Non-occupational post-exposure prophylaxis for HIV: a systematic review

Article history

The research reported in this issue of the journal was commissioned and funded by the HTA Programme on behalf of NICE as project number 07/40/01. The protocol was agreed in December 2007. The assessment report began editorial review in May 2008 and was accepted for publication in August 2008. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

None

Copyright statement

© 2009 Queen’s Printer and Controller of HMSO. This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NCCHTA, Alpha House, Enterprise Road, Southampton Science Park, Chilworth, Southampton SO16 7NS, UK.

2009 Queen’s Printer and Controller of HMSO

Description of underlying health problem

Human immunodeficiency virus is a sexually transmitted and bloodborne virus found primarily in the blood, semen or vaginal fluid of an infected person. HIV is transmitted in two main ways:

• by having unprotected sex (anal, vaginal or oral) with someone infected with HIV

• by sharing needles and syringes with someone infected with HIV.

Human immunodeficiency virus can also be transmitted through blood infected with HIV and being exposed as a fetus or infant to HIV before/during birth or through breastfeeding. Any person is at risk of infection with the virus if he or she is exposed to HIV through unprotected sex, contaminated blood products or HIV-infected bodily fluids. 1

Seroconversion (converting from HIV negative to HIV positive) occurs when antibodies to HIV can be detected in the blood after infection with the virus. In individuals who become infected with HIV after exposure to the virus, about 30–70% experience an acute seroconversion illness, typically between 2 and 6 weeks after exposure to the virus. The onset is acute and the illness lasts for 1–2 weeks. Its severity varies from a mild glandular fever-like illness with fever, sore throat, lymphadenopathy and a non-itchy maculopapular rash to a severe illness associated with mucocutaneous ulceration and neurological manifestations that requires treatment in hospital. 2

Human immunodeficiency virus has a prolonged ‘silent’ period during which it often remains undiagnosed, particularly as the seroconversion illness (if present) may have been very mild. More persistent or severe symptoms may not appear for 10 years or more after HIV first enters the body in adults, or within 2 years in children born with HIV infection. This period of asymptomatic infection varies greatly in each person. Some people may begin to have symptoms within a few months whereas others may be symptom-free for more than 10 years. 3

Human immunodeficiency virus acts by attacking and destroying CD4 (cluster of differentiation) cells. These cells are a type of white blood cell called T lymphocytes (or helper/inducer cells), which are important in the body’s immune system. Their depletion during HIV infection results in susceptibility to infection from opportunistic diseases such as tuberculosis, pneumonia and some cancers. 4 A CD4 cell count (a measure of the number of CD4 cells in a specified volume of blood) gives a measure of the degree to which an individual’s immune system is ‘compromised’. It helps to identify periods in which an individual is more vulnerable to opportunistic infections, consequently helping inform decisions to initiate antiretroviral treatment and therapies to prevent these infections. 4 Acquired immunodeficiency syndrome (AIDS) is diagnosed in the UK when an HIV-infected individual presents with an AIDS-defining illness, such as Pneumocystis carinii pneumonia, pulmonary tuberculosis or extrapulmonary tuberculosis. 5

The seroprevalence of HIV is the number of cases of HIV present in a specific population at a designated time, where a case is defined as someone who has HIV antibodies in their serum. 6 Information on the seroprevalence of HIV in the UK relies on case and test result reporting. However, this can only give information on diagnosed infections. It is therefore supplemented by a programme of unlinked anonymous surveys (using the residue of specimens collected for routine testing for other purposes), which provide information about the total seroprevalence, including both diagnosed and undiagnosed infections, in population subgroups. 6

The most effective methods for preventing HIV infection are preventive behaviours including sexual abstinence, having sexual relations only with a non-infected partner, correct condom use, abstinence from drug-injection use and consistent use of sterile equipment when using injection drugs. However, secondary prevention measures such as prophylactic antiretroviral drugs have been used to reduce the risk of HIV infection after occupational or non-occupational exposure. 7

Epidemiology

Globally there are an estimated 39.5 million people living with HIV. There were 4.3 million new infections in 2006, with 2.8 million (65%) of these occurring in sub-Saharan Africa and important increases in Eastern Europe and Central Asia, where there are some indications that infection rates have risen by more than 50% since 2004. In 2006, 2.9 million people died of AIDS-related illnesses. 8

The most recent figures for the UK estimate that in 2006 there were 73,000 people living with HIV in the UK, around one-third of whom had not yet been diagnosed. There were an estimated 7800 reports of new diagnoses of HIV infection in 2006. A total of 59% of these were among heterosexuals, 36% in men who have sex with men (MSM) and 2.5% in intravenous drug users. In terms of ethnic group, 46% of persons newly diagnosed were black African and 42% were white. 9

There are certain groups in the UK who are at higher risk of infection than others:

• homosexual men (MSM)

• injecting drug users (IDUs)

• men and women who have lived as adults in countries where heterosexual transmission of HIV is common (notably South, East and Central Africa)

• children, from their infected mothers during pregnancy and birth. 1

Table 1 shows the prevalence of HIV infection in different population subgroups in the UK. 10

Description of the intervention

Postexposure prophylaxis for HIV is the prompt administration of antiretroviral therapy following known or potential exposure to HIV infection in an attempt to prevent the establishment of infection. 11 Animal models show that, after initial exposure, HIV replicates within dendritic cells of the skin and mucosa before spreading through lymphatic vessels and developing into a systemic infection. This delay in systemic spread leaves a ‘window of opportunity’ for PEP using antiretroviral drugs designed to block replication of HIV. 12 However, the evidence for the effectiveness of PEP in preventing seroconversion after non-occupational exposure to HIV is unclear.

Current UK guidance on PEP for non-occupational potential or actual exposure to HIV, based on the limited evidence available on the effectiveness of PEP after occupational exposure,10,12,13 recommends combination therapies. Although there is no direct evidence that they are more effective in preventing HIV post exposure than monotherapies, combination therapies are more efficacious in treating HIV-infected patients and in preventing perinatal transmission than monotherapies and so it is theorised that a combination of drugs would enhance the effectiveness of PEP. 12 As yet, no antiretroviral drug has been licensed for use after non-occupational exposure to HIV in the UK. 13 The current drug regimen recommended for HIV PEP starter packs after non-occupational exposure14 is:

• one Combivir^® (GlaxoSmithKline) tablet (300 mg zidovudine + 150 mg lamivudine) twice daily, plus

• two Kaletra^® (Abbott)film-coated tablets (200 mg lopinavir + 50 mg ritonavir) twice daily.

Current UK guidance suggests that other drug combinations could be used when the physician considers them more appropriate for individual patients, such as including in the regimen ritonavir-boosted lopinavir, saquinavir or amprenavir. 13 However, the current evidence on which drug regimen to use, the effectiveness of that regimen in preventing seroconversion following non-occupational exposure to HIV and adherence rates to different regimens is unclear. The guidance is based upon effectiveness of antiretroviral therapy in individuals chronically infected with HIV and on limited data of toxicity in PEP.

There are potential risks associated with PEP following non-occupational exposure or potential exposure to HIV. The drugs used have side effects such as gastrointestinal upset (nausea and diarrhoea), diabetic exacerbation, dangerous interactions with other drugs and nephrolithiasis. 12 These side effects can increase non-adherence, which in turn can lead to seroconversion of the patient and the development of drug-resistant strains. 12 There is also the potential for an increase in risk behaviours if PEP is perceived as preventing HIV infection. 7

Current UK practice

Current UK practice for prescribing PEP after non-occupational exposure to HIV is based on guidance issued by the Department of Health13 and guidelines from the British Association for Sexual Health and HIV (BASHH). 10

The Department of Health guidance (2004) states that the lack of evidence of effectiveness of PEP following non-occupational exposure to HIV prevents a recommendation either in favour of or against its use. 13 It suggests that expert advice should be sought urgently from a physician experienced in the treatment of HIV (or a paediatrician in the case of a child) in the event of any non-occupational exposure to HIV that is considered to carry a high risk of HIV infection. 13 For optimal efficacy PEP should ideally be started within an hour of exposure, but as this time frame is unlikely to be met in non-occupational exposures to HIV the risk of PEP failure is increased. However, longer periods from exposure should not be considered an absolute contraindication to PEP. 13 A risk assessment of the circumstances surrounding the exposure should be made by the physician considering prescribing PEP, to determine the risk of infection. 13 The guidance states that all of the considerations that apply to the prescription of PEP after occupational exposure apply equally to non-occupational PEP from the point of a decision being reached that it is appropriate to prescribe it. 13 The current recommended drug regimen has been outlined in the previous section.

The BASHH guidelines make recommendations for the use of PEP following potential sexual exposure to HIV (PEPSE). 10 The recommendation is that PEPSE is given within 72 hours following unprotected vaginal or anal intercourse with an HIV-positive source or receptive anal intercourse with a source of unknown HIV status but from a group of > 10% HIV prevalence. It is suggested that patients complete 4 weeks of antiretroviral therapy and reattend for HIV testing at 3 months and 6 months post exposure. 10 The recommended drug regimen has been outlined in the previous section.

A recent audit of practice against these guidelines suggests that PEPSE is being prescribed and dispensed as the BASHH guidelines recommend, but that completion rates for the full course of medication [53%, 95% confidence interval (CI) 40.84–64.21] and attendance for 3 and 6 months postexposure HIV testing (12%, 95% CI 5.56–21.29) are low. 15

A survey of UK genitourinary medicine clinics in 1999 found that there were 242 requests for prophylactic antiretroviral drugs made at 56 clinics following a potential non-occupational exposure to HIV. 11 In total, 60% of these requests were made to nine clinics, six of which were located in the London area. The survey also found that there had been a fourfold increase in the number of requests for prophylactic antiretroviral drugs and a sevenfold increase in the number of prescriptions between 1997 and 1999. 11 Most of the requests had come from HIV-serodiscordant couples who had either had unprotected sex (13 cases, 29%) or had condom breakage during sex (10 cases, 22%).

Costs

One cost estimate suggests that the drug cost of a full 28-day course of PEP is approximately £600 (not including staff time,) whereas the lifetime costs of treatment for an HIV-positive individual are estimated to be between £135,000 and £181,000. 10

Issues specific to non-occupational HIV exposure

There are a number of factors specific to non-occupational HIV exposure that impact on establishing the effectiveness of PEP in this situation or that have particular implications which are different from those in occupational exposures. 16

Rationale for the study

There is growing clinical and patient enthusiasm for the use of non-occupational PEP to prevent HIV infection, although the reduction in the risk of seroconversion may be small, therapy can have unpleasant side effects and other issues as described may impact on effectiveness. No systematic review of the existing literature has been identified. Research is therefore needed to synthesise the available evidence on the effectiveness, harms and cost-effectiveness of non-occupational PEP for HIV.

From the perspective of the patient the pressing clinical issue is to prevent HIV infection. The wider NHS perspective is the most appropriate and cost-effective use of expensive antiretroviral drugs.

Search strategy

The following databases were searched for published studies and ongoing research, from inception to December 2007: the Cochrane Library (Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials), MEDLINE (Ovid), EMBASE (Ovid), PubMed, NHS Economic Evaluations Database (NHS EED), NHS Health Technology Assessment database (NHS HTA), Database of Abstracts of Reviews of Effectiveness (DARE), EconLit, National Research Register (NRR), Current Controlled Trials and ClinicalTrials.gov. Grey literature and conference proceedings were also searched. Searches were restricted to the English language and to human studies. Bibliographies of identified papers were assessed for other relevant studies. Investigators of studies were not contacted because of time constraints. Further details, including key search terms, can be found in Appendix 2.

