Clinical Infectious Diseases最新文献

Background: Few data are available on the real-world efficacy of receiving tenofovir-lamivudine-dolutegravir (-DTG) as human immunodeficiencyvirus (HIV) treatment, particularly among young people in West Africa. Here, we evaluated pharmaco-virological outcomes and resistance profiles among Togolese children and adolescents.

Methods: A cross-sectional study was conducted in Lomé, Togo, enrolling antiretroviral-treated people with HIV aged from 18 months to 24 years. Plasma HIV-1 viral load and antiretroviral concentrations were measured. Next-generation sequencing of protease, reverse transcriptase (RT), and integrase was performed on all samples with viral loads >200 copies/mL. Drug resistance mutations (DRMs) were identified and interpreted using the ANRS-MIE algorithm.

Results: 264 participants were enrolled (median age, 17 years); 226 received a DTG-based regimen for a median of 20.5 months. Among them, there was virological suppression at the 200-copies/mL threshold in 80.0% of the participants. Plasma DTG concentrations were adequate (ie, >640 ng/mL), suboptimal, and below the limit of quantification in 74.1%, 6.7%, and 19.2% of participants receiving DTG, respectively. Overall, viruses resistant to any of nucleoside RT inhibitors, non-NRTIs, and protease inhibitors were found in 52%, 66%, and 1.6% of participants, respectively. A major integrase inhibitor DRM was observed in 9.4% (n = 3/32; R263K, E138A-G140A-Q148R, and N155H) of participants with a viral load >200 copies/mL.

Conclusions: These first findings in a large series of adolescents in a low-income country showed a good virological response of 80% and the presence of an integrase DRM in 9.4% of virological failures, supporting the need to monitor DTG drug resistance to reduce the risk of resistance acquisition.

Background: Sepsis surveillance using electronic health record (EHR)-based data may provide more accurate epidemiologic estimates than administrative data, but experience with this approach to estimate population-level sepsis burden is lacking.

Methods: This was a retrospective cohort study including all adults admitted to publicly funded hospitals in Hong Kong between 2009 and 2018. Sepsis was defined as clinical evidence of presumed infection (clinical cultures and treatment with antibiotics) and concurrent acute organ dysfunction (≥2-point increase in baseline Sequential Organ Failure Assessment [SOFA] score). Trends in incidence, mortality, and case fatality risk (CFR) were modeled by exponential regression. Performance of the EHR-based definition was compared with 4 administrative definitions using 500 medical record reviews.

Results: Among 13 540 945 hospital episodes during the study period, 484 541 (3.6%) had sepsis by EHR-based criteria with 22.4% CFR. In 2018, age- and sex-adjusted standardized sepsis incidence was 756 per 100 000 (relative change: +2.8%/y [95% CI: 2.0%-3.7%] between 2009 and 2018) and standardized sepsis mortality was 156 per 100 000 (relative change: +1.9%/y; 95% CI: .9%-2.8%). Despite decreasing CFR (relative change: -0.5%/y; 95% CI: -1.0%, -.1%), sepsis accounted for an increasing proportion of all deaths (relative change: +3.9%/y; 95% CI: 2.9%-4.8%). Medical record reviews demonstrated that the EHR-based definition more accurately identified sepsis than administrative definitions (area under the curve [AUC]: .91 vs .52-.55; P < .001).

Conclusions: An objective EHR-based surveillance definition demonstrated an increase in population-level standardized sepsis incidence and mortality in Hong Kong between 2009 and 2018 and was much more accurate than administrative definitions. These findings demonstrate the feasibility and advantages of an EHR-based approach for widescale sepsis surveillance.

Background: People with human immunodeficiency virus (PWH) on first-line, nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy (ART) were routinely switched to tenofovir-lamivudine-dolutegravir. We examined virologic outcomes and drug resistance in ART programs in Malawi, where switching was irrespective of viral load, and Zambia, where switching depended on a viral load <1000 copies/mL in the past year.

Methods: We compared the risk of viremia (≥400 copies/mL) at 1 and 2 years by viral load at switch and between countries using exact methods and logistic regression adjusted for age and sex. We performed HIV-1 pol Sanger sequencing on plasma samples with viral load ≥1000 copies/mL.

