Last data update: Jun 03, 2024. (Total: 46935 publications since 2009)
Records 1-30 (of 41 Records) |
Query Trace: Sizemore E [original query] |
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Pharmacokinetic-pharmacodynamic evidence from a phase 3 trial to support flat-dosing of rifampicin for tuberculosis
Ngo HX , Xu AY , Velásquez GE , Zhang N , Chang VK , Kurbatova EV , Whitworth WC , Sizemore E , Bryant K , Carr W , Weiner M , Dooley KE , Engle M , Dorman SE , Nahid P , Swindells S , Chaisson RE , Nsubuga P , Lourens M , Dawson R , Savic RM . Clin Infect Dis 2024 BACKGROUND: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the Phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. METHODS: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months, TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models, and all trial-defined safety outcomes using logistic regression. RESULTS: Our model derived rifampicin exposure ranged from 4.57 mg·h/L to 140.0 mg·h/L with a median of 41.8 mg·h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to weight-banded dose. Exposure-efficacy analysis (N=680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared to those with exposure above the median. Exposure-safety analysis (N=722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events, or serious adverse events. CONCLUSIONS: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard of care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation. |
Pregnancy and infant outcomes following SARS-CoV-2 infection in pregnancy during Delta variant predominance - surveillance for emerging threats to pregnant people and infants: Pregnancy and infant outcomes during SARS-CoV-2 Delta variant predominance
Reeves EL , Neelam V , Carlson JM , Olsen EO , Fox CJ , Woodworth KR , Nestoridi E , Mobley E , Montero Castro S , Dzimira P , Sokale A , Sizemore L , Hall AJ , Ellington S , Cohn A , Gilboa SM , Tong VT . Am J Obstet Gynecol MFM 2023 6 (2) 101265 BACKGROUND: SARS-CoV-2 infection in pregnancy is associated with an increased risk of adverse birth outcomes such as preterm birth, stillbirth, and maternal and infant complications. Previous research suggests an increased risk of severe COVID-19 illness and stillbirth in pregnant people during delta variant predominance in 2021; however, those studies did not assess timing of infection during pregnancy, and few of them described COVID-19 vaccination status. OBJECTIVE: Using a large population-based cohort, this study compared pregnancy and infant outcomes and described demographic and clinical characteristics of pregnant people with SARS-CoV-2 infection prior to and during the delta variant period. STUDY DESIGN: This retrospective cohort analysis included persons with confirmed SARS-CoV-2 infection in pregnancy from 6 US jurisdictions reporting to the Surveillance for Emerging Threats to Pregnant People and Infants Network. Data were collected through case reports of polymerase chain reaction-positive pregnant persons and linkages to birth certificates, fetal death records, and immunization records. We described clinical characteristics and compared frequency of spontaneous abortion (<20 weeks of gestation), stillbirth (≥20 weeks), preterm birth (<37 weeks), small for gestational age, and term infant neonatal intensive care unit admission between the time periods of pre-delta and delta variant predominance. Study time periods were determined by when variants constituted more than 50% of sequences isolated according to regional SARS-CoV-2 genomic surveillance data, with time periods defined for pre-delta (March 3, 2020-June 25, 2021) and Delta (June 26, 2021-December 25, 2021). Adjusted prevalence ratios were estimated for each outcome measure using Poisson regression and were adjusted for continuous maternal age, race and ethnicity, and insurance status at delivery. RESULTS: Among 57,563 pregnancy outcomes, 57,188 (99.3%) were liveborn infants, 65 (0.1%) were spontaneous abortions, and 310 (0.5%) were stillbirths. Most pregnant persons were unvaccinated at the time of SARS-CoV-2 infection, with a higher proportion in pre-delta (99.4%) than in the delta period (78.4%). Of those with infections during delta and who were previously vaccinated, the timing from last vaccination to infection was a median of 183 days. Compared to pre-delta, infections during delta were associated with a higher frequency of stillbirths (0.7% vs 0.4%; adjusted prevalence ratio, 1.55; 95% confidence interval, 1.14-2.09) and preterm births (12.8% vs 11.9%; adjusted prevalence ratio, 1.14; 95% confidence interval, 1.07-1.20). The delta period was associated with a lower frequency of neonatal intensive care unit admission (adjusted prevalence ratio, 0.74; 95% confidence interval, 0.67-0.82) than in the pre-delta period. During the delta period, infection during the third trimester was associated with a higher frequency of preterm birth (adjusted prevalence ratio, 1.41; 95% confidence interval, 1.28-1.56) and neonatal intensive care unit admission (adjusted prevalence ratio, 1.21; 95% confidence interval, 1.01-1.45) compared to the first and second trimester combined. CONCLUSION: In this US-based cohort of persons with SARS-CoV-2 infection in pregnancy, the majority were unvaccinated, and frequencies of stillbirth and preterm birth were higher during the delta variant predominance period than in the pre-delta period. During the delta period, frequency of preterm birth and neonatal intensive care unit admission was higher among infections occurring in the third trimester vs those earlier in pregnancy. These findings demonstrate population-level increases of adverse fetal and infant outcomes, specifically in the presence of a COVID-19 variant with more severe presentation. |
Frequency of children diagnosed with perinatal hepatitis C, United States, 2018-2020
Newton SM , Woodworth KR , Chang D , Sizemore L , Wingate H , Pinckney L , Osinski A , Orkis L , Reynolds BD , Carpentieri C , Halai UA , Lyu C , Longcore N , Thomas N , Wills A , Akosa A , Olsen EO , Panagiotakopoulos L , Thompson ND , Gilboa SM , Tong VT . Emerg Infect Dis 2024 30 (1) 202-204 We describe hepatitis C testing of 47 (2%) of 2,266 children diagnosed with perinatal hepatitis C who were exposed during 2018-2020 in 7 jurisdictions in the United States. Expected frequency of perinatal transmission is 5.8%, indicating only one third of the cases in this cohort were reported to public health authorities. |
