Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study
BACKGROUND: Early antiretroviral therapy (ART) initiation (ie, within 3 months of infection) limits establishment of the HIV reservoir. However, the effect of early ART initiation on the long-term dynamics of the pool of infected cells remains unclear. METHODS: In this longitudinal analysis, we incl...
Guardado en:
| Autores principales: | , , , , , , , , , , , |
|---|---|
| Formato: | Artículo |
| Lenguaje: | inglés |
| Publicado: |
2021
|
| Materias: | |
| Acceso en línea: | Ver en el sistema de origen Ver en el sistema de origen Enlace permanente (DOI o Handle) Enlace permanente (DOI o Handle) |
| Etiquetas: |
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| _version_ | 1881508873347530752 |
|---|---|
| author | Marta Massanella Rachel Bender Ignacio Javier R. Lama Amélie Pagliuzza Sayan Dasgupta Ricardo Alfaro Jessica Ríos Carmela Ganoza Delia Pinto-Santini Trupti Gilada Ann Duerr Nicolas Chomont |
| author_browse | Amélie Pagliuzza Ann Duerr Carmela Ganoza Delia Pinto-Santini Javier R. Lama Jessica Ríos Marta Massanella Nicolas Chomont Rachel Bender Ignacio Ricardo Alfaro Sayan Dasgupta Trupti Gilada |
| author_facet | Marta Massanella Rachel Bender Ignacio Javier R. Lama Amélie Pagliuzza Sayan Dasgupta Ricardo Alfaro Jessica Ríos Carmela Ganoza Delia Pinto-Santini Trupti Gilada Ann Duerr Nicolas Chomont |
| author_sort | Marta Massanella |
| collection | Producción científica |
| description | BACKGROUND: Early antiretroviral therapy (ART) initiation (ie, within 3 months of infection) limits establishment of the HIV reservoir. However, the effect of early ART initiation on the long-term dynamics of the pool of infected cells remains unclear. METHODS: In this longitudinal analysis, we included cisgender men who have sex with men (MSM) and transgender women (aged 18-54 years) at high risk for HIV infection, enrolled in the ongoing longitudinal MERLIN study in Peru between Oct 28, 2014, and Nov 8, 2018. Participants were eligible if they had been infected with HIV less than 90 days before enrolment, and if they had cryopreserved peripheral blood mononuclear cell (PBMC) samples. Participants were stratified into three groups on the basis of whether they initiated ART at 30 days or less (acute group), at 31-90 days (early group), or more than 24 weeks (deferred group) after the estimated date of detectable infection. PBMC samples were collected before ART initiation and longitudinally for up to 4 years on ART. The main outcomes were to establish the size of the HIV reservoir before ART initiation and to assess the effect of the timing of ART initiation on the decay of the HIV reservoir over 4 years follow-up. We quantified viral load, and isolated CD4 cells to quantify total HIV DNA, integrated HIV DNA and 2-long terminal repeat circles. Longitudinal analysis of active and inducible HIV reservoirs were measured by quantifying the frequency of CD4 cells producing multiply-spliced HIV RNA ex vivo and after in-vitro stimulation with a tat/rev induced limiting dilution assay (TILDA). A mixed-effects model from the time of ART initiation was used to measure longitudinal decays in viral loads and each HIV reservoir measure in each of the three groups. FINDINGS: We included 56 participants in this analysis, all of whom were MSM: 15 were in the acute group, 19 were in the early group, and 22 were in the deferred group. Participants in all three groups had similar levels of all HIV reservoir markers before ART initiation. All participants, including those in the acute group, had a pool of transcriptionally silent HIV-infected cells before ART initiation, as indicated by a substantial increase in TILDA measures upon stimulation. Longitudinal analysis over 4 years of ART revealed a biphasic decay of all HIV persistence markers, with a rapid initial decline followed by a slower decay in all participants. During the first-phase decay, the half-lives of both total and integrated HIV DNA and TILDA measures were significantly shorter in the acute group than in the early and deferred groups. During the second-phase decay, HIV reservoir markers continued to decline only in participants in the acute group. INTERPRETATION: Participants who initiated ART within 30 days or less of HIV infection showed a steeper and more sustained decay in HIV reservoir measures, suggesting long-term benefit of acute ART initiation on reservoir clearance. FUNDING: The US National Institutes of Health and the Canadian Institutes for Health Research. |
