• 1. Optimizing Therapy with Antibacterial Agents: Use of Pharmacokinetic-Pharmacodynamic Principles in Pediatrics

  • 2. Economic Evidence at the Local Level: Options for Making it More Useful

  • 3. Intelligent Risk Communication: Can it be Improved?

  • 4. Biotherapeutics in the Era of Biosimilars: What Really Matters is Patient Safety

  • 5. Biosimilar Drugs: Concerns and Opportunities

  • 6. NICE Cost-Effectiveness Appraisal of Cholinesterase Inhibitors: Was the Right Question Posed? Were the Best Tools Used?

  • 7. Cardiac Repolarisation and Drug Regulation: Assessing Cardiac Safety 10 Years after the CPMP Guidance

  • 8. Methods for Causality Assessment of Adverse Drug Reactions: A Systematic Review

  • 9. Antiarrhythmics: Elimination and Dosage Considerations in Hepatic Impairment

  • 10. The Last Decade of Italian Pharmaceutical Policy: Instability or Consolidation?

  • 11. Data Resources for Investigating Drug Exposure during Pregnancy and Associated Outcomes: The General Practice Research Database (GPRD) as an Alternative to Pregnancy Registries

  • 12. Anticancer Therapy Targeting Telomeres and Telomerase: Current Status

  • 13. Detection of Spironolactone-Associated Hyperkalaemia Following the Randomized Aldactone Evaluation Study (RALES)

  • 14. Role of P-Glycoprotein Inhibition for Drug Interactions: Evidence from In Vitro and Pharmacoepidemiological Studies

  • 15. Predicting Oral Clearance in Humans: How Close Can We Get with Allometry?

  • 16. Analysis of Severe Hepatic Events Associated with Nevirapine-Containing Regimens: CD4+ T-Cell Count and Gender in Hepatitis C Seropositive and Seronegative Patients

  • 17. Dynamic Modelling of Infectious Diseases: An Application to the Economic Evaluation of Influenza Vaccination

Pharmaceutical medicine is an evolving discipline and research and development activity within the field is high. This section of the journal is intended to help you keep up-to-date with the latest advances worldwide in various aspects of pharmaceutical medicine. Each issue includes a section of articles published in recent issues of other Adis publications. Full text versions of these papers are available at www.adisonline.com.

1. Optimizing Therapy with Antibacterial Agents: Use of Pharmacokinetic-Pharmacodynamic Principles in Pediatrics

The appropriate dosage of antibacterial agents is essential in achieving both clinical and microbiologic success in the treatment of infections in children. By using in vitro experimental data and animal model outcome data, the pharmacokinetic-pharmacodynamic (PK-PD) parameters predictive of antibacterial effect have been elucidated. For time-dependent drugs such as β-lactams, the PK-PD parameter of interest is the percentage of time in a dosage interval for which drug concentrations remain above the minimum inhibitory concentration (MIC) of the infecting organism. For concentration-dependent drugs such as aminoglycosides, the PK-PD parameter of interest is the ratio of the area under the plasma concentration-time curve to the MIC. Recent studies using data on clinical and microbiologic outcomes from infected adults and children, combined with data on drug exposure, have confirmed the importance of these parameters and provided estimates of the PK-PD goals of therapy for various antibacterial agents. Application of these PK-PD principles allows rational dosage regimen selection, both for serious infections in critically ill children and for non-life-threatening community-acquired infections.

2. Economic Evidence at the Local Level: Options for Making it More Useful

Like other countries, Australia has had some success in incorporating economic evidence into national healthcare decisions. However, it has been recognized that this coverage does not extend to the local hospital or health region level. An extensive body of research has identified barriers to the use of economic evidence at the local level, leading some commentators to suggest that economic evaluation should only be targeted at national decision-making bodies. Yet, local decision makers in Australia and elsewhere make important choices about the uptake and diffusion of healthcare technologies. We propose a number of interrelated options to address the barriers that currently prohibit the use of economic evaluation by local decision makers in many jurisdictions. These include wider dissemination of user-friendly models, inclusion of assessments of the cost impact of interventions on various budgets, and the establishment of an authoritative body that ensures the production of high quality economic models. It is argued that these options can have a significant impact on the way economic evaluations are conducted, reported, disseminated and used.

