Karen I Barnes University of Cape Town Division of Pharmacology

1. Global access campaigns, national malaria guidelines and the appropriate use of antimalarials: Positive and negative aspects of enhancing global access to antimalarials Karen I Barnes University of Cape Town Division of Pharmacology Potential Conflict of interest: Funding for ACT implementation and monitoring and evaluation received from GFATM and WHO TDR.

2. Outline • Expectations • Some Achievements: • RBM • GFATM • MSF • Some Challenges: • Sustainability • Ensuring effective and evidence based policies and practices • Weak healthcare infrastructure • Unresolved questions on the role of ACTs • Conclusions

3. Expectations of Global Access Campaigns • To support for evidence-based practices to combat AIDS, TB and malaria, which are not achievable with local resources alone. • Success requires “access to healthcare” and not just “access to drugs”. • Decrease morbidity and mortality and the social and economic burden of disease. • Drug resistant infections will be effectively managed with better treatments and new strategies.

4. International consensus to implement ACTs Improve clinical cure rates Delay emergence of resistance Reduce transmission Widespread 1st line Rx with Artemisinin-based Combination Therapy (ACT) Cost effective

5. ACT delays resistance in NW Thailand Nosten F, et al (2000). Effects of artesunate – mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet; 356: 297-302.

6. ACT acts synergistically with vector control to decrease malaria transmission in KwaZulu Natal, South Africa A: DDT reintroduced B: IRS southern Mozambique C: Artemether-lumefantrine implemented

7. 2000: Year before adoption of AL 311,362 2002: 2nd year after adoption of AL 3,823 14,828 23,513 799 1,345 Findings 4: Economics costs of Malaria inpatients (SP vs. AL) (Manguzi hospital, KZN) in US$ /year 350,000 300,000 250,000 other malaria costs include capital costs, overhead costs, personnel and transport. 200,000 150,000 100,000 50,000 0 Other MalariaCosts Cost ofMalaria Tests Cost ofAntimalarials Total impact of 3 interventions

8. Cost of Antimalarials Cost of Malaria Tests Other Malaria Expenditures 7,288 4,429 5,271 3,583 1,694 120 Findings 2: Economics costs of Malaria outpatients (SP vs. AL) (Manguzi district, KZN) in US$ /year 98,758 100,000 other malaria expendiditures include capital costs, overhead costs, personnel and transport. 65,606 75,000 50,000 27,794 23,312 25,000 6,566 4,854 0 Clinic SP as 1st line Clinic AL as 1st line Hospital SP as 1st line Hospital AL as 1st line Total impact of 3 interventions

9. Cost savings to KwaZulu Natal DOH by combined interventions

10. Evaluation of AL intervention alone (Manguzi sub-district, KZN)

11. Achievements of Global Access to ACTs e.g. RBM • Position statement supporting 2001 recommendation of ACTs, recently reiterated. • Multiple financing mechanisms and mobilisation of international support. • Increased number and prequalification of manufacturers of artemisinin derivatives (artemether-lumefantrine, Novartis; artesunate, Sanofi). • Preferential pricing agreement(artemether-lumefantrine, Novartis). • Contributed to the development of systems of pharmacovigilance.

12. Achievements of Global Access to ACTs e.g. GFATM Global Fund to fight AIDS, TB and Malaria (established in 2002): • Has funded the fastest shift to ACT to date: • 20 countries (7/42 in Africa) have implemented ACTs • 16 African countries to have implemented ACTs by end 2004 • Committed funds to procure ACTs for 22 million patients (19 million in Africa) – compared to current ACT coverage of 10 000 - 20 000. • Pharmaceutical Services Management Assessment Tool (PSMAT). • Recently, strongly encouraged applications / grant revisions for funding of ACTs.

13. Achievements of Global Access to ACTs e.g. MSF MSF Campaign for Access to Essential Medicines • Evidence-based decision to implement ACTs in all MSF programmes. • Operational Research documenting successes and failures. • Assisting governments to implement ACTs. • Advocating for and increasing the availability and quality of ACTs.

14. Challenge 1: Sustainability • Can manufacturers (and artemisinin raw material) meet dramatic increase in demand? • Sustainability of foreign donor funding?

15. Challenge 1: Sustainability continued • Can manufacturers (and artemisinin raw material) meet dramatic increase in demand? • Depends on accurate and timely forecasting. • BUT • Antimalarial requirements generally fluctuate (particularly in areas of low intensity transmission) – and ACT requirements are even more challenging to forecast.

