Phase 1 study of safety and tolerability of an oral contraceptive containing low-dose ethinyl oestradiol combined with glecaprevir/pibrentasvir treatment in healthy premenopausal women.

Glecaprevir/pibrentasvir (GLE/PIB) is an approved guideline-recommended chronic hepatitis C virus infection treatment. GLE/PIB coadministration with ethinyl oestradiol (EE) is not recommended in current labels owing to a Phase 1 study observing Grade ≥2 alanine aminotransferase (ALT) elevation in 2 out of 12 healthy women cotreated for 11 days with GLE/PIB and oral contraceptive (OC) containing 35 µg/250 µg EE/norgestimate. No Grade ≥2 elevation was observed with low-dose (20 µg) EE (n = 14). This Phase 1 study examined safety/tolerability of GLE/PIB coadministered with an OC containing low-dose EE using a larger sample size and longer treatment duration. Healthy premenopausal women were treated with EE/levonorgestrel alone (20/100 µg, Cycles 1-2), followed by coadministration with GLE/PIB (300/120 mg; Cycles 3-4). A safety criterion of special interest was a confirmed Grade ≥2 ALT elevation (>3× upper normal limit). Adverse events (AEs) and study drugs concentrations were examined. Of 85 enrolled women, 72 initiated combined GLE/PIB + EE/levonorgestrel treatment, 66 completed the study and 19 discontinued prematurely (non-safety reason, n = 16; AE [deemed unelated to GLE/PIB], n = 3). No participant met the safety criterion of special interest of confirmed Grade ≥2 ALT elevation. No serious/Grade ≥3 AEs were reported. Study drug concentrations were within the expected ranges. GLE/PIB in combination with an OC containing low-dose EE was generally well tolerated with no confirmed Grade ≥2 ALT elevation and no evidence of drug-induced liver injury. No pattern to the reported AEs and no new safety issues were identified. This was a Phase 1 study of healthy volunteers, not a registered clinical trial.

Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis.

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.

Consensus guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease.

BACKGROUND: Improved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug-induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients. AIMS: To outline best practices for detection, assessment and management of suspected acute DILI during clinical trials in adults with the cholestatic liver diseases - Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). METHODS: This is one of the several papers developed by the IQ DILI Initiative, which is comprised of members from 16 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. The contents are the result of an extensive literature review, as well as in-depth discussions among industry, regulatory and academic DILI experts, to achieve consensus recommendations on DILI-related issues occurring during clinical trials for cholestatic liver diseases. RESULTS: Recommended best practices are outlined pertaining to hepatic eligibility criteria, monitoring of liver tests, approach to a suspected DILI signal, and hepatic discontinuation rules. CONCLUSIONS: This paper provides a framework for the approach to detection, assessment and management of suspected acute DILI occurring during clinical trials in adults with cholestatic liver disease.

Consensus: guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis.

BACKGROUND: The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials. AIMS: This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH. METHODS: This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic. RESULTS: Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules. CONCLUSIONS: This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH.

Correction to: Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial Experience.

In the original publication of the article, the ALT and AST values in Fig. 5a-e were capped at 10× ULN, which did not accurately reflect the narrative provided for each case. In this correction, the original Fig. 5a-e (Fig. 1a-e) and the correct Fig. 5a-5e (Fig. 2a-e) are published.

Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial Experience.

