Community-based provision of direct-acting antiviral therapy for hepatitis C: study protocol and challenges of a randomized controlled trial.

BACKGROUND: To achieve the World Health Organization hepatitis C virus (HCV) elimination targets, it is essential to increase access to treatment. Direct-acting antiviral (DAA) treatment can be provided in primary healthcare services (PHCS), improving accessibility, and, potentially, retention in care. Here, we describe our protocol for assessing the effectiveness of providing DAAs in PHCS, and the impact on the HCV care cascade. In addition, we reflect on the challenges of conducting a model of care study during a period of unprecedented change in HCV care and treatment. METHODS: Consenting patients with HCV infection attending 13 PHCS in Australia or New Zealand are randomized to receive DAA treatment at the local tertiary institution (standard care arm), or their PHCS (intervention arm). The primary endpoint is the proportion commenced on DAAs and cured. Treatment providers at the PHCS include: hepatology nurses, primary care practitioners, or, in two sites, a specialist physician. All PHCS offer opioid substitution therapy. DISCUSSION: The Prime Study is the first real-world, randomized, model of care study exploring the impact of community provision of DAA therapy on HCV-treatment uptake and cure. Although the study has faced challenges unique to this period of time characterized by changing treatment and service delivery, the data gained will be of critical importance in shaping health service policy that enables the elimination of HCV. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT02555475 . Registered on 15 September 2015.

Once daily ledipasvir/sofosbuvir fixed-dose combination with ribavirin in patients with inherited bleeding disorders and hepatitis C genotype 1 infection.

AIM: People with inherited bleeding disorders have been disproportionally affected by HCV. We assessed the fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) with the NS5B polymerase inhibitor sofosbuvir (SOF) with ribavirin (RBV) in patients with genotype 1 HCV and inherited bleeding disorders. METHODS: To be eligible, patients had to be over 18 years of age and have an inherited bleeding disorder. HCV treatment-naïve and -experienced patients could enrol. All patients received LDV 90 mg per SOF 400 mg once daily and weight-based RBV in a divided dose for 12 weeks. The primary efficacy endpoint was sustained virologic response (SVR), defined as HCV RNA below the limit of detection (15 IU mL-1 ) 12 weeks after the end of treatment (SVR12). RESULTS: Of the 14 patients enrolled, 8 (57%) had haemophilia A, 3 (21%) had haemophilia B and 2 (14%) had von Willebrand disease, and 1 (7%) had factor XIII deficiency. All 14 patients (100%, 95% CI: 77-100%) achieved SVR12. Treatment was well tolerated: all patients completed therapy, with mostly mild adverse events. No specific safety concerns associated with the patient's underlying bleeding disorders were noted. CONCLUSION: These results appear to suggest that people with HCV and inherited bleeding disorders can be safely and effectively treated with 12 weeks of LDV/SOF plus RBV.

Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 2.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality. In many countries, there is a lack of comprehensive epidemiological data that are crucial in implementing disease control measures as new treatment options become available. Published literature, unpublished data and expert consensus were used to determine key parameters, including prevalence, viremia, genotype and the number of patients diagnosed and treated. In this study of 15 countries, viremic prevalence ranged from 0.13% in the Netherlands to 2.91% in Russia. The largest viremic populations were in India (8 666 000 cases) and Russia (4 162 000 cases). In most countries, males had a higher rate of infections, likely due to higher rates of injection drug use (IDU). Estimates characterizing the infected population are critical to focus screening and treatment efforts as new therapeutic options become available.

Medical co-morbidities and practice.

All-oral treatments of hepatitis C (HCV) have been trialled in patients with hereditary bleeding disorders and found to be effective. Further refinements of dosing and duration are being established. Importantly for patient acceptability these regimens are interferon-free. Cohort studies in older patients with haemophilia direct the need for attention to weight control, exercice, assessment of cardiovascular risk, especially hypertension and detection of osteoporosis. Where patients live a long way from a comprehensive care centre, telemedicine connections can engage centre experts with the patient and his/her local practitioners in devising and monitoring care plans.

Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors.

Proton pump inhibitors have dramatically influenced the management of acid-peptic disorders in recent years. They all have a broadly similar mechanism of action and are extensively metabolized in the liver via cytochromes P450 2C19 and 3A4. There is some variation in their potential for drug interactions due to differences in enzyme inhibition. Relatively few serious adverse effects have been reported for the proton pump inhibitors. Comparative studies of acid suppression suggest that lansoprazole and pantoprazole have a potency similar to that of omeprazole on a mg for mg basis; however, rabeprazole may have a greater potency than omeprazole. Lansoprazole and rabeprazole display a more rapid onset of maximal acid suppression than the other proton pump inhibitors. Comparative studies using proton pump inhibitors for the treatment of reflux oesophagitis, duodenal ulcer healing and Helicobacter pylori eradication show little overall difference in outcome between the proton pump inhibitors when used in their standard doses. Lansoprazole and rabeprazole provide earlier and better symptom relief than the other proton pump inhibitors in some studies of peptic ulcer treatment. The few studies of gastric ulcer treatment suggest that there is an advantage in using the proton pump inhibitors that have a higher standard daily dose.

