Angela Devine

Improving the radical cure of vivax malaria (IMPROV): a study protocol for a multicentre randomised, placebo-controlled comparison of short and long course primaquine regimens

Plasmodium vivax malaria is a major cause of morbidity and recognised as an important contributor to mortality in some endemic areas. The current recommended treatment regimen for the radical cure of P. vivax includes a schizontocidal antimalarial, usually chloroquine, combined with a 14 day regimen of primaquine. The long treatment course frequently results in poor adherence and effectiveness. Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising safety. The proposed multicentre randomised clinical trial aims to provide evidence across a variety of endemic settings on the safety and efficacy of high dose short course primaquine in glucose-6-phosphate-dehydrogenase (G6PD) normal patients. This study is designed as a placebo controlled, double blinded, randomized trial in four countries: Indonesia, Vietnam, Afghanistan and Ethiopia. G6PD normal patients diagnosed with vivax malaria are randomized to receive either 7 or 14 days high dose primaquine or placebo. G6PD deficient (G6PDd) patients are allocated to weekly primaquine doses for 8 weeks. All treatment is directly observed and recurrent episodes are treated with the same treatment than allocated at the enrolment episode. Patients are followed daily until completion of treatment, weekly until 8 weeks and then monthly until 1 year after initiation of the treatment. The primary endpoint is the incidence rate (per person year) of symptomatic recurrent P. vivax parasitaemia over 12 months of follow-up, for all individuals, controlling for site, comparing the 7 versus 14-day primaquine treatment arms. Secondary endpoints are other efficacy measures such as incidence risk at different time points. Further endpoints are risks of haemolysis and severe adverse events. This study has been approved by relevant institutional ethics committees in the UK and Australia, and all participating countries. Results will be disseminated to inform P. vivax malaria treatment policy through peer-reviewed publications and academic presentations. Findings will contribute to a better understanding of the risks and benefits of primaquine which is crucial in persuading policy makers as well as clinicians of the importance of radical cure of vivax malaria, contributing to decreased transmission and a reduce parasite reservoir. ClinicalTrials.gov Identifier: NCT01814683. Registered March 18, 2013

Self-management support for moderate-to-severe chronic obstructive pulmonary disease: a pilot randomised controlled trial

BACKGROUND Better self management could improve quality of life (QoL) and reduce hospital admissions in chronic obstructive pulmonary disease (COPD), but the best way to promote it remains unclear. AIM To explore the feasibility, effectiveness and cost effectiveness of a novel, layperson-led, theoretically driven COPD self-management support programme. DESIGN AND SETTING Pilot randomised controlled trial in one UK primary care trust area. METHOD Patients with moderate to severe COPD were identified through primary care and randomised 2:1 to the 7-week-long, group intervention or usual care. Outcomes at baseline, 2, and 6 months included self-reported health, St Georges Respiratory Questionnaire (SGRQ), EuroQol, and exercise. RESULTS Forty-four per cent responded to GP invitation, 116 were randomised: mean (standard deviation [SD]) age 69.5 (9.8) years, 46% male, 78% had unscheduled COPD care in the previous year. Forty per cent of intervention patients completed the course; 35% attended no sessions; and 78% participants completed the 6-month follow-up questionnaire. Results suggest that the intervention may increase both QoL (mean EQ-5D change 0.12 (95% confidence interval [CI] = -0.02 to 0.26) higher, intervention versus control) and exercise levels, but not SGRQ score. Economic analyses suggested that with thresholds of £20 000 per quality-adjusted life-year gained, the intervention is likely to be cost-effective. CONCLUSION This intervention has good potential to meet the UK National Institute for Health and Clinical Excellence criteria for cost effectiveness, and further research is warranted. However, to make a substantial impact on COPD self-management, it will also be necessary to explore other ways to enable patients to access self-management education.

