Effect of HAART on the Progression of Liver Fibrosis in Patients with both HIV and HBV Infection

doi:10.12114/j.issn.1007-9572.2018.00.302

Abstract

Abstract: Background　Current studies have confirmed that the risk of hepatic fibrosis in human immunodeficiency virus（HIV）and hepatitis B virus（HBV）co-infected patients is higher than that in HBV-infected patients alone. Anti-HBV therapy can significantly improve hepatic fibrosis in HBV-infected patients. However，whether highly active antiretroviral therapy（HAART）can also improve hepatic fibrosis in HIV and HBV co-infected patients and whether there is difference between different schemes is still uncertain. Objective　To investigate whether HAART can improve liver fibrosis of patients infected with HIV and HBV and whether there is difference between different HAART schemes.Methods　A total of 128 patients with HIV and HBV infection initially treated in Liuzhou General Hospital from 2011 to 2017 were selected in this experiment.Patients were divided into TDF group（n=90） and non-TDF group（n=38）.Subjects in TDF group had not osteoporosis with normal renal insufficient whose treatment scheme included TDF.Non-TDF group members had osteoporosis and/or renal function whose treatment scheme did not include TDF.Gender，age，baseline indexes〔HIVRNA，HBVDNA，CD4 cell count，alanine aminotransferase（ALT），aspartate aminotransferase（AST），platelet count（PLT） and fibrosis-4（FIB-4）〕 and follow-up indexes（FIB-4 of the 3rd，6th，9th，12th，18th，24th，30th，36th，42th and 48th months after treatment） were recorded.The effects of different antiviral schemes and different time points for antiviral treatment on hepatic fibrosis in patients with HIV and HBV infection were compared by generalized estimating equation.Results　Age，AST in TDF group were higher than those in non-TDF group（P<0.05）.At baseline and after 9th，12th months of antiviral treatment，FIB-4 in TDF group was higher than that in non-TDF group（P<0.05）.The comparison results showed that the estimated marginal means of non-TDF group and TDF group were 0.308 3 and 0.435 0，respectively.The difference between both groups had statistical significance（P=0.033）.The results of repeated measures showed that the estimated marginal means of all patients' baseline after the 3rd，6th，9th，12th，18th，24th，30th，36th，42th and 48th month of antiviral treatment were 0.929 4，0.492 7，0.354 0，0.371 9，0.322 8，0.256 1，0.288 1，0.272 3，0.299 6，0.278 8 and 0.222 5，respectively.The time difference had statistical significance（Wald χ2= 35.078，P<0.001）.Conclusion　HAART can improve liver fibrosis of patients infected with HIV and HBV，and TDF scheme is better than non-TDF scheme.

Key words: Hepatitis B virus, HIV, Liver cirrhosis, Highly active antiretroviral therapy

