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Xinyi Ng,1 Chizoba Nwankwo,2 Jean Marie Arduino,2 Shelby Corman,1 Kathryn Eilene Lasch,1 Jacqueline Mary Lustrino,1 Sushma Patel,2 Heather Loryn Platt,2 Jingjun Qiu,2 Jan Sperl3 1Pharmerit International, LP, Bethesda, MD, USA; 2Merck & Co. Inc., Kenilworth, NJ, USA; 3Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Purpose: People chronically infected with hepatitis C virus (HCV) have diminished patient-reported outcomes (PROs). This study aimed to compare the impact of elbasvir/grazoprevir (EBR/GZR) treatment versus sofosbuvir with pegylated interferon and ribavirin (SOF/PR) on changes in PROs: 1) during the treatment period and 2) at posttreatment follow-up. Patients and methods: PRO data collected during the Phase III C-EDGE Head-2-Head (H2H) open-label study was analyzed. In this trial, patients infected with HCV were randomized 1:1 to receive either EBR/GZR or SOF/PR for 12 weeks. Patients self-administered the Short Form-36 version 2 (SF-36v2®) Health Survey Acute (1-week recall) Form and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale at baseline, during treatment, and posttreatment. Between-group differences in mean change of PRO scores from baseline were estimated during the treatment period and also at the posttreatment follow-up. Effect sizes were calculated to evaluate if the detected change in mean PRO scores is clinically meaningful between groups. Results: There were 255 patients (99.2% White, 54.1% female, 74.9% treatment naïve) included in the analysis. During the treatment period, significant declines in SF-36v2 scores were observed across all domains for the SOF/PR group. Compared to the SOF/PR group, the EBR/GZR group reported more improvement in scores across all SF-36v2 domain scores at the end of the treatment period. At treatment week 12, the between-group differences for 6 out of the 8 domain scores for these patients reflected at least moderate effects (effect sizes >0.5). No significant between-group differences in change in SF-36v2 scores from baseline were detected posttreatment. The decline in SF-36v2 scores observed during the treatment period for the SOF/PR group returned to near baseline scores or above posttreatment. Treatment with EBR/GZR did not impact fatigue scores, but treatment with SOF/PR led to increased fatigue scores during treatment which resolved by posttreatment follow-up week 12. Conclusion: This study demonstrated that HCV treatment with EBR/GZR resulted in a significantly better PRO profile as compared to SOF/PR. PROs are an important consideration as worsening PROs experienced during treatment may negatively influence adherence and ultimately contribute to an unfavorable clinical outcome. Clinical trials.gov Identifier: NCT02358044 Keywords: hepatitis, direct-acting antivirals, health-related quality of life, fatigue, patient-reported outcomes

Approximately one-quarter of people with HIV (PWH) in the U.S. receive coverage through the Medicare program; however, no prior real-world study has examined antiretroviral therapy (ART) gaps and adherence and associated factors in this population. This retrospective cohort analysis used 2013-2018 national Medicare fee-for-service claims data to identify all PWH initiated on a new ART regimen including protease inhibitors [PI], non-nucleoside reverse transcriptase inhibitors [NNRTIs], or integrase strand transfer inhibitors [INSTIs] between 1/1/2014 and 12/31/2017. Study outcomes included ART adherence (based on proportion of days covered [PDC]), continuous treatment gaps ranging from 1 to 6 days to ≥ 180 days, and discontinuation (continuous gap ≥ 90 days) in the 12-month follow-up period. Multivariable regressions were used to assess factors associated with ART adherence and discontinuation. The final sample included 48,627 PWH (mean age: 54.5 years, 74.4% male, 47.5% White, 89.8% disabled). Approximately 53.0% of PWH had a PDC ≥ 0.95, 30.2% had a PDC between 0.70 and < 0.95, and 16.8% had PDC < 0.70. Treatment gaps of at least ≥ 7-days (55.2%) and ≥ 30-days (26.2%) were common and 10.1% PWH discontinued treatment. Younger age, female sex, Black race, higher comorbidity score, mental health conditions, and substance use disorder were associated with higher odds of lower adherence and discontinuation (all p-values < 0.05). In conclusion, suboptimal adherence and treatment gaps in ART use were commonly observed among PWH in Medicare. Interventions and policies to mitigate barriers to adherence are urgently needed in this population to both improve their survival and increase the potential for ending the HIV epidemic in the US., (© 2023. The Author(s).)

