A. O'Leary

Pharmacoeconomic evaluation in Ireland: A review of the process

AbstractObjective: To describe the pharmacoeconomic assessment process in Ireland and to provide examples of recent appraisals and the subsequent impact on pricing and reimbursement decisions. Method: The pharmacoeconomic appraisals conducted by the National Centre for Pharmacoeconomics (NCPE) between September 2006 and February 2009 were reviewed. The NCPE recommendations and subsequent reimbursement decisions by the Health Service Executive (HSE) were recorded. Recommendations made by the NCPE were compared with those of UK agencies. The duration of the NCPE pharmacoeconomic process and the time from marketing authorization to reimbursement was estimated. The budget impact assessments from the pharmaceutical companies were reviewed and compared for consistency. Results: The NCPE conducted 12 single technology appraisals during the study period. Eight of the medicines assessed were either recommended as a cost-effective use of resources or recommended with certain restrictions, and were funded by the HSE. Of the four medicines that were not considered cost effective, two were reimbursed after a price reduction was negotiated and the remaining two were not. The NCPE recommendations concurred with those of the UK agencies for the majority of appraisals, with the exception of sunitinib and lapatinib. The average duration of the NCPE process was 2.7 months. The average time from marketing authorization to reimbursement was 7 months. The review of budget impact assessments highlighted a high degree of variability between submissions. Conclusions: The findings of this review highlight the efficiency of the pharmacoeconomic process and the acceptance of the NCPE recommendations by the HSE for pricing and reimbursement decisions. NCPE recommendations broadly concurred with those of UK agencies for the majority of appraisals.

Baseline prevalence and emergence of protease inhibitor resistance mutations following treatment in chronic HCV genotype-1-infected individuals.

BACKGROUND The HCV NS3/4A serine protease inhibitors (PIs) boceprevir (BOC), telaprevir (TVR) and simeprevir (SMV) are approved for treatment of chronic hepatitis C infection in combination with pegylated interferon and ribavirin. The present study investigated the prevalence of HCV NS3 drug resistance mutations (DRMs) associated with HCV genotype-1-infected individuals at baseline and in viral breakthrough following BOC and TVR treatment. METHODS HCV genotype-1-infected individuals were enrolled in a multicentre, prospective outcomes study. The HCV NS3 viral protease was analysed for DRMs at baseline (n=164) and at viral breakthrough (n=18) following BOC/TVR treatment. RESULTS Viral NS3 protease subtype analysis showed 65.2% (107/164) were HCV subtype-1a and 34.8% (57/164) were HCV subtype-1b infections. Naturally occurring PI DRMs in NS3 (V36L, T54S, V55A, Q80K/R and I132V) were identified in 57.3% (94/164) cases at baseline. The NS3 Q80K polymorphism was found in 43/107 (40.2%) of HCV subtype-1a and exclusively in clade 1 (43/82; 52.4%) versus clade 2 viruses (0/25; 0%, P<10(-6)). The pretreatment I132V variant was found in 78.9% (45/57) of subtype-1b. Of 18 patients who had viral breakthrough, the majority was subtype-1a (77.8%, 14/18). BOC/TVR-associated DRMs were detected in 94.4% (17/18), of which 64.7% (11/17) emerged on-treatment. CONCLUSIONS To ensure the most appropriate direct-acting antiviral-based treatment regimen is employed, baseline reporting of clade and resistance mutations for HCV subtype-1a using nucleotide sequence-based analysis is warranted prior to commencement of therapy.

Dapsone induced methaemoglobinaemia.

Dapsone, a sulphonamide derivative, has been formerly used in the treatment of malaria, leprosy and dermatitis herpetiformis. It has previously been indicated as a third or fourth line agent in the treatment of prophylaxis of Pneumocystis carinii pneumonia in patients infected with the human immunode® ciency virus (HIV). More recently, in their article Bozzette and colleagues have suggested that commencing co-trimoxazole or high dose dapsone rather than nebulized pentamidine was superior in patients with CD4 lymphocyte counts less than 100 ́ 106/L1. Similarly, Coker and colleagues suggest the use of dapsone and trimethoprim as second line treatment in those patients intolerant of co-trimoxazole2. Side effects associated with the use of dapsone included the development of methaemoglobinaemia, abnormal serum aminotransferase levels and haemolysis particularly in patients with glucose-6phosphate dehydrogenase (G6DP) de® ciency. We report 2 cases of methaemoglobinaemia secondary to dapsone therapy occurring in HIV-positive patients.