3. Intelligent Risk Communication: Can it be Improved?

Every year, regulators and scientists from academia and industry invest considerable time and effort into drug development, the assessment of safety, and subsequent risk-benefit communication. The observation of everyday medical practice lay press releases and drug information indicates that all these efforts do not do justice to the work and effort invested. Risk communication is a complex scientific activity, which, when done properly, benefits patients, and when done poorly, may lead to harm. There is much misunderstanding and confusion even between professionals in communicating risk-benefit information, as the association of risk with drug treatment is a difficult concept to accept. It is apparent that the concept of intelligent risk-benefit communication has to be developed extensively on many levels and with the co-operation of everyone involved (patients, physicians, regulators, scientists, journalists, lawyers and the government). This article addresses some key aspects of dealing with the risks associated with drug treatment in everyday practice, as consideration of these risks may be of benefit to all concerned in the future.

4. Biotherapeutics in the Era of Biosimilars: What Really Matters is Patient Safety

Unlike generics of chemical drugs, biosimilars are similar but not identical to the original product. Therefore questions are being raised, in relation to their safe use and pharmacovigilance, about the adequate naming of biotherapeutics in general and biosimilars in particular. What measures should be taken to ensure that healthcare professionals realise that biosimilars should not be merely considered as copies and, thus, that the patient may react differently upon substitution? Should prescribing practices be adapted? How does the arrival of biosimilars affect adequate pharmacovigilance within the context of unintentional substitution?

5. Biosimilar Drugs: Concerns and Opportunities

Patents for biologic agents first marketed in the 1980s are now beginning to expire, opening the door for ‘non-proprietary’ versions of these agents to enter the market. However, there are fundamental differences between biologics and traditional pharmaceuticals that preclude the extrapolation of existing regulatory processes for traditional generic agents to these new biologic products. These include differences in dimensions (molecular weight), synthesis, purification, stability, and immunogenicity. There is also controversy over the terminology of these biologic agents, with a number of terms put forward. European regulatory authorities have adopted the term ‘biosimilars’, while the US FDA prefers the term ‘follow-on biologics’. It is important that these terms are not used as synonyms for ‘generics’, and already there are moves to prevent classification of these products as ‘generics’. In this review, we focus on the differences that exist between generics and biosimilars, and assess the current scenario of problems and opportunities. Furthermore, we also attempt to highlight the problems with establishing regulatory guidelines and those associated with the introduction of these drugs into clinical practice.

6. NICE Cost-Effectiveness Appraisal of Cholinesterase Inhibitors: Was the Right Question Posed? Were the Best Tools Used?

The National Institute for Health and Clinical Excellence (NICE) recently issued updated guidance on the use of cholinesterase inhibitors in the treatment of Alzheimer’s disease. NICE initially recommended that cholinesterase inhibitors no longer be used, but final guidance restricted treatment to patients with disease of a moderately severe stage. This decision was based largely on results from a heavily criticised economic evaluation that used an adaptation of the Assessment of Health Economics in Alzheimer’s Disease (AHEAD) model. As the developers of the AHEAD model, we examined the appropriateness of NICE’s economic analyses and presentation of results. We attempted to replicate NICE’s results by modifying the original AHEAD model. Sensitivity analyses were then run using the modified AHEAD model to evaluate the extent of uncertainty in predictions.

The AHEADNICE analyses resulted in an incremental cost-effectiveness ratio for galantamine of £82 000 per QALY gained (year 2003 values) from the perspective of the UK NHS and Personal Social Services. This was later revised to £46 000 per QALY, compared with <£9000 per discounted QALY gained (year 2001 values) in the original AHEAD model. Using our modified AHEAD with effectiveness estimates matching those of AHEADNICE, we show that NICE’s choice and presentation of sensitivity analyses obscured the instability of their estimates.