| format | Article |
| id | oai:cris.upeu.edu.pe:20.500.15037/1762 |
| institution | UPeU |
| language | English |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| record_format | dspace |
| spelling | oai:cris.upeu.edu.pe:20.500.15037/17622026-10-30T16:16:42ZLong-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical studyMarta MassanellaRachel Bender IgnacioJavier R. LamaAmélie PagliuzzaSayan DasguptaRicardo AlfaroJessica RíosCarmela GanozaDelia Pinto-SantiniTrupti GiladaAnn DuerrNicolas ChomontHuman immunodeficiency virus (HIV)Term (time)Merlin (protein)MedicineAntiretroviral therapyVirologyBiologyImmunologyViral loadInternal medicinePhysicsCancerQuantum mechanicsSuppressorHuman immunodeficiency virus (HIV)Term (time)Merlin (protein)MedicineAntiretroviral therapyVirologyBiologyImmunologyViral loadInternal medicinePhysicsCancerSexual and Gender MinoritiesSexual and Gender MinoritiesSexual and Gender MinoritiesAdolescentAdolescentAdolescentAdultAdultAdultCanadaCanadaCanadaDNA, ViralDNA, ViralDNA, ViralFemaleFemaleFemaleHumansHumansHumansLeukocytes, MononuclearLeukocytes, MononuclearLeukocytes, MononuclearMaleMaleMaleMiddle AgedMiddle AgedMiddle AgedUnited StatesUnited StatesUnited StatesBiomarkersBiomarkersBiomarkersHIV-1 geneticsHIV-1 geneticsHIV-1 geneticsHIV Infections drug therapyHIV Infections drug therapyHIV Infections drug therapyHomosexuality, MaleHomosexuality, MaleHomosexuality, MaleNeurofibromin 2 therapeutic useNeurofibromin 2 therapeutic useNeurofibromin 2 therapeutic useAnti-Retroviral Agents therapeutic useAnti-Retroviral Agents therapeutic useAnti-Retroviral Agents therapeutic useYoung AdultYoung AdultYoung AdultLife Sciences Immunology and Microbiology Virology HIV Research and TreatmentHealth Sciences Medicine Infectious Diseases HIV/AIDS Research and InterventionsHealth Sciences Medicine Infectious Diseases HIV/AIDS drug development and treatmentBACKGROUND: Early antiretroviral therapy (ART) initiation (ie, within 3 months of infection) limits establishment of the HIV reservoir. However, the effect of early ART initiation on the long-term dynamics of the pool of infected cells remains unclear. METHODS: In this longitudinal analysis, we included cisgender men who have sex with men (MSM) and transgender women (aged 18-54 years) at high risk for HIV infection, enrolled in the ongoing longitudinal MERLIN study in Peru between Oct 28, 2014, and Nov 8, 2018. Participants were eligible if they had been infected with HIV less than 90 days before enrolment, and if they had cryopreserved peripheral blood mononuclear cell (PBMC) samples. Participants were stratified into three groups on the basis of whether they initiated ART at 30 days or less (acute group), at 31-90 days (early group), or more than 24 weeks (deferred group) after the estimated date of detectable infection. PBMC samples were collected before ART initiation and longitudinally for up to 4 years on ART. The main outcomes were to establish the size of the HIV reservoir before ART initiation and to assess the effect of the timing of ART initiation on the decay of the HIV reservoir over 4 years follow-up. We quantified viral load, and isolated CD4 cells to quantify total HIV DNA, integrated HIV DNA and 2-long terminal repeat circles. Longitudinal analysis of active and inducible HIV reservoirs were measured by quantifying the frequency of CD4 cells producing multiply-spliced HIV RNA ex vivo and after in-vitro stimulation with a tat/rev induced limiting dilution assay (TILDA). A mixed-effects model from the time of ART initiation