Completion, safety, and efficacy of tuberculosis preventive treatment regimens containing rifampicin or rifapentine: an individual patient data network meta-analysis
Winters N , Belknap R , Benedetti A , Borisov A , Campbell JR , Chaisson RE , Chan PC , Martinson N , Nahid P , Scott NA , Sizemore E , Sterling TR , Villarino ME , Wang JY , Menzies D . Lancet Respir Med 2023 11 (9) 782-790 BACKGROUND: 3 months of weekly rifapentine plus isoniazid (3HP) and 4 months of daily rifampicin (4R) are recommended for tuberculosis preventive treatment. As these regimens have not been compared directly, we used individual patient data and network meta-analysis methods to compare completion, safety, and efficacy between 3HP and 4R. METHODS: We conducted a network meta-analysis of individual patient data by searching PubMed for randomised controlled trials (RCTs) published between Jan 1, 2000, and Mar 1, 2019. Eligible studies compared 3HP or 4R to 6 months or 9 months of isoniazid and reported treatment completion, adverse events, or incidence of tuberculosis disease. Deidentified individual patient data from eligible studies were provided by study investigators and outcomes were harmonised. Methods for network meta-analysis were used to generate indirect adjusted risk ratios (aRRs) and risk differences (aRDs) with their 95% CIs. FINDINGS: We included 17 572 participants from 14 countries in six trials. In the network meta-analysis, treatment completion was higher for people on 3HP than for those on 4R (aRR 1·06 [95% CI 1·02-1·10]; aRD 0·05 [95% CI 0·02-0·07]). For treatment-related adverse events leading to drug discontinuation, risks were higher for 3HP than for 4R for adverse events of any severity (aRR 2·86 [2·12-4·21]; aRD 0·03 [0·02-0·05]) and for grade 3-4 adverse events (aRR 3·46 [2·09-6·17]; aRD 0·02 [0·01-0·03]). Similar increased risks with 3HP were observed with other definitions of adverse events and were consistent across age groups. No difference in the incidence of tuberculosis disease between 3HP and 4R was found. INTERPRETATION: In the absence of RCTs, our individual patient data network meta-analysis indicates that 3HP provided an increase in treatment completion over 4R, but was associated with a higher risk of adverse events. Although findings should be confirmed, the trade-off between completion and safety must be considered when selecting a regimen for tuberculosis preventive treatment. FUNDING: None. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section. |
Development of a standardized, laboratory result-based hepatitis C virus clearance cascade for public health jurisdictions
Montgomery MP , Sizemore L , Wingate H , Thompson WW , Teshale E , Osinubi A , Doshani M , Nelson N , Gupta N , Wester C . Public Health Rep 2023 333549231170044 During 2013-2016, an estimated 2.4 million people in the United States were living with hepatitis C virus (HCV) infection.1 With the availability of curative treatment since 2013, the United States has established a goal of eliminating hepatitis C as a public health threat by 2030.2 HCV clearance cascades (hereinafter, HCV cascades) are an important tool to track progress toward elimination, across jurisdictions and at a national level, and to identify disparities in access to testing and treatment. HCV cascades are a sequence of steps that follow progression from testing and treatment to clearance and subsequent infection and can be used to inform public health interventions to facilitate progression along the cascade. | Many HCV cascades are developed in a single or regional health system in which both treatment and laboratory data are available. However, an important goal for health departments is to develop population-level cascades that capture data on HCV infection status for all people living in a jurisdiction who might seek care across various health settings. In the absence of treatment information, which is not always readily available in health department surveillance systems, HCV laboratory results can be used to develop HCV cascades. Here, we describe a standardized, laboratory result–based HCV cascade developed by the Centers for Disease Control and Prevention (CDC) as a guide for health departments (Figure 1, Supplemental Material). |
A standardized approach for collection of objective data to support outcome determination for late-phase TB trials
Kurbatova EV , Phillips PP , Dorman SE , Sizemore EE , Bryant KE , Purfield AE , Ricaldi J , Brown NE , Johnson JL , Wallis CL , Akol JP , Ocheretina O , Van Hung N , Mayanja-Kizza H , Lourens M , Dawson R , Nhung NV , Pierre S , Musodza Y , Shenje J , Badal-Faesen S , Vilbrun SC , Waja Z , Peddareddy L , Scott NA , Yuan Y , Vernon A , Goldberg SV , Swindells S , Chaisson RE , Nahid P . Am J Respir Crit Care Med 2023 207 (10) 1376-1382 INTRODUCTION: We developed a standardized method, "Possible poor treatment response" (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary TB. We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcome for all participants were achieved. METHODS/DESIGN: A PPTR event was defined as the occurrence of one or more pre-specified triggers. Each PPTR required initiation of a standardized evaluation process that included obtaining multiple sputum samples for microbiology. RESULTS: Among 2,343 participants with culture-confirmed drug-susceptible TB, 454 individuals (19.4%) had a total of 534 individual PPTR events, of which 76.6% were microbiological (positive smear or culture at or after 17 weeks). At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome, and between 13.8 and 14.7% of participants with favorable and not assessable outcomes. 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve disease-free cure. DISCUSSION: Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT02410772. |
Sara Alert: An automated symptom monitoring tool for COVID-19 in 11 jurisdictions in the United States, June - August, 2021.
