臺灣博碩士論文加值系統

D型肝炎病毒(HDV)覆加感染會增加人類免疫不全病毒(HIV)與B型肝炎病毒(HBV)共同感染者肝炎發作與慢性肝臟併發症之風險。在台灣地區非靜脈藥物毒癮(IDU)的HIV患者中，約18至20%罹患慢性B型肝炎。在此回溯性觀察研究中，我們調查此一族群中，近期HDV覆加感染之血清流行病學，分析其發生率及相關危險因子，並建立real-time PCR方法定量HDV病毒量，以評估雞尾酒療法(HAART)治療HIV/HBV/HDV共同感染患者的效果。在1992年到2012年間，我們一共收集375位HIV與HBV共同感染者的血清檢體進行分析，其中包含241位男同性戀、49位異性戀、16位雙性戀、34位IDU患者及其它路徑感染患者35人。在HDV抗體篩選部分，我們發現有38位陽性(10.1%)，316位陰性(84.3%)以及2位equivocal(0.5%)。我們進一步用核酸定序分析抗體陽性患者的HDV基因型，發現主要型別為genotype 4(N=19)與genotype 2(N=9)。針對這些病人在不同時間點的基因定序分析，我們發現病人並沒有同時感染兩種病毒基因型的情況發生。接著我們計算HDV感染發生率：從HDV抗體陽性族群中，我們找到16位病人有血清轉陽的時間點，配合337位HDV抗體持續陰性患者，共追蹤1763.63年(PYFU)後，得到1992-2012年HDV感染總發生率為9.07/1000人年；西元1992-2001、2002-2006、2007-2012年的發生率逐年上升，分別為0、3.91、13.26/1000人年(P<0.05)。接著在16個HDV抗體陽轉病人中，排除一位靜脈毒癮者，再導入嵌入型病例對照研究法，分析HDV感染的相關因子。我們發現相較於HDV抗體持續陰性患者，HDV近期感染者的肝功能指數與梅毒指數皆較高，而其它相關因子，包括：HIV感染危險因子、CD4 T細胞數、HIV病毒量、HBV病毒量、使用lamivudine(3TC)或tenofovir(TDF)之治療藥物或者HCV共同感染等，在兩族群間無顯著差異。HIV/HBV/HDV近期感染患者有15位使用HAART抗病毒藥物治療，分析HDV抗體陽轉後病毒標記的分布，顯示HAART對於降低HIV與HBV病毒量有良好的效果，但對於降低HDV病毒量及HBsAg的效果則不明顯。接著，我們進一步比較HDV陽轉患者且有使用HAART的確切時間病人共8個，並配對相同治療時間的HIV/HBV且HDV陰性患者共15位，分析他們體內的病毒標記分布。結果顯示HBsAg在HDV Ab陰性與HDV Ab陽性時間點的分布量在HDV陽性族群較HDV陰性族群高，此外，HBsAg的下降程度在HDV抗體轉揚患者身上較高(P<0.05)，而這樣的現象可能與HDV RNA的升高有關。歸納結果，我們發現在台灣地區HIV與HBV共同感染族群中，HDV感染的盛行率為10.1%。HDV近期感染的發生率為9.07/1000人年，從西元1992-2001到2007-2012年間發生率有顯著增加，此現象與肝炎發作及梅毒指數相關。在HAART治療下，HIV/HBV/HDV共同感染者體內的HIV與HBV病毒量有明顯的治療效果，而對於HDV RNA與HBsAg則沒有明顯的抑制效果。因此，建議公共衛生政策方面應該要加強HIV/HBV共同感染族群間HDV的防治，對於HIV/HBV且非IDU的族群防治的重點在於宣導安全性行為以減少HDV感染的風險。

Super-infection with hepatitis D virus (HDV) in HIV/HBV-coinfected patients may increase risk for hepatitis flares and chronic hepatic complications. In this retrospective observational study, we aimed to determine the incidence of and factors associated with recent HDV super-infection among HIV/HBV-coinfected patients without injection drug use in Taiwan, where the prevalence of chronic HBV infection among HIV-infected patients were 18 to 20%. During the study period, 375 HIV/HBV-coinfected patients were enrolled, including 241 male homosexuals, 49 heterosexuals, 16 bisexuals, 34 injection drug users (IDUs) and 35 infected through other routes. We found 38 were HDV Ab positive(10.1%), 318 HDV Ab negative(84.3%) and 2 equivocal(0.5%). These patients were infected with HDV genotypes 2 (N=9) and 4 (N=19). No superinfected of other HDV genotypes were observed in these patients during follow up. After 1763.63 person-years of follow-up (PYFU), the overall incidence rate of HDV infection was 9.07 per 1000 PY, which increased from 0 in 1992-2001, 3.91 in 2002-2006 to 13.26 per 1000 PY in 2007-2012 (P<0.05). In the nested case-control study, we found that more patients with recent HDV infection had elevated aminotransferase levels and