Enhancing the rational use of antimalarials: The cost-effectiveness of rapid immunochromatographic dipsticks in sub-Saharan Africa

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Enhancing the rational use of antimalarials The
cost-effectiveness of rapid immunochromatographic
dipsticks in sub-Saharan Africa

• Chantal Morel, Sam Shillcutt, Paul Coleman,
  Catherine Goodman Anne Mills
• Health Economics and Financing Programme, Public
  Health Policy Department
• Disease Control Vector Biology Unit, Infectious
  and Tropical Diseases Department
• The London School of Hygiene Tropical Medicine

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Abstract

• Problem Statement The massive burden of malaria,
  along with a severe scarcity of economic
  resources, makes efficiency in antimalarial drug
  programs a critical issue in sub-Saharan Africa.
  Parasite resistance has developed to
  currently-used first line therapies, to which
  artemisinin-based combination therapies (ACTs)
  provide a cost-effective alternative. Rapid
  immunochromatographic dipsticks may be an
  efficient method in certain settings to allocate
  these more-expensive but more-effective drugs.
• Objectives This study evaluates the
  cost-effectiveness of using dipsticks to diagnose
  malaria in sub-Saharan Africa relative to
  presumptive antimalarial treatment for all people
  presenting to a clinic with fever. To set an
  upper limit for how much a decision maker should
  be willing to pay to reduce parameter-uncertainty
  within the model, the expected value of perfect
  information (EVPI) is calculated.
• Design A theoretical decision-analytic model is
  used to determine the probability that dipsticks
  are cost-effective across a spectrum of possible
  prevalence levels. Drug savings are measured
  according to unnecessary treatments avoided
  through improved accuracy of diagnosis. Given the
  uncertainty surrounding cost-effectiveness
  estimates, the per-person EVPI is calculated.
• Setting Sub-Saharan Africa.
• Population A hypothetical population presenting
  with fever to a clinic for treatment.
• Intervention Immunochromatographic dipsticks may
  be used to diagnose malaria in approximately 20
  minutes. After blood and buffer are mixed in a
  sample well, immersion of an antibody-covered
  strip will indicate the presence of malaria
  parasites.
• Outcome Measures Incremental Cost per Disability
  Adjusted Life Years (DALYs).
• Results At a ceiling ratio of US150/DALY
  averted, it is 95 certain that dipsticks are
  cost-effective where fewer than 15 of febrile
  patients have parasitemia, and not cost-effective
  above 55. The EVPI is greatest between 15 to
  55 prevalence with a peak at 33, the point at
  which uncertainty around the cost-effectiveness
  of dipsticks is at its maximum.
• Conclusions Based on criteria of economic
  efficiency, dipsticks should be used in areas
  where the proportion of febrile illnesses caused
  by malaria is low. The simplicity and clarity of
  this diagnostic strategy is likely to provide
  incentives to encourage people to seek treatment,
  encourage more rational use of ACTs, and impede
  the development of resistance to ACTs.

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Study Questions

• At what levels of malaria prevalence is dipstick
  diagnosis cost-effective relative to presumptive
  treatment?
• How much should a decision-maker be willing to
  pay to eliminate uncertainty about model
  parameters before making a decision?

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Introduction

• Inappropriate diagnosis of febrile illness is a
  common problem in sub-Saharan Africa.
  Presumptive treatment for malaria dominates where
  malaria is prevalent, which leads to excessive
  prescription of antimalarials and inappropriate
  treatment of non-malarial fevers. These fevers
  may become severe with delayed treatment. With
  the introduction of artemisinin-based combination
  therapies, presumptive treatment may no longer be
  affordable. Rapid dipstick tests are an
  inexpensive and simple diagnostic tool, and are
  currently being developed for use in endemic
  areas. This paper examines the cost-effectiveness
  of using dipsticks to diagnose malaria, given
  treatment with ACTs, across the possible range of
  malaria prevalence in low-income countries of
  sub-Saharan Africa.
• Beyond the scope of the cost-effectiveness
  analysis, it is important to consider the value
  of collecting additional information about
  parameter values. Both deciding to implement an
  intervention and deciding to obtain further
  information involve potential opportunity costs
  choosing a sub-optimal intervention, or spending
  money to confirm an existing recommendation. An
  EVPI analysis may be used to evaluate the maximum
  value that further information could add to the
  model. While EVPI does not determine the value of
  information given by studies with finite sample
  sizes, it provides a threshold above which the
  option to sample further can be rejected. This
  study estimates the EVPI for the overall model.

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Methods

• A simple decision tree, restricted to patients
  that present with fever to a public health
  facility, was developed to calculate incremental
  cost-effectiveness. The decision tree in Figure 1
  follows an individual patient entering the system
  through to being cured, dying, or surviving with
  neurological sequelae, according to the
  sensitivity and specificity of each diagnostic
  strategy and level of malaria prevalence.
  Evidence on the progression of non-malarial
  illnesses is lacking, and it was assumed that
  their consequences would be similar to untreated
  malaria.
• All parameter values, their associated
  uncertainty, were abstracted from a variety of
  sources and sub-Saharan African (SSA) countries.
  A population structure including 50 adults and
  50 children was assumed in the model.
• Costs, in 2002 US dollars, were calculated
  using the ingredients approach. Only direct costs
  of medical diagnosis and care were included in
  this analysis. A range of ACTs were considered,
  including artesunate-sulfadoxine-pyrimethemine,
  artemether-lumefantrine (Coartem), and
  artesunate-mefloquine1. Drugs recommended by the
  Integrated Management of Childhood Illness (IMCI)
  protocol for febrile illness were considered for
  negative diagnoses paracetamol, amoxicillin, and
  chloramphenicol2.