Hepatitis C virus (HCV) infection is common in dialysis patients and is associated with increased morbidity and mortality. We used the Dialysis Outcomes and Practice Patterns Study (DOPPS, 1996-2015) to assess trends in the prevalence, incidence, and risk factors for HCV infection as defined by a documented diagnosis or antibody positivity. Among prevalent hemodialysis patients, HCV prevalence was nearly 10% in 2012-2015. Prevalence ranged from 4% in Belgium to as high as 20% in the Middle East, with intermediate prevalence in China, Japan, Italy, Spain, and Russia. HCV prevalence decreased over time in most countries participating in more than one phase of DOPPS, and prevalence was around 5% among patients who had recently (<4 months) initiated dialysis. The incidence of HCV infection decreased from 2.9 to 1.2 per 100 patient-years in countries participating in the initial phase of DOPPS. Although most units reported no seroconversions, 10% of units experienced 3 or more cases over a median of 1.1 years. High HCV prevalence in the hemodialysis unit was a powerful facility-level risk factor for seroconversion, but the use of isolation stations for HCV-positive patients was not associated with significantly lower seroconversion rates. Overall, despite a trend toward lower HCV prevalence among hemodialysis patients, the prevalence of HCV infection remains higher than in the general population. Combined with a high prevalence of HCV infection among patients with Stage 5 CKD, high rates of HCV seroconversion in a subset of hemodialysis units may contribute to this disparity., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Studies evaluating the role of hepatitis C viral (HCV) infection on the progression of CKD are few and conflicting. Therefore, we evaluated the association of untreated HCV on kidney function decline in patients with stage 3-5 CKD., Design, Setting, Participants, & Measurements: This retrospective cohort study included members of Kaiser Permanente Southern California and Kaiser Permanente Mid-Atlantic States aged ≥18 years, with incident HCV and CKD diagnoses from January 1, 2004 to December 31, 2014. We used generalized estimating equations to compare the rate of change in eGFR between those with HCV and CKD versus CKD alone, adjusting for covariates. Cox proportional hazards models compared the risk of 25% decrease in eGFR and ESKD (defined as progression to eGFR<15 ml/min per 1.73 m 2 on two or more occasions, at least 90 days apart) in those with HCV and CKD versus CKD alone, adjusting for covariates., Results: We identified 151,974 patients with CKD only and 1603 patients with HCV and CKD who met the study criteria. The adjusted annual decline of eGFR among patients with HCV and CKD was greater by 0.58 (95% confidence interval [95% CI], 0.31 to 0.84) ml/min per 1.73 m 2 , compared with that in the CKD-only population (HCV and CKD, -1.61; 95% CI, -1.87 to -1.35 ml/min; CKD only, -1.04; 95% CI, -1.06 to -1.01 ml/min). Adjusted for covariates, the hazard for a 25% decline in eGFR and for ESKD were 1.87 (95% CI, 1.75 to 2.00) and 1.93 (95% CI, 1.64 to 2.27) times higher among those with HCV and CKD, respectively, compared with those with CKD only., Conclusions: Untreated HCV infection was associated with greater kidney function decline in patients with stage 3-5 CKD., (Copyright © 2018 by the American Society of Nephrology.)

Background: Newer direct acting antiviral agents against HCV (DAAs) are safe and efficacious in persons with chronic kidney disease (CKD). Whether approval of newer DAAs has resulted in more persons with CKD initiating HCV treatment remains unknown., Methods: We identified HCV+ persons in ERCHIVES between October 1999 and July 2016. We excluded HIV+ and HBsAg+ and those with missing baseline HCV RNA and baseline eGFR data. We identified persons initiated on any approved DAA-regimen through July 2016, by CKD stage. Logistic regression analyses were used to determine factors associated with treatment initiation., Results: Among 83 706 evaluable persons, 21.1% initiated treatment. Rates differed significantly by CKD stage: 22.1% for eGFR>90 mL/min/1.73 m 2 and CKD stage-2; 14.9% for CKD stage 3; and 8.0% for CKD stage-4/5. Those with CKD stage-3 were 33% less likely and those with CKD stage-4/5 were 60% less likely to initiate treatment with a DAA compared with those with baseline eGFR>90 mL/min/1.73 m 2 . Treatment initiation was less likely in HCV genotype 2 (OR 0.59; 95%CI 0.53,0.66) or 3 (OR 0.53; 95%CI 0.47,0.61) and those with diabetes (OR 0.87, 95% CI 0.81,0.94), cardiovascular disease (OR 0.77, 95% CI 0.70,0.84), alcohol abuse or dependence (OR 0.74, 95% CI 0.70,0.79) or cirrhosis (OR 0.86, 95% CI 0.80,0.92) at baseline., Conclusions: Persons with more advanced CKD are less likely to receive treatment for HCV despite recent data on safety and efficacy. Strategies are needed to improve treatment rates in the HCV/CKD population., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Chronic kidney disease (CKD) was a relative contraindication to hepatitis C virus (HCV) treatment in the interferon/ribavirin era., Aim: To determine the efficacy, tolerability and safety of sofosbuvir/ledipasvir (SOF/LDV) and paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimens in persons with CKD., Methods: We identified persons initiated on a SOF/LDV or PrOD regimen from October 30, 2014 to April 30, 2016. We excluded those with missing HCV genotype or eGFR values. We determined treatment completion and sustained virologic response (SVR) rates, and proportion developing worsening renal function or grade 3/4 haematologic toxicity., Results: Among 13 663 persons on SOF/LDV±ribavirin, 14% and 1% persons had CKD Stage 3 and 4-5 respectively, 67.8% completed treatment, 98.2% achieved SVR. Treatment completion or SVR rates did not decline with advanced CKD or ribavirin administration. Among 3961 persons on PrOD±ribavirin, 9% and 3% persons had CKD Stage 3 and 4-5, respectively, 74.0% completed treatment and 98.2% achieved SVR. A decrease in treatment completion rates was seen in CKD stage 4-5 and those on ribavirin, but this did not impact SVR rates. A >10 mL/min/1.73 m 2 drop in eGFR from baseline was observed in 30%-38% of persons with baseline eGFR ≥60 mL/min/1.73 m 2 , but in only 0%-6% with CKD4-5. Grade 3/4 anaemia was more frequent in persons with CKD4-5, but ribavirin co-administration did not appear to affect this., Conclusions: SOF/LDV and PrOD achieved high SVR rates in CKD population. Treatment completion rates were lower than expected. A decline in eGFR and development of anaemia were observed in a substantial proportion of persons, but the clinical implications remain unclear., (© 2018 John Wiley & Sons Ltd.)

