< 의료기관담당자용 > MERS 항바이러스제치료지침 2015. 6 월 메르스민관합동대책반 1
MERS 항바이러스제치료지침 (version 1.1) 2015-6-12 대한감염학회 대한화학요법학회 2
요약 1 MERS-CoV 감염이확진된환자에게는조기에항바이러스제치료를고려한다. 2 증상이있는 MERS-CoV 감염의심환자에게도조기에항바이러스제치료를고려한다 3 MERS-CoV 감염의심환자에서폐렴의다른원인병원체가확인되거나유전자검사 (RT- PCR) 결과가 48시간간격으로음성인경우항바이러스제치료중단을고려한다. 4 폐렴이동반된환자에서는 MERS-CoV 감염이의심되어도일반적인폐렴가능성을고려하여가능한한빨리적절한경험적항생제를투여해야한다. 이후검사결과에따라항생제를조정해야한다. 5 항바이러스제치료로 ribavirin + interferon α2a + lopinavir/ritonavir 병합요법을권한다 ( 표 1). 6 항바이러스제는 10-14일투여를권하지만환자상태에따라결정해야한다. 7 MERS 환자에서고용량스테로이드사용은권하지않는다. 1. MERS 나 SARS 치료에항바이러스제의역할이명확히증명되지는않았으나, 높은사망률과이환율을고려 할때질환초기에항바이러스제치료를적극적으로고려해야한다. 2. MERS-CoV 감염이확진된환자에게는조기에항바이러스제치료를고려한다. 증상 ( 발열또는호흡기증상 또는가슴 X 선사진침윤 ) 이있는 MERS-CoV 감염의심환자에게도조기에항바이러스제치료를고려한다. - SARS 감염에서입원 48 시간이내에 ribavirin 투여하였을때치료효과가있었다. 1 3. 폐렴이동반된환자에서는 MERS-CoV 감염이의심되어도일반적인폐렴가능성을고려하여가능한한빨 리적절한경험적항생제를투여해야한다. 이후검사결과에따라항생제를조정해야한다. 4. 항바이러스제치료로 ribavirin + interferon α2a + lopinavir/ritonavir 병합요법을권한다 ( 표 1). 2-8 Lopinavir/ritonavir를사용할수없을때에는 ribavirin + interferon α2a 투여를권한다. 4,5,8 Ribavirin에의한심한부작용이발생하였거나발생할우려가있을경우 interferon α2a + lopinavir/ritonavir 병합을고려할수있다. 9 - 기존연구에서는 interferon α2a (Pegasys, 180 μg SC once/week) 가사용되었다. 없으면 interferon β1a (Rebif, 44 μg SC three-times/week) 로대체할수있다. 5 Interferon α2b (Pegintron ) 를사용한임상연구는없으나 HCV감염치료용량인 1.5 μg/kg SC once/week를고려할수있다. - SARS 환자에게 ribavirin 고용량투여시 60% 에서 hemolytic anemia (Hb >2 g/dl 감소 ) 가발생하였으므로주의해야한다. 10,11 Bradycardia (<55/min), hypomagnesemia, hypocalcemia도흔한부작용이다. 12 - 표 1에제시한 ribavirin 고용량치료법은기존보고에서 SARS나 MERS 치료에주로사용한투여량이다. 1,4,5 임상자료가많은투여량이므로 ribavirin 고용량투여를우선적으로고려해야한다. 고용량 ribavirin 투여시 hemolytic anemia 및여러부작용발생이걱정이다. 그래서실험실적연구에서 interferon α와병합하면항바이러스효과를나타내는 ribavirin의농도를현저히감소시켰다는점과 13 안전성까지고려하여 RSV 등의호흡기바이러스감염치료에사용하는투여량을준용하여 14 중간용량의 ribavirin 치료법도제시하였다. - Ribavirin, interferon α2a 등의항바이러스제를투여하는동안매일혈액검사 ( 전혈구수, 신기능, 간기능 ) 를해야한다. 의식이있는환자에서정신병또는급성혼동이나타나는경우정신과적평가가필요하다. - Ribavirin 사용중심한부작용이발생하면투여용량을줄이거나중지한다. 1
- Ribavirin은기형유발부작용 (teratogenic) 이있으므로남녀모두치료후 6개월동안피임해야한다. 15 - Ribavirin 단독치료는권하지않는다. Interferon α2a과같이투여하기어려울경우 ribavirin + lopinavir/ritonavir 병합치료를고려할수있다. Lopinavir/ ritonavir는심한부작용발생이드문안전한약제다. 5. 항바이러스제치료기간은환자의상태에따라결정해야한다. 표 1 에제시한기간은 SARS 나 MERS 의일 반적인치료기간이다. 1,4,5,15 6. 고용량스테로이드장기간사용은기회감염, 무혈성괴사, 이차적인세균성감염, 지속적인바이러스복제등의부작용을초래하고 SARS에서도효과가명확히입증되지는않았기에 MERS 환자에게일상적사용은피해야한다. 9,16-18 - 승압제가필요한중증쇽상태에서는저용량스테로이드투여를고려할수있다. 19 - 고용량스테로이드치료는중증 SARS에서발열이지속되거나방사선소견과호흡부전이악화될때흔히사용되었으나효과를판정하기어려웠다. 17,20 SARS에의한 ARDS와일부특별한상황에서는항바이러스제를같이투여하면도움이된다는의견도있다. 20,21 스테로이드를고용량사용하는경우 SARS 치료에적용한 methylprednisolone 감량용법을고려할수있다. 22 7. Intravenous immunoglobulin (IVIG) 는근거가부족하여 MERS에서일상적인사용을권하지는않는다. - IVIG 사용은드물게급성신부전이나혈전증을초래한다. - SARS 치료로다른항바이러스제와 IVIG을사용한연구가있었으나효과에대하여결론을내릴수없었다. 17 8. MERS-CoV 감염환자의회복기혈장치료는안전성과효과에대한근거가부족하기때문에치료에반응이없는중증환자에서환자의동의 ( 불가한경우는보호자의동의 ) 하에시험적으로투여할수있다. 2