In the final NICE evaluation, the recommendation to delay treatment with cholinesterase inhibitors until patients have moderately severe disease was based on critical assumptions in the economic analyses that had little evidence to support them. The case of NICE’s guidance on cholinesterase inhibitors highlights the importance of transparent and valid economic evaluations and the dangers of using inappropriate modelling technologies, basing analyses on a limited subset of the available data, and insufficiently reflecting the uncertainty in estimates that are intended to inform decision makers.

7. Cardiac Repolarisation and Drug Regulation: Assessing Cardiac Safety 10 Years after the CPMP Guidance

December 2007 marks the 10-year anniversary of the first regulatory guidance for evaluation of drug-induced QT interval prolongation. A decade on, it seems surprising that this document, which was released by the Committee on Proprietary Medicinal Products, caused such acrimony in the industry. Sponsors now routinely evaluate their new drugs for an effect on cardiac electrophysiology in preclinical studies, in addition to obtaining ECGs in all phases of drug development and conducting a formal thorough QT study in humans.

However, concurrently, new concerns have also emerged on broader issues related to the cardiovascular safety of drugs because of their potential to shorten the QT interval as well as to induce proischaemic, profibrotic or prothrombotic effects. Drugs may also have an indirect effect by adversely affecting one or more of the cardiovascular risk factors (e.g. through fluid retention or induction of dyslipidaemia).

In addition to peroxisome proliferator-activated receptor agonists and cyclo-oxygenase 2 selective inhibitors, three other drugs, darbepoetin alfa, pergolide and tegaserod, provide a more contemporary regulatory stance on tolerance of cardiovascular risk of drugs and their benefit-risk assessment. This recent, more assertive, risk-averse stance has significant implications for future drug development. These include the routine evaluation of cardiovascular safety for certain classes of drugs. Drugs that are intended for long-term use will almost certainly require long-term clinical evaluation in studies that enrol populations that most closely resemble the ultimate target population. Novel mechanisms of action and biomarkers by themselves are no guarantee of improved safety or benefits. Even some traditional biomarkers have come to be viewed with scepticism. Requirements for more extensive and earlier postmarketing assessment of clinical benefits and rare, but serious risks associated with new medicinal products should create a new standard of evidence for industry and regulators and almost certainly result in better assessment of benefit/risk, more effective and balanced regulatory actions and better care for patients.

8. Methods for Causality Assessment of Adverse Drug Reactions: A Systematic Review

Numerous methods for causality assessment of adverse drug reactions (ADRs) have been published. The aim of this review is to provide an overview of these methods and discuss their strengths and weaknesses. We conducted electronic searches in MEDLINE (via PubMed), EMBASE and the Cochrane databases to find all assessment methods. Thirty-four different methods were found, falling into three broad categories: expert judgement/global introspection, algorithms and probabilistic methods (Bayesian approaches). Expert judgements are individual assessments based on previous knowledge and experience in the field using no standardized tool to arrive at conclusions regarding causality. Algorithms are sets of specific questions with associated scores for calculating the likelihood of a cause-effect relationship. Bayesian approaches use specific findings in a case to transform the prior estimate of probability into a posterior estimate of probability of drug causation. The prior probability is calculated from epidemiological information and the posterior probability combines this background information with the evidence in the individual case to come up with an estimate of causation. As a result of problems of reproducibility and validity, no single method is universally accepted. Different causality categories are adopted in each method, and the categories are assessed using different criteria. Because assessment methods are also not entirely devoid of individual judgements, inter-rater reliability can be low. In conclusion, there is still no method universally accepted for causality assessment of ADRs.

9. Antiarrhythmics: Elimination and Dosage Considerations in Hepatic Impairment

Many drugs, including most antiarrhythmics (some of which are now of limited clinical use) are eliminated by the hepatic route. If liver function is impaired, it can be anticipated that hepatic clearance will be delayed, which can lead to more pronounced drug accumulation with multiple dosing. Consequently, the potential risks of adverse events could be increased, especially as antiarrhythmics have a narrow therapeutic index.

