potassium administration & dosage, Survival Analysis, Treatment Outcome, Young Adult, Anti-Retroviral Agents administration & dosage, Diet Therapy methods, HIV Infections mortality, HIV Infections therapy
Abstract

Background: In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing ready-to-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only., Methods: We did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks' of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5-12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] <16-18 kg/m 2 or BMI-for-age Z scores <-3 for children). We did the randomisation with computer-generated, sequentially numbered tables with different block sizes incorporated within an online database. Randomisation was stratified by centre, age, and two other factorial randomisations, to 12 week adjunctive raltegravir and enhanced anti-infection prophylaxis (reported elsewhere). Clinic visits were scheduled at weeks 2, 4, 8, 12, 18, 24, 36, and 48, and included nurse assessment of vital status and symptoms and dispensing of all medication including ART and RUSF. The primary outcome was mortality at week 24, analysed by intention to treat. Secondary outcomes included absolute changes in weight, BMI, and mid-upper-arm circumference (MUAC). Safety was analysed in all randomly assigned participants. Follow-up was 48 weeks. This trial is registered with ClinicalTrials.gov (NCT01825031) and the ISRCTN registry (43622374)., Findings: Between June 18, 2013, and April 10, 2015, we randomly assigned 1805 participants to treatment: 897 to RUSF and 908 to no-RUSF. 56 (3%) were lost-to-follow-up. 96 (10·9%, 95% CI 9·0-13·1) participants allocated to RUSF and 92 (10·3%, 8·5-12·5) to no-RUSF died within 24 weeks (hazard ratio 1·05, 95% CI 0·79-1·40; log-rank p=0·75), with no evidence of interaction with the other randomisations (both p>0·7). Through 48 weeks, adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight, BMI, and MUAC than the no-RUSF group (p=0·004, 0·004, and 0·03, respectively). The most common type of serious adverse event was specific infections, occurring in 90 (10%) of 897 participants assigned RUSF and 87 (10%) of 908 assigned no-RUSF. By week 48, 205 participants had serious adverse events in both groups (p=0·81), and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group (p=0·45)., Interpretation: In severely immunocompromised HIV-infected individuals, providing RUSF universally at ART initiation, compared with providing RUTF to severely malnourished individuals only, improved short-term weight gain but not mortality. A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present., Funding: Joint Global Health Trials Scheme (UK Medical Research Council, UK Department for International Development, and Wellcome Trust)., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY NC ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Published
2018
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9. HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa.

Author

Kityo C, Thompson J, Nankya I, Hoppe A, Ndashimye E, Warambwa C, Mambule I, van Oosterhout JJ, Wools-Kaloustian K, Bertagnolio S, Easterbrook PJ, Mugyenyi P, Walker AS, and Paton NI

Subjects
Adult, Africa South of the Sahara epidemiology, Antiretroviral Therapy, Highly Active, CD4 Lymphocyte Count, Female, HIV Infections immunology, HIV Reverse Transcriptase genetics, HIV-1 drug effects, HIV-1 physiology, Humans, Male, Middle Aged, Mutation drug effects, Treatment Failure, Viral Load drug effects, Anti-HIV Agents therapeutic use, Drug Resistance, Viral drug effects, Drug Resistance, Viral genetics, HIV Infections drug therapy, HIV Infections virology, HIV-1 classification, HIV-1 genetics, Reverse Transcriptase Inhibitors therapeutic use
Abstract

Objective: To determine drug resistance mutation (DRM) patterns in a large cohort of patients failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy regimens in programs without routine viral load (VL) monitoring and to examine intersubtype differences in DRMs., Design: Sequences from 787 adults/adolescents who failed an NNRTI-based first-line regimen in 13 clinics in Uganda, Kenya, Zimbabwe, and Malawi were analyzed. Multivariable logistic regression was used to determine the association between specific DRMs and Stanford intermediate-/high-level resistance and factors including REGA subtype, first-line antiretroviral therapy drugs, CD4, and VL at failure., Results: The median first-line treatment duration was 4 years (interquartile range 30-43 months); 42% of participants had VL ≥100,000 copies/mL and 63% participants had CD4 <100 cells/mm. Viral subtype distribution was A1 (40%; Uganda and Kenya), C (31%; Zimbabwe and Malawi), and D (25%; Uganda and Kenya), and recombinant/unclassified (5%). In general, DRMs were more common in subtype-C than in subtype-A and/or subtype-D (nucleoside reverse transcriptase inhibitor mutations K65R and Q151M; NNRTI mutations E138A, V106M, Y181C, K101E, and H221Y). The presence of tenofovir resistance was similar between subtypes [P (adjusted) = 0.32], but resistance to zidovudine, abacavir, etravirine, or rilpivirine was more common in subtype-C than in subtype-D/subtype-A [P (adjusted) < 0.02]., Conclusions: Non-B subtypes differ in DRMs at first-line failure, which impacts on residual nucleoside reverse transcriptase inhibitor and NNRTI susceptibility. In particular, higher rates of etravirine and rilpivirine resistance in subtype-C may limit their potential utility in salvage regimens.