Bezold C , Sizemore E , Halter H , Bartlett D , Hay K , Ali H . Online J Public Health Inform 2022 14 (1) e7 OBJECTIVES: Health department personnel conduct daily active symptom monitoring for persons potentially exposed to SARS-CoV-2. This can be resource-intensive. Automation and digital tools can improve efficiency. We describe use of a digital tool, Sara Alert, for automated daily symptom monitoring across multiple public health jurisdictions. METHODS: Eleven of the 20 U.S. public health jurisdictions using Sara Alert provided average daily activity data during June 29 to August 30, 2021. Data elements included demographics, communication preferences, timeliness of symptom monitoring initiation, responsiveness to daily messages, and reports of symptoms. RESULTS: Participating jurisdictions served a U.S. population of over 22 million persons. Health department personnel used this digital tool to monitor more than 12,000 persons per day on average for COVID-19 symptoms. On average, monitoring began 3.9 days following last exposure and was conducted for an average of 5.7 days. Monitored persons were frequently < 18 years old (45%, 5,474/12,450) and preferred communication via text message (47%). Seventy-four percent of monitored persons responded to at least one daily automated symptom message. CONCLUSIONS: In our geographically diverse sample, we found that use of an automated digital tool might improve public health capacity for daily symptom monitoring, allowing staff to focus their time on interventions for persons most at risk or in need of support. Future work should include identifying jurisdictional successes and challenges implementing digital tools; the effectiveness of digital tools in identifying symptomatic individuals, ensuring appropriate isolation, and testing to disrupt transmission; and impact on public health staff efficiency and program costs. |
Timing of positive hepatitis C virus test results during and 1 year before pregnancy
Woodworth KR , Newton SM , Olsen EO , Tannis A , Sizemore L , Wingate H , Orkis L , Reynolds B , Longcore N , Thomas N , Bocour A , Wills A , Kim SY , Panagiotakopoulos L , Wester C , Delman Meaney D , Gilboa SM , Tong VT . Obstet Gynecol 2022 140 (6) 997-999 The incidence of hepatitis C virus (HCV) infection in reproductive-aged adults quadrupled during the past decade. Hepatitis C can progress to advanced liver disease and be transmitted perinatally. Highly effective curative hepatitis C treatment is available but is not recommended in pregnancy. Using the Surveillance for Emerging Threats to Mothers and Babies Network, we describe timing of positive RNA testing among pregnant people with HCV (HCV RNA detected during or within one year prior to pregnancy). Four US jurisdictions reported 1161 pregnancies during 2018-2021 among people with hepatitis C: 75.9% were multiparous; and 21.4% had their first peri-pregnancy HCV RNA detected prior to pregnancy, indicating potential missed treatment opportunities to improve maternal health and prevent perinatal transmission. |
Six-Month Outcomes of Infants Born to People With SARS-CoV-2 in Pregnancy.
Gosdin L , Wallace B , Lanzieri TM , Olsen EO , Lewis EL , Chang DJ , Khuwaja S , Chicchelly S , Ojo KD , Lush M , Heitner D , Longcore ND , Delgado-López C , Humphries BK , Sizemore L , Mbotha D , Hall AJ , Ellington S , Gilboa SM , Tong VT , Woodworth K . Pediatrics 2022 150 (6) OBJECTIVES: To assess the 6-month incidence of laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, postnatal care, hospitalization, and mortality among infants born to people with laboratory-confirmed SARS-CoV-2 infection during pregnancy by timing of maternal infection. METHODS: Using a cohort of liveborn infants from pregnancies with SARS-CoV-2 infections in the year 2020 from 10 United States jurisdictions in the Surveillance for Emerging Threats to Mother and Babies Network, we describe weighted estimates of infant outcomes from birth through 6 months of age from electronic health and laboratory records. RESULTS: Of 6601 exposed infants with laboratory information through 6 months of age, 1.0% (95% confidence interval: 0.8-1.1) tested positive, 19.1% (17.5-20.6) tested negative, and 80.0% (78.4-81.6) were not known to be tested for SARS-CoV-2. Among those ≤14 days of age, SARS-CoV-2 infection occurred only with maternal infection ≤14 days before delivery. Of 3967 infants with medical record abstraction, breastmilk feeding initiation was lower when maternal infection occurred ≤14 days before delivery compared with >14 days (77.6% [72.5-82.6] versus 88.3% [84.7-92.0]). Six-month all-cause hospitalization was 4.1% (2.0-6.2). All-cause mortality was higher among infants born to people with infection ≤14 days (1.0% [0.4-1.6]) than >14 days (0.3% [0.1-0.5]) before delivery. CONCLUSIONS: Results are reassuring, with low incidences of most health outcomes examined. Incidence of infant SARS-CoV-2, breastmilk feeding initiation, and all-cause mortality differed by timing of maternal infection. Strategies to prevent infections and support pregnant people with coronavirus disease 2019 may improve infant outcomes. |
Breast Milk Feeding of Infants at Birth Among People With Confirmed SARS-CoV-2 Infection in Pregnancy: SET-NET, 5 States, March 29, 2020-December 31, 2020.
Lewis EL , Smoots AN , Woodworth KR , Olsen EO , Roth NM , Yazdy M , Shephard H , Sizemore L , Wingate H , Dzimira P , Reynolds B , Lush M , Fuchs EL , Ojo K , Siebman S , Hall AJ , Azziz-Baumgartner E , Perrine C , Hsia J , Ellington S , Tong VT , Gilboa SM . Am J Public Health 2022 112 S787-s796 Objectives. To describe prevalence of breast milk feeding among people with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and examine associations between breast milk feeding, timing of maternal infection before delivery, and rooming-in status during delivery hospitalization. Methods. We performed a retrospective cohort study using data from Massachusetts, Minnesota, Nebraska, Pennsylvania, and Tennessee of whether people with confirmed SARS-CoV-2 infection during pregnancy in 2020 initiated breast milk feeding at birth. Results. Among 11114 (weighted number) people with SARS-CoV-2 infection in pregnancy, 86.5% (95% confidence interval [CI]=82.4%, 87.6%) initiated breast milk feeding during birth hospitalization. People with infection within 14 days before delivery had significantly lower prevalence of breast milk feeding (adjusted prevalence ratio [APR]=0.88; 95% CI=0.83, 0.94) than did those with infection at least 14 days before delivery. When stratified by rooming-in status, the association between timing of infection and breast milk feeding remained only among infants who did not room in with their mother (APR=0.77; 95% CI=0.68, 0.88). Conclusions. Pregnant and postpartum people with SARS-CoV-2 infection should have access to lactation support and be advised about the importance of breast milk feeding and how to safely feed their infants in the same room. (Am J Public Health. 2022;112(S8):S787-S796. https://doi.org/10.2105/AJPH.2022.307023). |
Innovative Approaches to COVID-19 Case Investigation and Contact Tracing.