摘要： 背景　目前研究已证实人类免疫缺陷病毒（HIV）和乙型肝炎病毒（HBV）双重感染者发生肝纤维化的风险比单纯HBV感染者增加，抗HBV治疗可显著改善HBV感染者的肝纤维化。但是，高效抗反转录病毒治疗（HAART）是否也可以改善HIV和HBV双重感染者的肝纤维化以及不同方案有无差别，目前尚无定论。目的　探讨HAART能否改善HIV和HBV双重感染者肝纤维化及不同HAART方案有无差别。方法　选取2011—2017年柳州市人民医院收治的初始治疗HIV和HBV双重感染者128例，合并骨质疏松和/或肾功能不全患者纳入非替诺福韦（TDF）组（38例），治疗方案不含TDF；无骨质疏松且肾功能正常患者纳入TDF组（90例），治疗方案含TDF。记录患者性别、年龄、基线指标〔HIV核糖核酸（HIVRNA）、HBV脱氧核糖核酸（HBVDNA）、CD4细胞计数、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、血小板计数（PLT），计算基于4因子的肝纤维化指数（FIB-4）〕和随访指标（抗病毒治疗后3、6、9、12、18、24、30、36、42个月和48个月的FIB-4）。采用广义估计方程比较不同抗病毒治疗方案和不同抗病毒治疗时间点对HIV和HBV双重感染者肝纤维化的影响。结果　TDF组年龄、AST均高于非TDF组（P<0.05）。TDF组患者基线以及治疗后9、12个月的FIB-4均高于非TDF组（P<0.05）。组间比较结果显示，非TDF组和TDF组估算边际均值分别为0.308 3和0.435 0，组间差异有统计学意义（P=0.033）；重复测量时间比较结果显示，全部患者基线以及治疗后3、6、9、12、18、24、30、36、42、48个月的估算边际均值分别为0.929 4、0.492 7、0.354 0、0.371 9、0.322 8、0.256 1、0.288 1、0.272 3、0.299 6、0.278 8和0.222 5，时间差异有统计学意义（Wald χ2=35.078，P<0.001）。结论　HAART具有改善HIV和HBV双重感染者肝纤维化作用，含TDF方案效果较优。

关键词: 乙型肝炎病毒, HIV, 肝硬化, 高效抗反转录病毒治疗

JIANG Zhongsheng,CHEN Tao,HU Jiaguang, et al. Effect of HAART on the Progression of Liver Fibrosis in Patients with both HIV and HBV Infection[J]. Chinese General Practice, 2019, 22(8): 925-930. DOI: 10.12114/j.issn.1007-9572.2018.00.302.
蒋忠胜,陈涛,胡家光等. 高效抗反转录病毒治疗对人类免疫缺陷病毒和乙型肝炎病毒双重感染者肝纤维化进展的影响研究[J]. 中国全科医学, 2019, 22(8): 925-930. DOI: 10.12114/j.issn.1007-9572.2018.00.302.

