Nirmatrelvir/ritonavir (N/R) reduces severe outcomes from coronavirus disease 2019 (COVID-19); however, rebound after treatment has been reported. We compared symptom and viral dynamics in ...individuals with COVID-19 who completed N/R treatment and similar untreated individuals.
We identified symptomatic participants who tested severe acute respiratory syndrome coronavirus 2-positive and were N/R eligible from a COVID-19 household transmission study. Index cases from ambulatory settings and their households contacts were enrolled. We collected daily symptoms, medication use, and respiratory specimens for quantitative polymerase chain reaction for 10 days during March 2022-May 2023. Participants who completed N/R treatment (treated) were propensity score matched to untreated participants. We compared symptom rebound, viral load (VL) rebound, average daily symptoms, and average daily VL by treatment status measured after N/R treatment completion or 7 days after symptom onset if untreated.
Treated (n = 130) and untreated participants (n = 241) had similar baseline characteristics. After treatment completion, treated participants had greater occurrence of symptom rebound (32% vs 20%; P = .009) and VL rebound (27% vs 7%; P < .001). Average daily symptoms were lower among treated participants without symptom rebound (1.0 vs 1.6; P < .01) but not statistically lower with symptom rebound (3.0 vs 3.4; P = .5). Treated participants had lower average daily VLs without VL rebound (0.9 vs 2.6; P < .01) but not statistically lower with VL rebound (4.8 vs 5.1; P = .7).
Individuals who completed N/R treatment experienced fewer symptoms and lower VL but rebound occured more often compared with untreated individuals. Providers should prescribe N/R, when indicated, and communicate rebound risk to patients.
Abstract
Background
Social vulnerability impacts the transmission of SARS-CoV-2 (SCV2) among household contacts. Understanding these correlates can inform interventions to prevent infection among ...close contacts. We examined whether the social vulnerability index (SVI), a composite measure of socioeconomic status, household characteristics, racial and ethnic minority status, and housing type and transportation, is associated with the risk of SCV2 infection among household contacts.
Overall Social Vulnerability Index Diagram
Methods
We used data from a multi-site, prospective, case-ascertained household transmission study with daily nasal swabs for 10 days and RT-PCR testing to detect SCV2 infections in household contacts. Age and gender were self-reported and vaccination status was self-reported and verified. We mapped households to 2020 census tracts and the 2020 SVI (Figure 1). We examined the association between census tract-level SVI (in quartiles) and the risk of infection among household contacts using Poisson regression with generalized estimating equations, accounting for household clustering.
Inclusion criteria for analysis in this study.
Inclusion criteria for analysis in this study.
Results
Among 1,171 household contacts from 719 households, 67.4% developed SCV2 infection. After adjusting for the age of the contact and study site, contacts living in the most vulnerable SVI quartiles, Q3 (Incidence Rate Ratio IRR 1.19, 95% CI 1.01-1.40) and Q4 (IRR=1.18, 95% CI 1.00-1.40), had higher rates of infection compared to those living in the least vulnerable quartile (Q1) at the census tract level. To describe the effect of SVI accounting for vaccination, we performed a second regression adjusting for vaccine receipt among participants. We found that Q3 (IRR 1.19, 95% CI 1.01-1.40) still had higher rates of infection compared to those living in the least vulnerable quartile (Q1). Q4 was directionally consistent but confidence bounds crossed 1 (IRR=1.17, 95% CI 0.99-1.39).
Conclusion
Household contacts from census tracts with greater social vulnerability at the census tract level had a greater risk of SCV2 infection. These risks held even after accounting for vaccine receipt among participants. Future public health interventions should focus on reducing infection and transmission among individuals living in areas with higher social vulnerability beyond vaccination coverage.
Disclosures
Carlos G. Grijalva, MD, MPH, AHRQ: Grant/Research Support|CDC: Grant/Research Support|FDA: Grant/Research Support|Merck: Advisor/Consultant|NIH: Grant/Research Support|Syneos Health: Grant/Research Support Suchitra Rao, MBBS, MSCS, Sequiris: Advisor/Consultant Edwin J. Asturias, MD, Hillevax: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Grant/Research Support Huong McLean, PhD, MPH, Seqirus: Grant/Research Support Edward Belongia, MD, Seqirus: Grant/Research Support Yvonne A. Maldonado, MD, Pfizer: Grant/Research Support|Pfizer: Site Investigator, DSMB member
Abstract
Background
Oseltamivir is the most common antiviral prescribed to treat influenza. There are limited data about oseltamivir receipt in uncomplicated influenza, including frequency of early ...discontinuation of oseltamivir.
