CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

134

SARS-CoV-2 Viral Clearance and Evolution Varies by Extent of Immunodeficiency Yijia Li 1 , Manish C. Choudhary 2 , James Regan 2 , Julie Boucau 3 , Anusha Nathan 3 , Tessa Speidel 4 , May Y. Liew 5 , Gregory E. Edelstein 2 , Michael S. Seaman 4 , Gaurav D. Gaiha 5 , Mark J. Siedner 5 , Amy K. Barczak 5 , Jacob E. Lemieux 5 , Jonathan Z. Li 2 , for the POSITIVES Study Team 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 Brigham and Women's Hospital, Boston, MA, USA, 3 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 4 Beth Israel Deaconess Medical Center, Boston, MA, USA, 5 Massachusetts General Hospital, Boston, MA, USA Background: Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged SARS-CoV-2 infection, but the immune defects that predispose to persistent COVID-19 remain incompletely understood. Methods: Participants enrolled in the POSt-VaccInaTIon Viral CharactEristics Study (POSITIVES), a prospective cohort study enrolling participants with confirmed SARS-CoV-2 infection. Participants were categorized based on the extent of immunocompromise into severe hematologic malignancy/ transplant group (S- HT), severe autoimmune/B-cell deficient (S-A), non-severe immunodeficiency (NS), and non- immunocompromised (None). Longitudinal nasal SARS-CoV-2 levels were measured with a quantitative PCR assay and viable virus levels were evaluated by viral culture. Neutralizing antibody, binding antibody to nucleocapsid, and T cell profiling (enzyme-linked immunosorbent spot [ELISpot] and Spike-specific proliferation assay) were performed in a subset of participants with available blood samples. Results: The median time to nasal viral RNA and culture clearance in the severe hematologic malignancy/transplant group (S-HT) were 72 and 40 days, respectively, which were significantly longer than clearance rates in the severe autoimmune/B-cell deficient (S-A), non-severe, and non-immunocompromised groups (P=0.002 Figure 1A and P<0.001 Figure 1B). Individuals with B-cell deficiency (S-A group) had an intermediate risk of persistent infection. Participants who were severely immunocompromised (S-HT and S-A) had greater SARS-CoV-2 evolution and a higher risk of developing antiviral treatment resistance. Both S-HT and S-A participants had severely diminished SARS-CoV-2-specific humoral responses. In contrast, S-A group had the highest level of SARS-CoV-2-specific CD4+ and CD8+ T cell proliferation response among all groups, while S-HT demonstrated neither antibody maturation nor increased T cell proliferation response to Spike peptide pools. NS and non-immunocompromised participants showed both increasing neutralizing antibody levels (until a plateau ~25-30 days post symptom onset) and SARS CoV-2-specific T cell responses. Conclusion: Our study demonstrated a hierarchy of immunocompromised conditions that increase the risk of delayed viral clearance and SARS-CoV-2 evolution, with the highest risk in those with severe hematologic malignancy/ transplant. The findings may be explained by the suppression of both SARS-CoV 2-specific B and T cell responses.

Oral Abstracts

135

Analysis of Emergent SARS-CoV-2 Antiviral Resistance and Its Association With Virologic Rebound Trevor J Tamura 1 , Fizah Yousuf 1 , Manish C. Choudhary 1 , Rinki Deo 1 , Anadela Navarrete Gomez 1 , Gregory E. Edelstein 1 , Julie Boucau 2 , Dessie Tien 3 , Tammy D. Vyas 3 , Robert W. Shafer 4 , Mark J. Siedner 3 , Amy K. Barczak 3 , Jacob E. Lemieux 3 , Jonathan Z. Li 1 , for the POSITIVES Study Team 1 Brigham and Women's Hospital, Boston, MA, USA, 2 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 3 Massachusetts General Hospital, Boston, MA, USA, 4 Stanford University, Stanford, CA, USA Background: Nirmatrelvir-ritonavir (N-R) and remdesivir (RDV) are SARS-CoV-2 antivirals that reduce the risk of hospitalization and progression to severe COVID-19. N-R and RDV resistance have been described previously, but the frequency and risk factors for emergent drug resistance remains unclear. Methods: We enrolled non-hospitalized participants with acute SARS-CoV-2 infection into the POSITIVES study, a prospective observational cohort, where we collected anterior nasal swabs thrice weekly during the first two weeks after diagnosis. From these samples, we performed deep sequencing of nsp5 among N-R treated (n=53) and untreated (n=42) participants and nsp12 among RDV treated (n=14) participants. We compared the incidence of emergent N-R resistance between N-R treated and untreated participants and evaluated its association with post-treatment virologic rebound, while also characterizing emergent RDV resistance. Results: Compared with untreated individuals, those treated with antivirals were older, more immunosuppressed, and had received more COVID-19 vaccinations, reflecting guidelines for N-R and RDV use. Emergent N-R mutations expected to at least confer moderate resistance (≥2.5-fold reduced susceptibility to N-R in vitro) were detected more often in those who received N-R than those who did not (5/53 [9%] vs 0/42 [0%], p=0.06). However, these mutations (E166V, H172Y, Q189K, P252L) were detected at low frequencies, with all but one mutation present in <25% of the viral population. Additionally, for those with detectable viral loads at follow-up timepoints after cessation of treatment, all (4/4) of the emergent resistance mutations subsequently reverted to wild type. Viral rebound occurred in 28% (15/53) of participants receiving N-R, but there was no difference in resistance emergence in those who experienced virologic rebound compared to those who did not (2/15 [13%] vs 3/38 [8%], p=0.6). Emergent RDV resistance mutations were detected in two immunosuppressed participants (14%). However, similar to the N-R mutations, all four mutations (V166L, N198S, V792I, M794I) were low-frequency and reverted to wild type at successive timepoints. Conclusion: Mutations that confer resistance emerge with N-R and RDV treatment, but they are transient, present at minor frequencies, and are not associated with virologic rebound. These data suggest that the risk of widespread dissemination of significant drug resistance to N-R and RDV remains low.

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CROI 2024