CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

308 DIFFERENTIAL DECAY OF INTACT AND DEFECTIVE PROVIRUS IN INDIVIDUALS ON SUPPRESSIVE ART

Methods: Peripheral blood mononuclear cells (PBMC) from 20 HIV+ subjects chronically suppressed on ART at <50 HIV-1 copies/ml were assessed for a) intact and defective pro-viral DNA by IPDA (Accelevir), b) integrated HIV DNA by Alu-gag PCR, c) integrated HIV Gag and Pol by droplet digital PCR (ddPCR) following pulsed-field gel electrophoresis (PFGE), and d) latency re-activation in vitro measured by both cell-associated tat/rev induced limiting dilution assay (TILDA), and by HIV p24 single molecule array (Simoa). Spearman tests were used to test relationships between HIV measures. Results: HIV DNA measures assessed by Alu-gag PCR or PFGE/ddPCR as well as in vitro latency re-activation assessed by TILDA or HIV p24 Simoa were positively associated with each other (e.g. HIV DNA measures assessed by Alu-gag PCR and in vitro latency re-activation assessed by TILDA: p=0.025, spearman’s rho=0.541). On the other hand, intact proviral DNA did not correlate with any HIV measure. However, hypermutated and/or 5’ deleted pro-viral DNA was positively associated with integrated HIV DNA assessed by Alu-gag PCR (p<0.001, spearman’s rho=0.909) and total Gag by PFGE/ddPC R (p=0.008, spearman’s rho=0.741), as well as with in vitro latency re-activation by HIV p24 Simoa (p=0.044, spearman’s rho=0.627). Conclusion: Alu-gag PCR or PFGE/ddPCR HIV DNA measures, as well as induced HIV p24 in HIV-1+ subjects chronically suppressed on ART best reflect hypermutated and/or deleted rather than intact pro-viral DNA. Sivaporn Gatechompol 1 , Anchalee Avihingsanon 1 , Lu Zheng 2 , Yajing Bao 2 , Stephen J. Kerr 1 , Nagalingeswaran Kumarasamy 3 , James G. Hakim 4 , Frank Maldarelli 5 , Rob Gorelick 6 , Jeffrey D. Lifson 6 , Mina C. Hosseinipour 7 , Joseph J. Eron 8 , Kiat Ruxrungtham 9 , for the ACTG NWCS 425 Team 1 HIV–NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand, 2 Harvard T.H. Chan School of Public Health, Boston, MA, USA, 3 Infectious Diseases Medical Center, Chennai, India, 4 University of Zimbabwe, Harare, Zimbabwe, 5 National Cancer Institute, Frederick, MD, USA, 6 Frederick National Laboratory for Cancer Research, Frederick, MD, USA, 7 University of North Carolina Project–Malawi, Lilongwe, Malawi, 8 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 9 Chulalongkorn University, Bangkok, Thailand Background: Tuberculosis, hepatitis B and C, sexually transmitted and tropical infections may contribute to higher residual viremia in virally suppressed people with HIV (PWH). The limited data describe residual viremia from low- and middle-income countries (LMIC). We assessed the prevalence, and factors associated with residual viremia in PWH, who were virally-suppressed on combination antiretroviral therapy (cART). We also compared residual viremia prevalence between the US and LMIC. Methods: The last available sample among PWH on cART and virally suppressed with plasma HIV RNA <400 copies/mL for ≥3 years from ACTG A5175 and A5208 were tested by the HMMCgag single copy assay (SCA). Detectable residual viremia was defined as having ≥1 copy/mL. Results: A total of 320 participants, 74 (23%) from US and 246 (77%) from LMIC, were analyzed. Median (IQR) age was 33 (28,40) years; duration of viral suppression 3.4 (3.1, 4.0) years and 48%were male (Table). In 85 participants with data available, 53%were subtype C, 42% subtype B and 5% other subtypes. Overall prevalence of residual viremia was 57% [95% CI, 52-63] with 51% [40-63] in US and 59% [53-65] in LMIC (Table). Among participants in LMIC, higher baseline RNA (r=0.29; p<0.001) and shorter virologic suppression duration (r= -0.19; p=0.002) were associated with higher SCA. There were no association between residual viremia and age, sex, race, prior AIDS-defining illness, HIV subtype, cART regimens and co-infection.The final multivariable model conducted in LMIC participants showed that higher baseline HIV RNA was associated with detectable residual RNA by SCA (OR 2.9, 95% CI 1.8, 4.6 for every log 10 increase, p< 0.001). After including both US and LMIC in the final model, baseline HIV RNA remained significant. No difference in SCA detectability was found between US and LMIC sites (OR 1.1 [0.6, 2.0], p=0.72) after adjusting for baseline RNA and parent study. Conclusion: To our knowledge, this is the first study to compare residual viremia in long-term virally suppressed PWH between US and LMIC. The prevalence of residual viremia between both groups were not different and more than half of the participants had detectable viremia. Higher baseline HIV RNA was independently associated with residual viremia.

