Clinical Infectious Diseases最新文献

Background: PAXLOVID consists of nirmatrelvir, an inhibitor of SARS-CoV-2 main protease (Mpro), copackaged with ritonavir, a pharmacokinetic enhancer. Nirmatrelvir/ritonavir received emergency use authorization in the United States in 2021 and was approved in 2023. However, there is limited published information on SARS-CoV-2 clinical resistance to nirmatrelvir/ritonavir.

Methods: To investigate SARS-CoV-2 resistance development to nirmatrelvir/ritonavir in treated patients, we analyzed baseline and matching post-baseline SARS-CoV-2 next-generation sequencing data from 1,862 participants (912 nirmatrelvir/ritonavir, 950 placebo) in EPIC-HR and EPIC-SR, which were Phase 2/3, randomized, double-blind, placebo-controlled trials in participants with mild-to-moderate COVID-19. Potential resistance-associated substitutions (RAS) were defined as those that were enriched in nirmatrelvir/ritonavir-treated participants or occurred at Mpro positions of interest, defined using nonclinical data. SARS-CoV-2 sequence databases were analyzed to characterize temporal frequencies of nirmatrelvir/ritonavir RAS in circulating viruses.

Results: In EPIC-HR, nirmatrelvir/ritonavir RAS included Mpro T21I (n=1), E166V (n=3), A173T (n=1), and T304I (n=1), with E166V being the clearest RAS observed. In EPIC-SR, no RAS were detected. Nirmatrelvir/ritonavir RAS were not associated with hospitalization or death. Analyses of SARS-CoV-2 sequence databases did not reveal concerning increases in the frequencies of nirmatrelvir/ritonavir RAS over time.

Conclusions: In clinical trials, emergence of SARS-CoV-2 resistance to nirmatrelvir/ritonavir was infrequent (<0.3%-1.1%). Surveillance data currently indicate a low frequency of circulating SARS-CoV-2 variants with nirmatrelvir/ritonavir RAS. Collectively, these results provide the most comprehensive analysis of SARS-CoV-2 resistance to nirmatrelvir/ritonavir in the clinical setting to date. Viral sequences should continue to be closely monitored to identify the potential emergence of nirmatrelvir/ritonavir-resistant variants.

Background: Treatment of hepatitis C virus (HCV) during pregnancy can cure maternal HCV and prevent perinatal HCV transmission. The primary objective was to compare the pharmacokinetics (PK) of sofosbuvir/velpatasvir (SOF/VEL) in pregnant versus nonpregnant people.

Methods: Pregnant people with chronic HCV infection were enrolled between 23-25 weeks' gestation and were provided SOF/VEL daily for 12 weeks. PK visits were performed at 3, 6 and 9 weeks. VEL, SOF and GS-331007 (the inactive metabolite of SOF) in plasma and the SOF active metabolite (007-TP) in peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) were measured and compared to historical data in non-pregnant people. Maternal adverse events, delivery outcomes, the sustained virologic response 12 weeks after therapy (SVR12), infant adverse events and HCV perinatal transmission were assessed.

Results: Fourteen participants were screened, and 11 enrolled. One participant discontinued treatment due to worsening of hyperemesis. VEL area under the curve (AUC) was similar to historic data in non-pregnant people, but the AUCs of SOF and GS-331007 were 38% higher and 38% lower, respectively. Concentrations of 007-TP in PBMCs were comparable or higher, whereas 007-TP in DBS were ∼50% lower in pregnancy vs. non-pregnant people. All 10 participants who completed treatment had undetectable HCV RNA at delivery. Two participants were lost to follow-up after delivery, but one had an HCV RNA through clinical care. All participants with data were cured (N=9) and none of the infants acquired HCV (N=8).

Conclusions: SOF/VEL exposures were not clinically different in pregnancy and support further evaluation of antenatal SOF/VEL treatment.

Funding: This study was supported by the NIH (R21HD101996), NIH/OWHR (K12HD043441), and Gilead Sciences (IN-US-342-5634).

Background: Hepatitis C virus (HCV) reinfection rates are substantially higher than primary infection rates among men who have sex with men (MSM) with human immunodeficiency virus (HIV) in European cohorts. The behaviors mediating this high rate of transmission among MSM are poorly characterized.

Methods: We performed a prospective cohort study in New York City (NYC) of MSM with HIV who cleared HCV to determine the incidence of and risk factors for HCV reinfection. We assessed the risk behaviors for primary HCV in NYC: receipt of semen in the rectum, and sexualized methamphetamine use, along with route of use. Multivariable analysis was performed with Andersen-Gill extension of the Cox proportional hazards model.

Results: From 2000 through 2018, among 304 MSM with HIV who cleared HCV, 42 reinfections occurred over 898 person-years, for an incidence rate of 4.7 per 100 person-years. Assessing 1245 postclearance visits, only receipt of semen into the rectum was associated with reinfection (hazard ratio, 9.7 [95% confidence interval: 3.3-28.3], P < .001); methamphetamine use was not.