Background: In the C-SURFER study, therapy with the all-oral elbasvir plus grazoprevir regimen for 12 weeks in patients with chronic hepatitis C virus (HCV) infection and stage 4-5 chronic kidney disease resulted in a high rate of virological cure compared with placebo. Here, we report sustained virological response (SVR), safety data, health-related quality-of-life (HRQOL), and virological resistance analyses in patients in C-SURFER who received immediate antiviral therapy or who received placebo before therapy., Methods: In this phase 3, multicentre, randomised, placebo-controlled study, we randomly assigned adults with HCV genotype 1 infection and stage 4-5 chronic kidney disease enrolled at 68 centres worldwide to either elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks beginning at week 16 (deferred treatment group). The primary safety and efficacy endpoints for the immediate treatment group and placebo phase of the deferred treatment group have been reported previously. Here, we report safety and efficacy data for the treatment phase of the deferred treatment group, as well as HRQOL assessed using the 36-Item Short Form Health Survey for all groups, and baseline and treatment-emergent resistance-associated substitutions (RASs). SVR at 12 weeks (SVR12) was assessed in the modified full analysis set (FAS), defined as all patients excluding those who did not receive at least one dose of study drug, who died, or who discontinued the study before the end of treatment for reasons determined to be unrelated to HCV treatment. This trial is registered with ClinicalTrials.gov, Number NCT02092350., Findings: Between March 30 and Nov 28, 2014, 235 patients were enrolled and received at least one dose of study drug. The modified FAS included 116 patients assigned to immediate treatment and 99 assigned to deferred treatment. 115 (99·1%; 95% CI 95·3-100·0) of 116 assigned to immediate treatment achieved SVR12 compared with 97 (98·0%; 92·9-99·7) of 99 assigned to deferred treatment. In patients with genotype 1a infections, SVR12 was achieved by 11 (84·6%) of 13 patients with detectable baseline NS5A RASs and in 98 (100%) of 98 without. HRQOL did not differ at week 12 between immediate treatment and the placebo phase of deferred treatment. Safety was generally similar between patients receiving immediate treatment and those receiving placebo in the deferred treatment group. One serious adverse event during deferred treatment (interstitial nephritis) and one during the placebo phase of deferred treatment (raised lipase concentration) were deemed related to study drug. Four patients died, one who received immediate treatment (cardiac arrest) and three who received deferred treatment (aortic aneurysm, pneumonia, and unknown cause); all four deaths were considered unrelated to study drugs. Of the three deaths in the deferred treatment group, one occurred during placebo treatment and two occurred before starting active treatment. There were no notable differences in aminotransferase elevations in the deferred treatment group compared with the immediate treatment group, and no patients in the deferred treatment group had total bilirubin elevations., Interpretation: These data add to the growing body of clinical evidence for the fixed-dose combination regimen of elbasvir plus grazoprevir for 12 weeks and support use of this therapy in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease., Funding: Merck Sharp & Dohme., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background/aims: Few studies explore the magnitude of the disease burden and health care utilization imposed by renal disease among patients with hepatitis C virus (HCV). We aimed to describe the characteristics, outcomes, and health care utilization and costs of patients with HCV with and without renal impairment., Methods: This retrospective analysis used 2 administrative claims databases: the US commercially insured population in Truven Health MarketScan® data (aged 20-64 years), and the US Medicare fee-for-service population in the Medicare 20% sample (aged ≥65 years). Baseline characteristics and comorbid conditions were identified from claims during 2011; patients were followed for up to 1 year (beginning January 1, 2012) to identify health outcomes of interest and health care utilization and costs., Results: In the MarketScan and Medicare databases, 35,965 and 10,608 patients with HCV were identified, 8.5 and 26.5% with evidence of renal disease (chronic kidney disease [CKD] or end-stage renal disease [ESRD]). Most comorbid conditions and unadjusted outcome rates increased across groups from patients with no evidence of renal disease to non-ESRD CKD to ESRD. Health care utilization followed a similar pattern, as did the costs., Conclusions: Our findings suggest that HCV patients with concurrent renal disease have significantly more comorbidity, a higher likelihood of negative health outcomes, and higher health care utilization and costs., (© 2017 S. Karger AG, Basel.)

