Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda

OBJECTIVES: We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring. METHODS: NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial]...

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Detalles Bibliográficos
Autores principales: Goodall, R. L., Dunn, D. T., Pattery, T., van Cauwenberge, A., Nkurunziza, P., Awio, P., Ndembi, N., Munderi, P., Kityo, C., Gilks, C. F., Kaleebu, P., Pillay, D., Chirara, M., Dunn, D., Gibb, D. M., Gilks, C., Goodall, R., Kapaata, A., Katuramur, M., Lyagoba, F., Magala, R., Magambo, B., Mataruka, K., McCormick, A., Mugarura, L., Musunga, T., Nabankkema, M., Nkalubo, J., Parry, C., Robertson, V., Spyer, M., Yirrell, D., Grosskurth, H., 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., Hughes, P., Aber, M., Medina Lara, A., Foster, S., Amurwon, J., Nyanzi Wakholi, B., Mugyenyi, P., 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., Namazzi, A., Bakeinyaga, G. T., Katabira, H., Abaine, D., Tukamushaba, J., Anywar, W., Ojiambo, W., Angweng, E., Murungi, S., Haguma, W., Atwiine, S., Kigozi, J., Latif, A., Hakim, J., 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., Muchabaiwa, L., Muzambi, M., Katabira, E., Ronald, A., Kambungu, A., Lutwama, F., 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
Materias:
Original Research
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4054985/
https://www.ncbi.nlm.nih.gov/pubmed/24633208
http://dx.doi.org/10.1093/jac/dku052
Descripción
Sumario:OBJECTIVES: We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring. METHODS: NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count <200 cells/mm(3)) to receive zidovudine/lamivudine plus abacavir (cABC arm) or nevirapine (cNVP arm). All virological tests were performed retrospectively, including resistance tests on week 96 plasma samples with HIV RNA levels ≥1000 copies/mL. Phenotypic resistance was expressed as fold-change in IC(50) (FC) relative to wild-type virus. RESULTS: HIV-1 RNA viral load ≥1000 copies/mL at week 96 was seen in 58/204 (28.4%) cABC participants and 21/159 (13.2%) cNVP participants. Resistance results were available in 35 cABC and 17 cNVP participants; 31 (89%) cABC and 16 (94%) cNVP isolates had a week 96 FC below the biological cut-off for tenofovir (2.2). In the cNVP arm, 16/17 participants had resistance mutations synonymous with high-level resistance to nevirapine and efavirenz; FC values for etravirine were above the biological cut-off in 9 (53%) isolates. In multivariate regression models, K65R, Y115F and the presence of thymidine analogue-associated mutations were associated with increased susceptibility to etravirine in the cABC arm. CONCLUSIONS: Our data support the use of tenofovir following failure of a first-line zidovudine-containing regimen and shed further light on non-nucleoside reverse transcriptase inhibitor hypersusceptibility.

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