syphilis than those without seroconversion. There were no differences in terms of risk behavior for HIV transmission, CD4 or plasma HIV RNA, plasma HBV DNA, receipt of lamivudine or tenofovir, or anti-HCV seropositivity between the case and control patients. We established a real-time PCR method for quantification of HDV RNA load to assess the effect of HAART. We found HAART reduced HIV and HBV viral load, but not HDV RNA load and HBsAg titer. Eight HDV seroconvertors and 15 HDV negative patients were compared with respect to the distribution of HBV DNA, HBsAg and HDV RNA. HBsAg titer in HDV negative patients was higher than that in HDV seroconvertors when HDV Ab were tested last negative and first positive. Besides, the HBsAg titer decreased in HDV seroconvertors more significantly in HDV negative patients (P<0.05), which was associated with HDV RNA. In the era of HAART, the overall incidence of recent HDV infection in HIV/HBV-coinfected patients was 9.07 per 1,000 PYFU, HDV seroconvertors increased significantly from 1992-2001 to 2007-2012 which was associated with hepatitis flares and syphilis despite treatment with lamivudine or tenofovir. HAART was effective for control of HIV and HBV replication, but ineffective in reducing HDV RNA load and HBsAg titer. We suggested the public health policy should pay attention to HDV prevention. For example, to make widely known the guidance of safety sexual behavior to reduce the risk of HDV infection in HIV/HBV and non-IDU group.

目錄
口試委員會審定書 i
誌謝 ii
中文摘要 iii
Abstract v
第一章 緒論 1
第一節 HDV介紹 1
第二節 病毒共同感染 5
第三節 研究動機 8
第二章 實驗材料與方法 11
第一節 研究對象的資料收集與分析 11
第二節 實驗設計 11
第三節 實驗材料 12
第四節 實驗方法與流程 14
第三章 實驗結果 18
第一節 受試者基本資料分析 18
第二節 受試者HDV盛行率、基因分型 18
第三節 HDV疾病發生率 21
第四節 HDV疾病相關因子分析 22
第五節 建立HDV病毒量REAL-TIME方法 24
第六節 類核苷酸藥物治療的評估 24
第七節 結論 28
第四章 討論 29
參考文獻 33

參考文獻
1.Rizzetto, M., Canese, M. G., Arico, S., Crivelli, O., Trepo, C., Bonino, F., and Verme, G. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut (1977) 18, 997-1003.
2.Rizzetto, M., Canese, M. G., Gerin, J. L., London, W. T., Sly, D. L., and Purcell, R. H. Transmission of the hepatitis B virus-associated delta antigen to chimpanzees. J Infect Dis (1980) 141, 590-602.
3.Rizzetto, M., Hoyer, B., Canese, M. G., Shih, J. W., Purcell, R. H., and Gerin, J. L. delta Agent: association of delta antigen with hepatitis B surface antigen and RNA in serum of delta-infected chimpanzees. Proc Natl Acad Sci U S A (1980) 77, 6124-8.
4.Wang, K. S., Choo, Q. L., Weiner, A. J., Ou, J. H., Najarian, R. C., Thayer, R. M., Mullenbach, G. T., Denniston, K. J., Gerin, J. L., and Houghton, M. Structure, sequence and expression of the hepatitis delta (delta) viral genome. Nature (1986) 323, 508-14.
