An economic evaluation and incremental analysis of the cost effectiveness of three universal childhood varicella vaccination strategies for Ireland.

BACKGROUND: The cost effectiveness of childhood varicella vaccination is uncertain, as evidenced by variation in national health policies. Within the European Economic Area (EEA), only 10 of 30 countries offer universally funded childhood varicella vaccination. This study estimates the cost effectiveness of universal childhood varicella vaccination for one EEA country (Ireland), highlighting the difference in cost effectiveness between alternative vaccination strategies. METHODS: An age-structured dynamic transmission model, simulating varicella zoster virus transmission, was developed to analyse the impact of three vaccination strategies; one-dose at 12 months old, two-dose at 12 and 15 months old (short-interval), and two-dose at 12 months and five years old (long-interval). The analysis adopted an 80-year time horizon and considered payer and societal perspectives. Clinical effectiveness was based on cases of varicella and subsequently herpes zoster and post-herpetic neuralgia avoided, and outcomes were expressed in quality-adjusted life-years (QALYs). Costs were presented in 2022 Irish Euro and cost effectiveness was interpreted with reference to a willingness-to-pay threshold of €20,000 per QALY gained. RESULTS: From the payer perspective, the incremental cost-effectiveness ratio (ICER) for a one-dose strategy, compared with no vaccination, was estimated at €8,712 per QALY gained. The ICER for the next least expensive strategy, two-dose long-interval, compared with one-dose, was estimated at €45,090 per QALY gained. From a societal perspective, all three strategies were cost-saving compared with no vaccination; the two-dose short-interval strategy dominated, yielding the largest cost savings and health benefits. Results were stable across a range of sensitivity and scenario analyses. CONCLUSION: A one-dose strategy was highly cost effective from the payer perspective, driven by a reduction in hospitalisations. Two-dose strategies were cost saving from the societal perspective. These results should be considered alongside other factors such as acceptability of a new vaccine within the overall childhood immunisation schedule, programme objectives and budget impact.

Cost-effectiveness of metabolic surgery for the treatment of type 2 diabetes and obesity: a systematic review of economic evaluations.

AIM: To systematically identify and appraise the international literature on the cost-effectiveness of metabolic surgery for the treatment of comorbid type 2 diabetes (T2D) and obesity. METHODS: A systematic search was conducted in electronic databases and grey literature sources up to 20 January 2021. Economic evaluations in a T2D population or a subpopulation with T2D were eligible for inclusion. Screening, data extraction, critical appraisal of methodological quality (Consensus Health Economic Criteria list) and assessment of transferability (International Society for Pharmacoeconomics and Outcomes Research questionnaire) were undertaken in duplicate. The incremental cost-effectiveness ratio (ICER) was the main outcome. Costs were reported in 2020 Irish Euro. Cost-effectiveness was interpreted using willingness-to-pay (WTP) thresholds of €20,000 and €45,000/quality-adjusted life year (QALY). Due to heterogeneity arising from various sources, a narrative synthesis was undertaken. RESULTS: Thirty studies across seventeen jurisdictions met the inclusion criteria; 16 specifically in a T2D population and 14 in a subpopulation with T2D. Overall, metabolic surgery was found to be cost-effective or cost-saving. Where undertaken, the results were robust to sensitivity and scenario analyses. Of the 30 studies included, 15 were considered high quality. Identified limitations included limited long-term follow-up data and uncertainty regarding the utility associated with T2D remission. CONCLUSION: Published high-quality studies suggest metabolic surgery is a cost-effective or cost-saving intervention. As the prevalence of obesity and obesity-related diseases increases worldwide, significant investment and careful consideration of the resource requirements needed for metabolic surgery programmes will be necessary to ensure that service provision is adequate to meet demand.

Another Step Toward Hepatitis C Elimination: An Economic Evaluation of an Irish National Birth Cohort Testing Program.