16. Forecasting Solutions • Short term: • Technical support, guidelines, better use of IT in drug management and “regional buffer supplies” urgently needed. • Longer term: • Operational research for predicting requirements and longer shelf-life. Climatic changes Vector control Epidemics Migration Weak information and drug management systems Age specific Higher drug cost per patient Increased treatment seeking Possibly decreased transmission and resistance RDTs

17. Challenge 1: Sustainability continued To ensure the sustainability of international donor funding:? • Efforts to decrease cost of ACTs • Increased demand and larger purchasing power of GACs is likely to decrease costs - “Buy bulk and save.” • In the future, synthetic artemisinins • Benefits (efficacy, safety, transmission, resistance, cost-effectiveness, macro-economic impact) need to be quantified and effectively communicated locally, regionally and internationally.

18. Challenge 2: Ensuring scientifically sound, evidence based policies • Future donor funding for malaria will not be improved by supporting ineffective regimens. • Currently use (and funding) of ineffective drugs remains prevalent. • Donors should only fill “gaps”. • Country autonomy should not be compromised. GFATM antimalarial procurement in Rounds 2&3 in millions of US dollars.

19. Challenge 2: Ensuring scientifically sound, evidence based policies cont. To ensure that the submissions are evidence based. • Acknowledge that many Ministries of Health take their leadership from international bodies, e.g WHO. • International recommendations should be consistent and scientifically sound and evidence based. • Recommendations should be complemented by Model ACT Standard Treatment Guidelines (WHO target Q3 2004). • Sound, comprehensive technical support needed to effectively implement these guidelines.

20. Challenge 2: Ensuring scientifically sound, evidence based policies. • Monitoring and Evaluation within “normal context of use” essential. • Standardised therapeutic efficacy studies and longer term follow up of treatment outcome cohorts. Future Research: • Measuring expected impact of ACTs on malaria transmission and resistance particularly in areas of higher intensity malaria transmission. • Measuring the macro-economic impact of ACTs as well as cost-effectiveness. • Qualitative research to understand formal and informal reasons why individual countries are requesting funding for ineffective treatment policies, and address these.

21. Challenge 3: Health System infrastructure “In a weak healthcare infrastructure – purchasing a more effective but more expensive drug is not the highest priority.” Effective chemotherapy is only part of the healthcare package – which must include: • early reliable diagnosis (Rapid Diagnosic Tests), • prevention of malaria (ITNs, IRS, IPT), • patient and community information, • efficient and reliable referral systems for severe malaria, • secure drug supply, • monitoring and evaluation of effectiveness and safety.

22. Changing malaria treatment policy is a complex and ongoing process, including…… Training Reliable drug availability and rational use Training Patient & community information Monitoring and Evaluation

23. Challenge 3: Health System infrastructure International funding, particularly GFATM, can and has used access to e.g. ACTs to galvanise and facilitate improvements in community healthcare seeking behaviour and in healthcare systems, particularly capacity building and retention and drug management systems. This requires innovative thinking and ongoing long term investment. If meticulously planned and implemented, this should result in an increase in the rational use of ACTs (and other medicines). Urgent Future Research • To quantify the benefits of the “ripple effects on other diseases” of improving the healthcare infrastructure to support the implementation of ACTs.

24. Challenge 4: Some unresolved operational research questions • What level of monotherapy resistance precludes its use in ACTs? • Do ACTs have a role in: • Intermittent Presumptive Treatment in pregnancy (IPTp)? • Intermittent Presumptive Treatment in infancy (IPTi)? • Home-based malaria treatment

25. Conclusions For the benefits of Global ACT Access Campaigns to outweigh the “risks”: • ACT should be used synergistically with other proven and effective malaria control interventions. • We must demonstrate and communicate the successes. This requires more investment in communication and human resource development and retention. Regional collaborations should support areas with limited resources. • We (donors, recipients and advisors) must be accountable for the failures and work in mutually beneficial partnerships to address these. • International recommendations and funding processes should not be static. • Long term operational research needs should not be an excuse for prolonging the use of clearly ineffective therapy. Challenges should be seen as opportunities to improve the healthcare system and not as a pretext for failing to deliver public health.

26. “The loss of life due to malaria is a crisis, but we can only beat it if we fight systematically together for long term, country owned solutions.” Vinand Nantulya, John Liden The Global Fund to fight AIDS, TB and Malaria

27. Challenge 2: Ensuring scientifically sound, evidence based policies. Standardisation of measures of antimalarial drug efficacy “Selective” and narrow definitions of antimalarial therapeutic effectiveness perpetuate confusion and prolong use of ineffective treatments. • Standardised internationally accepted definition of antimalarial drug efficacy is established. WHO. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. WHO/HTM/RBM/2003.50. • However claims are made of “sustained efficacy” when different “selective” definitions are applied e.g.Plowe CV et al. Sustained clinical efficacy of SP for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study. BMJ 2004; 328: 545-8. Sustained “Clinical efficacy” reported despite: • Parasitological cure rates at 28 days less than 40% throughout study 1998-2002 • Significant increases in anaemia documented. [Separate study differentiating recrudescences from re-infections through PCR found day 28 cure rate of only 23%].