INTRODUCTION: Fasiglifam (TAK-875) is a G protein-coupled receptor 40 agonist that was being investigated for treatment of type 2 diabetes mellitus (T2DM). A development program was terminated late in phase III clinical trials due to liver safety concerns. METHODS: The liver safety of fasiglifam was assessed from data based on six phase II and nine phase III double-blind studies and two open-label studies with emphasis on pooled data from 15 double-blind studies from both global and Japanese development programs. Taking into consideration different daily doses of fasiglifam administered in clinical studies, the primary comparisons were between all patients exposed to fasiglifam (any dose) versus placebo, and, where applicable, versus the two active comparators, sitagliptin or glimepiride. A Liver Safety Evaluation Committee consisting of hepatologists blinded to treatment assignments evaluated hepatic adverse events (AEs) and serious AEs (SAEs) for causal relationship to study drug. RESULTS: The analysis included data from 9139 patients with T2DM in 15 double-blind controlled studies who received either fasiglifam (n = 5359, fasiglifam group), fasiglifam and sitagliptin (n = 123), or a comparator agent (n = 3657, non-exposed group consisting of placebo and other antidiabetic agents). Exposure to treatment for more than 1 year ranged from 249 patients in the placebo arm, to 370 patients in the glimepiride arm and 617 patients in the fasiglifam 50 mg arm. The primary focus of the analysis was on the hepatic safety of fasiglifam. The overall safety profile based on treatment-emergent AEs (TEAEs), SAEs, deaths, and withdrawal due to AEs was similar between fasiglifam and placebo (excluding liver test abnormalities). However, there was an increased incidence rate of serum alanine aminotransferase (ALT) elevations > 3 × upper limit of normal (ULN), 5 × ULN, and 10 × ULN in fasiglifam-treated patients compared with those treated with placebo or active comparators. ALT elevations > 3 × ULN for fasiglifam were 2.7% compared with 0.8 and 0.5% for the active comparators and placebo. There did not appear to be a clear dose response in incidence of ALT elevations between patients receiving 25 or 50 mg daily. The cumulative incidence of elevations in serum ALT > 3 × ULN was higher in the first 6 months of treatment with fasiglifam compared with both placebo and the active comparators, but the rate of new ALT elevations appeared to be similar across all treatment groups thereafter. No demographic or baseline patient characteristics were identified to predict elevations exceeding ALT > 3 × ULN in fasiglifam-treated patients. The pattern of liver injury with fasiglifam was hepatocellular, and there were no reports of liver-related deaths, liver failure or life-threatening liver injury. Most fasiglifam-associated ALT elevations were asymptomatic and resolved promptly upon discontinuing treatment, but in two patients the recovery was prolonged. Importantly, three important serious liver injury cases were identified among fasiglifam-treated patients; one case was adjudicated to be a clear Hy's Law case and the two remaining cases were considered to closely approximate Hy's Law cases. CONCLUSIONS: Although the incidence of overall AEs, SAEs, and deaths was similar between fasiglifam and placebo, a liver signal was identified based primarily on the difference in liver chemistry values in the fasiglifam group compared with the placebo and active comparator groups. Three serious liver injuries were attributed to fasiglifam treatment. Clinical development of fasiglifam was halted due to these liver safety concerns.

Combining the G-protein-coupled receptor 40 agonist fasiglifam with sitagliptin improves glycaemic control in patients with type 2 diabetes with or without metformin: A randomized, 12-week trial.

AIMS: To evaluate the efficacy and safety of fasiglifam, an orally active G-protein-coupled receptor 40 agonist, in combination with the dipeptidyl peptidase-4 inhibitor sitagliptin, in patients with type 2 diabetes inadequately controlled with diet/exercise (± metformin). MATERIALS AND METHODS: In this randomized, double-blind, phase II study, 368 patients received once-daily placebo, sitagliptin 100 mg, fasiglifam 25 or 50 mg, or the combination of sitagliptin 100 mg plus fasiglifam 25 or 50 mg. The primary endpoint was change from baseline glycated haemoglobin (HbA1c) at 12 weeks; a key secondary endpoint was change in fasting plasma glucose (FPG). RESULTS: The fasiglifam 25 and 50 mg combination regimens produced significantly greater HbA1c reductions than sitagliptin (treatment differences of -0.45% and -0.61%; P < .01, respectively) or respective doses of fasiglifam monotherapy (-0.43% and -0.48%; P < .01) and significantly greater FPG reductions than sitagliptin (-1.1 mmol/L for both combination regimens; P < .01). Improved glycaemic control occurred by week 1 for FPG and week 4 for HbA1c in all groups. Hypoglycaemia rates were low (≤3.3%) and similar across treatments. Liver enzymes >3 × upper limit of normal occurred in four patients (fasiglifam 25 mg, n = 1; fasiglifam 50 mg, n = 2; 1 fasiglifam/sitagliptin 50/100 mg, n = 1). CONCLUSIONS: Combination of fasiglifam and sitagliptin provided significant additional effects on glycaemic control, with hypoglycaemia rates similar to placebo with or without metformin. This study provides supportive clinical evidence for the complementary mechanism of actions of this GPR40 agonist and DPP-4 inhibitor.

Clinical malaria and sickle cell disease among multiple family members in Chicago, Illinois.

Malaria is a disease of global importance and accounts for up to 500 million cases per year. Nearly all malaria cases in the United States occur among persons who have traveled to areas with ongoing malaria transmission. Among the cases of malaria reported in the United States in 2000-2005, 695 were in US residents under the age of 18 years. The association of malaria with the sickle cell hemoglobin is well described in Africa but is a rare occurrence in the United States. Here we report 5 cases of Plasmodium falciparum malaria in siblings of a family who had traveled to Africa without taking chemoprophylaxis. Two of the children had sickle cell anemia, and 1 of them developed severe life-threatening malaria and hemolysis. The 3 other siblings had sickle cell trait, 2 of whom had complicated malaria. Patients who have sickle cell disease and are infected with malaria are prone to hyperhemolytic crisis; therefore, this complication should be anticipated. The patients we describe emphasize the significance of prompt recognition of malaria and comorbidities and institution of appropriate treatment. The importance of antimalarial prophylaxis should be communicated to parents of children who are traveling to endemic areas as part of routine child care.