OBJECTIVES: We aimed to evaluate the cost-effectiveness of offering once-off birth cohort testing for hepatitis C virus (HCV) to people in Ireland born between 1965 and 1985, the cohort with the highest reported prevalence of undiagnosed chronic HCV infection. METHODS: Systematic and opportunistic HCV birth cohort testing programs, implemented over a 4-year timeframe, were compared with the current practice of population risk-based testing only in a closed-cohort decision tree and Markov model hybrid over a lifetime time horizon. Outcomes were expressed in quality-adjusted life-years (QALYs). Costs were presented from the health system's perspective in 2020 euro (€). Uncertainty was assessed via deterministic, probabilistic, scenario, and threshold analyses. RESULTS: In the base case, systematic testing yielded the largest cost and health benefits, followed by opportunistic testing and risk-based testing. Compared with risk-based testing, the incremental cost-effectiveness ratio for opportunistic testing was €14 586 (95% confidence interval €4185-€33 527) per QALY gained. Compared with opportunistic testing, the incremental cost-effectiveness ratio for systematic testing was €16 827 (95% confidence interval €5106-€38 843) per QALY gained. These findings were robust across a range of sensitivity analyses. CONCLUSIONS: Both systematic and opportunistic birth cohort testing would be considered an efficient use of resources, but systematic testing was the optimal strategy at willingness-to-pay threshold values typically used in Ireland. Although cost-effective, any decision to introduce birth cohort testing for HCV (in Ireland or elsewhere) must be balanced with considerations regarding the feasibility and budget impact of implementing a national testing program given high initial costs and resource use.

Effectiveness of rapid antigen testing for screening of asymptomatic individuals to limit the transmission of SARS-CoV-2: A rapid review.

Rapid antigen detection tests (RADTs) offer advantages over gold-standard reverse transcription polymerase chain reaction (RT-PCR) tests in that they are cheaper and provide faster results, thus enabling prompt isolation of positive SARS-CoV-2 cases and quarantine of close contacts. The aim of this study was to collate and synthesise empirical evidence on the effectiveness of rapid antigen testing for the screening (including serial testing) and surveillance of asymptomatic individuals to limit the transmission of SARS-CoV-2. A rapid review was undertaken in MEDLINE (EBSCO), EMBASE (OVID), Cochrane Library, Europe PMC and Google Scholar up until 19 July 2021, supplemented by a grey literature search. Of the identified 1222 records, 19 reports referring to 16 studies were included. Eight included studies examined the effectiveness of RADTs for population-level screening, four for pre-event screening and four for serial testing (schools, a prison, a university sports programme and in care homes). Overall, there is uncertainty regarding the effectiveness of rapid antigen testing for the screening of asymptomatic individuals to limit the transmission of SARS-CoV-2. This uncertainty is due to the inconsistent results, the relatively low number of studies identified, the predominantly observational and/or uncontrolled nature of the study designs used, and concerns regarding methodological quality. Given this uncertainty, more real-world research evidence in relevant settings, which is of good quality and timely, as well as economic evaluation, is required to inform public policy on the widespread use of RADTs in asymptomatic individuals.

Population-Based Testing for Undiagnosed Hepatitis C: A Systematic Review of Economic Evaluations.

