Review Multidisciplinary, evidence-based consensus guidelines for human papillomavirus (HPV) vaccination in high- risk populations, Spain, 2016 Xavier Martínez-Gómez1, Adrian Curran2, Magda Campins1, Laia Alemany3, José Ángel Rodrigo-Pendás1, Natalia Borruel 4 , Xavier Castellsagué3, Cristina Díaz-de-Heredia5, Fernando A Moraga-Llop6, Marta del Pino7,8, Aureli Torné7,8 1. Servei de Medicina Preventiva i Epidemiologia, Hospital Universitari Vall d’Hebron – Universitat Autònoma de Barcelona, Barcelona, España 2. Servei de Malalties Infeccioses, Hospital Universitari Vall d’Hebron – Universitat Autònoma de Barcelona, Barcelona, España 3. Programa de Recerca en Epidemiologia del Càncer, Institut Català d’Oncologia – IDIBELL CIBER Epidemiología y Salud Pública, Barcelona, España 4. Unitat d’Atenció Crohn-Colitis, Servei d’Aparell Digestiu; Hospital Universitari Vall d’Hebron – Universitat Autònoma de Barcelona, Barcelona, España 5. Servei d’Oncologia i Hematologia Pediàtrica, Hospital Universitari Vall d’Hebron - Universitat Autònoma de Barcelona, Barcelona, España 6. Asociación Española de Vacunología, Barcelona, España 7. Unidad de Ginecología Oncológica, Instituto Clínico de Ginecología y Obstetricia y Neonatología (ICGON), Hospital Clínic de Barcelona, Barcelona, España 8. Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Facultad de Medicina, Universidad de Barcelona, Barcelona, España Correspondence: Magda Campins (mcampins@vhebron.net) Citation style for this article: Martínez-Gómez Xavier, Curran Adrian, Campins Magda, Alemany Laia, Rodrigo-Pendás José Ángel, Borruel Natalia, Castellsagué Xavier, Díaz-de-Heredia Cristina, Moraga-Llop Fernando A, del Pino Marta, Torné Aureli. Multidisciplinary, evidence-based consensus guidelines for human papilloma virus (HPV) vaccination in high-risk populations, Spain 2016. Euro Surveill. 2019;24(7):pii=1700857. https://doi.org/10.2807/1560-7917.ES.2019.24.7.1700857 Article submitted on 22 Dec 2017 / accepted on 15 Oct 2018 / published on 14 Feb 2019 Introduction: Although human papillomavirus (HPV) developed a document to evaluate and establish evi- routine vaccination programmes have been imple- dence-based guidelines on HPV vaccination in high- mented around the world and recommendations have risk populations in Spain, based on best available been expanded to include other high-risk individuals, scientific evidence. current recommendations often differ between coun- tries in Europe, as well as worldwide. Aim: To find and Introduction summarise the best available evidence of HPV vacci- Human papillomavirus (HPV) is the main cause of nation in high-risk patients aiding clinicians and pub- uterine cervical cancer (UCC) and its precursor lesions lic health workers in the day-to-day vaccine decisions [1,2]. HPV can also be found in cancerous and precan- relating to HPV in Spain. Methods: We conducted a cerous lesions of the vulva and vagina [3,4], penis [5] systematic review of the immunogenicity, safety and anus [6], oropharyngeal cancer [7], anogenital warts efficacy/effectiveness of HPV vaccination in high-risk [8] and recurrent respiratory papillomatosis (RRP) [9]. populations between January 2006 and June 2016. Nearly 90% of all female genital HPV infections are HPV vaccination recommendations were established transient and resolve on their own in the next 2 years with levels of evidence according to the Grading of [10]. Persistence of HPV happens in 10% of infected Recommendations Assessment, Development and healthy women and 1% of them will develop neoplastic Evaluation (GRADE) system. Results: A strong recom- HPV-related lesions. In men, duration and persistence mendation about HPV vaccination was made in the fol- of HPV infections are shorter than in women [11]. lowing groups: HIV infected patients aged 9–26 years; men who have sex with men aged 9–26 years; women The estimated impact of newly diagnosed cases of with precancerous cervical lesions; patients with con- HPV-related disease is high around the world: annually genital bone marrow failure syndrome; women who there are 30.9 million cases of cervical precancerous have received a solid organ transplant or hematopoi- lesions, 32 million cases of genital condylomata and etic stem cell transplantation aged 9–26 years; and 630,000 cases of cancer (cervix, vagina, vulva, anus, patients diagnosed with recurrent respiratory papil- penis, oropharyngeal, oral cavity and larynx) diag- lomatosis. Conclusions: Data concerning non-routine nosed [12,13]. HPV vaccination in populations with a high risk of HPV infection and associated lesions were scarce. We have www.eurosurveillance.org 1 Box specific groups are mentioned [18] but some countries Individuals at high risk of human papillomavirus have begun to develop programmes [23]. infection and related diseases, Spain, January 2006–June 2016 In clinical practice, there is growing interest in expand- ing vaccine recommendations to patients at high-risk • HIV infected patients of HPV infection and development of related neo- plasms. Currently, information on HPV vaccination • MSM for these high-risk populations is scarce and recom- • Inflammatory bowel disease patients mendations for selective vaccination differ between countries in Europe. Several reasons may explain the • Women with precancerous cervical lesions lack of guidelines for vaccination in high-risk popula- • Patients with congenital bone marrow failure syndrome, tions, including: heterogeneity in the definition e.g. primary immunodeficiency or survivors of childhood age, sex, disease characteristics and variations in neoplasia the risk of infection, persistence or malignancy; lim- • Solid organ or haematopoietic stem cell transplant ited published clinical trial data (due to difficulties in recipients conducting appropriately powered studies on vaccine immunogenicity, safety and efficacy in individuals with • Patients with immunosuppressive or