5.Farci, P. Delta hepatitis: an update. J Hepatol (2003) 39 Suppl 1, S212-9.
6.Radjef, N., Gordien, E., Ivaniushina, V., Gault, E., Anais, P., Drugan, T., Trinchet, J. C., Roulot, D., Tamby, M., Milinkovitch, M. C., and Deny, P. Molecular phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta virus, suggesting a deltavirus genus of at least seven major clades. J Virol (2004) 78, 2537-44.
7.Taylor, J. M. Hepatitis delta virus. Virology (2006) 344, 71-6.
8.Kuo, M. Y., Goldberg, J., Coates, L., Mason, W., Gerin, J., and Taylor, J. Molecular cloning of hepatitis delta virus RNA from an infected woodchuck liver: sequence, structure, and applications. J Virol (1988) 62, 1855-61.
9.Jayan, G. C., and Casey, J. L. Inhibition of hepatitis delta virus RNA editing by short inhibitory RNA-mediated knockdown of ADAR1 but not ADAR2 expression. J Virol (2002) 76, 12399-404.
10.Jayan, G. C., and Casey, J. L. Increased RNA editing and inhibition of hepatitis delta virus replication by high-level expression of ADAR1 and ADAR2. J Virol (2002) 76, 3819-27.
11.Wong, S. K., and Lazinski, D. W. Replicating hepatitis delta virus RNA is edited in the nucleus by the small form of ADAR1. Proc Natl Acad Sci U S A (2002) 99, 15118-23.
12.Tseng, C. H., and Lai, M. M. Hepatitis delta virus RNA replication. Viruses (2009) 1, 818-31.
13.Li, Y. J., Stallcup, M. R., and Lai, M. M. Hepatitis delta virus antigen is methylated at arginine residues, and methylation regulates subcellular localization and RNA replication. J Virol (2004) 78, 13325-34.
14.Mu, J. J., Chen, D. S., and Chen, P. J. The conserved serine 177 in the delta antigen of hepatitis delta virus is one putative phosphorylation site and is required for efficient viral RNA replication. J Virol (2001) 75, 9087-95.
15.Tseng, C. H., Jeng, K. S., and Lai, M. M. Transcription of subgenomic mRNA of hepatitis delta virus requires a modified hepatitis delta antigen that is distinct from antigenomic RNA synthesis. J Virol (2008) 82, 9409-16.
16.Glenn, J. S., Watson, J. A., Havel, C. M., and White, J. M. Identification of a prenylation site in delta virus large antigen. Science (1992) 256, 1331-3.
17.Kuo, M. Y., Chao, M., and Taylor, J. Initiation of replication of the human hepatitis delta virus genome from cloned DNA: role of delta antigen. J Virol (1989) 63, 1945-50.
18.Chen, P. J., Chang, F. L., Wang, C. J., Lin, C. J., Sung, S. Y., and Chen, D. S. Functional study of hepatitis delta virus large antigen in packaging and replication inhibition: role of the amino-terminal leucine zipper. J Virol (1992) 66, 2853-9.
19.Chang, F. L., Chen, P. J., Tu, S. J., Wang, C. J., and Chen, D. S. The large form of hepatitis delta antigen is crucial for assembly of hepatitis delta virus. Proc Natl Acad Sci U S A (1991) 88, 8490-4.
20.Ryu, W. S., Bayer, M., and Taylor, J. Assembly of hepatitis delta virus particles. J Virol (1992) 66, 2310-5.
21.Bonino, F., Heermann, K. H., Rizzetto, M., and Gerlich, W. H. Hepatitis delta virus: protein composition of delta antigen and its hepatitis B virus-derived envelope. J Virol (1986) 58, 945-50.
22.Sureau, C., Guerra, B., and Lanford, R. E. Role of the large hepatitis B virus envelope protein in infectivity of the hepatitis delta virion. J Virol (1993) 67, 366-72.
23.Sureau, C., Guerra, B., and Lee, H. The middle hepatitis B virus envelope protein is not necessary for infectivity of hepatitis delta virus. J Virol (1994) 68, 4063-6.