Hospital-based directly observed therapy for HIV-infected children and adolescents to assess adherence to antiretroviral medications.

BACKGROUND: The introduction of highly active antiretroviral therapy for HIV led to significant declines in HIV-associated morbidity and mortality in children. Nonadherence to antiretroviral therapy is the leading cause of treatment failure in HIV-infected patients. The ability to recognize nonadherence is suboptimal, and differentiating it from other causes of inadequate viral suppression may be difficult. OBJECTIVES: The purpose of this work was to examine the efficacy of hospital-based directly observed therapy in assessing adherence to antiretroviral medications in HIV-infected children and adolescents suspected of nonadherence and failing other interventions. METHODS: The medical charts of all HIV-infected patients admitted to the University of Chicago Comer Children's Hospital for directly observed therapy from July 2004 to June 2006 were reviewed. Patients were hospitalized for 7 days. Data collected included demographics, clinical and immune class category, previous and current antiretroviral medications, viral resistance tests, HIV-1 RNA viral load, and CD4+ T-cell number and percentage before and after directly observed therapy. RESULTS: There were 9 perinatally infected patients with a total of 13 admissions. The median age was 13 years, and 8 had been treated with multiple antiretroviral regimens. Three common patterns of changes in the viral load over time were observed. In the first, the viral load dropped at the end of the directly observed therapy period and stayed low thereafter. In the second, the drop in the viral load seen at the end of the period was not sustained. In the third, there was no change in the viral load during or after the directly observed therapy period. Compared with the viral load at admission, the viral load at the end of directly observed therapy was lower in 8 patients with a mean +/- SD decrease of 0.8 +/- 0.55 log10 copies per mL. CONCLUSIONS: Short, hospital-based directly observed therapy was helpful in confirming nonadherence to antiretroviral medications, therefore impacting future therapeutic decisions in HIV-infected children and adolescents. Short, hospital-based directly observed therapy should be considered in patients with poor virological control for whom outpatient interventions have failed.

Immunogenicity, safety, and predictors of response after a pneumococcal conjugate and pneumococcal polysaccharide vaccine series in human immunodeficiency virus-infected children receiving highly active antiretroviral therapy.

BACKGROUND: The immunogenicity and safety of 2 doses of pneumococcal conjugate vaccine (PCV) and 1 dose of pneumococcal polysaccharide vaccine (PPV) were evaluated in human immunodeficiency virus (HIV)-infected children receiving highly active antiretroviral therapy (HAART). METHODS: Children 2 to <19 years, receiving stable HAART for > or =3-6 months, with HIV RNA PCR <30,000-60,000 copies/mL, received 2 doses of PCV and 1 dose of PPV at sequential 8-week intervals. Antibodies to pneumococcal serotypes (STs) 1 (PPV only) and 6B, 14, 19F, and 23F (PCV and PPV) were measured by ELISA. RESULTS: Two hundred sixty-three subjects were enrolled, of whom 225 met criteria for inclusion in the primary dataset. Antibody concentrations were low at entry, despite previous PPV in 75%. After vaccination, 76%-96% had concentrations > or =0.5 microg/mL and 62-88% > or =1.0 microg/mL to the 5 STs (geometric mean concentrations [GMCs] = 1.44-4.25 microg/mL). Incremental gains in antibody concentration occurred with each vaccine dose. Predictors of response included higher antibody concentration at entry, higher immune stratum (based on nadir CD4% before HAART and CD4% at screening), lower entry viral RNA, longer duration of the entry HAART regimen, and age <7 years. Response was more consistently related to screening CD4% than nadir CD4%. Seven percent had vaccine-related grade 3 events, most of which were local reactions. CONCLUSIONS: Two PCVs and 1 PPV were immunogenic and safe in HIV-infected children 2 to <19 years who were receiving HAART. Responses were suggestive of functional immune reconstitution. Immunologic status based on nadir and, especially, current CD4% and control of HIV viremia were independent determinants of response.

Epidemiology and treatment of community-associated methicillin-resistant Staphylococcus aureus in children.