Primary care Identification and Referral to Improve Safety of women experiencing domestic violence (IRIS): protocol for a pragmatic cluster randomised controlled trial

BackgroundDomestic violence, which may be psychological, physical, sexual, financial or emotional, is a major public health problem due to the long-term health consequences for women who have experienced it and for their children who witness it. In populations of women attending general practice, the prevalence of physical or sexual abuse in the past year from a partner or ex-partner ranges from 6 to 23%, and lifetime prevalence from 21 to 55%. Domestic violence is particularly important in general practice because women have many contacts with primary care clinicians and because women experiencing abuse identify doctors and nurses as professionals from whom they would like to get support. Yet health professionals rarely ask about domestic violence and have little or no training in how to respond to disclosure of abuse.Methods/DesignThis protocol describes IRIS, a pragmatic cluster randomised controlled trial with the general practice as unit of randomisation. Our trial tests the effectiveness and cost-effectiveness of a training and support programme targeted at general practice teams. The primary outcome is referral of women to specialist domestic violence agencies. Forty-eight practices in two UK cities (Bristol and London) are randomly allocated, using minimisation, into intervention and control groups. The intervention, based on an adult learning model in an educational outreach framework, has been designed to address barriers to asking women about domestic violence and to encourage appropriate responses to disclosure and referral to specialist domestic violence agencies. Multidisciplinary training sessions are held with clinicians and administrative staff in each of the intervention practices, with periodic feedback of identification and referral data to practice teams. Intervention practices have a prompt to ask about abuse integrated in the electronic medical record system. Other components of the intervention include an IRIS champion in each practice and a direct referral pathway to a named domestic violence advocate.DiscussionThis is the first European randomised controlled trial of an intervention to improve the health care response to domestic violence. The findings will have the potential to inform training and service provision.Trial registrationISRCTN74012786

The challenges of introducing routine G6PD testing into radical cure: a workshop report

The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings.

Cost-effectiveness of Identification and Referral to Improve Safety (IRIS), a domestic violence training and support programme for primary care: a modelling study based on a randomised controlled trial

Objective The Identification and Referral to Improve Safety (IRIS) cluster randomised controlled trial tested the effectiveness of a training and support intervention to improve the response of primary care to women experiencing domestic violence (DV). The aim of this study is to estimate the cost-effectiveness of this intervention. Design Markov model-based cost-effectiveness analysis. Setting General practices in two urban areas in the UK. Participants Simulated female individuals from the general UK population who were registered at general practices, aged 16 years and older. Intervention General practices received staff training, prompts to ask women about DV embedded in the electronic medical record, a care pathway including referral to a specialist DV agency and continuing contact from that agency. The trial compared the rate of referrals of women with specialist DV agencies from 24 general practices that received the IRIS programme with 24 general practices not receiving the programme. The trial did not measure outcomes for women beyond the intermediate outcome of referral to specialist agencies. The Markov model extrapolated the trial results to estimate the long-term healthcare and societal costs and benefits using data from other trials and epidemiological studies. Results The intervention would produce societal cost savings per woman registered in the general practice of UK£37 (95% CI £178 saved to a cost of £136) over 1 year. The incremental quality-adjusted life-year was estimated to be 0.0010 (95% CI −0.0157 to 0.0101) per woman. Probabilistic sensitivity analysis found 78% of model replications under a willingness to pay threshold of £20 000 per quality-adjusted life-year. Conclusions The IRIS programme is likely to be cost-effective and possibly cost saving from a societal perspective. Better data on the trajectory of abuse and the effect of advocacy are needed for a more robust model. Trial registration Current Controlled Trials, ISRCTN74012786.

The agreement between proxy and self-completed EQ-5D for care home residents was better for index scores than individual domains *

Objective Proxy measures are an alternative source of data for care home residents who are unable to complete the health utility measure, but the agreement levels between residents and care home staff for the EQ-5D have not been investigated previously. The objective of the present study was to examine the inter-rater agreement levels for the reporting of EQ-5D by care home residents and staff, adjusting for the impact of clustering. Study Design and Setting The data consist of EQ-5D scores for 565 pairs of care home residents and proxies and quality-adjusted life-years (QALYs) for 248 pairs. Cluster-adjusted agreement was compared for the domains, index scores, and QALYs from the EQ-5D. Factors influencing index score agreement are also described. Results The results show poor to fair agreement at the domain level (cluster-adjusted Kappa −0.03 to 0.26) and moderate agreement at the score level (cluster-adjusted intra-class correlation coefficient [ICC] 0.44–0.50) and for QALYs (cluster-adjusted ICC 0.59). A higher likelihood of depression and lower cognitive impairment were both associated with smaller discrepancy between proxy and self-completed scores. Conclusion Proxies appear to be an acceptable source of data for index scores and QALYs but may be less reliable if individual domains are considered.