24.Wu, J. C., Chen, P. J., Kuo, M. Y., Lee, S. D., Chen, D. S., and Ting, L. P. Production of hepatitis delta virus and suppression of helper hepatitis B virus in a human hepatoma cell line. J Virol (1991) 65, 1099-104.
25.Greco-Stewart, V. S., Schissel, E., and Pelchat, M. The hepatitis delta virus RNA genome interacts with the human RNA polymerases I and III. Virology (2009) 386, 12-5.
26.Modahl, L. E., Macnaughton, T. B., Zhu, N., Johnson, D. L., and Lai, M. M. RNA-Dependent replication and transcription of hepatitis delta virus RNA involve distinct cellular RNA polymerases. Mol Cell Biol (2000) 20, 6030-9.
27.Greco-Stewart, V. S., Miron, P., Abrahem, A., and Pelchat, M. The human RNA polymerase II interacts with the terminal stem-loop regions of the hepatitis delta virus RNA genome. Virology (2007) 357, 68-78.
28.Chou, H. C., Hsieh, T. Y., Sheu, G. T., and Lai, M. M. Hepatitis delta antigen mediates the nuclear import of hepatitis delta virus RNA. J Virol (1998) 72, 3684-90.
29.Reid, C. E., and Lazinski, D. W. A host-specific function is required for ligation of a wide variety of ribozyme-processed RNAs. Proc Natl Acad Sci U S A (2000) 97, 424-9.
30.Polson, A. G., Bass, B. L., and Casey, J. L. RNA editing of hepatitis delta virus antigenome by dsRNA-adenosine deaminase. Nature (1996) 380, 454-6.
31.Sureau, C., Fournier-Wirth, C., and Maurel, P. Role of N glycosylation of hepatitis B virus envelope proteins in morphogenesis and infectivity of hepatitis delta virus. J Virol (2003) 77, 5519-23.
32.Engelke, M., Mills, K., Seitz, S., Simon, P., Gripon, P., Schnolzer, M., and Urban, S. Characterization of a hepatitis B and hepatitis delta virus receptor binding site. Hepatology (2006) 43, 750-60.
33.Pascarella, S., and Negro, F. Hepatitis D virus: an update. Liver Int (2010) 31, 7-21.
34.Huang, C., Chang, S. C., Yu, I. C., Tsay, Y. G., and Chang, M. F. Large hepatitis delta antigen is a novel clathrin adaptor-like protein. J Virol (2007) 81, 5985-94.
35.Huang, C., Chang, S. C., Yang, H. C., Chien, C. L., and Chang, M. F. Clathrin-mediated post-Golgi membrane trafficking in the morphogenesis of hepatitis delta virus. J Virol (2009) 83, 12314-24.
36.Le Gal, F., Gault, E., Ripault, M. P., Serpaggi, J., Trinchet, J. C., Gordien, E., and Deny, P. Eighth major clade for hepatitis delta virus. Emerg Infect Dis (2006) 12, 1447-50.
37.Imazeki, F., Omata, M., and Ohto, M. Heterogeneity and evolution rates of delta virus RNA sequences. J Virol (1990) 64, 5594-9.
38.Wu, J. C., Chen, C. M., Sheen, I. J., Lee, S. D., Tzeng, H. M., and Choo, K. B. Evidence of transmission of hepatitis D virus to spouses from sequence analysis of the viral genome. Hepatology (1995) 22, 1656-60.
39.Ivaniushina, V., Radjef, N., Alexeeva, M., Gault, E., Semenov, S., Salhi, M., Kiselev, O., and Deny, P. Hepatitis delta virus genotypes I and II cocirculate in an endemic area of Yakutia, Russia. J Gen Virol (2001) 82, 2709-18.
40.Casey, J. L., Brown, T. L., Colan, E. J., Wignall, F. S., and Gerin, J. L. A genotype of hepatitis D virus that occurs in northern South America. Proc Natl Acad Sci U S A (1993) 90, 9016-20.