Inclusion and data extraction process

Titles and abstracts of studies identified by the search strategy were screened independently for inclusion by two reviewers. The full text of potentially eligible studies was obtained and examined independently for inclusion by two reviewers. Data from each of the included studies were extracted by two reviewers on standard data extraction forms. Any disagreements were resolved by consensus or arbitration by a third reviewer if necessary.

The process for identifying and including studies is illustrated in Appendix 2, Figure 1. The primary reason for excluding studies was that they did not meet the inclusion criteria; for example they did not have a comparator group or results were not presented separately for the intervention and comparator groups. A list of studies excluded at various stages of the process can be found in Appendix 3.

FIGURE 1.

Flowchart of clinical effectiveness studies.

Quality assessment

The methodological quality of included studies was assessed using modified formal tools specific to the design of the study and focusing on possible sources of bias. The clinical effectiveness study was assessed for quality using criteria developed by Spitzer et al. 18 Quality assessment of economic evaluations was conducted using a checklist adapted from those developed by Drummond and Jefferson19 and Philips and colleagues. 20

Quality criteria were applied to each included study independently by two reviewers. At each stage any differences in opinion were resolved through discussion or if necessary by arbitration by a third reviewer.

Inclusion criteria

The inclusion criteria used for studies of the clinical and cost-effectiveness of non-occupational PEP for HIV are shown below.

Data synthesis

Synthesis of data was through narrative review with full tabulation of results of all included studies. Full data extraction forms are shown in Appendices 4 and 5. Meta-analysis was not possible because of the limited data found.

Quantity and quality of research available

One published study met the inclusion criteria for the review, which was a cohort study conducted by Schechter and colleagues21 in Brazil (Table 3, Figure 1 in Appendix 2 and Appendix 4).

The methodological quality and the quality of reporting of the included study were generally weak (Table 4).

Significant selection bias may have occurred during the recruitment of study participants. Participants were recruited from an unreported number of eligible participants of a previous HIV seroincidence study of MSM. A total of 250 of those deemed eligible were contacted by telephone and the first 200 to agree to participate were included in this study. The authors do not report the total number of eligible participants in the previous study or how the 250 eligible participants that were telephoned were selected, nor do they report any attempt to minimise volunteer bias. No power calculation is provided to justify why 200 participants were needed.

Participants allocated themselves to the intervention or the control group depending on whether or not they initiated chemoprophylaxis after an eligible exposure by taking the 4-day supply of PEP that they had been given. If PEP was initiated, after 4 days the participant was assessed by study personnel to establish whether the exposure was considered a high enough risk to warrant a further 24 days of PEP. Further selection bias may have occurred at this point as the authors do not report what was considered to be a high-risk exposure or the procedure by which study personnel made such decisions. However, the authors do report the demographic and behavioural characteristics of all study participants, which suggests that there were no significant differences between those who did and those who did not use PEP over the course of the study.

The authors do not report blinding of study participants or personnel. Although it would not have been possible to have fully blinded both study personnel and participants, it may have been possible at the routine follow-up appointments to have blinded personnel to PEP use by participants. This could have reduced potential detection bias.

In the analysis the authors report that two participants had no follow-up data and were therefore excluded from analysis, meaning that an intention to treat analysis was not conducted. The authors report the seroincidence rate (incidence of seroconversions per 100 person-years) for all of the study participants together, compared with the expected number of incident HIV cases in the absence of PEP (modelled from the previous HIV incidence study). The authors state that they did this because of a lack of a control group (participants not taking PEP). However, the reported results seem to suggest that there is a control group with follow-up data (participants who did not initiate PEP after an eligible exposure). It is therefore not clear why the authors did not calculate the incidence of seroconversion for those who took PEP and for those who did not take PEP, to give an estimate of the effectiveness of PEP in preventing seroconversion for non-occupational exposures.

This study reports the use of PEP amongst a well-established cohort of high-risk sexually active MSM, aged 18–35 years, in Rio de Janeiro, Brazil. The study cohort may have some similarities with populations of MSM living in other big cities, although the limited age range of study participants prevents generalisation to populations of MSM as a whole. It is also not possible to generalise the findings of this study to the population as a whole, in which potential exposure to HIV may also occur through heterosexual sex or non-occupational needlestick injuries.

Assessment of effectiveness

Tables 5–9 present the results of the included cohort study21 in terms of seroincidence of HIV within the cohort, PEP use, non-completion of PEP, adverse events and reports of risky behaviours.

Summary of clinical effectiveness of PEP for non-occupational exposure to HIV

• One cohort study of PEP in a high-risk HIV-negative homosexual male cohort in Brazil met the inclusion criteria of the review. The methodological quality and the quality of the reporting of the study were generally weak.

• The seroconversion to HIV rate in this study was one in the PEP group and 10 in the non-PEP group.

• The results suggest that PEP made no difference to the expected seroconversion to HIV for this cohort.

• Over the course of the study the overall seroincidence (combining the PEP and non-PEP groups) was 2.9 per 100 person-years (95% CI 1.4–5.1). This was compared with the authors expected seroincidence of 3.1 per 100 person-years (p > 0.97 compared with the observed seroincidence of 2.9).

• PEP was rarely prescribed on more than two occasions per participant, with the majority (72.1%) receiving just one course.

• The number of non-completed courses appears to be low, with only 2 out of 68 not returning to complete the course and 7 out of 68 discontinuing because of adverse events.

• The authors report that, on average, high-risk sexual activities declined over time for both PEP and non-PEP users. This does not appear to be related to the decision to initiate PEP; both groups had access to interventions designed to prevent/reduce risk behaviour, including at each visit pre- and post-test counselling, provision of condoms and safer sex workshops.

• The authors conclude that the results from their study ‘argue against establishing a public health PEP programme in our population with the aim of having a major impact on HIV transmission’ because of the observed overall seroincidence of 2.9% being so similar to that expected for this population.

Quantity and quality of research available

Four economic evaluations22–25 met the inclusion criteria for the review and are shown in Table 10 (details in Figure 2 in Appendix 2 and Appendix 5).

FIGURE 2.

Flowchart of cost-effectiveness studies.

A summary of the methodological quality of reporting in the four included studies is shown in Table 11. Each of the cost-effectiveness studies outlined a well-defined question: to assess the cost-effectiveness of PEP for HIV following a non-occupational exposure. 22–25 The patient group was clearly stated in three of the four studies. 23–25 In the study by Pinkerton and colleagues22 the patient group is less clear as the authors have referred to a hypothetical cohort of 10,000 ‘patients’ (a cohort that includes women) but have used this term interchangeably with 10,000 ‘men who have sex with men’.

All of the studies clearly stated that their perspective was societal, with the analysis including all identifiable costs, regardless of who bore them. However, Pinkerton and colleagues22 stated only the monetary costs of PEP drugs and of treating a patient with HIV/AIDS. Herida and colleagues25 referred only to health sector costs in their study, despite employing a societal perspective.

Two of the studies23,25 gave a clear description of the interventions considered. One study24 does not describe the PEP programme employed, whereas in the other22 the intervention applied to a hypothetical cohort was assumed to be zidovudine, lamivudine and indivadir, or zidovudine and lamivudine only, but no further details are given. Three of the four studies22,24,25 employed the comparator of ‘no PEP’ whereas in the fourth study23 the comparator used is unclear.

The study types used were appropriate for economic analysis in each case; three of the four studies included both cost-effectiveness and cost–utility analyses22,23,25 and one employed a cost–utility analysis alone. 24

Each of the four studies is limited as the effectiveness of the intervention, PEP in non-occupational exposure to HIV, has not been established. The effectiveness parameter in each of the papers is based on the results of a case–control study undertaken in health-care workers who were prescribed zidovudine monotherapy. The dual or triple drug regimens considered in these cost-effectiveness studies are assumed to be as effective as zidovudine alone in this study of occupational exposure. Pinkerton and colleagues22 have taken their effectiveness parameter, the probability that PEP is effective, from the original study,26 set at 79%. The remaining three studies23–25 have taken their effectiveness parameter from the update of that study,27 in which effectiveness is set at 81%, although one of these studies25 reports that an effectiveness of 80% is used.

The effectiveness of PEP and its effects on the cost–utility ratios presented in the studies, along with other parameters, are clearly explored in sensitivity analyses in each of the studies. 22–25 Authors of two of the studies reported multivariate and threshold analyses in addition to the univariate sensitivity analysis. 22,23

Costs and consequences were judged to have been valued credibly in three of the four included studies. 22,23,25 Pinkerton and colleagues24 have calculated the costs of providing PEP from a previously published cost analysis.

Three of the four studies have used a lifetime horizon for analysis. 22,24,25 A shorter time horizon of 10 years has been employed for estimating long-term infection, but no justification has been given. 23 Discount rates are clearly reported in three studies. In two studies23,25 an annual rate of 3% was used to discount both costs and benefits, such as future savings in averted HIV-related medical costs. Pinkerton and colleagues22 used a 3% annual rate (applied to both costs and benefits) and altered this to 0% (undiscounted) and 5% in the sensitivity analysis. It is unclear if discounting has been applied in one of the 2004 Pinkerton and colleagues studies. 24

Incremental analysis was reported by only one of the studies. 22 The remaining three papers report cost–utility ratios but no incremental ratios. Pinkerton and colleagues23 compare their results with previously published papers.

Table 12 presents a summary of the external validity of the included cost-effectiveness studies. Three of the four studies are set in the US22–24 and the fourth in France,25 where the institutional health-care arrangements and resource costs, and access to them, are not comparable to those in England and Wales. It is unclear whether the patient groups are similar to those of interest in England and Wales as these studies are set in differing health-care systems but are conducted among the relevant population: those taking PEP after a non-occupational exposure.

Either the intervention in each of the four studies was not sufficiently clear for a judgement to be made of treatment comparability24,25 or the research protocol included such elements as counselling and adherence counselling that may not be a feature of clinical management. 23 Pinkerton and colleagues22 have assumed that the PEP in their study consists of triple combination therapy, which is comparable to that recommended in the UK, but no further details are given.

Assessment of cost-effectiveness

Summaries of the results of the four published economic evaluations in terms of cost–utility ratios for different population subgroups are shown in Tables 13–15.

Herida and colleagues25 found that the French PEP programme did not appear to be cost-effective overall, with a cost-effectiveness ratio of €996,104 per infection averted and €88,692 per quality-adjusted life-year (QALY) saved. However, the authors report major differences in the cost-effectiveness ratio according to the type of exposure. PEP after receptive anal intercourse with an HIV-infected individual (men –€22,141, women –€22,031 per QALY saved) and PEP to an intravenous drug user (IDU) after sharing a needle with an HIV-infected person (–€1141 per QALY saved) were cost saving. PEP was cost-effective for MSM having receptive anal intercourse with a partner of unknown status (€31,862 per QALY saved). PEP was not considered cost-effective (cost per QALY €50,000) for all other exposures considered in the analysis.

One-way sensitivity analyses were performed on the compliance and life expectancy of HIV-infected individuals in this study. 25 PEP after receptive anal intercourse with an HIV-infected individual remained cost saving (–€17,778 and –€18,860 per QALY saved for MSM and heterosexual women respectively). PEP to an IDU after needle sharing with an HIV-infected person remained cost-effective but was no longer cost saving (€18,445 per QALY saved). Further sensitivity analyses incorporating higher lifetime HIV costs resulting from longer survival resulted in the three exposure risks with negative ratios in the base case remaining cost saving but with higher cost ratios.

