Repositorio de Fundación Huesped

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Browsing Repositorio de Fundación Huesped by Author "Aboud, Michael"

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    Dolutegravir-based Antiretroviral Therapy for Patients Coinfected With Tuberculosis and Human Immunodeficiency Virus: A Multicenter, Noncomparative, Open-label, Randomized Trial
    (2019-03-28) Dooley, Kelly E; Kaplan, Richard; Mwelase, Noluthando; Grinsztejn, Beatriz; Ticona, Eduardo; Lacerda, Marcus; Sued, Omar; Belonosova, Elena; Ait-Khaled, Mounir; Angelis, Konstantinos; Brown, Dannae; Singh, Rajendra; Talarico, Christine L; Tenorio, Allan R; Keegan, Michael R; Aboud, Michael; International Study of Patients with HIV on Rifampicin ING study group
    Background The concurrent treatment of tuberculosis and human immunodeficiency virus (HIV) is challenging, owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir (DTG) were assessed in adults with HIV and drug-susceptible tuberculosis. Methods International Study of Patients with HIV on Rifampicin ING is a noncomparative, active-control, randomized, open-label study in HIV-1–infected antiretroviral therapy–naive adults (CD4+ ≥50 cells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were randomized (3:2) to receive DTG (50 mg twice daily both during and 2 weeks after tuberculosis therapy, then 50 mg once daily) or efavirenz (EFV; 600 mg daily) with 2 nucleoside reverse transcriptase inhibitors for 52 weeks. The primary endpoint was the proportion of DTG-arm participants with plasma HIV-1-RNA <50 copies/mL (responders) by the Food and Drug Administration Snapshot algorithm (intent-to-treat exposed population) at Week 48. The study was not powered to compare arms. Results For DTG (n = 69), the baseline HIV-1 RNA was >100 000 copies/mL in 64% of participants, with a median CD4+ count of 208 cells/mm3; for EFV (n = 44), 55% of participants had HIV-1 RNA >100 000 copies/mL, with a median CD4+ count of 202 cells/mm3. The Week 48 response rates were 75% (52/69, 95% confidence interval [CI] 65–86%) for DTG and 82% (36/44, 95% CI 70–93%) for EFV. The DTG nonresponses were driven by non–treatment related discontinuations (n = 10 lost to follow-up). There were no deaths or study drug switches. There were 2 discontinuations for toxicity (EFV). There were 3 protocol-defined virological failures (2 DTG, no acquired resistance; 1 EFV, emergent resistance to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors). The tuberculosis treatment success rate was high. Tuberculosis-associated IRIS was uncommon (4/arm), with no discontinuations for IRIS. Conclusions Among adults with HIV receiving rifampicin-based tuberculosis treatment, twice-daily DTG was effective and well tolerated. Clinical Trials Registration NCT02178592.
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    Segurança e eficácia da terapia antirretroviral baseada em dolutegravir, na semana 48, em adultos coinfectados hiv/tb
    (2018-12) Dooley, Kelly E; Kaplan, Richard; Mwelase, Noluthando; Grinsztejn, Beatriz; Ticona, Eduardo; Lacerda, Marcus; Sued, Omar; Belonosova, Elena; Ait‐Khaled, Mounir; Angelis, Kostas; Brown, Dannae; Singh, Rajendra; Talarico, Christine; Tenorio, Allan; Keegan, Michael; Aboud, Michael; Zajdenverg, Roberto
    Introdução: O tratamento concomitante da tuberculose e do HIV é desafiador devido às interações medicamentosas, à sobreposição de toxicidades e à síndrome de reconstituição imune (IRIS/SIRI). Objetivo: A eficácia e a segurança de dolutegravir (DTG) foram avaliadas nos adultos coinfectados com HIV e tuberculose. Metodologia: Inspiring é um estudo fase 3 b, aberto, não comparativo, com controle ativo, randomizado, em adultos que vivem com HIV‐1, virgens de tratamento (CD4+ > ou = 50 cels/mm3) com TB responsiva ao tratamento. Os participantes em tratamento para TB baseado em rifampicina até oito semanas foram randomizados (3:2) para receber DTG (50 mg duas vezes ao