Cost-Effectiveness of Health Care Interventions to Address Intimate Partner Violence: What Do We Know and What Else Should We Look for?

Intimate partner violence (IPV) creates a substantial burden of disease and significant costs to families, communities, and governments. Building the evidence for effective interventions to reduce violence and its sequelae requires increased use of economic evaluation to inform policy through the analysis of costs and potential savings of interventions. The authors review existing economic evaluations and present case studies of current research from the United Kingdom and Australia to illustrate the strengths and limitations of two approaches to generating economic evidence: economic evaluation alongside randomized controlled trials and economic modeling. Economic evaluation should always be considered in the design of IPV intervention research.

Modeling the impact of early antiretroviral therapy for adults coinfected with HIV and hepatitis B or C in South Africa

Objective:There has been discussion about whether individuals coinfected with HIV and hepatitis C virus (HCV) or hepatitis B virus (HBV) (∼30% of all people living with HIV) should be prioritized for early HIV antiretroviral therapy (ART). We assess the relative benefits of providing ART at CD4+ count below 500 cells/&mgr;l or immediate ART to HCV/HIV or HBV/HIV-coinfected adults compared with HIV-monoinfected adults. We evaluate individual outcomes (HIV/liver disease progression) and preventive benefits in a generalized HIV epidemic setting. Methods:We modeled disease progression for HIV-monoinfected, HBV/HIV-coinfected, and HCV/HIV-coinfected adults for differing ART eligibility thresholds (CD4+ <350 cells/&mgr;l, CD4+ <500 cells/&mgr;l, immediate ART eligibility upon infection). We report disability-adjusted life-years averted per 100 person-years on ART (DALYaverted/100PYonART) as a measure of the health benefits generated from incremental changes in ART eligibility. Sensitivity analyses explored impact on sexual HIV and vertical HIV, HCV, and HBV transmission. Results:For HBV/HIV-coinfected adults, a switch to ART initiation at CD4+ count below 500 cells/&mgr;l from CD4+ below 350 cells/&mgr;l generates 9% greater health benefits per year on ART (48 DALYaverted/100PYonART) than for HIV-monoinfected adults (44 DALYaverted/100PYonART). Additionally, ART at CD4+ below 500 cells/&mgr;l could prevent 25% and 32% of vertical transmissions of HIV and HBV, respectively. For HCV/HIV-coinfected adults, ART at CD4+ below 500 cells/&mgr;l generates 10% fewer health benefits (40 DALYaverted/100PYonART) than for HIV monoinfection, unless ART reduces progression to cirrhosis by more than 70% (33% in base-case). Conclusions:The additional therapeutic benefits of ART for HBV-related liver disease results in ART generating more health benefits among HBV/HIV-coinfected adults than HIV-monoinfected individuals, whereas less health benefits are generated amongst HCV/HIV coinfection in a generalized HIV epidemic setting.

The cost-effectiveness of herpes simplex virus-2 suppressive therapy with daily aciclovir for delaying HIV disease progression among HIV-1-infected women in South Africa.

Background: The Partners in Prevention HSV/HIV transmission trial (Partners HSV/HIV Transmission Study) showed that herpes simplex virus-2 (HSV-2) suppressive therapy with daily aciclovir could decrease HIV disease progression amongst HIV-1/HSV-2 coinfected individuals. The cost-effectiveness of daily aciclovir for delaying HIV-1 disease progression in women not eligible for antiretroviral therapy (ART) is estimated. Methods: Resource use/cost data for delivering daily aciclovir at a primary health care HIV clinic were collected in Johannesburg. Effectiveness estimates were obtained from the Partners HSV/HIV Transmission Study trial and epidemiologic data from South Africa. A Markov model simulated the cost-effectiveness of daily aciclovir on HIV-1 disease progression in ART-naive women. Therapy was given to all HIV-1-infected women. Cost-effectiveness was compared against cost per life-year gained (∼US

Dynamic Transmission Economic Evaluation of Infectious Disease Interventions in Low‐ and Middle‐Income Countries: A Systematic Literature Review

1200 per LYG) of ART provision in South Africa. Results: For an ART eligibility criteria of CD4 count <200 cells/&mgr;L and the cheapest internationally available aciclovir (US