Results: A total of 2832 PWH were eligible (Malawi 1422, Zambia 1410); the median age was 37 years, and 2578 (91.0%) were women. At switch, 77 (5.4%) were viremic in Malawi and 42 (3.0%) in Zambia (P = .001). Viremia at switch was associated with viremia at 1 year (adjusted odds ratio (OR), 6.15; 95% confidence interval [CI], 3.13-11.4) and 2 years (7.0; 95% CI, 3.73-12.6). Viremia was less likely in Zambia than in Malawi at 1 year (OR, 0.55; 0.32-0.94) and 2 years (OR, 0.33; 0.18-0.57). Integrase sequencing was successful for 79 of 113 eligible samples. Drug resistance mutations were found in 5 PWH (Malawi 4, Zambia 1); 2 had major mutations (G118R, E138K, T66A and G118R, E138K) leading to high-level dolutegravir resistance.

Conclusions: Restricting switching to dolutegravir-based ART to PWH with a viral load <1000 copies/mL may reduce subsequent viremia and, consequently, the emergence of dolutegravir drug resistance mutations.

Clinical trials registration: Clinicaltrials.gov (NCT04612452).

Background: Cryptococcal meningitis is a leading cause of AIDS-related mortality. Cryptococcal antigen (CrAg) predicts the development of meningitis. Historically, despite standard- of-care fluconazole, 25%-30% of asymptomatic CrAg-positive persons develop breakthrough meningitis or death. We evaluated whether adding single high-dose liposomal amphotericin B to standard pre-emptive fluconazole therapy could improve meningitis-free survival.

Methods: Participants with human immunodeficiency virus (HIV) and asymptomatic cryptococcal antigenemia in Uganda were randomized to liposomal amphotericin B (10 mg/kg once) with fluconazole or fluconazole alone through 24 weeks. We compared 24-week, meningitis-free survival time between treatment groups. After the second interim review, the Data Safety and Monitoring Board recommended no further enrollment of participants with low plasma CrAg lateral flow assay titers (≤1:80) due to futility. Herein, we present the results of participants with low plasma CrAg titers.

Results: 168 participants enrolled into the ACACIA trial had low plasma CrAg titers (≤1:80). During 24 weeks of follow-up, meningitis or death occurred in 14.5% (12/83) of participants randomized to liposomal amphotericin B with fluconazole versus 10.6% (9/85) assigned to fluconazole alone (hazard ratio, 1.42; 95% CI, .60-3.36; P = .431). Adverse events were more frequent in participants assigned to the intervention versus standard-of-care (28% vs 12%; P = .011).

Conclusions: Among CrAg-positive persons with low titers (≤1:80), the addition of single-dose liposomal amphotericin B to fluconazole as pre-emptive therapy provided no additional clinical benefit. This trial provides supportive evidence that, in asymptomatic populations with low plasma CrAg titers, lumbar punctures are likely unnecessary as administration of meningitis treatment did not improve outcomes.

Clinical trials registration: Clinicaltrials.gov (NCT03945448).

Background: The aim of this study was to evaluate the safety and efficacy of fecal microbiota, live-jslm (RBL; REBYOTA)-the first single-dose, broad consortia microbiota-based live biotherapeutic approved by the US Food and Drug Administration for preventing recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care (SOC) antibiotic treatment.

Methods: PUNCH CD3-OLS was a prospective, phase 3, open-label study, conducted across the US and Canada. Participants were aged ≥18 years with documented rCDI and confirmed use of SOC antibiotics. Participants with comorbidities including inflammatory bowel disease and mild-to-moderate immunocompromising conditions could be enrolled. A single dose of RBL was rectally administered within 24-72 hours of antibiotic completion. The primary endpoint was the number of participants with RBL- or administration-related treatment-emergent adverse events (TEAEs). Secondary endpoints included treatment success and sustained clinical response, at 8 weeks and 6 months after RBL administration, respectively.

Results: Overall, 793 participants were enrolled, of whom 697 received RBL. TEAEs through 8 weeks after administration were reported by 47.3% of participants; most events were mild or moderate gastrointestinal disorders. Serious TEAEs were reported by 3.9% of participants. The treatment success rate at 8 weeks was 73.8%; in participants who achieved treatment success, the sustained clinical response rate at 6 months was 91.0%. Safety and efficacy rates were similar across demographic and baseline characteristic subgroups.

Conclusions: RBL was safe and efficacious in participants with rCDI and common comorbidities. This is the largest microbiota-based live biotherapeutic study to date, and findings support use of RBL to prevent rCDI in a broad patient population.