The Role of Hepatitis C Virus Core Antigen Testing in the Era of Direct Acting Antiviral Therapies: What We Can Learn from the Protease Inhibitors

Direct-acting antiviral (DAA) therapies have revolutionised the treatment of hepatitis C virus (HCV). The financial cost of DAAs however is significant, and first generation protease inhibitors (PIs) also require frequent monitoring of viral RNA levels to guide treatment. In this context, we examined the relevance of HCV antigen testing to evaluate the potential role in monitoring virological response to HCV antiviral treatment with the PI-based triple therapies, telaprevir (TVR) and boceprevir (BOC). Chronic HCV-infected individuals (n = 152) enrolled in the Irish Hepatitis C Outcomes Research Network (ICORN) study were prospectively analysed for baseline markers and the early viral kinetics associated with SVR. The sustained virological response (SVR) rates in the cohort receiving TVR and BOC were 87.3% and 73.8%, respectively. Baseline factors associated with successful outcome in TVR therapy were age (P = 0.0098), IFNL3 genotype (P = 0.0330) and viral load (P = 0.0456). RNA level at week 4 (P = 0.0068) and viral antigen negativity at week 2 (P = 0.0359) were predictive of SVR for TVR-based therapy. In BOC therapy, prior interferon treatment (P = 0.0209) and IFNL3 genotype (P = 0.0410) were baseline predictors of SVR. Evidence of viraemia based either on viral RNA or antigen at week 4 predicted SVR in these patients. Our data showed that rapid decline of HCV antigen to negative level at week 2 in TVR treatment and <0.96 log fmol/l in BOC treatment after commencement of PI triple therapy were associated with SVR. HCV antigen measurement should be considered as a potential alternative for monitoring treatment response during DAA-based regimens.

Direct costs of interferon-based and interferon-free direct-acting antiviral regimens for the treatment of chronic hepatitis C infection

Given the increasing budget impact of Hepatitis C virus (HCV) treatment, robust real‐world cost data are essential for healthcare decision‐makers to evaluate and understand the costs and benefits of these treatments. To determine the direct cost of treating HCV infection in a hospital‐based ambulatory care setting in Ireland based on available data from the Irish national hepatitis C treatment registry. A microcosting study of the direct costs of patients with hepatitis C treated with interferon‐based and interferon‐free direct‐acting antiviral regimens was conducted. Attendance at the outpatient clinic for clinical assessment, the quantity of resources used per patient, the medication prescribed and the identification and timing of staff involvement was measured and combined to establish a mean cost of treatment per patient and a cost per sustained virological response (SVR). One hundred and sixty‐eight patients were included in the analysis; 119 treated with interferon‐based direct‐acting antiviral regimens and 47 treated with interferon‐free regimens. The mean costs of treatment with the interferon‐based regimens per patient were €38 286 (95% CI €35 305–€41 061). The cost per SVR was €62 457. The mean cost of treatment with interferon‐free regimens per patient was €55 734 (95% CI €50 906–€60 880). The cost per SVR was €81 873. Real‐world cost data provide valuable information to enhance reimbursement decisions. While the direct costs associated with hepatitis C treatment in Ireland are substantial, it is reasonable to expect that the mean cost of treatment and the cost per SVR will reduce as patients with less advanced disease are treated with interferon‐free therapies.

The Impact of Individual Patient Data in a Network Meta Analysis: An investigation into parameter estimation and model selection

The use of individual patient data (IPD) in network meta-analysis (NMA) is becoming increasingly popular. However, as most studies do not report IPD, most NMAs are performed using aggregate data for at least some, if not all, of the studies. We investigate the benefits of including varying proportions of IPD studies in an NMA. Several models have previously been developed for including both aggregate data and IPD in the same NMA. We performed a simulation study based on these models to examine the impact of additional IPD studies on the accuracy and precision of the estimates of both the treatment effect and the covariate effect. We also compared the deviance information criterion (DIC) between models to assess model fit. An increased proportion of IPD resulted in more accurate and precise estimates for most models and datasets. However, the coverage probability sometimes decreased when the model was misspecified. The use of IPD leads to greater differences in DIC, which allows us choose the correct model more often. We analysed a Hepatitis C network consisting of 3 IPD observational studies. The ranking of treatments remained the same for all models and datasets. We observed similar results to the simulation study: The use of IPD leads to differences in DIC and more precise estimates for the covariate effect. However, IPD sometimes increased the posterior SD of the treatment effect estimate, which may indicate between study heterogeneity. We recommend that IPD should be used where possible, especially for assessing model fit.

Do disparities between populations in randomized controlled trials and the real world lead to differences in outcomes

AIM To conduct a systematic review investigating reasons for the disparity between the efficacy and effectiveness rates reported in randomized controlled trials (RCTs) and observational studies of direct-acting antiviral treatment regimens licensed for use in genotype1 hepatitis C virus-infected individuals. METHODS This systematic review was conducted in accordance with the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses group. RESULTS Statistically significant (p < 0.05) differences in the baseline demographics and sustained virological response rates were observed between RCT and observational studies. CONCLUSION In order for outcomes from RCTs to be generalizable to the real world, greater consideration needs to be taken to include patient populations that are more representative of those awaiting treatment in the clinical setting.

