慢性乙型肝炎免疫耐受期的抗病毒治疗:系统综述

目的系统评价抗病毒治疗在免疫耐受期慢性乙型肝炎(CHB)患者中的有效性和安全性。方法检索PubMed、EMBASE、Cochrane library、中国知网、万方数据库自数据库建立至2020年9月抗病毒药物治疗免疫耐受期CHB的临床试验,进行质量评价后提取相关效应量并进行系统评价。主要结局指标为HBV DNA阴转率。结果共纳入9项研究821例患者。8项研究报道了治疗组中HBV DNA阴转率,6项研究中治疗组HBV DNA阴转率均超过60%,明显高于未治疗患者(0～29.1%),且联合治疗组优于单药治疗组。但在长期观察中,病毒学复发较常见。8项研究报告了HBeAg血清学转换,仅2项IFNα治疗儿童的研究中治疗组血清学转换率超过20%,高于未治疗组。HBsAg阴转出现在2项使用IFNα治疗的研究中,无研究观察到HBsAg血清学转换。1项研究报告了肝硬化和肝细胞癌(HCC)的风险,显示抗病毒治疗可降低患者肝硬化和HCC的风险。不良反应发生率在核苷(酸)类似物治疗中为4.1%～13.0%,在IFNα治疗中达到了100%,严重不良反应少见。结论免疫耐受期CHB患者给予抗病毒后绝大多数可出现满意的病毒学应答,但停药后易复发,且血清学转换率低。抗病毒治疗安全性良好。目前证据表明,对于该类患者如无明确疾病进展可动态观察。     

延长聚乙二醇干扰素疗程对普通干扰素治疗无应答的HBeAg阳性慢性乙型肝炎患者的疗效

目的:观察研究延长聚乙二醇干扰素α-2a(polyethylene glycol interferonα-2a,PEG-IFNα-2a)疗程对普通IFN治疗无应答的HBeAg阳性慢性乙型肝炎(chronic viral hepatitis B,CHB)患者的疗效.方法:A组27例为普通IFN治疗无应答的HBeAg阳性CHB患者,采用PEG-IFNα-2a治疗,疗程72 wk.B组31例患者为普通IFN治疗失败的HBeAg阳性CHB患者,采用PEGIFNα-2a治疗观察,疗程48 wk.治疗结束随访24 wk.检测HBsAg和HBeAg、抗-HBe,乙型肝炎病毒(hepatitis B virus,HBV)DNA及肝功能.结果:在治疗结束时,A组HBsAg阴转率、血清转换率、HBV DNA阴转率分别高于B组(14.8%vs 6.5%,48.1%vs 29.0%,66.7%vs45.1%,P0.05),差异有统计学意义.在治疗结束随访24 wk时,A组HbsAg阴转率、HBV DNA阴转率、HBeAg血清阴转率均高于B组(18.5%vs 6.5%,70.4%vs 38.7%,55.6%vs32.2%,P0.05),差异有统计学意义,A组ALT复常率高于B组,但两者差异无统计学意义.结论:延长PEG-IFNα-2a治疗疗程可以在普通IFN治疗无应答的HBeAg阳性CHB患者身上取得较好疗效,能帮助更多的患者获得理想的治疗终点.     

干扰素治疗慢性乙型肝炎的联合用药

干扰素(IFN)是目前治疗慢性乙型病毒性肝炎(CHB)的重要药物,抗病毒机理主要包括免疫调节作用和直接抗病毒作用,国内外报道(IFN)治疗结束后HBeAg和HBV DNA阴转率为30％～50％,停药1年后仅为20％～25％。且IFN治疗CHB存在副作用较大,患者顺应性较差,停药后易反跳,适应症较窄等局限性,故联合治疗已成为目前国内外治疗CHB临床研究热点。本文对近年IFN治疗CHB的联合用药作一综     

