Tesis

Efek Bedaquiline terhadap Interval QT pada Pasien Tuberkulosis Resistan Obat: Real World Data = Bedaquiline Effect on QT Interval of Drug Resistant Tuberculosis Patients: Real World Data.

Pendahuluan: Besarnya risiko pemanjangan interval QT oleh bedaquiline (BDQ) belum sepenuhnya dipahami. Seiring luasnya penggunaan BDQ, data keamanannya terhadap jantung dari seluruh dunia perlu dikumpulkan, termasuk dari Indonesia. Metode: Studi kohort retrospektif ini bertujuan menganalisis pengaruh BDQ terhadap interval QT pasien tuberkulosis resistan obat (TB-RO). Total 105 subjek berpartisipasi dari RSUD Dr. Saiful Anwar Malang (RSSA) dan RS Paru Dr. M. Goenawan Partowidigdo Cisarua (RSPG). Interval QT sebelum dan selama pengobatan diukur manual dan dikoreksi menggunakan formula Fridericia (QTcF). Profil interval QT dianalisis dari waktu ke waktu selama pengobatan BDQ, kemudian dibandingkan dengan profil interval QT shorter treatment regimen/STR (historical control) mengandung obat injeksi. Pemanjangan QTcF disebut bermakna klinis jika QTcF > 500 ms dan/atau pemanjangan QTcF terhadap baseline (∆QTcF) > 60 ms. Faktor-faktor risiko pemanjangan interval QT lainnya dianalisis, serta efek samping selama pengobatan BDQ dikumpulkan. Hasil: Nilai maksimal QTcF dan ∆QTcF terjadi setelah 3 bulan pengobatan BDQ. Pemanjangan QTcF bermakna klinis terjadi pada 37,1% subjek, namun tidak terdapat aritmia selama pengobatan. Pemanjangan interval QT menyebabkan pengobatan BDQ dihentikan sementara pada 15,2% subjek dan dihentikan permanen pada 6,7% subjek. Profil interval QT kelompok BDQ tidak berbeda bermakna dibandingkan STR. Terdapat 7 subjek yang meninggal (6,7%) pada kelompok BDQ dan 1 subjek meninggal (1,4%) pada kelompok STR. Subjek laki-laki berisiko 2,2 kali lebih tinggi dibandingkan perempuan untuk mengalami pemanjangan interval QTcF bermakna klinis (p < 0,008). Efek samping selama pengobatan yang banyak dilaporkan adalah mual, palpitasi, artralgia, serta hipokalemia, kelainan fungsi ginjal, dan hiperurisemia. Kesimpulan: Pemanjangan interval QT maksimal terjadi setelah bulan ke-3 pengobatan BDQ. Proporsi kematian lebih tinggi pada kelompok BDQ dibandingkan kelompok kontrol. Penyebab kematian tidak dapat dinilai karena keterbatasan data pemanjangan interval QT. Hanya 2 dari 7 kematian memiliki riwayat pemanjangan QT bermakna klinis selama pengobatan, dan semuanya tidak memiliki riwayat aritmia.
Kata Kunci: bedaquiline, tuberkulosis resistan obat, pemanjangan interval QT


Backgrounds: The magnitude of QT interval prolongation risk by bedaquiline (BDQ) is not fully elucidated. Along with widespread use of BDQ, cardiac safety data from all over the world needs to be collected, including from Indonesia. Methods: This retrospective cohort study aimed to analyze the effect of BDQ on the QT interval of drug resistant tuberculosis (DR-TB) patients. A total of 105 subjects were enrolled from Dr. Saiful Anwar Malang hospital and Dr. M. Goenawan Partowidigdo Cisarua hospital. The QT interval before and after therapy was measured manually and corrected using Fridericia formula (QTcF). The QT interval profile was analyzed over time during BDQ treatment, then compared with QT interval profile of shorter treatment regimens/STR containing injection (historical controls). Clinically significant QTcF prolongation was defined as QTcF > 500 ms, QTcF prolongation from baseline (∆QTcF) > 60 ms, or both. Other QT prolongation risk factors were analyzed, and side effect during BDQ treatment were documented. Results: The maximum QTcF and ∆QTcF were developed after three months of therapy. Clinically significant QTcF prolongation were observed in 37.1% subjects, and during BDQ no arrhythmias was occurs. Interval QT prolongation led to discontinuation of BDQ therapy in 15.2% subjects temporarily and in 6,7% subjects permanently. There were no significant differences in QT interval profile between BDQ and STR groups. During treatment, there were 7 deaths (6.7%) in BDQ groups compared with 1 death (1.4%) in STR group. Male subject had 2.2 times higher risk compared to female in experiencing clinically significant QTcF interval prolongation (p < 0.008). During treatment, common adverse reaction reported were nausea, palpitations and arthralgia, as well as hypokalemia, renal function abnormalities, and hyperuricemia. Conclusion: Maximum QT prolongation was observed after three months of BDQ therapy. Proportion of death was observed higher in BDQ group compared to control group. The cause of deaths could not be assessed due to limited data on QT interval prolongation. Only 2 of the 7 deaths had a history of clinically significant QT prolongation during treatment, and all deaths had no history of arrhythmias.
Keyword: bedaquiline, drug resistant tuberculosis, QT interval prolongation