Haddad MB , McLean JE , Feldman SS , Sizemore EE , Taylor MM . Public Health Rep 2022 137 333549221120454 Until COVID-19, the greatest national public health crisis was the 1918 influenza pandemic, which was covered extensively by Public Health Reports.1 -6 Extrapolating from their knowledge of tuberculosis, public health authorities at that time exhorted ill people to remain home to break the chain of respiratory transmission. 7 Other contemporaneous appeals that reverberate a century later include “avoid needless crowding,” “stay in the open air,” “wear a gauze mask over the nose and mouth,” and “keep away from houses where there are influenza cases.” 2 |
Rifapentine with and without moxifloxacin for pulmonary tuberculosis in people with HIV (S31/A5349)
Pettit AC , Phillips PP , Kurbatova E , Vernon A , Nahid P , Dawson R , Dooley KE , Sanne I , Waja Z , Mohapi L , Podany AT , Samaneka W , Savic RM , Johnson JL , Muzanyi G , Lalloo UG , Bryant K , Sizemore E , Scott N , Dorman SE , Chaisson RE , Swindells S . Clin Infect Dis 2022 76 (3) e580-e589 BACKGROUND: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 non-inferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had non-inferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the pre-specified subgroup of people with HIV (PWH). METHODS: PWH and CD4 + counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months post-randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% non-inferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV-status. PWH were enrolled in a staged fashion, to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz. RESULTS: 2,516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4 + count was 344 cells/μL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was non-inferior to control (absolute difference in unfavorable outcomes -7.4% [95% CI -20.8% to +6.0%]); the rifapentine regimen was not non-inferior to control (+7.5% [95% CI -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%). CONCLUSIONS: In people with HIV-associated DS-PTB with CD4 + counts ≥100 cells/μL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was non-inferior to the 6-month control regimen and was safe. |
SARS-CoV-2 infections among neonates born to pregnant people with SARS-CoV-2 infection: Maternal, pregnancy and birth characteristics.
Olsen EO , Roth NM , Aveni K , Santos P , Sizemore L , Halai UA , Nestoridi E , Barton JE , Mobley E , Siebman S , Fussman C , Mbotha D , Dzimira P , Silcox KM , Khuwaja S , Roscom D , Lush M , Chicchelly S , Delgado-López C , Schlosser L , Read J , Ellington SR , Hall AJ , Gilboa SM , Tong VT , Woodworth KR . Paediatr Perinat Epidemiol 2022 36 (4) 476-484 BACKGROUND: Multiple reports have described neonatal SARS-CoV-2 infection, including likely in utero transmission and early postnatal infection, but published estimates of neonatal infection range by geography and design type. OBJECTIVES: To describe maternal, pregnancy and neonatal characteristics among neonates born to people with SARS-CoV-2 infection during pregnancy by neonatal SARS-CoV-2 testing results. METHODS: Using aggregated data from the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET) describing infections from 20 January 2020 to 31 December 2020, we identified neonates who were (1) born to people who were SARS-CoV-2 positive by RT-PCR at any time during their pregnancy, and (2) tested for SARS-CoV-2 by RT-PCR during the birth hospitalisation. RESULTS: Among 28,771 neonates born to people with SARS-CoV-2 infection during pregnancy, 3816 (13%) underwent PCR testing and 138 neonates (3.6%) were PCR positive. Ninety-four per cent of neonates testing positive were born to people with infection identified ≤14 days of delivery. Neonatal SARS-CoV-2 infection was more frequent among neonates born preterm (5.7%) compared to term (3.4%). Neonates testing positive were born to both symptomatic and asymptomatic pregnant people. CONCLUSIONS: Jurisdictions reported SARS-CoV-2 RT-PCR results for only 13% of neonates known to be born to people with SARS-CoV-2 infection during pregnancy. These results provide evidence of neonatal infection identified through multi-state systematic surveillance data collection and describe characteristics of neonates with SARS-CoV-2 infection. While perinatal SARS-CoV-2 infection was uncommon among tested neonates born to people with SARS-CoV-2 infection during pregnancy, nearly all cases of tested neonatal infection occurred in pregnant people infected around the time of delivery and was more frequent among neonates born preterm. These findings support the recommendation for neonatal SARS-CoV-2 RT-PCR testing, especially for people with acute infection around the time of delivery. |
Timing of first positive hepatitis c polymerase chain reaction test among pregnant women with hepatitis c infection Surveillance for Emerging Threats to Mothers and Babies Network
Woodworth Kate , Newton Suzanne , Sizemore Lindsey , Wingate Heather , Wills Aprielle , Thomas Nadia , Reynolds Bethany , Foster Monique , Gupta Neil , Wester Carolyn , Meaney-Delman Data , Gilboa Suzanne , Tong Van . Am J Obstet Gynecol 2022 226 (2) 305-306 Incidence of hepatitis C virus (HCV) infection in women of reproductive age is increasing, leading to rising numbers of women with HCV infection in pregnancy and concerns of perinatal transmission. In April 2020, the Centers for Disease Control and Prevention (CDC) began recommending HCV screening during each pregnancy. We describe maternal characteristics and timing of HCV testing among pregnant women identified with HCV infection. | |
Efavirenz pharmacokinetics and HIV-1 viral suppression among patients receiving TB treatment containing daily high-dose rifapentine
Podany AT , Pham M , Sizemore E , Martinson N , Samaneka W , Mohapi L , Badal-Faesen S , Dawson R , Johnson JL , Mayanja H , Lalloo U , Whitworth WC , Pettit A , Campbell K , Phillips P , Bryant K , Scott N , Vernon A , Kurbatova E , Chaisson RE , Dorman S , Nahid P , Swindells S , Dooley KE , Fletcher CV . Clin Infect Dis 2021 75 (4) 560-566 BACKGROUND: A four-month regimen containing rifapentine and moxifloxacin has non-inferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with HIV-associated TB. METHODS: In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing ART (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB co-treatment (Weeks 4, 8, 12 and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if >80% of participants had mid-interval efavirenz concentrations meeting this target. RESULTS: EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs. without TB drugs was 0.79 [90% CI 0.72-0.85] in EFV1 and 0.84 [90% CI 0.69-0.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations >1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%. CONCLUSIONS: TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment. |
Sensitivity of Pregnancy Field on the COVID-19 Case Report Form Among Pregnancies Completed Through December 31, 2020: Illinois and Tennessee.
