SARS-CoV-2 Virologic Rebound With Nirmatrelvir-Ritonavir Therapy : An Observational Study.

BACKGROUND: Data are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir-ritonavir (N-R) and virologic rebound (VR). OBJECTIVE: To compare the frequency of VR in patients with and without N-R treatment for acute COVID-19. DESIGN: Observational cohort study. SETTING: Multicenter health care system in Boston, Massachusetts. PARTICIPANTS: Ambulatory adults with acute COVID-19 with and without use of N-R. INTERVENTION: Receipt of 5 days of N-R treatment versus no COVID-19 therapy. MEASUREMENTS: The primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log10 copies/mL that were also at least 1.0 log10 copies/mL higher than a prior viral load below 4.0 log10 copies/mL. RESULTS: Compared with untreated persons (n = 55), those taking N-R (n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) (P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected. LIMITATIONS: Observational study design with differences between the treated and untreated groups; positive viral culture result was used as a surrogate marker for risk for ongoing viral transmission. CONCLUSION: Virologic rebound occurred in approximately 1 in 5 people taking N-R, often without symptom rebound, and was associated with shedding of replication-competent virus. PRIMARY FUNDING SOURCE: National Institutes of Health.

Regional variation in weight change after the transition to dolutegravir in Uganda and South Africa.

BACKGROUND: People with HIV (PWH) on integrase inhibitor-based regimens may be at risk of excess weight gain, but it is unclear if this risk is consistent across settings. We assessed weight change over 48 weeks among PWH who were transitioned to tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD). DESIGN: We conducted a prospective cohort study at public-sector HIV clinics in Uganda and South Africa. METHODS: Eligible participants were adults who were transitioned to TLD. Weight was measured at enrollment, 24-, and 48-weeks post TLD transition. Our outcomes were weight change, change in waist circumference, and clinically significant weight gain, defined as ≥10% increase in weight from baseline, over 48 weeks. We used linear mixed-effects regression models, adjusted for demographic factors, to estimate weight gain and identify risk factors. RESULTS: Weight data were available for 428 participants in Uganda and 367 in South Africa. The mean weight change was 0.6 kg [95% CI: 0.1-1.0] in Uganda and 2.9 kg [2.3-3.4] in South Africa ( P  < 0.001). The mean change in waist circumference was 0.8 cm [95% CI: 0.0-1.5]) in Uganda and 2.3 cm [95% CI: 1.4-3.2] in South Africa ( P  = 0.012). Clinically significant weight gain occurred in 9.8% [7.0-12.6] of participants in Uganda and 18.0% [14.1-21.9] in South Africa ( P  < 0.001). After adjustment, PWH gained significantly less weight in Uganda than in South Africa. CONCLUSIONS: PWH in South Africa experienced significantly greater weight gain and increases in waist circumference compared to Uganda. Strategies to address weight gain in PWH should be carefully considered and may vary by region.

Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance.

In a subset of SARS-CoV-2 infected individuals treated with the oral antiviral nirmatrelvir-ritonavir, the virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used a mathematical model to describe the longitudinal viral load dynamics of 51 individuals treated with nirmatrelvir-ritonavir, 20 of whom rebounded. Target cell preservation, either by a robust innate immune response or initiation of nirmatrelvir-ritonavir near the time of symptom onset, coupled with incomplete viral clearance, appear to be the main factors leading to viral rebound. Moreover, the occurrence of viral rebound is likely influenced by time of treatment initiation relative to the progression of the infection, with earlier treatments leading to a higher chance of rebound. Finally, our model demonstrates that extending the course of nirmatrelvir-ritonavir treatment, in particular to a 10-day regimen, may greatly diminish the risk for rebound in people with mild-to-moderate COVID-19 and who are at high risk of progression to severe disease. Altogether, our results suggest that in some individuals, a standard 5-day course of nirmatrelvir-ritonavir starting around the time of symptom onset may not completely eliminate the virus. Thus, after treatment ends, the virus can rebound if an effective adaptive immune response has not fully developed. These findings on the role of target cell preservation and incomplete viral clearance also offer a possible explanation for viral rebounds following other antiviral treatments for SARS-CoV-2.

Emerging SARS-CoV-2 Resistance After Antiviral Treatment.