Hospital care techniques resulting in intact survival of a 380-g infant.

Intact survival of infants delivered before completion of the 26th week of gestation or weighing less than 500 g is a well known phenomenon. We recently cared for an infant whose birth weight was 380 g, making her one of the smallest survivors in the United States. Her hospitalization (including expenses), the techniques of our minimal intervention protocol and her 20-month (corrected) follow-up are presented together with a discussion of the moral, economic and social implications involved in the care of such an infant.

Cord blood gas patterns identifying newborns at increased risk of group B streptococcal sepsis.

The effect of group B streptococcal sepsis acquired in utero on umbilical cord gas values is not known. Hypothesizing that fetal acid-base balance may be affected, we sought to identify a pattern of cord gas values that might detect newborns at increased risk of group B streptococcal sepsis. This review encompassed all newborns from January 1, 1986 to March 31, 1990 who manifested group B streptococcal sepsis as confirmed by a positive blood culture. An increased-risk cord gas profile was identified as an arterial pH less than 7.18 with either an arterial carbon dioxide pressure less than 59 mmHg or bicarbonate level less than 19 mEq/L. This pattern was found in four of 11 newborns with group B streptococcal disease but in only 43 of 4290 controls, yielding a relative risk of 51.7 (95% confidence interval 13.1-224.9). Our results suggest that a mild metabolic acidosis characterized by these indices may serve as an indicator of increased risk of early-onset group B streptococcal disease.

Imitators of preeclampsia and HELLP syndrome.

The key to the differential diagnosis of these related conditions is knowledge of the natural history of each disease process; an awareness of how this usually translates in each instance into clinical and laboratory parameters; an appreciation for the wide spectrum of findings for each of these conditions, which are more aptly considered disease syndromes rather than single diseases; and the good fortune to encounter the patient early enough or midway in the course of her disease, prior to terminal stages when all subtle differences among disease syndromes almost disappear in a blur of grossly abnormal physiology and multiple organ failures.

Vaginal birth after cesarean section: the impact of patient resistance to a trial of labor.

In spite of the relative safety and medical advantages of vaginal birth after cesarean section, the procedure continues to be underutilized in the private practice setting. To evaluate the hypothesis that resistance by the patient often precludes a trial of labor, an observational study was conducted of all women with a history of one prior cesarean section who were delivered in 1989 at Ochsner Foundation Hospital. The choices of 167 women and the judgments of their obstetricians were longitudinally recorded during the antepartum and intrapartum course. Patients routinely received the patient guide of the American College of Obstetricians and Gynecologists for vaginal birth after cesarean section. Ultimately, 50% of patients who were encouraged by their obstetrician toward vaginal birth after cesarean section opted for an elective repeat cesarean section without a trial of labor. Reasons for patient resistance are enumerated and potential future remedial proposals are discussed.

Intact survival and 20-month follow-up of a 380-gram infant.

Intact survival of infants delivered before completion of the 26th week of gestation or weighing less than 500 g is a well-known phenomenon. We recently cared for an infant whose birthweight was 380 g, making her the second smallest survivor in the United States. Her hospitalization (including expenses) and 20-month (corrected) follow-up are presented along with a discussion of the implications involved in the care of such an infant.

Uterine activity in patients with cervical cerclage.

Cervical cerclage is the traditional management of cervical incompetence. Uterine activity among these patients has never been studied. This retrospective report details the contraction frequency in 96 patients with cerclage who underwent daily home uterine activity monitoring. Twenty-three percent (22) developed preterm labor and 12% (11) had preterm delivery related to failed tocolysis or rupture of the membranes. Uterine activity in the group who developed preterm labor was significantly greater than in those who labored at term. The objective contraction frequency data obtained by uterine activity monitoring are of clinical significance to physicians managing such patients.

Comparison of predelivery versus postdelivery Kleihauer-Betke stains in cases of fetal death.

A prospective study was undertaken to determine whether the delivery process could introduce a significant amount of fetal cells into the maternal circulation in patients with a fetal death. Sixty-six cases of fetal death were studied over a 39-month period. All patients had both predelivery and postdelivery Kleihauer-Betke stains performed. Of these, three (4.6%) had a massive fetomaternal hemorrhage. None of the postdelivery stains showed evidence of a significant fetomaternal hemorrhage unless results of the antepartum stain had also been positive. We conclude that the delivery process itself does not simulate a massive fetomaternal hemorrhage in cases of fetal death.

Intraoperative complications and unexpected pathology at the time of cesarean section.