biological treatment low-incidence diseases); and limitations associated • Patients with recurrent respiratory papillomatosis with establishing recommendations for patient groups not included in the product label. Some of these issues can be viewed in the Supplementary material. HIV: Human immunodeficiency virus; HPV: human papillomavirus; MSM: men who have sex with men. A guideline on HPV vaccination in high-risk individu- als, based on the review of current evidence by an independent and multidisciplinary expert panel, was recently released by the Spanish Association of Cervical HPV vaccination is an effective primary intervention to Pathology and Colposcopy [24]. This paper summa- prevent HPV infection and its associated disease bur- rises this evidence-base and process and depicts the den. Vaccination is used as part of a coordinated strat- guideline. egy with quality screening programmes and treatment services in cervical cancer prevention [14]. Three HPV Methods vaccines containing virus-like particles (VLPs) are cur- In October 2015, a steering committee was formed in rently available: the bivalent vaccine (VLPs of high-risk Spain to compile this guideline after a rigorous review HPV genotypes 16 and 18) [15]; the quadrivalent vac- of the HPV-associated disease burden and a system- cine (VLPs of genotypes 6, 11, 16 and 18) [16]; and the atic review of studies investigating the immunogenic- nonavalent vaccine (VLPs of genotypes 6, 11, 16, 18, ity, safety and efficacy of HPV vaccination in high-risk 31, 33, 45, 52 and 58) [17]. populations. This committee consisted of 10 Spanish professionals including gynaecologists, epidemiolo- In the first decade of HPV vaccine use, the main strat- gists, paediatricians, infectologists, haematologists, egy worldwide was routine vaccination programmes gastroenterologists and preventive medicine special- for adolescent and young women. In Europe, according ists with recognised expertise in the area. European Centre for Disease Control (ECDC) informa- tion reviewed in 2018, routine vaccination is included in Selection criteria the national immunisation schedule in the majority of This review included both randomised controlled trials countries (n = 29, 93.5%) [18]. In some countries, vac- (RCT) and observational studies (e.g. cohort studies, cine recommendations were later extended to include case reports) that assessed the effects of HPV vaccina- specific high-risk groups as the United States (US) tion on high-risk groups. where three doses of HPV vaccine are recommended for: (i) females and males aged 9–26 years with pri- Based on clinical expertise of the steering committee mary or secondary immunocompromising conditions and published literature, the following groups were that may reduce cell-mediated or humoral immunity, defined as individuals at high-risk of HPV infection and (ii) men who have sex with other men (MSM), (iii) HPV-related disease and were included in the guideline transgender persons aged 9–26 years, (iv) individu- on HPV vaccination in high-risk individuals (Box). als not adequately vaccinated and, (v) children with a The interventions of interest were the bivalent history of sexual abuse [19,20]. In Australia MSM and (Cervarix), quadrivalent (Gardasil) and nonavalent immunocompromised individuals are included [21] and (Gardasil 9) HPV vaccines. The outcomes of interest in Canada individuals with abnormal cervical cytol- were the efficacy, effectiveness, immunogenicity and ogy or a history of UCC and/or genital warts, MSM and safety of HPV vaccines. immunocompromised individuals [22] are included too. Currently, no global European recommendations for Studies that did not report original data e.g. editorials or reviews were excluded. 2 www.eurosurveillance.org Figure discussion between the reviewers until a consensus Flowchart of literature selection for review of human was reached. papillomavirus vaccination in high-risk populations, Spain, January 2006–June 2016 The agreement between reviewers in the selection pro- cess was computed using Stata/SE 14.2 for Windows PubMed search: (StataCorp LLC, College Station, Texas) and resulted 476 references retrieved in agreement of qualitative measures (Cohen’s Kappa = 0.98) [25]. 448 references excluded after screening the title and abstract Panel subgroups reviewed the initial literature search, selected references, evaluated evidence, drafted rec- 28 references selected for ommendations and summarised the evidence for each full-text reading section. The content of the guideline was decided by 6 publications excluded after the consensus panel; the evidence evaluation pro- full-text reading: • Duplicate data/report: 2 cess involved a systematic weighting of the quality • No original data (letter, editorial, review): 4 of evidence and the grade of recommendation using the Infectious Diseases Society of America (IDSA) ver- 22 studies selected for sion of the Grading of Recommendations Assessment, inclusion Development and Evaluation (GRADE) system [26,27]. 16 studies selected for inclusion from the personal files 38 studies included The developed guideline for Spain was reviewed and of the authors HIV-infection: references 35–43 endorsed by several groups acknowledged at the end of the article. Men who have sex with men: references 44, 54–58 Results Inflammatory bowel disease: reference 69 Women with precancerous cervical lesions: Human immunodeficiency virus (HIV) infection references 79–81 Congenital bone marrow failure syndrome: references 86,88 The prevalence of HPV infection in individuals with Solid organ or hematopoietic stem cell HIV infection is high [28-30]. Within this population, transplant: references 104–106 the number of sexual partners increases the risk of Immunosuppressive or biological treatment: references 115–119 infection and reinfection for multiple HPV genotypes Recurrent respiratory papillomatosis: and decreases the probability