Detoxification therapy of traditional Chinese medicine for genital tract high-risk human papillomavirus infection: A systematic review and meta-analysis

BackgroundPersistence of high-risk human papillomavirus (hr-HPV) infections is the most critical risk factor for cervical intraepithelial neoplasia (CIN) and cervical cancer (CC). Treatment of persistent oncogenic HPV-positive women after 12–24 months follow-up is still controversy. Detoxification therapy of Chinese medicine (DTCM) has been conducted recently. However, the conclusions are still unclear. We planned to conduct a systematic review and meta-analysis to explore DTCM in the treatment of persistent hr-HPV infections.MethodsNine electronic databases were systematically searched from their inception to 30 September 2018. Randomized controlled trials comparing DTCM with follow-up or placebo were included. Risk of bias was assessed by the Cochrane ‘Risk of Bias’ tool. Review Manager 5.3 was used for statistical analyses. Relative ratios (RR) and 95% confidence intervals were used for dichotomous data, and the mean difference (MD) was used for continuous data. We assessed the quality of trials by the GRADE.ResultsSeventeen RCTs from 2011 to 2018 with 1906 participants were included. The evidence showed that DTCM had a pooled efficacy difference in favor of increasing the HPV clearance rate compared to placebo groups (RR = 2.62, 95% CI 1.28 to 5.33, very low quality) and follow-up groups (RR = 1.88, 95% CI 1.60 to 2.22, low quality). The median HPV persistence tended to decline from 50% within six months to 41.5% at 12 months, and 31.5% at 24 months. A significantly increased regression rate of CIN was found in the DTCM compared with placebo groups (RR = 3.61, 95% CI 1.21 to 10.83, very low quality) and follow-up groups (RR = 1.79, 95% CI 1.31 to 2.45, very low quality). Additionally, we found DTCM have an impact on TNF-α (MD = 2.99, 95% CI 1.90 to 4.07; very low quality), IFN-α (MD = 3.47, 95% CI 2.42 to 4.52; very low quality), CD4+/CD8+ cells (MD = 0.21, 95% CI 0.05 to 0.37; very low quality) compared with follow up groups in some trials with small sample sizes. The major adverse events were genital mucosal irritation symptoms (10%, 5/50).ConclusionsDTCM have favorable outcomes on improving the HPV clearance rate, increasing the regression rate of CIN, and impacting the proportion of some immune cells and cytokine levels. However, most of the evidence was of low quality. Any future high-quality trials and a more extended follow-up period of 24 months or more should be performed.

背景：高危型人乳头瘤病毒（high-risk human papillomavirus, hr-HPV）持续感染是宫颈上皮内瘤变（cervical intraepithelial neoplasia, CIN）与宫颈癌（cervical cancer, CC）最关键的危险因素。针对随访12~24个月后仍持续感染致癌型HPV的女性，其治疗方案目前仍存在争议。近年来中药解毒疗法（Detoxification therapy of Chinese medicine, DTCM）逐渐应用于临床，但相关研究结论尚未明确。本研究拟开展系统评价与meta分析，以探讨中药解毒疗法治疗持续hr-HPV感染的疗效。
方法：系统检索建库至2018年9月30日的9个电子数据库，纳入对比中药解毒疗法与随访观察或安慰剂的随机对照试验。采用Cochrane偏倚风险工具评估纳入研究的偏倚风险，使用Review Manager 5.3软件进行统计分析。二分类资料采用相对比（relative ratios, RR）及95%置信区间（95% CI）进行效应量合并，连续性资料采用均数差（mean difference, MD）进行分析。采用GRADE分级体系评估研究证据质量。
结果：最终纳入2011年至2018年间的17项随机对照试验，共1906名受试者。Meta分析结果显示，相较于安慰剂组，中药解毒疗法可提高HPV清除率，合并效应量具有统计学差异（RR=2.62，95%CI 1.28~5.33，证据质量极低）；相较于随访观察组，中药解毒疗法同样可提高HPV清除率（RR=1.88，95%CI 1.60~2.22，证据质量低）。受试者的HPV中位持续感染率呈现下降趋势：6个月时为50%，12个月时降至41.5%，24个月时进一步降至31.5%。相较于安慰剂组，中药解毒疗法可显著提高宫颈上皮内瘤变的逆转率（RR=3.61，95%CI 1.21~10.83，证据质量极低）；相较于随访观察组，该疗法同样可显著提高宫颈上皮内瘤变逆转率（RR=1.79，95%CI 1.31~2.45，证据质量极低）。此外，在部分小样本试验中，相较于随访观察组，中药解毒疗法对肿瘤坏死因子-α（TNF-α，MD=2.99，95%CI 1.90~4.07，证据质量极低）、干扰素-α（IFN-α，MD=3.47，95%CI 2.42~4.52，证据质量极低）及CD4+/CD8+细胞比值（MD=0.21，95%CI 0.05~0.37，证据质量极低）均存在正向调控作用。研究中主要不良事件为生殖道黏膜刺激症状（10%，5/50）。
结论：中药解毒疗法可有效提高HPV清除率、提升宫颈上皮内瘤变逆转率，并可改善部分免疫细胞比例及细胞因子水平，但现有研究证据整体质量偏低。未来需开展高质量随机对照试验，并延长随访周期至24个月及以上，以进一步验证该疗法的临床价值。