The impact of 2-dose routine measles, mumps, rubella, and varicella vaccination in France on the epidemiology of varicella and zoster using a dynamic model with an empirical contact matrix.

PURPOSE: Varicella has a high incidence affecting the vast majority of the population in France and can lead to severe complications. Almost every individual infected by varicella becomes susceptible to herpes zoster later in life due to reactivation of the latent virus. Zoster is characterized by pain that can be long-lasting in some cases and has no satisfactory treatment. Routine varicella vaccination can prevent varicella. The vaccination strategy of replacing both doses of measles, mumps, and rubella (MMR) with a combined MMR and varicella (MMRV) vaccine is a means of reaching high vaccination coverage for varicella immunization. The objective of this analysis was to assess the impact of routine varicella vaccination, with MMRV in place of MMR, on the incidence of varicella and zoster diseases in France and to assess the impact of exogenous boosting of zoster incidence, age shift in varicella cases, and other possible indirect effects. METHODS: A dynamic transmission population-based model was developed using epidemiological data for France to determine the force of infection, as well as an empirically derived contact matrix to reduce assumptions underlying these key drivers of dynamic models. Scenario analyses tested assumptions regarding exogenous boosting, vaccine waning, vaccination coverage, risk of complications, and contact matrices. FINDINGS: The model provides a good estimate of the incidence before varicella vaccination implementation in France. When routine varicella vaccination is introduced with French current coverage levels, varicella incidence is predicted to decrease by 57%, and related complications are expected to decrease by 76% over time. After vaccination, it is observed that exogenous boosting is the main driver of change in zoster incidence. When exogenous boosting is assumed, there is a temporary increase in zoster incidence before it gradually decreases, whereas without exogenous boosting, varicella vaccination leads to a gradual decrease in zoster incidence. Changing vaccine efficacy waning levels and coverage assumptions are still predicted to result in overall benefits with varicella vaccination. IMPLICATIONS: In conclusion, the model predicted that MMRV vaccination can significantly reduce varicella incidence. With suboptimal coverage, a limited age shift of varicella cases is predicted to occur post-vaccination with MMRV. However, it does not result in an increase in the number of complications. GSK study identifier: HO-12-6924.

Cost-effectiveness of routine varicella vaccination using the measles, mumps, rubella and varicella vaccine in France: an economic analysis based on a dynamic transmission model for varicella and herpes zoster.

PURPOSE: Each year in France, varicella and zoster affect large numbers of children and adults, resulting in medical visits, hospitalizations for varicella- and zoster-related complications, and societal costs. Disease prevention by varicella vaccination is feasible, wherein a plausible option involves replacing the combined measles, mumps, and rubella (MMR) vaccine with the combined MMR and varicella (MMRV) vaccine. This study aimed to: (1) assess the cost-effectiveness of adding routine varicella vaccination through MMRV, using different vaccination strategies in France; and (2) address key uncertainties, such as the economic consequences of breakthrough varicella cases, the waning of vaccine-conferred protection, vaccination coverage, and indirect costs. METHODS: Based on the outputs of a dynamic transmission model that used data on epidemiology and costs from France, a cost-effectiveness model was built. A conservative approach was taken regarding the impact of varicella vaccination on zoster incidence by assuming the validity of the hypothesis of an age-specific boosting of immunity against varicella. FINDINGS: The model determined that routine MMRV vaccination is expected to be a cost-effective option, considering a cost-effectiveness threshold of €20,000 per quality-adjusted life-year saved; routine vaccination was cost-saving from the societal perspective. Results were driven by a large decrease in varicella incidence despite a temporary initial increase in the number of zoster cases due to the assumption of exogenous boosting. In the scenario analyses, despite moderate changes in assumptions about incidence and costs, varicella vaccination remained a cost-effective option for France. IMPLICATIONS: Routine vaccination with MMRV was associated with high gains in quality-adjusted life-years, substantial reduction in the occurrences of varicella- and zoster-related complications, and few deaths due to varicella. Routine MMRV vaccination is also expected to provide reductions in costs related to hospitalizations, medication use, and general-practitioner visits, as well as indirect costs, and it is expected to be a cost-effective intervention in France (GSK study identifier: HO-12-6924).

Medication adherence in schizophrenia: factors influencing adherence and consequences of nonadherence, a systematic literature review.