The present review summarizes the available pharmacokinetic data on the most popular antiarrhythmic drugs to identify the enzymes involved in the metabolism of the various agents and confirm whether liver disease affects their elimination. Despite long usage of some of these drugs (e.g. amiodarone, diltiazem, disopyramide, procainamide and quinidine), surprisingly few data are available in patients with liver disease, making it difficult to give recommendations for dosage adjustment. In contrast, for carvedilol, lidocaine (lignocaine), propafenone and verapamil, sufficient clinical studies have been performed. For these drugs, a marked decrease in systemic and/or oral clearance and significant prolongation of the elimination half-life have been documented, which should be counteracted by a 2- to 3-fold reduction of the dosage in patients with moderate to severe liver cirrhosis. For sotalol, disopyramide and procainamide, renal clearance contributes considerably to overall elimination, suggesting that dosage reductions are probably unnecessary in patients with liver disease as long as renal function is normal.

The hepatically eliminated antiarrhythmics are metabolized mainly by different cytochrome P450 (CYP) isoenzymes (e.g. CYP3A4, CYP1A2, CYP2C9, CYP2D6) and partly also by conjugations. As the extent of impairment in clearance is in the same range for all of these agents, it could be assumed that they have a common vulnerability and that, consequently, hepatic dysfunction will affect CYP-mediated phase I pathways in a similar fashion. The severity of liver disease has been estimated clinically by the validated Pugh score, and functionally by calculation of the clearance of probe drugs (e.g. antipyrine). Both approaches can be helpful in estimating/predicting impairments in drug metabolism, including antiarrhythmics.

In conclusion, hepatic impairment decreases the elimination of many antiarrhythmics to such an extent that dosage reductions are highly recommended in such populations, especially in patients with cirrhosis.

10. The Last Decade of Italian Pharmaceutical Policy: Instability or Consolidation?

Pharmaceutical policy in Italy has been reshaped as a result of the 1993–4 crisis in which it was revealed that pharmaceutical companies, policy makers and top Department of Health officers had constructed an illegal system to set prices. Following this crisis, the rise of technical competency and leadership in the Italian Department of Health and, since 2000, in the Drug Regulatory Agency (Agenzia Italiana del Farmaco; AIFA) has achieved major improvements in many aspects of Italian pharmaceutical policy. These improvements have included increased transparency of decision making, the use of evidence-based medicine principles for reimbursement and pricing, and the use of generic drugs to lower prices.

As a result of these changes, pharmaceutical expenditure has been controlled and equity has improved, mainly because copayments have been reduced, thus reducing private expenditure on reimbursable drugs. However, a short-term approach to cost containment has prevailed, and Italian pharmaceutical policy has neglected industrial parameters. Hence, the trend in pharmaceutical expenditure has been erratic, and Italy has not favoured localization of research and development and production in its territory.

The dominant issue of Italian health policy in recent years has been devolution of powers to regions, the intermediate tier of the Italian State. Overall, devolution has increased regional accountability on healthcare spending. However, regions react to enhanced freedom in different ways, reflecting their institutional capacity and competencies. This process has also affected pharmaceutical policy, more than in other decentralized healthcare systems (such as Germany and Spain). Such a situation is causing increasing regional variations and geographical equity concerns. In addition, the regional level appears rather inadequate to promote an industrial perspective unless it is supported by national initiatives.

11. Data Resources for Investigating Drug Exposure during Pregnancy and Associated Outcomes: The General Practice Research Database (GPRD) as an Alternative to Pregnancy Registries

Pregnancy registries are the most commonly used data resource for the postmarketing surveillance of drug teratogenicity. However, the limited sample size and potential selection bias in these registries has led us to investigate the potential of the UK General Practice Research Database (GPRD) as an alternative data source for monitoring drug safety during pregnancy. In addition, a literavascular ture review identified further observational data sources that monitor pregnancy outcomes for future evaluation.