41.Wu, J. C., Chiang, T. Y., and Sheen, I. J. Characterization and phylogenetic analysis of a novel hepatitis D virus strain discovered by restriction fragment length polymorphism analysis. J Gen Virol (1998) 79 ( Pt 5), 1105-13.
42.Su, C. W., Huang, Y. H., Huo, T. I., Shih, H. H., Sheen, I. J., Chen, S. W., Lee, P. C., Lee, S. D., and Wu, J. C. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology (2006) 130, 1625-35.
43.Wu, J. C. Functional and clinical significance of hepatitis D virus genotype II infection. Curr Top Microbiol Immunol (2006) 307, 173-86.
44.Niro, G. A., Smedile, A., Andriulli, A., Rizzetto, M., Gerin, J. L., and Casey, J. L. The predominance of hepatitis delta virus genotype I among chronically infected Italian patients. Hepatology (1997) 25, 728-34.
45.Rizzetto, M., Purcell, R. H., and Gerin, J. L. Epidemiology of HBV-associated delta agent: geographical distribution of anti-delta and prevalence in polytransfused HBsAg carriers. Lancet (1980) 1, 1215-8.
46.Gaeta, G. B., Stroffolini, T., Smedile, A., Niro, G., and Mele, A. Hepatitis delta in Europe: vanishing or refreshing? Hepatology (2007) 46, 1312-3.
47.Smedile, A., Rizzetto, M., and Gerin, J. L. Advances in hepatitis D virus biology and disease. Prog Liver Dis (1994) 12, 157-75.
48.Rizzetto, M., Bonino, F., and Verme, G. Hepatitis delta virus infection of the liver: progress in virology, pathobiology, and diagnosis. Semin Liver Dis (1988) 8, 350-6.
49.Cross, T. J., Rizzi, P., Horner, M., Jolly, A., Hussain, M. J., Smith, H. M., Vergani, D., and Harrison, P. M. The increasing prevalence of hepatitis delta virus (HDV) infection in South London. J Med Virol (2008) 80, 277-82.
50.Rizzetto, M., Verme, G., Recchia, S., Bonino, F., Farci, P., Arico, S., Calzia, R., Picciotto, A., Colombo, M., and Popper, H. Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment. Ann Intern Med (1983) 98, 437-41.
51.Zachou, K., Yurdaydin, C., Drebber, U., Dalekos, G. N., Erhardt, A., Cakaloglu, Y., Degertekin, H., Gurel, S., Zeuzem, S., Bozkaya, H., Schlaphoff, V., Dienes, H. P., Bock, T. C., Manns, M. P., and Wedemeyer, H. Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis. Liver Int (2009) 30, 430-7.
52.Williams, V., Brichler, S., Radjef, N., Lebon, P., Goffard, A., Hober, D., Fagard, R., Kremsdorf, D., Deny, P., and Gordien, E. Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene. J Gen Virol (2009) 90, 2759-67.
53.Gordien, E., Rosmorduc, O., Peltekian, C., Garreau, F., Brechot, C., and Kremsdorf, D. Inhibition of hepatitis B virus replication by the interferon-inducible MxA protein. J Virol (2001) 75, 2684-91.
54.Schaper, M., Rodriguez-Frias, F., Jardi, R., Tabernero, D., Homs, M., Ruiz, G., Quer, J., Esteban, R., and Buti, M. Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D. J Hepatol (2010) 52, 658-64.
55.Castellares, C., Barreiro, P., Martin-Carbonero, L., Labarga, P., Vispo, M. E., Casado, R., Galindo, L., Garcia-Gasco, P., Garcia-Samaniego, J., and Soriano, V. Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome. J Viral Hepat (2008) 15, 165-72.
56.Sheng, W. H., Hung, C. C., Kao, J. H., Chang, S. Y., Chen, M. Y., Hsieh, S. M., Chen, P. J., and Chang, S. C. Impact of hepatitis D virus infection on the long-term outcomes of patients with hepatitis B virus and HIV coinfection in the era of highly active antiretroviral therapy: a matched cohort study. Clin Infect Dis (2007) 44, 988-95.
57.Rizzetto, M. Hepatitis D: thirty years after. J Hepatol (2009) 50, 1043-50.