Background: Staphylococcus aureus is the most common and most important pathogen following knee and hip arthroplasty procedures. Understanding the epidemiology of invasive S. aureus infections is important to quantify this serious complication., Methods: This nested retrospective cohort analysis included adult patients who had undergone insertion of knee or hip prostheses with clean or clean-contaminated wound class at 11 hospitals between 2003-2006. Invasive S. aureus infections, non-superficial incisional surgical site infections (SSIs) and blood stream infections (BSIs), were prospectively identified following each procedure. Prevalence rates, per 100 procedures, were estimated., Results: 13,719 prosthetic knee (62%) and hip (38%) insertion procedures were performed. Of 92 invasive S. aureus infections identified, SSIs were more common (80%) than SSI and BSI (10%) or BSI alone (10%). The rate of invasive S. aureus infection/100 procedures was 0.57 [95% CI: 0.43-0.73] for knee insertion and 0.83 [95% CI: 0.61-1.08] for hip insertion. More than half (53%) were methicillin-resistant. Median time-to-onset of infection was 34 and 26 days for knee and hip insertion, respectively. Infection was associated with higher National Healthcare Safety Network risk index (p ≤ 0.0001)., Conclusions: Post-operative invasive S. aureus infections were rare, but difficult-to-treat methicillin-resistant infections were relatively common. Optimizing preventative efforts may greatly reduce the healthcare burden associated with S. aureus infections.

Staphylococcus aureus is a well-recognized, clinically important cause of nosocomial infections, and as such, a vaccine to prevent S. aureus infections would be an important achievement. A Phase IIB/III study of V710, a vaccine containing iron-regulated surface determinant B (IsdB), demonstrated significant sero-conversion rates in cardiovascular surgery patients following a single pre-surgery immunization. However, the vaccine was not efficacious in preventing bacteremia or deep sternal wound infection post-surgery, thus raising the possibility that IsdB might not be available for immune recognition during infection. The purpose of the work described herein was to evaluate and quantify the naturally occurring anti-IsdB levels at baseline and over time during infection, to understand whether IsdB is expressed during a S. aureus infection in hospitalized non-vaccinated patients. We evaluated baseline and follow-up titers in 3 populations: (1) healthy subjects, (2) hospitalized patients with non-S. aureus infections, and (3) hospitalized patients with S. aureus infections. Baseline anti-IsdB levels generally overlapped between the 3 groups, but were highly variable within each group. In healthy subjects, baseline and follow-up levels were highly correlated (Spearman's rho = 0.93), and the geometric mean fold-rise (GMFR) in anti-IsdB levels between study entry and last value was 0.9-fold (95% confidence interval (CI): 0.8 to 1.0 ; p = 0.09), showing no trend over time. The convalescent GMFR in anti-IsdB levels from baseline was 1.7-fold (95% CI: 1.3 to 2.2, p = 0.0008) during S. aureus infection, significantly different from the 1.0-fold GMFR (95% CI: 0.9-1.2, p = 0.60) in non-S. aureus infection, p = 0.005. Additionally, S. aureus isolates (51) obtained from the hospitalized patient group expressed the IsdB protein in vitro. Collectively, these data suggest that IsdB expression levels rise substantially following infection with S. aureus, but not with other pathogens, and IsdB is likely well-conserved across S. aureus strains.

