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VIEWS: 35 PAGES: 38

									   Drug Resistance as a
Global Health Policy Priority
   Global Ministerial Forum on Research for Health
                 November 18, 2008
                      Bamako, Mali




Susan Foster, Martha Gyansa-Lutterodt & Rachel Nugent
           Drug Resistance Working Group
Session Objectives
   To communicate the evidence that drug resistance is an
    important global (also African) policy priority;

   To articulate a common solution framework based on
    the risk factors for resistance across treatments for
    HIV/AIDS, malaria, TB and other key microbial
    infections;

   To share the CGD Drug Resistance Working Group’s
    preliminary recommendations for the set of incentives,
    governance capabilities and actions, and financing
    mechanisms that could reduce drug resistance globally.

                            2
Session Overview
I.     Introduction to the CGD DRWG, our presenters today and
       brief summary of what the DRWG aims to achieve

II.    Is drug resistance currently an important global policy
       priority? An overview of the reasons why it should be

III.   The drug resistance problem from a West African
       perspective (malaria, tuberculosis, other neglected diseases)

IV.    Working towards a common solution framework to address
       drug resistance across diseases

V.     Preliminary recommendations and conclusion

VI.    Q&A

                                 3
           Introduction to the
     Center for Global Development,
the CGD’s Drug Resistance Working Group
        and our presenters today



                    4
About the Center for Global Development
Independent, non-partisan think tank
Focus on the effects of rich-country policies on poor
countries
Promote policy alternatives
Research Areas:
    Development Aid Effectiveness
    Global Health & Education
    Debt
    Migration
    Trade
    Climate Change

                                 5
Features of CGD Working Groups
   Leading experts in public health, economics and other social science
    and technical fields
   Original, focused research on high-priority global health policy / finance
    issues
   Improve the outcomes of donor decision-making in global health with:
        Expanded evidence-base
        New people and perspectives
        Innovative solutions/ approaches
        Active communication and outreach


     Supported with a grant from the Bill & Melinda Gates Foundation
                                    6
        Working Group Timeline


                       Background                                  Consultation           Final report
                         paper                                        draft                  launch
      Initial                        Working Group                           Stakeholder        Outreach &
 Conceptualization                     Meetings                             Consultations      Dissemination
• Problem definition                • In-depth topic exploration        • Staff draft distributed for
                                                                                                         • Materials
                                                                          feedback from broad set of
   • Conceptual                     • Targeted analyses                                                    developed for
                                                                          stakeholders
     framework/summary of                                                                                  specific
     empirical research             • Analysis of potential solutions   • Considered by WG &               audiences Policy Impact
                                    • Proposed policy                     reflected in revised product
   • Identification/invitation of                                                                           • Briefs,
     working group members            recommendations                                                         journal
                                                                                                              articles,
   • Development of timeline                                                                                  etc.
   • Outline of outreach strategy                                                                        • Large & small
     and goals for policy impact                                                                           events



                                                                7
DRWG Statement of Purpose
    The Drug Resistance Working Group will generate critical thinking about:

         Magnitude and nature of emergence and spread of drug resistance

                Differences across diseases and regions

         Implications of drug resistance for multiple stakeholders

         Specific actions and investments by international actors to create a
          systematic response to resistance

    Resulting in analytically-based policy recommendations for:

         Multi- and bilateral funders

         Technical agencies

         Policymakers in developing countries

                                         8
         Drug Resistance
         as an important
global public health policy priority




                9
Impacts of drug resistance
   Resistance limits the effective useful lifespan of drugs
       Makes industry less interested in research and development

   Older antibiotics to treat common infectious diseases are
    often more toxic e.g. chloramphenicol and gentamicin, or
    more expensive e.g. amoxiclav, or both

   Treatment options become more limited
       Higher 2nd and 3rd line treatment costs
       Some conditions become untreatable – XDR-TB, MRSA, will
        cholera and shigella be next?




                                10
Why is drug resistance
a global public health policy priority?
   Resistance causes avoidable mortality and morbidity,
    undermining renewed global health efforts

   Resistance occurs across major infectious diseases
       Drug use for one condition affects resistance for other conditions,
        e.g. cotrimoxazole for HIV affects use for ARI

   Resistance means spending more on drugs to get the
    same effect, in an era of extreme competition for
    health budgets

   Resistance knows no barriers and requires international
    coordination to control
                                 11
Incentives to slow resistance are lacking
   Divergence between private and social interests and incentives
         As a parent, I want to treat my child with antibiotics - I am not concerned
          about the common good!