Manning SE , Bennett A , Ellington S , Goyal S , Harvey E , Sizemore L , Wingate H . Matern Child Health J 2021 26 (2) 1-7 PURPOSE: The considerable volume of infections from SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), has made it challenging for health departments to collect complete data for national disease reporting. We sought to examine sensitivity of the COVID-19 case report form (CRF) pregnancy field by comparing CRF data to the gold standard of CRF data linked to birth and fetal death certificates. DESCRIPTION: CRFs for women aged 15-44 years with laboratory-confirmed SARS-CoV-2 infection were linked to birth and fetal death certificates for pregnancies completed during January 1-December 31, 2020 in Illinois and Tennessee. Among linked records, pregnancy was considered confirmed for women with a SARS-CoV-2 specimen collection date on or prior to the delivery date. Sensitivity of the COVID-19 CRF pregnancy field was calculated by dividing the number of confirmed pregnant women with SARS-CoV-2 infection with pregnancy indicated on the CRF by the number of confirmed pregnant women with SARS-CoV-2 infection. ASSESSMENT: Among 4276 (Illinois) and 2070 (Tennessee) CRFs that linked with a birth or fetal death certificate, CRF pregnancy field sensitivity was 45.3% and 42.1%, respectively. In both states, sensitivity varied significantly by maternal race/ethnicity, insurance, trimester of prenatal care entry, month of specimen collection, and trimester of specimen collection. Sensitivity also varied by maternal education in Illinois but not in Tennessee. CONCLUSION: Sensitivity of the COVID-19 CRF pregnancy field varied by state and demographic factors. To more accurately assess outcomes for pregnant women, jurisdictions might consider utilizing additional data sources and linkages to obtain pregnancy status. |
Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis
Dorman SE , Nahid P , Kurbatova EV , Phillips PPJ , Bryant K , Dooley KE , Engle M , Goldberg SV , Phan HTT , Hakim J , Johnson JL , Lourens M , Martinson NA , Muzanyi G , Narunsky K , Nerette S , Nguyen NV , Pham TH , Pierre S , Purfield AE , Samaneka W , Savic RM , Sanne I , Scott NA , Shenje J , Sizemore E , Vernon A , Waja Z , Weiner M , Swindells S , Chaisson RE . N Engl J Med 2021 384 (18) 1705-1718 BACKGROUND: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. METHODS: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months. RESULTS: Among 2516 participants who had undergone randomization, 2343 had a culture positive for Mycobacterium tuberculosis that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group. CONCLUSIONS: The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.). |
Optimizing drug inventory management with a web-based information system: The TBTC study 31/ACTG A5349 experience
Scott NA , Lee KK , Sadowski C , Kurbatova E , Goldberg SV , Nsubuga P , Kitshoff R , Whitelaw C , Thuy HN , Batra K , Allen-Blige C , Davis H , Kim J , Phan M , Fedrick P , Chiu KW , Heilig CM , Sizemore E . Contemp Clin Trials 2021 105 106377 INTRODUCTION: Efficient management of study drug inventory shipments is critical to keep research sites enrolling into multisite clinical treatment trials. A standard manual drug-management process used by the Tuberculosis Trials Consortium (TBTC), did not accommodate import permit approval timelines, shipment transit-times and time-zone differences. We compared a new web-based solution with the manual process, during an international 34-site clinical trial conducted by the TBTC and the AIDS Clinical Trials Group (ACTG); TBTC Study 31/ACTG A5349. MATERIAL AND METHODS: We developed and implemented a technological solution by integrating logistical and regulatory requirements for drug importation with statistical simulations that estimated stock-out times in an online Drug Management Module (DMM). We measured the average shipment-related drug stock-outs and time to drug availability, to assess the efficiency of the DMM compared to the manual approach. RESULTS: An Interrupted Time-Series (ITS) analysis showed a 15% [p-value = 0.03; 95% C.I. (-28.8%, -2.0%)] reduction in average shipment-related study drug stock-out after DMM implementation. The DMM streamlined the restocking process at study sites, reducing median transit-time for sites associated with a depot by 2 days [95% C.I. (-3.0, -1.0)]. Under the DMM, study drugs were available for treatment assignment on the day received, compared to one day after receipt under the manual process. DISCUSSION: The DMM provided TBTC's Data and Coordinating Center and site staff with more efficient procedures to manage and consistently maintain study drug inventory at enrolling sites. This DMM framework can improve efficiency in future multicenter clinical trials. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (Identifier: NCT02410772) on April 8, 2015. |
Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis
Bryant KE , Yuan Y , Engle M , Kurbatova EV , Allen-Blige C , Batra K , Brown NE , Chiu KW , Davis H , Elskamp M , Fagley M , Fedrick P , Hedges KNC , Narunsky K , Nassali J , Phan M , Phan H , Purfield AE , Ricaldi JN , Robergeau-Hunt K , Whitworth WC , Sizemore EE . Contemp Clin Trials 2021 104 106355 INTRODUCTION: With the growing use of online study management systems and rapid availability of data, timely data review and quality assessments are necessary to ensure proper clinical trial implementation. In this report we describe central monitoring used to ensure protocol compliance and accurate data reporting, implemented during a large phase 3 clinical trial. MATERIAL AND METHODS: The Tuberculosis Trials Consortium (TBTC) Study 31/AIDS Clinical Trials Group (ACTG) study A5349 (S31) is an international, multi-site, randomized, open-label, controlled, non-inferiority phase 3 clinical trial comparing two 4-month regimens to a standard 6 month regimen for treatment of drug-susceptible tuberculosis (TB) among adolescents