Drug Resistance as a Global Health Policy Priority Susan Foster, Martha Gyansa-Lutterodt & Rachel Nugent Drug Resistance Working Group Global Ministerial.

Drug Resistance as a Global Health Policy Priority

Susan Foster, Martha Gyansa-Lutterodt & Rachel Nugent

Drug Resistance Working Group

Global Ministerial Forum on Research for Health

November 18, 2008Bamako, Mali

2

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.

3

Session OverviewI. 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

4

Introduction to the

Center for Global Development,

the CGD’s Drug Resistance Working Group

and our presenters today

5

About the Center for Global DevelopmentIndependent, 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

6

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

7

• Problem definition

•Conceptual framework/summary of empirical research

•Identification/invitation of working group members

•Development of timeline

•Outline of outreach strategy and goals for policy impact

Initial Conceptualizati

on

Working Group

Meetings• In-depth topic exploration

•Targeted analyses

•Analysis of potential solutions

•Proposed policy recommendations

Background paper

Final report launch

Working Group Timeline

Stakeholder Consultations

Outreach & Disseminatio

n•Staff draft distributed for feedback from broad set of stakeholders

•Considered by WG & reflected in revised product

Policy Impact

Consultationdraft

•Materials developed for specific audiences

•Briefs, journal articles, etc.

•Large & small events

8

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

9

Drug Resistance

as an important

global public health policy priority

10

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?

11

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

12

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

13

The supply of new antibiotics is drying up

Zero?

Total number of new antibacterial agents introduced

14

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

15

Drug prices comparedDrug Price/

unitUnits/ dose

Price/dose

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 tab/cap

$0.02 28 $0.47

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

16

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

17

Friend or foe?

Resistance increases as drug access improves and urbanization increases (more informal sector options?)

Source: MMV

Over 20

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

18

Drug Resistance:

a global snapshot

19

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

20

Multidrug resistance in S. pneumoniaeIn 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)

% r

esis

tant

21

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

22

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

23

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

24

Drug Resistance:

a West African snapshot

25

Political map of West Africa

Drug resistance challenges: selected findings on malaria

26

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

IMPACTo Huge resource allocationo Monotherapies still availableo Substandard /counterfeit ACTs still

circulating in the regional markets (Minzi et al,2003, Amin et al, 2005, Bates et al, 2008)

27

Resistance of P. falciparum around the world: when to switch to ACT?

To CQ To SP To mefloquine

East Africa ~ 50-60% ~10-20% Central Africa ~ 50-60% ~10% Southern Africa ~ 10-30% ~10-20% West Africa ~ 10-30% ~10%

Eastern Mediterranean Generally above 40% Below 20%

Western Pacific Generally above 40% ~20-40% Between 10-

20%

Southeast Asia ~40% Around 20% More than 20%

South America Over 80% Close to 20% Central America ~10%

Drug resistance challenges: selected findings on TB and neglected diseases

28

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 limitedFor example, concern has been raised about schistosomiasis and resistance to praziquantel…

In short:

29

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

30

Towards a

common solution framework

and a snapshot of

potential recommendations

Common solution framework to address resistance across diseases

31

Resistance

Drug Technology Factors

long drug half-life, cross-

resistance, treatment

length and complexity,

monotherapy

Behavioral Factors

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

Health

Systems

Factors

Poor quality

, unregulated

prescribing/dispensing, weak

infection control, la

ck of rapid

diagnostic tools, poor

surveillance

32

Common health system factors that drive resistance across diseasesKey “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

33

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

34

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) transactionPoor quality/lack of diagnostic tests can lead to over-prescriptionEvidence that providers may not trust negative diagnostic resultCultural preferences/beliefs and gender-related issuesPharmaceutical industry efforts to influence prescribing behavior

And there are also factors that motivate or demotivate behaviors during the patient-provider interaction

35

Common drug and drug technology factors that drive resistance

Key “drug and drug technology” drivers include:Drug half-lifeMonotherapy 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 classesLength 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?

Issues Bacterial Infections TB Malaria HIV

Inappropriate Use Contributes to ↑ Drug Resistance Yes Yes Yes Yes

Need for New Drug Development Yes Yes Yes Yes

Detection of Pathogen Reasonably Easy and Feasible Easy Easy Easy

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

FeasibleDifficult, Expensive, Limited Availability

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

with limited availability

Observed Treatment No Yes DOTS No No

Antimicrobial Treatment Single Agent, Short Duration

Multiple Agents, Long Duration ≥1 Agent, Short Duration Multiple Agents, Lifelong

HIV Interaction Some: Especially Nosocomial Risk

Massive: Personal & Nosocomial Risk Possibly N/A

Potential Impact of One Program on Another

Yes; Some Antibiotics Could

Affect Malaria Resistance

Little; Except for Rifampicin Use on

Staph. Spp.

Some; e.g. doxycyline, sulphadoxine-

pyrimethamine

Yes; e.g. cotrimoxazole + isoniazid prophylaxis

Comparison of Disease-Related Resistance Issues(adapted from the 2001 WHO Global Strategy for Containment of Antimicrobial 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_Resistance38