Herida and colleagues25 also performed threshold analyses for exposures with cost-effectiveness ratios under €200,000 per QALY saved, using minimum values of prevalence, per-contact HIV transmission or compliance required to achieve the cost-saving threshold (€0 per QALY saved) or the cost-effective threshold (€50,000 per QALY saved). The authors reported that PEP for MSM after receptive anal intercourse with a partner of unknown HIV status was cost saving for a per-contact transmission risk of at least equal to 0.0411 or an HIV prevalence of at least 0.208. For needle sharing with an individual of unknown serostatus the authors reported that cost-effectiveness occurred with a compliance of ≥ 0.92 with both the highest values of prevalence (0.21) and of the per-contact transmission risk (0.0092). The cost-effectiveness ratio was reached for a per-contact transmission risk equal to 0.0208 for receptive vaginal intercourse with an HIV-infected partner.

Pinkerton and colleagues’23 cost–utility analysis of a PEP programme for 401 participants with possible non-occupational exposure to HIV found that the use of PEP prevented an estimated 1.59 HIV infections (1.26 infections after adjusting for continuing risk behaviours over the subsequent 10 years), with an overall cost–utility ratio of US$14,449 per QALY saved. In total, 96% of averted infections were among men who reported exposure through receptive anal intercourse with other men.

The authors report that the PEP programme was cost saving amongst men who have receptive anal intercourse with other men, and when the partner was known to be HIV positive. 23 The overall cost–utility ratio for men reporting exposure through male–male sex (receptive or insertive anal intercourse, receptive oral intercourse or ‘other’) was US$8607 per QALY saved, whereas the cost–utility ratio for all other exposures combined was US$258,667 per QALY saved. The cost per QALY saved for exposure by injecting drugs and male–female receptive anal sex was US$86,462 and US$165,289 respectively.

The results of the sensitivity analyses reported by the authors suggest that the PEP programme remained cost-effective when the effectiveness of PEP was set as low as 48% (base case 81%) and as long as PEP completion rates were greater than 29%. 23 The programme also remained cost-effective regardless of the percentage of partners known to be infected with HIV or the prevalence of infection among partners whose HIV status was unknown.

The cost–utility ratio was most sensitive to the receptive anal intercourse transmission probability. 23 The authors report that the PEP programme would be cost saving overall if this probability exceeded 0.033 and would be cost-effective (defined by the authors as a cost–utility ratio of US$60,000 per QALY saved) for probabilities as small as 0.009 (the base case was set at 0.02).

The Pinkerton and colleagues study24 of PEP in 96 metropolitan statistical areas in the US estimated the respective mean and median cost–utility ratios to be US$15,728 and US$15,367 per QALY saved, with 63.9 HIV infections averted. PEP was cost saving for male–male and male–female receptive anal intercourse exposures (see Tables 13–15). Cost–utility ratios for needle sharing and needlestick exposures were US$97,867 and $159,686 per QALY saved respectively. The cost–utility ratio exceeded $380,000 per QALY saved for all other types of exposure.

The authors report24 that the sensitivity analysis suggests that the results are moderately sensitive to PEP effectiveness and somewhat sensitive to the proportion of people completing the PEP regimen, the proportion of PEP clients with known infected source partners and the lifetime costs of medical care and lost QALYs associated with a case of HIV infection.

The authors24 conclude that PEP is only cost-effective in limited circumstances such as following receptive anal intercourse with a partner at high risk of infection and possibly following other high-risk exposures with a partner known to be infected. The authors state that PEP was highly cost-effective for MSM, less cost-effective for IDUs and high-risk women, and probably not cost-effective for general population exposures or heterosexual men. 24

The study by Pinkerton and colleagues22 evaluating the cost-effectiveness of PEP for a hypothetical cohort of 10,000 patients reporting sexual intercourse with a partner of unknown HIV status estimated that 19.62 HIV infections would be averted following receptive anal intercourse, 0.59 following insertive anal intercourse, 0.11 following receptive vaginal intercourse and 0.07 following insertive vaginal intercourse.

In this study22 the base-case analysis suggested that PEP is only cost-effective for receptive anal intercourse (all other cost–utility ratios exceeded US$750,000 per QALY saved). The cost–utility ratio following receptive anal intercourse among MSM was US$6354 per QALY saved. This became cost saving if the probability that the source partner was HIV positive was greater than 0.25 (see Tables 13–15).

The sensitivity analysis reported by Pinkerton and colleagues22 showed that PEP following receptive anal intercourse was always cost-effective across a range of values. PEP following receptive vaginal intercourse became cost-effective when the probability that the source partner was HIV positive was at least 0.73. The authors report that triple therapy was unlikely to be cost-effective relative to double therapy as the additional drug costs were not offset by treatment savings. The results did not appear to be sensitive to repeated exposure to HIV and PEP. 22

Economic evaluation

One of the aims of the current report was to draw together the best available evidence to estimate the cost-effectiveness of non-occupational PEP for HIV in a UK setting. The current authors explored the feasibility of developing a de novo economic model, either by adapting an existing cost-effectiveness model or by constructing a new one. However, the available data to inform any cost-effectiveness analysis are very sparse, making it inappropriate to model the cost-effectiveness of non-occupational PEP for HIV at the present time. The limitation in the extent of the evidence for the clinical effectiveness of non-occupational PEP for HIV is the main reason for arriving at this conclusion, that is, the effectiveness of non-occupational PEP is unknown. Only one study met the systematic review criteria for assessing the clinical effectiveness of non-occupational PEP, and the authors state that the study design and relatively small number of seroconversions do not allow conclusions about the effectiveness of PEP in preventing infection. In addition, there were limited data for other model parameters, such as per-exposure transmission probabilities, prevalence of HIV among different population groups and treatment compliance. Any modelling using such data inputs will be of limited value.

However, should better quality and more relevant data become available, the modelling frameworks presented by Pinkerton and colleagues23 and Herida and colleagues25 may be useful starting points for cost-effectiveness analysis. Although these studies should be viewed with caution, because the clinical effectiveness was informed from one study of the use of PEP in an occupational setting and was based on assumptions that the same conditions exist in a non-occupational setting, they have been conducted in an appropriate way and appear to have internal validity in terms of model structure. Any model should incorporate PEP adverse events and completion rates as these have important economic consequences.

Summary of cost-effectiveness of PEP for non-occupational exposure to HIV

• Four economic evaluations met the inclusion criteria of the review.

• The methodological quality of the four studies is mixed. Each had a well-defined question, stated a reasonable study type and perspective and undertook a clear sensitivity analysis. However, each of the studies is constrained by a lack of published data on the clinical effectiveness of PEP after non-occupational exposure, the per-exposure transmission risk, the compliance with medication and the prevalence of HIV infection amongst different population subgroups.

• In addition, external validity appears to be poor. None of the studies was clearly generalisable to the UK. Lack of detailed information on the PEP regimes used in all of the studies prevented comparison with UK clinical management, as did the lack of information on study participants.

• Results from the included studies suggest that PEP following non-occupational exposure to HIV is cost saving for:

  • men who have unprotected receptive anal intercourse with men, whether the source partner is known to be HIV positive or not

  • heterosexuals after unprotected receptive anal intercourse

  • intravenous drug users sharing a needle with a known HIV-positive person.

• PEP following non-occupational exposure to HIV was cost-effective for all male–male intercourse (unprotected receptive and insertive anal intercourse, unprotected receptive oral sex and ‘other’).

• PEP following non-occupational exposure to HIV was possibly cost-effective for intravenous drug users and high-risk women.

• In general, sensitivity analyses did not greatly alter the base-case findings. Some sensitivity to the following parameters was noted:

  • transmission probability following receptive anal intercourse

  • effectiveness of PEP

  • proportion of clients completing PEP

  • proportion of clients with known HIV-positive partners

  • lifetime costs of treatment and number of lost QALYs

  • receptive vaginal intercourse (which became cost-effective) when the probability of the source partner being HIV positive was ≥ 0.73.

• In summary, although the results of the studies are consistent and suggest that non-occupational PEP may be cost-effective, the results should be treated with caution. It may not be appropriate to make assumptions that the same conditions exist in a non-occupational setting as in an occupational setting. The generalisibility to the UK of studies conducted in the US and France is not clear. Although transmission risks for specific sexual practices are likely to be the same, sexual behaviour and HIV incidence may not be similar and local costs may be different.

• Because of limited data, especially on the effectiveness of non-occupational PEP for HIV, no de novo economic evaluation was conducted in the present study.

Completion of treatment

Completion of treatment rates in the four studies are shown in Table 17. Garcia and colleagues28 found that participants who received dual therapy were more likely to complete PEP (68%) than those who received three drugs (53%) (p = 0.01). In the high severity group 21% interrupted the use of protease inhibitor and completed PEP with two drugs, with the main reason for interruption being toxicity. Compliance at 6 months of follow-up was similar in both the medium and the high severity groups [odds ratio (OR) 1.0, 95% CI 0.8–1.3]. 28 In the San Francisco PEP study,29 over all groups, 78% of participants completed 4 weeks of treatment. Significantly more patients treated with didanosine plus stavudine completed 4 weeks of therapy than did those receiving zidovudine plus lamivudine (94% versus 76%, p = 0.01). However, the higher rates of completion seen in participants using didanosine plus stavudine may have been due to the study protocol. This discouraged participants from changing to zidovudine plus lamivudine if they developed tolerable adverse events, in an attempt to provide treatment against a possibly resistant strain. In contrast, those taking zidovudine plus lamivudine who experienced adverse events were encouraged to switch to didanosine plus stavudine to complete their treatment course. Among participants who completed 4 weeks of therapy, the percentage of participants reporting complete adherence during the 4 days before the clinic visit ranged from 78% to 84%. 29

The percentage of participants receiving Combivir and Kaletra who completed the course of PEP was 23.9% in the high-risk group and 33.2% in the unknown-risk group in the study of sexual assault survivors by Loutfy and colleagues. 30 This study found that health-care provider-perceived moderate or high participant anxiety at the initial visit, assault by a stranger or an assailant known to the participant less than 24 hours previously or absence of concomitant physical assault were predictors of completion. Reasons for discontinuation included adverse events (81.2%), interference with usual routine (42%), inability to take time away from work, school or other commitments (21.7%) and reassessment of HIV risk (18.8%). In the study by Shoptaw and colleagues31 86% of participants were dispensed the full 28-day supply of PEP and 64% of participants receiving zidovudine plus lamivudine completed treatment.

Assessment of toxicity

Toxicity results are shown in Table 18. In one study28 93% of the participants receiving three drugs reported at least one side effect, compared with 66% of the participants receiving two drugs (p < 0.01). Digestive discomfort was the most common side effect and was statistically more common in participants who received three drugs (p < 0.01). 28 Severe side effects were seen in patients receiving three drugs and hospitalisation occurred in six cases, as a result of Stevens–Johnson syndrome (n = 1), nephrolithiasis (n = 2) and severe gastrointestinal symptoms (n = 3). 28 In the San Francisco study29 subjective toxicity for all study groups included nausea (52%), fatigue (44%), headache (24%), diarrhoea (15%) and anorexia (12%). Toxicity was the main reason for discontinuing treatment (n = 27, 8%). 29

The most common adverse events experienced in both observational studies were also fatigue (58.5%30 and 48%31) and nausea (49.5%30 and 45%31). Loutfy and colleagues30 report that the majority of sexual assault survivors (77.1%) reported at least one adverse event (median 3, range 1–8) of grade 2–4 severity [adverse events were graded 1–4 using the US National Institute of Allergy and Infectious Diseases standardised toxicity grading system (grade 4 most severe)]. Three participants discontinued PEP because of adverse events, but no further details were given. The authors reported that participants who experienced vomiting were less likely to complete PEP than those who did not (OR 0.27, 95% CI 0.12–0.6, p = 0.0007). 30 Shoptaw and colleagues31 describe one participant requiring hospitalisation for suicide ideation, but this was not thought to be as a result of the study medication.