Importance: Previous studies have identified mutations in SARS-CoV-2 strains that confer resistance to nirmatrelvir, yet how often this resistance arises and its association with posttreatment virologic rebound is not well understood. Objective: To examine the prevalence of emergent antiviral resistance after nirmatrelvir treatment and its association with virologic rebound. Design, Setting, and Participants: This cohort study enrolled outpatient adults with acute COVID-19 infection from May 2021 to October 2023. Participants were divided into those who received antiviral therapy and those who did not. The study was conducted at a multicenter health care system in Boston, Massachusetts. Exposure: Treatment regimen, including none, nirmatrelvir, and remdesivir. Main Outcomes and Measures: The primary outcome was emergent SARS-CoV-2 antiviral resistance, defined as the detection of antiviral resistance mutations, which were not present at baseline, were previously associated with decreased antiviral efficacy, and emerged during or after completion of a participant's treatment. Next-generation sequencing was used to detect low frequency mutations down to 1% of the total viral population. Results: Overall, 156 participants (114 female [73.1%]; median [IQR] age, 56 [38-69] years) were included. Compared with 63 untreated individuals, the 79 who received nirmatrelvir were older and more commonly immunosuppressed. After sequencing viral RNA from participants' anterior nasal swabs, nirmatrelvir resistance mutations were detected in 9 individuals who received nirmatrelvir (11.4%) compared with 2 of those who did not (3.2%) (P = .09). Among the individuals treated with nirmatrelvir, those who were immunosuppressed had the highest frequency of resistance emergence (5 of 22 [22.7%]), significantly greater than untreated individuals (2 of 63 [3.1%]) (P = .01). Similar rates of nirmatrelvir resistance were found in those who had virologic rebound (3 of 23 [13.0%]) vs those who did not (6 of 56 [10.7%]) (P = .86). Most of these mutations (10 of 11 [90.9%]) were detected at low frequencies (<20% of viral population) and reverted to the wild type at subsequent time points. Emerging remdesivir resistance mutations were only detected in immunosuppressed individuals (2 of 14 [14.3%]) but were similarly low frequency and transient. Global Initiative on Sharing All Influenza Data analysis showed no evidence of increased nirmatrelvir resistance in the United States after the authorization of nirmatrelvir. Conclusions and Relevance: In this cohort study of 156 participants, treatment-emergent nirmatrelvir resistance mutations were commonly detected, especially in individuals who were immunosuppressed. However, these mutations were generally present at low frequencies and were transient in nature, suggesting a low risk for the spread of nirmatrelvir resistance in the community with the current variants and drug usage patterns.

SARS-CoV-2 viral clearance and evolution varies by type and severity of immunodeficiency.

Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the immune defects that predispose an individual to persistent coronavirus disease 2019 (COVID-19) remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants with COVID-19. The median times to nasal viral RNA and culture clearance in individuals with severe immunosuppression due to hematologic malignancy or transplant (S-HT) were 72 and 40 days, respectively, both of which were significantly longer than clearance rates in individuals with severe immunosuppression due to autoimmunity or B cell deficiency (S-A), individuals with nonsevere immunodeficiency, and nonimmunocompromised groups (P < 0.01). Participants who were severely immunocompromised had greater SARS-CoV-2 evolution and a higher risk of developing resistance against therapeutic monoclonal antibodies. Both S-HT and S-A participants had diminished SARS-CoV-2-specific humoral responses, whereas only the S-HT group had reduced T cell-mediated responses. This highlights the varied risk of persistent COVID-19 across distinct immunosuppressive conditions and suggests that suppression of both B and T cell responses results in the highest contributing risk of persistent infection.

Multiple cardiovascular risk factor care in 55 low- and middle-income countries: A cross-sectional analysis of nationally-representative, individual-level data from 280,783 adults.