and adults with a sample size of 2500 participants. RESULTS: Central monitoring utilized primary study data in a five-tiered approach, including (1) real-time data checks & topic-specific intervention reports, (2) missing forms reports, (3) quality assurance metrics, (4) critical data reports and (5) protocol deviation identification, aimed to detect and resolve quality challenges. Over the course of the study, 240 data checks and reports were programed across the five tiers used. DISCUSSION: This use of primary study data to identify issues rapidly allowed the study sponsor to focus quality assurance and data cleaning activities on prioritized data, related to protocol compliance and accurate reporting of study results. Our approach enabled us to become more efficient and effective as we informed sites about deviations, resolved missing or inconsistent data, provided targeted guidance, and gained a deeper understanding of challenges experienced at clinical trial sites. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (Identifier: NCT02410772) on April 8, 2015. |
Optimising pyrazinamide for the treatment of tuberculosis
Zhang N , Savic RM , Boeree MJ , Peloquin C , Weiner M , Heinrich N , Bliven-Sizemore E , Phillips PP , Hoelscher M , Whitworth W , Morlock G , Posey J , Stout JE , Mac Kenzie W , Aarnoutse R , Dooley KE . Eur Respir J 2021 58 (1) Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from TBTC Studies 27 and 28 and PanACEA MAMS-TB, multi-center Phase 2 trials in which participants received rifampicin (range 10-35 mg·kg(-1)), pyrazinamide (range 20-30 mg·kg(-1)), plus two companion drugs. Pyrazinamide pharmacokinetic-pharmacodynamic (PK/PD) and PK-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (Cmax) was associated with shorter time to culture conversion (TTCC) and higher probability of two-month culture conversion (p-value<0.001). Parametric survival analyses showed that relationships varied geographically, with steeper PK-PD relationships seen among non-African than African participants. In PanACEA MAMS-TB (n=363), TTCC decreased as pyrazinamide Cmax increased and varied by rifampicin Cmax (p-value<0.01). Modeling and simulation suggested that very high doses of pyrazinamide (>4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with Grade 3 or higher liver function tests, LFT), and no relationship was seen between pyrazinamide Cmax and LFT levels.Pyrazinamide's microbiologic efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel. |
A Preparedness Model for Mother-Baby Linked Longitudinal Surveillance for Emerging Threats.
Woodworth KR , Reynolds MR , Burkel V , Gates C , Eckert V , McDermott C , Barton J , Wilburn A , Halai UA , Brown CM , Bocour A , Longcore N , Orkis L , Lopez CD , Sizemore L , Ellis EM , Schillie S , Gupta N , Bowen VB , Torrone E , Ellington SR , Delaney A , Olson SM , Roth NM , Whitehill F , Zambrano LD , Meaney-Delman D , Fehrenbach SN , Honein MA , Tong VT , Gilboa SM . Matern Child Health J 2021 25 (2) 1-9 INTRODUCTION: Public health responses often lack the infrastructure to capture the impact of public health emergencies on pregnant women and infants, with limited mechanisms for linking pregnant women with their infants nationally to monitor long-term effects. In 2019, the Centers for Disease Control and Prevention (CDC), in close collaboration with state, local, and territorial health departments, began a 5-year initiative to establish population-based mother-baby linked longitudinal surveillance, the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET). OBJECTIVES: The objective of this report is to describe an expanded surveillance approach that leverages and modernizes existing surveillance systems to address the impact of emerging health threats during pregnancy on pregnant women and their infants. METHODS: Mother-baby pairs are identified through prospective identification during pregnancy and/or identification of an infant with retrospective linking to maternal information. All data are obtained from existing data sources (e.g., electronic medical records, vital statistics, laboratory reports, and health department investigations and case reporting). RESULTS: Variables were selected for inclusion to address key surveillance questions proposed by CDC and health department subject matter experts. General variables include maternal demographics and health history, pregnancy and infant outcomes, maternal and infant laboratory results, and child health outcomes up to the second birthday. Exposure-specific modular variables are included for hepatitis C, syphilis, and Coronavirus Disease 2019 (COVID-19). The system is structured into four relational datasets (maternal, pregnancy outcomes and birth, infant/child follow-up, and laboratory testing). DISCUSSION: SET-NET provides a population-based mother-baby linked longitudinal surveillance approach and has already demonstrated rapid adaptation to COVID-19. This innovative approach leverages existing data sources and rapidly collects data and informs clinical guidance and practice. These data can help to reduce exposure risk and adverse outcomes among pregnant women and their infants, direct public health action, and strengthen public health systems. |
Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.
Weiner M , Gelfond J , Johnson-Pais TL , Engle M , Johnson JL , Whitworth WC , Bliven-Sizemore E , Nsubuga P , Dorman SE , Savic R . J Antimicrob Chemother 2020 76 (3) 582-586 BACKGROUND: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered. OBJECTIVES: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated. METHODS: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575. RESULTS: The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10). CONCLUSIONS: Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups. |
Using an Established Outbreak Response Plan and Molecular Epidemiology Methods in an HIV Transmission Cluster Investigation, Tennessee, January-June 2017.