표 1. MERS-CoV 감염의치료 Medication a Normal renal function (CrCl >50 ml/min) A. Ribavirin, high dose c 1200 mg po q8h for 4 600 mg po q8h for 4-6 Ribavirin, alternative intermediate dose d 2000 mg po loading dose 10 mg/kg po q8h for 10 B. Interferon α2a f 180 mcg per week for 2 weeks C. Lopinavir/ritonavir g Lopinavir/ritonavir 400 mg/100 mg po q12h for 10 D. Covalescent plasma h 300-500 ml of full plasma (3-5 ml/kg) Impaired renal function b (CrCl 20-50 ml/min) 600 mg po q8h for 4 200 mg po q8h for 4-6 200 mg po q8h for 10 Hemodialysis or CrCl <20 ml/min 200 mg po q6h for 4 200 mg po q12h for 4-6 200 mg po q12h for 10 e a Ribavirin에의한부작용발생시용량을줄이거나사용을중지한다. b 지속적신대체요법 (continuous renal replacement therapy, CRRT) 을시행할때는 plasma removal rate에따라 ribavirin 용량을조절해야하나계산이어려운경우에는 CrCl 20-50 ml/min 시투여량을사용한다. c SARS-CoV 또는 MERS-CoV 치료에사용하는일반적인용량이다 (Omrani AS et al. Lancet Infect Dis 2014; 14: 1090). d Ribavirin에의한 cytopenia, hemolytic anemia 등의부작용발생을예방할목적으로감량한용량이다. Ribavirin + interferon α 병합에 in vitro synergistic effect가있음을근거로안전성까지고려하여 RSV 치료에사용하는용량을준용하였다. e 투석환자나심한신기능저하자에서는 fatal hemolytic anemia 발생을우려하여 ribavirin 사용을권하지않는다. Ribavirin 치료시 hemolytic anemia 등의심한부작용발생을주의깊게관찰해야한다. f Pegylated interferon α2a (Pegasys ; Roche Pharmaceuticals) 이며피하투여 (subcutaneous injection) 한다. 대체약제로 interferon β1a (Rebif, 44 μg SC three-times/week) 또는 interferon α2b (Pegintron, 1.5 μg/kg SC once/week) 가있다. g Lopinavir/ritonavir (Kaletra ) 는주로간에의해서대사되므로심한간기능저하시에는주의해야한다. h 추후고려해볼수있다. 3
표 2. Pegylated interferon 과 ribavirin 의부작용 15 Side effects Pegylated interferon Ribavirin Common >5% Serious (<1% to <5%) Neutropenia Depression / Anxiety / Irritability Fatigue / Headache Chills and rigors / Fever Weight loss / Dizziness Myalgia / Arthralgia Nausea / Anorexia / Diarrhea Dyspnea / Cough Alopecia / Rash / Pruritus Suicidal attempt Suicidal ideation Severe depression / Psychosis Aggressive behavior Relapse of drug addiction Nerve palsy (facial, oculomotor) Cardiomyopathy / Myocardial infarction / Angina pectoris Pericardial effusion Retinal ischemia Retinal artery or vein thrombosis Blindness / Decreased visual acuity Optic neuritis Transient ischemic attack Supraventricular arrhythmia Anemia Pruritus Rash Fatigue and weakness Nausea Nasal stuffiness Symptomatic anemia Myocardial infarction Angina pectoris Cerebrovascular accident Acute gout Gallstones Fetal loss Fetal abnormalities * 참고문헌 1. Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA. Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)-possible lessons from a systematic review of SARS-CoV therapy. Int J Infect Dis 2013;17:e792-8. 2. Chan KS, Lai ST, Chu CM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J 2003;9:399-406. 3. Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004;59:252-6. 4. Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis 2014;14:1090-5. 5. Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-alpha2a or IFN-beta1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother 2015. 6. de Wilde AH, Jochmans D, Posthuma CC, et al. Screening of an FDA-approved compound library identifies four smallmolecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 2014;58:4875-84. 7. Spanakis N, Tsiodras S, Haagmans BL, et al. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. Int J Antimicrob Agents 2014;44:528-32. 8. Khalid M, Al Rabiah F, Khan B, Al Mobeireek A, Butt TS, Al Mutairy E. Ribavirin and interferon-alpha2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus: a preliminary report of two cases. Antivir 4
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