Chantal M. Morel

Cost-effectiveness of malaria diagnostic methods in sub-Saharan Africa in an era of combination therapy

OBJECTIVE To evaluate the relative cost-effectiveness in different sub-Saharan African settings of presumptive treatment, field-standard microscopy and rapid diagnostic tests (RDTs) to diagnose malaria. METHODS We used a decision tree model and probabilistic sensitivity analysis applied to outpatients presenting at rural health facilities with suspected malaria. Costs and effects encompassed those for both patients positive on RDT (assuming artemisinin-based combination therapy) and febrile patients negative on RDT (assuming antibiotic treatment). Interventions were defined as cost-effective if they were less costly and more effective or had an incremental cost per disability-adjusted life year averted of less than US

Discovery research: the scientific challenge of finding new antibiotics

150. Data were drawn from published and unpublished sources, supplemented with expert opinion. FINDINGS RDTs were cost-effective compared with presumptive treatment up to high prevalences of Plasmodium falciparum parasitaemia. Decision-makers can be at least 50% confident of this result below 81% malaria prevalence, and 95% confident below 62% prevalence, a level seldom exceeded in practice. RDTs were more than 50% likely to be cost-saving below 58% prevalence. Relative to microscopy, RDTs were more than 85% likely to be cost-effective across all prevalence levels, reflecting their expected better accuracy under real-life conditions. Results were robust to extensive sensitivity analysis. The cost-effectiveness of RDTs mainly reflected improved treatment and health outcomes for non-malarial febrile illness, plus savings in antimalarial drug costs. Results were dependent on the assumption that prescribers used test results to guide treatment decisions. CONCLUSION RDTs have the potential to be cost-effective in most parts of sub-Saharan Africa. Appropriate management of malaria and non-malarial febrile illnesses is required to reap the full benefits of these tests.

Stoking the antibiotic pipeline

The dwindling supply of new antibiotics largely reflects regulatory and commercial challenges, but also a failure of discovery. In the 1990s the pharmaceutical industry abandoned its classical ways of seeking antibiotics and instead adopted a strategy that combined genomics with high-throughput screening of existing compound libraries. Too much emphasis was placed on identifying targets and molecules that bound to them, and too little emphasis was placed on the ability of these molecules to permeate bacteria, evade efflux and avoid mutational resistance; moreover, the compound libraries were systematically biased against antibiotics. The sorry result is that no antibiotic found by this strategy has yet entered clinical use and many major pharmaceutical companies have abandoned antibiotic discovery. Although a raft of start-up companies-variously financed by venture capital, charity or public money--are now finding new antibiotic compounds (some of them very promising in vitro or in early trials), their development through Phase III depends on financial commitments from large pharmaceutical companies, where the discouraging regulatory environment and the poor likely return on investment remain paramount issues.

The urgent need for new antibacterial agents

New antibiotics to tackle multidrug resistant bacteria are much needed. Chantal Morel and Elias Mossialos show how financial incentives might be used to persuade drug companies to develop them

The economics of malaria in pregnancy--a review of the evidence and research priorities.

I find it continually amazing that society as a whole does not recognize the consequences of rising antimicrobial resistance as the threat it most certainly is. This is not for a lack of sustained activity by those who share these concerns. Far from it. Since 1997 there have been a plethora of enquiries, reports and recommendations—many from important bodies in both Europe and North America, yet little meaningful action has materialized. Some might consider this to be rather negative and an overstatement, yet can they point out a concrete outcome to all this activity? I like to think that the UK has led the way in raising concerns that antibiotic use, especially overuse (in animals as well as man) will hasten the day when these essential agents will lose their efficacy. The Swann Committee first brought this to our attention in 1969, and in 1998 a House of Lords report starkly stated that antimicrobial resistance was a ‘major threat to public health’. Most recently, the Infectious Diseases Society of America (IDSA) and the European Union, among others, have voiced their concerns. In 2009 the WHO called antibiotic resistance one of the three greatest threats to human health, and in 2011 the focus of World Health Day was ‘Combating Antibiotic Resistance’. However, antimicrobial resistance moves on in an inexorable fashion and the prospects for new agents are as bleak as ever. Perhaps it is us, the health professionals, who are at fault, either in the nature of our message, or in approaching the wrong groups who cannot influence outcomes? The BSAC has changed tack in its report on ‘The Urgent Need’, as outlined in the articles accompanying this one. – 9 Rather than restate the concerns surrounding antimicrobial resistance, its surveillance and how it might be contained (or more accurately, how its progress might be slowed), the BSAC adopted a different approach, focusing on the barriers to discovery and development of new technologies that might combat resistance (including new antimicrobial agents) and how these might be overcome. The Working Party of the BSAC examined three areas, namely research, regulation and economics. While recognizing that these areas are not distinct and there is much important overlap, the Working Party was challenged to suggest a practical framework for action. Critically there was an awareness on the part of the Working Party that the BSAC cannot undertake this immense task on its own, and co-operation with others is key. I do not wish to précis the report here, but rather make some personal comments on what I consider to be a few important areas. In research there is a major concern that international expertise in natural product discovery is being rapidly lost—how long has it been since such an antibacterial compound has been marketed? Overoptimism in genomics and highthroughput screening as the answer to the discovery of new agents in the 1990s would appear to have put back the cause by at least a decade. Research into how to influence the public’s perceptions of the risks confronting them (hence the political response) is also needed. Most certainly the regulatory issues relating to the licensing of new antimicrobials are extremely important. The bureaucrats are risk averse, yet do not take account of the risks to society of their inaction. This would change if political concerns were more loudly voiced. It is my personal opinion that it is changes in the economic field that are most likely to yield results. We were not the first to expound the economic arguments. Everything the Working Party heard from industry makes me believe that the marketplace must change. A course of antibiotics costs a few pounds or dollars and can save lives. In hospital practice we shudder if the costs rise into the hundreds. The angiogenesis inhibitor bevacizumab (trade name Avastin) is one of the most expensive widely marketed drugs. In 2008 sales generated nearly US