Similar to the epidemiology of methicillin-sensitive Staphylococcus aureus, community-associated methicillin-resistant S. aureus infections occur in children in different regions of the USA and throughout the world. Although minor skin and soft-tissue infections predominate, life-threatening invasive disease and death can result. The novel genetic elements, staphylococcal cassette chromosome mec IV and V, explain the narrow antibiotic resistance pattern, and suggest the mechanism of spread among staphylococci. Panton-Valentine leukocidin apparently plays a role in its pathogenesis. Clindamycin therapy is often effective for treatment, but inducible resistance can develop if the isolate exhibits macrolide resistance due to the erm mechanism. Other drugs displaying in vitro activity against community-associated methicillin-resistant S. aureus include trimethoprim-sulfamethoxazole, tetracyclines, quinolones, linezolid and vancomycin. While experience in pediatric patients is limited, daptomycin, ketolides, glycylcyclines, newer glycopeptides and beta-lactamase-stable cephalosporins may be useful in the future. Further research could include well-designed studies of mechanisms of virulence, continued surveillance of changes in pathogenicity and susceptibility, as well as treatment effectiveness.

Treatment of community-acquired methicillin-resistant Staphylococcus aureus in children.

PURPOSE OF REVIEW: The concept of methicillin-resistant Staphylococcus aureus (MRSA) associated with broad resistance, nosocomial acquisition, and known risk factors has recently been expanded. A new type of MRSA that is resistant to fewer antibiotics has emerged in pediatric practice since the mid-1990s. These isolates are community acquired and have been reported from diverse geographic regions. Awareness of these organisms is important for appropriate treatment of S. aureus infections in children. RECENT FINDINGS: Community-acquired MRSA (CA-MRSA) isolates are similar in many respects to community-acquired methicillin-susceptible S. aureus (CA-MSSA). There are usually no differences in risk factors between children with CA-MRSA infections and those with CA-MSSA infections or their household contacts. In one study, however, multivariate analysis showed that age greater than 1 year and health care contact in the preceding month were significant risk factors for CA-MRSA. Skin and soft tissue infections are the most common manifestations, although serious invasive infections and death may occur. Pneumonia has been reported more often in children with CA-MRSA than in those with CA-MSSA. Clindamycin is an effective therapy for CA-MRSA, but there is a risk for development of clindamycin resistance during treatment of a CA-MRSA that is clindamycin susceptible and inducibly erythromycin resistant. Trimethoprim-sulfamethoxazole is likely to be effective, and linezolid is a new option for treatment. SUMMARY: The appearance of CA-MRSA has important implications for therapy of infections caused by S. aureus in children. Three specific issues are the development of resistance during clindamycin therapy, insufficient data on the use of trimethoprim-sulfamethoxazole in serious CA-MRSA infections, and the appropriate role for newer antibiotics such as linezolid.

Clindamycin treatment of methicillin-resistant Staphylococcus aureus infections in children.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) with a narrower antibiotic resistance pattern have emerged. There is a risk for the appearance of resistance during clindamycin therapy of erythromycin-resistant MRSA infections because of the linked resistance mechanisms. METHODS: We analyzed clindamycin-susceptible MRSA organisms from children (1987 to 2000) along with clinical data. Antibiotic susceptibilities of organisms were tested, pulsed field gel electrophoresis (PFGE) was done and the linked resistance mechanism was detected by the D test. RESULTS: An average of 11 clindamycin-susceptible MRSA per year were obtained from children since 1993. Of 88 isolates 33 (38%) were erythromycin-resistant. The latter were less often community-acquired (45% vs. 69%), more often from infants <1 month of age (24% vs. 4%) and less likely to be in the community acquisition-associated PFGE Group 1 (62% vs. 87%) than those that were susceptible. The D test was positive in 31 of 33 erythromycin-resistant isolates. A 9-month-old boy with pneumonia/empyema caused by a clindamycin-susceptible, erythromycin-resistant, D test-positive MRSA developed a PFGE-identical clindamycin-resistant isolate and clinical relapse during clindamycin treatment. In contrast a 12-year-old girl with abscesses caused by a similar MRSA developed another abscess after clindamycin therapy, but the organism was unchanged in susceptibility. CONCLUSIONS: Erythromycin resistance was present in 38% of clindamycin-susceptible MRSA in children, and clindamycin resistance was detected during treatment in one child. Clindamycin remains a treatment option if the clinician is notified of the risk by the microbiology laboratory and the clinical situation is suitable.

Chronic vulvovaginitis caused by antibiotic-resistant Shigella flexneri in a prepubertal child.

A 7-year 8-month-old girl was diagnosed with a prolonged course of vulvovaginitis caused by Shigella flexneri. The child was symptomatic with intermittent vaginal bleeding, dysuria and foul smelling vaginal discharge for a 3-year period. Initial attempts to resolve the infection with successive courses of antibiotic therapy using ampicillin, trimethoprim-sulfamethoxazole, cefixime and amoxicillin/clavulanic acid failed. The child's infection was finally resolved by a 14-day course of ciprofloxacin.