社论:医疗设备另一种药物以打击青少年B型肝炎病毒

StephenW

Editorial

Another drug in the armamentarium to combat hepatitis B virus in adolescents
医疗设备另一种药物以打击青少年B型肝炎病毒

Philip Rosenthal M.D


Chronic hepatitis B virus (HBV) remains a significant worldwide problem despite the introduction and use of hepatitis B vaccines for four decades. HBV morbidity and mortality account for millions of dollars and immeasurable suffering. Chronically infected children are at increased risk to develop liver disease and hepatocellular carcinoma. So what can we do to alter unfavorable outcomes? We know from adult studies that suppression of viral loads translates into improved outcomes; adapting this approach to children and adolescents should theoretically have similar advantageous results. In this issue of HEPATOLOGY, Murray et al.1 report on the favorable results of a randomized, placebo-controlled trial of tenofovir disoproxil fumarate (DF) in adolescents (12 to <18 years of age) with chronic hepatitis B. Subjects were randomized to tenofovir DF 300 mg (n = 52) or placebo (n = 54) once daily for 72 weeks. The primary endpoint was virologic response (HBV DNA <400 copies/mL) at week 72. As might be anticipated, a virologic response was observed in 89% (46/52) of patients who received tenofovir DF and 0% (0/54) of patients who received placebo (P < 0.001). Treatment response was not affected by prior HBV treatment. Furthermore, no resistance to tenofovir DF developed through week 72. Among patients with an alanine aminotransferase (ALT) greater than the upper limit of normal at baseline, normalization of ALT occurred in 74% of patients receiving tenofovir DF and 31% of patients receiving placebo (P < 0.001). The rate of grade 3/4 adverse events was higher among patients treated with placebo (24%) than patients treated with tenofovir DF (10%). No patients met the safety endpoint of a 6% decrease in spine bone mineral density at week 72. The authors concluded that tenofovir DF therapy in HBV-infected adolescents was well tolerated and highly effective at suppressing HBV DNA and normalizing ALT values in both treatment-naïve adolescents and those with prior exposure to HBV therapy.

There are several potential limitations of this study. Most of the subjects enrolled in this study were Caucasian patients from Poland and had HBV genotypes A and D. In the United States, genotypes A and C are most common, so whether these results translate into similar findings in adolescents with genotype C is currently unknown.2 Tenofovir DF has been associated with decreased bone density and osteoporotic fracture risk in human immunodeficiency virus–positive patients.3 Over 72 weeks of therapy, no significant decrease in spine bone mineral density was observed, but whether this observation will persist in adolescents with chronic HBV after a longer period of use of tenofovir DF is not known.

ALT, alanine aminotransferase; DF, disoproxil fumarate; HBV, hepatitis B virus.

It is quite gratifying to witness the continued pipeline of pharmaceuticals to combat HBV infection being studied and ultimately receiving approval for use in children and adolescents. It was not that long ago that there were no approved medications or very few limited drugs to treat HBV. Although universal use of HBV vaccine will ultimately prove to be the single greatest public health measure to combat chronic HBV infection, for those unfortunate children and adolescents afflicted with the disease, medications such as tenofovir DF hold the promise of allowing long and healthy lives. Although this study was limited to adolescents, future study of tenofovir DF in younger children is being initiated. Many questions regarding the best therapy for patients with chronic HBV infection remain: Are there combinations of drugs that will improve seroconversion? Are there regimens that will allow shorter duration of therapy? Are there different regimens that will improve virologic responses in different genotypes? Does early age treatment decrease the risks of future hepatocellular carcinoma occurrence? Do quantitative hepatitis B surface antigen measurements better predict response to therapy? Certainly, continued investigations with new drugs and regimens will answer these important questions. Eradication of chronic HBV infection is closer than ever.

StephenW

慢性乙型肝炎病毒（HBV）四十年来，尽管乙肝疫苗的引进和使用的仍然是一个重大的全球性问题。乙肝发病率和死亡率帐户数百万美元和难以估量的痛苦。慢性感染的儿童发展肝脏疾病和肝癌的风险增加。所以，我们能做些什么来改变不利的结果吗？我们知道，从成人的研究，抑制病毒载量转化为改进的成果，这种方法适应于儿童和青少年，理论上应该有类似的有利结果。在这个问题上的杂志，穆雷等人1报告的有利结果的随机，安慰剂对照试验，富马酸替诺福韦酯（DF），青少年（12至<18岁）与慢性B型肝炎的主题是随机的替诺福韦DF 300毫克组（n = 52）或安慰剂组（n = 54），每天一次72周。主要终点是在72周时的病毒学应答（HBV DNA <400拷贝/毫升）。正如预期，病毒学反应，观察在89％（46/52）的患者替诺福韦DF和0％（0/54）的患者接受安慰剂（P <0.001）。治疗前HBV治疗的反应并没有受到影响。此外，无耐药性替诺福韦DF开发的通过72周。发生在患者的丙氨酸氨基转移酶（ALT）大于正常上限在基线ALT正常化74％的患者接受替诺福韦DF和31％的患者接受安慰剂（P <0.001）。治疗的患者与安慰剂组（24％）比替诺福韦DF（10％）患者中的3/4级不良事件率较高。没有满足患者的脊柱骨矿物密度下降了6％，在72周时的安全性终点。作者得出结论：在HBV感染的青少年，替诺福韦DF治疗的耐受性良好，非常有效地抑制HBV DNA和ALT复常值都治疗过的青少年和那些与之前曝光的HBV治疗。

本研究有几个潜在的局限性。参加这项研究的受试者来自波兰的白人患者HBV基因型A和D在美国，基因型A和C是最常见的，因此，无论这些结果转化为类似的发现在青少年中，C基因型是目前未知0.2替诺福韦DF一直伴随着人类免疫缺陷病毒阳性患者骨密度下降和骨质疏松性骨折的危险性超过72周的治疗，没有观察到脊柱骨矿物密度显着下降，但这个观察是否会坚持在青少年慢性HBV替诺福韦DF使用了一段时间后还没有已知的。

ALT，谷丙转氨酶，DF，诺福韦酯;乙肝病毒，乙肝病毒。

见证了持续的战斗HBV感染的药品，正在研究，并最终获得批准用于儿童和青少年的管道，这是很可喜的。这不是很久以前，有没有批准的药物或几个有限的药物来治疗HBV。虽然乙肝疫苗的普遍使用将最终被证明是最大的单一的公共健康措施，以打击慢性HBV感染者，为这些不幸的儿童和青少年患有这种疾病，药物如替诺福韦DF的承诺，允许长期和健康的生活。虽然这项研究是有限的青少年，在年幼的儿童替诺福韦DF今后的研究正在启动。关于慢性HBV感染患者的最佳治疗仍然有很多问题：是否有药物组合，这将提高血清学转换？是否有方案，将可缩短治疗时间？是否有不同的方案，这将提高病毒学反应不同基因型吗？从小治疗，减少未来的肝癌发生的风险吗？做定量的乙肝表面抗原的测量更准确地预测对治疗的反应吗？当然，新的药物和治疗方案的继续调查，将回答这些重要的问题。消除慢性HBV感染者比以往任何时候都更接近。