International cooperation to improve access to and sustain effectiveness of antimicrobials

2.7 billion for Genentech, yet it has only modest effects on patient survival in a number of cancers. This is not to say it should not be used, but rather that there should be a rebalancing of risks and, more importantly, benefits. I would suggest that antimicrobials (other than a few antifungals) should be at a higher premium. Antimicrobial development must allow pharmaceutical companies realistic returns on their investment. This is crucial if society is to obtain new agents. So what actions should the BSAC undertake? The Working Party has suggested a number of short-, mediumand long-term activities. These, realistically, revolve around communication, in its broadest sense, with clinicians and academics, but possibly more importantly, with opinion formers in the UK and further afield. Such a programme of work, which will not be cheap, should include other parties and could usefully include the participation of the pharmaceutical industry.

The Millennium Development Goals Fail Poor Children: The Case for Equity-Adjusted Measures

Malaria in pregnancy is a major public-health problem in the developing world. However, on review of the evidence, we found its economic impact is not well documented. Adequately capturing the economic burden of malaria in pregnancy requires good epidemiological data including effects to the mother and baby, and better understanding of the long-term health and economic costs of malaria in pregnancy. We reviewed evidence on coverage, equity, cost, and cost-effectiveness of interventions to tackle malaria in pregnancy and found that although key interventions are highly cost effective, coverage is currently inadequate and fails to reach the poor. The evidence on interventions to improve treatment of malaria in pregnancy is scarce, and fails to adequately capture the benefits. There is also lack of data on cost-effectiveness of other interventions, especially outside of Africa, in low transmission settings, and for non-falciparum malaria. Research priorities on the economics of malaria in pregnancy are identified.

Human resources estimates and funding for antibiotic stewardship teams are urgently needed

Securing access to effective antimicrobials is one of the greatest challenges today. Until now, efforts to address this issue have been isolated and uncoordinated, with little focus on sustainable and international solutions. Global collective action is necessary to improve access to life-saving antimicrobials, conserving them, and ensuring continued innovation. Access, conservation, and innovation are beneficial when achieved independently, but much more effective and sustainable if implemented in concert within and across countries. WHO alone will not be able to drive these actions. It will require a multisector response (including the health, agriculture, and veterinary sectors), global coordination, and financing mechanisms with sufficient mandates, authority, resources, and power. Fortunately, securing access to effective antimicrobials has finally gained a place on the global political agenda, and we call on policy makers to develop, endorse, and finance new global institutional arrangements that can ensure robust implementation and bold collective action.

The economic burden of malaria on the household in south-central Vietnam

Daniel Reidpath and colleagues use the fourth Millennium Development Goal (MDG) as an illustrative example to highlight the potential to neglect equity in the race to achieve the MDGs.

Cost-Effectiveness of Long-Lasting Insecticide-Treated Hammocks in Preventing Malaria in South-Central Vietnam

1) Lorraine University, EA 4360 APEMAC, Nancy, France 2) Nancy University Hospital, Infectious Diseases Department, Nancy, France 3) ESCMID Study Group for Antimicrobial stewardshiP (ESGAP) 4) University of Geneva Medical School, Geneva, Switzerland 5) London School of Economics, London, United Kingdom 6) Infectious Diseases, Internal Medicine 1, DZIF Centre, Tübingen University, Germany 7) European Committee on Infection Control (EUCIC) 8) University Medical Centre Ljubljana, Slovenia 9) Faculty of Medicine, University of Ljubljana, Slovenia 10) University Hospital Carl Gustav Carus at the TU Dresden, Division of Infectious Diseases, Dresden, Germany 11) Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium 12) Infection Control Program and Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland 13) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London, London, UK 14) Leeds Teaching Hospitals NHS Trust, Leeds, UK 15) Division of Infectious Diseases, Department of Medicine, Sinai Health System, University Health Network, University of Toronto, Toronto, Canada 16) Ninewells Hospital and Medical School, Dundee, UK 17) British Society for Antimicrobial Chemotherapy (BSAC), Birmingham, UK 18) Paediatric Infectious Diseases Research Group, St Georges, University of London, London, UK 19) IQ Healthcare, Radboud University Medical Centre, Nijmegen, The Netherlands 20) National Centre for Antimicrobial Stewardship, Royal Melbourne Hospital at the Peter Doherty Institute, Melbourne, Australia 21) Centre for Disease Dynamics, Economics & Policy, New Delhi, India 22) Division of Infectious Diseases & HIV Medicine, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa