The importance of HPV16 in anal cancer prevention
Authors: Ulrike Wieland, Alexander Kreuter
Journal: The Lancet Infectious Diseases (2017)

Like cervical cancer, anal cancer and its direct precursor lesion, high-grade anal intraepithelial neoplasia (AIN), are caused by persistent infections with human papillomaviruses (HPV).1Clark MA Hartley A Geh JI Cancer of the anal canal.Lancet Oncol. 2004; 5: 149-157Summary Full Text Full Text PDF PubMed Scopus (148) Google Scholar The natural history of HPV in cervical cancer has been comprehensively investigated. In the more than 40 HPV types infecting the anogenital tract, high-risk HPV-types and possible or probable high-risk types for the development of cervical cancer have been defined.2Bouvard V Baan R Straif K et al.A review of human carcinogens—Part B: biological agents.Lancet Oncol. 2009; 10: 321-322Summary Full Text Full Text PDF PubMed Google Scholar Cervical cancer is preventable by regular screening. Many countries are currently replacing cytological Pap-screening by primary HPV-screening or HPV and cytology co-testing in women over the age of 30 years.3Ronco G Dillner J Elfström KM et al.Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials.Lancet. 2014; 383: 524-532Summary Full Text Full Text PDF PubMed Scopus (1093) Google Scholar By contrast with cervical cancer, anal cancer screening is still a matter of debate, even for high-risk populations such as men who have sex with men and HIV-positive individuals.4Gosens KC Richel O Prins JM Human papillomavirus as a cause of anal cancer and the role of screening.Curr Opin Infect Dis. 2017; 30: 87-92Crossref PubMed Scopus (24) Google Scholar, 5Machalek DA Poynten M Jin F et al.Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis.Lancet Oncol. 2012; 13: 487-500Summary Full Text Full Text PDF PubMed Scopus (702) Google Scholar In other unsettled aspects of anal cancer screening, a gap of knowledge exists on the carcinogenicity of different HPV types in the anus. In The Lancet Infectious Diseases, Chunqing Lin and colleagues6Lin C Franceschi S Clifford G Human papillomavirus types from infection to cancer in the anus: a systematic review and meta-analysis, according to gender and HIV status.Lancet Infect Dis. 2017; (published online Nov 17.)http://dx.doi.org/10.1016/S1473-3099(17)30653-9Summary Full Text Full Text PDF Scopus (206) Google Scholar have substantially contributed to close this gap. They have done a large and comprehensive systematic review and meta-analysis of type-specific anal HPV prevalence in HIV-negative and HIV-positive individuals of both sexes. The meta-analysis includes 95 studies from five continents and comprises more than 18 600 individuals covering the full spectrum of anal diagnoses from normal anal cytology to low-grade and high-grade dysplasia and anal cancer. Lin and colleagues have calculated type-specific HPV prevalence ratios and have shown that HPV16 is by far the most carcinogenic HPV type in the anus, both in HIV-negative and HIV-positive individuals of both sexes (cancer to normal prevalence ratio 5·0, 95%CI 3·8–6·6 in HIV-negative patients; 2·3, 95%CI 1·9–2·7 in HIV-positive patients). HPV16-positivity increased with the severity of anal diagnosis and HPV16 was the only high-risk type that also increased from high-grade dysplasia to anal cancer. By contrast, other high-risk types such as HPV18, 31, 33, 45, 52, and 58 dropped in anal cancer compared with high-grade AIN. However, HPV16-positive cancers were less frequent in HIV-positive compared with HIV-negative patients (67·1% vs 85·5%).6Lin C Franceschi S Clifford G Human papillomavirus types from infection to cancer in the anus: a systematic review and meta-analysis, according to gender and HIV status.Lancet Infect Dis. 2017; (published online Nov 17.)http://dx.doi.org/10.1016/S1473-3099(17)30653-9Summary Full Text Full Text PDF Scopus (206) Google Scholar The findings of Lin and colleagues have important implications for both primary prevention of anal cancer by prophylactic HPV vaccination and secondary prevention by anal cancer screening. The quadrivalent HPV vaccine was highly efficacious in preventing AIN in males in a randomised controlled trial.7Palefsky JM Giuliano AR Goldstone S et al.HPV vaccine against anal HPV infection and anal intraepithelial neoplasia.N Engl J Med. 2011; 365: 1576-1585Crossref PubMed Scopus (684) Google Scholar Both its successor, the nine-valent HPV vaccine, and the bivalent HPV vaccine were shown to be safe and immunogenic in women and men.8WHOHuman papillomavirus vaccines: WHO position paper, May 2017.Wkly Epidemiol Rec. 2017; 92: 241-268PubMed Google Scholar Long term efficacy data for the prevention of cervical infection and disease in young women are available for all three HPV vaccines.8WHOHuman papillomavirus vaccines: WHO position paper, May 2017.Wkly Epidemiol Rec. 2017; 92: 241-268PubMed Google Scholar, 9Huh WK Joura EA Giuliano AR et al.Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 years: a randomised, double-blind trial.Lancet. 2017; (published online Sept 5.)http://dx.doi.org/10.1016/S0140-6736(17)31821-4Summary Full Text Full Text PDF PubMed Scopus (240) Google Scholar Hence it can be extrapolated from the findings of Lin and colleagues that the majority of high-grade AIN and anal cancer could be prevented by gender-neutral vaccination of young girls and boys with either HPV vaccine. For the future prevention of anal cancer in HIV-positive patients, the use of broad-spectrum or broadly cross-reactive vaccines in gender-neutral childhood vaccination programmes will be important, because non-HPV16-positive anal cancer and infections with multiple HPV-types are more frequent in these patients than in HIV-negative individuals. Nevertheless, up to 25% of anal cancer in HIV-positive patients would not be covered by the nine-valent HPV vaccine, assuming that cross-protection does not occur.6Lin C Franceschi S Clifford G Human papillomavirus types from infection to cancer in the anus: a systematic review and meta-analysis, according to gender and HIV status.Lancet Infect Dis. 2017; (published online Nov 17.)http://dx.doi.org/10.1016/S1473-3099(17)30653-9Summary Full Text Full Text PDF Scopus (206) Google Scholar, 10Wieland U Brockmeyer NH Kreuter A A 9-valent HPV vaccine in women.N Engl J Med. 2015; 372: 2566Crossref PubMed Scopus (1) Google Scholar Several experts have suggested that anal cancer prevention for high-risk populations with screening programmes similar to those implemented for cervical cancer might be effective.4Gosens KC Richel O Prins JM Human papillomavirus as a cause of anal cancer and the role of screening.Curr Opin Infect Dis. 2017; 30: 87-92Crossref PubMed Scopus (24) Google Scholar, 11Esser S Kreuter A Oette M et al.German-Austrian guidelines on anal dysplasia and anal cancer in HIV-positive individuals: prevention, diagnosis, and treatment.J Dtsch Dermatol Ges. 2015; 13: 1302-1319Crossref PubMed Scopus (35) Google Scholar, 12Palefsky JM Anal cancer prevention in HIV-positive men and women.Curr Opin Oncol. 2009; 21: 433-438Crossref PubMed Scopus (73) Google Scholar Prospective studies on the validation of anal cancer screening are ongoing.4Gosens KC Richel O Prins JM Human papillomavirus as a cause of anal cancer and the role of screening.Curr Opin Infect Dis. 2017; 30: 87-92Crossref PubMed Scopus (24) Google Scholar Anal cytology followed by high-resolution anoscopy (in case of abnormal findings) or direct use of high-resolution anoscopy currently are the primary means for anal cancer prevention.4Gosens KC Richel O Prins JM Human papillomavirus as a cause of anal cancer and the role of screening.Curr Opin Infect Dis. 2017; 30: 87-92Crossref PubMed Scopus (24) Google Scholar The findings of Lin and colleagues corroborate the outstanding carcinogenicity of HPV16 and could step up the role of HPV-testing in anal cancer screening. This might be particularly true for countries with well accepted gender-neutral HPV vaccination programmes in which effects on HPV prevalence are already visible on a population level. HPV detection and typing followed by risk stratification (HPV16-induced vs non-HPV16-induced lesions) could help identifying those AIN lesions that are most likely to progress to cancer. Vice versa, in high-grade lesions induced by HPV-types associated with a higher probability of persistence or regression, a closely monitored wait and see strategy might be appropriate to avoid unnecessary treatment. There is still a long way to go until anal cancer screening in high-risk populations will be as established as cervical cancer screening. The study of Lin and colleagues constitutes an important step in this direction. AK has received fees for lectures from Actelion and InfectoPharm, and had advisory board memberships with Sanofi Pasteur, Merck Sharp & Dohme, and AbbVie. UW declares no competing interests. UW is supported by the German Federal Ministry of Health (grant number 1369-401). Human papillomavirus types from infection to cancer in the anus, according to sex and HIV status: a systematic review and meta-analysisHPV16 is by far the most carcinogenic HPV type in the anus, with enrichment of HPV16 even from high-grade lesions to anal cancer, both in individuals who are HIV negative and those who are HIV positive. Nevertheless, the fraction of anal cancer attributable to HPV16 is smaller in the HIV-positive population. Full-Text PDF Open Access