BACKGROUND AND OBJECTIVES: Recognising the significant public health threat posed by hepatitis C, international targets have been established by the World Health Organization with the aim of eradicating the hepatitis C virus (HCV) by 2030. With the availability of safe and effective therapies, the greatest challenge to achieving elimination is the identification and treatment of those currently undiagnosed. This systematic review aimed to identify and appraise the international literature on the cost-effectiveness of birth cohort, universal, and age-based general population testing for identifying people with undiagnosed chronic HCV infection. METHODS: A comprehensive literature search was undertaken in Medline, Embase and grey literature sources to identify studies published between 1 January 2000 and 17 July 2020. Retrieved citations were independently reviewed by two reviewers according to pre-defined eligibility criteria. Data extraction and critical appraisal were completed in duplicate. Study quality, relevance and credibility were assessed using the Consensus for Health Economic Criteria and the ISPOR questionnaires. All costs were reported in 2019 Irish Euro following adjustment for inflation and purchasing power parity. Willingness-to-pay (WTP) thresholds of €20,000 and €45,000 were adopted as reference points for interpreting cost-effectiveness in the narrative synthesis. The systematic review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. RESULTS: Overall, 4622 citations were retrieved in the literature search. Of these, 27 studies met the inclusion criteria. Six (22%) of the 27 studies were rated as low quality, 17 (63%) were moderate quality and four (15%) were high quality. Compared with no testing or risk-based testing: 14 of 16 (88%) cost-utility analyses found that birth cohort testing was cost effective, eight of nine (89%) analyses found that universal testing was cost effective, and eight of eight (100%) analyses found that age-based general population testing was cost effective. Cost effectiveness was influenced by disease prevalence and progression, testing and treatment uptake, treatment eligibility of those identified by testing, the cost of treatment and the proportion of those treated that achieve sustained virological response. CONCLUSION: Overall, the international evidence supports the potential cost effectiveness of birth cohort, universal, and age-based general population testing, but is caveated by study generalisability, specifically the transferability of findings from one jurisdiction to another, and institutional variations in healthcare delivery systems and budgetary constraints. The cost effectiveness of each approach will vary according to population- and health system-specific characteristics such as epidemiological context, testing coverage, linkage to care and capacity to treat. Given issues regarding the transferability of economic evaluations (for example, model inputs and assumptions) and the significant resources required to implement these interventions, jurisdiction-specific economic evaluations and budget impact analyses will likely be required to inform investment and implementation decisions. REGISTRATION: PROSPERO, CRD42019127159. Registered 29 April 2019.

Cost-Effectiveness Analysis of a National Pre-Exposure Prophylaxis (PrEP) Program in Ireland.

OBJECTIVES: To estimate the cost-effectiveness of introducing a publicly funded pre-exposure prophylaxis (PrEP) program in Ireland. METHODS: We constructed a state-transition Markov model. This was a cross-sectional population model that tracked all HIV-negative men who have sex with men (MSM) in Ireland over their lifetime. Access to a publicly funded PrEP program (medications + frequent monitoring) in high-risk MSM was compared with no PrEP. The primary outcome measure was the incremental cost-effectiveness ratio (ICER). RESULTS: In the base case, introducing a PrEP program was considered cost saving and provided significant health benefits to the population. Univariate sensitivity analysis demonstrated that PrEP efficacy and HIV incidence had the greatest impact on cost-effectiveness. Including an increase in sexually transmitted infections had a negligible impact on the results. Efficacy was a significant driver in the model. PrEP was cost saving at all efficacy values above 60%, and at the lowest reported efficacy in MSM (44% in the iPrEX trial), the ICER was €4711/QALY (highly cost-effective). Event-based dosing (administration during high-risk periods only) was associated with additional cost savings. We estimated that 1705 individuals (95% CI: 617-3452) would join the program in year 1. The incremental budget impact was €1.5m (95% CI: €0.5m to €3m) in the first year and €5.4m over 5 years (95% CI: €1.8m to €11.5m), with 173 cases of HIV averted over 5 years. CONCLUSION: We found that the introduction of a PrEP program would be considered cost saving in the first cost-effectiveness analysis of its kind in Ireland.

Early Health Economic Modelling - Optimizing Development for Medical Device Developers? Comment on "Problems and Promises of Health Technologies: The Role of Early Health Economic Modeling".

This commentary considers the positive and negative consequences of early economic modelling and explores potential future directions. Early economic modelling offers device manufacturers an opportunity to assess the potential value of an innovation at an early stage of development. Early modelling can direct resources into potentially viable technologies and reduce investment in technologies with limited prospect of value. However, it is unclear whether early modelling is sufficiently specific to identify innovations with low value. It may be that early modelling is more useful for directing data gathering to reduce decision uncertainty. Early modelling is of primary benefit to the manufacturer and may have both positive and negative consequences for reimbursement processes that should be considered.

Acute ischaemic stroke: a systematic review of the cost-effectiveness of emergency endovascular therapy using mechanical thrombectomy.