Background: Major postoperative infections (MPIs) are poorly understood complications of cardiac surgery. We examined the epidemiology, microbiology, and outcome of MPIs occurring after cardiac surgery., Methods: The study cohort was drawn from the Society of Thoracic Surgeon National Cardiac Database and comprised adults who underwent cardiac surgery at 5 tertiary hospitals between 2000 and 2004. We studied the incidence, microbiology, and risk factors of MPI (bloodstream or chest wound infections within 30 days after surgery), as well as 30-day mortality. We used multivariate regression analyses to evaluate the risk of MPI and mortality., Results: MPI was identified in 341 of 10,522 patients (3.2%). Staphylococci were found in 52.5% of these patients, gram-negative bacilli (GNB) in 24.3%, and other pathogens in 23.2%. High body mass index, previous coronary bypass surgery, emergency surgery, renal impairment, immunosuppression, cardiac failure, and peripheral/cerebrovascular disease were associated with the development of MPI. Median postoperative duration of hospitalization (15 days vs 6 days) and mortality (8.5% vs 2.2%) were higher in patients with MPIs. Compared with uninfected individuals, odds of mortality were higher in patients with S aureus MPIs (adjusted odds ratio, 3.7) and GNB MPIs (adjusted odds ratio, 3.0)., Conclusions: Staphylococci accounted for the majority of MPIs after cardiac surgery. Mortality was higher in patients with Staphylococcus aureus- and GNB-related MPIs than in patients with MPIs caused by other pathogens and uninfected patients. Preventive strategies should target likely pathogens and high-risk patients undergoing cardiac surgery., (Copyright © 2012 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Hepatitis C virus (HCV) genotypes influence response to therapy, and recently approved direct-acting antivirals are genotype-specific. Genotype distribution information can help to guide antiviral development and elucidate infection patterns. HCV genotype distributions were studied in a diverse cross-section of patients in the Northern California Kaiser Permanente health plan. Associations between genotype and race/ethnicity, age, and sex were assessed with multivariate logistic regression models. The 10,256 patients studied were median age 56 years, 62% male, 55% White non-Hispanic. Overall, 70% were genotype 1, 16% genotype 2, 12% genotype 3, 1% genotype 4, <1% genotype 5, and 1% genotype 6. Blacks (OR 4.5 [3.8-5.5]) and Asians (OR 1.2 [1.0-1.4]) were more likely to have genotype 1 than 2/3 versus non-Hispanic Whites. Women less likely had genotype 1 versus 2/3 than did men (OR 0.86 [0.78-0.94]). Versus non-Hispanic Whites, Asians (OR 0.38 [0.31-0.46]) and Blacks (OR 0.73 [0.63-0.84]) were less likely genotype1a than 1b; Hispanics (OR 1.3 [1.1-1.5]) and Native Americans (OR 1.9 [1.2-2.8]) more likely had genotype 1a than 1b. Patients age ≥65 years less likely had genotype 1a than 1b versus those age 45-64 (OR 0.34 [0.29-0.41]). The predominance of genotype 1 among all groups studied reinforces the need for new therapies targeting this genotype. Racial/ethnic variations in HCV genotype and subtype distribution must be considered in formulating new agents and novel strategies to successfully treat the diversity of hepatitis C patients., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: To determine the epidemiological characteristics of postoperative invasive Staphylococcus aureus infection following 4 types of major surgical procedures.design. Retrospective cohort study., Setting: Eleven hospitals (9 community hospitals and 2 tertiary care hospitals) in North Carolina and Virginia., Patients: Adults undergoing orthopedic, neurosurgical, cardiothoracic, and plastic surgical procedures., Methods: We used previously validated, prospectively collected surgical surveillance data for surgical site infection and microbiological data for bloodstream infection. The study period was 2003 through 2006. We defined invasive S. aureus infection as either nonsuperficial incisional surgical site infection or bloodstream infection. Nonparametric bootstrapping was used to generate 95% confidence intervals (CIs). P values were generated using the Pearson chi2 test, Student t test, or Wilcoxon rank-sum test, as appropriate., Results: In total, 81,267 patients underwent 96,455 procedures during the study period. The overall incidence of invasive S. aureus infection was 0.47 infections per 100 procedures (95% CI, 0.43-0.52); 227 (51%) of 446 infections were due to methicillin-resistant S.aureus. Invasive S. aureus infection was more common after cardiothoracic procedures (incidence, 0.79 infections per 100 procedures [95%CI, 0.62-0.97]) than after orthopedic procedures (0.37 infections per 100 procedures [95% CI, 0.32-0.42]), neurosurgical procedures (0.62 infections per 100 procedures [95% CI, 0.53-0.72]), or plastic surgical procedures (0.32 infections per 100 procedures [95% CI, 0.17-0.47]) (P < .001). Similarly, S. aureus bloodstream infection was most common after cardiothoracic procedures (incidence, 0.57 infections per 100 procedures [95% CI, 0.43-0.72]; P < .001, compared with other procedure types), comprising almost three-quarters of the invasive S. aureus infections after these procedures. The highest rate of surgical site infection was observed after neurosurgical procedures (incidence, 0.50 infections per 100 procedures [95% CI, 0.42-0.59]; P < .001, compared with other procedure types), comprising 80% of invasive S.aureus infections after these procedures., Conclusion: The frequency and type of postoperative invasive S. aureus infection varied significantly across procedure types. The highest risk procedures, such as cardiothoracic procedures, should be targeted for ongoing preventative interventions.

Objective: Staphylococcus aureus infections after cardiac surgery result in significant morbidity and mortality. Identifying patients at elevated risk for these infections preoperatively could facilitate efforts to reduce infection rates. The objectives of this study were to estimate the incidence of postoperative S. aureus infections in cardiac surgery patients, to identify preoperative risk factors for these infections, and to establish a patient risk profile by means of data available to clinicians prior to surgery., Design: Cohort study., Setting: Eight medical centers that participate in the Society of Thoracic Surgeons National Cardiac Database., Patients: Patients who were undergoing elective cardiac surgery during the period January 1, 2000 through December 31, 2004., Methods: Clinical and microbiological data from 16,386 patients were combined. Multivariable stepwise logistic regression analysis was performed to predict S. aureus infection, which was defined by culture results., Results: Of the 16,386 patients, 205 (1.3%) developed S. aureus bloodstream or chest wound infection within 90 days after surgery. On multivariable analysis, bootstrap-validated preoperative risk factors for S. aureus bloodstream or chest wound infection included a body mass index greater than 40 (adjusted odds ratio [aOR], 1.9 [95% confidence interval {CI}, 1.1-3.2]), chronic renal failure (aOR, 1.8 [95% CI, 1.1-2.9]), and chronic lung disease (aOR, 1.4 [95% CI, 1.0-2.0]). Only 8 patients had all 3 risk factors., Conclusions: Although preoperative risk factors can be easily identified, the majority of patients who developed S. aureus infections after cardiac surgery did not have any risk factors. Preventive measures should not be restricted to a select group of cardiac surgery patients and should rather address the entire patient population.

