EARLY ANTIRETROVIRAL TREATMENT HIV Cure Research Training Curriculum

EARLY ANTIRETROVIRAL TREATMENT HIV Cure Research Training Curriculum (CUREiculum) Early Antiretroviral (ART) Treatment Module by: Scientific Leads: Dr. Jintanat Ananworanich, U. S. Military HIV Research Program (MHRP) with input from Sidaction team (France) Community Lead: Jeffrey Taylor, Collaboratory of AIDS Researchers for Eradication (CARE) Contributor: Karine Dubé, CARE The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure research science accessible to the community and the HIV research field. Last updated April 2015

Module Objectives • Understand why early ART is an important HIV cure research strategy • Explain that HIV latency is established very early during HIV infection • Describe the Fiebig states during acute HIV infection • Appreciate that early ART can result in a smaller reservoir size • Identify examples of clinical studies involving early ART

The HIV infection pathway

Natural history of HIV infection Pantaleo G et al. NEJM, 1993

Why is early ART important? One of the most effective ways to contain the HIV reservoir, preserve immunity and reduce immune activation May optimize responses to immune-based interventions aimed at achieving HIV remission Is essential to prevent sexual transmission of HIV during acute infection May be a critical step in clinical research towards HIV cure

HIV persistence Cell Death Resting State

Strategies to eliminate HIV persistence Vaccine Before HIV Infection “Shock and Kill” ART Acute HIV Infection Eliminate Infected Cells Chronic HIV Infection Viral Load Suppressed Possible interventions: HIV RNA • Latency reversing agents • Broadly neutralizing antibody • Gene-editing therapy

When is HIV latency established? HIV latency (or persistence) is established early in acute HIV infection in all CD 4+ T cell subsets These cells carry integrated but transcriptionally silent HIV viral genome Small number of dormant HIV infected cells (including central and transitional memory CD 4+ T cells) persist indefinitely and are not eliminated by ARV drugs or by the immune system HIV persistence is the main barrier to cure

When is HIV latency established? v HIV latency is established in acute HIV infection v Latency persists despite early and long-term ART v Pool of latently infected cells is stable with little to no decay in the presence of long-term ART Archin N et al. PNAS, 2011

When is HIV latency established? Establishment of the SIV reservoirs occurred as early as three days postinfection v Treatment with ART 3 days post-SIVmac 51 in rhesus macaques blunts viremia (viral RNA and proviral DNA) in the PBMCs but proviral DNA was already detected in tissues v Early ART at Days 3, 7 and 10 reduces the size of the viral reservoirs but does not prevent establishment of viral reservoir v Viral rebound occurred in all animals that were treated at Day 3 v Whitney JB et al. Nature, 2014

What are the Fiebig stages? Virus concentration in extracellular fluid of plasma (copies per ml) Stage 1 107 106 105 104 103 102 Eclipse Phase 101 100 10 -1 10 -2 10 -3 10 -4 105 Limit of detection of assay for Plasma viral RNA T 0 Initial infection 0 5 10 15 20 25 30 35 40 45 50 70 80 90 100 Days following HIV-1 Transmission Adapted from Mc. Michael AJ, Nature Reviews Immunology, 2010

Virus concentration in extracellular fluid of plasma (copies per ml) What are the Fiebig stages? 107 Symptoms Begin 106 105 104 103 102 Eclipse Phase 101 Limit of detection of assay for Plasma viral RNA T 0 10 -1 10 -2 10 -3 10 -4 105 Reservoir Established 0 5 10 15 20 25 30 35 40 45 50 70 80 90 100 Days following HIV-1 Transmission Adapted from Mc. Michael AJ, Nature Reviews Immunology, 2010

What are the Fiebig stages? RNA P 24 Antigen Possible presence of P 24 Antigen 4 Y 2 Specific EIA Present on Western Blot 1 Y Y Plasma Viral RNA (copies per ml) 3 Days following HIV-1 Transmission

What are the Fiebig stages? STAGE 1 STAGE 2 RNA P 24 Antigen Possible presence of P 24 Antigen STAGE 4 Y Y STAGE 3 Specific EIA Present on Western Blot Y

Earlier ART = smaller reservoir size? Key points: 1 Earlier treatment = smaller reservoir size 2 Benefits of early ART is maximal in the first few weeks of infection 3 But subset of latently infected cells may persist indefinitely

What do we measure with total HIV DNA? Integrated HIV DNA Total HIV DNA Replication. Competent Provirus Large Small Very small Ho YC et al. Cell, 2014

Early ART also alters the distribution of the reservoir in CD 4+ T cell subsets Ananworanich J et al. Curr Opin HIV/AIDS, 2015

Early ART also alters the distribution of the reservoir in CD 4+ T cell subsets Key points: 1 Long-lived viral reservoir may be the biggest obstacle to HIV cure 2 5 When patients treated during primary infection, the central memory T cells are preserved When patients treated during primary infection, transitional memory T cells (with short half-life) contribute most to reservoir ART limits persistence of HIV reservoir in all CD 4+ T cell subsets (Chomont) Resting CD 4+ T cells also have different functional and phenotypic properties 6 They may support latency through different mechanisms 7 But there is patient-to-patient variability 3 4

Long-term ART initiated during AHI key to achieving low HIV reservoirs and normal T cell counts Hocqueloux L et al. JAC, 2013 Patients treated during primary acute infection Patients treated during chronic infection

Pivotal clinical early ART studies Update from Thai Studies: RV 254/SEARCH 010: Early ART limits persistence of HIV reservoir in long-lived CD 4+ T cell subsets • Most participant enrolled at Fiebig I and III • Very early ART protects all memory CD 4+ T cell subsets from infection, including long-lived TCM cells • ART in Fiebig I is associated with preservation of poly-functional gut Th 17 cells; however, elevated plasma biomarkers of gut repair and microbial translation persist

Early ART limits persistence of HIV reservoir in long-lived CD 4+ T cell subsets (RV 254/SEARCH 010) 0% 63% Duration of HIV at ART initiation 100% Long-lived central memory CD 4+ T cells Fiebig I Chronic Nicolas Chomont Updated from Ananworanich J, 2013 CROI

Post-treatment control present at sustained remission Viro-Immunological Sustained CONtrol after Treatment Interruption VISCONTI Sáez-Cirion et al. PLo. S Pathogens, 2013

VISCONTI cohort VISCONTI Cohort • Durable control of HIV infection after treatment interruption initiated during primary infection • Different from HIV controllers (natural viral control = never received treatment) • Treated within the first 2 months of infection • Able to control viremia without ART > 9 years • Most of VISCONTI patients had no protective HLA class I alleles (but neutral or high-risk alleles) and weak CD 8+ T cell responses (no favorable genetic profile) • Low HIV DNA level and shorter time to ART initiation from onset of infection predicted post-treatment control (PTC) • Mechanism of viral control is different between PTC and elite controllers • Need more research to understand the mechanism of viral control Sáez-Cirion et al. PLo. S Pathogens, 2013

Pediatric studies: a form of early ART

Mississippi child: timeline of events TH BIR 30 rs u ho hs t n o on m m 18 23 o m 6 4 Long term remission for 27 months Begins ART Stops ART No HIV detected in blood plasma HIV detected in blood at 2 separate time points HIV detected in blood plasma Persaud D et al. NEJM, 2013 Persaud et al. IAS 2014

Pediatric studies: a form of early ART Mississippi Child • Started ART at <2 days of life, remained on ART for 18 months and was able to remain suppressed for 27 months without ART • Transient but encouraging HIV remission • A remarkable progress for the field: – – Re-affirmed the concept that HIV could persist in latent HIV reservoirs Evidence that early ART could prolong the time to viral load rebound Showed that current HIV reservoir test may not be sensitive enough Showed that only a small number of latently infected cells could rekindle HIV infection

Ethical and social considerations 1 How early is “early enough” 2 Early ART will not be “curative” 3 Treatment interruptions not medically recommended 4 Perception of “vulnerability” vs. “healthy” patients 5 Potential impacts (positive or negative) on interpersonal relationships (e. g. adults will not be cured by early ART alone; risk of curative misconception) (standardized and controlled clinical studies; active and frequent monitoring) (e. g. medical vulnerability vs. how patients perceive themselves)

Implementation challenges Difficult to identify people in AHI Recruitment and time of initiation of antiretroviral treatment Difficult to compare studies (variable timing of ART initiation and ways to measure reservoir) Scalability Patient-topatient variability given stochastic nature of rebound

Conclusions and key points ART started during AHI can limit the size of the HIV reservoir Treatment in earliest AHI (Fiebig I) may skew distribution of latently infected cells to shorter lived memory CD 4+ T cells HIV persistence established early in AHI in memory CD 4+ T cells and can persist indefinitely ART in AHI may be the first critical step in clinical research aimed at HIV cure/remission

Module collaborators