Summary of adverse events of PEP for non-occupational exposure to HIV

• There is limited evidence in terms of quantity and quality, with two comparative studies and two prospective observational studies reporting adverse events and/or treatment completion rates for non-occupational PEP for HIV.

• One comparative study reported a significantly higher degree of toxicity and therapy discontinuation among sexual assault victims taking a three-drug regimen compared with those taking a two-drug therapy. Digestive discomfort was the most common side effect and was significantly higher in participants who received three drugs. PEP therapy was completed by 68% of participants receiving dual therapy and 53% of those receiving triple therapy.

• A second comparative study reported statistically higher completion rates among participants taking didanosine plus stavudine compared with those taking zidovudine plus lamivudine, although this may have been due to the study protocol. Complete adherence at 4 weeks was 78% overall, ranging from 40% to 79% for different drug combinations. Toxicity was the main reason for discontinuation of treatment, with nausea and fatigue being the most common side effects.

• One prospective observational study reported low completion of treatment rates, with 23.9% in the high-risk group and 33.2% in the unknown-risk group completing the course of PEP. The most common adverse events experienced by the participants were fatigue and nausea.

• A second prospective observational study also found that fatigue and nausea were the most commonly experienced adverse events and that the majority of participants experienced adverse events. PEP therapy was completed by 64% of participants.

Statement of principal findings

Strengths and limitations of the assessment

The review has certain strengths:

• It is independent of any vested interest.

• The review brings together the evidence for the clinical effectiveness and the cost-effectiveness of non-occupational PEP for HIV and adverse event data by applying consistent methods of critical appraisal, presentation and transparency.

• The review was guided by the principles of undertaking a systematic review. Before undertaking the review the methods were set out in a research protocol (Appendix 1) and this was commented on by an advisory group. The protocol defined the research question, inclusion criteria, quality criteria, data extraction process and methods employed to undertake the different stages of the review.

• An advisory group has informed the review from its initiation, through the development of the research protocol and completion of the report.

In contrast, there were certain limitations placed upon the review:

• The number and type of studies available for inclusion in the review was limited. No RCTs were identified and the economic evaluations were not conducted in the UK.

• Synthesis of the included studies was through narrative review. Because of the limitations of the literature, meta-analysis was not possible.

• Time and resource constraints for this short report together with the lack of effectiveness data for the use of non-occupational PEP for HIV prevented the development of an economic evaluation and so the assessment of cost-effectiveness was limited to a systematic review of existing cost-effectiveness studies.

Other relevant issues

• Only one cohort study met the systematic review inclusion criteria for the assessment of the clinical effectiveness of non-occupational PEP for HIV. The study design and relatively small number of seroconversions do not allow conclusions to be made about the effectiveness of PEP in preventing infection. However, results suggest that PEP made no difference to the expected HIV seroconversion rate for a high-risk HIV-seronegative homosexual male cohort in Rio de Janeiro, Brazil.

• One of the issues of concern is that PEP may be relied upon as a primary form of HIV prevention and will fail to reduce or may actually increase high-risk exposures because it is perceived to fully prevent virus transmission. In the included study PEP was not associated with an increase in reported high-risk behaviour. Reported high-risk behaviour declined slightly for the cohort as a whole but these results should be viewed with caution because of the potential for under-reporting of self-reported high-risk activities.

• Various assumptions were made in the studies considering the cost-effectiveness of non-occupational PEP for HIV. Of most concern is the use of the estimate of effectiveness from the occupational PEP setting, which is based on the assumption that the same conditions exist in the non-occupational setting as in the occupational setting.

• Other assumptions are acknowledged in the studies. For example, in the study conducted in France25 compliance could only be estimated from the database for 47% of PEP prescriptions and so overall compliance was estimated at 0.75. However, overestimation of compliance would improve the cost-effectiveness ratio. There were no available data for lifetime HIV/AIDS costs in France and so these were estimated by the authors. The model did not take into account the possibility that some patients seeking PEP may continue at-risk behaviour. The study also did not consider PEP adverse events. The authors state that taking these into account would further reduce the cost-effectiveness ratio of the overall PEP programme. The number of HIV infections predicted by the model was higher than that actually seen; however, HIV serology 6 months after PEP initiation was only available for 18% of patients and so the authors suggest that the true number of PEP failures may be higher.

• Pinkerton and colleagues24 acknowledge that there are a number of issues of uncertainty in their study of non-occupational PEP in US metropolitan statistical areas. The results were most sensitive to the effectiveness of PEP and the per-exposure transmission probability for receptive anal intercourse. The lack of evidence of effectiveness of PEP for non-occupational exposures to HIV means that the results should be interpreted with caution. With regard to per-exposure transmission probabilities, the probabilities used in this study did not take into account variations in infectiousness over the course of HIV disease, interpersonal variability or potential reductions from the use of highly active antiretroviral therapy.

• Pinkerton and colleagues conclude from their hypothetical cohort study22 that, from an economic effectiveness perspective, PEP should be restricted to partners of infected persons (e.g. serodiscordant couples), patients reporting unprotected receptive anal intercourse (including condom breakage) and possibly cases in which there is a substantial likelihood that the partner is infected.

• Various uncertainties, such as HIV prevalence rates, per-exposure transmission rates, completion of treatment and the impact of the number of pills prescribed daily, HIV status of partner and incomplete suppression of virus, some of which may vary in different locales, must be considered when modelling cost-effectiveness. Also, the potential for PEP programmes to incorporate risk counselling and the opportunity for intensive prevention counselling at the time of medication with PEP to influence future exposures must also be considered.

Non-occupational PEP for HIV

It is not possible to draw conclusions on the clinical effectiveness of non-occupational PEP for HIV because of the limited evidence in terms of the quantity and quality of studies. Only one small cohort study was identified that met the inclusion criteria for the systematic review. Cost-effectiveness has been assessed in four economic evaluations using evidence on effectiveness taken from the use of PEP in the occupational setting. Results are consistent across studies and suggest that non-occupational PEP may be cost-effective, especially in certain population subgroups. Although the studies have been conducted in an appropriate way and have internal validity in terms of the structure of the model and plausible results, the assumptions and data sources mean that the results should be treated with caution. The generalisibility to the UK of studies conducted in the US and France is not clear. Although transmission risks for specific sexual practices are likely to be the same, sexual behaviour and HIV incidence may not be similar and local costs may be different.

Research priorities

The most important research need is a comparative study to establish the effectiveness of using non-occupational PEP compared with not using PEP, preferably within the UK using the currently recommended intervention. Data are also needed on HIV prevalence, seroconversion rates, per-exposure transmission, adverse events, treatment compliance rates, viral resistance rates, high-risk behaviours and effects of intensive counselling in different population groups. Some of these issues will be addressed by the NONOPEP project, which is an MRC-funded surveillance programme of PEP for non-occupational exposure to HIV. The study aims to describe current PEP prescribing practices and the demographic and exposure characteristics of individuals presenting for PEP; to evaluate the problems associated with taking antiretroviral therapy such as adverse events; to assess whether seroconversion has occurred and within which groups; and to contribute to a wider European study on the efficacy of PEP in the non-occupational setting. Data have been collected on individuals by means of a paper questionnaire, submitted to the Communicable Disease Surveillance Centre at baseline (presentation at clinic) and at three follow-up intervals (4 weeks, 3 months and 6 months). This study is due for submission shortly. Although there are challenges in conducting this research because of factors such as self-referral and follow-up of participants and self-reported outcomes, data generated from this study will be useful for informing any future economic modelling of the cost-effectiveness of non-occupational PEP in the UK.

Contribution of authors

Jackie Bryant was responsible for protocol development, the screening of the clinical effectiveness studies for inclusion, analysis and interpretation of the clinical effectiveness studies, the screening of the cost-effectiveness studies for inclusion, analysis and interpretation of the cost-effectiveness studies, writing the report and project management and report editing. Susan Hird was responsible for protocol development, the screening of the clinical effectiveness studies for inclusion, data extraction and critical appraisal of the clinical effectiveness studies, analysis and interpretation of the clinical effectiveness studies, screening of the cost-effectiveness studies for inclusion, data extraction and critical appraisal of the cost-effectiveness studies, analysis and interpretation of the cost-effectiveness studies and report writing. Louise Baxter was responsible for the screening of the clinical effectiveness studies for inclusion, data extraction and critical appraisal of the clinical effectiveness studies, analysis and interpretation of the clinical effectiveness studies, the screening of the cost-effectiveness studies for inclusion, data extraction and critical appraisal of the cost-effectiveness studies, analysis and interpretation of the cost-effectiveness studies and report writing.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health.

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   By Cullum N, Nelson EA, Flemming K, Sheldon T.

10. Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review.

    By Hampson SE, Skinner TC, Hart J, Storey L, Gage H, Foxcroft D, et al.

11. Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review.

    By Jobanputra P, Parry D, Fry-Smith A, Burls A.

12. Statistical assessment of the learning curves of health technologies.

    By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF, Russell IT.

13. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review.

    By Dinnes J, Cave C, Huang S, Major K, Milne R.

14. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of debriding agents in treating surgical wounds healing by secondary intention.

    By Lewis R, Whiting P, ter Riet G, O’Meara S, Glanville J.

15. Home treatment for mental health problems: a systematic review.

    By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

16. How to develop cost-conscious guidelines.

    By Eccles M, Mason J.

17. The role of specialist nurses in multiple sclerosis: a rapid and systematic review.

    By De Broe S, Christopher F, Waugh N.

18. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity.

    By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

19. The clinical effectiveness and cost-effectiveness of pioglitazone for type 2 diabetes mellitus: a rapid and systematic review.

    By Chilcott J, Wight J, Lloyd Jones M, Tappenden P.

20. Extended scope of nursing practice: a multicentre randomised controlled trial of appropriately trained nurses and preregistration house officers in preoperative assessment in elective general surgery.

    By Kinley H, Czoski-Murray C, George S, McCabe C, Primrose J, Reilly C, et al.

21. Systematic reviews of the effectiveness of day care for people with severe mental disorders: (1) Acute day hospital versus admission; (2) Vocational rehabilitation; (3) Day hospital versus outpatient care.

    By Marshall M, Crowther R, Almaraz- Serrano A, Creed F, Sledge W, Kluiter H, et al.

22. The measurement and monitoring of surgical adverse events.

    By Bruce J, Russell EM, Mollison J, Krukowski ZH.

23. Action research: a systematic review and guidance for assessment.

    By Waterman H, Tillen D, Dickson R, de Koning K.

24. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer.

    By Ward S, Morris E, Bansback N, Calvert N, Crellin A, Forman D, et al.

25. A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.

    By Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M.

26. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature.

    By Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al.

27. The cost-effectiveness of magnetic resonance imaging for investigation of the knee joint.

    By Bryan S, Weatherburn G, Bungay H, Hatrick C, Salas C, Parry D, et al.

28. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer.

    By Forbes C, Shirran L, Bagnall A-M, Duffy S, ter Riet G.

29. Superseded by a report published in a later volume.

30. The role of radiography in primary care patients with low back pain of at least 6 weeks duration: a randomised (unblinded) controlled trial.