of HPV clearance [29]. references 122, 125–132 Compared with the general population, the persistence of HPV in people living with HIV significantly increases HIV: Human immunodeficiency virus. the risk of HPV-related cancers and condylomata. Three risk subgroups can be identified in the overall Search strategy HIV-infected population: HIV-infected women, HIV- An electronic search was carried out using PubMed infected men who have sex exclusively with women to find studies published in English from January (MSW) and HIV-infected MSM. While UCC screening 2006 to June 2016. The search terms were a combina- programmes and the improvement in HIV disease con- tion of the names and synonyms of the different risk trol have led to a decrease in the incidence of UCC in groups, the HPV vaccines and the outcomes of inter- HIV-infected women, the incidence of anal cancer in est. The details of the search strategies are presented this population is 30 per 100,000 person-years (US, in the Supplementary material. 1996–2007) [31], and the prevalence of condylomata is 5–7% vs 1% in the general population (US, 1991–1998) All authors conducted unstructured electronic searches [32,33]. In line with this, HIV-infected MSW in the US and reviewed their personal files for relevant published during 1996–2007 have an incidence of anal cancer papers. that was significantly higher compared with men with- out HIV infection (46 vs two/100,000 person-years) [31]. Selection process The prevalence of condylomata in HIV-infected MSW in Two authors (XMG and JARP) independently screened Spain from 2005 to 2009 was 15% [34]. The incidence the titles and abstracts of the articles identified by of anal cancer in the US during 1996–2007 is especially the PubMed search and selected articles for full-text high in MSM with HIV (131/100,000 person-years; rate reading in accordance with the selection criteria. Full ratio = 80.3 compared with men without HIV) [31], and texts for the relevant references were independently the prevalence of condylomata in HIV-infected MSM in evaluated by XMG and JARP to determine their inclu- Spain from 2005 to 2009 was 28% [34]. sion. Reference lists of included articles were screened to consider further potentially eligible studies (Figure). Any discrepancies in study selection were resolved by www.eurosurveillance.org 3 Rationale for recommendations Rationale for recommendations Nine papers of HPV vaccination in HIV population were Six papers of HPV vaccination in MSM population were selected [35-43]. Available data on the immunogenicity selected (Supplementary material Table S2). One study and safety of HPV vaccines in people with HIV infection evaluated the immunogenicity, efficacy and safety of support its use for the prevention of HPV-related can- the qHPV vaccine against HPV in healthy males aged cers and genital warts; however, there are limited data 16–26 years [54]. Of the 4,065 men enrolled in the on the efficacy of the vaccine (Supplementary material study, 602 were MSM. Antibody GMTs were lower in Table S1). MSM vs MSW [55]. In MSM, the efficacy of the vaccine for prevention of persistent genital infection by any of The efficacy results obtained in RCT of MSM [44] can- the genotypes in the vaccine was 43.6%, while the effi- not be generalised to the HIV population, since the cacy for the prevention of persistent anal infection by characteristics of the included individuals (age 16–26 HPV 6, 11, 16 or 18 was 94.9% [44,54]. The vaccine was years; ≤ 5 lifetime sexual partners; no history of sexu- effective in preventing 77.5% of the high-grade squa- ally transmitted infections) differ from the majority of mous intraepithelial lesions (HSIL)/anal intraepithelial MSM with HIV seen in clinical practice. Prospective, neoplasia (AIN) secondary to HPV 6, 11, 16 or 18, and RCT evaluating the efficacy of HPV vaccines in the 70.2% of the genital warts [44]. prevention of recurrence in people with HIV receiving treatment for condylomata or premalignant lesions are The qHPV vaccine has also been evaluated in MSM ongoing [45-47]. patients aged 26 years or older. It was effective in the prevention of anal condyloma in a study of 313 MSM Ideally, people with HIV who receive a HPV vaccine without story of anal condyloma or with history of pre- should be on antiretroviral treatment and have good vious HPV-related anal condyloma who had been recur- immune-virological control at the time of vaccination. rence-free for at least 12 months (hazard ratio = 0.45; p < 0.05) [56]; it also reduced the incidence of HSIL (AIN) Summary of previous guidelines or consensus in another study of 202 MSM aged 18 years and older recommendations (83.7% of them aged over 30 years) who were treated The European Acquired Immune Deficiency Syndrome for histologically confirmed HSIL (AIN) [57]. The recur- (AIDS) Clinical Society guidelines recommend HPV vac- rence rate of HSIL (AIN) in vaccinated MSM vs those not cination in all individuals with HIV; however, they state vaccinated was 10.2 vs 15.7 per 100 person-years [57]. that in situations where there is an established HPV infection, vaccine efficacy is questionable [48]. The US One study assessed the immunogenicity and safety guidelines recommend vaccination for HIV females and of the nonavalent vaccine vs placebo [58]. This trial males through age 26 years [19,20,49]. included 313 MSM aged 16–26 years in addition to 1,106 MSW and 1,101 women who had neither received The 2013 IDSA clinical practice guideline for vaccina- previous HPV vaccination nor had history of HPV- tion of the immunocompromised host, recommends related lesions. The per-protocol analysis showed that, the administration of three-dose of quadrivalent HPV in MSM, the seroconversion rate for different HPV (qHPV) vaccine for females and males with HIV aged types was 99.5–100%; the GMTs in MSM were lower 11–26 years [27]. compared with MSW and women (ratio of 0.6–0.8 and 