Methods
Individuals who tested positive for influenza were identified from outpatient clinics, emergency departments, or surveillance testing at seven sites in the United States from December 2021–March 2023. Index cases and their household contacts (HHC) enrolled ≤6 days after the first illness in the household, completed symptom/medication logs, and collected nasal swabs for influenza testing daily for 10 days. Oseltamivir receipt was classified by daily logs (ever/never receipt, and duration of use: early discontinuation 1–2 days, 3–4 days, or ≥5 days) among eligible persons (Methods 1). Addresses linked to the 2020 Social Vulnerability Index by census tract. Odds of oseltamivir receipt were estimated using binomial regression with household clustering.
Methods upload 1: Analytic flow diagram for assessment of use and discontinuation of oseltamivir in household settings, United States 2021-22 and 2022-23 influenza seasons.
Discontinuation was defined as use for 1-2 days, compared to use for 3-4 or ≥5 days. If the participant reported oseltamivir on the first or last day of follow-up and did not report use for at least 3 days, the duration of oseltamivir usage was considered “censored” and discontinuation was not described.
Results
Of 737 household members, 142 individuals (90/235 index cases, 40/284 infected HHC, 12/218 uninfected HHC) reported oseltamivir. Oseltamivir receipt was more common among those recruited in 2022–23 vs. 2021–22 and by participants who self-reported pre-existing conditions vs. those who did not. Oseltamivir receipt was less common among children 5–11 vs. adults 18–49 years (Results 1). Individuals from the most vulnerable census tracts were least likely to receive oseltamivir (Results 2). Among symptomatic infected persons, oseltamivir was typically initiated within 2 days of symptoms (76%). Of 126 individuals whose duration of oseltamivir was not censored by the start or end of follow-up, 19% reported receipt on only 1-2 days, 17% for 3-4 days, and 63% for ≥5 days. Compared to those who reported ≥5 days of oseltamivir receipt, people who took oseltamivir for 1–2 days had similar reported symptoms, including gastrointestinal symptoms, on the first day of illness and first day of oseltamivir (Results 3).
Results upload 1: Characteristics of individuals who did and did not report use of oseltamivir among individuals in households with a known influenza case, United States, 2021-22 and 2023-24 influenza seasons.
Results Upload 2. Social vulnerability of individuals who did and did not report use of oseltamivir among individuals in geocoded households with a known influenza case, United States, 2021-22 and 2023-24 influenza seasons.
Conclusion
Over a third of index cases received oseltamivir, and receipt differed by age and social vulnerability status. In this analysis, early discontinuation was not associated with initial symptom burden or symptoms, including gastrointestinal side-effects, after initiating oseltamivir.
Disclosures
Edward Belongia, MD, Seqirus: Grant/Research Support Yvonne A. Maldonado, MD, Pfizer: Grant/Research Support|Pfizer: Site Investigator, DSMB member Suchitra Rao, MBBS, MSCS, Sequiris: Advisor/Consultant Huong McLean, PhD, MPH, Seqirus: Grant/Research Support Joshua Petrie, PhD, CSL Seqirus: Grant/Research Support Edwin J. Asturias, MD, Hillevax: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Grant/Research Support Carlos G. Grijalva, MD, MPH, AHRQ: Grant/Research Support|CDC: Grant/Research Support|FDA: Grant/Research Support|Merck: Advisor/Consultant|NIH: Grant/Research Support|Syneos Health: Grant/Research Support
Abstract
Background
Understanding the transmissibility of respiratory viruses by symptoms is important for public health.