Background: Mild, transient alanine aminotransferase (ALT) elevations were seen in Phase I studies of caspofungin and cyclosporin A (CsA)., Methods: We conducted a retrospective chart review at four sites to characterize the hepatic safety in patients receiving > or =1 day of both drugs over a 20-month period. Investigators assessed reasons for discontinuing concomitant therapy and the presence/etiology of any hepatotoxicity., Results: Forty patients receiving concomitant therapy for 1-290 days (median 17.5 days) were identified. Although common, liver enzyme abnormalities were frequently attributed to other comorbidities or medications. ALT and/or aspartate aminotransferase (AST) elevations occurred in 14 patients (35%). Five had AST elevations at least possibly related to caspofungin/CsA, but none were >3.6 times the normal upper limit. No ALT elevations were related to caspofungin/CsA. Two of 4 patients had discontinuation of therapy because of hepatotoxicity possibly related to caspofungin/CsA. No serious adverse events occurred because of caspofungin., Conclusions: These data do not suggest a significant risk of clinically relevant hepatotoxicity with concomitant caspofungin/CsA.

Background: Determining who responds to asthma therapies, particularly leukotriene modifiers, continues to be explored., Objective: We sought to identify patient characteristics predictive of response to montelukast., Methods: We used data from 2 clinical trials in which children with asthma received either montelukast or placebo. Symptoms, beta-agonist use, and unanticipated health resource use caused by asthma were recorded in validated daily diaries for children 2 to 5 (n = 689) and 6 to 14 (n = 336) years old. We defined primary end points of days without asthma in 2- to 5-year-old patients (24 hours without symptoms, beta-agonist use, or asthma attack) and change in percent predicted FEV(1) in 6- to 14-year-old children. Asthma attack was defined by the use of rescue oral corticosteroids or by an unscheduled visit to a medical provider. Patients were grouped according to baseline characteristics, such as family history of asthma, personal history of allergy, frequency of asthma symptoms, eosinophilia, and concomitant use of inhaled corticosteroids or cromolyn. We examined the stratum-specific effects of montelukast on the percentage of days without asthma, change in percent predicted FEV(1), asthma attack, and a variety of secondary symptom and FEV(1) end points., Results: We did not identify characteristics that predicted response to montelukast in either preschool or 6- to 14-year-old children. These findings were consistent across all symptom and FEV(1) outcomes. There was also no differential response to montelukast in either age group when asthma attack was the outcome., Conclusion: The patient characteristics studied do not appear to provide an indication of who will benefit most from treatment with montelukast.

Latent-class analysis was used to evaluate the usefulness of markers of hepatitis C virus (HCV) infection in characterizing the true, underlying infection in a community-based Japanese population. Antibodies to HCV were detected in 24%, HCV RNA in 22%, and HCV core protein in 19% of stored serum samples from 372 adults. A 2-class model suggested that positive results for any 2 virus markers defined the current HCV infection class, with an estimated prevalence of 22% (95% confidence interval, 18%-26%). The sensitivity for detection of current HCV infection was highest for anti-HCV (97%) and was more moderate for HCV RNA (91%) and HCV core protein (85%). The specificity for each marker was > or =96%. In general, the association between demographic factors and current HCV infection status was strengthened by use of latent-class analysis that combined data for markers of HCV infection, when compared with results of logistic regression analysis for each marker separately.

Our objective was to assess whether HIV-1 RNA levels provide additional prognostic information beyond CD4(+) T lymphocyte counts in the prediction of subsequent HIV-1 disease progression among patients with advanced HIV-1 disease. In a nested case-control study conducted in patients with baseline CD4(+) T lymphocyte counts < 300 cells/mm(3) and receiving nucleoside reverse transcriptase inhibitors, 102 patients who progressed to an AIDS-defining event or death were matched within 10 CD4(+) T lymphocyte cells/mm(3) to patients who did not progress. The relationship between plasma HIV-1 RNA levels and HIV-1 disease progression was studied using conditional logistic regression analysis, which adjusts for the matching by baseline CD4(+) T lymphocytes. We observed a 0.10 log(10) copies/ml difference in baseline HIV-1 RNA levels between cases and their matched controls (p = 0.027). The relative risk for HIV-1 disease progression increased with increasing baseline HIV-1 RNA levels (odds ratio [OR] for a 3-fold higher HIV-1 RNA level, 1.42; 95% confidence interval [CI], 1.08--1.86), and remained important when also controlling for clinical status at baseline and CD4(+) T lymphocytes at 2 months (p = 0.038). Higher baseline HIV-1 RNA levels were associated with HIV-1 disease progression among patients with a baseline CD4(+) T lymphocyte count of 100 cells/mm(3) or greater (OR, 1.80; 95% CI, 1.15--2.81), but not among patients with a baseline CD4(+) T lymphocyte count < 100 cells/mm(3) (OR, 1.09; 95% CI, 0.73--1.63). We concluded that HIV-1 RNA levels predict subsequent HIV-1 disease progression independent of CD4(+) T lymphocyte counts. The magnitude and importance of the prognostic information contained in the HIV-1 RNA levels appear to depend on the CD4(+) T lymphocyte counts.