   Drug efficacy is a diminishing resource – a public good, shared by
    all
         Yet there is no mechanism for control or rationing of this resource (no
          OPEC of antibiotics!)
         Most incentives are for more, not less, use

        A transnational issue – crosses borders and regions, but no
         control body (or even tracking body)
         Resistance which develops in one area soon spreads
        Tension between preventive and therapeutic AB use
        Pharmaceutical industry incentives are mixed
                                       12
The supply of new antibiotics is drying up




                                                            Zero?


      Total number of new antibacterial agents introduced

                              13
Newer antibiotics are more expensive
   Amoxicillin and clavulanic acid is 20 times more
    expensive than ampicillin
   The change in standard therapy for malaria from
    chloroquine (CQ) and sulfadoxine/pyrimethamine
    (SP) to artemisinin containing therapy (ACT) has
    increased the cost of treating a case of malaria by a
    factor of 10 or more
   It costs up to 500 times as much to treat drug-
    resistant TB compared to standard TB




                            14
Drug prices compared
                 Drug                 Price/   Units/ dose   Price/dose
                                        unit
Amoxicillin 250 mg tab/cap            $0.02            28      $0.43
Amoxicillin/clavulanic acid           $0.30            28      $8.40
Ampicillin 250 mg tab/cap             $0.01            28      $0.41
Azithromycin 250 mg tab/cap           $0.22              6     $1.31
Chloramphenicol 250 mg tab/cap        $0.01            28      $0.39
Ciprofloxacin 250 mg tab/cap          $0.02            56      $1.09
Cotrimoxazole (b) 400+80 mg           $0.02            28      $0.47
tab/cap
Doxycycline 100 mg tab/cap            $0.01            11      $0.11
Erythromycin 250 mg tab/cap           $0.03            40      $1.05
Penicillin V 250 mg tab/cap           $0.01            56      $0.71
Tetracycline 250 mg tab/cap           $0.01            36      $0.27

                                 15
The cost of poor diagnosis
    Much of the expenditure on drugs is wasted
     because they are not appropriate or indicated for
     the patient’s condition
    Antibiotics may be given for acute respiratory
     infections which are viral in origin, or
     antimalarials given for pneumonia: young, febrile
     children are often treated empirically for malaria,
     when in fact they have pneumonia (Kallander,
     Nsungwa-Sabiiti et al. 2004)
    Antibiotics continue to be used where resistance
     is already very high


                           16
Friend or foe?
                      Resistance
                      increases as drug
                      access improves
                      and urbanization
                      increases (more
                      informal sector
                      options?)

                      Over 20 informal
                      sector drug outlets
                      along a 2 km
                      stretch of road in a
                      new urban
                      settlement in East
                      Africa



Source: MMV

                 17
Drug Resistance:
a global snapshot




       18
Ciprofloxacin resistance increasing
   Consistent increase in the median MIC* of V. cholerae O1
    strains isolated at the Dhaka Hospital:
        0.003 μg/mL in 1994
        0.023 μg/mL in 2001
        0.38 to 0.5 μg/mL in 2005
          Source: A.S.G. Faruque, J HEALTH POPUL NUTR 2007
            Jun;25(2):241-243
   MIC, minimum inhibitory concentration, is the minimum
    concentration of antibiotic which will inhibit the growth of the
    isolated microorganism


                               19
Multidrug resistance in S. pneumoniae
     In Asia a very high % of S. pneumoniae isolates collected
        during 2001-2002 were multi-drug resistant (to penicillin,
        erythromycin and ciprofloxacin) (Song et al, 2004)
% resistant




                                20
Multidrug resistant cholera in
Bangladesh is rapidly rising – over 7 months!




 Strains resistant to furazolidone, trimethoprim/sulphamethoxazole,
 tetracycline, and erythromycin
 Source: A.S.G. Faruque, J HEALTH POPUL NUTR 2007 Jun;25(2):241-243
                                   21
The current situation
    HIV/AIDS – lots of activity: lifelong therapy,
     industrialized market
       Main issue is price


    Malaria – after artemisinin, le déluge?

