The stories told by veterans with dementia provide new insights into person-centered care for healthcare professionals. In this qualitative exploratory study, life review in seven WW II veterans with mild-moderate dementia was examined. Participants with mild-moderate dementia were selected from a larger study of seventy oldest-old veterans. Semi-structured interviews were conducted to elicit testimonial language about memorable war experiences, including their perception and evaluations of the war. The interviewer provided questions and prompts to facilitate responses when necessary. Despite decreased declarative memory manifested via reduction in details and specificity of information within narratives, participants demonstrated a desire to share their war time experiences. Veterans selected appropriate memories to share, indicating their preserved sense of self. They provided a general evaluation of their wartime experiences when prompted. Veterans expressed various types of identity related to both their social origin and their experience of participating in the war. Identities of social origin revealed cultural identities which were expressed via their sense of humor. Wartime identities include being a survivor, a patriot, and a tolerant person. Veterans also described how the GI Bill helped them become college educated. This study suggests that identity is relatively preserved more so in individuals with mild versus moderate dementia when producing autobiographical stories. The process of life review brings identity to the surface. Acknowledging the identity of individuals with dementia is essential to care as it recognizes the value of the person. Additionally, eliciting significant autobiographical memories serves as a valuable means of social engagement and connection.


Infection with human papilloma virus (HPV) is related to a great number of cutaneous and mucosal manifestations. The spectrum of HPV ranges from inapparent infections, through various clinical benign presentations including cutaneous and mucosal disease, to malignant and premalignant conditions. New HPV types are currently described in the literature; many of them are characterized as high-risk types due to their oncogenic potential. Knowledge regarding their epidemiology and pathogenesis is important to understand not only infection and disease processes, but also to formulate the clinical and laboratory basis for diagnosis, therapeutics, and prophylactic measures. This non-systematic review aims to discuss and to update those aspects, with an emphasis on relevant topics for dermatologists. HPV infection and related diseases in the Brazilian scenario are highlighted, including common dermatologic conditions seen at clinics as well as the condition of a public health problem as a sexually transmitted infection. The oncogenicity of the virus and the variety of clinical outcomes – especially in the immunocompromised individuals – are addressed. The high prevalence of infection by the human papilloma virus (HPV) and its relationship with diseases, ranging from benign conditions in the skin and mucous membranes to the most frequent sexually transmitted infection (STI), indicate its importance in the public health scenario and the role of the dermatologist as one of the professionals trained to diagnose and treat many of these diseases.In turn, advances in treatment are incorporated more slowly into the therapeutic arsenal, showing the importance of early diagnosis and health education as preventive measures. In this non-systematic review, the authors searched for articles that would aid in updating and discussing the aspects of epidemiology, pathogenesis, and main clinical manifestations related to HPV.via direct contact, although skin lesions can be transmitted indirectly, via contaminated surfaces.Currently, approximately 218 types of HPV have been isolated and identified as causing infections in humans.Cutaneous warts (CWs) related to non-sexually transmitted HPV types have completely different epidemiological characteristics and are mainly caused by types 1, 2, 4, 27, and 57.10via public toilets and changing rooms was not statistically relevant in that study.The main risk factors found in school patients were close family members with CWs and families with multiple children. Transmission Genital HPV lesion is the most prevalent STI in the world.The peak incidence of infection occurs about 10 years after sexarche, usually between 24 and 30 years of age for both sexes. Although the prevalence decreases with age, studies show a second late peak of incidence in women in the fifth decade.In the anogenital region, HPV – especially types 16 and 18 – is involved in the pathogenesis of malignant tumors, with involvement in practically 100% of cervical cancer cases, 85% of anal tumors, and 50% of penile and vulvar tumors.The rates of oral HPV infection in healthy individuals vary between 0% and 20%, depending on the population studied.Immunosuppression is an important risk factor for HPV lesions. Studies suggest that temporary changes in the immunity of pregnant women may be the explanation for the higher rates of HPV infection in this group when compared with patients who are not pregnant.20Over millions of years, PVs have evolved in parallel