During cesarean section, operative complications include injury to the uterus, urinary tract, and bowel. A variety of types of fetal injuries have been reported, and some are associated with permanent handicap. The relative risk of intraoperative complications varies widely depending on such clinical variables as gestational age, station of the presenting part, and the experience of the operating physician. Ideally, each physician should be able to review his or her rate and type of complications so that continuous improvement in technique is fostered. Gynecologic tumors (malignant and benign) are rarely associated with pregnancy, and their incidental finding at the time of cesarean section is also rare. Management of malignant tumors depends greatly on the stage of the tumor. Conservative management of early-stage malignant ovarian tumors is permissible. More advanced malignant ovarian tumors and malignant tumors of the uterus and fallopian tube should be treated aggressively with removal of the reproductive organs.

Rh sensitization after third-trimester fetal death.

Three primigravidas developed Rh sensitization after unexplained third-trimester fetal death. One patient manifested sensitization after the diagnosis of fetal death had been made but before delivery occurred. The other two demonstrated anti-D antibodies early in the next pregnancy, despite having received postpartum Rh immunoglobulin. Unsensitized Rh-negative women with unexplained third-trimester fetal death should be screened routinely for fetomaternal hemorrhage when fetal death is discovered, so that adequate prophylaxis against Rh sensitization can be given.

Immune thrombocytopenia: effects of maternal gamma globulin infusion on maternal and fetal serum, platelet, and monocyte IgG.

A 24-year-old woman with lupus-like serologic abnormalities had immune thrombocytopenia that resolved after splenectomy, but increased quantities of platelet surface IgG persisted. Three years later, during the 36th week of her first pregnancy, gamma globulin (400 mg/kg daily for 5 days) was administered intravenously to decrease the risk and/or severity of immune thrombocytopenia in her infant. The infusion produced marked but transient elevations of maternal concentrations of serum IgG and quantities of monocyte surface IgG, but no significant changes in Fc receptor-mediated rosetting of peripheral blood monocytes with antibody-sensitized platelets occurred. Modest increases in quantities of platelets and plasma platelet-specific IgG were demonstrated. The infant, delivered by cesarean section 2 days after the end of the infusion, had a normal platelet count; cord blood had a normal concentration of serum IgG, but an elevated quantity of platelet surface IgG (by comparison with values for normal adults). Infant values of plasma platelet-specific IgG, monocyte surface IgG, and monocyte/platelet rosettes also were within the range of normal for adults. Anticytomegalovirus antibody was present in large amounts in the gamma globulin infused, first appeared in maternal serum after therapy, and was detected in cord serum. The significance of these observations to the management of immune neonatal thrombocytopenia is discussed.

Use of the erythrocyte rosette test to screen for excessive fetomaternal hemorrhage in Rh-negative women.

The possibility of Rh immune globulin failure exists when a fetomaternal hemorrhage exceeds 25 to 30 ml of whole blood and only one 300 micrograms vial of Rh immune globulin is administered. In this prospective study of 1000 consecutive Rh-negative women who were delivered of Rh-positive newborn infants, the presence of fetal erythrocytes in maternal blood was identified with use of both the Du test read microscopically and the erythrocyte rosette test. All positive tests prompted fetomaternal hemorrhage quantification with use of a modified Kleihauer-Betke acid elution test. Nineteen patients demonstrated a positive rosette test, and the only positive Du tests were in five of these 19. Six of the nineteen had levels of greater than 30 ml of whole blood for an incidence of 0.6% for fetomaternal hemorrhage exceeding the protective capabilities of the standard Rh immune globulin dosage. In experiments with simulated fetomaternal hemorrhage, all 79 samples, containing from 2.5 to 70 ml of fetal whole blood, were positive according to the erythrocyte rosette test. Applying the Du test to the same samples resulted in a 30% false negative rate at the level of a 30 ml simulated hemorrhage. Based on sufficient sensitivity, ease of interpretation, and reasonable cost, the rosette test appears to be a superior screening test for excessive fetomaternal hemorrhage in Rh immune globulin candidates.

Anti-D antibodies in D- and Du-positive women: a cause of hemolytic disease of the newborn.

Regardless of the decrease in Rh sensitization as a cause of hemolytic disease of the newborn, antenatal antibody screening must be performed in all patients to detect not only anti-D sensitization, but other less common antibodies capable of provoking hemolytic disease of the newborn. The relative incidence of hemolytic disease of the newborn due to sensitization to such irregular antibodies as Kell, Kidd, and Duffy is increasing. We report here five patients who had D- or Du-positive blood with antenatal anti-D sensitization, and whose neonates had hemolytic disease of the newborn of varying severity. Blood that is D- and Du-positive with anti-D has been classified by Tippett; such blood types lack part of the D mosaic and are considered to be "D variants" yet are typed routinely as Rh positive. Anti-D antibody produced by D- and Du-positive blood is indistinguishable from the ordinary variety of anti-D.