PURPOSE: Although good evidence exists regarding the clinical effectiveness of mechanical thrombectomy for people with acute ischaemic stroke, cost-effectiveness should also be considered. The aim of this study was to systematically review the evidence of cost-effectiveness of emergency endovascular therapy using mechanical thrombectomy in the management of acute ischaemic stroke. METHODS: The search was carried out in PubMed, EMBASE, Cochrane Library, and a grey literature search. Studies were included if they compared the costs and consequences of mechanical thrombectomy added to usual medical care compared to usual care alone for people with acute ischaemic stroke in the anterior and/or posterior region. Study quality was assessed using two appraisal tools tailored to economic evaluations. FINDINGS: Thirteen studies were identified including twelve cost-utility analyses and one cost-benefit analysis. Studies could be dichotomised into those that evaluated first-generation (n = 4) and second-generation (n = 9) mechanical thrombectomy devices. Six studies had low applicability, six had moderate applicability, and one had high applicability to other settings. All cost-utility studies reported incremental cost-effectiveness ratios that would be considered cost-effective under typical willingness-to-pay thresholds. CONCLUSIONS: If the outcomes of the trials underpinning the evidence of clinical effectiveness can be replicated, then mechanical thrombectomy is likely to be cost-effective by typical willingness-to-pay thresholds. This finding holds under the assumption that no investment is required to develop stroke centres to the standard required to provide a safe emergency endovascular service and that additional expenditure on timely patient transport is not required.

Economic Evaluation of Selective Neonatal Bacillus Calmette-Guérin Vaccination of High-risk Infants in Ireland.

BACKGROUND: In Western Europe, currently only Ireland and Portugal continue to provide universal neonatal bacillus Calmette-Guérin (BCG) vaccination programs, despite not being considered as high tuberculosis (TB) incidence countries. Other European countries only vaccinate infants considered at high risk of contracting TB. We evaluated the cost-effectiveness of selective BCG vaccination compared with strategies of universal and no vaccination. METHODS: An economic model was used to simulate a cohort from birth to life expectancy, taking the perspective of the publicly funded healthcare system. BCG protection was modeled to last 15 years. International vaccine efficacy data were combined with Irish epidemiologic and cost data. The model took into account long-term sequelae associated with TB meningitis and severe adverse reactions relating to the BCG vaccine. A fully probabilistic model was used to incorporate uncertainty across all parameters. RESULTS: At &OV0556;139,557 per quality-adjusted life year, selective vaccination was not cost-effective relative to a program of no vaccination. The incremental cost-effectiveness of universal vaccination was &OV0556;2.55 million per quality-adjusted life year relative to selective vaccination. There was substantial uncertainty regarding the effectiveness of BCG vaccination. The cost-effectiveness of selective vaccination could be substantially improved by reducing the cost of administering the vaccine. CONCLUSIONS: In the absence of changes to other aspects of TB control, a switch to selective vaccination will result in increased cases of childhood TB. Although not considered cost-effective, selective vaccination may be preferable to no vaccination until other changes to TB control may be implemented to reduce the risk of TB in children.

CONTRIBUTION OF STAKEHOLDER ENGAGEMENT TO THE IMPACT OF A HEALTH TECHNOLOGY ASSESSMENT: AN IRISH CASE STUDY.

OBJECTIVES: The aim of this study was to illustrate the contribution of stakeholder engagement to the impact of health technology assessment (HTA) using an Irish HTA of a national public access defibrillation (PAD) program. BACKGROUND: In response to draft legislation that proposed a PAD program, the Minister for Health requested that Health Information and Quality Authority undertake an HTA to inform the design and implementation of a national PAD program and the necessary underpinning legislation. The draft legislation outlined a program requiring widespread installation and maintenance of automatic external defibrillators in specified premises. METHODS: Stakeholder engagement to optimize the impact of the HTA included one-to-one interviews with politicians, engagement with an Expert Advisory Group, public and targeted consultation, and positive media management. RESULTS: The HTA quantified the clinical benefits of the proposed PAD program as modest, identified that substantial costs would fall on small/medium businesses at a time of economic recession, and that none of the programs modeled were cost-effective. The Senator who proposed the Bill actively publicized the HTA process and its findings and encouraged participation in the public consultation. Participation of key stakeholders was important for the quality and acceptability of the HTA findings and advice. Media management promoted public engagement and understanding. The Bill did not progress. CONCLUSIONS: The HTA informed the decision not to progress with legislation for a national PAD program. Engagement was tailored to ensure that key stakeholders including politicians and the public were informed of the HTA process, the findings, and the advice, thereby maximizing acceptance. Appropriate stakeholder engagement optimizes the impact of HTA.

