Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288): a prospective strategy study

A5288 Team

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)e588-e600
JournalThe Lancet HIV
Volume6
Issue number9
DOIs
StatePublished - Sep 2019
Externally publishedYes

Fingerprint

Tenofovir
Ritonavir
Viral Load
Prospective Studies
etravirine
Reverse Transcriptase Inhibitors
Lamivudine
Hepatitis B Surface Antigens
Protease Inhibitors
Nucleosides
Drug Resistance
Therapeutics
Lopinavir
National Institutes of Health (U.S.)
Random Allocation
Darunavir
Raltegravir Potassium
HIV-1
History
Genotype

ASJC Scopus subject areas

  • Epidemiology
  • Immunology
  • Infectious Diseases
  • Virology

Cite this

Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288) : a prospective strategy study. / A5288 Team.

In: The Lancet HIV, Vol. 6, No. 9, 09.2019, p. e588-e600.

Research output: Contribution to journalArticle

@article{24f331e05f624295afeb3b47d4b2fa19,
title = "Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288): a prospective strategy study",
abstract = "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.",
author = "{A5288 Team} and Beatriz Grinsztejn and Hughes, {Michael D.} and Justin Ritz and Robert Salata and Peter Mugyenyi and Evelyn Hogg and Linda Wieclaw and Robert Gross and Catherine Godfrey and Cardoso, {Sandra W.} and Aggrey Bukuru and Mumbi Makanga and Sharlaa Faesen and Vidya Mave and {Wangari Ndege}, Beatrice and {Nerette Fontain}, Sandy and Wadzanai Samaneka and Rode Secours and {van Schalkwyk}, Marije and Rosie Mngqibisa and Lerato Mohapi and Javier Valencia and Patcharaphan Sugandhavesa and Esmelda Montalban and Anchalee Avihingsanon and Santos, {Breno R.} and Nagalingeswaran Kumarasamy and Cecilia Kanyama and Schooley, {Robert T.} and Mellors, {John W.} and Wallis, {Carole L.} and Collier, {Ann C.} and B. Grinsztejn and Mugyenyi, {P. N.} and A. Collier and R. Salata and C. Godfrey and E. Hogg and M. Hughes and J. Ritz and L. Wieclaw and T. Sise and Mellors, {J. W.} and C. Wallis and Fletcher, {C. V.} and M. Gandhi and R. Gross and Schooley, {R. T.} and R. Walensky and {van Schalkwyk}, M.",
year = "2019",
month = "9",
doi = "10.1016/S2352-3018(19)30146-8",
language = "English (US)",
volume = "6",
pages = "e588--e600",
journal = "The Lancet HIV",
issn = "2352-3018",
publisher = "Elsevier Limited",
number = "9",

}

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

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 - Grinsztejn, B.

AU - Mugyenyi, P. N.

AU - Collier, A.

AU - Salata, R.

AU - Godfrey, C.

AU - Hogg, E.

AU - Hughes, M.

AU - Ritz, J.

AU - Wieclaw, L.

AU - Sise, T.

AU - Mellors, J. W.

AU - Wallis, C.

AU - Fletcher, C. V.

AU - Gandhi, M.

AU - Gross, R.

AU - Schooley, R. T.

AU - Walensky, R.

AU - van Schalkwyk, M.

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.

UR - http://www.scopus.com/inward/record.url?scp=85071621751&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071621751&partnerID=8YFLogxK

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 -