Reply to Calcagno et al

TO THE EDITOR—In their comment regarding our meta-analysis, Calcagno et al make a very salient point with regard to the longer half-life of telaprevir and the impact this may have on its therapeutic robustness in the setting of less-thanoptimal adherence [1]. However, in the clinical trials examined by our metaanalysis, although adherence was not explicitly measured or reported, the discontinuation rates were very similar between the 2 agents and the rates of failure with resistance mutations were also low [2]. The subgroup of relapsers, in whom the difference between the 2 agents was detected, looked at a patient population with proven sensitivity to pegylated interferon and ribavirin and presumably with adherence that was adequate to result in an end-of-treatment response with standard of care. Therefore, it is unlikely that differences in patient adherence to treatment would account for the difference in efficacy detected by our analysis. That being said, the point regarding adherence is well made, especially as these treatment regimens are being rolled out into standard clinical practice and away from the idealized setting of a randomized clinical trial. The pharmacokinetic properties of telaprevir may allow some “forgiveness” in practice where adherence is likely to be lower than that found in a clinical trial setting. If there is indeed a benefit from a pharmacokinetic perspective in patients with poorer adherence, it would be expected that this would become more evident with increasing availability of real-world effectiveness data. In the setting of hepatitis C virus (HCV) treatment, there has been much work done looking at barriers to HCV treatment and care in both HCV-monoinfected and HCV/human immunodeficiency virus (HIV)–coinfected populations [3, 4]. Numerous factors have been identified relating to (1) HCV treatment and side effects, (2) provider experience with HCV patients, and (3) patient perceptions of treatment success and side effects [5]. Shorter durations of treatment and increased treatment success rates have been cited by patients as important factors in deciding whether to proceed with HCV treatment [6]. The shorter duration of triple therapy with telaprevir vs boceprevir and the resultant reduced duration of additive side effects may also influence the decision of which third agent to use, especially in the setting of concerns regarding patient adherence to treatment. In HIV care and other areas of therapeutics, pill burden and regimen complexity also have a role in adherence [7, 8]. The data on the validity of twice-daily dosing of telaprevir may allow reduced regimen complexity and improve adherence [9]. Our meta-analysis did not detect a difference in efficacy between the 2 agents in the overall populations, in keeping with international treatment guidelines, which do not state a preference for either agent [10]. Thus, along with host genetic and clinical factors, viral kinetics, and the pharmacokinetics of ribavirin, consideration of patient preference and adherence and the pharmacokinetics of the third agent will be important when it comes to individualizing the treatment paradigm for a particular patient.

PMD83 The Cost Impact of Modifying Patterns of Self-Monitoring of Blood Glucose in an Irish Type 2 Diabetes Cohort

The annual rate of first ICD implant (per million-persons) increased, from 55 in 2000 to 236 by 2008. The use of ICD in Lombardy was approximately 2 times higher than in Europe and 3-4 times lower than in US. The replacement rate was around 10 (per hundred implant-year) with a peak in 2005. The hospitalization for a first ICD implant cost €23,814 (CI95%, 23,676-23,960) on average. During follow-up, 15.4% of patients died and the HS bore a mean annual cost of €4,354 (CI95% 4,226-4,485) per-capita: 17% due to drugs, 12% to outpatient visits and 71% to hospitalizations. Younger patients reported lower costs in drug treatments and outpatient visits and a higher expenditure for hospitalizations. CONCLUSIONS: ICD use is growing and it’s important to assess the efficacy and the burden of this therapy, given the economic implications and differences in use among countries. Health care administrative databases are a useful tool, as they provide information about large unselected populations.

HIV-associated dyslipidaemia among HIV antibody-positive patients in Ireland: prevalence and management strategies.

prevalent HIV infection gleaned from the National Health and Nutrition Examination Surveys (NHANES) conducted from 1999 to 2006. The NHANES samples are representative of the non-institutionalized population of the United States aged 18–49 years and include nearly 12,000 participants. Multivariate analyses, which controlled for history of homosexual contact and injection drug use, revealed that in non-Hispanic black men, lifetime number of sex partners was not positively associated with prevalent HIV infection. The special attention to black men’s HIV prevalence is merited not only because they comprise the single most severely affected demographic group (by sex and race) in the United States, but also because their HIV infection base rate is sufficiently high to allow stable statistical associations. It is surprising that this lack of association was neither discussed, nor its crucial implication elaborated by McQuillan and her colleagues. This finding is consistent with other studies showing no association between number of sex partners and prevalent HIV infection, especially studies that adequately controlled for sex of participants, heterosexual anal intercourse, male homosexual activity and non-sexual blood exposures. – 5 The substantial independent association between prevalent HSV-2 infection and prevalent HIV infection in the NHANES data also is unlikely to represent sexual HIV transmission. In randomized trials, HSV-2 suppressive therapy reduced genital ulcers substantially but led to a non-significant tendency toward increasing the risk of acquiring HIV. HIV infection often precedes HSV-2 infection. and prior HIV infection is associated with incident HSV-2 infection perhaps due to immunosuppression. In sum, McQuillan and colleagues’ report adds to the epidemiological and microbiological – 14 evidence that penile– vaginal intercourse in reasonably healthy adults – as opposed to anal intercourse or blood exposures – is not a significant mode of HIV transmission.