BACKGROUND: Nonadherence to medication is a recognized problem and may be the most challenging aspect of treatment. METHODS: We performed a systematic review of factors that influence adherence and the consequences of nonadherence to the patient, healthcare system and society, in patients with schizophrenia. Particular attention was given to the effect of nonadherence on hospitalization rates, as a key driver of increased costs of care. A qualitative systematic literature review was conducted using a broad search strategy using disease and adherence terms. Due to the large number of abstracts identified, article selection was based on studies with larger sample sizes published after 2001. Thirty-seven full papers were included: 15 studies on drivers and 22 on consequences, of which 12 assessed the link between nonadherence and hospitalization. RESULTS: Key drivers of nonadherence included lack of insight, medication beliefs and substance abuse. Key consequences of nonadherence included greater risk of relapse, hospitalization and suicide. Factors positively related to adherence were a good therapeutic relationship with physician and perception of benefits of medication. The most frequently reported driver and consequence were lack of insight and greater risk of hospitalization respectively. CONCLUSIONS: Improving adherence in schizophrenia may have a considerable positive impact on patients and society. This can be achieved by focusing on the identified multitude of factors driving nonadherence.

Dosing frequency and adherence in chronic psychiatric disease: systematic review and meta-analysis.

BACKGROUND: The purpose of this study was to investigate the impact of dosing frequency on adherence in severe chronic psychiatric and neurological diseases. METHODS: A systematic literature review was conducted for articles in English from medical databases. Diseases were schizophrenia, psychosis, epilepsy, bipolar disorder, and major depressive disorder. RESULTS: Of 1420 abstracts screened, 12 studies were included. Adherence measures included Medication Event Monitoring System (MEMS(®)), medication possession ratio, medication persistence, and refill adherence. Three schizophrenia and one epilepsy study used MEMS, and all showed a trend towards higher adherence rates with less frequent dosing regimens. Three depression and one schizophrenia study used the medication possession ratio; the pooled odds ratio of being adherent was 89% higher (ie, 1.89, 95% credibility limits 1.71-2.09) on once-daily versus twice-daily dosing. Two studies in depression and one in all bupropion patients assessed medication persistence and refill adherence. The pooled odds ratio for the two depression studies using medication persistence was 2.10 (95% credibility limits 1.86-2.37) for once-daily versus twice-daily dosing. For refill adherence after 9 months, 65%-75% of patients on once-daily versus 56% on twice-daily dosing had at least one refill. In all but one of the studies using other measures of adherence, adherence rates were higher with once-daily dosing compared with more frequent dosing regimens. No relevant studies were identified for bipolar disorder or psychosis. CONCLUSION: Differences in study design and adherence measures used across the studies were too large to allow pooling of all results. Despite these differences, there was a consistent trend of better adherence with less frequent dosing.

A network meta-analysis of the efficacy of inhaled antibiotics for chronic Pseudomonas infections in cystic fibrosis.

BACKGROUND: Various inhaled antibiotics are currently used for treating chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients, however their relative efficacies are unclear. We compared the efficacy of the inhaled antibiotics tobramycin (TIP, TIS-T, TIS-B), colistimethate sodium (colistin) and aztreonam lysine for inhalation (AZLI) based on data from randomised controlled trials. METHODS: In the base case, efficacies of antibiotics were compared using a network meta-analysis of seven trials including change from baseline in forced expiratory volume in 1 second (FEV(1)) % predicted, P. aeruginosa sputum density and acute exacerbations. RESULTS: The tobramycin preparations, AZLI and colistin, showed comparable improvements in efficacy in terms of FEV1% predicted at 4 weeks; the difference in % change from baseline (95%CrI) for TIP was compared to TIS-T (-0.55, -3.5;2.4), TIS-B (-0.64, -7.1;5.7), AZLI (3.64, -1.0;8.3) and colistin (5.77, -1.2;12.8). CONCLUSION: We conclude that all studied antibiotics have comparable efficacies for the treatment of chronic P. aeruginosa lung infection in CF.

Delivering outpatient antibiotic therapy (OPAT) in an Acute Medical Unit.

Outpatient antibiotic therapy (OPAT) is being developed and practised in an increasing number of acute hospitals within the United Kingdom. This article is a review of the OPAT service delivered by a large inner city hospital over the last two years. The service demonstrates the key elements of OPAT demonstrating different delivery models, aspects of patient selection, spectrum of infections treated, choice and delivery of antimicrobials, efficacy, patient safety, outcomes, and the cost-effectiveness of this programme.

Cost–effectiveness of catch-up programs in human papillomavirus vaccination.