Initial feasibility studies focused on the ability of the GPRD to capture pregnancy outcomes for a range of drug class exposures, all of which are currently under investigation in pregnancy registries, during pregnancy. The comparator pregnancy registries were identified via a MEDLINE search, whilst eligible pregnancies, in which women received one or more prescriptions for the drug of interest during pregnancy, were identified in the GPRD using the mother-baby link. The number of pregnancy outcomes following exposure to medication for a range of conditions with varying prevalence, including depression, migraine, epilepsy, herpes simplex and HIV, captured by the two data sources were compared. For depression, a relatively prevalent condition, the GPRD recorded the same number of mean annual intrauterine exposures to fluoxetine as the pregnancy registry (118 exposures/year). Ascertainment of intrauterine exposure to drug treatments for less prevalent conditions was found to be higher for the pregnancy registries than the GPRD; for the older antiepileptic drugs (valproate and carbamazepine), the pregnancy registry recorded between four and five times as many mean annual exposures as the GPRD. Virtually no antiretroviral exposures (three) were identified during the time period of interest on the GPRD, compared with 3946 in the Antiretroviral Pregnancy Registry.

Data from the GPRD meet established criteria for evaluating outcomes of pregnancy. For prevalent conditions, it has the potential to replace or work alongside standard pregnancy registries and the alternative data sources identified. Further studies are now needed to assess its ability to replicate known teratogenic associations.

12. Anticancer Therapy Targeting Telomeres and Telomerase: Current Status

Normal human somatic cells undergo telomeric attrition causing replicative senescence. Most immortal cancer cells cope with this by upregulating the active form of telomerase. Long-term inhibition of telomerase results in telomeric attrition and highly specific killing of cancer cells, in which the maintenance of telomere length is reliant on telomerase activity. Unfortunately, telomere erosion requires many cell divisions, possibly opening the way for acquired drug resistance. Recent attempts to solve this problem include the development of drugs that are more potent catalytic inhibitors, deny telomerase access to the telomere in situ, or affect telomere structure; some of these drugs have entered clinical trials. Combinations of these approaches may ultimately produce the best clinical results. This article reviews the latest results in both basic and applied telomere research that indicate the most promising avenues for future anticancer drug development in this area.

13. Detection of Spironolactone-Associated Hyperkalaemia Following the Randomized Aldactone Evaluation Study (RALES)

Introduction: A population-based analysis has suggested that the publication of the RALES (Randomized Aldactone Evaluation Study) in late 1999 was associated with both the wider use of spironolactone to treat heart failure and a corresponding increase in hyperkalaemia-associated morbidity and mortality in patients also being treated with ACE inhibitors.

Objectives: To gain further insight into the reporting of spironolactone-associated hyperkalaemia in an independent dataset by analysing the spontaneous reporting experience in relation to the publication of RALES, and to determine whether the implementation of a commonly used data mining algorithm (DMA) might have directed the attention of safety reviewers to the spironolactone/hyperkalaemia association in advance of epidemiological findings.

Methods: We calculated the reporting rate of spironolactone-associated hyperkalaemia per 1000 reports per year from 1970 through to the end of 2005 by identifying relevant cases in the US FDA Adverse Event Reporting System. We did this for reports of spironolactone-associated hyperkalaemia (where spironolactone was listed as a suspect drug) and according to whether the reports listed an ACE inhibitor as a co-suspect or concomitant medication. A further statistical analysis of the overall reporting of spironolactone (suspect drug)-associated hyperkalaemia was also performed. We also performed 3-dimensional (3-D; drug-drug-event) disproportionality analyses using a DMA known as the multi-item gamma-Poisson shrinker, which allows the calculation and display of a 3-D disproportionality metric known as the ‘interaction signal score’ (INTSS). This metric is a measure of the strength of a higher order reporting relationship of a triplet (i.e. drug-drug-event) association above and beyond what would be expected from the largest disproportionalities associated with the individual 2-way associations.

