ADDIS ABABA UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MICROBIOLOGY, IMMUNOLOGY AND PARASITOLOGY EVALUATION OF THE EFFICACY OF ARTEMETHER LUMEFANTRINE (AL) IN PATIENTS WITH UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA IN GENDE WUHA HEALTH CENTER , NORTH WEST ETHIOPIA Principal Investigator: Feven Wudneh (Msc.) Advisors: Ato Tadesse Kebede (Assi Prof) Ato Ashenafi Assefa (Msc.) A thesis Submitted to the School of Graduate Studies of Addis Ababa University School of Medicine, Department of Microbiology, Immunology and Parasitology in partial fulfillment of the requirements for Master’s Degree in Medical Parasitology JUNE, 2015 ADDIS ABABA, ETHIOPIA DECLARATION This thesis is my original work and has never been presented in this or any other University and that all the source materials used for the thesis have been duly acknowledged. _______________________ ____________________ PI Signature _______________________ ____________________ Date of Submission Place Approval of the thesis This thesis has been submitted for examination with my appraisal as a university advisor: ______________________________ __________________ Advisor Signature ______________________________ __________________ Examiner Signature ______________________________ __________________ Examiner Signature i ACKNOWLEDGEMENT I would like to express my deepest gratitude to my advisor, Tadesse Kebede (Asst.prof.) from DMIP and Ashenafi Assefa from EPHI for their guidance, constructive suggestions and comments. I am grateful to all the patients who agreed to participate in the study and all Gende Wuha Health Center staffs who supplied me valuable information about the study area and my co-workers, Ato Dereje Tadesse(a laboratory technician), Sr. Abeba Mulu (a Nurse) and Ato Desta Chane (a Home visitor). I would also like to acknowledge AFRO, World Health Organization for the fund and Ato Moges Kassa for giving me the chance to participate in this study. Finally, I would like to thank my husband, Yabibal Gebeyehu, my daughter, Saron Yabibal, my father, Wudneh Mengesha and all other members of my family for their consistent moral support in doing this thesis. ii ACRONYMS ACT: Artemisinin- based Combination therapy ACPR: Adequate clinical and parasitological Response CDC: Center for Disease Control CQ: Chloroquine EPHI: Ethiopian public health institution ETF: Early threatment failure FMOH: Federal ministry of health GDP: Gross Domestic Product ICH: International conference on harmonization IRS: Indoor residual spraying LCF: Late clinical failure LLINS: Long-lasting insecticidal netss OPD: Outpatient department PMI: Project management institute RDT: Rapid Diagnostic Test SP: Sulphadoxine -pyrimethamine SNNP: Southern nation nationalities and peoples SUFI: Scale up for impact TTF: Total treatment failure URTI: Upper Respiratory Tract Infection UNICEF: United nation international children emergency fund WHO: World health organization iii TABLE OF CONTENTS Contents Page No DECLARATION…………………………………………………………………………………i ACKNOWLEDGMENT……………………………………………….......................................ii ACRONYMS……………………………………………………………………………………iii TABLE OF CONTENTS………………………………………………………………………..iv LIST OF FIGURES……………………………………………………………………………...vii LIST OF TABLES……………………………………...……………………………………....viii ABSTRACT................................................................................................................ix 1. INTRODUCTION 1.1. Back ground and Statement of the problem……………………………………………..1 1.2. Global Malaria Burden………………………………………………………………......3 1.3. Malaria in Ethiopia……………………………………………………………………....4 1.4. Malaria Prevalence in Gende Wuha City………………………………………………..5 1.5. Anti - Malaria Interventions………………………………………………………..........6 1.5.1. Vector Control…………………………………………………………………….6 1.5.2. Artemether-Lumefantrine (Coartem®) as treatment……………………………...6 1.6. Anti - malarial drug resistance…………………………………………………………...8 1.7. Statement of the problem………………………………………………………………..10 2. OBJECTIVES………………………………………………………………………………...11 2.1. General Objective……………………………………………………………………….11 2.2. Specific Objective…………………………………………………………………….....11 3. MATERIALS AND METHODS……………………………………………………………..12 3.1. Study Area………………………………………………………………………………12 3.2. Study Periods……………………………………………………………………………13 3.3. Study Design…………………………………………………………………………….13 3.4. Study Population………………………………………………………………………...13 3.5. Inclusion and Exclusion criteria…………………………………………………………14 3.5.1. Inclusion criteria……………………………………………………………....14 3.5.2. Exclusion Criteria……………………………………………………...……...14 iv 3.6. Sample size ………………………………………………………………………….