TY - JOUR
T1 - Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288)
T2 - a prospective strategy study
AU - A5288 Team
AU - Grinsztejn, Beatriz
AU - Hughes, Michael D.
AU - Ritz, Justin
AU - Salata, Robert
AU - Mugyenyi, Peter N.
AU - Hogg, Evelyn
AU - Wieclaw, Linda
AU - Gross, Robert
AU - Godfrey, Catherine
AU - Cardoso, Sandra W.
AU - Bukuru, Aggrey
AU - Makanga, Mumbi
AU - Faesen, Sharlaa
AU - Mave, Vidya
AU - Wangari Ndege, Beatrice
AU - Nerette Fontain, Sandy
AU - Samaneka, Wadzanai
AU - Secours, Rode
AU - van Schalkwyk, Marije
AU - Mngqibisa, Rosie
AU - Mohapi, Lerato
AU - Valencia, Javier
AU - Sugandhavesa, Patcharaphan
AU - Montalban, Esmelda
AU - Avihingsanon, Anchalee
AU - Santos, Breno R.
AU - Kumarasamy, Nagalingeswaran
AU - Kanyama, Cecilia
AU - Schooley, Robert T.
AU - Mellors, John W.
AU - Wallis, Carole L.
AU - Collier, Ann C.
AU - Sise, T.
AU - Fletcher, C. V.
AU - Gandhi, M.
AU - Walensky, R.
AU - Mansfield, B.
AU - Mugerwa, H.
AU - Ndege, B. W.
AU - Kadam, D.
AU - Fontain, S. N.
AU - Nakibuuka, L.
AU - Nassolo, H.
AU - Anthony, P.
AU - Kulkarni, V.
AU - Nsubuga, M.
AU - van Wyk, J.
AU - Rooney, J.
AU - van Delft, Y.
AU - Leavitt, R.
N1 - Funding Information:
This study was supported by NIAID (award numbers UM1 AI068636 , UM1 AI068634 [ ACTG Statistical and Data Management Center ], UM1 AI069423 , and UM1 AI069481 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID. AbbVie, Gilead Sciences, Janssen Pharmaceuticals, and Merck & Company provided the study drugs. We thank the study participants, the staff at the sites, and the other members of the A5288 team. We also thank the staff members at the virology and genotyping laboratories for their work in testing for the primary endpoint and the genotyping. We thank Dimagi, which consulted individually with the sites to tailor the set-up and maintenance of the automated system, addressing issues such as how to prevent power interruptions from disrupting service.
Funding Information:
MDH, JR, and VM report grants from National Institutes of Health (NIH), during the conduct of the study. RG reports grants from NIH, during the conduct of the study, and personal fees from Pfizer, outside the submitted work. CG is an employee of the study sponsor (NIH). LM reports grants from the National Institute of Allergy and Infectious Diseases (NIAID) and NIH, during the conduct of the study, and grants from Janssen Pharmaceutica, Merck Sharp & Dohme Corp, ViiV Healthcare, Johnson and Johnson, Pfizer Pharmaceuticals, and Bristol-Myers Squibb and non-financial support from Kowa Pharmaceuticals America and Sanofi-Aventis, outside the submitted work. RTS reports grants from NIAID, during the conduct of the study, and grants from Gilead Sciences, Monogram Biosciences, and Pfizer and personal fees from CytoDyn, Monogram Biosciences, and Vir Biotechnology, outside the submitted work. JWM reports grants from NIH, during the conduct of the study, and personal fees from the University of Pittsburgh, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck, and Xi'an Yufan Biotechnologies, grants from Gilead Sciences and Janssen Pharmaceuticals, and share options in Cocrystal Pharma, Inc, outside the submitted work. JWM also has a patent pending (patent number 8 815 829). CLW reports personal fees from International Partnership for Microbicides, Right-to-Care, and MSD-Merck, outside the submitted work. ACC reports grants from NIH, during the conduct of the study, and personal fees from Merck & Co and grants from Bristol-Myers Squibb, outside the submitted work. All other authors declare no competing interests.