0.7–0.9, respectively, depending on the genotype ana- Recommendations in HIV patients lysed) [58]. Data on the efficacy of HPV vaccination HPV vaccination is recommended in both male and for prevention of lesions are not available. No specific female individuals with HIV from 9–26 years (quality data on the safety of HPV vaccines in the MSM popula- of evidence: moderate; recommendation: strong). HIV- tion were described in most of the studies evaluated. positive people aged 26 years and older could also benefit from HPV vaccination (quality of evidence low; Summary of previous guidelines or consensus recommendation: weak). The use of any of the avail- recommendations able vaccines is indicated, although the quadrivalent The Advisory Committee on Immunisation Practices or nonavalent vaccines are preferred given the high (ACIP) recommends routine HPV vaccination for MSM prevalence of anogenital warts in these patients. aged 9–26 years, including transgender persons [20]. Men who have sex with men Recommendations in men who have sex with men MSM have a high risk of HPV infection and HPV-related HPV vaccination is recommended in MSM aged 9–26 disease than MSW [50], with the incidence of anal neo- years (quality of evidence: moderate; recommendation: plasia being nearly 20 times higher in MSM [51]. The strong). MSM aged 26 years and older may also benefit annual recurrence rate of high-grade anal lesions fol- from HPV vaccination (quality of evidence: very low; lowing treatment may be up to 50% [52]. Data from the recommendation: weak). The use of any of the avail- US suggest that MSM have a higher rate of condyloma able vaccines is indicated, although the quadrivalent than women do, but a lower rate than MSW [53]. or nonavalent vaccines are preferred given the high prevalence of anogenital warts in MSM. 4 www.eurosurveillance.org Inflammatory bowel disease Recommendations in inflammatory bowel disease Treatment of inflammatory bowel disease IBD (Crohn’s patients disease and ulcerative colitis) often includes immu- HPV vaccination is recommended for women with nosuppressants, which increase the risk of HPV IBD aged 9–26 years (quality of evidence: low; rec- persistence. Compared with patients not receiving ommendation: weak). Although vaccination can be immunosuppressive treatment, patients with IBD administered at any time, it is preferable to vaccinate receiving azathioprine show a higher incidence of cuta- at the time of diagnosis and before the use of immu- neous warts and skin and genital herpes flares [59]. nosuppressive or biological therapies, to ensure higher Although some studies have reported the development immunogenicity. There are no data supporting HPV or worsening of genital condyloma in patients with IBD vaccination in men with IBD. treated with anti-tumour necrosis factor (TNF) antibod- ies such as infliximab and etanercept [60,61], other Women with HPV infection and precancerous studies suggest no relationship between the use of TNF cervical lesions antibodies and persistent HPV infection [62]. In Spain, a large-scale study estimate that the preva- lence of HPV infection is 13.4% and 7.9% in women Controversy remains regarding to the increased risk aged 26–45 and 46–65 years, respectively, compared of HPV infection and UCC in patients with IBD vs the with 28.8% in women aged 18–25 years [74]. Rates of general population. A study of 40 patients with IBD precancerous cervical lesions are reported between showed a higher incidence of abnormal cervical cytol- 0.4 and 0.7%; the estimated number of women aged ogy in women with IBD compared with similar healthy 18 years or older with HSIL (CIN) in Spain is in the range controls (42% vs 7%; p < 0.001), and a higher incidence of 54,087–92,423 [75]. of lesions [63]. In this study, the use of immunosup- pressants for at least 6 months was also associated Rationale for recommendations to an increased risk of abnormal cytology (Odds ratio A substantial proportion of adult women become (OR): 1.5; 95% confidence interval (CI): 1.2–4.1; p value infected with HPV, particularly genotypes 16 and 18. = 0.021) [63]. A study of 116 women with IBD showed an The probability of persistence increases with age, increased rate of abnormal cervical cytology [64], while which consequently increases the risk of precancerous a population-based study of patients with Crohn’s dis- lesions or UCC developing. Women with precancerous ease demonstrated an increased risk of UCC and dys- cervical lesions have a 5–25% risk of recurrence and plasia [65]. Another study showed an increased risk of an increased risk of developing UCC compared with the both low-grade squamous intraepithelial lesions (LSIL), general population [76]. This increased risk is mainly HSIL and UCC in patients with IBD vs a control group due to persistent HPV. Moreover, while in general the (incidence rate ratio for UCC in Crohn’s disease: 1.53; HPV infection clears after treatment, natural immunity 95% CI: 1.04–2.27) [66]. Case–control studies have not does not provide complete protection against reactiva- shown an increased risk of histological or cytological tion or reinfection by the same HPV genotype [75]. cervical abnormalities in women with IBD [67,68]. Three papers of HPV vaccination in women with Rationale for recommendations HPV infection and precancerous cervical lesions One paper of HPV vaccination in IBD population was were selected (Supplementary material Table S4). selected (Supplementary material Table S3). One study Precancerous lesions are generally diagnosed in investigating the profile of the qHPV vaccine in patients women aged 25 years or older; data about HPV vaccina- with IBD showed an adequate immunogenicity and tion in this group of women are limited. However, a few safety profile [69]. Similar antibody titres were induced studies focused on adult women and showed that both in patients with IBD and healthy controls, although qHPV