    By Kendrick D, Fielding K, Bentley E, Miller P, Kerslake R, Pringle M.

31. Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients.

    By McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen N, et al.

32. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.

    By Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N.

33. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.

    By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G.

34. Depot antipsychotic medication in the treatment of patients with schizophrenia: (1) Meta-review; (2) Patient and nurse attitudes.

    By David AS, Adams C.

35. A systematic review of controlled trials of the effectiveness and cost-effectiveness of brief psychological treatments for depression.

    By Churchill R, Hunot V, Corney R, Knapp M, McGuire H, Tylee A, et al.

36. Cost analysis of child health surveillance.

    By Sanderson D, Wright D, Acton C, Duree D.

1. A study of the methods used to select review criteria for clinical audit.

   By Hearnshaw H, Harker R, Cheater F, Baker R, Grimshaw G.

2. Fludarabine as second-line therapy for B cell chronic lymphocytic leukaemia: a technology assessment.

   By Hyde C, Wake B, Bryan S, Barton P, Fry-Smith A, Davenport C, et al.

3. Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin’s lymphoma: a systematic review and economic evaluation.

   By Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, et al.

4. A systematic review of discharge arrangements for older people.

   By Parker SG, Peet SM, McPherson A, Cannaby AM, Baker R, Wilson A, et al.

5. The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation.

   By Peters J, Stevenson M, Beverley C, Lim J, Smith S.

6. The clinical effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology assessment.

   By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

7. The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review.

   By Berry E, Kelly S, Westwood ME, Davies LM, Gough MJ, Bamford JM, et al.

8. Promoting physical activity in South Asian Muslim women through ‘exercise on prescription’.

   By Carroll B, Ali N, Azam N.

9. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation.

   By Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, et al.

10. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models.

    By Richards RG, Sampson FC, Beard SM, Tappenden P.

11. Screening for gestational diabetes: a systematic review and economic evaluation.

    By Scott DA, Loveman E, McIntyre L, Waugh N.

12. The clinical effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic review and economic evaluation.

    By Clegg AJ, Colquitt J, Sidhu MK, Royle P, Loveman E, Walker A.

13. The clinical effectiveness of trastuzumab for breast cancer: a systematic review.

    By Lewis R, Bagnall A-M, Forbes C, Shirran E, Duffy S, Kleijnen J, et al.

14. The clinical effectiveness and cost-effectiveness of vinorelbine for breast cancer: a systematic review and economic evaluation.

    By Lewis R, Bagnall A-M, King S, Woolacott N, Forbes C, Shirran L, et al.

15. A systematic review of the effectiveness and cost-effectiveness of metal-on-metal hip resurfacing arthroplasty for treatment of hip disease.

    By Vale L, Wyness L, McCormack K, McKenzie L, Brazzelli M, Stearns SC.

16. The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation.

    By Woolacott NF, Jones L, Forbes CA, Mather LC, Sowden AJ, Song FJ, et al.

17. A systematic review of effectiveness and economic evaluation of new drug treatments for juvenile idiopathic arthritis: etanercept.

    By Cummins C, Connock M, Fry-Smith A, Burls A.

18. Clinical effectiveness and cost-effectiveness of growth hormone in children: a systematic review and economic evaluation.

    By Bryant J, Cave C, Mihaylova B, Chase D, McIntyre L, Gerard K, et al.

19. Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: a systematic review and economic evaluation.

    By Bryant J, Loveman E, Chase D, Mihaylova B, Cave C, Gerard K, et al.

20. Clinical medication review by a pharmacist of patients on repeat prescriptions in general practice: a randomised controlled trial.

    By Zermansky AG, Petty DR, Raynor DK, Lowe CJ, Freementle N, Vail A.

21. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation.

    By Jobanputra P, Barton P, Bryan S, Burls A.

22. A systematic review and economic evaluation of computerised cognitive behaviour therapy for depression and anxiety.

    By Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G, Chilcott J.

23. A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer.

    By Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Reimsma R.

24. A systematic review of the effectiveness of interventions based on a stages-of-change approach to promote individual behaviour change.

    By Riemsma RP, Pattenden J, Bridle C, Sowden AJ, Mather L, Watt IS, et al.

25. A systematic review update of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists.

    By Robinson M, Ginnelly L, Sculpher M, Jones L, Riemsma R, Palmer S, et al.

26. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS.

    By Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al.

27. A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in a bronchiectasis clinic.

    By Caine N, Sharples LD, Hollingworth W, French J, Keogan M, Exley A, et al.

28. Clinical effectiveness and cost – consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders.

    By Adi Y, Ashcroft D, Browne K, Beech A, Fry-Smith A, Hyde C.

29. Treatment of established osteoporosis: a systematic review and cost–utility analysis.

    By Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd Jones M.

30. Which anaesthetic agents are cost-effective in day surgery? Literature review, national survey of practice and randomised controlled trial.

    By Elliott RA Payne K, Moore JK, Davies LM, Harper NJN, St Leger AS, et al.

31. Screening for hepatitis C among injecting drug users and in genitourinary medicine clinics: systematic reviews of effectiveness, modelling study and national survey of current practice.

    By Stein K, Dalziel K, Walker A, McIntyre L, Jenkins B, Horne J, et al.

32. The measurement of satisfaction with healthcare: implications for practice from a systematic review of the literature.

    By Crow R, Gage H, Hampson S, Hart J, Kimber A, Storey L, et al.

33. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review.

    By Garside R, Round A, Dalziel K, Stein K, Royle R.

34. A comparative study of hypertonic saline, daily and alternate-day rhDNase in children with cystic fibrosis.

    By Suri R, Wallis C, Bush A, Thompson S, Normand C, Flather M, et al.

35. A systematic review of the costs and effectiveness of different models of paediatric home care.

    By Parker G, Bhakta P, Lovett CA, Paisley S, Olsen R, Turner D, et al.

1. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study.

   By Egger M, Jüni P, Bartlett C, Holenstein F, Sterne J.

2. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of home versus hospital or satellite unit haemodialysis for people with end-stage renal failure.

   By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al.

3. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn’s disease.

   By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

4. A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus negative.

   By Chilcott J, Lloyd Jones M, Wight J, Forman K, Wray J, Beverley C, et al.

5. Systematic review and evaluation of the use of tumour markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma.

   By Riley RD, Burchill SA, Abrams KR, Heney D, Lambert PC, Jones DR, et al.

6. The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model.

   By Roderick P, Davies R, Raftery J, Crabbe D, Pearce R, Bhandari P, et al.

7. The clinical effectiveness and cost-effectiveness of routine dental checks: a systematic review and economic evaluation.

   By Davenport C, Elley K, Salas C, Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

8. A multicentre randomised controlled trial assessing the costs and benefits of using structured information and analysis of women’s preferences in the management of menorrhagia.

   By Kennedy ADM, Sculpher MJ, Coulter A, Dwyer N, Rees M, Horsley S, et al.

9. Clinical effectiveness and cost–utility of photodynamic therapy for wet age-related macular degeneration: a systematic review and economic evaluation.

   By Meads C, Salas C, Roberts T, Moore D, Fry-Smith A, Hyde C.

10. Evaluation of molecular tests for prenatal diagnosis of chromosome abnormalities.

    By Grimshaw GM, Szczepura A, Hultén M, MacDonald F, Nevin NC, Sutton F, et al.

11. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).

    By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM.

12. The effectiveness and cost-effectiveness of ultrasound locating devices for central venous access: a systematic review and economic evaluation.

    By Calvert N, Hind D, McWilliams RG, Thomas SM, Beverley C, Davidson A.

13. A systematic review of atypical antipsychotics in schizophrenia.

    By Bagnall A-M, Jones L, Lewis R, Ginnelly L, Glanville J, Torgerson D, et al.

14. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study.

    By Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, et al.

15. Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation.

    By Boland A, Dundar Y, Bagust A, Haycox A, Hill R, Mujica Mota R, et al.

16. Screening for fragile X syndrome: a literature review and modelling.

    By Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A.

17. Systematic review of endoscopic sinus surgery for nasal polyps.

    By Dalziel K, Stein K, Round A, Garside R, Royle P.

18. Towards efficient guidelines: how to monitor guideline use in primary care.

    By Hutchinson A, McIntosh A, Cox S, Gilbert C.

19. Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

    By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

20. Prioritisation of health technology assessment. The PATHS model: methods and case studies.

    By Townsend J, Buxton M, Harper G.

21. Systematic review of the clinical effectiveness and cost-effectiveness of tension-free vaginal tape for treatment of urinary stress incontinence.

    By Cody J, Wyness L, Wallace S, Glazener C, Kilonzo M, Stearns S, et al.

22. The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation.

    By Loveman E, Cave C, Green C, Royle P, Dunn N, Waugh N.

23. The role of modelling in prioritising and planning clinical trials.

    By Chilcott J, Brennan A, Booth A, Karnon J, Tappenden P.

24. Cost–benefit evaluation of routine influenza immunisation in people 65–74 years of age.

    By Allsup S, Gosney M, Haycox A, Regan M.

25. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

    By Wight J, Chilcott J, Holmes M, Brewer N.

26. Can randomised trials rely on existing electronic data? A feasibility study to explore the value of routine data in health technology assessment.

    By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

27. Evaluating non-randomised intervention studies.

    By Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al.

28. A randomised controlled trial to assess the impact of a package comprising a patient-orientated, evidence-based self- help guidebook and patient-centred consultations on disease management and satisfaction in inflammatory bowel disease.

    By Kennedy A, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, et al.

29. The effectiveness of diagnostic tests for the assessment of shoulder pain due to soft tissue disorders: a systematic review.

    By Dinnes J, Loveman E, McIntyre L, Waugh N.

30. The value of digital imaging in diabetic retinopathy.

    By Sharp PF, Olson J, Strachan F, Hipwell J, Ludbrook A, O’Donnell M, et al.

31. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy.

    By Law M, Wald N, Morris J.

32. Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

    By Ward S, Kaltenthaler E, Cowan J, Brewer N.

33. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: a systematic review.

    By Hummel S, Paisley S, Morgan A, Currie E, Brewer N.

34. Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system.

    By Royle P, Waugh N.

35. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

    By Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K.

36. A randomised controlled trial to evaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients by nurses.

    By Boland A, Haycox A, Bagust A, Fitzsimmons L.

37. Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women’s physical and psychological health needs.

    By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ, Knowles H, et al.

38. Estimating implied rates of discount in healthcare decision-making.

    By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.

39. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling.

    By Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, et al.

40. Treatments for spasticity and pain in multiple sclerosis: a systematic review.

    By Beard S, Hunn A, Wight J.

41. The inclusion of reports of randomised trials published in languages other than English in systematic reviews.

    By Moher D, Pham B, Lawson ML, Klassen TP.

42. The impact of screening on future health-promoting behaviours and health beliefs: a systematic review.

    By Bankhead CR, Brett J, Bukach C, Webster P, Stewart-Brown S, Munafo M, et al.

1. What is the best imaging strategy for acute stroke?

   By Wardlaw JM, Keir SL, Seymour J, Lewis S, Sandercock PAG, Dennis MS, et al.

2. Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

   By Mant J, McManus RJ, Oakes RAL, Delaney BC, Barton PM, Deeks JJ, et al.

3. The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling.

   By Garside R, Stein K, Wyatt K, Round A, Price A.

4. A systematic review of the role of bisphosphonates in metastatic disease.

   By Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al.

5. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda^®) for locally advanced and/or metastatic breast cancer.

   By Jones L, Hawkins N, Westwood M, Wright K, Richardson G, Riemsma R.

