初步研究显示pritelivir对HSV-2感染有效

《新英格兰医学杂志》1月15日在线发表的一项小型概念验证研究显示，在被开发用于治疗单纯疱疹病毒(HSV)感染的新一类抗病毒药物中，pritelivir是首个可抑制病毒脱落和病变形成的药物。该试验性药物可通过靶向于HSV解旋酶-引物酶复合物来抑制HSV复制。该研究结果表明，该药可在其他方面健康的男性和女性中降低生殖器粘膜上HSV脱落的频率，并且在发生突破性脱落的情况下可使脱落的病毒量减少98%以上。此外，pritelivir还显著减少生殖器病变存在的天数。研究者表示，由于该研究没有充分把握度评估药物对症状性复发的影响，因此需将研究结果视为初步结果，并在未来研究中进一步探讨(N. Engl. J. Med. 2014 Jan. 15 [doi:10.1056/NEJMoa1301150])。

研究者指出，由于在接受日剂量75 mg/kg至1,000 mg/kg处理的猴子中进行的毒理学研究观察到不明原因的皮肤和血液学结果，因此美国食品药品管理局于2013年5月要求暂停pritelivir的临床开发。这些剂量是人用剂量75 mg的70倍至900倍以上。在当前的人体研究中未观察到此类不良事件。

在当前的双盲、剂量探索研究中，华盛顿大学西雅图分校过敏和传染病科教授Anna Wald医生及其同事在155例患有HSV-2感染11年(中位数)且每年复发达9次但在其他方面健康的男性和女性中对该药的安全性和疗效进行了评估。这些患者的中位年龄为41岁。大部分(67%)为女性，75%为白人。这些患者在美国7个医学中心接受治疗和随访。研究期间，患者每天提供生殖器皮肤和黏膜拭子进行HSV检测，并每天写日记记录生殖器体征和症状。

患者被随机分入以下5组，接受28天的治疗：pritelivir日剂量5 mg组(33例)、日剂量25 mg组(32例)、日剂量75 mg组(29例)；pritelivir周剂量400 mg组(31例)；每日安慰剂组(30例)。

结果显示，75-mg抑制HSV-2的有效性最大。对照(安慰剂)组在16.6%的天数里观察到HSV脱落。相比之下，pritelivir日剂量5 mg组、日剂量25 mg组、日剂量75 mg组和周剂量400 mg组观察到HSV脱落的天数比例分别为18.2% 、9.3%、2.1%和5.3%。

该药在男性中的有效性与在女性中相似。使用75 mg pritelivir的男性在3.2%的天数中发生HSV脱落，而使用安慰剂的男性在12.5%的天数中发生HSV脱落。相似地，使用75 mg pritelivir的女性在1.6%的天数中发生HSV脱落，而使用安慰剂的女性在18.3%的天数中发生HSV脱落。

在检测到HSV脱落的情况下，安慰剂组DNA拷贝的log-10中位数为5.1，5-mg pritelivir组为4.5，25-mg pritelivir组为3.6，75-mg pritelivir组为2.4，400-mg pritelivir组为3.6。因此，在75-mg剂量水平，pritelivir使突破性脱落中的HSV DNA量降低98%以上。

研究者还评估了患者患有生殖器病变的天数比例。75-mg pritelivir组该比例为1.2%，而安慰剂组为9%，5-mg pritelivir组为12.5%，25-mg pritelivir组为3.5%，400-mg pritelivir组为1.2%。

虽然1个月的疗程较短，但研究期间未观察到不良事件或实验室异常模式。3例患者因不良事件停止治疗：1例患者出现中度头痛、恶心、胸痛和呼吸困难；第2例患者怀疑患有系统性红斑狼疮，该事件导致患者进一步参与研究的资格被取消；第3例患者因轻度焦虑退出。

另6例患者因其他原因退出或失访，1例因怀孕退出，另1例未依从研究方案。最后1例患者在完成治疗后2周发生胰腺炎，但研究者认为该事件与药物相关，因为该患者既往曾发生酒精相关胰腺炎且研究者认为该患者在研究结束后再次饮酒。

虽然pritelivir显著降低病毒脱落率，但一些突破性脱落仍然发生。未来研究需探讨增加pritelivir日剂量是否能够完全消除病毒脱落。由于pritelivir靶向的是与阿昔洛韦等核苷类似物不同的通路，因此未来研究还应探讨联合治疗的有效性。

该研究获AiCuris公司资助。Wald医生声明与Agenus等多家公司存在联系。其他研究者披露诸多经济利益关系。

随刊述评：Pritelivir可代替或与阿昔洛韦联用

阿拉巴马大学伯明翰分校儿科、微生物学、医学和神经外科的Richard J. Whitley医生和Mark Prichard医生表示，pritelivir和这一新类别的抗人单纯病毒药物中的其他药物可积极抑制对阿昔洛韦类药物产生耐药的病毒，因此可代替核苷类药物用于治疗许多患者。核苷类似物耐药常见于免疫低下的宿主，特别是干细胞移植受者和AIDS抗病毒治疗失败的患者。如Wald医生及其同事所报告，pritelivir与阿昔洛韦合用在目前成为可能，尤其是对于HSV感染危及生命的患者。目前评估这种可能性的研究正在进行中。

Whitley医生声明与N and N Scientific公司和Gilead公司存在联系。Prichard医生声明无相关经济利益冲突(N. Engl. J. Med. 2014 Jan. 15 [doi:10.1056/NEJMe1313982])。

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By: MARY ANN MOON, Oncology Practice

Pritelivir, "the first in a new class of antiviral agents developed for the treatment of herpes simplex infections," suppressed viral shedding and lesion formation in a small proof-of-concept study funded by the drug’s manufacturer and reported online Jan. 15 in the New England Journal of Medicine.