We reviewed cost–effectiveness models that combine routine vaccination with the human papillomavirus (HPV) vaccine with temporary catch-up programs. Cost–effectiveness results of catch-up programs are variable, and we reviewed methods and underlying assumptions to get more insight into any factor with a potential impact on cost-effectiveness. Results were dependent on differences between models used, their design and input data. Modeling aspects and assumptions were not always sufficiently described, making comparison difficult. Despite this, several differences between models likely to impact results were identified. All models used dynamic transmission modeling techniques except for one, which did not incorporate the effect of herd immunity. Catch-up strategies varied between models and comparator strategies were not necessarily the same. Cervical diseases outcomes were considered in all base cases, but the impact of genital warts was not always considered. Our article suggests that a conclusion on cost–effectiveness should be based on a fully transparent model including all possible benefits of vaccination.

Estimation of the incidence of genital warts and the cost of illness in Germany: a cross-sectional study.

BACKGROUND: Human papillomavirus (HPV) is a necessary cause of cervical cancer. HPV is also responsible for benign condylomata acuminata, also known as genital warts. We assessed the incidence of genital warts in Germany and collected information on their management to estimate the annual cost of disease. METHODS: This was a multi-centre observational (cross-sectional) study of genital warts in Germany. Data were collected from gynecologists, dermatologists, and urologists seeing patients with genital warts between February and April 2005. The number of patients with new and recurrent genital warts was used to estimate the incidence in Germany. We assessed resource use for patients with genital warts seen during a two-month period as well as retrospective resource use twelve months prior to the inclusion visit through a chart review. The mean costs of treatment of patients with genital warts from third-party payer and societal perspectives were estimated, and the total annual cost of genital warts was then calculated. RESULTS: For the incidence calculation 217 specialists provided information on 848 patients and 214 specialists provided resource use data for 617 patients to assess resource consumption. The incidence of new and recurrent cases of genital warts was 113.7 and 34.7 per 100 000, respectively, for women aged 14-65 years consulting gynecologists. The highest incidence was observed in women aged 14-25 years (171.0 per 100 000) for new cases and in women aged 26-45 years (53.1 per 100 000) for recurrent cases. The sample size for males was too small to allow a meaningful estimate of the incidence. The mean direct cost per patient with new genital warts was estimated at 378 euros (95% CI: 310.8-444.9); for recurrent genital warts at 603 euros (95% CI: 436.5-814.5), and for resistant genital warts at 1,142 euros (95% CI: 639.6-1752.3). The overall cost to third-party payers was estimated at 49.0 million euros, and the total societal cost at 54.1 million euros, corresponding to an average cost per patient of 550 euros and 607 euros, respectively. CONCLUSION: The societal burden and costs of managing and treating genital warts in Germany are considerable. A vaccination programme using the quadrivalent human papillomavirus vaccine could provide a substantial health benefit and reduce the costs associated with genital warts in Germany.

Adjunctive treatment with moxonidine versus nitrendipine for hypertensive patients with advanced renal failure: a cost-effectiveness analysis.

BACKGROUND: Systemic hypertension often accompanies chronic renal failure and can accelerate its progression to end-stage renal disease (ESRD). Adjunctive moxonidine appeared to have benefits versus adjunctive nitrendipine, in a randomised double-blind six-month trial in hypertensive patients with advanced renal failure. To understand the longer term effects and costs of moxonidine, a decision analytic model was developed and a cost-effectiveness analysis performed. METHODS: A Markov model was used to extrapolate results from the trial over three years. All patients started in a non-ESRD state. After each cycle, patients with a glomerular filtration rate below 15 ml/min had progressed to an ESRD state. The cost-effectiveness analysis was based on the Dutch healthcare perspective. The main outcome measure was incremental cost per life-year gained. The percentage of patients progressing to ESRD and cumulative costs were also compared after three years. In the base case analysis, all patients with ESRD received dialysis. RESULTS: The model predicted that after three years, 38.9% (95%CI 31.8-45.8) of patients treated with nitrendipine progressed to ESRD compared to 7.5% (95%CI 3.5-12.7) of patients treated with moxonidine. Treatment with standard antihypertensive therapy and adjunctive moxonidine was predicted to reduce the number of ESRD cases by 81% over three years compared to adjunctive nitrendipine. The cumulative costs per patient were significantly lower in the moxonidine group 9,858 euro (95% CI 5,501-16,174) than in the nitrendipine group 37,472 euro (95% CI 27,957-49,478). The model showed moxonidine to be dominant compared to nitrendipine, increasing life-years lived by 0.044 (95%CI 0.020-0.070) years and at a cost-saving of 27,615 euro (95%CI 16,894-39,583) per patient. Probabilistic analyses confirmed that the moxonidine strategy was dominant over nitrendipine in over 98.9% of cases. The cumulative 3-year costs and LYL continued to favour the moxonidine strategy in all sensitivity analyses performed. CONCLUSION: Treatment with standard antihypertensive therapy and adjunctive moxonidine in hypertensive patients with advanced renal failure was predicted to reduce the number of new ESRD cases over three years compared to adjunctive nitrendipine. The model showed that adjunctive moxonidine could increase life-years lived and provide long term cost savings.

