UJI EFIKASI TERAPI KOMBINASI ARTESUNATE + AMODIAQUINE PADA MALARIA FALCIPARUM TANPA KOMPLIKASI DI KABUPATEN BANJARNEGARA PROPINSI JAWA TENGAH

Abstract

Background: Despite malaria eradication program in Banjarnegara district, incidence of malaria is still increasing including outbreaks during 2002-2003. One of the causes is drug resistance problem i.e. chloroquine resistant falciparum malaria that was firstly reported in the district in 1989. Treatment failure to sulphadoxin-pyrimethamine (SP), as a second line drug for uncomplicated falciparum malaria, was reported in the district in 2001. In Banjamegara, treatment failure rates of CQ and SP are >75% and <25%, respectively. Artemisinin-based combination therapy (ACT). such as artemether or artesunate combined with mefloquine has been the standard treatment in areas of multidrug resistance in Southeast Asia. The combination of artesunate plus amodiaquine (AS+AQ) improved treatment efficacy for uncomplicated falciparum malaria compared to amodiaquine alone in some African countries. The national antimalarial drug policy has to be changed due to the fact that choloquine resistant falciparurn malaria is widespread and SP resistant falciparum malaria is increasing in some areas of Indonesia. Objectives: To know the efficacy and tolerability of ACT (AS+AQ) in patients with uncomplicated falciparum malaria in Banjamegam district. Subjects and methods: The study was conducted during period of October 2003 to March 2004, in outpatient clinics of the community health centers (CHCPTuskesmas"): Madukara, Petuguran, Wanadadi, Banjamegara lI, Kendaga and Banjamiangu I, in Banjamegara district, Central Java Province, Indonesia. The methods (including subjects criteria) used in this study were based on the WHO protocol for assessment of therapeutic efficacy of antimalarial drugs for uncomplicated falciparum malaria (2001 & 2003). Artesunate 4 mg/kgBW single dose on DO (day-0), Dl and D2, combined with Amodiaquine with a dose of 25 mg/kgBB were given for three days orally i.e. 10mg/kgBW on DO, DI and 5mg/kgBW on D2. All patients will receive a single dose of Primaquine 0,75mg/kgBW at D28. If the body's axillary temperature 38°C, paracetamol 10 mg/kgBW every 8 hours if needed. To get a better compliance of treatment, subjects were directly observed and supervised by community health workers in taking medicine. Doctors and nurses working in the CHC's were trained by the researchers before the study is started. Clinical observations on the possibility of side-effects of the study drugs and the appearance of a danger signs of severe and complicated malaria were conducted during the interventions (outpatient follow-up is 28 days). Therapeutic responses were assessed by parasitologically and clinically to D28. Classification of therapeutic response is based on the WHO protocol (2001) such as ETF (early treatment failure), LPF (late parasitological failure), LCPF (late clinical and parasitological failure) and ACPR (adequate clinical and parasitological responses) as primary outcomes. FCT (fever clear•nce time), PCT (parasites clearance time) and gametocyte carrier rates were calculated as secondary outcomes. To distinguish between re-infection and recrudescence as treatment failures, genotype markers were tested by PCR methods. Results: Fourty-three patients (male: 53.5%) with uncomplicated falciparum malaria were included in the study, one patient lost to follow up after D7. ACPR at D14 was 95.2% and ACPR at D28 was 80.9% (PCR. corrected). No early treatment failure was found. LCF was 7.1% while LW was 11.9%. Gametocyte carrier rates at D7 and D14 was 7% and 5%, respectively. The median of FCT and PCT was 1 (range 0-2) and 1 (1-7) days, respectively. No serious side effects were reported by 13 (30%) of patients on Dl; nausea and dizziness as major symptoms and all patients were symptoms-free at D7. The administration of primaquine on D28 should be re-evaluated and may be changed to earlier days of treatment such as on DO. Conclusions: The combination of artesunate+amodiaquine for 3 days showed a good clinical