乙肝病毒基因型对武汉地区慢性乙型肝炎患者干扰素α-2b疗效的影响

目的:探讨武汉地区慢性乙型肝炎(CHB)患者HBV基因型对干扰素α-2b疗效的影响。方法:以患者年龄、性别、基线指标进行匹配,按照基因分型结果分组,比较干扰素治疗48周时的应答情况。结果:在治疗48周结束时,基因B型HBV感染的患者完全应答率和HBeAg阴转率分别为43.8%(28/64)和68.2%(15/22),显著高于C型患者的完全应答率[22.2%(10/45)]和HBeAg阴转率[28.6%(4/14)]。结论:CHB患者HBV的基因型可影响干扰素α-2b的治疗效果,基因B型在治疗48周时应答情况优于基因C型。     

粘病毒抵抗蛋白A和真核细胞起始因子2α调节区2基因多态性与慢性乙型肝炎干扰素治疗效果的相关性

目的探讨IFN诱导的粘病毒抵抗蛋白A(MxA)和真核细胞起始因子2α调节区2 (eIF-2α-reg2)基因的单核苷酸多态性(SNP)与CHB患者IFN治疗效果的关系。方法采用前瞻性研究方法,262例CHB患者签署知情同意书后予IFNα治疗12个月,随访至停药后6个月时评价疗效,分为持续应答和非持续应答。应用PCR及限制片段长度多态性的分析方法,检测患者MxA启动子-88、-123位点及eIF-2α-reg2的SNP,并比较SNP与IFN疗效的关系。结果262例CHB患者IFN治疗的应答情况为持续应答50例(19.1%),非持续应答212例(80.9%)。MxA启动子-88位点(G/T),GG型患者与GT型CHB患者IFN疗效比较,差异有统计学意义(OR 5.3,95%置信区间2.46～11.43,P<0.01);TT型与GT型患者的疗效比较,差异有统计学意义(OR 4.1, 95%置信区间1.86～9.09,P<0.01)。MxA启动子-123位点(C/A)、eIF-2α-reg2位点(A/G)各基因型及MxA启动子-88与-123组成4种可能的单体型患者IFN疗效比较,差异均无统计学意义(P>0.05)。结论MxA启动子-88位点为GT基因型的CHB患者对IFN治疗反应好,可作为IFN疗效的预测指标。     

重组干扰素α-2a,α-2b治疗慢性乙型肝炎疗效比较

探讨不同亚型α干扰素（IFNα-2α，IFNα-2b）治疗慢性乙型肝炎的疗效差异。110例慢性乙型肝炎（CHB）患者被随机分为IFNα-2α，治疗组（52例）和IFNα-2b治疗组（58例）。IFNα-2α治疗组采用IFNα-2a（因特芬）每日3MU肌注，IFNα-2b治疗组采用IFNα-2b（隆化诺）每日3MU肌注，30天后改隔日3MU肌注，疗程6月。观察两组用药3月，6月后血清ALT昨常率，HBeAg阴转率，HBV－DNA阴转率和治疗反应率。ALT复常率两组无明显差异（P＞0．05）。HBeAg阴转率：IFNα－2b治疗组（51.7%,67.2%)，明显优于IFNα－2a治疗组（32.7%,44.2%)，两组差异明显（P＜0．05）。HBV DNA阴转率：6月后IFNα－2b治疗组（58．6％），明显优于IFNα-2α治疗组（34．6％），两组差异明显（P＜0．05）。治疗后完全反应率：IFNα－2b治疗组（46．6％） ，明显优于IFNα-2α治疗组（21．2％），两组间有极显著差异（P＜0．01）。干扰素α-2b亚型治疗慢性乙型肝炎疗效明显优于干扰素α-2α，亚型。     