    Tuberculosis – much too little attention given the
     size of the problem!
       Industry not very interested, relying on PPPs


    Bacterial infections – many pathogens, short duration
     of therapy (7-10 d), complex
       Companies just not interested in this field!
       Need to use what we have as well as possible

                             22
A strategy for antibiotics –
to use the little we have
   Much (perhaps most?) outpatient antibiotic use is for
    children, maternal, and adults with HIV

   Specifically for a few conditions:
      Pneumonia and ARI
      Diarrheal disease (often inappropriate)
      Infections
          Earache, throat
          Wounds and skin infections
      Tuberculosis (both children and adults, esp. w/ HIV)
      Maternal infections and sepsis


   If we get these right, major progress could be made

                            23
   Drug Resistance:
a West African snapshot




          24
Political map of West Africa




                    25
Drug resistance challenges:
selected findings on malaria
   Chloroquine and sulphadoxine/pyrimethamine resistance
    has been reported throughout West Africa (Spencer et al
    1986, Amukoye et al 1997, and in Ghana (Neequaye 1986,
    Koram et al, 2005)
   Led to change in treatment policy of ACTs across the sub
    region
   IMPACT
     o Huge resource allocation
     o Monotherapies still available
     o Substandard /counterfeit ACTs still circulating in the
       regional markets (Minzi et al,2003, Amin et al, 2005,
       Bates et al, 2008)


                               26
Resistance of P. falciparum
around the world: when to switch to ACT?
                                                             To
                            To CQ           To SP
                                                         mefloquine
East Africa               ~ 50-60%          ~10-20%
Central Africa            ~ 50-60%           ~10%
Southern Africa           ~ 10-30%          ~10-20%
West Africa               ~ 10-30%           ~10%
                        Generally above
Eastern Mediterranean                      Below 20%
                             40%
                        Generally above                  Between 10-
Western Pacific                             ~20-40%
                             40%                             20%
                                                          More than
Southeast Asia              ~40%          Around 20%
                                                             20%
South America             Over 80%        Close to 20%
Central America                              ~10%




                                   27
Drug resistance challenges:
selected findings on TB and neglected diseases
   Mycobacterium tuberculosis drug resistant to at least
    streptomycin, isoniazid and rifampin has been reported
    (van der Werf TS et al 1989, Lawn et al 2001, and Owusu-
    Dabo et al, 2006)
     o New medicines for TB slow to emerge
     o Situation exacerbated by HIV/AIDs co-infection
   Onchocerciasis worms non-responsive to ivermectin have
    been reported with an increase in the rate of re-
    population by adult worms (Osei-Antweneboana et al,
    2007)

   Data on other neglected diseases is limited
      For example, concern has been raised about
       schistosomiasis and resistance to praziquantel…
                               28
In short:
    Drug resistance is not limited to the developed world;
     indeed it is present in Sub-Saharan Africa with grave
     consequences
    The drivers of resistance are well known and very
     challenging for West Africa, stemming primarily from
       Weak health systems
       Behavioral issues – including, but also going beyond,
         those behaviors resulting from low literacy and high
         poverty levels
       Drug and diagnostics technologies – limited research
         in Africa
    It is clear that a global framework for action is required

                              29
        Towards a
common solution framework
     and a snapshot of
potential recommendations



            30
Common solution framework
to address resistance across diseases




                  Resistance



                    (Patient): poor
                    adherence, self-
                    medication, cultural
                    preferences/beliefs
                    (Provider):unclear
                    diagnosis, financial
                    incentives, industry
                    promotion


                     Behavioral
                       31
                     Factors
Common health system
factors that drive resistance across diseases
Key “health system” drivers include:
   Paucity or poor quality of resistance surveillance efforts
   Lack of connection between resistance situation and drug selection/procurement
   Lack of high-quality rapid diagnostic and monitoring tests and algorithms
   Lack of or poor quality services
         Lack of education and training among dispensers accompanied by poor monitoring and enforcement

         Lack of or weak implementation of infection control policies

   Direct/indirect costs of accessing services: one possible cause of poor adherence
   Lack of/poor implementation of regulations governing prescribing and dispensing
  Under and over-prescription of (usually broad-spectrum) antibiotics, when not
clear pathogen is viral or bacterial = inappropriate drug use


