OBJECTIVES: Therapies to achieve sustained antiretroviral therapy-free HIV remission will require validation in analytic treatment interruption (ATI) trials. Identifying biomarkers that predict time to viral rebound could accelerate the development of such therapeutics. DESIGN: A pooled analysis of participants from six AIDS Clinical Trials Group ATI studies to identify predictors of viral rebound. METHODS: Cell-associated DNA (CA-DNA) and CA-RNA were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay. RESULTS: Participants who initiated antiretroviral therapy (ART) during acute/early HIV infection and those on a non-nucleoside reverse transcriptase inhibitor-containing regimen had significantly delayed viral rebound. Participants who initiated ART during acute/early infection had lower levels of pre-ATI CA-RNA (acute/early vs. chronic-treated: median <92 vs. 156 HIV-1 RNA copies/10 CD4 cells, P < 0.01). Higher pre-ATI CA-RNA levels were significantly associated with shorter time to viral rebound (≤4 vs. 5-8 vs. >8 weeks: median 182 vs. 107 vs. <92 HIV-1 RNA copies/10 CD4 cells, Kruskal-Wallis P < 0.01). The proportion of participants with detectable plasma residual viremia prior to ATI was significantly higher among those with shorter time to viral rebound. CONCLUSION: Higher levels of HIV expression while on ART are associated with shorter time to HIV rebound after treatment interruption. Quantification of the active HIV reservoir may provide a biomarker of efficacy for therapies that aim to achieve ART-free HIV remission.
OBJECTIVES: Therapies to achieve sustained antiretroviral therapy-free HIV remission will require validation in analytic treatment interruption (ATI) trials. Identifying biomarkers that predict time to viral rebound could accelerate the development of such therapeutics. DESIGN: A pooled analysis of participants from six AIDS Clinical Trials Group ATI studies to identify predictors of viral rebound. METHODS: Cell-associated DNA (CA-DNA) and CA-RNA were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay. RESULTS:Participants who initiated antiretroviral therapy (ART) during acute/early HIV infection and those on a non-nucleoside reverse transcriptase inhibitor-containing regimen had significantly delayed viral rebound. Participants who initiated ART during acute/early infection had lower levels of pre-ATI CA-RNA (acute/early vs. chronic-treated: median <92 vs. 156 HIV-1 RNA copies/10 CD4 cells, P < 0.01). Higher pre-ATI CA-RNA levels were significantly associated with shorter time to viral rebound (≤4 vs. 5-8 vs. >8 weeks: median 182 vs. 107 vs. <92 HIV-1 RNA copies/10 CD4 cells, Kruskal-Wallis P < 0.01). The proportion of participants with detectable plasma residual viremia prior to ATI was significantly higher among those with shorter time to viral rebound. CONCLUSION: Higher levels of HIV expression while on ART are associated with shorter time to HIV rebound after treatment interruption. Quantification of the active HIV reservoir may provide a biomarker of efficacy for therapies that aim to achieve ART-free HIV remission.