The HIQA's Health Technology Assessment of Breast Screening: Highlighting Some of the Challenges Posed by Evaluations of Screening Programs.

A review of the Health Information and Quality Authority's (HIQA) assessment of breast cancer surveillance cancer criticized how the results were presented and interpreted. The health technology assessment (HTA) investigated surveillance options for women aged less than 50 years who were at elevated risk of breast cancer. Surveillance strategies using digital mammography, magnetic resonance imaging, or a combination of the two modalities were modeled on the basis of diagnostic test accuracy. The HTA faced a number of issues, including the use of diagnostic test accuracy as a surrogate for long-term outcomes; modeling interventions that were not considered acceptable to clinicians; and extrapolating for screening intervals and age ranges not directly supported by available evidence. The evaluation of screening programs gives rise to challenges in terms of balancing an adequate exploration of the possible options while also being cognizant of what is appropriately supported by evidence. In this article, the authors of the HIQA report discuss the challenges posed by this particular HTA.

Cost-Effectiveness of a National Opportunistic Screening Program for Atrial Fibrillation in Ireland.

OBJECTIVES: To evaluate the cost-effectiveness of a national atrial fibrillation screening program in Ireland involving annual opportunistic pulse palpation of all those older than 65 years during general practitioner consultations, with an electrocardiogram being performed if an irregular pulse is detected. METHODS: A probabilistic Markov model was used to simulate costs and clinical outcomes in a hypothetical cohort of men and women with and without screening over the course of 25 years, using a societal perspective. RESULTS: Screening was associated with an incremental cost-effectiveness ratio of €23,004/quality-adjusted life-year compared with routine care. Nevertheless, if the relative risk of stroke and systematic embolism in screen-detected patients is more than 12% lower than that in patients with atrial fibrillation identified through routine practice, then screening would not be considered cost-effective at a willingness-to-pay threshold of €45,000/quality-adjusted life-year. An analysis comparing alternative combinations of start age and screening interval found that less frequent screening with a later start age may be more cost-effective than an annual screening from age 65 years. CONCLUSIONS: Annual opportunistic screening of men and women aged 65 years and older in primary care in Ireland is likely to be cost-effective using conventional willingness-to-pay thresholds, assuming that those detected through screening have a comparable stroke risk profile as those detected through routine practice. Raising the start age of screening or increasing the screening interval may improve the cost-effectiveness of a prospective screening program.

Cost-effectiveness of a national public access defibrillation programme.

AIM: Proposed Irish legislation aimed at increasing survival from out-of-hospital-cardiac-arrest (OHCA) mandates the provision of automated external defibrillators (AEDs) in a comprehensive range of publicly accessible premises in urban and rural areas. This study estimated the clinical and cost effectiveness of the legislation, compared with alternative programme configurations involving more targeted AED placement. METHODS: We used a cost-utility analysis to estimate the costs and consequences of public access defibrillation (PAD) programmes from a societal perspective, based on AED deployment by building type. Comparator programmes ranged from those that only included building types with the highest incidence of OHCA, to the comprehensive programme outline in the proposed legislation. Data on OHCA incidence and outcomes were obtained from the Irish Out-of-Hospital-Cardiac-Arrest Register (OHCAR). Costs were obtained from the Irish health service, device suppliers and training providers. RESULTS: The incremental cost effectiveness ratio (ICER) for the most comprehensive PAD scheme was €928,450/QALY. The ICER for the most scaled-back programme involving AED placement in transport stations, medical practices, entertainment venues, schools (excluding primary) and fitness facilities was €95,640/QALY. A 40% increase in AED utilisation when OHCAs occur in a public area could potentially render this programme cost effective. CONCLUSION: National PAD programmes involving widespread deployment of static AEDs are unlikely to be cost-effective. To improve cost-effectiveness any prospective programmes should target locations with the highest incidence of OHCA and be supported by efforts to increase AED utilisation, such as improving public awareness, increasing CPR and AED training, and establishing an EMS-linked AED register.

Using prediction intervals from random-effects meta-analyses in an economic model.