Clinical trials registration: NCT03931941.

Background: Incidence estimates of post-acute sequelae of SARS-CoV-2 infection, also known as long-COVID, have varied across studies and changed over time. We estimated long-COVID incidence among adult and pediatric populations in three nationwide research networks of electronic health records (EHR) participating in the RECOVER Initiative using different classification algorithms (computable phenotypes).

Methods: This EHR-based retrospective cohort study included adult and pediatric patients with documented acute SARS-CoV-2 infection and two control groups-- contemporary COVID-19 negative and historical patients (2019). We examined the proportion of individuals identified as having symptoms or conditions consistent with probable long-COVID within 30-180 days after COVID-19 infection (incidence proportion). Each network (the National COVID Cohort Collaborative (N3C), National Patient-Centered Clinical Research Network (PCORnet), and PEDSnet) implemented its own long-COVID definition. We introduced a harmonized definition for adults in a supplementary analysis.

Results: Overall, 4% of children and 10-26% of adults developed long-COVID, depending on computable phenotype used. Excess incidence among SARS-CoV-2 patients was 1.5% in children and ranged from 5-6% among adults, representing a lower-bound incidence estimation based on our control groups. Temporal patterns were consistent across networks, with peaks associated with introduction of new viral variants.

Conclusion: Our findings indicate that preventing and mitigating long-COVID remains a public health priority. Examining temporal patterns and risk factors of long-COVID incidence informs our understanding of etiology and can improve prevention and management.

Background: Little is known about antibiotic prescribing for respiratory tract infections (RTIs) in virtual versus in-person urgent care.

Methods: In this retrospective study, we used electronic health record data from Cleveland Clinic Health System. We identified RTI patients via International Classification of Diseases, Tenth Revision, Clinical Modification, codes and assessed whether the visit resulted in an antibiotic. We described differences in diagnoses and prescribing by setting (virtual versus in-person). We used mixed effects logistic regression to model the odds of antibiotic receipt by urgent care setting. We applied the model first to all physicians and second only to those who saw patients in both settings.

Results: There were 69 189 in-person and 19 003 virtual visits. Fifty-eight percent of virtual visits resulted in an antibiotic compared with 43% of in-person visits. Sinusitis diagnoses were more than twice as common in virtual versus in-person care (36% vs 14%) and were associated with high rates of prescribing in both settings (95% in-person, 91% virtual). Compared with in-person care, virtual urgent care was positively associated with a prescription (odds ratio, 1.64; 95% confidence interval [CI]: 1.53-1.75). Among visits conducted by 39 physicians who saw patients in both settings, odds of antibiotic prescription in virtual care were 1.71 times higher than in in-person care (95% CI: 1.53-1.90).

Conclusions: Antibiotic prescriptions were more common in virtual versus in-person urgent care, including among physicians who provided care in both platforms. This appears to be related to the high rate of sinusitis diagnosis in virtual urgent care.

Background: Our study addresses the sepsis research gap in lower- and middle-income countries, notably India. Here, we investigate community-acquired sepsis comprehensively and explore the impact of tropical microbiology on etiology and outcomes.

Methods: MARS-India was a prospective observational study from December 2018 to September 2022 in a tertiary-care hospital in South India. Adult patients within 24 hours of intensive care unit (ICU) admission meeting the Sepsis-3 definition were enrolled, with 6 months of follow-up.

Results: More than 4000 patients were screened on ICU admission, with 1000 unique patients meeting the inclusion criteria. Median age was 55 (interquartile range, 44-65) years, with a male preponderance (66%). Almost half the cohort resided in villages (46.5%) and 74.6% worked in the primary sector. Mortality in-hospital was 24.1%. Overall, about 54% had confirmed microbiological diagnosis and >18% had a viral cause of sepsis. Surprisingly, we identified leptospirosis (10.6%), scrub typhus (4.1%), dengue (3.7%), and Kyasanur forest disease (1.6%) as notable causes of sepsis. All of these infections showed seasonal variation around the monsoon. In community-acquired infections, we observed substantial resistance to third-generation cephalosporins and carbapenems.

Conclusions: In India, sepsis disproportionally affects a younger and lower-socioeconomic demographic, yielding high mortality. Tropical and viral sepsis carry a significant burden. Analyzing local data, we pinpoint priorities for public health and resources, offering valuable insights for global sepsis research. Clinical Trials Registration. NCT03727243.