The drug is the first in its class that inhibits HSV replication by targeting the HSV helicase–primase enzyme complex. Findings from this study showed that the investigational agent markedly reduced both the frequency of HSV shedding on the genital mucosa in otherwise healthy men and women and, when breakthrough shedding did occur, decreased the quantity of virus shed by more than 98%, said Dr. Anna Wald, professor in the division of allergy and infectious diseases at the University of Washington in Seattle, and her associates.

Pritelivir also significantly reduced the number of days when genital lesions were present. Because the study was not powered to assess the effect on symptomatic recurrences, this must be considered a preliminary finding to be explored in future studies, they added.

The investigators noted that the Food and Drug Administration placed a hold on the clinical development of pritelivir in May 2013 "because of unexplained dermal and hematologic findings in a toxicology study of monkeys treated with daily doses ranging from 75 mg per kg to 1,000 mg per kg." These doses were 70 to more than 900 times as high as a dose of 75 mg in humans. No such adverse events were observed in this trial.

Dr. Wald and her colleagues assessed the drug’s safety and efficacy in their double-blind, dose-finding study that involved 155 otherwise healthy men and women who had had HSV 2 infection for a median of 11 years and who had up to nine recurrences each year. The median age of the study subjects was 41 years. Most (67%) were women, and 75% were white.

These participants were treated and followed at seven medical centers in the United States. They provided daily swabs of genital skin and mucosa for HSV detection and kept diaries of genital signs and symptoms throughout the trial.

The patients were randomly assigned to five study groups: pritelivir at daily doses of 5 mg (33 subjects), 25 mg (32 subjects), or 75 mg (29 subjects); a weekly dose of 400 mg (31 subjects); or daily placebo (30 subjects). They were treated for 28 days.

The 75-mg dose was found to have the greatest effectiveness against HSV 2.

HSV shedding in the reference (placebo) group occurred on 16.6% of days. In comparison, HSV shedding occurred on 18.2% of days with 5-mg pritelivir; 9.3% of days with 25 mg; 2.1% of days with 75 mg; and 5.3% of days with 400 mg weekly, Dr. Wald and her associates reported (N. Engl. J. Med. 2014 Jan. 15 [doi:10.1056/NEJMoa1301150]).

The drug was similarly effective in men and women. For example, HSV shedding occurred on 3.2% of days in men taking 75-mg pritelivir, compared with 12.5% of days in men taking placebo. Similarly, HSV shedding occurred on 1.6% of days in women taking 75-mg pritelivir, compared with 18.3% of days in women taking placebo, they said.

When HSV shedding was detected, the median log-10 number of DNA copies was 5.1 with placebo, 4.5 with 5-mg pritelivir, 3.6 with 25-mg pritelivir, 2.4 with 75-mg pritelivir, and 3.6 with 400-mg pritelivir. Thus, at the 75-mg dose, pritelivir reduced the quantity of HSV DNA in breakthrough shedding by more than 98%.

The researchers also assessed the percentage of days on which study participants had genital lesions. The rate was 1.2% of days in the 75-mg group, compared with 9% with placebo, 12.5% with 5-mg pritelivir, 3.5% with 25-mg pritelivir, and 1.2% with 400-mg pritelivir.

"No pattern of adverse events or laboratory abnormalities emerged during the study," although the 1-month duration of treatment was short, Dr. Wald and her associates wrote. Three participants discontinued treatment because of adverse events: one patient reported moderate headache, nausea, chest pain, and dyspnea; the second was suspected to have systemic lupus erythematosus, which disqualified her from participating further; and the third withdrew because of mild anxiety.

Six other patients withdrew for other reasons or were lost to follow-up, one withdrew because she became pregnant, and another was noncompliant with the study protocol. One final patient developed pancreatitis 2 weeks after completing treatment, but this was considered to be unrelated to the drug because the patient had had prior episodes of alcohol-related pancreatitis and was believed to have resumed drinking when the study ended.

Although pritelivir markedly reduced the rate of viral shedding, some breakthrough shedding still occurred. "The question of whether further increases in the daily dose of pritelivir would completely abrogate viral shedding will have to be addressed in additional studies," they said.

Since pritelivir targets a different pathway than nucleoside analogues such as acyclovir, future studies also should investigate the effectiveness of combination therapy, the investigators added.

This study was funded by AiCuris. Dr. Wald reported ties to Agenus, Amgen, Genentech, Genocea, Gilead, and Vical. Her associates reported numerous relevant financial disclosures.

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Possible alternative or addition to acyclovir

Pritelivir, and presumably other agents in this new class of anti–human simplex virus drugs, is active against viruses that develop resistance to drugs in the acyclovir class, making it an attractive alternative to the nucleoside agents for many patients, according to Dr. Richard J. Whitley and Mark Prichard, Ph.D.

"Resistance to the nucleoside analogues is encountered regularly in the immunocompromised host, particularly in recipients of stem-cell transplants and patients in whom antiviral therapy for AIDS has failed," they said.

And, as Dr. Wald and her associates reported, combination therapy with pritelivir and acyclovir may now be possible, especially for patients with life-threatening HSV infection. "Studies to assess this opportunity are under way," they added.

Dr. Whitley and Dr. Prichard are with the departments of pediatrics, microbiology, medicine, and neurosurgery at the University of Alabama at Birmingham. Dr. Whitley reported ties to N and N Scientific and Gilead; Dr. Prichard reported no relevant conflicts of interest. These remarks were taken from their editorial accompanying Dr. Wald’s report (N. Engl. J. Med. 2014 Jan. 15 [doi:10.1056/NEJMe1313982]).