Wester C William, Okezie Okechukwu A, Thomas Ann Muir, Bussmann Hermann, Moyo Sikhulile, Muzenda Tanaka, Makhema Joseph, van Widenfelt Erik, Musonda Rosemary, Novitsky Vladimir, Gaolathe Tendani, Ndwapi Ndwapi, Essex Max, Kuritzkes Daniel R, DeGruttola Victor, Marlink Richard G
Botswana-Harvard School of Public Health AIDS Initiative Partnership for HIV Research and Education, Gaborone, Botswana.
J Acquir Immune Defic Syndr. 2007 Nov 1;46(3):318-22. doi: 10.1097/QAI.0b013e3181568e3f.
The ability of nucleoside reverse transcriptase inhibitors (NRTIs) to inhibit human mitochondrial polymerase-gamma results in impaired synthesis of mitochondrial enzymes that generate adenosine triphosphate (ATP) by oxidative phosphorylation. This has been associated with several long-term mitochondrial toxicities, which include lactic acidosis and pancreatitis, peripheral neuropathy, and lipoatrophy.
Enrolled highly active antiretroviral therapy (HAART)-treated adults have completed nearly 2 years of follow-up as part of the ongoing randomized clinical trial Adult Antiretroviral Treatment and Drug Resistance (Tshepo) study. All patients were intensively screened for the presence of ARV-related toxicities.
Six hundred fifty adults (69% female) were initiated on NRTI-based HAART. Overall, 2.0% of patients developed moderate to severe symptomatic hyperlactatemia, with 7 (1.0%), all female, diagnosed with lactic acidosis. Female gender (P = 0.008) and being overweight, namely having a body mass index (BMI) of greater than 25 (P = 0.001), were predictive for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis. Older age (age >40 years) showed a statistical trend (P = 0.053) as a predictor for the development of toxicity, whereas exposure to d4T and/or ddI for 6 or more months was not predictive (P = 0.102). Those diagnosed with lactic acidosis had a mean BMI of 32.38 (interquartile range [IQR] = 29.4 to 35) at the time of toxicity and had been receiving HAART for a mean of 12.1 months (IQR = 7 to 20.8). Four of the 7 (57%) died of lactic acidosis and/or hemorrhagic pancreatitis; these 4 patients also had a comorbid diagnosis of severe clinical pancreatitis with grade 3/4 lipase elevations and abdominal symptoms at the time of their demise.
Rates of lactic acidosis appear to be higher in southern Africa when compared with rates previously described elsewhere. Risk factors for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis appear to be multifactorial but include female gender and having a BMI of greater than 25. Additional studies are ongoing to evaluate for other possible risk factors, such as host genetic differences.
核苷类逆转录酶抑制剂（NRTIs）抑制人线粒体聚合酶γ的能力会导致通过氧化磷酸化产生三磷酸腺苷（ATP）的线粒体酶合成受损。这与多种长期线粒体毒性有关，包括乳酸酸中毒、胰腺炎、周围神经病变和脂肪萎缩。
作为正在进行的随机临床试验“成人抗逆转录病毒治疗与耐药性（Tshepo）研究”的一部分，纳入接受高效抗逆转录病毒治疗（HAART）的成年人已完成近2年的随访。所有患者都接受了关于抗逆转录病毒药物相关毒性的密集筛查。
650名成年人（69%为女性）开始接受基于NRTIs的HAART治疗。总体而言，2.0%的患者出现中度至重度症状性高乳酸血症，其中7名（1.0%）女性被诊断为乳酸酸中毒。女性（P = 0.008）和超重，即体重指数（BMI）大于25（P = 0.001），是中度至重度症状性高乳酸血症或乳酸酸中毒发生的预测因素。年龄较大（年龄>40岁）作为毒性发生的预测因素显示出统计学趋势（P = 0.053），而接受司他夫定（d4T）和/或去羟肌苷（ddI）治疗6个月或更长时间则无预测性（P = 0.102）。那些被诊断为乳酸酸中毒的患者在毒性发生时的平均BMI为32.38（四分位间距[IQR]=29.4至35），且接受HAART治疗的平均时间为12.1个月（IQR = 7至20.8）。7名患者中有4名（57%）死于乳酸酸中毒和/或出血性胰腺炎；这4名患者在死亡时还合并诊断为严重临床胰腺炎，脂肪酶升高至3/4级并有腹部症状。
与其他地区先前描述的发生率相比，南部非洲乳酸酸中毒的发生率似乎更高。中度至重度症状性高乳酸血症或乳酸酸中毒发生的危险因素似乎是多因素的，但包括女性和BMI大于25。正在进行其他研究以评估其他可能的危险因素，如宿主基因差异。