6. Effectiveness and efficiency of guideline dissemination and implementation strategies.

   By Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L, et al.

7. Clinical effectiveness and costs of the Sugarbaker procedure for the treatment of pseudomyxoma peritonei.

   By Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P.

8. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use.

   By Morgan K, Dixon S, Mathers N, Thompson J, Tomeny M.

9. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome.

   By Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ.

10. A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography.

    By Kaltenthaler E, Bravo Vergel Y, Chilcott J, Thomas S, Blakeborough T, Walters SJ, et al.

11. The use of modelling to evaluate new drugs for patients with a chronic condition: the case of antibodies against tumour necrosis factor in rheumatoid arthritis.

    By Barton P, Jobanputra P, Wilson J, Bryan S, Burls A.

12. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

    By Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S.

13. Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

    By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, Cowan J.

14. Routine examination of the newborn: the EMREN study. Evaluation of an extension of the midwife role including a randomised controlled trial of appropriately trained midwives and paediatric senior house officers.

    By Townsend J, Wolke D, Hayes J, Davé S, Rogers C, Bloomfield L, et al.

15. Involving consumers in research and development agenda setting for the NHS: developing an evidence-based approach.

    By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

16. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

    By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al.

17. Does early magnetic resonance imaging influence management or improve outcome in patients referred to secondary care with low back pain? A pragmatic randomised controlled trial.

    By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al.

18. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis.

    By Clark W, Jobanputra P, Barton P, Burls A.

19. A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

    By Bridle C, Palmer S, Bagnall A-M, Darba J, Duffy S, Sculpher M, et al.

20. Liquid-based cytology in cervical screening: an updated rapid and systematic review and economic analysis.

    By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

21. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.

    By Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al.

22. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

    By Dretzke J, Cummins C, Sandercock J, Fry-Smith A, Barrett T, Burls A.

23. Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

    By Dretzke J, Sandercock J, Bayliss S, Burls A.

24. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.

    By Dündar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al.

25. Development and validation of methods for assessing the quality of diagnostic accuracy studies.

    By Whiting P, Rutjes AWS, Dinnes J, Reitsma JB, Bossuyt PMM, Kleijnen J.

26. EVALUATE hysterectomy trial: a multicentre randomised trial comparing abdominal, vaginal and laparoscopic methods of hysterectomy.

    By Garry R, Fountain J, Brown J, Manca A, Mason S, Sculpher M, et al.

27. Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-β and glatiramer acetate for multiple sclerosis.

    By Tappenden P, Chilcott JB, Eggington S, Oakley J, McCabe C.

28. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

    By Dalziel K, Round A, Stein K, Garside R, Price A.

29. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.

    By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the VenUS Team.

30. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.

    By Mowatt G, Vale L, Brazzelli M, Hernandez R, Murray A, Scott N, et al.

31. A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.

    By Claxton K, Ginnelly L, Sculpher M, Philips Z, Palmer S.

32. The Social Support and Family Health Study: a randomised controlled trial and economic evaluation of two alternative forms of postnatal support for mothers living in disadvantaged inner-city areas.

    By Wiggins M, Oakley A, Roberts I, Turner H, Rajan L, Austerberry H, et al.

33. Psychosocial aspects of genetic screening of pregnant women and newborns: a systematic review.

    By Green JM, Hewison J, Bekker HL, Bryant, Cuckle HS.

34. Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

    By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

35. Coronary artery stents: a rapid systematic review and economic evaluation.

    By Hill R, Bagust A, Bakhai A, Dickson R, Dündar Y, Haycox A, et al.

36. Review of guidelines for good practice in decision-analytic modelling in health technology assessment.

    By Philips Z, Ginnelly L, Sculpher M, Claxton K, Golder S, Riemsma R, et al.

37. Rituximab (MabThera^®) for aggressive non-Hodgkin’s lymphoma: systematic review and economic evaluation.

    By Knight C, Hind D, Brewer N, Abbott V.

38. Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.

    By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al.

39. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J.

40. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment- elevation acute coronary syndromes: a systematic review and economic evaluation.

    By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

41. Provision, uptake and cost of cardiac rehabilitation programmes: improving services to under-represented groups.

    By Beswick AD, Rees K, Griebsch I, Taylor FC, Burke M, West RR, et al.

42. Involving South Asian patients in clinical trials.

    By Hussain-Gambles M, Leese B, Atkin K, Brown J, Mason S, Tovey P.

43. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.

    By Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N.

44. Identification and assessment of ongoing trials in health technology assessment reviews.

    By Song FJ, Fry-Smith A, Davenport C, Bayliss S, Adi Y, Wilson JS, et al.

45. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine

    By Warren E, Weatherley-Jones E, Chilcott J, Beverley C.

46. Supplementation of a home-based exercise programme with a class-based programme for people with osteoarthritis of the knees: a randomised controlled trial and health economic analysis.

    By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N, Roberts CR, et al.

47. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation.

    By Green C, Colquitt JL, Kirby J, Davidson P, Payne E.

48. Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

    By Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith CM, Ellis N, et al.

49. Generalisability in economic evaluation studies in healthcare: a review and case studies.

    By Sculpher MJ, Pang FS, Manca A, Drummond MF, Golder S, Urdahl H, et al.

50. Virtual outreach: a randomised controlled trial and economic evaluation of joint teleconferenced medical consultations.

    By Wallace P, Barber J, Clayton W, Currell R, Fleming K, Garner P, et al.

1. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

   By Ozolins M, Eady EA, Avery A, Cunliffe WJ, O’Neill C, Simpson NB, et al.

2. Do the findings of case series studies vary significantly according to methodological characteristics?

   By Dalziel K, Round A, Stein K, Garside R, Castelnuovo E, Payne L.

3. Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

   By Wilson BJ, Torrance N, Mollison J, Wordsworth S, Gray JR, Haites NE, et al.

4. Randomised evaluation of alternative electrosurgical modalities to treat bladder outflow obstruction in men with benign prostatic hyperplasia.

   By Fowler C, McAllister W, Plail R, Karim O, Yang Q.

5. A pragmatic randomised controlled trial of the cost-effectiveness of palliative therapies for patients with inoperable oesophageal cancer.

   By Shenfine J, McNamee P, Steen N, Bond J, Griffin SM.

6. Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography.

   By Taylor P, Champness J, Given- Wilson R, Johnston K, Potts H.

7. Issues in data monitoring and interim analysis of trials.

   By Grant AM, Altman DG, Babiker AB, Campbell MK, Clemens FJ, Darbyshire JH, et al.

8. Lay public’s understanding of equipoise and randomisation in randomised controlled trials.

   By Robinson EJ, Kerr CEP, Stevens AJ, Lilford RJ, Braunholtz DA, Edwards SJ, et al.

9. Clinical and cost-effectiveness of electroconvulsive therapy for depressive illness, schizophrenia, catatonia and mania: systematic reviews and economic modelling studies.

   By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S.

10. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology.

    By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

11. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris^®) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

    By Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, et al.

12. A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.

    By Dinnes J, Deeks J, Kirby J, Roderick P.

13. Cervical screening programmes: can automation help? Evidence from systematic reviews, an economic analysis and a simulation modelling exercise applied to the UK.

    By Willis BH, Barton P, Pearmain P, Bryan S, Hyde C.

14. Laparoscopic surgery for inguinal hernia repair: systematic review of effectiveness and economic evaluation.

    By McCormack K, Wake B, Perez J, Fraser C, Cook J, McIntosh E, et al.

15. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.

    By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al.

16. A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.

    By Peveler R, Kendrick T, Buxton M, Longworth L, Baldwin D, Moore M, et al.

17. Clinical effectiveness and cost-effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation.

    By Hartwell D, Colquitt J, Loveman E, Clegg AJ, Brodin H, Waugh N, et al.

18. A randomised controlled comparison of alternative strategies in stroke care.

    By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

19. The investigation and analysis of critical incidents and adverse events in healthcare.

    By Woloshynowych M, Rogers S, Taylor-Adams S, Vincent C.

20. Potential use of routine databases in health technology assessment.

    By Raftery J, Roderick P, Stevens A.

21. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.

    By Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al.

22. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.

    By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

23. A systematic review to examine the impact of psycho-educational interventions on health outcomes and costs in adults and children with difficult asthma.

    By Smith JR, Mugford M, Holland R, Candy B, Noble MJ, Harrison BDW, et al.

24. An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.

    By Roderick P, Nicholson T, Armitage A, Mehta R, Mullee M, Gerard K, et al.

25. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

    By Wilson J, Connock M, Song F, Yao G, Fry-Smith A, Raftery J, et al.

26. Indirect comparisons of competing interventions.

    By Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, et al.

27. Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

    By Robinson M, Palmer S, Sculpher M, Philips Z, Ginnelly L, Bowens A, et al.

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

29. The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

    By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al.

30. Systematic review on urine albumin testing for early detection of diabetic complications.

    By Newman DJ, Mattock MB, Dawnay ABS, Kerry S, McGuire A, Yaqoob M, et al.

31. Randomised controlled trial of the cost-effectiveness of water-based therapy for lower limb osteoarthritis.

    By Cochrane T, Davey RC, Matthes Edwards SM.

32. Longer term clinical and economic benefits of offering acupuncture care to patients with chronic low back pain.

    By Thomas KJ, MacPherson H, Ratcliffe J, Thorpe L, Brazier J, Campbell M, et al.

33. Cost-effectiveness and safety of epidural steroids in the management of sciatica.

    By Price C, Arden N, Coglan L, Rogers P.

34. The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis.

    By Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL.

35. Conceptual framework and systematic review of the effects of participants’ and professionals’ preferences in randomised controlled trials.

    By King M, Nazareth I, Lampe F, Bower P, Chandler M, Morou M, et al.

36. The clinical and cost-effectiveness of implantable cardioverter defibrillators: a systematic review.

    By Bryant J, Brodin H, Loveman E, Payne E, Clegg A.

37. A trial of problem-solving by community mental health nurses for anxiety, depression and life difficulties among general practice patients. The CPN-GP study.

    By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J, Pickering R, et al.

38. The causes and effects of socio-demographic exclusions from clinical trials.

    By Bartlett C, Doyal L, Ebrahim S, Davey P, Bachmann M, Egger M, et al.

39. Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.

    By Epps H, Ginnelly L, Utley M, Southwood T, Gallivan S, Sculpher M, et al.

40. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study.

    By Hobbs FDR, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al.

41. Displaced intracapsular hip fractures in fit, older people: a randomised comparison of reduction and fixation, bipolar hemiarthroplasty and total hip arthroplasty.

    By Keating JF, Grant A, Masson M, Scott NW, Forbes JF.

42. Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland.

    By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, Major KA, et al.

43. The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

    By Castelnuovo E, Stein K, Pitt M, Garside R, Payne E.

44. Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

    By Knowles R, Griebsch I, Dezateux C, Brown J, Bull C, Wren C.

45. The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.

    By Clegg AJ, Scott DA, Loveman E, Colquitt J, Hutchinson J, Royle P, et al.

46. The effectiveness of the Heidelberg Retina Tomograph and laser diagnostic glaucoma scanning system (GDx) in detecting and monitoring glaucoma.

    By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

47. Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.

    By Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, et al.

48. Systematic review of effectiveness of different treatments for childhood retinoblastoma.

    By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K, Riemsma R.

49. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis.

    By Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, et al.

50. The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

    By Dretzke J, Frew E, Davenport C, Barlow J, Stewart-Brown S, Sandercock J, et al.

1. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease.

   By Loveman E, Green C, Kirby J, Takeda A, Picot J, Payne E, et al.