58.Wedemeyer, H., and Manns, M. P. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol (2010) 7, 31-40.
59.Erhardt, A., Gerlich, W., Starke, C., Wend, U., Donner, A., Sagir, A., Heintges, T., and Haussinger, D. Treatment of chronic hepatitis delta with pegylated interferon-alpha2b. Liver Int (2006) 26, 805-10.
60.Castelnau, C., Le Gal, F., Ripault, M. P., Gordien, E., Martinot-Peignoux, M., Boyer, N., Pham, B. N., Maylin, S., Bedossa, P., Deny, P., Marcellin, P., and Gault, E. Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up. Hepatology (2006) 44, 728-35.
61.Niro, G. A., Ciancio, A., Gaeta, G. B., Smedile, A., Marrone, A., Olivero, A., Stanzione, M., David, E., Brancaccio, G., Fontana, R., Perri, F., Andriulli, A., and Rizzetto, M. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology (2006) 44, 713-20.
62.Everson, G. T. Treatment of patients with hepatitis C virus on the waiting list. Liver Transpl (2003) 9, S90-4.
63.Sun, Y., Chang, B., Teng, G., Zhang, W., Zhao, J., Zou, Z., and Li, B. Combination Therapy for Patients Decompensated Liver Cirrhosis with HCV Infection. Hepatogastroenterology 60.
64.Di Martino, V., Thevenot, T., Colin, J. F., Boyer, N., Martinot, M., Degos, F., Coulaud, J. P., Vilde, J. L., Vachon, F., Degott, C., Valla, D., and Marcellin, P. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology (2002) 123, 1812-22.
65.Yurdaydin, C. A multicenter randomised study comparing the efficacy of pegylated interferon‑alfa‑2a plus adevofir dipivoxil vs. pegylated interferon‑alfa‑2a plus placebo vs. adevofir dipivoxil for the treatment of chronic delta hepatitis: The hep‑net/international delta hepatitis intervention trial (HID‑IT). Hepatology (2006) 44, 230A.
66.Wedemeyer, H. 72 WEEK DATA OF THE HIDIT-I TRIAL: A MULTICENTER RANDOMISED STUDY COMPARING PEGINTERFERON a-2a PLUS ADEFOVIR VS. PEGINTERFERON a-2a PLUS PLACEBO VS. ADEFOVIR IN CHRONIC DELTA HEPATITIS. J. Hepatol. (2007) 46, S4.
67.Yurdaydin, C., Bozkaya, H., Gurel, S., Tillmann, H. L., Aslan, N., Okcu-Heper, A., Erden, E., Yalcin, K., Iliman, N., Uzunalimoglu, O., Manns, M. P., and Bozdayi, A. M. Famciclovir treatment of chronic delta hepatitis. J Hepatol (2002) 37, 266-71.
68.Wolters, L. M., van Nunen, A. B., Honkoop, P., Vossen, A. C., Niesters, H. G., Zondervan, P. E., and de Man, R. A. Lamivudine-high dose interferon combination therapy for chronic hepatitis B patients co-infected with the hepatitis D virus. J Viral Hepat (2000) 7, 428-34.
69.Lau, D. T., Doo, E., Park, Y., Kleiner, D. E., Schmid, P., Kuhns, M. C., and Hoofnagle, J. H. Lamivudine for chronic delta hepatitis. Hepatology (1999) 30, 546-9.
70.Yurdaydin, C., Bozkaya, H., Onder, F. O., Senturk, H., Karaaslan, H., Akdogan, M., Cetinkaya, H., Erden, E., Erkan-Esin, O., Yalcin, K., Bozdayi, A. M., Schinazi, R. F., Gerin, J. L., Uzunalimoglu, O., and Ozden, A. Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon. J Viral Hepat (2008) 15, 314-21.
71.Garripoli, A., Di Marco, V., Cozzolongo, R., Costa, C., Smedile, A., Fabiano, A., Bonino, F., Rizzetto, M., Verme, G., Craxi, A., and et al. Ribavirin treatment for chronic hepatitis D: a pilot study. Liver (1994) 14, 154-7.