Results: Visual inspection of a graph of the reporting frequency of spironolactone (suspect drug)-associated hyperkalaemia per 1000 reports was highly suggestive of a change point. The t-test on the arcsine-transformed data showed a significant difference in reporting of spironolactone-hyperkalaemia combination through 1999 compared with 2000 onwards (p<0.001). When examining the reporting time trends according to the presence or absence of an ACE inhibitor, the change point seemed to be mostly attributable to an increase in the number of spironolactone (suspect drug)-associated hyperkalaemia reports with ACE inhibitors listed as a co-suspect drug. No obvious change points in INTSSs for spironolactone-ACE inhibitor-hyperkalaemia reports were observed.

Discussion: Although we could not pinpoint the relative contribution of many possible artifacts in the reporting process, as well as increased drug exposure, increased adverse event incidence and/or a change in patient monitoring practices, to our findings, we observed a notable change in reporting frequency of spironolactone-associated hyperkalaemia in temporal proximity to the publication of RALES. Evidence of this was provided by a trend analysis depicted in a simple graph that was supported by statistical analysis. The observed trend was in large part due to increased reporting of spironolactone-associated hyperkalaemia with reported co-medication with ACE inhibitors.

Conclusion: These findings are consistent with those originally reported in an epidemiological analysis. In this retrospective exercise, a simple graph was more illuminating than more complex data mining analyses.

14. Role of P-Glycoprotein Inhibition for Drug Interactions: Evidence from In Vitro and Pharmacoepidemiological Studies

Objectives: We determined in vitro the potency of macrolides as P-glycoprotein inhibitors and tested in hospitalised patients whether coadministration of P-glycoprotein inhibitors leads to increased serum concentrations of the P-glycoprotein substrates digoxin and digitoxin.

Methods: In vitro, the effect of macrolides on polarised P-glycoprotein-mediated digoxin transport was investigated in Caco-2 cells. In a pharmacoepidemiological study, we analysed the serum digoxin and digitoxin concentrations with and without coadministration of P-glycoprotein inhibitors in hospitalised patients.

Results: All macrolides inhibited P-glycoprotein-mediated digoxin transport, with concentrations producing 50% inhibition (IC50) values of 1.8, 4.1, 15.4, 21.8 and 22.7 μmol/L for telithromycin, clarithromycin, roxithromycin, azithromycin and erythromycin, respectively. Coadministration of P-glycoprotein inhibitors was associated with increased serum concentrations of digoxin (1.3±0.6 vs 0.9±0.5 ng/mL, p<0.01). Moreover, patients receiving macrolides had higher serum concentrations of cardiac glycosides (p<0.05).

Conclusion: Macrolides are potent inhibitors of P-glycoprotein. Drug interactions between P-glycoprotein inhibitors and substrates are likely to occur during hospitalisation.

15. Predicting Oral Clearance in Humans: How Close Can We Get with Allometry?

Background: Oral clearance (CL/F) is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies. Throughout the pharmaceutical industry, many drugs are administered via the oral route; however, there are only a handful of published scaling studies for the prediction of oral pharmacokinetic parameters.

Methods: We evaluated the predictive performances of four different allometric approaches — simple allometry (SA), the rule of exponents, the unbound CL/F approach, and the unbound fraction corrected intercept method (FCIM) — for the prediction of human CL/F and the oral area under the plasma concentration-time curve (AUC). Twenty-four compounds developed at Johnson and Johnson Pharmaceutical Research and Development, covering a wide range of physicochemical and pharmacokinetic properties, were selected. The CL/F was predicted using these approaches, and the oral AUC was then estimated using the predicted CL/F.

Results: The results of this study indicated that the most successful predictions of CL/F and the oral AUC were obtained using the unbound CL/F approach in combination with the maximum lifespan potential or the brain weight as correction factors based on the rule of exponents. We also observed that the unbound CL/F approach gave better predictions when the exponent of SA was between 0.5 and 1.2. However, the FCIM seemed to be the method of choice when the exponent of SA was <0.50 or >1.2.

Conclusions: Overall, we were able to predict CL/F and the oral AUC within 2-fold of the observed value for 79% and 83% of the compounds, respectively, by selecting the allometric approaches based on the exponents of SA.