The diffusive properties of immature bovine articular cartilage were determined using two different-sized, uncharged solutes (glucose 180 Da, and dextran 10k Da). Radioactively tagged glucose and dextran were diffused into the cartilage for transport times of 5, 15, and 60 min, and the diffusion and partition coefficients were calculated by fitting the experimental data to a one-dimensional diffusion model. The diffusion and partition coefficients for the two solutes averaged 6.08 +/- 2.19 and 5.09 +/- 2.51 (x 10(-6) cm2/s) and 0.712 +/- 0.149 and 0.615 +/- 0.120, respectively. Both coefficients were significantly greater for glucose compared to the larger dextran. While no statistical differences could be found in the diffusive properties of these solutes in immature cartilage compared to their diffusive properties in mature cartilage, there was some evidence that the larger dextran solute might diffuse faster in the earlier time periods. Finally, the bulk fluid contents between the two types of cartilage were not different even though the immature tissue was significantly thicker (1.6 times) than the mature tissue. Our results indicate that the solute diffusion properties of articular cartilage, at least with respect to uncharged solutes, do not change during skeletal maturation.

Transport of nutrients, cytokines, pharmacologic agents, and matrix components through articular cartilage is critical for the viability and structural integrity of the tissue. To understand the role of the extracellular matrix in regulating this process, we measured the diffusivity of three uncharged solutes of different molecular size (glucose, MW 180; inulin, MW 5000; dextran, MW 70,000) into intact cartilage and cartilage that had its proteoglycan (PG) component removed. Solute diffusivity was measured by performing transient (nonsteady state) one-dimensional diffusion tests using radiolabelled solutes. Compared to intact cartilage, the diffusivity of glucose was unchanged after PG removal, inulin was unchanged but dextran increased by 1.7 times after 71% PG removal, and both inulin and dextran increased by 1.6 and 2.0 times, respectively, after 93% PG removal. The diffusivities of inulin and dextran were inversely proportional to the PG content. While no change was found in the tissue's bulk fluid content, PG depletion resulted in an increase in fluid content in the upper regions of the tissue and a decrease in the lower regions. These results indicate that in intact tissue small uncharged solutes have free mobility through the inter-molecular and intra-molecular PG volumes, larger molecules have limited intra-molecular mobility, and very large molecules are excluded from the intra-molecular space.

Objective: To determine if serologic marker responses to zidovudine treatment during the first year of antiretroviral therapy could predict subsequent HIV disease progression independently of absolute CD4 lymphocyte responses., Methods: We conducted a case-control study in patients with asymptomatic HIV disease, who were initiating zidovudine therapy in a randomized, prospective trial. A total of 102 patients who progressed to AIDS or advanced AIDS-related complex and 177 randomly selected controls matched by baseline CD4 cell count and duration of follow-up had serum samples (from prior to and at 8, 16, 32 and 48 weeks of zidovudine treatment) assayed for acid-disassociated HIV p24 antigen, beta 2-microglobulin (beta 2M), neopterin, soluble interleukin (IL)-2 receptor, soluble CD4 protein and soluble CD8 protein., Results: Median time to event for cases was 20.2 months; median follow-up on study was 35.4 months for controls. After controlling for absolute CD4 count at baseline, increased baseline serum concentrations of HIV p24 antigen, beta 2M, neopterin, and soluble IL-2 receptor were highly predictive of increased risk of HIV disease progression. In a multiple logistic regression model, controlling for baseline marker values, change in beta 2M consistently added independent value to change in CD4 count in predicting subsequent risk of disease progression., Conclusions: Monitoring serum immunologic markers, in particular beta 2M, in addition to absolute CD4 lymphocyte counts prior to and within the first 4 months after initiating dideoxynucleoside therapy can increase the accuracy of estimations of subsequent long-term risk of clinical HIV disease progression. This information may be useful to clinicians and patients who are making decisions about initiating or changing antiretroviral therapy.

Objective: To compare the safety and efficacy of continuing zidovudine therapy with that of zalcitabine alone or zalcitabine and zidovudine used together., Design: A randomized, double-blind, controlled trial., Setting: AIDS Clinical Trials units and National Hemophilia Foundation sites., Patients: 1001 patients with symptomatic human immunodeficiency (HIV) disease and 300 or fewer CD4 cells/mm3 or asymptomatic HIV disease and 200 or fewer CD4 cells/mm3 who had tolerated zidovudine therapy for 6 months or more., Intervention: Patients were randomly assigned to receive zidovudine, 600 mg/d; zalcitabine, 2.25 mg/d; or zidovudine, 600 mg/d, and zalcitabine, 2.25 mg/d., Measurements: The primary end point was time to disease progression or death., Results: The median follow-up time was 17.7 months. The estimated 12-month event-free rates were 70%, 67%, and 73%, respectively, for the zidovudine, zalcitabine, and combination groups (P = 0.26). A trend analysis showed significantly lower progression rates for combination therapy compared with zidovudine therapy as the pretreatment CD4 cell count increased (P = 0.027). For patients with 150 or more CD4 cells/mm3, those receiving combination therapy were less likely to have disease progression or to die than were those receiving zidovudine (relative risk, 0.51; 95% CI, 0.28 to 0.93; P = 0.029). We observed no difference between the zalcitabine and zidovudine groups (relative risk, 0.74; CI, 0.40 to 1.36; P = 0.33). For patients with 50 to 150 CD4 cells/mm3 or fewer than 50 CD4 cells/mm3, we found no differences among the treatment groups (P = 0.69 and P = 0.57, respectively). Severe toxic effects occurred less frequently among patients with 150 or more CD4 cells/mm3., Conclusions: We found no overall benefits of zalcitabine used alone or with zidovudine. However, a trend analysis suggested a better outcome for combination therapy compared with zidovudine as the pretreatment CD4 cell count increased.