Michael J. Peluso 1 , Peter Bacchetti 1 , Kristen D. Ritter 2 , Subul A. Beg 3 , Jun Lai 3 , Jeffrey Martin 1 , Peter W. Hunt 1 , Timothy J. Henrich 1 , Janet Siliciano 3 , Robert Siliciano 3 , Gregory Laird 2 , Steven G. Deeks 1 1 University of California San Francisco, San Francisco, CA, USA, 2 Accelevir Diagnostics, Baltimore, MD, USA, 3 Johns Hopkins University School of Medicine, Baltimore, MD, USA Background: The latent HIV-1 reservoir is established early in the course of infection and persists despite suppressive antiretroviral therapy (ART). The relative stabilities of the intact and defective HIV genomes over time during effective ART have not been fully characterized. Understanding variability in the rate of change of the reservoir size, correlates of this variability, and factors associated with rapid decay is likely to be useful in the design and interpretation of HIV cure interventions. Methods: We used the intact proviral DNA assay (IPDA) to estimate the rate of change of intact and defective proviruses in HIV-infected adults on suppressive ART over several years. We used linear spline models with a knot at seven years; these included a random intercept and slope up to the knot. We also estimated the influence of covariates on levels at the start of suppression and rates of change. Results: We studied 81 individuals for a median of 7.3 (IQR 5.9-9.6) years. In a model allowing for a change in the rate of decline, we found evidence for more rapid declines in intact genomes from initial suppression through seven years (16.0% per year decline; CI -23.0%, -8.4%) followed by a slower rate (3.6% per year; CI -8.1%, +1.1%). The estimated half-life of the reservoir was 4.0 years (CI 2.6-7.9) until year seven and 19.0 years (CI 8.2-infinite) thereafter. Intact provirus declined at a faster rate than defective provirus (p<0.001). There was substantial variability between individuals in the rate of decline until year seven. In multivariate models, individuals with higher CD4+ T-cell count nadir values had a faster rate of decline. A subset of individuals (n=7) were estimated to have very rapid declines (>30% per year). Conclusion: These results demonstrate a non-linear decay of viral genomes over time. Intact proviral genomes decay more rapidly than defective ones. The mechanism for this difference is not clear, but could involve cells with intact genomes experiencing increased cytopathic effects or enhanced immune targeting due to virus protein production. These findings provide evidence that the biology of the replication-competent (intact) reservoir differs from that of the replication-incompetent (non-intact) pool of proviruses.

310 RISK AND PREVALENCE OF RESIDUAL VIREMIA AFTER cART IN RESOURCE-LIMITED COUNTRIES

Poster Abstracts

309 DISTINCT HIV RESERVOIR MEASURES CORRELATE WITH DEFECTIVE BUT NOT INTACT PROVIRAL DNA Emmanouil Papasavvas 1 , Livio Azzoni 1 , Brian Ross 1 , Matthew Fair 1 , Amelie Pagliuzza 2 , Steven Lada 3 , Guoxin Wu 4 , Paul Zuck 4 , Pablo Tebas 5 , Karam Mounzer 6 , Jay Kostman 6 , Douglas D. Richman 3 , Nicolas Chomont 2 , Bonnie J. Howell 4 , Luis Montaner 1 1 Wistar Institute, Philadelphia, PA, USA, 2 Université de Montréal, Montreal, QC, Canada, 3 University of California San Diego, La Jolla, CA, USA, 4 Merck & Co, Inc, West Point, PA, USA, 5 University of Pennsylvania, Philadelphia, PA, USA, 6 Philadelphia FIGHT, Philadelphia, PA, USA Background: A major priority for HIV cure strategies remains how best to measure persistence of HIV despite suppressive antiretroviral therapy (ART) in chronic HIV infection. Several assays have been developed to measure the HIV reservoir. We assessed the association between five distinct HIV measures on ART (intact and defective pro-viral DNA, integrated HIV DNA, integrated HIV Gag and Pol, and inducible RNA or p24).

CROI 2020 106