Sizemore L , Fill MM , Mathieson SA , Black J , Brantley M , Cooper K , Garrett J , Switzer WM , Peters PJ , Wester C . Public Health Rep 2020 135 (3) 33354920915445 INTRODUCTION: In April 2017, the Tennessee Department of Health (TDH) was notified of an increase in the number of persons newly diagnosed with HIV in eastern Tennessee in the same month. Two were identified as persons with a history of injection drug use (IDU) and named each other as syringe-sharing partners, prompting an investigation into a possible HIV cluster among persons with a history of IDU. MATERIALS AND METHODS: TDH and public health staff members in eastern Tennessee collaborated to implement procedures outlined in TDH's HIV/hepatitis C virus (HCV) Outbreak Response Plan, including conducting enhanced interviewing and using a preestablished database for data collection and management. To complement contact tracing and enhanced interviewing, TDH partnered with the Centers for Disease Control and Prevention to conduct molecular HIV analyses. RESULTS: By June 27, 2017, the investigation had identified 31 persons newly diagnosed with HIV infection; 8 (26%) self-reported IDU, 4 of whom were also men who have sex with men (MSM). Of the remaining 23 persons newly diagnosed with HIV infection, 10 were MSM who did not report IDU, 9 reported high-risk heterosexual contact, and 4 had other or unknown risk factors. Molecular analysis of the 14 HIV-1 polymerase genes (including 7 of the 8 persons self-reporting IDU) revealed 3 distinct molecular clusters, one of which included 3 persons self-reporting IDU. PRACTICE IMPLICATIONS: This investigation highlights the importance of implementing an established Outbreak Response Plan and using HIV molecular analyses in the event of a transmission cluster or outbreak investigations. Future HIV outbreak surveillance will include using Global Hepatitis Outbreak Surveillance Technology to identify HCV gene sequences as a potential harbinger for HIV transmission networks. |
Norovirus seroprevalence among adults in the United States: Analysis of NHANES serum specimens from 1999-2000 and 2003-2004
Kirby AE , Kienast Y , Zhu W , Barton J , Anderson E , Sizemore M , Vinje J , Moe CL . Viruses 2020 12 (2) Norovirus is the most common cause of epidemic and endemic acute gastroenteritis. However, national estimates of the infection burden are challenging. This study used a nationally representative serum bank to estimate the seroprevalence to five norovirus genotypes including three GII variants: GI.1 Norwalk, GI.4, GII.3, GII.4 US95/96, GII.4 Farmington Hills, GII.4 New Orleans, and GIV.1 in the USA population (aged 16 to 49 years). Changes in seroprevalence to the three norovirus GII.4 variants between 1999 and 2000, as well as 2003 and 2004, were measured to examine the role of population immunity in the emergence of pandemic GII.4 noroviruses. The overall population-adjusted seroprevalence to any norovirus was 90.0% (1999 to 2000) and 95.9% (2003 to 2004). Seroprevalence was highest to GI.1 Norwalk, GII.3, and the three GII.4 noroviruses. Seroprevalence to GII.4 Farmington Hills increased significantly between the 1999 and 2000, as well as the 2003 and 2004, study cycles, consistent with the emergence of this pandemic strain. Seroprevalence to GII.4 New Orleans also increased over time, but to a lesser degree. Antibodies against the GIV.1 norovirus were consistently detected (population-adjusted seroprevalence 19.1% to 25.9%), with rates increasing with age. This study confirms the high burden of norovirus infection in US adults, with most adults having multiple norovirus infections over their lifetime. |
High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial
Dorman SE , Nahid P , Kurbatova EV , Goldberg SV , Bozeman L , Burman WJ , Chang KC , Chen M , Cotton M , Dooley KE , Engle M , Feng PJ , Fletcher CV , Ha P , Heilig CM , Johnson JL , Lessem E , Metchock B , Miro JM , Nhung NV , Pettit AC , Phillips PPJ , Podany AT , Purfield AE , Robergeau K , Samaneka W , Scott NA , Sizemore E , Vernon A , Weiner M , Swindells S , Chaisson RE . Contemp Clin Trials 2020 90 105938 INTRODUCTION: Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen. METHODS/DESIGN: S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority. DISCUSSION: This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels. TRIAL REGISTRATION: NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1. |
Notes from the field: Acute hepatitis A virus infection among previously vaccinated persons with HIV infection - Tennessee, 2018
Brennan J , Moore K , Sizemore L , Mathieson SA , Wester C , Dunn JR , Schaffner W , Jones TF . MMWR Morb Mortal Wkly Rep 2019 68 (14) 328-329 Complete immunization against hepatitis A requires 2 doses of a monovalent vaccine or 3 doses of a combined hepatitis A and hepatitis B vaccine; approximately 90% of vaccinated persons achieve protective antibody levels after a single dose of either product (1). However, persons living with human immunodeficiency virus (HIV) infection might not develop the same level of immunity after hepatitis A virus (HAV) vaccination as do immunocompetent persons (2,3). Compared with immunocompetent persons, seroconversion rates among persons with HIV infection are lower and are further affected by CD4 count and HIV viral load at the time of the first dose of vaccine (3). In addition, time to seroconversion is longer (3), and duration of protection wanes earlier (4) among persons with HIV infection. During an outbreak, evaluating predictors of a better vaccine response (CD4 count and HIV viral load at the time of first vaccination) is generally not feasible. Routine assessment of immune response after vaccination is not recommended for persons in general, nor for those with HIV infection (1); therefore, providers use a documented history of HAV vaccination to guide decisions regarding administration of HAV postexposure prophylaxis (PEP). However, compared with vaccination among the general population, a previous hepatitis A vaccination in persons with HIV infection after a high-risk exposure (e.g., household member or sexual contact) might not reliably protect against illness. The Tennessee Department of Health (TDH) sought to determine the frequency at which persons with HIV infection who were previously vaccinated for hepatitis A developed HAV infection during an HAV outbreak. |
Bacterial factors that predict relapse after tuberculosis therapy
Colangeli R , Jedrey H , Kim S , Connell R , Ma S , Chippada Venkata UD , Chakravorty S , Gupta A , Sizemore EE , Diem L , Sherman DR , Okwera A , Dietze R , Boom WH , Johnson JL , Mac Kenzie WR , Alland D . N Engl J Med 2018 379 (9) 823-833 BACKGROUND: Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment. METHODS: Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 mug per milliliter for isoniazid and 1.0 mug per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01-009 study (validation cohort). RESULTS: In the development cohort, the mean (+/-SD) MIC of isoniazid below the breakpoint was 0.0334+/-0.0085 mug per milliliter in the relapse group and 0.0286+/-0.0092 mug per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695+/-0.0276 and 0.0453+/-0.0223 mug per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). Higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences. In an analysis of receiver-operating-characteristic curves of relapse based on these MIC values, the area under the curve (AUC) was 0.779. In the development cohort, the AUC in a multivariable model that included MIC values was 0.875. In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively. The use of a model score for the MIC values of isoniazid and rifampin to achieve 75.0% sensitivity in cross-validation analysis predicted relapse with a specificity of 76.5% in the development cohort and a sensitivity of 70.0% and a specificity of 100% in the validation cohort. CONCLUSIONS: In pretreatment isolates of M. tuberculosis with decrements of MIC values of isoniazid or rifampin below standard resistance breakpoints, higher MIC values were associated with a greater risk of relapse than lower MIC values. (Funded by the National Institute of Allergy and Infectious Diseases.). |
Elevated Plasma Moxifloxacin Concentrations and SLCO1B1 g.-11187G>A Polymorphism in Adults with Pulmonary Tuberculosis.