vaccine and the bivalent HPV vaccine are immu- 49% of the IBD patients were receiving immunosup- nogenic, effective and safe in this age group [77,78]. pressants and 51% were receiving anti-TNF antibodies. Immunisation with the qHPV vaccine resulted in 64.9% Some major adverse events were detected (exacerba- (95% CI: 20.1–86.3) efficacy in preventing new cervi- tions of IBD (n = 2), pneumonia (n = 1), ovarian tor- cal lesions by any HPV genotype in treated women [79]. sion (n = 1), acute sinus pain (n = 1)), but none of them Another study of 737 women undergoing cervical coni- appeared to be related to HPV vaccination. sation showed that the qHPV vaccine was associated with a 65% reduction in HPV recurrence at 2 years, Summary of previous guidelines or consensus regardless of genotype (2.5% vs 7.2% recurrences in recommendations vaccinated and unvaccinated women, respectively) All guidelines regarding prevention of opportunistic [80]. The post-treatment risk reduction of new lesions infections in patients with IBD recommend regular following bivalent vaccine immunisation in women with clinical screening and HPV vaccination, particularly in surgically treated cervical lesions was 88.2% (95% CI: patients receiving immunosuppressants [70-73]. 14.8–99.7), regardless of genotype [81]. These studies demonstrate that HPV vaccination in women with cervi- cal lesions who undergo treatment results in a signifi- cant reduction in the risk of new lesions. No specific www.eurosurveillance.org 5 safety data on the HPV vaccines in these populations cancer survivors had 150% and 40% more HPV-related was identified in any of the studies evaluated. malignancies, respectively, than the general popula- tion [85]. Summary of previous guidelines or consensus recommendations Rationale for recommendations In Spain, a consensus guideline from several scien- Two papers of HPV vaccination in CBMFS, primary tific societies recommends HPV vaccination in sexually immunodeficiency or survivors of childhood neopla- active women. Because of the increased risk of HPV sia were selected (Supplementary material Table S5). infection and increased persistence of infection with Patients with Fanconi’s anaemia and dyskeratosys con- age in women with prior HPV infection and viral clear- genita have a similar immune response to HPV vaccina- ance, the intention of this recommendation is to protect tion to that of the general population [86]. against reinfection and to reduce the risk of developing new lesions and UCC in women receiving treatment for While live-attenuated vaccines are not feasible in cervical lesions [75]. patients with primary immunodeficiency, inactivated or subunit vaccines are considered safe [87] and could Recommendations in women with HPV infection and play an important role in the prevention of both malig- precancerous cervical lesions nancy and warts. Immunisation of a WHIM patient with HPV vaccination is recommended in women undergo- the qHPV vaccine induced neutralising antibodies and ing treatment for precancerous cervical lesions (qual- a cellular immune response, indicating that patients ity of evidence: moderate; recommendation: strong). with WHIM syndrome may benefit from HPV vaccination Patients with precancerous cervical lesions who have [88]. No safety data were reported in any of the studies not yet been treated, may benefit from HPV vaccination analysed. Although most survivors of childhood neo- (quality of evidence: low; recommendation: strong). plasia recover their immunity within 6 months of the Ideally, the vaccine should be administered early, end of chemotherapy or immunosuppressive therapy, either at diagnosis or before cervical conisation. the immunogenicity to HPV vaccines in this population is not well known so additional studies are needed. Congenital bone marrow failure syndrome, primary immunodeficiency or survivors of Summary of previous guidelines or consensus childhood neoplasia recommendations Congenital bone marrow failure syndrome (CBMFS) is ACIP recommends routine HPV vaccination to primary a group of heterogeneous diseases associated with immunodeficiency patients aged 9–26 years [20]. inadequate blood cell production, constitutional mal- The Children’s Oncology Group recommends HPV vac- formations and predisposition to cancer. Patients with cination for all female survivors of childhood cancer Fanconi’s anaemia and dyskeratosis congenita, both [89,90]. congenital bone marrow failure syndromes, are at risk of gynaecological and head and neck squamous cell Recommendations in patients with congenital bone carcinomas [82]. The increased risk of cancer in these marrow failure syndrome, primary immunodeficiency patients means that cancer prevention strategies are or survivors of childhood neoplasia essential. HPV vaccination of patients with CBMFS is recom- mended (quality of evidence: low; recommendation: Certain primary immunodeficiency conditions, such as strong). epidermodysplasia verruciformis, hyper-IgE syndrome, idiopathic CD4 lymphopaenia, GATA2 deficiency and HPV vaccination may benefit patients with primary Warts-hypogammaglobulinaemia, infections and mye- immunodeficiency (quality of evidence: very low; rec- lokathesis (WHIM) or Netherton’s syndrome, have the ommendation: weak). The use of any of the available presence of cutaneous warts as one of the main clinical vaccines is indicated, although the quadrivalent or manifestations of the disease [83]. Patients with these nonavalent vaccines are preferred given the high prev- conditions are more susceptible to persistent HPV alence of anogenital warts in these patients. infection because of an impaired immune response to the virus, an increased risk of extensive skin involve- Survivors of childhood neoplasia can benefit from HPV ment and a higher risk of precancerous cervical lesions vaccination (quality of evidence: very low; recommen- progressing to malignancy. dation: weak). Survivors