Biomarkers for the clinical development of antiviral therapies.

With the morbidity and mortality associated with the COVID-19 pandemic that we are witnessing this year, the risks posed by emerging viral diseases to global health are all too obvious. This pandemic highlights the importance of antiviral drug discovery, which targets emerging viral pathogens, as well as existing pathogenic viruses that undergo continuous evolution. Drug discovery and development is a long and resource intensive process; however, the use of biomarkers can accelerate clinical development of antivirals by providing information regarding diagnosis of specific viral infections, status of infection, potential safety parameters, and antiviral responses. In clinical practice, many of the biomarkers initially utilized to support clinical development are also used for patient care. While viral load is a standard and essential biomarker used to detect the desired viral suppression induced by an antiviral agent, it has become apparent that additional biomarkers, whether related to the virus, the host or as a consequence of the drug's mechanistic effects, are also important for monitoring clinical outcomes associated with an antiviral therapy. This review summarizes the biomarkers used in the clinical development (as well as in clinical practice, where appropriate) of antiviral therapies for hepatitis C virus, hepatitis B virus, human immunodeficiency virus, and severe acute respiratory syndrome coronavirus 2.

Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Children With Chronic HCV: Part 2 of the DORA Study.

BACKGROUND AND AIMS: Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV-infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years. APPROACH AND RESULTS: Children with chronic HCV infection, genotype 1-6, with or without compensated cirrhosis, were divided into three cohorts by age-cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)-and given weight-based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady-state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug-related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults. CONCLUSIONS: A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV-infected children 3 to < 12 years old.

Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Adolescents With Chronic Hepatitis C Virus: Part 1 of the DORA Study.

The pangenotypic regimen of glecaprevir and pibrentasvir (G/P) is approved to treat adults with chronic hepatitis C virus (HCV) infection and has yielded high cure rates in adults in clinical trials. Approved treatment options for pediatrics may include ribavirin. A pangenotypic regimen for pediatric patients remains an unmet need. DORA is an ongoing phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics (PK), safety, and efficacy of G/P in pediatric patients with chronic HCV. This analysis includes Part 1 of the study, conducted in adolescent patients 12-17 years of age given the adult regimen of G/P (300 mg/120 mg) once daily for 8-16 weeks according to the indication durations used in adults. Patients were either treatment naïve or experienced with interferon-based regimens. The primary PK endpoint was steady-state exposures for glecaprevir and pibrentasvir; the primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). The secondary efficacy endpoints were on-treatment virologic failure, relapse, and reinfection. Safety and tolerability were monitored. Part 1 enrolled 48 adolescent patients infected with genotypes 1, 2, 3, or 4, of whom 47 were administered G/P. All 47 patients (100%) achieved SVR12. No on-treatment virologic failures or relapses occurred. PK exposures of glecaprevir and pibrentasvir were comparable to exposures in adults. No adverse events (AEs) led to treatment discontinuation, and no serious AEs occurred. Conclusion: Adolescent patients with chronic HCV infection treated with G/P achieved a comparable exposure to adults, 100% SVR12 rate, and safety profile consistent with that in adults. This pangenotypic regimen demonstrated 100% efficacy within the adolescent population in as little as 8 weeks of treatment.

Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection.

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent. CONCLUSION: Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000).

Multistate US Outbreak of Rapidly Growing Mycobacterial Infections Associated with Medical Tourism to the Dominican Republic, 2013-2014(1).

During 2013, the Maryland Department of Health and Mental Hygiene in Baltimore, MD, USA, received report of 2 Maryland residents whose surgical sites were infected with rapidly growing mycobacteria after cosmetic procedures at a clinic (clinic A) in the Dominican Republic. A multistate investigation was initiated; a probable case was defined as a surgical site infection unresponsive to therapy in a patient who had undergone cosmetic surgery in the Dominican Republic. We identified 21 case-patients in 6 states who had surgery in 1 of 5 Dominican Republic clinics; 13 (62%) had surgery at clinic A. Isolates from 12 (92%) of those patients were culture-positive for Mycobacterium abscessus complex. Of 9 clinic A case-patients with available data, all required therapeutic surgical intervention, 8 (92%) were hospitalized, and 7 (78%) required ≥3 months of antibacterial drug therapy. Healthcare providers should consider infection with rapidly growing mycobacteria in patients who have surgical site infections unresponsive to standard treatment.

Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort Study.