Conclusions: The high HCV reinfection rate over almost 2 decades demonstrates that sexual transmission of HCV is not inefficient or unusual and that direct-acting antiviral treatment is not sufficient for HCV elimination among MSM in NYC. The contrasts between both the rates of and risk factors for primary and HCV reinfection suggest that HCV prevalence is highly heterogenous among sexual networks and that sexualized methamphetamine use, rather than mediating transmission, is instead a surrogate marker for the highest HCV prevalence networks. As neither condoms nor treatment have been successful strategies for HCV prevention in NYC, novel interventions are needed to stem this sexually transmitted HCV epidemic.

Background: Limited data exist on the effects of intrapartum azithromycin on the prevalence of carriage and antibiotic resistance of Enterobacterales.

Methods: We conducted a randomized trial in The Gambia and Burkina Faso where women received intrapartum azithromycin (2 g) or placebo. We determined the impact of treatment on the prevalence of carriage and antibiotic resistance of Escherichia coli and Klebsiella pneumoniae by analyzing rectal swabs (RS), nasopharyngeal swabs (NPS), breast milk, and rectovaginal swabs (RVS). Bacteria were isolated microbiologically; antibiotic susceptibility was confirmed with an E-test. Prevalence ratios (PRs) with 95% confidence intervals (CIs) were used for comparison between arms.

Results: In infants, E. coli carriage in RS was lower in the intervention than in the placebo arm at day 6 (63.0% vs 75.2%; PR, 0.84; 95% CI, .75-.95) and day 28 (52.7% vs 70.4%; 0.75; 0.64-0.87) post-intervention. Prevalence of azithromycin-resistant E. coli was higher in the azithromycin arm at day 6 (13.4% vs 3.6%; 3.75; 1.83-7.69) and day 28 (16.4% vs 9.6%; 1.71; 1.05-2.79). For K. pneumoniae, carriage in RS was higher in the intervention than in the placebo arm at day 6 (49.6% vs 37.2%, 1.33; 1.08-1.64) and day 28 (53.6% vs 32.9%, 1.63; 1.31-2.03). Prevalence of azithromycin-resistant K. pneumoniae was higher in the azithromycin arm at day 28 (7.3% vs 2.1%; 3.49; 1.30-9.37). No differences were observed for other sample types.

Conclusions: Intrapartum azithromycin decreased E. coli carriage but increased both K. pneumoniae carriage and azithromycin resistance in both bacteria. These data need to be considered together with efficacy results to balance the potential short- and long-term impact of the intervention. Clinical Trials Registration.  www.clinicaltrials.gov: NCT03199547.

Background: The advent of short-course, curative treatment with direct-acting antivirals (DAA) has given promise for the global elimination of hepatitis C virus (HCV) infections by 2030. Virological failure occurs in 2%-12% of persons receiving curative DAA treatment and may be presaged by pre-existing polymorphisms or result from selection of drug resistant variants during therapy.

Methods: We conducted a systematic review to assess the prevalence of HCV resistance associated substitutions (RAS) among individuals with chronic hepatitis C infection who had virological failure following initial or re-treatment with pan-genotypic DAA regimens. We included 34 and 22 studies assessing RAS in people with virological failure published between January 2014 and July 2023. Pooled RAS prevalence was estimated using random-effects meta-analysis.

Results: The pooled prevalence of RAS in people with virological failure following initial DAA treatment was 78.0% (95% confidence interval [CI]: 62.0-92.0) for sofosbuvir/velpatasvir, 81.0% (95% CI: 67.0-93.0) for sofosbuvir/daclatasvir, and 79.0% (95% CI: 70.0-87.0) for glecaprevir/pibrentasvir, with a high prevalence of resistance to the NS5A inhibitors. Among those with virological failure following re-treatment regimens, RAS were present in 93.0% (95% CI: 83.0-99.0) for sofosbuvir/velpatasvir/voxilepravir and in 100% (95% CI: 92.0-100) for glecaprevir/pibrentasvir, with resistance driven by RAS to NS5A inhibitors.

Discussion: At least 1 RAS is present in a high proportion of the few individuals with virological failure following initial or re-treatment with pan-genotypic DAA regimens. There is a need for ongoing surveillance for DAA-associated resistance, to assess risk factors for their development and clinical impact to inform best practice strategies for re-treatment.

Navigating the combined adult and pediatric infectious disease (ID) fellowship application, interview, and matching process requires careful consideration from applicants and programs alike. Currently, it is functional but not streamlined, and as the ID community is facing recruitment and workforce challenges, it is important to be transparent about this process for applicants while emphasizing areas of potential improvement for fellowship programs. As it stands, this process requires foresight from the applicant and coordination between the adult and pediatric fellowship programs. This perspective article provides an anecdote and discusses issues and suggestions for troubleshooting, including, but not limited to: strategic approach to applications, interviews, and ranking; mentorship; geographic preference; and program saturation.