of childhood, adolescent or young adult- Solid organ or haematopoietic stem cell hood cancer e.g. Hematopoietic stem cell transplanta- transplantation tion (HSCT) recipients, post-transplant survivors with Patients who have undergone solid organ transplanta- chronic graft-vs-host disease receiving immunosup- tion need life-long immunosuppressive therapy, which pressive therapy, individuals with a history of pelvic increases their risk of complications associated with radiation and those with Hodgkin’s lymphoma, are also persistent HPV infection. Studies have shown that at risk of adverse outcomes associated with HPV infec- immunosuppressed transplant recipients have an tion [84]. In one US study, male and female long-term increased presence of HPV in the oral cavity, higher 6 www.eurosurveillance.org prevalence of genital warts [91], high oncogenic HPV that are secreted by the virally stimulated keratinocyte. in squamous cell skin cancer [92], an increased risk of If the immune response is sufficient HPV lesions may anal cancer [93-95] and UCC [96-98]. regress, but this resolution of HPV lesions is not gener- ally seen in the immunosuppressed patients resulting Patients who have undergone HSCT have an increased in severe, persistent and extensive manifestations of risk of developing solid organ cancer [99]. In some HPV disease [108]. Among patients undergoing thera- studies, this risk was double that of the general popu- peutic immunosuppression, evidence is restricted to lation [100,101]. The increase in survival after HSCT has some disease types e.g. systemic lupus erythemato- been associated with an increased prevalence of HSIL sus (SLE) or juvenile idiopathic arthritis (JIA) and rarely in these women [102,103]. stratified by therapeutic modality or dosage. Rationale for recommendations Some studies have shown an increase in the prevalence Three papers of HPV vaccination in solid organ of HPV infection, dysplasia and premalignant lesions in or haematopoietic stem cell transplantation were patients with SLE and those with kidney failure under- selected [104-106] (Supplementary material Table S6). going haemodialysis [107,109]. A systematic review of Epidemiological data show a high risk of gynaecologi- studies in patients with SLE concluded that they are cal and other cancers in transplant recipients [102]. at higher risk of cervical dysplasia and precancerous Limited data are available on the immunogenicity and lesions. However, most studies show a similar preva- efficacy of HPV vaccination in individuals who have lence of UCC in patients with SLE compared with the undergone solid organ transplantation, and no infor- general population [110]. A delay in HPV clearance and mation exists for HSCT recipients. a greater persistence of infection and HPV-associated lesions in SLE patients could be explained by altera- Summary of previous guidelines or consensus tions in the innate and adaptive immune response in recommendations this population [111]. However, the role of immunosup- ACIP recommends routine HPV vaccination for those pressants as a predisposing factor to HPV-associated aged 9–26 years for transplant patients [20]. cervical lesions is unconfirmed [102,112]. The 2013 Infectious Diseases Society of America (IDSA) TNF blockers are widely used to treat chronic inflam- clinical practice guideline for vaccination of the immu- matory diseases. TNF plays an essential part in host nocompromised host recommends that physicians defence and the immune response. Although uncom- consider the administration of three doses of HPV vac- mon, cases of extensive cutaneous HPV lesions cine 6–12 months after HSCT for female patients aged have been reported following TNF blocking therapy 11–26 years and qHPV vaccine for males aged 11–26 [61,113,114]. years. The HPV vaccine series should also be adminis- tered to solid organ transplant candidates aged 11–26 Rationale for recommendations years [27]. The high rates of HPV infection and associated lesions in immunocompromised individuals justify the need to Recommendations in solid organ or haematopoietic consider vaccination in this population [107]. Although stem cell transplant recipients published data are limited to some groups of patients, HPV vaccination is recommended in female transplant evidence suggests that women with SLE are at an recipients aged 9–26 years (quality of evidence: low; increased risk of developing HPV-related lesions. As recommendation: strong). Female patients aged 26 SLE is an immune disorder that predominantly affects years and older may also benefit from HPV vaccination, women, most subjects in studies evaluating the risk of particularly those with chronic graft vs host disease HPV infection and lesions in SLE patients are women following HSCT (quality of evidence: very low; recom- [110]. mendation: weak). If possible, vaccination should be provided before solid organ transplantation and prefer- Five papers of HPV vaccination in patients with immu- ably before the use of immunosuppressive or biological nosuppressive or biological treatment were selected. therapies to ensure high immunogenicity. Vaccination (Supplementary material Table S7) [115-119]. In the larg- is not recommended within 6 months post-transplan- est study, administration of the qHPV vaccine resulted tation. Patients undergoing HSCT should be vaccinated in similar seroconversion rates to the general popula- 6–12 months after transplantation, even if vaccinated tion 12 months post-vaccination [115]. Lower serocon- beforehand. version rates were seen in patients receiving treatment with prednisolone or mycophenolate mofetil. There Immunosuppressive or biological treatment were no safety issues or an increased risk of SLE flares Immunosuppression is an important risk factor for cer- seen with vaccination [115]. vical HPV infection [107]. HPV has a predilection for epithelial cells and causes an abnormal proliferation