Cancer Epidemiology Research Program, Catalan Institute of Oncology, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain; Clinical Research Department, London School of Hygiene & Tropical Medicine, London, UK.
Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Lancet HIV. 2020 Apr;7(4):e262-e278. doi: 10.1016/S2352-3018(19)30434-5. Epub 2020 Feb 25.
The effect of antiretroviral therapy (ART) on the natural history of anal high-risk HPV and anal lesion progression is not well established. We reviewed the association of ART and other HIV-related factors on anal HPV infection, anal intraepithelial neoplasia (AIN), and anal cancer among people living with HIV.
For this systematic review and meta-analysis, we searched MEDLINE and EMBASE for studies published between Jan 1, 1996, and Oct 30, 2019, that reported the association of HIV-related exposures (ART or highly active ART [HAART], HIV-RNA plasma viral load [PVL], and nadir or current CD4 cell count) with outcomes of anal high-risk HPV prevalence, incidence, and persistence; prevalence, incidence, progression, or regression of anal histological and cytological abnormalities; and anal cancer incidence. Effect estimates were extracted whenever available; otherwise, they were calculated from raw data. We assessed the risk of bias of included studies using the Newcastle-Ottawa scale, and random-effects meta-analyses were done to examine heterogeneity using the I statistic. This study is registered on the PROSPERO database, CRD42018007271.
We identified 6777 studies, of which 5377 were excluded before full-text review. 122 studies providing estimates for 130 distinct populations matched the inclusion criteria. The populations comprised 417 006 people living with HIV (women, men who have sex with men, and men who have sex with women). 41 (32%) population estimates were not stratified by sex or sexual orientation. People living with HIV receiving ART had 35% lower high-risk HPV prevalence than ART-naive people (crude odds ratio [OR] 0·65, 95% CI 0·54-0·79; I 12·1%, p=0·31) in 18 studies, and prolonged ART use was associated with a 10% reduction per year in high-risk HPV prevalence in two studies (adjusted OR 0·90, 0·85-0·95; I 0%, p=0·88). People living with HIV with undetectable PVL had lower HSIL-AIN2+ prevalence than those with detectable PVL (crude OR 0·84, 0·72-0·98; I 0%, p=0·80) in 16 studies, particularly if sustained for more than 1 year (crude OR 0·62, 0·47-0·81; I 0%, p=0·51). ART was not associated with anal cancer incidence when adjusted for years living with HIV in three studies (adjusted hazard ratio [HR] 1·11, 95% CI 0·68-1·80; I 0%, p=0·57), but ART users with sustained undetectable HIV PVL had 44% lower risk of anal cancer than those without (adjusted HR 0·56, 0·44-0·70; I 0%, p=0·94) and for each increase in nadir CD4 cell counts of 100 cells per μL, there was a 40% decrease in anal cancer incidence (crude HR 0·60, 0·46-0·78; I 21·7%, p=0·26).
Effective ART use and early initiation at high nadir CD4 counts might reduce anal high-risk HPV infection and anal cancer risk. Although most studies were cross-sectional in design and few adjusted for potential confounders, this analysis provides comprehensive estimates of the effect of ART and HIV-related factors on the natural history of anal HPV-related disease in people living with HIV.
EU Marie Skłodowska-Curie Actions programme.
抗逆转录病毒疗法（ART）对肛门高危 HPV 和肛门病变进展的自然史的影响尚未得到很好的确立。我们回顾了 ART 和其他与 HIV 相关的因素对 HIV 感染者肛门 HPV 感染、肛门上皮内瘤变（AIN）和肛门癌的影响。
为了进行这项系统评价和荟萃分析，我们在 1996 年 1 月 1 日至 2019 年 10 月 30 日期间，在 MEDLINE 和 EMBASE 上搜索了报告 HIV 相关暴露（ART 或高效抗逆转录病毒治疗 [HAART]、HIV 病毒载量 [PVL] 和最低或当前 CD4 细胞计数）与肛门高危 HPV 流行率、发病率和持续性；肛门组织学和细胞学异常的流行率、发病率、进展或消退；以及肛门癌发病率之间关联的研究。只要有可用的效应估计值，就会提取出来；否则，从原始数据中计算。我们使用纽卡斯尔-渥太华量表评估纳入研究的偏倚风险，并使用 I 统计量评估异质性的随机效应荟萃分析。这项研究在 PROSPERO 数据库中注册，CRD42018007271。
我们共确定了 6777 项研究，其中 5377 项在全文审查前被排除。122 项研究提供了 130 个不同人群的估计值，符合纳入标准。这些人群包括 417006 名 HIV 感染者（女性、男男性接触者和男女性接触者）。41 项（32%）人群估计值未按性别或性取向分层。与未接受 ART 的 HIV 感染者相比，接受 ART 的 HIV 感染者高危 HPV 流行率低 35%（未校正优势比 [OR] 0·65，95%CI 0·54-0·79；I²12·1%，p=0·31），18 项研究中，长期使用 ART 与高危 HPV 流行率每年降低 10%相关，两项研究中（校正 OR 0·90，0·85-0·95；I²0%，p=0·88）。病毒载量不可检测的 HIV 感染者的高级别鳞状上皮内瘤变-2+（HSIL-AIN2+）流行率低于病毒载量可检测的 HIV 感染者（未校正 OR 0·84，0·72-0·98；I²0%，p=0·80），尤其是如果持续时间超过 1 年（未校正 OR 0·62，0·47-0·81；I²0%，p=0·51）。在三项研究中，对 HIV 感染者的生存年数进行调整后，ART 与肛门癌发病率无关（校正危害比 [HR] 1·11，95%CI 0·68-1·80；I²0%，p=0·57），但持续不可检测 HIV 病毒载量的 ART 使用者的肛门癌风险比无此情况者低 44%（校正 HR 0·56，0·44-0·70；I²0%，p=0·94），每增加 100 个/μL 的最低 CD4 细胞计数，肛门癌发病率降低 40%（未校正 HR 0·60，0·46-0·78；I²21·7%，p=0·26）。
有效的 ART 应用和在高最低 CD4 计数时尽早开始应用可能会降低肛门高危 HPV 感染和肛门癌的风险。尽管大多数研究为横断面设计，且很少有研究对潜在混杂因素进行调整，但这项分析提供了全面的估计值，说明了 ART 和与 HIV 相关的因素对 HIV 感染者肛门 HPV 相关疾病自然史的影响。
欧盟玛丽·居里行动计划。