72.Wedemeyer, H., Yurdaydin, C., Dalekos, G. N., Erhardt, A., Cakaloglu, Y., Degertekin, H., Gurel, S., Zeuzem, S., Zachou, K., Bozkaya, H., Koch, A., Bock, T., Dienes, H. P., and Manns, M. P. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med (2011) 364, 322-31.
73.Sheldon, J., Ramos, B., Toro, C., Rios, P., Martinez-Alarcon, J., Bottecchia, M., Romero, M., Garcia-Samaniego, J., and Soriano, V. Does treatment of hepatitis B virus (HBV) infection reduce hepatitis delta virus (HDV) replication in HIV-HBV-HDV-coinfected patients? Antivir Ther (2008) 13, 97-102.
74.Jardi, R., Rodriguez, F., Buti, M., Costa, X., Cotrina, M., Galimany, R., Esteban, R., and Guardia, J. Role of hepatitis B, C, and D viruses in dual and triple infection: influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference. Hepatology (2001) 34, 404-10.
75.Komla-Soukha, I., and Sureau, C. A tryptophan-rich motif in the carboxyl terminus of the small envelope protein of hepatitis B virus is central to the assembly of hepatitis delta virus particles. J Virol (2006) 80, 4648-55.
76.Hourioux, C., Sureau, C., Poisson, F., Brand, D., Goudeau, A., and Roingeard, P. Interaction between hepatitis delta virus-encoded proteins and hepatitis B virus envelope protein domains. J Gen Virol (1998) 79 ( Pt 5), 1115-9.
77.Kao, J. H., Chen, P. J., Lai, M. Y., and Chen, D. S. Hepatitis D virus genotypes in intravenous drug users in taiwan: decreasing prevalence and lack of correlation with hepatitis B virus genotypes. J Clin Microbiol (2002) 40, 3047-9.
78.Chang, S. Y., Yang, C. L., Ko, W. S., Liu, W. C., Lin, C. Y., Wu, C. H., Su, Y. C., Chang, S. F., Chen, M. Y., Sheng, W. H., Hung, C. C., and Chang, S. C. Molecular epidemiology of hepatitis D virus infection among injecting drug users with and without human immunodeficiency virus infection in Taiwan. J Clin Microbiol (2011) 49, 1083-9.
79.Huo, T. I., Wu, J. C., Lin, R. Y., Sheng, W. Y., Chang, F. Y., and Lee, S. D. Decreasing hepatitis D virus infection in Taiwan: an analysis of contributory factors. J Gastroenterol Hepatol (1997) 12, 747-51.
80.Hsu, H. M., Wang, Y. F., Lo, S. H., Sun, H. C., Yip, K. K., Chen, J. S., Chuang, C. H., and Chen, D. S. Hepatitis D virus infection among intravenous drug abusers in Taiwan: analysis of risk factors and liver function tests. J Med Virol (1990) 31, 76-81.
81.Chu, F. Y., Chiang, S. C., Su, F. H., Chang, Y. Y., and Cheng, S. H. Prevalence of human immunodeficiency virus and its association with hepatitis B, C, and D virus infections among incarcerated male substance abusers in Taiwan. J Med Virol (2009) 81, 973-8.
82.Epidemiology of Hepatitis Delta Virus infection in HIV-infected individuals in Taiwan. Retrovirology 9 Suppl 1, P49.
83.Sun, H. Y., Chang, S. Y., Yang, Z. Y., Lu, C. L., Wu, H., Yeh, C. C., Liu, W. C., Hsieh, C. Y., Hung, C. C., and Chang, S. C. Recent hepatitis C virus infections in HIV-infected patients in Taiwan: incidence and risk factors. J Clin Microbiol 50, 781-7.
84.Lin, H. H. Epidemiology of Hepatitis Delta Virus infection in HIV-infected individuals in Taiwan. Retrovirology (2012) 9, Suppl 1.
85.Lee, C. Z., Lin, J. H., Chao, M., McKnight, K., and Lai, M. M. RNA-binding activity of hepatitis delta antigen involves two arginine-rich motifs and is required for hepatitis delta virus RNA replication. J Virol (1993) 67, 2221-7.