2. FOOD: a multicentre randomised trial evaluating feeding policies in patients admitted to hospital with a recent stroke.

   By Dennis M, Lewis S, Cranswick G, Forbes J.

3. The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: systematic reviews.

   By Black C, Bagust A, Boland A, Walker S, McLeod C, De Verteuil R, et al.

4. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise the seizure focus in people with refractory epilepsy being considered for surgery.

   By Whiting P, Gupta R, Burch J, Mujica Mota RE, Wright K, Marson A, et al.

5. Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies.

   By Dundar Y, Dodd S, Dickson R, Walley T, Haycox A, Williamson PR.

6. Systematic review and evaluation of methods of assessing urinary incontinence.

   By Martin JL, Williams KS, Abrams KR, Turner DA, Sutton AJ, Chapple C, et al.

7. The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

   By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

8. Surveillance of Barrett’s oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

   By Garside R, Pitt M, Somerville M, Stein K, Price A, Gilbert N.

9. Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.

   By Main C, Bojke L, Griffin S, Norman G, Barbieri M, Mather L, et al.

10. Evaluation of molecular techniques in prediction and diagnosis of cytomegalovirus disease in immunocompromised patients.

    By Szczepura A, Westmoreland D, Vinogradova Y, Fox J, Clark M.

11. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

    By Wu O, Robertson L, Twaddle S, Lowe GDO, Clark P, Greaves M, et al.

12. A series of systematic reviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers.

    By Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al.

13. Randomised clinical trial, observational study and assessment of cost-effectiveness of the treatment of varicose veins (REACTIV trial).

    By Michaels JA, Campbell WB, Brazier JE, MacIntyre JB, Palfreyman SJ, Ratcliffe J, et al.

14. The cost-effectiveness of screening for oral cancer in primary care.

    By Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, et al.

15. Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

    By Goodacre S, Sampson F, Stevenson M, Wailoo A, Sutton A, Thomas S, et al.

16. Systematic review of the effectiveness and cost-effectiveness of HealOzone^® for the treatment of occlusal pit/fissure caries and root caries.

    By Brazzelli M, McKenzie L, Fielding S, Fraser C, Clarkson J, Kilonzo M, et al.

17. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment.

    By Lewis SW, Davies L, Jones PB, Barnes TRE, Murray RM, Kerwin R, et al.

18. Diagnostic tests and algorithms used in the investigation of haematuria: systematic reviews and economic evaluation.

    By Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, et al.

19. Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: randomised controlled trial.

    By Kennedy TM, Chalder T, McCrone P, Darnley S, Knapp M, Jones RH, et al.

20. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1.

    By Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, et al.

21. Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation.

    By Wright M, Grieve R, Roberts J, Main J, Thomas HC, on behalf of the UK Mild Hepatitis C Trial Investigators.

22. Pressure relieving support surfaces: a randomised evaluation.

    By Nixon J, Nelson EA, Cranny G, Iglesias CP, Hawkins K, Cullum NA, et al.

23. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.

    By King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G, et al.

24. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review.

    By Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al.

25. Effectiveness and cost-effectiveness of salicylic acid and cryotherapy for cutaneous warts. An economic decision model.

    By Thomas KS, Keogh-Brown MR, Chalmers JR, Fordham RJ, Holland RC, Armstrong SJ, et al.

26. A systematic literature review of the effectiveness of non-pharmacological interventions to prevent wandering in dementia and evaluation of the ethical implications and acceptability of their use.

    By Robinson L, Hutchings D, Corner L, Beyer F, Dickinson H, Vanoli A, et al.

27. A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost–utility for these groups in a UK context.

    By Buxton M, Caine N, Chase D, Connelly D, Grace A, Jackson C, et al.

28. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Takeda A, Davidson P, Price A.

29. An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.

    By Harvey S, Stevens K, Harrison D, Young D, Brampton W, McCabe C, et al.

30. Accurate, practical and cost-effective assessment of carotid stenosis in the UK.

    By Wardlaw JM, Chappell FM, Stevenson M, De Nigris E, Thomas S, Gillard J, et al.

31. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

    By Woolacott N, Bravo Vergel Y, Hawkins N, Kainth A, Khadjesari Z, Misso K, et al.

32. The cost-effectiveness of testing for hepatitis C in former injecting drug users.

    By Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, et al.

33. Computerised cognitive behaviour therapy for depression and anxiety update: a systematic review and economic evaluation.

    By Kaltenthaler E, Brazier J, De Nigris E, Tumur I, Ferriter M, Beverley C, et al.

34. Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy.

    By Williams C, Brunskill S, Altman D, Briggs A, Campbell H, Clarke M, et al.

35. Psychological therapies including dialectical behaviour therapy for borderline personality disorder: a systematic review and preliminary economic evaluation.

    By Brazier J, Tumur I, Holmes M, Ferriter M, Parry G, Dent-Brown K, et al.

36. Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.

    By Whiting P, Westwood M, Bojke L, Palmer S, Richardson G, Cooper J, et al.

37. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme.

    By O’Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A.

38. A comparison of the cost-effectiveness of five strategies for the prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.

    By Brown TJ, Hooper L, Elliott RA, Payne K, Webb R, Roberts C, et al.

39. The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease: systematic review.

    By Waugh N, Black C, Walker S, McIntyre L, Cummins E, Hillis G.

40. What are the clinical outcome and cost-effectiveness of endoscopy undertaken by nurses when compared with doctors? A Multi-Institution Nurse Endoscopy Trial (MINuET).

    By Williams J, Russell I, Durai D, Cheung W-Y, Farrin A, Bloor K, et al.

41. The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation.

    By Pandor A, Eggington S, Paisley S, Tappenden P, Sutcliffe P.

42. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.

    By Chen Y-F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al.

43. Telemedicine in dermatology: a randomised controlled trial.

    By Bowns IR, Collins K, Walters SJ, McDonagh AJG.

44. Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

    By Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C.

45. Clinical effectiveness and cost-effectiveness of laparoscopic surgery for colorectal cancer: systematic reviews and economic evaluation.

    By Murray A, Lourenco T, de Verteuil R, Hernandez R, Fraser C, McKinley A, et al.

46. Etanercept and efalizumab for the treatment of psoriasis: a systematic review.

    By Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Bravo Vergel Y, et al.

47. Systematic reviews of clinical decision tools for acute abdominal pain.

    By Liu JLY, Wyatt JC, Deeks JJ, Clamp S, Keen J, Verde P, et al.

48. Evaluation of the ventricular assist device programme in the UK.

    By Sharples L, Buxton M, Caine N, Cafferty F, Demiris N, Dyer M, et al.

49. A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.

    By Yao G, Albon E, Adi Y, Milford D, Bayliss S, Ready A, et al.

50. Amniocentesis results: investigation of anxiety. The ARIA trial.

    By Hewison J, Nixon J, Fountain J, Cocks K, Jones C, Mason G, et al.

1. Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation.

   By Dundar Y, Bagust A, Dickson R, Dodd S, Green J, Haycox A, et al.

2. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of docetaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer.

   By Collins R, Fenwick E, Trowman R, Perard R, Norman G, Light K, et al.

3. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection.

   By Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, et al.

4. The clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fragility fractures in postmenopausal women.

   By Stevenson M, Davis S, Lloyd-Jones M, Beverley C.

5. A systematic review of quantitative and qualitative research on the role and effectiveness of written information available to patients about individual medicines.

   By Raynor DK, Blenkinsopp A, Knapp P, Grime J, Nicolson DJ, Pollock K, et al.

6. Oral naltrexone as a treatment for relapse prevention in formerly opioid-dependent drug users: a systematic review and economic evaluation.

   By Adi Y, Juarez-Garcia A, Wang D, Jowett S, Frew E, Day E, et al.

7. Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.

   By Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M.

8. Epidemiological, social, diagnostic and economic evaluation of population screening for genital chlamydial infection.

   By Low N, McCarthy A, Macleod J, Salisbury C, Campbell R, Roberts TE, et al.

9. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.

   By Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, et al.

10. Exercise Evaluation Randomised Trial (EXERT): a randomised trial comparing GP referral for leisure centre-based exercise, community-based walking and advice only.

    By Isaacs AJ, Critchley JA, See Tai S, Buckingham K, Westley D, Harridge SDR, et al.

11. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Hartwell D, Davidson P, Price A, Waugh N.

12. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

    By Tappenden P, Jones R, Paisley S, Carroll C.

13. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment.

    By Wilson J, Yao GL, Raftery J, Bohlius J, Brunskill S, Sandercock J, et al.

14. A systematic review and economic evaluation of statins for the prevention of coronary events.

    By Ward S, Lloyd Jones M, Pandor A, Holmes M, Ara R, Ryan A, et al.

15. A systematic review of the effectiveness and cost-effectiveness of different models of community-based respite care for frail older people and their carers.

    By Mason A, Weatherly H, Spilsbury K, Arksey H, Golder S, Adamson J, et al.

16. Additional therapy for young children with spastic cerebral palsy: a randomised controlled trial.

    By Weindling AM, Cunningham CC, Glenn SM, Edwards RT, Reeves DJ.

17. Screening for type 2 diabetes: literature review and economic modelling.

    By Waugh N, Scotland G, McNamee P, Gillett M, Brennan A, Goyder E, et al.

18. The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Mealing S, Roome C, Snaith A, et al.

19. The clinical effectiveness and cost-effectiveness of gemcitabine for metastatic breast cancer: a systematic review and economic evaluation.

    By Takeda AL, Jones J, Loveman E, Tan SC, Clegg AJ.

20. A systematic review of duplex ultrasound, magnetic resonance angiography and computed tomography angiography for the diagnosis and assessment of symptomatic, lower limb peripheral arterial disease.

    By Collins R, Cranny G, Burch J, Aguiar-Ibáñez R, Craig D, Wright K, et al.

21. The clinical effectiveness and cost-effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome: a systematic review.

    By Colquitt JL, Kirby J, Green C, Cooper K, Trompeter RS.

22. A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions.

    By Fayter D, Nixon J, Hartley S, Rithalia A, Butler G, Rudolf M, et al.

23. Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections.

    By McCormack K, Rabindranath K, Kilonzo M, Vale L, Fraser C, McIntyre L, et al.

24. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis.

    By McLoughlin DM, Mogg A, Eranti S, Pluck G, Purvis R, Edwards D, et al.

25. A randomised controlled trial and economic evaluation of direct versus indirect and individual versus group modes of speech and language therapy for children with primary language impairment.

    By Boyle J, McCartney E, Forbes J, O’Hare A.

26. Hormonal therapies for early breast cancer: systematic review and economic evaluation.

    By Hind D, Ward S, De Nigris E, Simpson E, Carroll C, Wyld L.

27. Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review.

    By Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A.

28. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation.

    By McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, et al.

29. Prenatal screening and treatment strategies to prevent group B streptococcal and other bacterial infections in early infancy: cost-effectiveness and expected value of information analyses.

    By Colbourn T, Asseburg C, Bojke L, Philips Z, Claxton K, Ades AE, et al.

30. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review.

    By Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, et al.

31. A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial.

    By Prescott RJ, Kunkler IH, Williams LJ, King CC, Jack W, van der Pol M, et al.

32. Current practice, accuracy, effectiveness and cost-effectiveness of the school entry hearing screen.

    By Bamford J, Fortnum H, Bristow K, Smith J, Vamvakas G, Davies L, et al.

33. The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation.

    By Black C, Cummins E, Royle P, Philip S, Waugh N.

34. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis.

    By Thompson Coon J, Rogers G, Hewson P, Wright D, Anderson R, Cramp M, et al.

