Sulkowski M S, Thomas D L, Chaisson R E, Moore R D
Department of Medicine, Johns Hopkins University Schools of Medicine, Baltimore, MD 21287, USA.
JAMA. 2000 Jan 5;283(1):74-80. doi: 10.1001/jama.283.1.74.
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.
To ascertain if incidence of severe hepatotoxicity during antiretroviral therapy is similar for all antiretroviral drug combinations, and to define the role of chronic viral hepatitis in its development.
Prospective cohort study.
University-based urban HIV clinic.
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.
Severe hepatotoxicity, defined as a grade 3 or 4 change in levels of serum alanine aminotransferase and aspartate aminotransferase, evaluated before and during therapy.
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% CI, 0.15%-28.7%), and indinavir(6.8%; 95% CI, 3.0%-13.1 %). Although chronicviral 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.
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.
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，据传闻与肝毒性有关，尤其是在合并感染丙型或乙型肝炎病毒的患者中。
确定抗逆转录病毒治疗期间严重肝毒性的发生率在所有抗逆转录病毒药物组合中是否相似，并确定慢性病毒性肝炎在其发生过程中的作用。
前瞻性队列研究。
大学附属城市HIV诊所。
1996年1月至1998年1月期间共298例接受新抗逆转录病毒治疗的患者，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182天），87例（29%）接受双核苷类似物方案（中位随访时间167天）。分别有154例（52%）和8例（2.7%）患者存在慢性丙型和乙型肝炎病毒感染。
严重肝毒性，定义为治疗前和治疗期间血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平出现3级或4级变化。
298例患者中有31例（10.4%）出现严重肝毒性（95%置信区间[CI]，7.2%-14.4%）。使用利托那韦与更高的毒性发生率相关（30%；95%CI，17.9%-44.6%）。然而，在其他治疗组中，即核苷类似物（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%），未检测到肝毒性发生率有显著差异。虽然慢性病毒性肝炎与接受非利托那韦方案治疗的患者发生严重肝毒性的风险增加相关（相对风险，3.7；95%CI，1.0-11.8），但大多数慢性丙型或乙型肝炎病毒感染患者（88%）未出现明显毒性作用。丙型肝炎感染患者使用任何蛋白酶抑制剂的严重毒性发生率为12.2%（13/107；95%CI，6.6%-19.9%）。在多因素逻辑回归中，只有利托那韦（调整优势比[AOR]，8.6；95%CI，3.0-24.6）和CD4细胞计数增加超过0.05×10⁹/L（AOR，3.6；95%CI，1.0-12.9）与严重肝毒性相关。严重肝毒性患者未出现不可逆结局。
我们的数据表明，使用利托那韦可能会增加严重肝毒性的风险。虽然肝毒性在慢性病毒性肝炎患者中可能更常见，但这些数据不支持对合并感染乙型或丙型肝炎病毒的患者停用蛋白酶抑制剂治疗。