Methods
Persons who tested positive for SARS-CoV-2 and their household ...contacts (HHC) were recruited from 7 US sentinel sites or by remote invitation nationwide during Sep. 2021—Mar. 2023. The household primary case was the person with the earliest symptom onset or positive test. Starting ≤6 days after primary case onset, primary cases and HHC completed symptom logs (daily, retrospective since onset and for 10 days post-enrollment) and collected nasal or saliva specimens (daily for 10 days) that were tested by RT-PCR. Infected individuals were counted as having developed fever, lower respiratory symptoms (LRS: wheezing, chest tightness/pain, shortness of breath, cough), other symptoms (fatigue, aches, abdominal pain, diarrhea, vomiting, change of taste/smell, headache, sore throat, runny nose, nasal congestion), or as being asymptomatic based on all logs. Risk of secondary infection (any PCR positivity) among eligible, tested HHC (Methods 1) by symptoms of primary cases was estimated using Poisson regression with generalized estimating equations. We estimated days from onset to last PCR positive in a survival model.
Methods upload 1. Enrolled and analytically included household members in case-ascertained studies of household transmission of SARS-CoV-2, United States, Sept 2021 - Mar 2023.
Results
This analysis included 842 households (839 primary cases, 836 infected HHC, and 615 uninfected HHC, median household size of 2). Most primary cases (99%) and infected HHC (81%) were symptomatic (Results 1). Primary cases had higher frequencies of fever or LRS than infected HHC (Results 2). HHC exposed to primary cases who developed fever or LRS were more likely to become infected than HHC exposed to primary cases who did not have fever or LRS (Results 3). Post-hoc comparisons by individual symptoms supported this for fever and all LRS but chest pain (fever: IRR 1.31 95% CI: 1.13-1.52; cough: IRR 1.54 95% CI 1.21 – 1.95; wheezing: IRR 1.20 95% CI 1.08 – 1.35; shortness of breath IRR 1.15, 95% CI 1.04 – 1.27). Primary cases with fever or LRS were PCR positive for a median of 14 days (95% CI: 14 – 15) post-onset, compared to 10 days (95% CI: 9 – 11) for cases who did not have fever or LRS.
Results upload 1. Characteristics of included household members in case-ascertained studies of household transmission of SARS-CoV-2, United States, Sep 2021 - Mar 2023.
Results upload 2. Proportion of primary cases and infected household contacts who experienced individual symptoms.
Results upload 3. Unadjusted and adjusted risk of household contacts becoming infected with SARS-CoV-2, by symptoms in the primary case.
Conclusion
Contacts of primary cases with fever or lower respiratory symptoms may have been more likely to become infected than contacts of primary cases without, suggesting higher transmissibility.
Disclosures
Joshua Petrie, PhD, CSL Seqirus: Grant/Research Support Yvonne A. Maldonado, MD, Pfizer: Grant/Research Support|Pfizer: Site Investigator, DSMB member Suchitra Rao, MBBS, MSCS, Sequiris: Advisor/Consultant Edward Belongia, MD, Seqirus: Grant/Research Support Huong McLean, PhD, MPH, Seqirus: Grant/Research Support Edwin J. Asturias, MD, Hillevax: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Grant/Research Support Carlos G. Grijalva, MD, MPH, AHRQ: Grant/Research Support|CDC: Grant/Research Support|FDA: Grant/Research Support|Merck: Advisor/Consultant|NIH: Grant/Research Support|Syneos Health: Grant/Research Support
Abstract
Background
Nirmatrelvir/ritonavir (N/R) protects against severe outcomes after SARS-CoV-2 (SCV2) infection, but patients and studies have described symptom and viral rebound after treatment. ...Our aim was to compare symptom and viral trajectories during acute illness among individuals with COVID-19 treated with N/R compared to similar individuals who did not receive any COVID-19 treatment.
Methods
This analysis included participants enrolled ≤ 6 days of index symptom onset in a US household transmission study who tested SCV2-positive, Mar. 2022–Mar. 2023. We followed participants for 10 days after enrollment, obtaining demographics, clinical history, daily symptoms (list of 15), medications, and specimens for SCV2 quantitative PCR. Symptomatic participants eligible for N/R were included (Fig. 1). We used propensity score matching to select untreated participants who were similar to N/R treated participants (Table 1). We assessed symptoms and viral load (when ≥ 2 nasal swab results were available) from N/R completion (N/R treated) or after seven days since symptom onset (untreated) to the end of follow up. We defined symptom rebound as an increase of ≥ 2 symptoms and viral load rebound as an increase of ≥ 0.5 log10(IU/mL) over a minimum of 5 log10(IU/mL). We used Wilcoxon Test to compare mean daily symptoms and viral loads and logistic regression to calculate odds of rebound.