                                               32
Common behavioral factors
that drive resistance across diseases
 Factors motivating or demotivating patients:
    Poor quality/lack of services
    Health worker attitudes
    Drug and supply availability and access
    Direct and indirect costs
    Community and/or family-level disease associated stigma
    Cultural preferences/beliefs
    Gender-related issues




                              33
Common behavioral factors
that drive resistance across diseases (2)
 Factors motivating or demotivating providers:
  Who gains where financially along the patient-
    prescriber-dispenser (possible drug) transaction
  Poor quality/lack of diagnostic tests can lead to over-
    prescription
  Evidence that providers may not trust negative
    diagnostic result
  Cultural preferences/beliefs and gender-related issues
  Pharmaceutical industry efforts to influence prescribing
    behavior

    And there are also factors that motivate or demotivate
    behaviors during the patient-provider interaction
                           34
Common drug and drug
technology factors that drive resistance
 Key “drug and drug technology” drivers include:
  Drug half-life
  Monotherapy favors acquired resistance; combination
   therapies are challenging to formulate
  What possibility is there that the pathogen will
   “become” re-sensitive to a given drug?
  Cross-resistance across and within drug classes
  Length and complexity of treatment: impact on
   adherence and resistance selection pressure
  Absolute levels of drug use, fitness and virulence
  What alternatives might there be to using drugs?




                         35
Comparison of Disease-Related Resistance Issues
(adapted from the 2001 WHO Global Strategy for Containment of Antimicrobial Resistance)
             Issues                 Bacterial Infections             TB                      Malaria                         HIV
  Inappropriate Use Contributes
                                            Yes                     Yes                         Yes                          Yes
      to ↑ Drug Resistance
       Need for New Drug
                                            Yes                     Yes                         Yes                          Yes
          Development
                                     Reasonably Easy
     Detection of Pathogen                                          Easy                       Easy                          Easy
                                       and Feasible

                                     Reasonably Easy                                Difficult, Expensive, Rarely     Difficult, Expensive,
 Detection of in vitro resistance                          Feasible but Expensive
                                       and Feasible                                            Feasible              Limited Availability


   Diagnostics Able to Detect                                                                                      Yes, but expensive and
                                       Yes, but slow               Some                         No
          Resistance                                                                                               with limited availability

      Observed Treatment                    No                 Yes  DOTS                       No                            No

                                    Single Agent, Short    Multiple Agents, Long
    Antimicrobial Treatment                                                         ≥1 Agent, Short Duration       Multiple Agents, Lifelong
                                         Duration                Duration


                                     Some: Especially       Massive: Personal &
         HIV Interaction                                                                     Possibly                        N/A
                                     Nosocomial Risk         Nosocomial Risk


                                        Yes; Some
                                                              Little; Except for      Some; e.g. doxycyline,
     Potential Impact of One         Antibiotics Could                                                             Yes; e.g. cotrimoxazole +
                                                             Rifampicin Use on           sulphadoxine-
      Program on Another              Affect Malaria                                                                 isoniazid prophylaxis
                                                                 Staph. Spp.            pyrimethamine
                                       Resistance
Snapshot of potential DRWG recommendations
   Health Systems:
        Establish cross-disease laboratory systems based on molecular technologies
        Build on WHONET to insert resistance into public health surveillance systems
        Add resistance to HealthMap and other informal surveillance systems
        Scale up ADDO/similar approaches to franchise or certify dispensers
        Proliferation of GMP  Industry self-regulation for QA (e.g. ISO)
        Continuing professional education; the role of professional assns. and drug reps
   Behavioral:
        Cross-country drug regulatory networks (ex. WADRAN)
        Drug dispenser checklist (potential to work with FIP)
        Options to improve consumer education
   Technology:
        Public, web-based compound library showcase to accelerate early-stage product
         development
   Other:
        Health and Development Conference on Resistance
                                           37
Conclusion
   Next steps
        Last working group meeting in early December to solidify
         recommendations
        Continue consultation sessions through to end January 2009
        Launch WG report in April/May
        Outreach and dissemination  IMPACT
   We need your thoughts: how to have input
        Please attend our open session on 20 November here in Bamako
         (Hotel Laico el Farouk 9:30-11:30, Room Kafo) to give input on
         our preliminary recommendations
   Sign up for Monthly CGD Drug Resistance e-newsletter
        http://www.cgdev.org/Drug_Resistance
                                  38

								
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