Weiner M , Gelfond J , Johnson-Pais TL , Engle M , Peloquin CA , Johnson JL , Sizemore EE , Mac Kenzie WR . Antimicrob Agents Chemother 2018 62 (5) Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against Mycobacterium tuberculosis However, moxifloxacin plasma concentrations are variable between patients. We evaluated whether human gene polymorphisms affect moxifloxacin plasma concentrations in tuberculosis patients from two geographic regions. We enrolled a convenience sample of 49 adults with drug-sensitive pulmonary tuberculosis from Africa and the United State s enrolled in two treatment trials of moxifloxacin as part of multidrug therapy. Pharmacokinetic parameters were evaluated by noncompartmental techniques. Human single-nucleotide polymorphisms of transporter genes were evaluated with analysis of covariance on moxifloxacin exposure and peak concentration (Cmax). Moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC0-24) and Cmax were significantly increased by drug mg/kg dosage and genotype of variant g.-11187G>A in the SLCO1B1 gene (rs4149015), but not by geographic region. Median moxifloxacin AUC0-24 was 46% higher and Cmax 30% higher in 4 (8% of) participants who had the SLCO1B1 g.-11187 AG genotype compared with 45 participants who had the wild type GG genotype (median from model, AUC0-24 34.4 vs. 23.6 mug*h/mL, P =.005; Cmax 3.5 vs. 2.7 mug/mL, P =.009, ANCOVA). Because moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals, and prolonged QTc intervals are associated with cardiac arrhythmia, further study is needed to evaluate risk associated with the SLCO1B1 g.-11187G>A variant. |
Epidemiology and risk factors for hepatitis C virus infection in a high-prevalence population
Fill MA , Sizemore LA , Rickles M , Cooper KC , Buecker CM , Mullins HL , Hofmeister MG , Abara WE , Foster MA , Asher AK , Schaffner W , Dunn JR , Jones TF , Wester C . Epidemiol Infect 2018 146 (4) 1-7 To understand increasing rates of hepatitis C virus (HCV) infection in Tennessee, we conducted testing, risk factor analysis and a nested case-control study among persons who use drugs. During June-October 2016, HCV testing with risk factor assessment was conducted in sexually transmitted disease clinics, family planning clinics and an addiction treatment facility in eastern Tennessee; data were analysed by using multivariable logistic regression. A nested case-control study was conducted to assess drug-using risks and behaviours among persons who reported intranasal or injection drug use (IDU). Of 4753 persons tested, 397 (8.4%) were HCV-antibody positive. HCV infection was significantly associated with a history of both intranasal and IDU (adjusted odds ratio (aOR) 35.4, 95% confidence interval (CI) 24.1-51.9), IDU alone (aOR 52.7, CI 25.3-109.9), intranasal drug use alone (aOR 2.6, CI 1.8-3.9) and incarceration (aOR 2.7, CI 2.0-3.8). By 4 October 2016, 574 persons with a reported history of drug use; 63 (11%) were interviewed further. Of 31 persons who used both intranasal and injection drugs, 26 (84%) reported previous intranasal drug use, occurring 1-18 years (median 5.5 years) before their first IDU. Our findings provide evidence that reported IDU, intranasal drug use and incarceration are independent indicators of risk for past or present HCV infection in the study population. |
HIV testing and HIV service delivery to populations at high risk attending sexually transmitted disease clinics in the United States, 2011-2013
Seth P , Wang G , Sizemore E , Hogben M . Am J Public Health 2015 105 (11) e1-e8 OBJECTIVES: We evaluated HIV testing and service delivery in Centers for Disease Control and Prevention (CDC)-funded sexually transmitted disease (STD) clinics. METHODS: We assessed HIV testing, HIV positivity, receipt of HIV test results, linkage to medical care, and referral services from 61 health department jurisdictions from 2011 to 2013. RESULTS: In 2013, 18.6% (621 010) of all CDC-funded HIV-testing events were conducted in STD clinics, and 0.8% were newly identified as HIV-positive. In addition, 27.3% of all newly identified HIV-positive persons and 30.1% of all newly identified HIV-positive men who have sex with men were identified in STD clinics. Linkage to care within any time frame was 63.8%, and linkage within 90 days was 55.3%. Although there was a decrease in first-time HIV testers in STD clinics from 2011 to 2013, identification of new positives increased. CONCLUSIONS: Although linkage to care and referral to partner services could be improved, STD clinics appear successful at serving populations disproportionately affected by HIV. These clinics may reach persons who may not otherwise seek HIV testing or medical services and provide an avenue for service provision to these populations. |
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