References

［1］LIAN X，BI S，YANG W，et al．Epidemiological serosurvey of hepatitis B in China-declining HBV prevalence due to hepatitis B vaccination［J］．Vaccine，2009，27（47）：6550-6557．DOI：10.1016/j.vaccine.2009.08.048.
［2］XIE J，HAN Y，QIU Z，et al．Prevalence of hepatitis B and C viruses in HIV-positive patients in China：a cross-sectional study［J］．J Int AIDS Soc，2016，19（1）：20659．DOI：10.7448/IAS.19.1.20659.
［3］GITAU S N，VINAYAK S，SILABA M，et al．High prevalence of liver fibrosis in patients with human immunodeficiency virus monoinfection and human immunodeficiency virus hepatitis-B co-infection as assessed by shear wave elastography：study at a teaching hospital in Kenya［J］．J Clin Imaging Sci，2016，6：22．DOI：10.4103/2156-7514.183582.
［4］CHEN B，YE B，ZHANG J，et al．RDW to platelet ratio：a novel noninvasive index for predicting hepatic fibrosis and cirrhosis in chronic hepatitis B［J］．PLoS One，2013，8（7）：e68780．DOI：10.1371/journal.pone.0068780.
［5］ERDOGAN S，DOGAN H O，SEZER S，et al．The diagnostic value of non-invasive tests for the evaluation of liver fibrosis in chronic hepatitis B patients［J］．Scand J Clin Lab Invest，2013，73（4）：300-308．DOI：10.3109/00365513.2013.773592.
［6］HOU J L，XU D，SHI G，et al．Long-term telbivudine treatment results in resolution of liver inflammation and fibrosis in patients with chronic hepatitis B［J］．Adv Ther，2015，32（8）：727-741．DOI：10.1007/s12325-015-0232-2.
［7］中华医学会感染病学分会艾滋病学组.艾滋病诊疗指南［J］．中华传染病杂志，2006，24（2）：133-144．DOI：10.3760/j.issn:1000-6680.2006.02.021.
AIDS Group，Chinese Society of Infectious Diseases，Chinese Medical Association.Guideline for AIDS diagnosis and treatment［J］．Chinese Journal of Infectious Diseases，2006，24（2）：133-144．DOI：10.3760/j.issn:1000-6680.2006.02.021.
［8］中华医学会感染病学分会艾滋病学组.艾滋病诊疗指南（2011版）［J］．中华传染病杂志，2011，29（10）：629-640．DOI：10.3760/cma.j.issn.1000-6680.2011.10.018.
AIDS Group，Chinese Society of Infectious Diseases，Chinese Medical Association.Guidelines for AIDS diagnosis and treatment（2011）［J］．Chinese Journal of Infectious Diseases，2011，29（10）：629-640．DOI：10.3760/cma.j.issn.1000-6680.2011.10.018.
［9］中华医学会感染病学分会艾滋病学组.艾滋病诊疗指南第三版（2015版）［J］．中华传染病杂志，2015，33（5）：385-401．DOI：10.3760/cma.j.issn.1000-6680.2015.10.001.
AIDS Group，Chinese Society of Infectious Diseases，Chinese Medical Association.Guidelines for AIDS diagnosis and treatment third edition（2015 edition）［J］．Chinese Journal of Infectious Diseases，2015，33（5）：385-401．DOI：10.3760/cma.j.issn.1000-6680.2015.10.001.
［10］中华医学会肝病学分会，中华医学会感染病学分会.慢性乙型肝炎防治指南（2010年版）［J］．中华肝脏病学杂志（电子版），2011，19（1）：40-56．DOI：10.3969/j.issn.1674-7380.2011.01.011.
Chinese Society of Hepatology，Chinese Medical Association，Chinese Society of Infectious Diseases，Chinese Medical Association.Guideline of prevention and treatment for chronic hepatitis B（2010 version）［J］．Chinese Journal of Liver Diseases（Electronic Version），2011，19（1）：40-56．DOI：10.3969/j.issn.1674-7380.2011.01.011.
［11］中华医学会肝病学分会，中华医学会感染病学分会.慢性乙型肝炎防治指南（2015更新版）［J］．中华肝脏病学杂志，2015，23（12）：888-905．DOI：10.3760 /cma.j.issn.1007-3418.2015.12.002.
Chinese Society of Hepatology，Chinese Medical Association，Chinese Society of Infectious Diseases，Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B：a 2015 update［J］．Chinese Journal of Hepatology，2015，23（12）：888-905．DOI：10.3760 /cma.j.issn.1007-3418.2015.12.002.
［12］HONG F，SAIMAN Y，SI C，et al．X4 human immunodeficiency virus type 1 gp120 promotes human hepatic stellate cell activation and collagen Ⅰ expression through interactions with CXCR4［J］．PLoS One，2012，7（3）：e33659．DOI：10.1371/journal.pone.0033659.
［13］BRUNO R，GALASTRI S，SACCHI P，et al．Gp120 modulates the biology of human hepatic stellate cells：a link between HIV infection and liver fibrogenesis［J］．Gut，2010，59（4）：513-520．DOI：10.1136/gut.2008.163287.
［14］PRICE J C，SEABERG E C，BADRI S，et al．HIV monoinfection is associated with increased aspartate aminotransferase-to-platelet ratio index，a surrogate marker for hepatic fibrosis［J］．J Infect Dis，2012，205（6）：1005-1013．DOI：10.1093/infdis/jir885.
［15］夏璐，杨长青.肝纤维化治疗的研究进展［J］．中华肝脏病杂志，2017，25（8）：566-570．DOI：10.3760/cmaj.issnl0Cr7-34182017.08.003.
XIA L，YANG C Q.Research advances in the treatment of hepatic fibrosis［J］．Chinese Journal of Hepatology，2017，25（8）：566-570．DOI：10.3760/cmaj.issnl0Cr7-34182017.08.003.
［16］钟水清，楼克忻.阿福德韦对慢性乙型病毒性肝炎患者血浆细胞因子及肝纤维化指标的影响［J］．中国全科医学，2010，13（36）：4074-4076．DOI：10.3969/j.issn.1007-9572.2010.36.008．
ZHONG S Q，LOU K X.The effect of Adefovir on the plasma level of cytokine and hepatic fibrosis index in patients with chronic hepatitis B［J］．Chinese General Practice，2010，13（36）：4074-4076．DOI：10.3969/j.issn.1007-9572.2010.36.008．
［17］BARANOVA A，LAL P，BIRERDINC A，et al．Non-invasive markers for hepatic fibrosis［J］．BMC Gastroenterol，2011，11：91．DOI：10.1186/1471-230x-11-91.
［18］STERLING R K，LISSEN E，CLUMECK N，et al．Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection［J］．Hepatology，2006，43（6）：1317-1325．DOI：10.1002/hep.21178.
［19］ZHANG Z，WANG G，KANG K，et al．The diagnostic accuracy and clinical utility of three noninvasive models for predicting liver fibrosis in patients with HBV infection［J］．PLoS One，2016，11（4）：e0152757．DOI：10.1371/journal.pone.0152757.