Case-ascertained household transmission study participants were included in this analysis if they were enrolled in March 2022 (first report of nirmatrelvir/ritonavir) or after and tested positive for SARS-CoV-2 (n=2075). We included symptomatic N/R eligible participants who had non-missing data for propensity score model variables and daily specimens and symptoms (n=1224) and then excluded N/R treated participants who did not complete N/R in 5-6 days according to EUA (n=108). Propensity score matching was performed by calculating propensity score of nirmatrelvir/ritonavir use based on age, sex, race/ethnicity, prior COVID-19, recruitment method, participant type, medical care access, COVID-19 vaccination history, comorbidities, and predominant variant at the time of index onset. The best covariate balance was achieved using nearest propensity score matching method with a ratio of 2:1 no treatment to N/R treated. Those that did not match to a treated participant were excluded (n=768). The two recruitment sources collected different specimen types (sentinel sites collected nasal swabs and remote recruitment collected saliva) and used different viral load quantification standards. Because of this, viral load analysis was limited to only those that collected nasal swabs and had at least two viral load results after nirmatrelvir/ritonavir completion or, for the no treatment participants, after day 7 since symptom onset. N/R=nirmatrelvir/ritonavir; SCV2=SARS-CoV-2; EUA=Emergency Use Agreement
Results
N/R treated (n=116) and untreated (n=232) participants had similar baseline characteristics (Table 1). Median days from symptom onset to N/R initiation was 2 days (IQR=1-3). Symptom rebound occurred among 32% of N/R treated and 19% of untreated participants (OR=1.95; 95% CI=1.17, 3.24; Fig. 2). Mean daily symptoms were lower among N/R treated (1.6 vs 2.0; p=0.2) and significantly lower among N/R treated when rebound did not occur (0.8 vs 1.5; p=0.01). Viral load rebound occurred among 25% of N/R treated and 13% of untreated participants (OR=2.31; 95% CI=1.17, 4.55) and mean daily viral load was significantly lower among N/R treated overall (1.5 vs 2.7), without rebound (1.1 vs 2.5), and with rebound (4.8 vs 5.6, all p < 0.05, Fig. 3).
The following symptoms were elicited daily from participants: fever/feverish/chills, cough, sore throat, runny nose, nasal congestion, fatigue/feeling run down, wheezing, trouble breathing/shortness of breath, chest tightness/chest pain, loss of smell/loss of taste, headache, abdominal pain, diarrhea, vomiting, and muscle or body aches. Symptom rebound was defined as an increase of at least two symptoms after the completion of nirmatrelvir/ritonavir or, when no treatment was reported, after seven days since symptom onset. Daily symptoms after end of treatment were averaged from the day after the last day of nirmatrelvir/ritonavir or, if no treatment, day eight since symptom onset to the last available symptom diary follow up. N/R=nirmatrelvir/ritonavirFigure 3.Viral load trajectory during the first two weeks after symptom onset by nirmatrelvir/ritonavir treatment and viral load rebound visualized by (A) median viral load each day since symptom onset and proportion with viral load rebound and (B) average daily viral load after nirmatrelvir/ritonavir completion or seven days since symptom onset
Nasal swabs were tested for SARS-CoV-2 by PCR using the Panther Fusion Hologic system. Viral load as logIU/mL was determined using WHO standard. Negative results were set to zero and below limit of quantification (3 logIU/mL) results were set to 1.5 logIU/mL. Viral load rebound was defined as an increase of at least 0.5 logIU/mL (with a threshold of 5 logIU/mL) after the completion of nirmatrelvir/ritonavir or, if no treatment was reported, after seven days since symptom onset. Daily viral load after end of treatment was averaged from the day after the last day of nirmatrelvir/ritonavir or, if no treatment, day eight since symptom onset to the last available viral load result. N/R=nirmatrelvir/ritonavir; IU=international units
Conclusion
In outpatient settings, N/R treated individuals had fewer symptoms and lower viral loads, but greater odds of symptom and viral rebound compared to similar untreated individuals.