The prevalence of multiple age-related cardiovascular disease (CVD) risk factors is high among individuals living in low- and middle-income countries. We described receipt of healthcare services for and management of hypertension and diabetes among individuals living with these conditions using individual-level data from 55 nationally representative population-based surveys (2009-2019) with measured blood pressure (BP) and diabetes biomarker. We restricted our analysis to non-pregnant individuals aged 40-69 years and defined three mutually exclusive groups (i.e., hypertension only, diabetes only, and both hypertension-diabetes) to compare individuals living with concurrent hypertension and diabetes to individuals with each condition separately. We included 90,086 individuals who lived with hypertension only, 11,975 with diabetes only, and 16,228 with hypertension-diabetes. We estimated the percentage of individuals who were aware of their diagnosis, used pharmacological therapy, or achieved appropriate hypertension and diabetes management. A greater percentage of individuals with hypertension-diabetes were fully diagnosed (64.1% [95% CI: 61.8-66.4]) than those with hypertension only (47.4% [45.3-49.6]) or diabetes only (46.7% [44.1-49.2]). Among the hypertension-diabetes group, pharmacological treatment was higher for individual conditions (38.3% [95% CI: 34.8-41.8] using antihypertensive and 42.3% [95% CI: 39.4-45.2] using glucose-lowering medications) than for both conditions jointly (24.6% [95% CI: 22.1-27.2]).The percentage of individuals achieving appropriate management was highest in the hypertension group (17.6% [16.4-18.8]), followed by diabetes (13.3% [10.7-15.8]) and hypertension-diabetes (6.6% [5.4-7.8]) groups. Although health systems in LMICs are reaching a larger share of individuals living with both hypertension and diabetes than those living with just one of these conditions, only seven percent achieved both BP and blood glucose treatment targets. Implementation of cost-effective population-level interventions that shift clinical care paradigm from disease-specific to comprehensive CVD care are urgently needed for all three groups, especially for those with multiple CVD risk factors.

SARS-CoV-2 virologic rebound with nirmatrelvir-ritonavir therapy.

Objective: To compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate the validity of symptoms to detect rebound and the incidence of emergent nirmatrelvir-resistance mutations after rebound. Design: Observational cohort study. Setting: Multicenter healthcare system in Boston, Massachusetts. Participants: We enrolled ambulatory adults with a positive COVID-19 test and/or a prescription for nirmatrelvir-ritonavir. Exposures: Receipt of 5 days of nirmatrelvir-ritonavir treatment versus no COVID-19 therapy. Main Outcome and Measures: The primary outcome was COVID-19 virologic rebound, defined as either (1) a positive SARS-CoV-2 viral culture following a prior negative culture or (2) two consecutive viral loads ≥4.0 log10 copies/milliliter after a prior reduction in viral load to <4.0 log10 copies/milliliter. Results: Compared with untreated individuals (n=55), those taking nirmatrelvir-ritonavir (n=72) were older, received more COVID-19 vaccinations, and were more commonly immunosuppressed. Fifteen individuals (20.8%) taking nirmatrelvir-ritonavir experienced virologic rebound versus one (1.8%) of the untreated (absolute difference 19.0% [95%CI 9.0-29.0%], P=0.001). In multivariable models, only N-R was associated with VR (AOR 10.02, 95%CI 1.13-88.74). VR occurred more commonly among those with earlier nirmatrelvir-ritonavir initiation (29.0%, 16.7% and 0% when initiated days 0, 1, and ≥2 after diagnosis, respectively, P=0.089). Among participants on N-R, those experiencing rebound had prolonged shedding of replication-competent virus compared to those that did not rebound (median: 14 vs 3 days). Only 8/16 with virologic rebound reported worsening symptoms (50%, 95%CI 25%-75%); 2 were completely asymptomatic. We detected no post-rebound nirmatrelvir-resistance mutations in the NSP5 protease gene. Conclusions and Relevance: Virologic rebound occurred in approximately one in five people taking nirmatrelvir-ritonavir and often occurred without worsening symptoms. Because it is associated with replication-competent viral shedding, close monitoring and potential isolation of those who rebound should be considered.

SARS-CoV-2 Viral Clearance and Evolution Varies by Extent of Immunodeficiency.

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. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants with COVID-19. 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<0.001). Participants who were severely immunocompromised had greater SARS-CoV-2 evolution and a higher risk of developing antiviral treatment resistance. Both S-HT and S-A participants had diminished SARS-CoV-2-specific humoral, while only the S-HT group had reduced T cell-mediated responses. This highlights the varied risk of persistent COVID-19 across immunosuppressive conditions and suggests that suppression of both B and T cell responses results in the highest contributing risk of persistent infection.