OBJECTIVES: In a large cohort of children with intestinal failure (IF), we sought to determine the cumulative incidence of achieving enteral autonomy and identify patient and institutional characteristics associated with enteral autonomy. STUDY DESIGN: A multicenter, retrospective cohort analysis from the Pediatric Intestinal Failure Consortium was performed. IF was defined as severe congenital or acquired gastrointestinal diseases during infancy with dependence on parenteral nutrition (PN) >60 days. Enteral autonomy was defined as PN discontinuation >3 months. RESULTS: A total of 272 infants were followed for a median (IQR) of 33.5 (16.2-51.5) months. Enteral autonomy was achieved in 118 (43%); 36 (13%) remained PN dependent and 118 (43%) patients died or underwent transplantation. Multivariable analysis identified necrotizing enterocolitis (NEC; OR 2.42, 95% CI 1.33-4.47), care at an IF site without an associated intestinal transplantation program (OR 2.73, 95% CI 1.56-4.78), and an intact ileocecal valve (OR 2.80, 95% CI 1.63-4.83) as independent risk factors for enteral autonomy. A second model (n = 144) that included only patients with intraoperatively measured residual small bowel length found NEC (OR 3.44, 95% CI 1.36-8.71), care at a nonintestinal transplantation center (OR 6.56, 95% CI 2.53-16.98), and residual small bowel length (OR 1.04 cm, 95% CI 1.02-1.06 cm) to be independently associated with enteral autonomy. CONCLUSIONS: A substantial proportion of infants with IF can achieve enteral autonomy. Underlying NEC, preserved ileocecal valve, and longer bowel length are associated with achieving enteral autonomy. It is likely that variations in institutional practices and referral patterns also affect outcomes in children with IF.

Negative pressure wound therapy technologies for chronic wound care in the home setting: A systematic review.

The use of negative pressure wound therapy (NPWT) is increasing in both the inpatient and outpatient settings. We conducted a systematic review on the efficacy and safety of NPWT for the treatment of chronic wounds in the home setting. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature, up to June 2014. Two independent reviewers screened search results. Seven studies met our criteria for inclusion. Six of the studies compared NPWT devices to other wound care methods and one study compared two different NPWT technologies. Data were limited by variability in the types of comparator groups, methodological limitations, and poor reporting of outcomes. We were unable to draw conclusions about the efficacy or safety of NPWT for the treatment of chronic wounds in the home setting due to the insufficient evidence. Consensus is needed on the methods of conducting and reporting wound care research so that future studies are able inform decisions about the use of NPWT in the home environment for chronic wounds.

Resolution of a fungal mycotic aneurysm after a contaminated steroid injection: a case report.

BACKGROUND: In the past ten years there have been three separate outbreaks of fungal contaminated steroid injections from compounding pharmacies. The 2012 outbreak of central nervous system fungal infections associated with contaminated methylprednisolone produced by a United States compounding pharmacy has led to 750 infections (151 with meningitis and paraspinal infections and 325 cases with paraspinal infections without meningitis) and 64 deaths as of October 23, 2013. Exserohilum rostratum has been the predominant pathogen identified by culture, polymerase chain reaction or antibody tests. According to previous reports, cerebral involvement with phaeohyphomycosis has a high risk of morbidity and mortality. CASE PRESENTATION: We report a 41 year-old Caucasian woman who received a lumbar methylprednisolone injection from a contaminated lot in August 2012. She was diagnosed with fungal meningitis by cerebrospinal fluid pleocytosis and positive (1, 3) beta-D-glucan after cultures and polymerase chain reaction were negative. Two weeks after onset of therapy, she developed a 4.1 mm superior cerebellar artery mycotic aneurysm associated with new stroke symptoms, which resolved with thirty-two weeks of antifungal treatment. CONCLUSIONS: This is the rare case report of successful medical management of a cerebral mycotic aneurysm with stroke symptoms related to a presumed phaeohyphomycosis in an immunocompetent individual. Further studies are needed to determine the utility of cerebrospinal fluid (1, 3) beta-D-glucan in diagnosing and monitoring patients with meningitis thought to be related to fungal infection.

Antimicrobial stewardship in long-term care facilities.

Although antimicrobial stewardship has been shown to improve microbiologic susceptibility patterns, decrease drug toxicities, and lower overall drug costs in the inpatient setting, there are few studies assessing programs in the long-term care (LTC) setting. Implementing antimicrobial stewardship programs in LTC settings can be challenging as the LTC setting houses a unique population of frail and older adults with several preexisting conditions and multiple risk factors for colonization with multidrug-resistant organisms. Antimicrobial stewardship has an important role in decreasing inappropriate antibiotic use, encouraging targeted treatment of specific disease states, and limiting the untoward effects and costs of antimicrobials in this vulnerable population.