….14 3.7. Treatment and dosing procedure………………………………………………………...15 3.8. Follow-up procedure and evaluation………………………………………………........15 3.9. Hemoglobin measurement…………………………………………………………........15 3.10. Assessment of adverse events…………………………………………………….........16 3.11. With drawl after enrollment……………………………………………………............16 3.12. Lost to follow up………………………………………………………………………17 3.13. Other medication…………………………………………………………………….....17 3.14. Study end points………………………………………………………………………..17 3.15. Classification of treatment outcome………...…………………………………….18 3.16. Laboratory procedures………………………………………………………………....18 3.17. Screening and Follow up of the study Participants…………………………………….20 3.18.Statistical analyses……………………………………………………………………..22 3.19. Ethical Considerations…………………………………………………………………22 4. RESULT……………………………………………………………………………………....23 4.1. Cure Rate of Coartum…………………………………………………………………...23 4.2. Parasite Clearance……………………………………………………………………….24 4.3. Fever Clearance………………………………………………………………………....25 4.4. Gametocyte Clearance…………………………………………………………………..25 4.5. Hemoglobin Recovery…………………………………………………………………..25 4.6. Adverse Events following Coartum Treatment………………………………………....26 4.7. Discussion…………………………………………………………………………….....27 4.8. Conclusion……………………………………………………………………………....29 RECOMMENDATION………………………………………………………………………..30 REFERENCES…….………….…………………………………………………………..…...31 ANNEXES………………..……………………………………………………………………36 Annex I. Weight based administration of Coartem………………………………………..36 Annex II. Assessment of drug administration at home……………………………….......36 Annex III. List of Medications with antimalarial activity that should not be used during the study period……….……………………………………………….36 Annex IV. Patient screening form…………………………………………………..…….37 v Annex V. Patient Follow-up Card………………………………………………………..…..37 Annex VI. Patient Record Sheet….……………………………..………………...………..…38 Annex VII. Adult Consent Form ………….………………………………………..………...39 Annex VIII. Children Consent ……. ……………….…..………….………………………..43 Annex IX. Case Record Form…………………………………….....…...............................47 vi LIST OF FIGURES Figure 1. Prevalence of malaria infection in Gende Wuha Health Center from Sep 2006 to Aug 2006……………………………………………………………………………………………....5 Figure 2. Location Map of metema district…………………………………………………….12 Figure 3. The follow-up of patients through the trial at Gende Wuha Health Center…...……...21 Figure 4. Parasite clearance following Coartem® -treatment of plasmodium falciparum malaria infected Patients in Gende Wuha Health Center………………………………………………...23 Figure 5.Fever clearance in Coartem® -treated plasmodium falciparum malaria patients during the follow up Period in Gende Wuha Health Center………...…………………………………..24 vii LIST OF TABLES Table 1. Characteristics of the study participants included on the 28 day follow-up in vivo Coartem® efficacy study at the time of enrollment in Gende Wuha Health Center , 2014/2015…..…….……………………………………………………....22 Table 2. Cure rate of Coartem® treated plasmodium falciparum malaria infected study participants in Gende Wuha Health Center, 2014/2015……..…...……………..…23 Table 3. Resolution of anemia observed in plasmodium falciparum malaria infected study participants following Coartem® treatment in Gende Wuha Health Center, 2014/2015………………………………………………………………………….25 Table 4. Characteristic clinical signs and symptoms reported by patients before and after taking Coartem® treatment in Gende Wuha Health Center, 2014/2015……….....25 viii Abstract Background: Most malaria control strategies depend on safe and effective drugs, although, drug resistance is the most serious problem in achieving control of malaria. Artemether/Lumefantrine (coartum®) has been used as a first-line treatment for uncomplicated Plasmodium falciparum infection since 2004 in Ethiopia. The spread of Plasmodium falciparum resistance to almost all available affordable mono-therapy, in many malaria endemic regions, is a serious impediment on malaria control. As a result there is a need to a periodic evaluation of efficacy of antimalarial drugs. Objective: The aim of this study was to evaluate the efficacy and safety of Coartem® for the treatment of uncomplicated Plasmodium falciparum infections in patients attending Gende Wuha Health Center Gondar Zone, North-West Ethiopia. Method: One arm prospective in vivo evaluation of the efficacy of artemether/lumefantrine (AL) was conducted in patients with uncomplicated Plasmodium falciparum infection. Standard six dose regimen of AL was given twice daily for 3 days under supervision and clinical and parasitological responses during a 28 day follow-up period were assess ed using a standardized drug efficacy record form, on days 0, 1 ,2, 3, 7, 14, 21, 28 and adverse drug events as well as Hgb changes were also investigated. Result: A total of 81 P. falciparom mono infected patients were included in the study, majority 82.4% were males. Overall, the 28-day clinical and parasitological cure rate was