Factor VIII von Willebrand protein in haemolytic uraemic syndrome and systemic vasculitides.

von Willebrand protein (vWF) is reduced by dithiothreitol (DTT) and, as a result, is not detected by enzyme-linked immunosorbent assay (ELISA). Plasma samples from normal subjects, children with haemolytic uraemic syndrome (HUS), and adults with vasculitis and vWF prepared from endothelium were treated with DTT before vWF assay. vWF in HUS and vasculitis resembled the endothelial form in being resistant to reduction. DTT modification of the ELISA assay may be useful as a marker of disease severity in conditions associated with endothelial cell damage.

Intraperitoneal penetration of cefpirome.

Twenty-six patients undergoing elective gastrointestinal surgery received a 1 g intravenous dose of cefpirome before operation. Serum and peritoneal fluid samples, obtained 0.5-7.6 h following administration, were assayed for cefpirome by a microbiological assay. The serum half-life of cefpirome was 2.1 h. The mean concentration of cefpirome in peritoneal fluid 0-2 h after administration was 44.4 micrograms/ml. The half-life of cefpirome in peritoneal fluid was 2 h, with mean concentrations of less than 10 micrograms/ml measured 6 h after administration. The mean percentage of intraperitoneal penetration of cefpirome over the study period was 97.7%. The therapeutic implications are discussed.

Tissue penetration and pharmacokinetics of lomefloxacin following multiple doses.

The pharmacokinetics of lomefloxacin were studied after three days of oral administration of 400 mg/day lomefloxacin. Following the final dose the concentrations in serum, urine and cantharidin-induced inflammatory fluid were measured by a microbiological assay. The mean peak serum level was 4.9 mg/l at a mean time of 0.8 h. The mean serum elimination half-life was 6.2 h. The mean maximum inflammatory fluid level attained was 3.2 mg/l at 2.7 h. Urinary recovery accounted for the greater part of lomefloxacin's elimination.

Pharmacokinetics and tissue penetration of cefpirome, a new cephalosporin.

The pharmacokinetics and tissue penetration (as measured by a blister fluid model) of cefpirome were studied in six male volunteers following a 1 g intravenous dose. A mean peak serum concentration (at 5 min) of 97.4 mg/l was followed by rapid distribution into an apparent volume of 21.3 1. The serum elimination half-life was 2.3 h. Cefpirome penetrated rapidly into inflammatory fluid with a mean peak concentration of 39.2 mg/l at 1.9 h. The mean inflammatory fluid elimination half-life was 2.5 h. The availability of the drug in inflammatory fluid was high with a mean per cent penetration of 123%. The plasma and renal clearances were 109.5 and 82.1 ml/min respectively. Twenty-four hour urinary recovery was 75.5% of the administered dose. This study suggests that a twice daily dosage may be sufficient to treat tissue infections with susceptible pathogens.

A comparison of the pharmacokinetics and tissue penetration of spiramycin and erythromycin.

The pharmacokinetics of two orally administered macrolides, spiramycin and erythromycin, were compared in six healthy male volunteers in a single dose cross-over study. Penetration of these antimicrobial agents into inflammatory fluid was studied. Spiramycin was administered in a 2 g dose and erythromycin in a 500 mg dose. Spiramycin (Tmax = 3.3 h) and erythromycin (Tmax = 1.2 h) were well absorbed reaching mean plasma Cmax of 3.1 mg/l and 2.1 mg/l, respectively. The relative bioavailability of erythromycin compared to spiramycin appeared to be three- to four-fold greater. The mean plasma elimination half-life was 3.8 h for spiramycin and 1.6 h for erythromycin. The percentage penetration of the antibiotics into inflammatory fluid was good, being 66% for spiramycin and 54% for erythromycin. Both antimicrobial agents attained inflammatory fluid Cmax of 0.7 mg/l by 4-4.8 h. Spiramycin persisted in the inflammatory fluid with a mean elimination half-life of 7.7 h compared to 2.2 h for erythromycin. Twenty-four hour urinary recovery of the administered dose of each antimicrobial agent was less than 5%.