Two studies evaluating the immunogenicity and safety of keratinocytes, which may manifest as benign warts of HPV vaccines in JIA patients have been published or malignant neoplasms. The host immune response to [118,119]. One was a prospective cohort study includ- HPV infection is initiated by cytokines and chemokines ing 68 females aged 12–18 years with JIA who were www.eurosurveillance.org 7 Table Summary of recommendations regarding human papillomavirus vaccination in high-risk populations Quality of Recommendation High-risk population Summary and recommendations evidence strength HPV vaccination is recommended in HIV patients through age Moderate Strong 26, regardless of gender HIV infection HIV-positive patients aged ≥ 26 years may also benefit from Low Weak HPV vaccination HPV vaccination in MSM through age 26 is recommended Moderate Strong MSM MSM aged ≥ 26 years may benefit from HPV vaccination Very Low Weak HPV vaccination is recommended in women with IBD through IBD Low Weak age 26 HPV vaccination is recommended in women treated for Moderate Strong Women with premalignant precancerous cervical lesions cervical lesions Women with untreatable intraepithelial lesions may benefit Low Strong from HPV vaccination CBMFS HPV vaccination is recommended in patients with CBMFS Low Strong Patients with primary immunodeficiency may benefit from HPV Primary immunodeficiency Very low Weak vaccination Survivors of childhood cancer may benefit from HPV Survivors of childhood neoplasia Very low Weak vaccination HPV vaccination is recommended in women through age 26 Low Strong who have received a solid organ transplant or HSCT Solid organ transplantation or HSCT Female patients aged ≥ 26 years may benefit from HPV vaccination, particularly those with chronic graft-vs-host Very low Weak disease after HSCT HPV vaccination is recommended in women receiving Immunosuppressive or biological immunosuppressive and/or biological treatment through age Low Weak treatment 26 (in particular women with SLE or JIA) HPV vaccination is recommended in patients diagnosed with RRP Low Strong RRP through age 26 CBMFS: congenital bone marrow failure syndrome; HIV: human immunodeficiency virus; HPV: human papillomavirus; HSCT: haematological stem cell transplantation; IBD: inflammatory bowel disease; JIA: juvenile idiopathic arthritis; MSM: men who have sex with men; RRP: recurrent respiratory papillomatosis; SLE: systemic lupus erythematosus. vaccinated with bivalent HPV vaccine. The vaccine Summary of previous guidelines or consensus showed a strong HPV 16/18-specific antibody response recommendations that was comparable with the response seen in healthy The evidence-based recommendations on vaccination female adolescents; HPV-specific geometric mean in patients with autoimmune rheumatic diseases from concentrations (GMCs) were consistently lower in JIA the European League against Rheumatism specify that patients. No effect of methotrexate or anti-TNF treat- HPV vaccination should be considered in women with ment on the vaccine response was observed and no SLE aged less than 26 years [120]. safety concerns were found [118]. Another prospective cohort study including 21 female patients with JIA aged ACIP recommends routine HPV vaccination for immuno- 12–25 years and 21 healthy controls immunised with suppressed patients aged 9–26 years [20]. bivalent HPV vaccine showed significantly lower HPV 16 neutralising antibody titres in JIA patients than con- The 2013 IDSA clinical practice guideline for vaccina- trols, but no significant difference in HPV-18 antibody tion of the immunocompromised host recommends titres. Immunoresponse to the vaccine did not seem to HPV vaccination for females and males 11–26 years old be affected by the type of anti-rheumatic therapy the with chronic inflammatory diseases on immunosup- patients were receiving. The vaccine was safe and well pressive medications [27]. tolerated [119]. Recommendations in patients receiving At present, there are no published data from ran- immunosuppressive or biological treatment domised clinical trials on the efficacy, immunogenic- HPV vaccination is recommended in women receiving ity or safety of HPV vaccination in patients receiving immunosuppressive and/or biological treatment aged immunosuppressive and/or biological treatment. 9–26 years, in particular, women with SLE or JIA (qual- ity of evidence: low; recommendation: weak). While the vaccine can be given at any time, administration before 8 www.eurosurveillance.org the use of immunosuppressive or biological therapies and treatment, HPV vaccination is crucial in the preven- is preferable. There are no data supporting HPV vac- tion of uterine cervical cancer. cination in males receiving immunosuppressive or bio- logical therapy. In all high-risk populations, based on the summary and recommendations, the quality of evidence was found Recurrent respiratory papillomatosis to be very low to moderate. A strong recommenda- Recurrent respiratory papillomatosis (RRP) is charac- tion about HPV vaccination was made in HIV infected terised by the presence of multiple papilloma in the patients aged 9–26 years; men who have sex with men airway that cause obstructive symptoms such as short- aged 9–26 years; women with precancerous cervical ness of breath, hoarseness or stridor [121]. The disease lesions; patients with congenital bone marrow failure may occur in children (aged ≤ 17 years) or adults [9,122]. syndrome; women who have received a solid organ The incidence of both juvenile and adult forms of RRP transplant or hematopoietic stem cell transplantation is estimated at 3–7 per 100,000 individuals [123,124]. aged 9–26 years; and patients diagnosed with recur- HPV infection is the cause of RRP, with genotypes 6 rent respiratory papillomatosis. In the rest of high-risk and 11 present in 90–95% of cases [9]. categories with only a weak recommendation (HIV- positive patients aged ≥ 26 years, MSM aged ≥ 26, IBD, Rationale for recommendations patients with primary immunodeficiency, survivors of Nine papers of HPV vaccination in patients with childhood neoplasia, women who have received a solid recurrent respiratory papillomatosis were selected organ transplant or hematopoietic stem cell transplan- (Supplementary material Table S8). No randomised tation aged ≥26 years and patients in immunosuppres- clinical trials on the efficacy of HPV vaccine have been sive or biological treatment), the quality of evidence conducted in individuals with RRP. Several studies was low or very low. Further studies are needed. have investigated the effectiveness of the quadrivalent vaccine in both juvenile RRP [122,125-131] and adult RRP [122,126,130,132] Supplementary material Table Note S8). Vaccination-induced partial or complete remission Author Xavier Castellsagué passed away 12 June 2016. in a substantial proportion of the RRP patients, and no remarkable adverse effects were reported. Acknowledgements Summary of previous guidelines or consensus We would like to thank Sheridan Henness, PhD, and Sarah recommendations Greig, PhD, of Springer Healthcare Communications who There are no guideline or consensus documents that wrote the outline and first draft of this manuscript. This specifically recommend HPV vaccination in patients medical writing assistance was funded by the Spanish with RRP. Association of Cervical Pathology and Colposcopy (AEPCC). Recommendations in patients with RRP The guideline on HPV vaccination in high-risk individuals HPV vaccination is recommended in patients with RRP was reviewed and endorsed by the Spanish Association of Cervical Pathology and Colposcopy (Asociación Española aged 9–26 years (quality of evidence: low; recommen- de Patología Cervical y Colposcopia (AEPCC)), the Spanish dation: strong). Given the relationship of RRP to HPV Association of Paediatrics (Asociación Española de Pediatría genotypes 6 and 11, the use of the quadrivalent or (AEP)), the Spanish Association of Vaccinology (Asociación nonavalent vaccine is recommended. Despite scarce Española de Vacunología (AEV)), the Spanish Society of data, the potential benefit should outweigh the risk Paediatric Haematology and Oncology (Sociedad Española de Hematología y Oncología Pediátricas (SEHOP)), the of vaccination; therefore compassionate use may be Spanish Society of Haematology and Haemostasis (Sociedad considered in juvenile patients who are under the age Española de Hematología y Hemoterapia (SEHH)), the indicated in the summary of product characteristics for Spanish Society of Primary Care Doctors (Sociedad Española the vaccine. de Médicos de Atención Primaria (SEMERGEN)), the Spanish Society of Community and Family Medicine (Sociedad Española de Medicina de Familia y Comunitaria (semFYC)), the Summary of recommendations Spanish Society of Preventive Medicine, Public Health and Data concerning non-routine HPV vaccination in popu- Hygiene (Sociedad Española de Medicina Preventiva, Salud lations with a high risk of HPV infection and associ- Pública e Higiene (SEMPSPH)), the Study Group of Sexually ated lesions are scarce, and recommendations differ Transmitted Diseases of the Spanish Society of Infectious between countries. The evidence-based recommen- Diseases and Clinical Microbiology (Grupo de Estudio de las Infecciones de Transmisión Sexual (GeITS) de la Sociedad dations for HPV vaccination in high-risk populations Española de Enfermedades Infecciosas y Microbiología conducted by an independent expert panel are summa- Clínica (SEIMC)) and the Spanish Working Group in Crohn’s rised in Table. Disease and Ulcerative Colitis (Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU)). Conclusions Systematic HPV vaccination is considered the most effective intervention for controlling the infection and Conflict of interest preventing HPV-related disease burden. Along with Several authors have received economical funds for research other interventions, such as information, screening through their working institutions from Sanofi Pasteur MSD www.eurosurveillance.org 9 and MSD and received speakers’ fees from GSK and/or Obstet Gynaecol. 2018;47:14-26. https://doi.org/10.1016/j. bpobgyn.2017.08.006 PMID: 29037457 Sanofi Pasteur MSD and MSD. 14. World Health Organization (WHO). Human papillomavirus vaccines: WHO position paper, May 2017. Wkly Epidemiol Rec. 2017;92(19):241-68. PMID: 28530369 Authors’ contributions 15. GlaxoSmithKline. Cervarix suspension for injection: summary of product characteristics: GlaxoSmithKline; 2012. Available All authors have contributed to bibliographic search, criti- from: http://www.ema.europa.eu/docs/en_GB/document_ cal review of papers, GRADE classification of recommenda- library/EPAR_-_Product_Information/human/000721/ WC500024632.pdf tions and manuscript writing. Xavier Martínez and José Ángel 16. Merck Sharp & Dohme BV. Gardasil suspension for injection: Rodrigo Pendás designed and carried out the electronic bib- summary of product characteristics. Stockholm: Merck Sharp liographic search, selected the references for full-text read- & Dohme BV;2011. Available from: http://www.ema.europa.eu/ ing after the screening of the title and abstract of all the docs/en_GB/document_library/EPAR_-_Product_Information/ studies retrieved and selected the papers finally included. human/000703/WC500021142.pdf Xavier Martínez and Magda Campins have also drafted the 17. Merck Sharp & Dohme BV. Gardasil 9 suspension for injection: first version of the manuscript and have incorporated all the summary of product characteristics. Merck Sharp & Dohme BV; 2015. Available from: http://www.ema.europa.eu/docs/ modifications recommended by the other authors. en_GB/document_library/EPAR_-_Product_Information/ human/003852/WC500189111.pdf 18. European Centre for Disease Prevention and Control (ECDC). 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