［20］刘克洲．WHO 颁布的首部慢性乙型肝炎防治指南解读［J］．中华临床感染病杂志，2015，8 （3）：193-195．DOI：10.3760/cma.j.issn.1674-2397.2015.03.001.
LIU K Z．Interpretation of World Health Organization's first guideline for chronic hepatitis B［J］．Chinese Journal of Clinical Infectious Diseases，2015，8 （3）：193-195．DOI：10.3760/cma.j.issn.1674-2397.2015.03.001.
［21］LI Y，XIE J，HAN Y，et al．Combination antiretroviral therapy is associated with reduction in liver fibrosis scores in HIV-1-infected subjects［J］．Medicine（Baltimore），2016，95（5）：e2660．DOI：10.1097/MD.0000000000002660.
［22］WEI Q，LIN H，DING Y，et al．Liver fibrosis after antiretroviral therapy in a longitudinal cohort of sexually infected HIV patients in eastern China［J］．Biosci Trends，2017，11（3）：274-281．DOI：10.5582/bst.2017.01071.
［23］BLACKARD J T，WELGE J A，TAYLOR L E，et al．HIV mono-infection is associated with FIB-4—a noninvasive index of liver fibrosis - in women［J］．Clin Infect Dis，2011，52（5）：674-680．DOI：10.1093/cid/ciq199.
［24］李雪原，张雪雷，仇丽霞.广义估计方程处理重复测量数据的参数解释［J］．中国药物与临床，2015，15（2）：167-170．DOI：10.11655/zgywylc2015.02.006.
LI X Y，ZHANG X L，QIU L X.Parameter interpretation of generalized estimating equations on repeated measurement data［J］．Chinese Remedies & Clinics，2015，15（2）：167-170．DOI：10.11655/zgywylc2015.02.006.
［25］BOYD A，LASNIER E，MOLINA J M，et al．Liver fibrosis changes in HIV-HBV-coinfected patients：clinical，biochemical and histological effect of long-term tenofovir disoproxil fumarate use［J］．Antivir Ther，2010，15（7）：963-974．DOI：10.3851/IMP1649.
［26］FERRARI D，GAMBARI R，IDZKO M，et al．Purinergic signaling in scarring［J］．FASEB J，2016，30（11）：3-12．DOI：10.1096/fj.15-274563.
［27］FEIG J L，MEDIERO A，CORCIULO C，et al．The antiviral drug tenofovir，an inhibitor of pannexin-1-mediated ATP release，prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin［J］．PLoS One，2017，12（11）：e0188135．DOI：10.1371/journal.pone.0188135.

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