Disertasi

TERAPI PROFILAKSIS SEKUNDER DOSIS RENDAH DIBANDINGKAN TERAPI ON-DEMAND UNTUK MENCEGAH PROGRESIVITAS ARTROPATI PADA ANAK PENYANDANG HEMOFILIA A BERAT: Kajian pada Luaran Klinis, Skor Muskuloskeletal, Ultrasonografi Sendi, Kadar C-Terminal Telopeptide of Collagen Type II Urin dan Terbentuknya Inhibitor Faktor VIII. = SECONDARY LOW-DOSE PROPHYLAXIS VERSUS ON-DEMAND TREATMENT TO PREVENT PROGRESSIVITY OF ARTHROPATHY IN CHILDREN WITH SEVERE HEMOPHILIA A: Clinical Outcome, Musculoskeletal Scores, Joint Ultrasonography, Urinary C-Terminal Telopeptide of Collagen Type II and Inhibitor Factor VIII.

Hemartrosis berulang dan artropati merupakan morbiditas utama pada hemofilia A berat. Bagi negara berkembang seperti Indonesia, terapi profilaksis dosis standar tidak terjangkau karena memerlukan biaya yang sangat mahal. Penelitian ini bertujuan mengetahui efektivitas terapi profilaksis sekunder dosis rendah dibandingkan terapi on-demand pada anak hemofilia A berat. Uji klinis acak terbuka selama 24 minggu telah dilakukan pada anak hemofilia A berat berusia 4–18 tahun dengan riwayat perdarahan sendi berulang, di Poliklinik Hematologi Departemen Ilmu Kesehatan Anak FKUI/RSCM. Subjek dialokasikan secara acak menjadi dua kelompok yaitu kelompok profilaksis dan on-demand. Kelompok profilaksis mendapat terapi faktor VIII 10 IU/kgBB 2 kali seminggu, sedangkan kelompok on-demand mendapat terapi sesuai protokol standar. Luaran primer adalah kekerapan perdarahan sendi dan luaran sekunder adalah skor HJHS) dan skor ultrasonografi (HEAD-US). Penelitian ini juga membandingkan kadar CTX-II urin dan inhibitor faktor VIII (Bethesda Assay) pada kedua kelompok. Sejak bulan Juni 2015–Februari 2016 didapatkan 50 subjek yang memenuhi kriteria inklusi. Kekerapan perdarahan sendi pada kelompok profilaksis (5 ± 4,3) lebih baik dari pada kelompok on-demand (8 (3–30)), IK95% 0.9–6.99; p = 0,009. Perubahan skor HJHS pada kedua kelompok menunjukkan perbaikan klinis pada kelompok profilaksis dan perburukan pada kelompok on-demand, walaupun tidak bermakna secara statistik (IK95% -0.99–3; p = 0,320). Skor HEAD-US kelompok profilaksis lebih baik dibandingkan kelompok on-demand (IK95% 2– 8,81; p = 0,003). Perubahan kadar CTX-II urin pada kedua kelompok berbeda bermakna (IK95% 2.777–16.742; p < 0,001). Tidak didapatkan subjek yang terbentuk inhibitor faktor VIII pada kedua kelompok selama penelitian. Dari hasil penelitian ini disimpulkan bahwa terapi profilaksis sekunder dosis rendah efektif mengurangi kekerapan perdarahan sendi, memperbaiki skor HEAD-US dan kadar CTX-II urin, dibandingkan terapi on-demand.
Kata kunci. CTX-II, HEAD-US, hemofilia A berat, HJHS, inhibitor faktor VIII, profilaksis dosis rendah.



Repeated joint bleeds leading to irreversible progressive joint damage (hemophilic arthropathy) is the main problem in children with hemophilia. Current standard prophylacytic treatment in developed countries is beyond our capability as Indonesia has constraint resources. This study aimed to investigate the efficacy and safety of low dose secondary prophylaxis compare to on-demand treatment in children with severe hemophilia A. An open, randomized controlled trial was conducted on severe hemophilia A children aged 4–18 years in Pediatric Hematology-Oncology Division Dr. Cipto Mangunkusumo Hospital for 24 weeks. Eligible subjects were randomized into 2 groups: prophylaxis and on-demand group. All subjects were evaluated at week-0 and week-24 for inhibitor factor VIII (Bethesda Assay), ultrasonography (HEADUS scores) of six index joints (bilateral knees, ankles and elbows), HJHS (version 2.1, 2011) and urinary CTX-II (EIA). Subjects in prophylaxis group received factor VIII 10 IU/kgBW 2 times per week for 24 weeks. Any bleeding episodes in both groups were treated according to standard treatment (on-demand). During June 2015–February 2016 there were 50 subjects enrolled in the study. Mean age in prophylaxis group was 12 ± 3.5 years and median age in on-demand group was 11.9 (6.518.2) years. Mean frequency of joint bleeds in prophylaxis group was 5 ± 4.3 compare to 8 (3–30) in on-demand group (95%CI 0.9–6.99; p = 0.009). Mean difference of HJHS between two groups was not significant (95% CI -0.99–3; p = 0.320). HEAD-US scores and urinary CTX-II in prophylaxis group was significantly better compare to on-demand group (95%CI 2–8.81; p = 0.003 and 95%CI 2,777–16,742; p < 0.001 respectively). No subjects showed showed inhibitor factor VIII in both groups. We conclude that secondary low dose prophylaxis was effective to decrease joint bleeding episodes and improved HJHS scores, HEAD-US scores and urinary CTX-II, compared to on-demand treatment.
Key words : CTX-II, HEAD-US, HJHS, inhibitor factor VIII, low dose prophylaxis, severe hemophilia A.