Published
2017
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10. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

Author

Mugyenyi P, Walker AS, Hakim J, Munderi P, Gibb DM, Kityo C, Reid A, Grosskurth H, Darbyshire JH, Ssali F, Bray D, Katabira E, Babiker AG, Gilks CF, Grosskurth H, Munderi P, Kabuye G, Nsibambi D, Kasirye R, Zalwango E, Nakazibwe M, Kikaire B, Nassuna G, Massa R, Fadhiru K, Namyalo M, Zalwango A, Generous L, Khauka P, Rutikarayo N, Nakahima W, Mugisha A, Todd J, Levin J, Muyingo S, Ruberantwari A, Kaleebu P, Yirrell D, Ndembi N, Lyagoba F, Hughes P, Aber M, Lara AM, Foster S, Amurwon J, Wakholi BN, Whitworth J, Wangati K, Amuron B, Kajungu D, Nakiyingi J, Omony W, Fadhiru K, Nsibambi D, Khauka P, Mugyenyi P, Kityo C, Ssali F, Tumukunde D, Otim T, Kabanda J, Musana H, Akao J, Kyomugisha H, Byamukama A, Sabiiti J, Komugyena J, Wavamunno P, Mukiibi S, Drasiku A, Byaruhanga R, Labeja O, Katundu P, Tugume S, Awio P, Namazzi A, Bakeinyaga GT, Katabira H, Abaine D, Tukamushaba J, Anywar W, Ojiambo W, Angweng E, Murungi S, Haguma W, Atwiine S, Kigozi J, Namale L, Mukose A, Mulindwa G, Atwiine D, Muhwezi A, Nimwesiga E, Barungi G, Takubwa J, Murungi S, Mwebesa D, Kagina G, Mulindwa M, Ahimbisibwe F, Mwesigwa P, Akuma S, Zawedde C, Nyiraguhirwa D, Tumusiime C, Bagaya L, Namara W, Kigozi J, Karungi J, Kankunda R, Enzama R, Latif A, Hakim J, Robertson V, Reid A, Chidziva E, Bulaya-Tembo R, Musoro G, Taziwa F, Chimbetete C, Chakonza L, Mawora A, Muvirimi C, Tinago G, Svovanapasis P, Simango M, Chirema O, Machingura J, Mutsai S, Phiri M, Bafana T, Chirara M, Muchabaiwa L, Muzambi M, Mutowo J, Chivhunga T, Chigwedere E, Pascoe M, Warambwa C, Zengeza E, Mapinge F, Makota S, Jamu A, Ngorima N, Chirairo H, Chitsungo S, Chimanzi J, Maweni C, Warara R, Matongo M, Mudzingwa S, Jangano M, Moyo K, Vere L, Mdege N, Machingura I, Katabira E, Ronald A, Kambungu A, Lutwama F, Mambule I, Nanfuka A, Walusimbi J, Nabankema E, Nalumenya R, Namuli T, Kulume R, Namata I, Nyachwo L, Florence A, Kusiima A, Lubwama E, Nairuba R, Oketta F, Buluma E, Waita R, Ojiambo H, Sadik F, Wanyama J, Nabongo P, Oyugi J, Sematala F, Muganzi A, Twijukye C, Byakwaga H, Ochai R, Muhweezi D, Coutinho A, Etukoit B, Gilks C, Boocock K, Puddephatt C, Grundy C, Bohannon J, Winogron D, Gibb DM, Burke A, Bray D, Babiker A, Walker AS, Wilkes H, Rauchenberger M, Sheehan S, Spencer-Drake C, Taylor K, Spyer M, Ferrier A, Naidoo B, Dunn D, Goodall R, Darbyshire JH, Peto L, Nanfuka R, Mufuka-Kapuya C, Kaleebu P, Pillay D, Robertson V, Yirrell D, Tugume S, Chirara M, Katundu P, Ndembi N, Lyagoba F, Dunn D, Goodall R, McCormick A, Lara AM, Foster S, Amurwon J, Wakholi BN, Kigozi J, Muchabaiwa L, Muzambi M, Weller I, Babiker A, Bahendeka S, Bassett M, Wapakhabulo AC, Darbyshire JH, Gazzard B, Gilks C, Grosskurth H, Hakim J, Latif A, Mapuchere C, Mugurungi O, Mugyenyi P, Burke C, Jones S, Newland C, Pearce G, Rahim S, Rooney J, Smith M, Snowden W, Steens JM, Breckenridge A, McLaren A, Hill C, Matenga J, Pozniak A, Serwadda D, Peto T, Palfreeman A, Borok M, and Katabira E

Subjects
Adenine analogs & derivatives, Adenine therapeutic use, Adolescent, Adult, Africa epidemiology, Aged, Anemia epidemiology, CD4 Lymphocyte Count, Creatinine analysis, Dideoxynucleosides therapeutic use, Disease Progression, Female, Glomerular Filtration Rate, HIV Infections classification, HIV Infections mortality, HIV-1 genetics, HIV-Associated Lipodystrophy Syndrome epidemiology, Hemoglobins analysis, Humans, Lamivudine therapeutic use, Male, Middle Aged, Neutropenia epidemiology, Neutrophils metabolism, Nevirapine therapeutic use, Organophosphonates therapeutic use, RNA, Viral metabolism, Tenofovir, Urea analysis, Viral Load, Zidovudine therapeutic use, Anti-Retroviral Agents therapeutic use, Drug Monitoring, HIV Infections drug therapy
Abstract

Background: HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa., Methods: In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779., Findings: Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases)., Interpretation: ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment., Funding: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Published
2010
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