dia até duas semanas após término do tratamento da TB, seguido por 50 mg uma vez ao dia) ou EFV (600 mg uma vez ao dia) com dois ITRNs por 52 semanas. O desfecho primário foi a proporção de voluntários em uso de DTG com HIV‐1 < 50 c/mL (respondedores). Resultado: Os participantes foram randomizados para DTG (n = 69) ou EFV (n = 44). A proporção de respondedores na semana 48 (ITT‐E) foi 52/69 (75%) para DTG e 36/44 (82%) para EFV. Ausência de resposta ao DTG foi decorrente primordialmente por interrupções não relacionadas ao tratamento: 11 voluntários (16%) com DTG e três (7%) com EFV descontinuaram por razões não relacionadas ao tratamento, embora suprimidos (principalmente por perda de seguimento). Houve duas falhas virológicas definidas pelo protocolo (PDVF), mas sem emergência de mutações de resistência ao tratamento (RAMs) no braço de DTG e uma PDVF com EFV, com RAMs para ITRN e ITRNN. A mediana de aumento da contagem de CD4+ na semana 48 foi de 220 cels/mm3 com DTG e 190 cels/mm3 com EFV. Dois voluntários em uso de EFV interromperam o tratamento por eventos adversos. As taxas de IRIS associada à TB foram baixas (DTG, n = 4 [6%]; EFV, n = 4 [9%]). Nenhum participante interrompeu o tratamento por causa de IRIS nem por eventos hepáticos. O sucesso do tratamento da tuberculose foi de 61/69 (88%) e 39/44 (89%) com DTG e EFV, respectivamente. A mediana de concentração mínima de DTG durante o uso de dolutegravir duas vezes ao dia com rifampicina foi semelhante à de dolutegravir uma vez ao dia sem rifampicina. Discussão/conclusão: Esses resultados revelam que dolutegravir (DTG) é eficaz e bem tolerado em adultos coinfectados por TB e HIV que recebem tratamento para tuberculose com rifampicina.
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    Three-year durable efficacy of dolutegravir plus lamivudine in antiretroviral therapy - naive adults with HIV-1 infection
    (2022-01-01) Cahn, Pedro; Sierra Madero, Juan; Arribas, Jose; Antinori, Andrea; Ortiz, Roberto; Clarke, Amanda E; Hung, Chien-Ching; Rockstroh, Jürgen K; Girard, Pierre-Marie; Sievers, Jörg; Man, Choy Y; Urbaityte, Rimgaile; Brandon, Daisy J; Underwood, Mark; Pappa, Keith A; Curtis, Lloyd; Smith, Kimberly Y; Gartland, Martin; Aboud, Michael; van Wyk, Jean; Wynne, Brian
    [ABSTRACTS]. OBJECTIVE: To assess efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) vs. DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the prespecified 144-week secondary analyses of GEMINI-1 and GEMINI-2. DESIGN: Identical, multicenter, phase III, randomized, non-inferiority studies (double-blind through 96 weeks). METHODS: Participants with HIV-1 RNA ≤500 000 copies/ml and no major viral resistance mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized 1:1 to once-daily DTG + 3TC or DTG + TDF/FTC. RESULTS: At week 144, DTG + 3TC (N = 716) was noninferior to DTG + TDF/FTC (N = 717) in proportion of participants achieving HIV-1 RNA <50 copies/ml (Snapshot algorithm) in the pooled analysis (82% vs. 84%, respectively; adjusted treatment difference [95% confidence interval (CI)], -1.8% [-5.8, 2.1]), GEMINI-1 (-3.6% [-9.4, 2.1]), and GEMINI-2 (0.0% [-5.3, 5.3]). Twelve DTG + 3TC participants and nine DTG + TDF/FTC participants met protocol-defined confirmed virologic withdrawal (CVW) criteria; none developed treatment-emergent resistance. One DTG + 3TC participant who did not meet CVW criteria developed M184V at week 132 and R263R/K at week 144, conferring a 1.8-fold change in susceptibility to DTG; non-adherence to therapy was reported. Significantly fewer drug-related adverse events occurred with DTG + 3TC vs. DTG + TDF/FTC (20% vs. 27%; relative risk [95% CI], 0.76 [0.63-0.92]). Renal and bone biomarker changes favored DTG + 3TC. CONCLUSIONS: Three-year durable efficacy, long-term tolerability, and high barrier to resistance support first-line use of DTG + 3TC for HIV-1 treatment (see Supplemental Digital Content 1, http://links.lww.com/QAD/C297; video abstract).