A standardized assay in 96-well microtiter plates for syncytium-inducing (SI) human immunodeficiency virus type 1 phenotype detection using MT-2 cells has been developed. SI variants were found in 67% of the patients with advanced human immunodeficiency virus disease. The occurrence of the SI phenotype increased with lower CD4+ counts. There was no association between p24 antigenemia and the SI phenotype.

Serum p24 antigen levels were examined in subjects from three clinical trials of zidovudine to determine whether the pattern of change in serum p24 antigen during the first 8-16 weeks of therapy was associated with human immunodeficiency virus type 1 (HIV-1) disease progression or death. Among 406 patients with AIDS and a first episode of Pneumocystis carinii pneumonia, 65% had measurable pretreatment concentrations of serum p24 antigen (> or = 10 pg/mL). Changes during treatment were not associated with reduced mortality. In 637 mildly symptomatic patients, 24% had measurable concentrations, and changes were marginally associated with increased time until more advanced disease. Among 683 asymptomatic patients, 18% had measurable concentrations, and changes were not associated with increased time until progression. Despite the small number of clinical events and the low rate of serum p24 antigen positivity in the latter two studies, pretreatment serum p24 antigen levels were predictive of clinical outcome; subsequent measurements appear to be of limited use in evaluating zidovudine therapy.

Human immunodeficiency virus type 1 (HIV-1) isolates resistant to zidovudine (ZDV) have previously been demonstrated to exhibit in vitro cross-resistance to other similar dideoxynucleoside agents which contain a 3'-azido group. However, cross-resistance to didanosine (ddI) or dideoxycytidine (ddC) has been less well documented. ZDV, ddI, and ddC susceptibility data have been collected from clinical HIV-1 isolates obtained by five clinical centers and their respective retrovirology laboratories. All subjects were treated only with ZDV. Clinical HIV-1 isolates were isolated, amplified, and assayed for drug susceptibility in standardized cultures of phytohemagglutinin-stimulated donor peripheral blood mononuclear cells obtained from healthy seronegative donors. All five cohorts showed a correlation between decreased in vitro susceptibility to ZDV and decreased susceptibility to ddI and ddC. For each 10-fold decrease in ZDV susceptibility, an average corresponding decrease of 2.2-fold in ddI susceptibility was observed (129 isolates studied; P < 0.001, Fisher's test of combined significance). Similarly, susceptibility to ddC decreased 2.0-fold for each 10-fold decrease in ZDV susceptibility (82 isolates studied; P < 0.001, Fisher's test of combined significance). These data indicate that a correlation exists between HIV-1 susceptibilities to ZDV and ddI or ddC for clinical HIV-1 isolates.

A standardized antiviral drug susceptibility assay for clinical human immunodeficiency virus type 1 (HIV-1) isolates has been developed for use in clinical trials. The protocol is a two-step procedure that first involves cocultivation of patient infected peripheral blood mononuclear cells (PBMC) with seronegative phytohemagglutinin-stimulated donor PBMC to obtain an HIV-1 stock. The virus stock is titrated for viral infectivity (50% tissue culture infective dose) by use of serial fourfold virus dilutions in donor PBMC. A standardized inoculum of 1,000 50% tissue culture infective doses per 10(6) cells is used in the second step of the procedure to acutely infect seronegative donor PBMC in a 7-day microtiter plate assay with triplicate wells containing zidovudine (ZDV) concentrations ranging from 0 to 5.0 microM. The ZDV 50% inhibitory concentrations (IC50) for reference ZDV-susceptible and ZDV-resistant HIV-1 isolates ranged from 0.002 to 0.113 microM and from 0.15 to > 5.0 microM, respectively. Use of this consensus protocol reduced interlaboratory variability for ZDV IC50 determinations with reference HIV-1 isolates. Among eight laboratories, the coefficient of variation ranged from 0.85 to 1.25 with different PBMC protocols and was reduced to 0.39 to 0.98 with the standardized assay. Among the clinical HIV-1 isolates assayed by the standardized drug susceptibility assay, the median ZDV IC50 increased gradually with more ZDV therapy. This protocol provides an efficient and reproducible means to assess the in vitro susceptibility to antiretroviral agents of virtually all clinical HIV-1 isolates.

With evidence of segregation at a major locus for a quantitative trait having been found, a logical next step is to select a subset of the pedigrees to include in a linkage study to map the major locus. Ideally this subset should include much of the linkage information in the sample but include only a fraction of the pedigrees. We previously described a strategy for selecting pedigrees for linkage analysis of a quantitative trait on the basis of a pedigree likelihood-ratio statistic. For quantitative traits controlled by a major locus with a rare dominant allele, the likelihood-ratio strategy extracted nearly all the information for linkage while typically requiring marker data on only about one-third of the pedigrees. Here, we describe a new strategy to select pedigrees for linkage analysis on the basis of the expected number of potentially informative meioses in each pedigree. We demonstrate that this informative-meioses strategy provides an efficient and more general means to select pedigrees for a linkage study of a quantitative trait.