was used to measure longitudinal decays in viral loads and each HIV reservoir measure in each of the three groups. FINDINGS: We included 56 participants in this analysis, all of whom were MSM: 15 were in the acute group, 19 were in the early group, and 22 were in the deferred group. Participants in all three groups had similar levels of all HIV reservoir markers before ART initiation. All participants, including those in the acute group, had a pool of transcriptionally silent HIV-infected cells before ART initiation, as indicated by a substantial increase in TILDA measures upon stimulation. Longitudinal analysis over 4 years of ART revealed a biphasic decay of all HIV persistence markers, with a rapid initial decline followed by a slower decay in all participants. During the first-phase decay, the half-lives of both total and integrated HIV DNA and TILDA measures were significantly shorter in the acute group than in the early and deferred groups. During the second-phase decay, HIV reservoir markers continued to decline only in participants in the acute group. INTERPRETATION: Participants who initiated ART within 30 days or less of HIV infection showed a steeper and more sustained decay in HIV reservoir measures, suggesting long-term benefit of acute ART initiation on reservoir clearance. FUNDING: The US National Institutes of Health and the Canadian Institutes for Health Research.Articlehttps://pubmed.ncbi.nlm.nih.gov/34841369http://www.thelancet.com/article/S2666524721000100/pdfhttps://doi.org/10.1016/s2666-5247(21)00010-010.1016/s2666-5247(21)00010-0https://hdl.handle.net/20.500.15037/1762W3135967114enThe Lancet Microbe2666-52472021-03-232026-06-13T14:21:44Z2026-06-13T14:21:44Z |
| spellingShingle | Human immunodeficiency virus (HIV) Term (time) Merlin (protein) Medicine Antiretroviral therapy Virology Biology Immunology Viral load Internal medicine Physics Cancer Quantum mechanics Suppressor Human immunodeficiency virus (HIV) Term (time) Merlin (protein) Medicine Antiretroviral therapy Virology Biology Immunology Viral load Internal medicine Physics Cancer Sexual and Gender Minorities Sexual and Gender Minorities Sexual and Gender Minorities Adolescent Adolescent Adolescent Adult Adult Adult Canada Canada Canada DNA, Viral DNA, Viral DNA, Viral Female Female Female Humans Humans Humans Leukocytes, Mononuclear Leukocytes, Mononuclear Leukocytes, Mononuclear Male Male Male Middle Aged Middle Aged Middle Aged United States United States United States Biomarkers Biomarkers Biomarkers HIV-1 genetics HIV-1 genetics HIV-1 genetics HIV Infections drug therapy HIV Infections drug therapy HIV Infections drug therapy Homosexuality, Male Homosexuality, Male Homosexuality, Male Neurofibromin 2 therapeutic use Neurofibromin 2 therapeutic use Neurofibromin 2 therapeutic use Anti-Retroviral Agents therapeutic use Anti-Retroviral Agents therapeutic use Anti-Retroviral Agents therapeutic use Young Adult Young Adult Young Adult Life Sciences Immunology and Microbiology Virology HIV Research and Treatment Health Sciences Medicine Infectious Diseases HIV/AIDS Research and Interventions Health Sciences Medicine Infectious Diseases HIV/AIDS drug development and treatment Marta Massanella Rachel Bender Ignacio Javier R. Lama Amélie Pagliuzza Sayan Dasgupta Ricardo Alfaro Jessica Ríos Carmela Ganoza Delia Pinto-Santini Trupti Gilada Ann Duerr Nicolas Chomont Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study |
| title | Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study |
| title_full | Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study |
| title_fullStr | Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study |
| title_full_unstemmed | Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study |
| title_short | Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study |
| title_sort | long term effects of early antiretroviral initiation on hiv reservoir markers a longitudinal analysis of the merlin clinical study |