1. Bloland (2001) WHO 2. WHO (1999) IMCI
Information Package
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Methods

• Health outcomes were measured in terms of DALYs
  averted, calculated according to standard
  methods. Full compliance with diagnosis and
  treatment was assumed on the part of the patient
  and the health worker.
• Parameter uncertainty was quantified using
  probabilistic sensitivity analysis, and
  incremental cost-effectiveness ratios (ICERs)
  were determined. The probability dipsticks are
  cost-effective was evaluated using a ceiling
  ratio equal to US150/DALY averted (?)1. ICERs
  were converted to net-benefits using the
  following formula.
• Net Benefit Effects ? Costs
• Expected Value of Perfect Information (EVPI)
  was calculated according to methods shown in
  Figure 22. The average net-benefit of the optimal
  strategy at each iteration was used to
  approximate the expected value of making a
  decision under complete certainty. The
  difference between this and expected net benefit
  with current uncertainty is the EVPI.

1. WHO (1996) Investing in Health Research and
Development, Report of the Ad Hoc Committee on
Health Research 2. Fenwick (2000) York
Discussion Paper
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Figure 1 Simple decision tree model
sensitivity, a
True positive
malaria, p
1-a
False negative
Suspected malaria
specificity, b
True negative
1-p
1-b
False positive

• Give all suspected malaria ACTs a1 and b 0
• Use dipstick before giving ACTs a?0.95 and b
  ?0.95

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Figure 2 Calculation of EVPICeiling Ratio
150/DALY averted
Iterations Net Benefit Dipsticks Net Benefit PT Net Benefit WPI
1 40 20 40
2 20 25 25
3 35 25 35
4 25 30 30
Average 30 25 32.50
EVPI 32.50 - 30 2.50 32.50 - 30 2.50
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Figure 3 Incremental Net-benefit
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Figure 4 Probability Cost-Effective and EVPI
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Discussion of Results

• Rapid dipstick tests will introduce a
  tradeoff between reducing the prescription of
  antimalarials with reducing the sensitivity of
  diagnosis. Our model indicates that where 15 or
  fewer fevers are caused by malaria, dipsticks are
  the dominant strategy, and should be used in
  public health care clinics to diagnose malaria.
  This result is most sensitive to malaria
  prevalence and the cost and accuracy of
  dipsticks. When prevalence is high, the
  probability that a person will return for
  treatment if symptoms become severe is important.
  
• Reducing amounts of antimalarials
  prescribed may affect drug pressure on parasites,
  which would impact the growth of drug resistance.
  However, improved diagnosis may increase
  compliance to ACTs (around 40)1, and use of the
  public health care system among people receiving
  antimalarials (around 50)2. Thus, the net effect
  on drug pressure is unclear.
• Improved information on prevalence may help
  health planners more effectively target
  preventive and treatment measures towards people
  who need them most, both within the context of
  malaria and across disease areas.

1. Depoortere (2004) TMIH 2. Foster (1991) WHO
Bull
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Limitations and Further Work

• This analysis is limited in several respects.
  It assumes that patients and health workers will
  follow the mode of action suggested by the
  dipstick results, restricting drug treatment to
  those with positive tests. In reality, patients
  who test negative may be given antimalarials.
  Health workers may lack faith in test quality,
  and patients may demand drugs anyway. In areas of
  high transmission intensity, some patients may be
  immune to levels of malaria parasites that cause
  illness in others. The interaction of these
  factors pose complex questions for diagnostics
  that are not dealt with in this model.
• Further work is necessary to clarify the causes
  of treatable febrile illness in people who
  incorrectly receive antimalarials. Some evidence
  exists to suggest that pneumonia, salmonella,
  meningitis, and other illnesses are common.
  Treatments and outcomes for these diseases
  differ, and studies are needed to determine their
  relative contributions to misdiagnosis.
• Our EVPI estimate provides only a rough
  estimate of the maximum amount a decision-maker
  should be willing to pay for perfect information
  in the entire model. A more useful analysis would
  estimate the value of testing individual
  parameters according to the power associated with
  specific sample sizes. A Bayesian two-step
  Monte-Carlo simulation approach has recently been
  developed to make this analysis possible1.

1. Brennan (2004) J. Health Economics
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Conclusion and Policy Implications

• Rapid dipstick tests are highly effective and
  simple tools for diagnosing malaria. Our model
  suggests that they should be used where 15 or
  fewer people that present to public health
  clinics with fever have malaria. These results
  should not be interpreted according to endemicity
  as transmission intensity and parasitemia are not
  linearly correlated. Further information to
  reduce uncertainty around model parameters may be
  useful between 15 and 55 prevalence. However,
  if these studies are projected to cost more than
  US2.20 per person, decision-makers should
  proceed with the choice to adopt dipsticks.
• Dipsticks represent a significant investment,
  costing between US0.50 and US1.85 per test1, or
  about one-half as much as first-line treatment
  with ACTs2. Currently, 42 of malaria costs are
  borne by households in SSA, with 39 covered by
  donors3. The international community must
  contribute to this efficient use of resources to
  combat this disease.

1. Kindermans (2002) 2. Bloland (2001) 3.
WHO (2003) Africa Malaria Report