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目前,使用最广泛的LTBI治疗方案是6~9H方案[异烟肼(H),1次/d,6~9个月],其他方案如3HR[异烟肼联合利福平(R);1次/d,共3个月)或4R(利福平;1次/d,共4个月)也被推荐和使用。但近年的研究发现,3HP方案[异烟肼联合利福喷丁(P);各0.9g,1次/周,共12次]预防性治疗的有效性与9H方案效果相当且具有更高的完成率[3-4]。故各国指南推荐,对于无药物不耐受或有药物相互作用的患者,与较长疗程6~9H方案相比,应首选短疗程的含利福霉素为主的治疗方案[5-6]。截至2021年6月,36个国家报告了使用含利福喷丁的短程方案,较2020年增加了7个国家[2]。但3HP方案在中国临床应用经验及国内相关的研究和文献均较少。为此,笔者拟前瞻性分析应用含3HP方案治疗风湿性疾病合并LTBI患者的安全性和完成率,为临床应用提供参考和借鉴。
对象和方法
一、 研究对象
采用前瞻性研究方法,参照入组标准纳入2019年6—12月深圳市第三人民医院结核科门诊收治的风湿免疫性疾病合并LTBI患者,给予3HP方案预防性治疗LTBI,观察用药期间不良反应发生率,记录完成率,并随访2年观察活动性结核病的发病情况。本研究经深圳市第三人民医院伦理委员会批准(伦审科研字[2019-015-02]号),且所有患者均签署知情同意书。
纳入标准:(1)年龄范围为18~65岁;(2)自愿接受3HP治疗;(3)同意签署知情同意书;(4)临床确诊的风湿免疫性疾病合并LTBI(使用IGRA方法确诊)患者。
排除标准:(1)活动性结核病患者;(2)与耐多药结核病密切接触的LTBI者;(3)合并严重肾功能损伤(血清肌酐超过正常上限的1.5倍)或肝功能损伤[丙氨酸氨基转移酶(ALT)和(或)天冬氨酸氨基转移酶(AST)水平超过正常上限的2.5倍]的患者;(4)HIV抗体阳性或AIDS患者;(5)有严重心血管疾病,如心力衰竭、心律失常或心肌梗死后状态;(6)有精神障碍或精神评估不合格者。
二、 研究方法
记录患者的性别、年龄、基础风湿性疾病及用药情况;观察并记录患者在治疗第1、2、3个月末用药反应和治疗完成情况;在患者停药后的第6、12、24个月末进行随访,并记录期间进展为活动性结核病情况。其中,用药期间不良事件依据通用术语标准[6]对其进行评级,以评价3HP方案的安全性。其中,1级:轻微症状,不需要停药或干预,患者可耐受或自行缓解;2级:需要停药或用药干预,可以恢复正常;3级:必须停药并干预,不能完全恢复正常;4级:危及患者生命;5级:导致患者死亡。
三、统计学处理
采用SPSS 20.0 软件进行数据的统计分析。人口学特征和不良事件记录等采用描述性分析;计数资料使用“例(率/构成比,%)”描述。
结果
一、患者一般资料
共计纳入38例患者,其中,男性18例(47.4%),女性20例(52.6%);年龄范围为21~65岁,平均年龄为(40.2±1.9)岁;强直性脊柱炎20例(52.6%)、类风湿性关节炎14例(36.9%)、系统性红斑狼疮4例(10.5%)。均使用风湿免疫性疾病基础用药,在此基础上有6例(15.8%)加用中成药、17例(44.7%)加用生物制剂、10例(26.3%)加用泼尼松片(1~2片/次,1次/d),19例(50.0%)曾使用止痛药物、12例(31.6%)使用除糖皮质激素外的免疫抑制剂(如甲氨蝶呤、环磷酰胺、柳氮磺嘧啶和羟氯喹)。
二、3HP方案治疗情况、完成率和活动性结核病发病率
1.不良反应发生情况:38例患者治疗过程中不良事件发生率为15.8%(6例)。其中,服药第1~2周内出现失眠、头晕、皮疹的患者各1例,出现消化道反应者2例,均自行缓解,不良反应分级均为1级;用药1个月后出现药物性肝损伤患者1例,伴有恶心呕吐、ALT和AST升高(分别为110U/L和75U/L),该患者既往无基础肝病,予以停用3HP方案,改为9H方案行预防性抗结核治疗,不良反应分级为2级。
2.完成率:除药物性肝损伤患者外,37例(97.4%)患者均完成了3HP方案治疗。
3.活动性结核病发生情况:随访2年,完成3HP方案治疗的患者均未进展为活动性结核病。
讨论
一、LTBI预防性抗结核治疗的现状