OBJECTIVES: When incorporating treatment effect estimates derived from a random-effect meta-analysis it is tempting to use the confidence bounds to determine the potential range of treatment effect. However, prediction intervals reflect the potential effect of a technology rather than the more narrowly defined average treatment effect. Using a case study of robot-assisted radical prostatectomy, this study investigates the impact on a cost-utility analysis of using clinical effectiveness derived from random-effects meta-analyses presented as confidence bounds and prediction intervals, respectively. METHODS: To determine the cost-utility of robot-assisted prostatectomy, an economic model was developed. The clinical effectiveness of robot-assisted surgery compared with open and conventional laparoscopic surgery was estimated using meta-analysis of peer-reviewed publications. Assuming treatment effect would vary across studies due to both sampling variability and differences between surgical teams, random-effects meta-analysis was used to pool effect estimates. RESULTS: Using the confidence bounds approach the mean and median ICER was €24,193 and €26,731/QALY (95%CI: €13,752 to €68,861/QALY), respectively. The prediction interval approach produced an equivalent mean and median ICER of €26,920 and €26,643/QALY (95%CI: -€135,244 to €239,166/QALY), respectively. Using prediction intervals, there is a probability of 0.042 that robot-assisted surgery will result in a net reduction in QALYs. CONCLUSIONS: Using prediction intervals rather than confidence bounds does not affect the point estimate of the treatment effect. In meta-analyses with significant heterogeneity, the use of prediction intervals will produce wider ranges of treatment effect, and hence result in greater uncertainty, but a better reflection of the effect of the technology.

Global patient safety and antiretroviral drug-drug interactions in the resource-limited setting.

Scale-up of HIV treatment services may have contributed to an increase in functional health facilities available in resource-limited settings and an increase in patient use of facilities and retention in care. As more patients are reached with medicines, monitoring patient safety is increasingly important. Limited data from resource-limited settings suggest that medication error and antiretroviral drug-drug interactions may pose a significant risk to patient safety. Commonly cited causes of medication error in the developed world include the speed and complexity of the medication use cycle combined with inadequate systems and processes. In resource-limited settings, specific factors may contribute, such as inadequate human resources and high disease burden. Management of drug-drug interactions may be complicated by limited access to alternative medicines or laboratory monitoring. Improving patient safety by addressing the issue of antiretroviral drug-drug interactions has the potential not just to improve healthcare for individuals, but also to strengthen health systems and improve vital communication among healthcare providers and with regulatory agencies.

Cost-effectiveness of prion filtration of red blood cells to reduce the risk of transfusion-transmitted variant Creutzfeldt-Jakob disease in the Republic of Ireland.

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a rare, progressive fatal noninflammatory neurodegenerative disease. Ireland has the second highest rate of vCJD in the world with an ongoing risk of vCJD transmission through blood transfusion. Prion-removing filters have been developed to reduce the risk of vCJD transmission. This study aimed to evaluate the cost-effectiveness of implementing a policy of prion filtration of red blood cells (RBCs) in the Republic of Ireland. STUDY DESIGN AND METHODS: A cost-effectiveness model was developed to simulate the likelihood of RBC recipients developing clinical vCJD as a result of being transfused with infected RBCs. Model variables were collected from published literature and expert opinion. Costs were estimated based on the processing changes required to implement prion filtration. RESULTS: In the absence of prion filtration, it is estimated that two individuals will develop clinical vCJD arising from RBC transfusions over a 10-year time horizon. The discounted life-years lost will be 18.5 years. With prion filtration, there will be no deaths or life-years lost. The discounted cost of universal prion filtration is €68.2 million over 10 years with a corresponding incremental cost-effectiveness ratio of €3.7 million per life-year gained. In 25.3% of simulations there were no deaths from vCJD infection through infected blood transfusions, irrespective of prion filtration. CONCLUSION: Prion filtration is considered not cost-effective by traditional measures. Although numerous non-cost-effective blood safety strategies have been implemented in the past, consideration should be given to the most efficient use of finite resources in transfusion medicine.

Health Technology Assessment International 7th Annual Meeting: Dublin, Ireland, 6­9 June 2010.

