Drug Management for Malaria within LSDI region Barnes K1, Kishuna A, Camba T, Streat EA, Lee C, Wilkins J, Durrheim DN 1 University of Cape Town Division of Pharmacology

Abstract Problem Statement: Early effective case management is a cornerstone of malaria control in the tropics. This depends on effective management, reliable supply, and rational use of antimalarials. Stock-outs of vital antimalarials result in disease progression to severe malaria and increased malaria transmission. Irrational antimalarial use results in treatment failure and increased drug resistance while fueling malaria transmission. Objectives: To identify and address weaknesses in antimalarial drug management, supply, and use in four LSDI areas in South Africa and southern Mozambique, where the public sector is in the process of phasing in the implementation of artemisinin-based combination therapy. Design: Before/after study with no control group. Setting: Health care facilities in Mpumalanga and KwaZulu-Natal provinces, South Africa (low-intensity malaria transmission), and in Namaacha and Matatuine districts, Mozambique (moderate-intensity malaria transmission, following effective vector management). Study Population: A sample of central-, provincial-, and district-level health care facilities (Mpumalanga, 31; KwaZulu-Natal, 21; Namaacha, 7; Matatuine, 12). Outcome Measures and Intervention: The Drug Management for Malaria (DMM) Manual was used as an indicator-based approach to assess antimalarial management systems. Interventions were then developed to address those problems that could be resolved by study participants in partnership with ministries of health. The success of these interventions was then assessed by repeating appropriate components of the DMM Manual. Results: Problems identified in South Africa included the high purchase price paid for antimalarials when compared with international median prices, and the fact that 40% of facilities in Mpumalanga did not have inventory control systems. In KwaZulu-Natal, there were 164 health care facility days without artemether-lumefantrine, resulting in 36.2% of patients being treated with ineffective therapy, although this proportion decreased to 8% within three months of AL implementation. In Mozambique, there were 258 health care facility days without vital antimalarials in Namaacha, but few stockouts in Matatuine.[2] Inadequate patient information had been provided at all sites, although the majority of patients and caregivers in Mozambique could accurately describe how to take chloroquine. The effect of interventions to reduce antimalarial prices in South Africa, to prevent stock-outs, and to improve patient education and adherence will be presented. Conclusions: The DMM Manual is generally a useful tool for assessing antimalarial management, supply, and use, although a few modifications were required for the study sites. It has been possible to develop successful interventions to address some of the limitations identified.

Benefits of ACT depend on widespread coverage and rational use Improve clinical cure rates Delay emergence of resistance Reduce transmission 1st line Rx with Artemisinin-based Combination Therapy (ACT) ? Treatment Coverage Rational Use

Objectives and study design To optimise the implementation of artemisinin-based combination therapy, by identifying and addressing weaknesses in drug management, availability and use. Study Sites: Mozambique: Namaacha and Matatuine districts South Africa: KwaZulu Natal and Mpumalanga Provinces Study design: Cross-sectional; Before-after; No control group. Based on Drug Management for Malaria Manual1 Pharmaceutical Management Review at National and Provincial levels Health Care Facility Review Public sector facilities (MPU = 16; KZN = 15; NAM = 7; MAT = 12) Private sector facilities (MPU = 15; KZN = 6) Structured Interviews, document review, physical inventory checks, case record reviews, simulated purchases, direct observation, exit interviews 1Clark M. Drug Management for Malaria Manual (Draft Version 2000). Published for USAID by the Rational Pharmaceutical Management Project. Arlington, VA. Management Sciences for Health

Procurement…… SA vs. International median price Mpumalanga KwaZulu Natal Chloroquine 3 times higher 2.5 times higher Sulfadoxine-pyrimethamine 7 times higher 13.5 times higher Quinine 6 times higher 7.5 times higher Primaquine 82 times higher 96 times higher Co-artemether Not available 1.5 times higher

Drug Availability Mpumalanga KwaZulu Natal Matatuine Namaacha Average availability of unexpired antimalarials Public: 96% (33-100%) Private: 37% (0-71%) Public: 99% (83-100%) Private: 38% (29-57%) Public: 93% (50-100%) Public: 57% Level of Stockouts Depots (2) Regional hospital (1) Health post (1) Health posts (6) Average Time out of stock 1st line 0.6% (37 days) 3.3% (164 days) 0.18% (4 days) 11.8 (258 days)

Drug Use Mpumalanga KwaZulu Natal Matatuine / Namacha Compliance with STGs 81.4% (495/608) 60.8% (162/267) 96% 357/415 % Treated with ineffective therapy 2.5% (15/608) 36.2% (96/267) NA HCPs provided some patient information 93.5% (87/93) 62% (31/50) 18% (16/89) Patients advised when to return 57% (53/93) 14% (7/50) 0% Patients advised on potential adverse events 29% (27/93) 8% (4/50) Patients correctly describe how to take treatment 69.5% (57/82) 63.9% (39/61) 78.7% (70/89)

Interim Assessment of Interventions Price Negotiations: Artemether-lumefantrine ZAR 44.46/adult course = USD 6.39 i.e. 2.5X International Median price Artesunate-SP: NA Drug management KZN MCP informed HCF that they covered initial Artemether-lumefantrine costs so that SP stocks could be replaced by AL at no cost to HCF. By May 2001 93.4% of patients treated with artemether-lumefantrine. Mpumalanga: Malaria Control Programme facilitating AS/SP management and distribution while improved provincial systems being developed. Southern Mozambique: Strengthened drug management system, focusing on antimalarials, introduced in March 2004. Training and education material Specific treatment guidelines, training material, wallcharts, patient education material developed for public and private sector healthcare providers at each site, based on weaknesses identified in DMM . High compliance reported in patients followed up: Mpumalanga: 99% (636/638) KwaZulu Natal 94% (66/70)

Public Health Impact 1: >85% decrease in malaria notifications in KwaZulu Natal A: DDT reintroduced (traditional homesteads) B: IRS southern Mozambique C: Artemether-lumefantrine implemented

Public health impact 2: 47% decrease in Malaria Notifications in Mpumalanga IRS southern Mozambique AS/SP implemented

Limitations of this study Follow-up assessments to quantify the effectiveness of interventions not completed. Stock records not always adequate for quantifying stockouts. Ethical concerns precluded conducting “simulation patient” component of DMM in private sector. Sample size limited for exit interviews and patient encounter observations. Treatment seeking and compliance not assessed through DMM (but were assessed separately through household surveys and focus group discussions).

Future Research Agenda Quantitative evaluation of the effectiveness and sustainability of each intervention to improve drug management, availability and use, in both public and private sectors. Qualitative evaluation of drug use patterns by healthcare providers and patients. Process and impact of integrating vertical drug supply management of antimalarials into routine pharmaceutical services.

Acknowledgements The authors gratefully acknowledge the data collectors and the key informants, staff and patients participating at each of the study sites. Financial support for piloting the DMM Manual was kindly provided by Management Sciences for Health, and the UNDP / World Bank / WHO Special Programme for Research and Training in tropical Diseases (TDR) provides core funding for the SEACAT evaluation within which this study was nested.