Authors: Meghan K Rothenberger; Brandon F Keele; Stephen W Wietgrefe; Courtney V Fletcher; Gregory J Beilman; Jeffrey G Chipman; Alexander Khoruts; Jacob D Estes; Jodi Anderson; Samuel P Callisto; Thomas E Schmidt; Ann Thorkelson; Cavan Reilly; Katherine Perkey; Thomas G Reimann; Netanya S Utay; Krystelle Nganou Makamdop; Mario Stevenson; Daniel C Douek; Ashley T Haase; Timothy W Schacker Journal: Proc Natl Acad Sci U S A Date: 2015-02-23 Impact factor: 11.205
Authors: Courtney V Fletcher; Kathryn Staskus; Stephen W Wietgrefe; Meghan Rothenberger; Cavan Reilly; Jeffrey G Chipman; Greg J Beilman; Alexander Khoruts; Ann Thorkelson; Thomas E Schmidt; Jodi Anderson; Katherine Perkey; Mario Stevenson; Alan S Perelson; Daniel C Douek; Ashley T Haase; Timothy W Schacker Journal: Proc Natl Acad Sci U S A Date: 2014-01-27 Impact factor: 11.205
Authors: Thomas A Rasmussen; Martin Tolstrup; Christel R Brinkmann; Rikke Olesen; Christian Erikstrup; Ajantha Solomon; Anni Winckelmann; Sarah Palmer; Charles Dinarello; Maria Buzon; Mathias Lichterfeld; Sharon R Lewin; Lars Østergaard; Ole S Søgaard Journal: Lancet HIV Date: 2014-09-15 Impact factor: 12.767
Authors: Maria J Buzón; Marta Massanella; Josep M Llibre; Anna Esteve; Viktor Dahl; Maria C Puertas; Josep M Gatell; Pere Domingo; Roger Paredes; Mark Sharkey; Sarah Palmer; Mario Stevenson; Bonaventura Clotet; Julià Blanco; Javier Martinez-Picado Journal: Nat Med Date: 2010-03-14 Impact factor: 53.440
Authors: Nancie M Archin; Kara S Keedy; Amy Espeseth; Herbert Dang; Daria J Hazuda; David M Margolis Journal: AIDS Date: 2009-09-10 Impact factor: 4.177
Authors: Datsen George Wei; Vicki Chiang; Elizabeth Fyne; Mini Balakrishnan; Tiffany Barnes; Michael Graupe; Joseph Hesselgesser; Alivelu Irrinki; Jeffrey P Murry; George Stepan; Kirsten M Stray; Angela Tsai; Helen Yu; Jonathan Spindler; Mary Kearney; Celsa A Spina; Deborah McMahon; Jacob Lalezari; Derek Sloan; John Mellors; Romas Geleziunas; Tomas Cihlar Journal: PLoS Pathog Date: 2014-04-10 Impact factor: 6.823
Authors: Elizabeth Hamlyn; Fiona M Ewings; Kholoud Porter; David A Cooper; Giuseppe Tambussi; Mauro Schechter; Court Pedersen; Jason F Okulicz; Myra McClure; Abdel Babiker; Jonathan Weber; Sarah Fidler Journal: PLoS One Date: 2012-08-31 Impact factor: 3.240
Authors: Nancie M Archin; Jennifer L Kirchherr; Julia Am Sung; Genevieve Clutton; Katherine Sholtis; Yinyan Xu; Brigitte Allard; Erin Stuelke; Angela D Kashuba; Joann D Kuruc; Joseph Eron; Cynthia L Gay; Nilu Goonetilleke; David M Margolis Journal: J Clin Invest Date: 2017-07-17 Impact factor: 14.808
Authors: Jibreel Jumare; Sara Sunshine; Hayat Ahmed; Samer S El-Kamary; Laurence Magder; Laura Hungerford; Tricia Burdo; Lindsay M Eyzaguirre; Anya Umlauf; Mariana Cherner; Alash'le Abimiku; Man Charurat; Jonathan Z Li; William A Blattner; Walter Royal Journal: J Neurovirol Date: 2017-02-27 Impact factor: 2.643
Authors: Karine Dubé; David Evans; Lynda Dee; Laurie Sylla; Jeff Taylor; Asheley Skinner; Bryan J Weiner; Sandra B Greene; Stuart Rennie; Joseph D Tucker Journal: AIDS Res Hum Retroviruses Date: 2017-07-10 Impact factor: 2.205
Authors: Catherine N Le; Paula Britto; Sean S Brummel; Risa M Hoffman; Jonathan Z Li; Patricia M Flynn; Taha E Taha; Anne Coletti; Mary Glenn Fowler; Ronald J Bosch; Rajesh T Gandhi; Karin L Klingman; James A McIntyre; Judith S Currier Journal: AIDS Date: 2019-11-15 Impact factor: 4.177
Authors: Alexander O Pasternak; Marlous L Grijsen; Ferdinand W Wit; Margreet Bakker; Suzanne Jurriaans; Jan M Prins; Ben Berkhout Journal: JCI Insight Date: 2020-03-26