Funding Information:
This study was supported by NIAID (award numbers UM1 AI068636, UM1 AI068634 [ACTG Statistical and Data Management Center], UM1 AI069423, and UM1 AI069481). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID. AbbVie, Gilead Sciences, Janssen Pharmaceuticals, and Merck & Company provided the study drugs. We thank the study participants, the staff at the sites, and the other members of the A5288 team. We also thank the staff members at the virology and genotyping laboratories for their work in testing for the primary endpoint and the genotyping. We thank Dimagi, which consulted individually with the sites to tailor the set-up and maintenance of the automated system, addressing issues such as how to prevent power interruptions from disrupting service.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/9
Y1 - 2019/9
N2 - Background: Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance patterns, partly due to reduced access to viral load monitoring. We aimed to evaluate use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to improve adherence in individuals presenting with second-line viral failure. Methods: A5288 was a phase 4, third-line ART strategy study done at 19 urban sites in ten countries that enrolled adult participants with confirmed plasma HIV-1 RNA (viral load) of 1000 copies per mL or more after more than 24 weeks of protease inhibitor-based second-line ART. The primary objective was to use antiretrovirals (raltegravir, etravirine, and ritonavir-boosted darunavir) and diagnostic monitoring technologies, including viral load, genotyping, and adherence support to achieve viral load suppression (defined as ≤200 copies per mL) in 65% or more of participants. ART history and real-time drug resistance genotypes were used to assign participants to one of four cohorts: cohort A (no lopinavir resistance) stayed on second-line ART and cohorts B (B1, best available nucleoside reverse transcriptase inhibitors [NRTIs] plus ritonavir-boosted darunavir plus raltegravir; B2, ritonavir-boosted darunavir plus raltegravir plus etravirine; B3, ritonavir-boosted darunavir, raltegravir, and either tenofovir plus emtricitabine or tenofovir plus lamivudine), C (ritonavir-boosted darunavir plus raltegravir plus tenofovir-emtricitabine or tenofovir plus lamivudine), and D (best available NRTIs plus ritonavir-boosted darunavir plus raltegravir) were defined by increasing levels of resistance and received appropriate regimens, including new antiretrovirals. Participants in Cohort B without detectable hepatitis B surface antigen were assigned by blocked randomisation to cohorts B1 and B2, and those with detectable hepatitis B surface antigen were assigned to cohort B3. The trial is registered with ClinicalTrials.gov, number NCT01641367. Findings: From Jan 10, 2013, to Sept 10, 2015, 545 participants were enrolled. 287 (53%) were assigned to cohort A, 74 (14%) to B1, 72 (13%) to B2, eight (1%) to B3, 70 (13%) to C, and 34 (6%) to D. Overall, 349 (64%, 95% CI 60–68) participants achieved viral suppression at week 48, with proportions varying from 125 (44%) of 287 in cohort A to 65 (88%) of 74 in cohort B1, 63 (88%) of 72 in B2, eight (100%) of eight in B3, 63 (90%) of 70 in C, and 25 (74%) of 34 in D. Participants in cohort A remained on their second-line protease inhibitor, and had the most participants with grade 3 or higher adverse events (147 [51%]). Interpretation: Targeted real-time genotyping to select third-line ART can appropriately allocate more costly antiretrovirals to those with greater levels of HIV drug resistance. Funding: National Institutes of Health.
AB - Background: Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance patterns, partly due to reduced access to viral load monitoring. We aimed to evaluate use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to improve adherence in individuals presenting with second-line viral failure. Methods: A5288 was a phase 4, third-line ART strategy study done at 19 urban sites in ten countries that enrolled adult participants with confirmed plasma HIV-1 RNA (viral load) of 1000 copies per mL or more after more than 24 weeks of protease inhibitor-based second-line ART. The primary objective was to use antiretrovirals (raltegravir, etravirine, and ritonavir-boosted darunavir) and diagnostic monitoring technologies, including viral load, genotyping, and adherence support to achieve viral load suppression (defined as ≤200 copies per mL) in 65% or more of participants. ART history and real-time drug resistance genotypes were used to assign participants to one of four cohorts: cohort A (no lopinavir resistance) stayed on second-line ART and cohorts B (B1, best available nucleoside reverse transcriptase inhibitors [NRTIs] plus ritonavir-boosted darunavir plus raltegravir; B2, ritonavir-boosted darunavir plus raltegravir plus etravirine; B3, ritonavir-boosted darunavir, raltegravir, and either tenofovir plus emtricitabine or tenofovir plus lamivudine), C (ritonavir-boosted darunavir plus raltegravir plus tenofovir-emtricitabine or tenofovir plus lamivudine), and D (best available NRTIs plus ritonavir-boosted darunavir plus raltegravir) were defined by increasing levels of resistance and received appropriate regimens, including new antiretrovirals. Participants in Cohort B without detectable hepatitis B surface antigen were assigned by blocked randomisation to cohorts B1 and B2, and those with detectable hepatitis B surface antigen were assigned to cohort B3. The trial is registered with ClinicalTrials.gov, number NCT01641367. Findings: From Jan 10, 2013, to Sept 10, 2015, 545 participants were enrolled. 287 (53%) were assigned to cohort A, 74 (14%) to B1, 72 (13%) to B2, eight (1%) to B3, 70 (13%) to C, and 34 (6%) to D. Overall, 349 (64%, 95% CI 60–68) participants achieved viral suppression at week 48, with proportions varying from 125 (44%) of 287 in cohort A to 65 (88%) of 74 in cohort B1, 63 (88%) of 72 in B2, eight (100%) of eight in B3, 63 (90%) of 70 in C, and 25 (74%) of 34 in D. Participants in cohort A remained on their second-line protease inhibitor, and had the most participants with grade 3 or higher adverse events (147 [51%]). Interpretation: Targeted real-time genotyping to select third-line ART can appropriately allocate more costly antiretrovirals to those with greater levels of HIV drug resistance. Funding: National Institutes of Health.
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U2 - 10.1016/S2352-3018(19)30146-8
DO - 10.1016/S2352-3018(19)30146-8
M3 - Article
C2 - 31371262
AN - SCOPUS:85071621751
VL - 6
SP - e588-e600
JO - The Lancet HIV
JF - The Lancet HIV
SN - 2352-3018
IS - 9
ER -