Clostridium difficile in the Pediatric Population of Monroe County, New York.

BACKGROUND: Clostridium difficile infection (CDI) incidence in hospitalized children has increased over the past decade and disease has been reported in the community. Therefore, population surveillance that includes nonhospitalized cases is important to accurately estimate the burden of CDI in children. We describe the epidemiology of CDI in the pediatric population of Monroe County, New York. METHODS: Active, laboratory, and population-based surveillance for CDI has been ongoing in Monroe County through the Emerging Infections Program of the Centers for Disease Control and Prevention since 2010. Infants less than 12 months of age are excluded. RESULTS: In 2010, the incidence of CDI in the pediatric population was 33.8 per 100 000 population, which increased to 45.8 in 2011and remained stable in 2012. Seventy-one percent of the CDI cases were community-associated, 60% had an underlying medical condition, and 71% received antibiotics before their illness. The North American pulsed-field gel electrophoresis type 1 (NAP1) epidemic strain was identified in 27% of cultured stool specimens. CONCLUSIONS: Clostridium difficile infection has emerged as a disease affecting children in both the community and hospital settings, with a higher proportion of community illness in our population. The majority of children with CDI had chronic underlying conditions and prior antibiotic exposure. To prevent CDI in this population, the judicious use of antibiotics, especially in the outpatient setting, may be the best strategy. Further population-based studies are warranted to determine preventable risk factors for CDI in the pediatric population.

Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium.

OBJECTIVE: To characterize the natural history of intestinal failure (IF) among 14 pediatric centers during the intestinal transplantation era. STUDY DESIGN: The Pediatric Intestinal Failure Consortium performed a retrospective analysis of clinical and outcome data for a multicenter cohort of infants with IF. Entry criteria included infants <12 months receiving parenteral nutrition (PN) for >60 continuous days. Enteral autonomy was defined as discontinuation of PN for >3 consecutive months. Values are presented as median (25th, 75th percentiles) or as number (%). RESULTS: 272 infants with a gestational age of 34 weeks (30, 36) and birth weight of 2.1 kg (1.2, 2.7) were followed for 25.7 months (11.2, 40.9). Residual small bowel length in 144 patients was 41 cm (25.0, 65.5). Diagnoses were necrotizing enterocolitis (71, 26%), gastroschisis (44, 16%), atresia (27, 10%), volvulus (24, 9%), combinations of these diagnoses (46, 17%), aganglionosis (11, 4%), and other single or multiple diagnoses (48, 18%). Prescribed medications included oral antibiotics (207, 76%), H2 blockers (187, 69%), and proton pump inhibitors (156, 57%). Enteral feeding approaches varied among centers; 19% of the cohort received human milk. The cohort experienced 8.9 new catheter-related blood stream infections per 1000 catheter days. The cumulative incidences for enteral autonomy, death, and intestinal transplantation were 47%, 27%, and 26%, respectively. Enteral autonomy continued into the fifth year after study entry. CONCLUSIONS: Children with IF endure significant mortality and morbidity. Enteral autonomy may require years to achieve. Improved medical, nutritional, and surgical management may reduce time on PN, mortality, and need for transplantation.

Use of complementary and alternative medicines by ambulatory patients.

BACKGROUND: Complementary and alternative medicines (CAM) include a number of different modalities to improve health. The popularity of such healing methods has increased, although reports of problems and adverse effects have also increased. Difficulties have also been identified in communication between patients and their providers. Previous reports concerning CAM may have undersampled lower socioeconomic groups as a result of the telephone survey techniques used. METHODS: All patients with valid appointments for internal medicine resident teaching clinics at 2 publicly supported centers were considered for eligibility. Patients were surveyed about current medications and a variety of CAM modalities. Medical records were reviewed for demographic information and to confirm diagnoses, allergies, medications, and any documented adverse effects. RESULTS: Use of CAM was common by 85.4% of patients, including those using some form of diet, exercise, and prayer. A smaller number (32.3%) were currently using alternate health care providers and products. About 5% of the population used 6 products or more. Use by this primarily poor urban population appeared similar to that in previous reports, with some exceptions. Expensive modalities were less frequently used, whereas use of prayer appears more prevalent. CONCLUSIONS: Complementary and alternate medical modalities are as commonly used by poor urban populations as by the general population. Quantification of use depends on the types of CAM used and the time frame asked. Although much of the use does not appear to be maladaptive, a small percentage of individuals have enthusiastically adapted CAM in ways that would not be endorsed by most allopathic physicians.