대한내과학회지 : 제 90 권제 6 호 2016 http://dx.doi.org/10.3904/kjm.2016.90.6.481 특집 (Special Review) - HIV 감염의최신지견 HIV 감염치료의최신지견 서울대학교의과대학내과학교실, 보라매병원감염내과 방지환 Recent Advances of Antiretroviral Agents Ji Hwan Bang Division of Infectious Diseases, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University, College of Medicine, Seoul, Korea The treatment of human immunodeficiency virus is under constant development. This report reviews recent advances in antiretroviral agents. (Korean J Med 2016;90:481-486) Keywords: HIV; Antiretroviral drugs 서론 Human immunodeficiency virus (HIV) 치료제연구에는많은인력과자원이투입되고있다. 한편, HIV 치료제의효과는 CD4+ T세포수치가얼마나잘오르느냐, 말초혈액 HIV RNA가얼마나잘억제되느냐를기준으로다른만성질환치료제에비해비교적단기간내에평가할수있다. 위의 2가지요인때문에 HIV 치료제는매우빠른속도로개발되고있다. 상황이이렇기때문에감염을전공한의사라고하더라도지속적으로관심을가지지않으면새로개발되는신약에대해깊은지식을알수없는경우가많다. 이에본글에서는최근에국내에도입되었거나, 비교적가까운시일내에국내에도입될것으로예상되는치료제를간단히소개하고자한다 (Table 1) [1] 새로운뉴클레오시드유사체역전사효소억제제 (newer NRTI) 현재국내에서사용중인 tenofovir dipivoxil fumarate (TDF) 는주요지침에서권고되는뉴클레오시드유사체이다 [2 5]. 그러나 TDF는신장독성 [6 7] 골밀도감소 [8 9] 등의부작용이문제가될수있다. 이러한문제를극복하기위해개발된약제가 tenofovir alafenamide fumarate (TAF) 이다. Tenofovir를포함한 NRTI 계열의항레트로바이러스제는표적세포안으로들어가서약효를발휘하는데, TAF 형태로 tenofovir를투여하면 TDF 형태로투여했을때보다세포내침투율이높다 [10]. 이런이유로, TAF 형태로 tenofovir를투여하면적은용량으로도충분한효과를낼수있고, 전신적인부작용은적을거라는이론적인장점이있다. Correspondence to Ji Hwan Bang, M.D., Ph.D. Division of Infectious Diseases, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University, College of Medicine, 5 Gil 20, Boramae-Road, Dongjak-Gu, Seoul 07061, Korea Tel: +82-2-870-3209, Fax: +82-2-831-2826, E-mail: roundbirch@gmail.com Copyright c 2016 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 481 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 90, No. 6, 2016 - Table 1. Newer antiretroviral agents [1] Agents Status Comments Tenofovir alafenamide fumarate (TAF) Marketed in US and many Fewer bone and renal adverse events than TDF European countries Doravirine (MK 1439) Phase III Higher resistance barrier than NNRTIs currently marketed Fostemsavir (BMS 663068) Phase III Attachment inhibitor BMS 955176 Phase II Maturation inhibitor Cabotegravir Phase IIb Integrase inhibitor. Both oral and long acting injection formation are under developing Rilpivirine long acting injection formulation Phase IIb Studied with cabotegravir long acting injection formation Bictegravir (GS 9883) Phase III Integrase inhibitor. Does not require pharmacokinetic boosting MK 8591 Phase I NRTTI. Both oral and long acting injection formulation are under developing TDF, tenofovir dipivoxil fumarate; NNRTI, non nucleoside reverse transcriptase inhibitor; NRTTI, nucleoside reverse transcriptase translocation inhibitor. 