Cost-utility analysis of antiviral use under pandemic influenza using a novel approach - linking pharmacology, epidemiology and heath economics.

Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) - dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients' quality of life. Integrating PK/PD-EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.

Previously diagnosed influenza infections and the risk of developing epilepsy.

Several epidemiological studies suggest a possible involvement of viral infection in the development of epilepsy. While recent research from in vitro studies increasingly supports the role of herpes simplex virus type 1 (HSV-1) in the pathogenesis of epilepsy, little is known about the role of other viral infections such as influenza. Using data from the Clinical Practice Research Datalink (CPRD), we conducted a matched case-control analysis to assess the association between GP-diagnosed influenza infections and the risk of developing an incident diagnosis of epilepsy. During the study period 11 244 incident epilepsy cases and 44 976 matched control patients were identified. Prior exposure to influenza was reported in 7·5% of epilepsy cases and 6·7% of controls [adjusted odds ratio (aOR) 1·12, 95% confidence interval (CI) 1·03-1·22]. Prior history of 'complicated influenza', i.e. influenza associated with a possible super-infection, was associated with a slightly increased epilepsy risk (aOR 1·64, 95% CI 1·10-2·46), particularly if recorded within the 2 months preceding the epilepsy diagnosis (aOR 6·03, 95% CI 1·10-33·2). Our findings suggest that prior influenza exposure does not appear to materially alter the risk of developing epilepsy. By contrast, influenza episodes accompanied by complications were associated with a slightly increased epilepsy risk.

Pharmacokinetic-pharmacodynamic determinants of oseltamivir efficacy using data from phase 2 inoculation studies.

Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC(50)] = 0.18 nM) or B/Yamagata (IC(50) = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC(0-24)), minimum concentration of OC in plasma (C(min)), and maximum concentration of OC in plasma (C(max)). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC(0-24 )evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC(0-24) threshold (~14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.

Effectiveness of co-artemether in an unsupervised outpatient setting for the treatment of falciparum malaria.

OBJECTIVES: To assess artemether-lumefantrine effectiveness in the treatment of falciparum malaria in an unsupervised outpatient setting in Africa. DESIGN: Open label prospective study. SETTING: Occupational health clinic, Mozambique. SUBJECTS: Semi-immune Mozambican adults. OUTCOME MEASURES: 28-day treatment failures. RESULTS: 54/54 subjects were smear negative on day 2, and at 'day 28' (range 26-34 days). CONCLUSIONS: Artemether-lumefantrine is effective in semi-immune adults in an unsupervised outpatient setting in Southern Africa, with no evidence of recrudescence.

Falciparum malaria presenting with pruritic rashes.

Rash is not generally believed to be a symptom of malaria. Two cases of acute falciparum malaria in non-immune residents of Mozambique who presented with pruritic rashes are reported. One case exhibited classical urticaria, the other a pruritic papular rash. Review of the literature reveals cases of malaria from India, East Africa, France, and the USA presenting with urticaria or a pruritic rash. Previous exposure to malaria may be a factor in these presentations. Physicians should not discount the diagnosis of malaria in patients with a history of exposure if they present with a rash. This may be of particular importance in travellers returned from malarious areas to developed countries.

Haemoglobinuria in a case of Falciparum malaria treated with co-artemether.

The first reported case of haemoglobinuria in a patient treated with co-artemether for falciparum malaria is described.

Successful co-artemether (artemether-lumefantrine) clearance of falciparum malaria in a patient with severe cholera in Mozambique.

Background. Both falciparum malaria and cholera occur in Mozambique and other resource poor African countries. We report successful parasite clearance by oral co-artemether of coincidental falciparum malaria in a patient suffering severe cholera. Methods. A case report. Results. Parasite clearance was observed at day 3. Conclusions. Oral artemether is sufficiently absorbed in the face of co-existent severe cholera to effect parasitological clearance of P. falciparum. This may be of relevance in resource poor tropical settings when a malaria patient presents with a simultaneous secretory diarrhoea, and a limited drug choice is available.

Pancreatitis complicating adult immunisation with a combined mumps measles rubella vaccine. A case report and literature review.

We report a case of pancreatitis and parotitis in an adult male following immunisation with a trivalent mumps-measles-rubella vaccine. Presentation was 21 days after vaccination, with the patient making a full recovery without intervention. A literature review revealed only five other such cases, with the Urabe strain of attenuated mumps virus appearing to be disproportionately represented. The Urabe vaccine strain has been withdrawn in some countries as it has been implicated disproportionately in the genesis of post-vaccination aseptic meningitis. Temporal separation of pancreatitis onset from vaccination raises the possibility that pancreatitis as a complication of mumps vaccination is under reported.

Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study.

Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.

Sperm size in patients with inflammatory bowel disease on sulfasalazine therapy.

The size of the heads of spermatozoa from eight men with chronic inflammatory bowel disease (IBD) treated with sulfasalazine (SS) were measured by image analysis. These were compared with the size of sperm heads from noncolitic men with normal semen indices and with the sperm head size of noncolitic oligospermic men. The patients on SS therapy had a significantly larger sperm head size for the 99th percentile than the noncolitic oligospermic men. After withdrawal of the drug, sperm head size increased further before becoming smaller. The size did not return to that of the sperm of men with normal semen indices during the period studied. Possible mechanisms for the increase in sperm size are discussed and its association with the reversible infertility caused by SS medication.

Sulphasalazine and male infertility: reversibility and possible mechanism.

Earlier observations on infertility related to sulphasalazine treatment were extended and semen samples obtained from 28 patients with inflammatory bowel disease on treatment with sulphasalazine at 2-4 g per day. Semen was examined for changes in density, motility, and morphology before, during, and after withdrawal of sulphasalazine. Gross semen abnormalities were seen in 18 patients on this drug for more than two months. Semen quality improved after sulphasalazine had been withdrawn for more than two months and 10 pregnancies are reported after sulphasalazine withdrawal. Preliminary endocrine and acetylator phenotype studies do not elucidate the mechanism of this important new side-effect of this drug. The time course of the drug's effect on semen quality is consistent with the hypothesis that sulphasalazine or a metabolite, possibly sulphapyridine, is directly toxic to developing spermatozoa. These studies confirmed the preliminary report and suggest that prolonged treatment with sulphasalazine may universally depress semen quality and cause reversible infertility.