A record number of delegates from industry, academia and health policy convened at the 7th Annual Meeting of Health Technology Assessment International (HTAi) which was held in Dublin, Ireland in June 2010. The theme of this year's meeting was 'Maximizing the Value of HTA'. The scientific program covered a broad range of topics from coverage with evidence development to timeliness of conducting HTAs, early engagement with stakeholders, value of information analysis, patient involvement and international collaboration. There was also a lively social program with the conference dinner held at the Guinness Storehouse.

Steady-state pharmacokinetic comparison of generic and branded formulations of stavudine, lamivudine and nevirapine in HIV-infected Ugandan adults.

BACKGROUND: We aimed to compare the steady-state pharmacokinetic parameters and tolerability of Triomune 40 (stavudine 40 mg, lamivudine 150 mg and nevirapine 200 mg) and branded formulations of these drugs in HIV-infected Ugandans. METHODS: This includes a randomized, open-label, cross-over study of HIV-infected patients stable on therapy for 1 month. Patients were randomized to generic or branded formulation. Plasma pharmacokinetics were assessed after 1 month. The following day, alternate formulation was administered, and 1 month later, drug pharmacokinetics were re-assessed. Plasma pharmacokinetics were determined using HPLC-UV detection. Similarity between steady-state pharmacokinetic parameters was assessed using the US Food and Drug Administration standards for bioequivalency testing. Tolerability was assessed using questionnaires. RESULTS: Sixteen (10 females) patients completed the study. Median (IQR) age, weight and CD4 count were 37 (33.7-40) years, 65 (63.4-66) kg and 292 (220.7-344.5) cells/mm(3), respectively. All patients received co-trimoxazole. The geometric mean ratio (90% CI) for stavudine, lamivudine and nevirapine was 0.92 (0.78-1.08), 1.11 (0.95-1.30) and 0.84 (0.64-1.11), respectively, for C(max), and 0.83 (0.70-0.97), 1.06 (0.94-1.20) and 0.88 (0.71-1.10), respectively, for AUC. Stavudine plasma concentrations were significantly lower for the generic formulation. Pharmacokinetic parameter inter-individual variability ranged from 29% to 99%. There were no differences in tolerability for the two formulations. CONCLUSIONS: Pharmacokinetic profiles of generic and branded drugs were similar. Differences particularly with regard to stavudine were demonstrated. Surveillance of the quality of generic antiretroviral drugs in the target populations is needed. Capacity building for pharmacokinetic research in resource-limited settings is a priority.

The cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia.

OBJECTIVE: To assess the cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia, as implementation at the local health centre level has yet to be undertaken in many resource-limited countries despite recommendations in recent updated World Health Organization (WHO) guidelines. DESIGN: A probabilistic decision analytical model of HIV/AIDS progression in children based on the CD4 cell percentage (CD4%) was populated with data from the placebo-controlled Children with HIV Antibiotic Prophylaxis trial that had reported a 43% reduction in mortality with cotrimoxazole prophylaxis in HIV-infected children aged 1-14 years. METHODS: Unit costs (US$ in 2006) were measured at University Teaching Hospital, Lusaka. Cost-effectiveness expressed as cost per life-year saved, cost per quality adjusted life-year (QALY) saved, cost per disability adjusted life-year (DALY) averted was calculated across a number of different scenarios at tertiary and primary healthcare centres. RESULTS: : Cotrimoxazole prophylaxis was associated with incremental cost-effectiveness ratios (ICERs) of US$72 per life-year saved, US$94 per QALY saved and US$53 per DALY averted, i.e. substantially less than a cost-effectiveness threshold of US$1019 per outcome (gross domestic product per capita, Zambia 2006). ICERs of US$5 or less per outcome demonstrate that cotrimoxazole prophylaxis is even more cost-effective at the local healthcare level. The intervention remained cost-effective in all sensitivity analyses including routine haematological and CD4% monitoring, varying starting age, AIDS status, cotrimoxazole formulation, efficacy duration and discount rates. CONCLUSION: Cotrimoxazole prophylaxis in HIV-infected children is an inexpensive low technology intervention that is highly cost-effective in Zambia, strongly supporting the adoption of WHO guidelines into essential healthcare packages in low-income countries.