慢性乙型肝炎患者外周血单个核细胞穿孔素表达与干扰素抗病毒疗效的关系

目的研究慢性乙型肝炎(CHB)患者干扰素(IFN)治疗前、后外周血单个核细胞(PBMC)中穿孔素表达情况,探讨其对IFN抗病毒疗效的影响。方法采用免疫细胞化学技术检测35例CHB患者IFNα-2b治疗前、后PBMC中穿孔索的表达。结果IFNα～2b治疗前、后PBMC穿孔素的表达分别为7．9%±4．6%和15．3%±6．4%,较治疗前明显上升,t=6．53,P＜0．01,差异有统计学意义。IFNα-2b治疗后完全应答者有12例、部分应答者14例、无应答者9例。IFN治疗后完全应答组穿孔索的表达为19．2%±5．2%,部分应答组为14．2%±5．5%,无应答组为11．7%±6．7%,完全应答组与部分应答组比较,t=2．33,P＜0．05；完全应答组与无应答组比较,t=2．89,P＜0．01,差异有统计学意义。结论CHB患者IFN治疗可以使PBMC中穿孔素的表达升高,PBMC中穿孔素的表达可能与IFN抗病毒疗效有密切的关系。     

恩替卡韦治疗慢性乙型肝炎的早期临床观察

目的 评价恩替卡韦抗病毒治疗慢性乙型肝炎(CHB)24周的疗效和安全性.方法 70例CHB患者分为治疗组和对照组.治疗组(30例)予恩替卡韦0.5mg口服,每日一次.对照组(40例)予干扰素α-2b 3MU,肌肉注射,隔日一次.结果 治疗组治疗8周时HBV DNA水平较治疗前显著下降;治疗12周,HBVDNA阴转率为26.7%、HBeAg阴转率为33.3%,显著优于对照组,表现出较高的抗病毒早期应答率;治疗24周,HBVDNA阴转率为56.7%、HBeAg阴转率为73.3%,与对照组比较及治疗组自身比较差异显著,肝功能复常率为100%,提示有较良好的维持应答反应.治疗过程中未发生与观察药物相关的严重不良反应.结论 恩替卡韦能快速、强效地抑制乙肝病毒复制,安全性和耐受性良好.     

干扰素α与阿德福韦酯不同联合方法治疗HBeAg阳性慢性乙型肝炎的疗效

目的 观察IFNα联合阿德福韦酯(ADV)治疗HBeAg阳性慢性乙型肝炎(CHB)的临床疗效,探讨理想的联合治疗方案.方法 2005年1月至2009年6月纳入河北医科大学第三医院HBeAg阳性CHB患者156例.56例患者HBV DNA≥1×107拷贝/mL、或纤维化分期≥S3、或既往单药治疗失败(复发)者,予以初始IFNα联合ADV治疗;52例未达上述指标患者接受初始IFNα单药治疗.24周时依据患者HBV DNA、HBeAg、HBsAg变化调整治疗方案:16例取得早期应答的初始IFNα联合ADV治疗组患者调整为IFNα单药维持治疗,其余患者与初始IFNα单药治疗组未达到早期应答者共同接受IFNα联合ADV治疗.另选48例作为标准治疗组,接受全程IFNα单药治疗.48周时复评全部患者HBV DNA、HBeAg、HBsAg定量,并决定是否延长疗程.最终于72周评估患者疗效、安全性、耐药复发等,数据行卡方检验.结果 治疗24周,初始IFNα联合ADV治疗组早期应答率达28.6%,其中HBV DNA阴转率、ALT复常率(53.6%,62.5%)与初始IFNα单药治疗组(32.7%,x2=4.78;40.4%,x2=5.21)、标准治疗组(27.1%,x2=5.28;37.5%,x2=6.46)比较,差异均有统计学意义(均P<0.05),且HBeAg阴转率较标准治疗组更高(39.3%比18.8%,x2=7.48,P<0.05).48周时,初始IFNα联合ADV治疗组16例取得早期应答者停用ADV后,5例HBeAg复阳,3例病毒学反弹;HBV DNA阴转率为73.2%,HBeAg转换率为41.1%,HBsAg清除率为12.5%.其中96例接受不同联合方法治疗的患者HBV DNA阴转率、HBeAg转换率、HBsAg清除率分别为65.6%、33.3%和8.3%.72周时不同联合方法治疗组患者整体复发率与标准治疗组相当,HBsAg清除率上升2.7%.结论 IFNa联合ADV抗病毒治疗对提高应答率优势明显.结合患者基线特征、治疗反应,制订不同联合方案,不失为当前CHB抗病毒优化治疗理想策略之一.