当前,为了降低结核病发病率,WHO对LTBI预防性抗结核治疗越来越重视,然而其治疗完成率为24%~98%不等,主要原因与患者顾忌药物不良反应、治疗时间长、经济负担等多种因素有关[7]。经典的治疗LTBI方案是6~9H方案,其安全性及有效性高,但完成率仅为50%左右;而现有的4R、3HR、3HP(3HP和1HP)方案可将使用时间缩短至3~4个月,极大地提高了完成率,目前报道的完成率为80%左右[8],而且含利福霉素治疗方案的预防性治疗在减少活动性结核病发病率方面的效能与6H方案效能相当,因此,含利福霉素方案在结核病低流行国家逐渐得到推广应用,尤其是3HP方案在很多国家的指南中均被推荐使用,比如韩国[9]、欧洲[10],但目前在中国仍鲜有应用3HP方案治疗LTBI的研究报道。
有研究发现,21.8%的风湿性疾病患者外周血γ-干扰素释放试验呈阳性,表明风湿性疾病患者合并LTBI的比例偏高[11]。随着越来越多的风湿性疾病患者使用免疫抑制剂和生物制剂,合并活动性结核病的风险也随之增加[12];其中,抗肿瘤坏死因子的治疗导致LTBI的再激活和播散已有相关报道[13]。这使得生物制剂使用前进行结核病筛查及预防性治疗越来越受到重视[14]。国外的研究表明,虽然针对LTBI患者进行预防性抗结核治疗并不能完全消除激活潜伏的结核分枝杆菌的风险,但对接受生物制剂治疗的LTBI患者进行预防性抗结核治疗能够减少活动性结核病的发生[15]。因此,针对合并LTBI的风湿性疾病患者,预防性抗结核治疗是有效且具有良好的耐受性[16-17]。
二、3HP方案在风湿性疾病合并LTBI患者中的应用探索
既往的研究认为,6H方案治疗LTBI具有降低活动性结核病和不良反应发生率的优势[18],但该方案的主要问题是完成率低。日本的研究表明,6H方案的治疗完成率仅为66%,低于含利福平方案(86%),但医疗费用相当[19];还有研究发现,在实施6H方案时,有25%的患者不能坚持到5个月,且随着用药时间的延长,不良反应也增多[20],药物性肝损伤的发生率可达6.6%[21],而因为肝功能损伤导致异烟肼反复停药后再使用,又进一步延长了治疗时间[22]。因此,相对于6~9H方案,在疗效相当的情况下使用含利福霉素的方案具有更好的依从性[23]。尤其是对于风湿性疾病患者,往往需要长期使用免疫抑制剂,用药不良反应多,故认为在考虑风湿性疾病合并LTBI患者用药安全的情况下,更应推荐使用短程方案进行治疗以减少长时间用药带来的危害[24]。近年来,越来越多的文献推荐使用3HP方案治疗LTBI者,该方案不仅在减少活动性结核病发病率和保证安全性方面与其他方案相当,其总体完成率也更高[25-26]。
本研究患者除1例因肝功能损伤停用3HP方案外,其他患者均完成治疗疗程,完成率高达97.4%,这种高完成率与国外报道基本一致,该报道将3HP方案应用于11例器官移植患者中,完成率达到了100%[27]。同样,该方案在HIV感染者中的使用也是安全有效的[28],即使在老年人群和肾功能衰竭患者中,其完成率也可以达到70%和82%,较9H方案的完成率(61%)显著升高[29⇓⇓-32]。Yang等[33]在中国儿童中使用3HP治疗LTBI者,也报道了100%的完成率。这种高完成率可能与3HP方案服药方便有关,相较于其他方案的多次用药,3HP方案每周1次共12次的服药方式可能更容易让患者接受,依从性较高。
本研究使用3HP方案用于风湿性疾病合并LTBI患者的不良反应发生率为15.8%,且等级均为轻度。但既往有研究发现,因发生药物不良反应而停用3HP方案治疗的患者达9%[34]。特别对于老年患者,3HP方案发生严重不良反应的风险总体为11.2%[30],且年龄≥80岁的患者治疗中断的风险最高[35]。另外,也有文献报道,血液透析合并LTBI患者使用3HP方案的不良事件发生率高达69.2%[36]。分析不同研究不良反应发生率的差异,我们发现不良反应的严重程度可能与患者的年龄和基础疾病相关,年龄大和基础疾病较重的患者更容易出现不良反应,本组研究患者平均年龄为39.2岁,属于中青年且无其他严重基础疾病,总体耐受性相对良好,但15.8%的不良反应发生率仍然提示我们在用药过程中仍需密切观察患者用药反应,尽量保证用药安全。
既往研究表明,风湿性疾病合并LTBI患者进展为活动性结核病的风险相比普通人群明显升高;而且,LTBI者进展为活动性结核病主要发生于感染的2年内,预防性治疗能够减少活动性结核病的发病率[16]。本组患者完成3HP方案后随访2年,未发现进展为活动性结核病患者,与上述研究一致,提示3HP方案可能具有减少LTBI进展为活动性结核病的作用。
