Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection
Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection
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DOI：
10.1001/jama.283.1.74
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发表时间：
2000-01-05
影响因子：
120.7
通讯作者：
Moore, RD
中科院分区：
文献类型：
--
作者：
Sulkowski, MS;Thomas, DL;Moore, RD
背景使用抗逆转录病毒药物，包括蛋白酶抑制剂，治疗人类免疫缺陷病毒（HIV）感染与肝毒性有关，特别是在合并感染丙型肝炎或B病毒的患者中。并明确慢性病毒性肝炎在其发展中的作用。设计前瞻性队列研究。1996年1月至1998年1月期间，共有298名患者接受了新的抗逆转录病毒疗法，其中211例（71%）接受蛋白酶抑制剂作为联合治疗的一部分（中位随访时间为182天），87例（29%）接受双重核苷类似物方案（中位随访时间为167天）。慢性丙型肝炎和B病毒感染分别为154例（52%）和8例（10%）。主要结果测量严重肝毒性，定义为血清丙氨酸转氨酶和天冬氨酸转氨酶水平的3级或4级变化，结果298例患者中，31例（10.4%）出现严重肝毒性，95%可信区间（CI）为7.2%~ 14.4%。利托那韦的使用与较高的毒性发生率相关（30%; 95% CI，17.9%-44.6%）。然而，其他治疗组（即核苷类似物）的肝毒性发生率无显著差异（5.7%; 95% CI，1.2%-12.9%）、奈非那韦（5.9%; 95% CI，1.2%-16.2%）、沙奎那韦（5.9%; 95% CI，0.15%-28.7%）和茚地那韦（6.8%; 95% CI，3.0%-13.1%）。尽管慢性病毒性肝炎与接受非利托那韦治疗的患者中严重肝毒性风险增加相关（相对风险，3.7; 95% CI，1.0-11.8），但大多数慢性丙型肝炎或B病毒感染患者（88%）未出现显著毒性作用。在丙型肝炎感染患者中使用任何蛋白酶抑制剂的重度毒性发生率为12.2%（13/107; 95% CI，6.6%-19.9%）。在多变量logistic回归分析中，只有利托那韦（校正比值比[AOR]，8.6; 95%CI，3.0-24.6）和CD 4细胞计数增加超过0.05 × 10（9）/L（AOR，3.6; 95%CI，1.0-12.9）与重度肝毒性相关。没有不可逆的结果被认为是在患者严重hepatoxic.Conclusions我们的数据表明，使用利托那韦可能会增加严重的肝毒性的风险。虽然肝毒性在慢性病毒性肝炎患者中可能更常见，但这些数据并不支持对合并感染B或C型肝炎病毒的患者停止蛋白酶抑制剂治疗。
Context Use of antiretroviral drugs, including protease inhibitors, for treatment of human immunodeficiency virus (HIV) infection has been anecdotally associated with hepatotoxicity, particularly in persons coinfected with hepatitis C or B virus.Objectives To ascertain if incidence of severe hepatotoxicity during antiretroviral therapy is similar for ail antiretroviral drug combinations, and to define the role of chronic viral hepatitis in its development.Design Prospective cohort study.Setting University-based urban HIV clinic.Patients A total of 298 patients who were prescribed new antiretroviral therapies between January 1996 and January 1998, 211 (71%) of whom received protease inhibitors as part of combination therapy (median follow-up, 182 days) and 87 (29%) of whom received dual nucleoside analog regimens (median follow-up, 167 days). Chronic hepatitis C and B virus infection was present in 154 (52%) and 8 (2.7%) patients, respectively.Main Outcome Measure Severe hepatotoxicity, defined as a grade 3 or 4 change in levels of serum alanine aminotransferase and aspartate aminotransferase, evaluated before and during therapy.Results Severe hepatotoxicity was observed in 31 (10.4%) of 298 patients (95% confidence interval [CI], 7.2%-14.4%). Ritonavir use was associated with a higher incidence of toxicity (30%; 95% CI, 17.9%-44.6%). However, no significant difference was detected in hepatotoxicity incidence in other treatment groups, ie, nucleoside analogs (5.7%; 95% CI, 1.2%-12.9%), nelfinavir (5.9%; 95% CI, 1.2%-16.2%), saquinavir (5.9%; 95% Cl, 0.15%-28.7%), and indinavir (6.8%; 95% CI, 3.0%-13.1%). Although chronic viral hepatitis was associated with an increased risk of severe hepatotoxicity among patients prescribed nonritonavir regimens (relative risk, 3.7; 95% CI, 1.0-11.8), most patients with chronic hepatitis C or B virus infection (88%) did not experience significant toxic effects. Rate of severe toxicity with use of any protease inhibitor in patients with hepatitis C infection was 12.2% (13/107; 95% CI, 6.6%-19.9%). In multivariate logistic regression, only ritonavir (adjusted odds ratio [AOR], 8.6; 95% CI, 3.0-24.6) and a CD4 cell count increase of more than 0.05 x 10(9)/L (AOR, 3.6; 95% CI, 1.0-12.9) were associated with severe hepatotoxicity. No irreversible outcomes were seen in patients with severe hepatotoxicity.Conclusions Our data indicate that use of ritonavir may increase risk of severe hepatotoxicity. Although hepatotoxicity may be more common in persons with chronic viral hepatitis, these data do not support withholding protease inhibitor therapy from persons coinfected with hepatitis B or C virus.