Disclosures
Joshua Petrie, PhD, CSL Seqirus: Grant/Research Support Suchitra Rao, MBBS, MSCS, Sequiris: Advisor/Consultant Edward Belongia, MD, Seqirus: Grant/Research Support Edwin J. Asturias, MD, Hillevax: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Grant/Research Support Huong McLean, PhD, MPH, Seqirus: Grant/Research Support Yvonne A. Maldonado, MD, Pfizer: Grant/Research Support|Pfizer: Site Investigator, DSMB member Carlos G. Grijalva, MD, MPH, AHRQ: Grant/Research Support|CDC: Grant/Research Support|FDA: Grant/Research Support|Merck: Advisor/Consultant|NIH: Grant/Research Support|Syneos Health: Grant/Research Support
Abstract
Background
COVID-19 vaccines reduce the risk of symptomatic SARS-CoV-2 infection, but it is unclear the extent to which vaccines or prior infection reduce the risk of infection in high ...transmission settings like households.
Methods
We screened individuals who tested positive for SARS-CoV-2 (index cases) recruited at 7 sentinel testing sites and through a nationwide effort during Sep 2021–Apr 2023. Index cases and their households (HH) were enrolled ≤6 days after the index case’s illness onset. Household contacts (HHC) had daily self-collected nasal swabs or saliva samples tested by RT-PCR for SARS-CoV-2. We determined COVID-19 vaccination status by plausible self-report (with date) or vaccination records, and prior SARS-CoV-2 infection by self-reported prior positive test (with year) or anti-nucleocapsid antibodies assessed at enrollment. We considered HHC with prior COVID-19 and ≥2 COVID-19 vaccine doses as having “hybrid immunity”, and assessed the effects of ≥2 vaccine doses, prior COVID-19, or hybrid immunity on the risk of PCR-confirmed SARS-CoV-2 infection among HHC by GEE Poisson regression adjusted for age of the HHC, recruitment strategy, household density (ppl/bedroom), and enrollment month.
Results
We included 1,324 HHC (Fig 1); 73% enrolled May–Nov 2022, when Omicron BA.4/5 predominated; 28% were aged < 18 years (Table 1). Most (89%) had some immunity to COVID-19: 54% from vaccination only, 7% from infection only, and 26% from hybrid immunity. Most HHC without immunity to SARS-CoV-2 were children (64%). Of HHCs, 61% became SARS-CoV-2 positive during follow-up. In a model that accounted for all sources of immunity (figure 2), prior vaccination or prior infection alone did not provide significant protection, only HHC with hybrid immunity had significantly reduced risk of infection (adjusted relative risk: 0.80, 95% confidence interval: 0.68, 0.94; Fig 2). The risk of infection was lowest (43%) when the HHC’s last immunizing event (vaccination or infection) occurred ≤6 months before the index case’s illness onset.
Eligibility and inclusion of HH contacts in analysis of COVID-19 transmission
Figure 1
Table 1
Demographic characteristics of HH contacts by COVID-19 vaccination or prior COVID-19
Figure 2
Adjusted relative risk of infection among HH contacts by COVID-19 vaccination or prior COVID-19
Conclusion
The risk of SARS-CoV-2 infection among HHCs continues to be high. While vaccination alone was not effective at preventing SARS-CoV-2 infection, HHCs with hybrid immunity from recent vaccination or prior infection had the lowest risk of infection.
Disclosures
Yvonne A. Maldonado, MD, Pfizer: Grant/Research Support|Pfizer: Site Investigator, DSMB member Huong McLean, PhD, MPH, Seqirus: Grant/Research Support Suchitra Rao, MBBS, MSCS, Sequiris: Advisor/Consultant Joshua Petrie, PhD, CSL Seqirus: Grant/Research Support Edwin J. Asturias, MD, Hillevax: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Grant/Research Support Edward Belongia, MD, Seqirus: Grant/Research Support Carlos G. Grijalva, MD, MPH, AHRQ: Grant/Research Support|CDC: Grant/Research Support|FDA: Grant/Research Support|Merck: Advisor/Consultant|NIH: Grant/Research Support|Syneos Health: Grant/Research Support
