Lessons Learned from Transient Remission Cases: Clues to Biomarkers of HIV Rebound Katherine Luzuriaga, MD University of Massachusetts Medical School Worcester, MA USA

New pediatric infections (MTCT) cut by 50% between 2001 and 2012: 900,000 new infections prevented since million children < 15 yrs living with HIV 1.5 million HIV-1+ women give birth each year; only ~68% receive ART for PMTCT 240, 000 children acquire HIV-1: one new infection every 2 minutes UNAIDS, 2014 Global Eradication of Pediatric HIV-1 Infection

Rationale for Early cART Rapid tempo of disease progression in HIV infected infants Median viral loads > 10 5 copies/ml over first 2 years of life High rates of viral production Less robust adaptive HIV-specific immunity Ready identification of infants at risk and ability to make early nucleic acid-based rapid diagnosis Early cART reduces HIV-related morbidity and mortality (Violari et al, NEJM, 2008) Early HIV diagnosis and cART are globally recommended as standard of care

Early cART restricts the latent reservoir Persaud et al. AIDS, 2012 Restricted latent reservoir if treated 6 wk (blue circles) Reservoir decays over the first 2 yrs in early-treated infants (half-life 11 months [95% CI: 6 to 30 months] Remains detectable in most (60%) at two years of age

Lower PBMC DNA Levels In Children With Younger Age at Virologic Control Persaud et al, JAMA Pediatr, 2014 Median LTR DNA circles detectable in 20% of youth: Proviral DNA copy number higher in those with detectable (median = 191) than in those with undetectable (median = 23) 2-LTR circles

Clearance of HIV-specific Antibodies is a Hallmark of Early Effective cART in Infants EIA negative at 15 months: A.Durable HIV RNA suppression to < 400: 11 (73%) of 15 infants B.Early tx, incomplete /transient suppression: None (0%) of 5 C. HIV-uninfected infants born to HIV-infected women: 5 (100%) of 5 D. HIV- infected infants first treated > 12 mo: None (0%) of 4 Luzuriaga et al, J Virol, 2000

Low Proviral DNA Loads in Children with HIV-1 Negative or Indeterminate Wb Persaud et al, JAMA Pediatr, 2014.

Early and Very Early Therapy Restrict the Size and Modify the Persistence of HIV-1 Reservoirs Luzuriaga, CROI, 2014; Persaud, CROI, 2015; Luzuriaga, JID, 2014; Persaud, JAMA Peds, 2014; Ananworanich, AIDS, 2014; van Zyl, JID, 2015; Bitnun, CID, 2014 Contribution to the proviral reservoir: T TM > T CM, EM

HIV Remission Following Very Early cART AZT/ 3TC/ NVP AZT/ 3TC/ LPV/r AZT/ 3TC/ EFV +RAL  ARV administered 31 hours - 18 months  Remission 28 months off cART No detectable HIV-1 in routine or scRNA assay No replication-competent virus recovered No detectable HIV-1 specific antibodies or CD4/CD8+ T cells Absence of host factors associated with elite control  Viral Rebound at age 46 months Persaud et al, NEJM, 2013; Luzuriaga, NEJM, 2015 SC RNA: 9 copies/ml

HIV-1 rebound despite limited proviral and latent reservoirs Bitnun, CID, 2014; Giacomet, PIDJ, 2014; Persaud, NEJM, 2014; Luzuriaga, NEJM, 2015; Vigano, J Peds, 2006

Summary: Early/Very Early cART Alters HIV- 1 Persistence in Children Limits proviral and replication competent reservoirs Size correlated with the rapidity of control of HIV replication Decay rapidly over first year of therapy Slower decay with prolonged suppression of HIV replication Decay in HIV proviral reservoirs over time in absence of HIV-specific immune responses suggests that early cART limits infection of long-lived cells Contribution to the proviral reservoir: T TM > T CM, EM

Markers for low-level proviral and latent reservoirs Plasma RNA below detection limits of single copy assays Lack of detectable 2 LTR DNA circles Absence of T cell activation Lack of HIV-specific antibodies, and CD4 and CD8+ T cell responses Luzuriaga et al, J Virol, 2000; Persaud et al, JAMA Peds, 2014; Ananworanich et al, AIDS, 2014

 Adults: 5-15% treated during PHI On cART mo (median 36 mo) Remission off cART: mo (median 89 mo) Low level T cell activation and HIV-specific T cell responses Low circulating HIV-1 DNA levels (median 52 c/10 6 PBMC), with progressive decline over time in some  Pediatric case Infected despite infant ARV prophylaxis Received cART ~3 mo – 6 years Plasma HIV-1 RNA < 50 for 12 years, except for blips at 1, 2, 11, and 14 years; now < 4-9 c/ml HIV-1 DNA copies per million PBMC Pathways to Remission: Post-Treatment Controllers Saez-Cirion, PLoS Pathogens, 2013 Saez-Cirion, IAS, 2015

 IMPAACT P1115: Very Early Intensive Treatment of HIV-Infected infants to achieve HIV remission: A proof of concept study  IMPAACT P1107: Cord Blood Transplantation with CCR5Δ32 Donor Cells in HIV-Infected Subjects who Require Bone Marrow Transplantation for any Indication and its Observed Effects on HIV-1 Persistence Current Protocols

Early/Very cART and HIV Persistence in Children  HIV positive infants and children with persistent suppression of HIV on cART are excellent candidates for additional strategies aimed at remission, particularly therapeutic vaccines: Normal immune responses Absent HIV-specific immunity Limited viral diversity

Acknowledgements Children and Families Hannah Gay and Deborah Persaud Persaud Lab: Carrie Ziemniak, Ya Hui Chen Luzuriaga Lab: Margaret McManus, Linda Lambrecht, Joyce Pepe, Robin Brody, Keri Sanborn, Jim Coderre, Mohan Somasundaran Collaborators: Matthew Strain, Danielle Murray, Douglas Richman, Tae-Wook Chun Manuel Garber, Barbara Tabak Funding: NIAID, NICHD, AmFAR, JHU CFAR, UMMS CFAR, UMass Center for Clinical and Translational Science