16. Analysis of Severe Hepatic Events Associated with Nevirapine-Containing Regimens: CD4+ T-Cell Count and Gender in Hepatitis C Seropositive and Seronegative Patients

Background: Nevirapine-containing regimens have been associated with a risk of significant elevations of liver transaminase levels. Higher risk in antiretroviral-naive populations has been related to gender and CD4+ T-cell count (women with CD4+ T-cell counts of ≥250/mm3 or men with CD4+ T-cell counts of ≥400/mm3, i.e. group at risk). However, recent studies do not confirm this association in HIV populations comprising patients who are antiretroviral-experienced. Moreover, the predictive value of gender and CD4+ T-cell count on the risk of raised transaminase levels has been poorly investigated in populations of patients coinfected with hepatitis C virus (HCV).

Methods: Analysis of HIV-positive patients receiving nevirapine-containing regimens for the first time was conducted. Grade ≥III hepatotoxicity (i.e. ≥5 × upper limit of normal in alanine aminotranferase or aspartate aminotransferase levels) was the primary endpoint. Univariate and multivariable Cox proportional hazard regression models were separately conducted among HCV-antibody (Ab)-positive and HCV-Ab-negative patients.

Results: Amongst 905 patients, 49% were HCV-Ab-positive and 79% were antiretroviral-experienced. Grade ≥III liver transaminase elevations developed in 7.1% of patients, accounting for an incidence of 2.47 (95% CI 1.97, 3.09) per 100 patient-years of follow-up. HCV-Ab reactivity was associated with a 3-fold increase in risk of developing relevant liver transaminase elevations (95% CI 1.75, 5.3; p<0.001), whereas gender and CD4+ T-cell count did not impact significantly. When analysis was performed in HCV-Ab-negative patients, the outcome was independently correlated with the group at risk (hazard ratio [HR] 3.66; 95% CI 1.20, 11.14; p=0.022). By contrast, in HCV-Ab-positive patients, the group at risk was not significantly associated with the outcome.

Conclusions: Most of the excess rates of relevant raised transaminase levels in patients prescribed nevirapine-containing regimens could be attributed to HCV co-infection. Gender and CD4+ T-cell count appeared to have a statistically significant impact on the risk of relevant transaminase level elevations in HCV-negative, but not in HCV-positive patients, probably due to a diluting effect of HCV. Incidence of hepatic events after nevirapine-containing regimens did not appear to be a major concern in our cohort of patients who were mainly antiretroviral-experienced and negative for HCV-Ab. Preferably, nevirapine should be avoided in HCV co-infected patients and in males with CD4+ T-cell counts of ≥400/mm3 or females with CD4+ T-cell counts of ≥250/mm3.

17. Dynamic Modelling of Infectious Diseases: An Application to the Economic Evaluation of Influenza Vaccination

Objective: To evaluate the economic efficiency of influenza vaccination using both dynamic and static modelling approaches.

Setting: The Spanish National Health System.

Design and methods: We modelled the progress of an influenza epidemic in Spain according to the epidemiological pattern of susceptible->infective->resistant, employing a non-linear system of ordinary differential equations that enables the measurement of epidemiological effects of an anti-influenza vaccination. We used a decision tree to represent the repercussion on healthcare resources use and on financial resources. The same analyses were conducted using a static approach, and the results were compared. Healthcare costs were valued in €, year 2005 values.

Results: For the base case, the impact of the healthcare intervention (vaccination) was not efficient from the perspective of the healthcare payer when using a static approach (return rate 0.28 per € invested in vaccination). Nevertheless, it was efficient when employing a dynamic approach (return rate 1.22 per €). Furthermore, a considerable freeing of healthcare resources would have been produced over the entire influenza season.

Conclusions: The indirect effect of vaccination on the non-vaccinated individuals (the ‘herd immunity effect’) can be greater than the direct effect on individuals vaccinated. This implies that the herd immunity effect needs to be taken into consideration in the economic evaluations of prophylactic measures employed against infectious diseases.