Abstract：

Objective To investigate the efficacy of interferon α(IFNα)and adefovir dipivoxil (ADV)combination therapy in HBeAg positive chronic hepatitis B(CHB)patients and to explore the optimized strategy for individualized treatment.Methods A total of 156 HBeAg positive CHB patients were enrolled in the study from January 2005 to June 2009 in the Third Affiliated Hospital of Hebei Medical University.Fifty-six CHB patients with hepatitis B virus(HBV)DNA≥1 X 107copy/mLand/or liver fibrosis stage≥S3,or previous monotherapy failure(relapse)were treated with initial IFNα and ADV combination therapy.Fifty-two patients who didn't meet any of the above baseline characteristics received initial IFNα monotherapy.The remaining 48 patients treated with IFNα monotherapy for full treatment duration were considered as control.At week 24 of treatment,the treatment regimens were adjusted according to quantitative changes of HBV DNA,HBeAg and HBsAg:16 patients who achieved early response in group of initial IFNα and ADV combination therapy subsequently received IFNα monotherapy,the other patients in group of initial combination therapy together with patients who did not achieved early response in group of initial IFNα monotherapy subsequently received IFNα and ADV combination treatment.The HBV DNA levels,HBeAg and HBsAg titers were detected at the end of 48 weeks of treatment to determine the treatment duration.The treatment efficacy,safety,drug resistance and relapse rates were finally evaluated at week 72.All data were analyzed using chi square test.Results At week 24,the early response rate in group of initial combination therapy was 28.6%,and the HBV DNA negative rate and alanine aminotransferase(ALT)normalization rate were significantly higher than those in groups of initial IFNα monotherapy and control(53.6%vs 32.7%vs 27.1%and 62.5%vs 40.4%vs 37.5%,respectively,P<0.05);in addition,HBeAg loss rate was higher than control group(39.3%vs 18.8%,x2=7.48;P<0.05).At week 48,five of 16 patients who achieved early response developed HBeAg reversion and three cases accompanied with virological breakthrough in group of initial combination therapy after switching to IFNα monotherapy,while the rates of HBV DNA negative,HBeAg seroconversion and HBsAg clearance were 73.2%,41.1%and 12.5%,respectively.The HBV DNA negative rate,HBeAg seroconversion rate and HBsAg clearance rate in 96 patients Who had received different combination treatment regimens were 65.6%,33.3%and 8.3%,respectively.At week 72,the relapse rate in individualized treatment group was comparable to those in control group,while HBsAg clearance rate increased 2.7%in individualized treatment group.Conclusions IFNα and ADV combination treatment could improve early biochemical and virological responses.Individualized treatment strategy based on baseline characteristics and treatment responses may be helpful for optimizing antiviral treatment in CHB patients.     

干扰素-γ基因多态性与干扰素治疗慢性乙肝患者持久应答的关系

目的探讨干扰素-γ(IFN-γ)启动子基因874位点的单核苷酸多态性(SNP)与IFNα-2b治疗慢性乙肝(CHB)持久应答的关系。方法选择CHB患者106例,应用PCR-SSP技术分析宿主的IFN-γ启动子基因874位点的SNP,患者给予IFNα-2b治疗1年,随访1年,比较SNP与IFNα-2b疗程结束时完全应答、停药后随访1年完全应答(持久应答)的关系。结果在标准疗程结束时,完全应答的患者中三种基因型的分布无统计学差异(χ2=3.594 9,P=0.165 7)。而在持久应答患者中三种基因型的分布有统计学差异,TT基因型患者的持久应答率高于其他两种基因型患者(χ2=6.639 8,P=0.036 1)。结论 CHB患者对IFNα-2b治疗的持久应答与IFN-γ基因型有一定关联性,尤其与TT基因型关联更大。     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Presence of immunoreactive growth hormone and prolactin in the ovine pineal gland