response for uncomplicated falciparum malaria therapy in Banjamegara district This ACT was well tolerated and had no serious side effects Latar belakang : Meskipun terdapat program pemberantasan malaria di Kabupaten Banjamegara, insiden malaria masih tetap tinggi termasuk tedadinya kejadian luar biasa pada tahun 2002-2003. Salah satu penyebabnya adalah masalah resistensi obat. Malaria falcipanun resisten chloroquine (CQ) pertama kali dilaporkan pada tahun 1989. Kegagalan terapi terhadap sulphadoxin-pyrimethamine (SP), sebagai obat lini kedua terhadap malaria falciparum dilaporkan terjadi pada tahtm 2001. Di Kabupaten Banjamegara, angka kegagalan terapi terhadap CQ dan SP masing-masing >75% dan < 25%. Artemisinin-based combination therapy (ACT) seperti artemether atau artesunate yang dikombinasi dengan mefloquine telah menjadi terapi standar di daerah multidrug resistance di Asia tenggara. Kombinasi artesunate dengan amodiaquine (AS+AQ) meningkatkan efikasi terapi malaria falciparum tanpa komplikasi dibandingkan hanya dengan terapi AQ saja di beberapa negara Afrika. Kebijakan nasional pengobatan malaria akan diubah berdasarkan fakta bertambah luasnya daerah malaria falcipamm resisten CQ dan meningkatnya daerah malaria falciparum resisten SP di Indonesia. Objektif : Untuk mengetahui efikasi terapi dan tolerabilitas kombinasi AS+AQ pada pasien dengan malaria falciparum tanpa komplikasi di Kabupaten Banjamegara. Subjek dan Metode : Penelitian dilakukan dalam periode Oktober 2003 — Maret 2004 pada pasien rawat jalan di enam puskesmas : Madukara, Petuguran, Wanadadi, Banjamegara II, Kendaga dan Banjarmangu I, Kabupaten Banjamegara, Propinsi Jawa Tengah, Indonesia Metode yang digunakan (terniasuk kriteria inklusi) berdasar protokol WHO untuk efikasi terapi obat anti malaria pada malaria faciparum tanpa komplikasi (tahun 2001 dan 2003). Artesunate 4mg/kgBB dosis tunggal per oral diberikan pada HO, Hi dan H2, dikombinasikan dengan Amodiaquine 25mg/kgBB per oral untuk 3 had : 10mg/kgBB pada HO dan HI serta 5mg/kgBB pada 112. Seluruh pasien mendapatkan primaquine 0,75mg/kgBB per oral pada 1128. Bila suhu aksiler > 38°C, diberikan parasetamol 10mg/kgBB setiap 8 jam. Agar didapatkan compliance pengobatan yang baik maka pada saat pasien minum obat dilakukan pengawasan langsung oleh petugas puskesmas. Dokter dan perawat puskesmas dilatih terlebih dulu sebelum penelitian dilakukan. Observasi lclinis terhadap kemungkinan adanya efek samping obat dan adanya tanda bahaya malaria berat diamati selama periode intervensi. Respon terapi diamati berdasarkan dapatan klinis dan parasitologis selama 28 hari. Klasifikasi respon terapi berdasar protokol WHO (2001). Penilaian hasil primer meliputi Kegagalan pengobatan dini (KPD), Kegagalan klinis dan parasitologis kasep (KKK), Kegagalan parasitologis kasep (KPaK) dan Respon klinis dan parasitologis memadai (RKPaM). Penilaian hasil sekunder meliputi FCT (fever clearance time), PCT (parasites clearance time) dan GCR (gametocyte carder rates). Untuk membedakan reinfeksi dengan rekrudensi akibat kegagalan terapi diperiksa genotype marker dengan menggunakan metode Pat Hasil : Empat puluh tiga pasien (laki-laki 53,5%) dengan malaria falciparum tanpa komplikasi diikutsertakan'dalam penelitian ini, seorang pasien loss to follow up pada 117. RKPaM pada H14 : 95,2% dan pada 1128 : 80,9% (PCR corrected). Tidak didapatkan KPD. KKK 7,1% sedangkan KPaK 11,9%. GCR pada 117 dan 1114 masing-masing 7% dan 5%. Median FCT dan PCT masing-masing 1 (range 0-2) had dan 1 (range 1-7) had. Tidak ada keluhan efek samping serius yang dilaporkan oleh 13 (30%) pasien pada HI. Mual dan dizziness merupakan keluhan efek samping terbanyak, dan seluruh pasien sudah tidak ada keluhan setelah 117. Pemberian primaquine pada 1128 perlu dievaluasi dan dapat diberikan lebih awal, yaitu pada 110. Kesimpulan : Kombinasi artesunate+amodiaquine selama 3 had menunjukkan respon klinis yang baik terhadap pengobatan malaria falciparum tanpa komplikasi di Kabupaten Banjarnegara. ACT ini dapat ditoleransi dengan baik dan tidak didapatkan efek samping yang serius.