이를확인하기위해치료경험이없는 HIV 환자에게 TAF (TAF/emtricitabine/elvitegravir/cobicistat 복합제 ) 또는 TDF (TDF/emtricitabine/elvitegravir/cobicistat 복합제 ) 가포함된치료제를투여한 2개의무작위임상연구가시행되었다 [11]. 이들연구에대한 96주중간결과를보면 HIV RNA < 50 copies/ml로억제된비율은, TAF가포함된치료제를투여한군에서는 86.6%, TDF 가포함된약물을투여받은군에서는 85.2% 로비슷하였다. 한편, 이들연구에서단백뇨, 알부민뇨, 세뇨관성단백뇨, 근위세뇨관손상등의부작용은 TAF 포함약제를투여받은군에서더적었다. 또한척추및고관절골밀도감소도 TAF 포함약제투여군에서훨씬적었다. TAF의효과및부작용개선정도는이미기존에다른약제를복용하고있던환자에서도확인되었다. 기존에항레트로바이러스치료를받고바이러스가잘억제되며 egfr 30 69 ml/min 환자들 ( 이중 65% 가 TDF가포함된약물을복용중 ) 을 TAF가포함된제제 (TAF/emtricitabine/elvitegravir/cobicistat) 로변경한연구의 48주중간결과에서, TAF 포함제제로바꾼후단백뇨, 알부민뇨, 세뇨관단백뇨가호전되었다 [12]. 또한, TDF 포함제제 (TDF/emtricitabine/elvitegravir/cobicistat, TDF/emtricitabine + efavirenz, TDF/emtricitabine + boosted atazanavir 중의하나 ) 로치료받고있던환자를대상으로일부는기존약을그대로복용하고일부는 TAF 포함제제 (TAF + emtricitabine + elvitegravir + cobicistat) 로변경한연구의 48주중간결과에서, 치료효과는서로비슷하거나 TAF 포함제제로변경한군에서근소하게좋았으며, 신장 독성, 골밀도감소등의부작용은 TAF 포함제제로변경한군에서더적었다 [13]. 이상의결과를요약하면, TAF는 TDF와효과는비슷하면서신장독성, 골밀도감소등의부작용은 TDF에비해적다고할수있겠다. TAF는 TAF/emtricitabine/elvitegravir/cobicistat 복합제형태로국내에도조만간출시될예정이다. 새로운비뉴클레오시드유사체역전사효소억제제 (newer NNRTI) 기존 1세대 nevirapine, efavirenz 등의기존 1세대 NNRTI 는내성장벽이낮고, 간독성, 중추신경계부작용, 피부발진등이흔히나타나는것이문제였다 [14,15]. 2세대 NNRTI인 etravirine과 rilpivirine은흔한 NNRTI 내성돌연변이인 K103N이있어도효과가유지되고, 기존 1세대 NNRTI에비해부작용이적다는장점이있다 [16,17]. 그러나이들약제역시 Y181C/I/V 돌연변이가있으면효과가현저히떨어진다는문제가있다. 최근개발되고있는 doravirine( 개발명 MK 1439) 은 K103N, Y181C, G190A, E101K, E138K, K103N/Y181C 등의내성돌연변이가있어도효과가있으며약물상호작용이나부작용도기존 1세대 NNRTI에비해적다는장점을가진약물이다 [18]. 최근발표된 2상임상연구 48주결과에서 doravirine 포함제제 (tenofovir/emtricitabine + doravirine) 투여군과 efavirenz 포함제제 (tenofovir/emtricitabine/efavirenz) 투여군에서바이러 - 482 -
- Ji Hwan Bang. Recent advances in antiretroviral agents - 스억제비율은각각 77.8% 와 78.7% 로유사했으며, 중추신경계부작용은 doravirine 투여군에서훨씬적었다 [19]. 요약하면 doravirine은기존 NNRTI와효과는비슷하면서, 내성장벽은높으며중추신경계부작용은적다는장점이있다. 새로운단백분해효소억제제 (newer PI) PI계열의약물을사용할때에는저용량의 ritonavir와함께투여하는것을추천하는데, 이는 ritonavir 가함께투여한 PI 의대사를막아서이들약물의혈중농도와효과를높이기때문이다 ( 이를 pharmacokinetic boosting 이라고한다 ). 그러나 ritonavir 는소화기계부작용, 고지혈증등의부작용이흔히나타나는문제가있다 [20]. 최근에는이러한문제점을극복하기위해 ritonavir 대신 cobicistat으로 pharmacokinetic boosting을하는약물이개발되었다. 