Abstract: The use of antisera raised against bovine growth hormone (GH) and ovine prolactin (PRL) enabled the detection of related immunoreactive (ir) sequences of proteins in ovine pineal tissue. The isolation of PRL-like ir-material was accomplished using a 0.25 M ammonium sulphate (pH 5.5) extraction followed by ethanol precipitation, whereas the resulting 2.0 M ammonium sulphate (pH 7.0) precipitate contained a GH-like immunoreactivity. Gel chromatography of the GH-like immunoreactivity (Sephadex G-100) indicated the presence of several GH-like fragments ranging in the M_r range of 7,000 to 55,000. Analyses of the PRL-like ir-material found in pineal tissue on HPLC using a TSK 545-DEAE column led to the resolution into a single peak of immunoreactivity. A single peak of activity was also observed following chromatofocusing and hydrophobic interaction chromatography of the ir-peak from the TSK 545-DEAE column. The PRL-like ir-material inhibited the binding of [¹²⁵I]ovine PRL-S14 to anti-ovine PRL antibodies without showing an affinity for binding to anti-rat PRL or anti-bovine GH antibodies. Scatchard analysis of the binding of pineal PRL-like ir-material and pituitary ovine PRL-S14 to liver membranes from day-20 pregnant rats revealed similar affinity constants (K_a of 4.7 ± 0.2 × 10⁹ M^-1). In addition, the replication of Nb 2 Node rat lymphoma cells was stimulated by pineal PRL-like ir-material, an effect known to be specific for lactogenic hormones. The pineal PRL-like immunoreactivity appeared on sodium dodecyl sulfate polyacrylamide gels as a single major band of M_r 24,000. The functional status of PRL-and GH-like ir-material in the ovine pineal remains to be determined, but evidence is presented that the overall protein synthesis rate of the rat pineal responded to circulating concentrations of PRL.     

Microbiology of human immunodeficiency virus anorectal disease

PURPOSE: Individuals who are seropositive for the human immunodeficiency virus are at high risk for opportunistic infection and anorectal disorders. Little prospective information is available regarding anorectal pathogens in these patients. METHODS: One hundred sixty-three HIV-seropositive patients presented to the colorectal clinic between 1989 and 1992. Forty-seven (29 percent) patients were thought to have an infectious process and were prospectively studied using a standardized multiculture protocol. RESULTS: Mean age was 33 (range, 19–59) years. All were male; high-risk behavior accounted for 87 percent of HIV transmissions. Presenting complaints included anorectal pain (79 percent), pus per anum (28 percent), and blood per anum (26 percent). Examination revealed perianal tenderness (60 percent), condyloma (38 percent), perianal ulcers (38 percent), and anal fissures (34 percent). Sixty-six sets of cultures were performed; 28 patients had one set, 15 had two sets, and 4 had three sets. Thirty-two of these 47 patients (68 percent) had positive cultures including herpes (50 percent), cytomegalovirus (25 percent),Neisseria gonorrhoeae (16 percent), chlamydia (16 percent), acidfast bacilli (2 percent), and others (9 percent). Six of 32 patients with positive cultures had more than one organism cultured. Sixteen (50 percent) patients with positive cultures were treated medically, 8 (25 percent) were treated surgically and 8 (25 percent) were treated with both modalities. Sixty-one procedures were performed on 17 patients for condylomata. Eighteen patients had 20 procedures for abscesses, 50 percent of whom had positive cultures for other than common bowel flora; all improved. Fourteen patients underwent 33 procedures for perianal fistulas.Mycobacterium fortuitum was cultured from one patient who required 13 procedures for abscesses and fistulas. Forty-five (96 percent) patients were followed for an average of 12.5 months ±2.9 SEM (range, 1–94 months). Symptoms were improved or resolved in 22 of 32 (69 percent) patients with positive cultures and in 11 of 13 (84 percent) with negative cultures. CONCLUSIONS: Specific pathogens may often be identified in human immunodeficiency virus-seropositive patients with anorectal disorders if aggressively sought. Although patients without specific pathogens identified may be expected to improve with planned empiric treatment, positive identification allows more directed therapy.