| topic | Human immunodeficiency virus (HIV) Term (time) Merlin (protein) Medicine Antiretroviral therapy Virology Biology Immunology Viral load Internal medicine Physics Cancer Quantum mechanics Suppressor Human immunodeficiency virus (HIV) Term (time) Merlin (protein) Medicine Antiretroviral therapy Virology Biology Immunology Viral load Internal medicine Physics Cancer Sexual and Gender Minorities Sexual and Gender Minorities Sexual and Gender Minorities Adolescent Adolescent Adolescent Adult Adult Adult Canada Canada Canada DNA, Viral DNA, Viral DNA, Viral Female Female Female Humans Humans Humans Leukocytes, Mononuclear Leukocytes, Mononuclear Leukocytes, Mononuclear Male Male Male Middle Aged Middle Aged Middle Aged United States United States United States Biomarkers Biomarkers Biomarkers HIV-1 genetics HIV-1 genetics HIV-1 genetics HIV Infections drug therapy HIV Infections drug therapy HIV Infections drug therapy Homosexuality, Male Homosexuality, Male Homosexuality, Male Neurofibromin 2 therapeutic use Neurofibromin 2 therapeutic use Neurofibromin 2 therapeutic use Anti-Retroviral Agents therapeutic use Anti-Retroviral Agents therapeutic use Anti-Retroviral Agents therapeutic use Young Adult Young Adult Young Adult Life Sciences Immunology and Microbiology Virology HIV Research and Treatment Health Sciences Medicine Infectious Diseases HIV/AIDS Research and Interventions Health Sciences Medicine Infectious Diseases HIV/AIDS drug development and treatment |
| topic_facet | Human immunodeficiency virus (HIV) Term (time) Merlin (protein) Medicine Antiretroviral therapy Virology Biology Immunology Viral load Internal medicine Physics Cancer Quantum mechanics Suppressor Human immunodeficiency virus (HIV) Term (time) Merlin (protein) Medicine Antiretroviral therapy Virology Biology Immunology Viral load Internal medicine Physics Cancer Sexual and Gender Minorities Sexual and Gender Minorities Sexual and Gender Minorities Adolescent Adolescent Adolescent Adult Adult Adult Canada Canada Canada DNA, Viral DNA, Viral DNA, Viral Female Female Female Humans Humans Humans Leukocytes, Mononuclear Leukocytes, Mononuclear Leukocytes, Mononuclear Male Male Male Middle Aged Middle Aged Middle Aged United States United States United States Biomarkers Biomarkers Biomarkers HIV-1 genetics HIV-1 genetics HIV-1 genetics HIV Infections drug therapy HIV Infections drug therapy HIV Infections drug therapy Homosexuality, Male Homosexuality, Male Homosexuality, Male Neurofibromin 2 therapeutic use Neurofibromin 2 therapeutic use Neurofibromin 2 therapeutic use Anti-Retroviral Agents therapeutic use Anti-Retroviral Agents therapeutic use Anti-Retroviral Agents therapeutic use Young Adult Young Adult Young Adult Life Sciences Immunology and Microbiology Virology HIV Research and Treatment Health Sciences Medicine Infectious Diseases HIV/AIDS Research and Interventions Health Sciences Medicine Infectious Diseases HIV/AIDS drug development and treatment |
| url | https://pubmed.ncbi.nlm.nih.gov/34841369 http://www.thelancet.com/article/S2666524721000100/pdf https://doi.org/10.1016/s2666-5247(21)00010-0 https://hdl.handle.net/20.500.15037/1762 |
| work_keys_str_mv | AT martamassanella longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT rachelbenderignacio longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT javierrlama longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT ameliepagliuzza longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT sayandasgupta longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT ricardoalfaro longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT jessicarios longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT carmelaganoza longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT deliapintosantini longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT truptigilada longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT annduerr longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy AT nicolaschomont longtermeffectsofearlyantiretroviralinitiationonhivreservoirmarkersalongitudinalanalysisofthemerlinclinicalstudy |