313명의 HIV 감염인 (295명은기존항레트로바이러스치료경험이없는사람 ) 을대상으로한단일치료법연구 48주결과 cobicistat boosted darunavir (DRV/c) 포함치료를받은사람의 81% 가바이러스가잘억제되었다 [21]. 한편, 상기연구에서복통, 설사, 구역, 구토등의부작용빈도는 ritonavir boosted darunavir (DRV/r) 를투여한기존의연구결과에비해비슷하거나적었다 [22]. 한편, cobicistat boosted atazanavir (ATV/c) 가포함된치료제와 ritonavir boosted atazanavir (ATV/r) 가포함된치료제의효과를 144주간비교한연구에서 ( 양군모두상기약물에 tenofovir/emtricitabine을병용투여 ), 바이러스억제효과는서로비슷했고, 설사와혈중지질상승은 ATV/c 투여군에서더적었다 [23]. 요약하면, cobicistat은기존 ritonavir 대신 PI 계열약제의 pharmacokinetic booster로투여할수있으며, 비슷한 boosting 효과를기대할수있으며, 부작용은적거나비슷할것으로기대된다. 한편, cobicistat boosted darunavir, cobicistat boosted atazanavir 모두복합제형태로출시되었기때문에, 상대적으로약물개수가적고 pharmacokinetic boosting을위해추가로약을복용하지않아도된다는장점이있다. DRV/c 복합제는이미국내에출시되었으며, ATV/c 도조만간출시될예정이다. 새로운통합효소억제제 (newer INSTI) INSTI 계열의약제는비교적최근에개발되었기때문에기존약제에내성인환자에게도사용이가능하고부작용이적다는장점이있지만, 내성장벽이높지못하다는단점이있다 [24 26]. 최근국내에도출시되어사용되고있는 dolutegravir는기존 INSTI 보다내성장벽이높은약물로주목받고있다. 기존치료력이없는환자를대상으로 abacavir/lamivudine/dolutegravir 복합제와 tenofovir/emtricitabine/efavirenz 복합제의효과를비교한 3상연구 144주결과에서 abacavir/lamivudine/dolutegravir 복합제를투여한군은 71% 에서 tenofovir/emtricitabine/efavirenz 복합제를투여한군은 63% 에서바이러스가억제되었다 (p = 0.010) [27]. 한편, 치료력이없는환자에서 dolutegravir (+ 2NRTIs) 와같은 INSTI 계열약물인raltegravir (+ 2NRTIs) 의효과를비교한연구 96주결과를보면전반적으로양군간의치료효과는비슷했다 [28]. 그러나, 치료시작전말초혈액 HIV RNA > 100,000 copies/ml 인군에서는 dolutegravir군은 78% 에서바이러스가억제되었음에반해 raltegravir 군은 63% 에서만억제되었다 (p = 0.026). 치료력이없는환자에서 dolutegravir(+ 2NRTIs) 와 DRV/r(+ 2NRTIs) 의효과를비교한연구도있다 [29,30]. 96주째결과에서각각 80% 및 68% 의피험자에서바이러스가억제되었다 (p = 0.02). 한편, 이연구에서치료후총콜레스테롤, 저밀도지질단백콜레스테롤, 중성지방상승정도는 dolutegravir 투여군에서더적었다. 주목할만한사실은치료력이없는환자를대상으로 dolutegravir의효과를확인한위 3개의연구에서 dolutegravir 내성이발현된사례는없었다는것이다. 치료력이있는환자에서 dolutegravir의효과를확인한연구도있다. 2개이상의항레트로바이러스제에내성이지만, INSTI 는투여받아본적없고, INSTI 에대한내성도없는환자를대상으로 dolutegravir (+ 개별환자별적절한약물조합 ) 과 raltegravir (+ 개별환자별적절한약물조합 ) 의효과를비교한연구의 48주째분석에서, 바이러스가억제된환자비율은각각 71% 와 64% 로 dolutegravir 투여군에서더좋은결과를보였다 (p = 0.03) [31]. 요약하면, dolutegravir는 1세대 INSTI 또는다른계열의약제와유사하거나우월한효과를가지고있으며, 내성장벽도 - 483 -