三、本研究存在的不足
本研究存在以下局限性:一是本研究属于单中心小样本前瞻性研究,目前纳入的患者数较少,仅有初期研究数据,尚不能对3HP方案在减少活动性结核病发病率方面的作用形成最终结论,后续需扩大样本量并延长随访时间以进一步评价。二是未能对不同基础风湿性疾病、不同免疫抑制剂使用患者进行分层分析,不能评价合并症对预防性抗结核治疗的影响。
综上,本研究开展了国内首个应用3HP方案预防性治疗风湿性疾病合并LTBI患者的前瞻性研究,初期结果显示该方案具有完成率高、不良反应少、患者依从性好等优点。这一探索为3HP方案在风湿性疾病合并LTBI患者中的应用提供了临床参考,但该方案的远期疗效仍有待进一步验证。
利益冲突 所有作者均声明不存在利益冲突
作者贡献 王玉香:撰写初稿并负责数据统计;陈秋奇、余鑫鑫和詹森林:负责随访和数据整理;张培泽和邓国防:负责临床病例管理
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Latent tuberculosis infection (LTBI) accounts for almost a quarter of the world population, and, in 5-10% of the subjects with impaired immune-response against M. tuberculosis growth, it may progress to active tuberculosis (TB). In this review, we focus on the need to propose a screening for LTBI including preventive therapy offer in rheumatic patients undergoing therapy with biological drugs. Areas covered: We report on evidence that biologics are associated with an increased risk of active TB reactivation. This effect seems to be mainly limited to treatment with anti-tumor necrosis factor (TNF) agents, while non-anti-TNF-targeted biologics are not likely associated to any increased risk. We introduce the concept that the patients' coexisting host-related risk factors, such as comorbidities, are crucial to identify those at higher risk to reactivate TB. We report that preventive TB therapy is well tolerated in patients treated with biological drugs. Expert commentary: Availability of non-anti-TNF targeted biologics, that are not associated with an increased risk of TB reactivation, offers a great opportunity to tailor a therapeutic intervention at low/absent TB risk. After proper LTBI screening investigations, preventive TB therapy has been demonstrated to be effective and well-tolerated to reduce the risk of TB reactivation in rheumatic patients requiring biological drugs.
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