HPV Clearance by Folic Acid Supplementation

描述（由申请方提供）：高危（HR）人乳头瘤病毒（HPV），尤其是HPV 16感染被认为是宫颈上皮内瘤变（CIN）发生的必要步骤，CIN是宫颈癌（CC）的一组前驱病变。我们最近的数据表明，叶酸水平较高的女性有能力清除HR-HPV感染，包括HPV 16，HR-HPV阳性女性，特别是叶酸水平较低的HPV 16阳性女性，更有可能被诊断为CIN（OR=9，p <0.0001）。如果补充叶酸可以提高HPV 1.6的清除率并降低CIN的发生率，那么它将是一种具有临床意义的干预措施。我们建议通过每天补充5 mg叶酸进行为期12个月的双盲、安慰剂对照试验，研究补充叶酸对HPV 16和其他17种特定类型HPV的清除率以及CIN发病率的影响。主要假设：1）在12个月的研究期间，补充5 mg叶酸的女性中清除特定类型HPV（HPV 16和任何其他类型）的女性比例高于安慰剂组。2)补充5 mg叶酸的患者的CIN发生率低于安慰剂组。次要假设：循环和/或宫颈细胞叶酸水平较低、存在微核、整体DNA低甲基化、整合的HPV 16或入组时宫颈细胞中HPV 16的高病毒载量将降低叶酸补充剂对HPV清除和预防宫颈病变（小于CIN 1）进展为CIN 2或3的有效性。这将是第一个干预试验，旨在评估叶酸对特定类型HR-HPV的影响，其在HR-HPV相关CIN发病率中的保护作用，以及叶酸对HR-HPV行为的作用机制。这将大大有助于了解叶酸在宫颈癌发生中的作用机制。公共信息：感染某些类型的人乳头瘤病毒（HPV），这是性传播，被认为是宫颈上皮内瘤变（CIN），宫颈癌（CC）的前驱病变的发生的必要步骤。控制这些感染将提供一个具有成本效益的长期战略，以减少CC的负担。我们最近完成的研究强烈表明，补充安全的维生素（叶酸）可能会降低HPV相关的CC风险。因为这项研究将在HPV 16阳性的女性中进行，HPV 16是CC最流行和最强大的致病因子，这项研究的公共卫生意义可能是巨大的，并将补充HPV疫苗研究。

DESCRIPTION (provided by applicant): Infection with high-risk (HR) human papillomaviruses (HPVs), especially HPV 16, is considered a necessary step in the genesis of cervical intraepithelial neoplasia (CIN), a group of precursor lesions for cervical cancer (CC). Our recent data demonstrated that women with higher folate status have the ability to clear HR-HPV infections, including HPV 16, and that HR-HPV positive women, especially HPV 16-positive women who have lower folate status, are significantly more likely to be diagnosed with CIN (OR=9, p <0.0001). If supplementation with folic acid can enhance the clearance of HPV 1.6 and decrease the incidence of CIN, it would represent a clinically significant intervention. We propose to investigate the effect of supplementation with folic acid on the clearance of HPV 16 and of any of 17 other specific types of HPVs, and on the incidence of CIN, by conducting a 12-month double-blind, placebo-controlled trial of supplementation with 5 mg of folic acid per day. Primary hypotheses: 1) The proportion of women who clear a given specific type of HPV (HPV 16 and any other type present) during the 12 month study period will be higher among those supplemented with 5 mg of folic acid than among those given a placebo. 2) Incidence of CIN will be lower among those supplemented with 5 mg of folic acid than among those given a placebo. Secondary hypothesis: Lower levels of circulating and/or cervical cell folate, the presence of micronuclei, global DNA hypomethylation, integrated HPV 16, or a high viral load of HPV 16 in cervical cells at enrollment will reduce the effectiveness of folic acid supplementation on HPV clearance and on prevention of the progression of cervical lesions (less than CIN 1) to CIN 2 or 3. This will be the first intervention trial designed to evaluate folate's effects on specific types of HR-HPV, its protective role in HR- HPV associated incidence of CIN, and the mechanisms of action of folate on the behavior of HR-HPV. It will aid greatly in understanding the mechanisms of action of folate in cervical carcinogenesis. Public information: Infection with certain types of human papillomaviruses (HPVs), which are sexually transmitted, is considered a necessary step in the genesis of cervical intraepithelial neoplasia (CIN), precursor lesions for cervical cancer (CC). Control of these infections would offer a cost-effective long-term strategy to reduce the CC burden. Our recently completed studies strongly suggest that supplementation with a safe vitamin (folic acid) may reduce the HPV associated risk of CC. Because this study will be conducted among women positive for HPV 16, the most prevalent and powerful causative agent of CC, the public health significance of this study could be enormous and will complement HPV vaccine studies.