35. The Birmingham Rehabilitation Uptake Maximisation Study (BRUM). Homebased compared with hospital-based cardiac rehabilitation in a multi-ethnic population: cost-effectiveness and patient adherence.

    By Jolly K, Taylor R, Lip GYH, Greenfield S, Raftery J, Mant J, et al.

36. A systematic review of the clinical, public health and cost-effectiveness of rapid diagnostic tests for the detection and identification of bacterial intestinal pathogens in faeces and food.

    By Abubakar I, Irvine L, Aldus CF, Wyatt GM, Fordham R, Schelenz S, et al.

37. A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

    By Marson AG, Appleton R, Baker GA, Chadwick DW, Doughty J, Eaton B, et al.

38. Clinical effectiveness and cost-effectiveness of different models of managing long-term oral anti-coagulation therapy: a systematic review and economic modelling.

    By Connock M, Stevens C, Fry-Smith A, Jowett S, Fitzmaurice D, Moore D, et al.

39. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.

    By Soares-Weiser K, Bravo Vergel Y, Beynon S, Dunn G, Barbieri M, Duffy S, et al.

40. Taxanes for the adjuvant treatment of early breast cancer: systematic review and economic evaluation.

    By Ward S, Simpson E, Davis S, Hind D, Rees A, Wilkinson A.

41. The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation.

    By Burr JM, Mowatt G, Hernández R, Siddiqui MAR, Cook J, Lourenco T, et al.

42. Acceptability, benefit and costs of early screening for hearing disability: a study of potential screening tests and models.

    By Davis A, Smith P, Ferguson M, Stephens D, Gianopoulos I.

43. Contamination in trials of educational interventions.

    By Keogh-Brown MR, Bachmann MO, Shepstone L, Hewitt C, Howe A, Ramsay CR, et al.

44. Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers.

    By Facey K, Bradbury I, Laking G, Payne E.

45. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Rogers G, Dyer M, Mealing S, et al.

46. Drug-eluting stents: a systematic review and economic evaluation.

    By Hill RA, Boland A, Dickson R, Dündar Y, Haycox A, McLeod C, et al.

47. The clinical effectiveness and cost-effectiveness of cardiac resynchronisation (biventricular pacing) for heart failure: systematic review and economic model.

    By Fox M, Mealing S, Anderson R, Dean J, Stein K, Price A, et al.

48. Recruitment to randomised trials: strategies for trial enrolment and participation study. The STEPS study.

    By Campbell MK, Snowdon C, Francis D, Elbourne D, McDonald AM, Knight R, et al.

49. Cost-effectiveness of functional cardiac testing in the diagnosis and management of coronary artery disease: a randomised controlled trial. The CECaT trial.

    By Sharples L, Hughes V, Crean A, Dyer M, Buxton M, Goldsmith K, et al.

50. Evaluation of diagnostic tests when there is no gold standard. A review of methods.

    By Rutjes AWS, Reitsma JB, Coomarasamy A, Khan KS, Bossuyt PMM.

51. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding.

    By Leontiadis GI, Sreedharan A, Dorward S, Barton P, Delaney B, Howden CW, et al.

52. A review and critique of modelling in prioritising and designing screening programmes.

    By Karnon J, Goyder E, Tappenden P, McPhie S, Towers I, Brazier J, et al.

53. An assessment of the impact of the NHS Health Technology Assessment Programme.

    By Hanney S, Buxton M, Green C, Coulson D, Raftery J.

1. A systematic review and economic model of switching from nonglycopeptide to glycopeptide antibiotic prophylaxis for surgery.

   By Cranny G, Elliott R, Weatherly H, Chambers D, Hawkins N, Myers L, et al.

2. ‘Cut down to quit’ with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis.

   By Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P, Moore D.

3. A systematic review of the effectiveness of strategies for reducing fracture risk in children with juvenile idiopathic arthritis with additional data on long-term risk of fracture and cost of disease management.

   By Thornton J, Ashcroft D, O’Neill T, Elliott R, Adams J, Roberts C, et al.

4. Does befriending by trained lay workers improve psychological well-being and quality of life for carers of people with dementia, and at what cost? A randomised controlled trial.

   By Charlesworth G, Shepstone L, Wilson E, Thalanany M, Mugford M, Poland F.

5. A multi-centre retrospective cohort study comparing the efficacy, safety and cost-effectiveness of hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids. The HOPEFUL study.

   By Hirst A, Dutton S, Wu O, Briggs A, Edwards C, Waldenmaier L, et al.

6. Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling.

   By Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L, et al.

7. The use of economic evaluations in NHS decision-making: a review and empirical investigation.

   By Williams I, McIver S, Moore D, Bryan S.

8. Stapled haemorrhoidectomy (haemorrhoidopexy) for the treatment of haemorrhoids: a systematic review and economic evaluation.

   By Burch J, Epstein D, Baba-Akbari A, Weatherly H, Fox D, Golder S, et al.

9. The clinical effectiveness of diabetes education models for Type 2 diabetes: a systematic review.

   By Loveman E, Frampton GK, Clegg AJ.

10. Payment to healthcare professionals for patient recruitment to trials: systematic review and qualitative study.

    By Raftery J, Bryant J, Powell J, Kerr C, Hawker S.

11. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation.

    By Chen Y-F, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al.

12. The clinical effectiveness and cost-effectiveness of central venous catheters treated with anti-infective agents in preventing bloodstream infections: a systematic review and economic evaluation.

    By Hockenhull JC, Dwan K, Boland A, Smith G, Bagust A, Dundar Y, et al.

13. Stepped treatment of older adults on laxatives. The STOOL trial.

    By Mihaylov S, Stark C, McColl E, Steen N, Vanoli A, Rubin G, et al.

14. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

    By Goodyer IM, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al.

15. The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation.

    By Hind D, Tappenden P, Tumur I, Eggington E, Sutcliffe P, Ryan A.

16. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration: a systematic review and economic evaluation.

    By Colquitt JL, Jones J, Tan SC, Takeda A, Clegg AJ, Price A.

17. Systematic review of the clinical effectiveness and cost-effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of coronary artery disease.

    By Mowatt G, Cummins E, Waugh N, Walker S, Cook J, Jia X, et al.

18. Structural neuroimaging in psychosis: a systematic review and economic evaluation.

    By Albon E, Tsourapas A, Frew E, Davenport C, Oyebode F, Bayliss S, et al.

19. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in adults and children aged 12 years and over.

    By Shepherd J, Rogers G, Anderson R, Main C, Thompson-Coon J, Hartwell D, et al.

20. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in children under the age of 12 years.

    By Main C, Shepherd J, Anderson R, Rogers G, Thompson-Coon J, Liu Z, et al.

21. Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation.

    By Ara R, Tumur I, Pandor A, Duenas A, Williams R, Wilkinson A, et al.

22. Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study.

    By Underwood M, Ashby D, Carnes D, Castelnuovo E, Cross P, Harding G, et al.

23. A prospective randomised comparison of minor surgery in primary and secondary care. The MiSTIC trial.

    By George S, Pockney P, Primrose J, Smith H, Little P, Kinley H, et al.

24. A review and critical appraisal of measures of therapist–patient interactions in mental health settings.

    By Cahill J, Barkham M, Hardy G, Gilbody S, Richards D, Bower P, et al.

25. The clinical effectiveness and cost-effectiveness of screening programmes for amblyopia and strabismus in children up to the age of 4–5 years: a systematic review and economic evaluation.

    By Carlton J, Karnon J, Czoski-Murray C, Smith KJ, Marr J.

26. A systematic review of the clinical effectiveness and cost-effectiveness and economic modelling of minimal incision total hip replacement approaches in the management of arthritic disease of the hip.

    By de Verteuil R, Imamura M, Zhu S, Glazener C, Fraser C, Munro N, et al.

27. A preliminary model-based assessment of the cost–utility of a screening programme for early age-related macular degeneration.

    By Karnon J, Czoski-Murray C, Smith K, Brand C, Chakravarthy U, Davis S, et al.

28. Intravenous magnesium sulphate and sotalol for prevention of atrial fibrillation after coronary artery bypass surgery: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Frampton GK, Tanajewski L, Turner D, Price A.

29. Absorbent products for urinary/faecal incontinence: a comparative evaluation of key product categories.

    By Fader M, Cottenden A, Getliffe K, Gage H, Clarke-O’Neill S, Jamieson K, et al.

30. A systematic review of repetitive functional task practice with modelling of resource use, costs and effectiveness.

    By French B, Leathley M, Sutton C, McAdam J, Thomas L, Forster A, et al.

31. The effectiveness and cost-effectivness of minimal access surgery amongst people with gastro-oesophageal reflux disease – a UK collaborative study. The reflux trial.

    By Grant A, Wileman S, Ramsay C, Bojke L, Epstein D, Sculpher M, et al.

32. Time to full publication of studies of anti-cancer medicines for breast cancer and the potential for publication bias: a short systematic review.

    By Takeda A, Loveman E, Harris P, Hartwell D, Welch K.

33. Performance of screening tests for child physical abuse in accident and emergency departments.

    By Woodman J, Pitt M, Wentz R, Taylor B, Hodes D, Gilbert RE.

34. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation.

    By Rodgers M, McKenna C, Palmer S, Chambers D, Van Hout S, Golder S, et al.

35. Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement.

    By Lourenco T, Armstrong N, N’Dow J, Nabi G, Deverill M, Pickard R, et al.

36. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.

    By Wang D, Cummins C, Bayliss S, Sandercock J, Burls A.

1. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation.

   By McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, et al.

2. Thrombophilia testing in people with venous thromboembolism: systematic review and cost-effectiveness analysis.

   By Simpson EL, Stevenson MD, Rawdin A, Papaioannou D.

3. Surgical procedures and non-surgical devices for the management of non-apnoeic snoring: a systematic review of clinical effects and associated treatment costs.

   By Main C, Liu Z, Welch K, Weiner G, Quentin Jones S, Stein K.

4. Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea–hypopnoea syndrome: a systematic review and economic analysis.

   By McDaid C, Griffin S, Weatherly H, Durée K, van der Burgt M, van Hout S, Akers J, et al.

5. Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review.

   By Sutcliffe P, Hummel S, Simpson E, Young T, Rees A, Wilkinson A, et al.

6. The harmful health effects of recreational ecstasy: a systematic review of observational evidence.

   By Rogers G, Elston J, Garside R, Roome C, Taylor R, Younger P, et al.

7. Systematic review of the clinical effectiveness and cost-effectiveness of oesophageal Doppler monitoring in critically ill and high-risk surgical patients.

   By Mowatt G, Houston G, Hernández R, de Verteuil R, Fraser C, Cuthbertson B, et al.

8. The use of surrogate outcomes in model-based cost-effectiveness analyses: a survey of UK Health Technology Assessment reports.

   By Taylor RS, Elston J.

9. Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) – a randomised controlled trial.

   By Potter J, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al.

10. Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation.

    By Pilgrim H, Lloyd-Jones M, Rees A.

11. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.

    By Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, et al.

12. Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of new psychometric methods.

    By Hobart J, Cano S.

13. Treatment of severe ankle sprain: a pragmatic randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of three types of mechanical ankle support with tubular bandage. The CAST trial.

    By Cooke MW, Marsh JL, Clark M, Nakash R, Jarvis RM, Hutton JL, et al. , on behalf of the CAST trial group.

Health Technology Assessment Programme

1. Director, NIHR HTA Programme, Professor of Clinical Pharmacology, University of Liverpool

2. Director, Medical Care Research Unit, University of Sheffield