- 대한내과학회지 : 제 90 권제 6 호통권제 670 호 2016 - 상대적으로높은것으로보인다. Dolutegravir는단독제제, abacavir/lamivudine/dolutegravir 복합제제형태로출시되었다. 새로운개념의치료제들매일약을복용하는것은매우불편한일이다. 그런불편을줄이기위한연구도진행되고있는데, 그중대표적인것이나노입자를이용한주사제이다. 나노입자를이용한 cabotegravir (INSTI 의일종 ) 주사와 rilpivirine (NNRTI 의일종 ) 주사제를 8주간격으로투여해서항레트로바이러스치료를하는것이다 [32]. 이런치료법이성공하면매일약을먹어야하는불편함이없어진다는점에서획기적인발전이라고할수있다. MK 8591은구조적으로 NRTI 와유사하나 3 OH를가지고있으며, 역전사효소의전위를방해하는새로운기전의약제이다 [33]. MK 8591는새로운기전의약제라는점에서도주목받지만, 경구로투여시 1번복용으로 1주일, 주사제형태로투여시 1번투여로 1년가까운기간동안효과를기대할수있다는점때문이다 [34]. 한편, 그외에다른기전에의한치료제도개발되고있다. 성숙억제제는단백분해효소억제제와는다른기전으로 HIV 의성숙을방해하며대표적인것이 BMS 955176이다 [35]. 그리고 HIV가 gp120과부착하는것을억제하는약제 (fostemsavir, 개발명 BMS 663068) [36] 도연구중이다. HIV 완치를염두에둔치료제도개발중이다. 휴면상태에있는기억 T세포에 proviral DNA 는기존약제로치료할수없기때문에완치의가장큰걸림돌중의하나이다. 이를다시활성화시켜서치료하는전략 ( 이른바 shock and kill treatment) 에대한연구도활발히진행중이다 [37 43]. 결론이상에서살펴본바와같이 HIV 치료에있어서, 기존약제의단점을보완한약제, 새로운기전의약제, 완치를위한약제가끊임없이연구되고있다. 그리고그중일부는가까운시일내에임상에도입될것으로보인다. 이러한새로운발전을기반으로 HIV 환자들이더좋은치료를받을수있기를기대해본다. 중심단어 : 사람면역결핍바이러스 ; 항레트로바이러스제 REFERENCES 1. Clayden P, Collins S, Frick M, et al. 2015 pipeline report: HIV, hepatitis C virus (HCV), and tuberculosis (TB) drugs, diagnostics, vaccines, preventive technologies, research toward a cure, and immune-based and gene therapies in development. 2015. 2. AIDSinfo. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents [Internet]. Rockville (USA): AIDSinfo, c2016 [cited 2016 Jun 7]. Available from: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. 3. Korean Society for AIDS. The 2015 clinical guidelines for the diagnosis and treatment of HIV/AIDS in HIV-infected Koreans. Infect Chemother 2015;47:205-211. 4. Ryom L, Boesecke C, Gisler V, et al. Essentials from the 2015 European AIDS Clinical Society (EACS) guidelines for the treatment of adult HIV-positive persons. HIV Med 2016;17:83-88. 5. Günthard HF, Aberg JA, Eron JJ, et al. Antiretroviral treatm ent of adult HIV infection: 2014 recommendations of the International Antiviral Society USA Panel. JAMA 2014;312: 410-425. 6. Karras A, Lafaurie M, Furco A, et al. Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 2003;36:1070-1073. 7. Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis 2006;42:283-290. 8. Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis 2010;51:963-972. 9. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011;203:1791-1801. 10. Eisenberg EJ, He GX, Lee WA. Metabolism of GS-7340, a novel phenyl monophosphoramidate intracellular prodrug of PMPA, in blood. Nucleosides Nucleotides Nucleic Acids 2001;20:1091-1098. 11. Wohl D, Oka S, Clumeck N, et al. Brief report: a randomized, double-blind comparison of tenofovir alafenamide - 484 -
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