with the species they have infected, having great cellular specificity for epithelial tissues and an enormous degree of adaptation. They are a group of viruses with marked species-specificity and are capable of producing subclinical infections, of long evolution with low viral replication; clinical infections, through the evasion of the host’s immune mechanisms; in addition, they participate in the process of carcinogenesis of tumors of the cutaneous, anogenital, and oral region.The Papillomaviridae family includes two subfamilies, Firstpapillomavirinae, with more than 50 genera and 130 species, and Secondpapillomavirinae, with one genus and one species.22Sparus aurata papillomavirus type 1; SaPV1) to 8,607 nucleotides . The viral capsid consists of 72 pentamers of the main L1 protein and 12 molecules of the secondary L2 protein. It infects fish, reptiles, birds and, mainly, mammals.PV measures approximately 50 nm in diameter and has an non-enveloped capsid with icosahedral symmetry; its DNA consists of a double helix with a genome ranging from 5,748  or long control region (LCR) and two groups of open read frames (ORFs) that are designated as early (E) or late (L). The core genes E1, E2, L1, and L2 fulfill essential functions during the life cycle of the virus in the epithelium. The E5, E6, and E7 genes are considered accessory and have evolved to facilitate viral replication in the squamous epithelium, not being present in all types of PVs. The genes encode proteins with specific functions during the viral cycle. The URR or LCR region is located between the ORFs L1 and E6; it contains the origin of viral replication, and is a site for viral and cellular transcription factors. The E1 protein is an ATP-dependent DNA helicase, important in the replication and amplification of the viral genome in the nucleus of infected cells. The E2 protein regulates the viral life cycle, is a co-activator of the viral genome replication by recruiting the E1 protein, and works as a transcription factor for the E6 and E7 proteins. The L1 protein is the main maker of the viral capsid, while the L2 protein, in addition to composing the capsid, is involved in the encapsidation of viral DNA and in the entry and traffic of the virus in the nucleus. The L1 protein is highly immunogenic, and serves as the basis for vaccines used to prevent HPV infection. The E4 viral protein has some characteristics of the core proteins and is expressed in the late stages of the viral cycle; it binds to cytokeratins, producing their rupture and contributing to the release and transmission of the virus. The E5 protein is a hydrophobic transmembrane protein, present in the alpha genus, with a role of evading the immune response and apoptosis. Proteins E6 and E7 are related to the amplification of the viral genome and to carcinogenesis, in some types of HPV.HPV infection occurs when viral particles reach exposed basal cells, usually by microtrauma in the epithelium. It shows tropism by stem cells from different mucosal and cutaneous epithelia, whose differences are believed to influence the pattern of gene expression of the virus. The places where the infection appears to be facilitated are: transition epithelium in the uterine cervix and anal region, specialized epithelia of the salivary glands of the oral cavity and tonsillar crypts of the oropharynx, hair follicles, eccrine and apocrine glands, in addition to the epidermis.The virus binds to the heparan sulfate proteoglycans of the basal cells and exposed basement membrane, which serves as a primary receptor. This binding happens with the L1 protein, which induces changes in the viral capsid that bind it to another receptor, not yet identified. The internalization of the capsid, which occurs similarly to a macropinocytosis mechanism, can take two to four hours. The entry of the viral genome into the nucleus is mediated by the L2 protein. Thereafter, infection begins by viral genome transcription.The viral replication cycle has three phases: an initial amplification of DNA, with the participation of proteins E1 and E2; a phase of maintenance of viral replication that occurs in the proliferating infected cells; and a phase of genome amplification and formation of new viruses that occurs when the cells complete their differentiation. The maintenance phase can last for months or years. Viral capsid proteins encapsidize viral DNA to form viral particles that are released as epithelial cells are detached.HPV, in general, completes its life cycle in epithelial cells; does not produce viremia, cell lysis, or inflammation; and remains protected from the immune system through mechanisms of evasion of the innate immune response, in addition to delaying the adaptive immune response. As a rule, this phenomenon is correlated with persistent HPV infections and an increased chance of progression to neoplasms.Keratinocytes are sentinel cells of the immune system and can initiate a response to viral pathogens. Proteins E6 and E7 from HR-HPV  interfere in this response. HPV infection does not activate or recruit Langerhans cells, antigen-presenting cells present in the squamous epithelium. They do not respond to the HPV capsid, unlike dermal dendritic cells, which are able to initiate an immune response to the viral L1 protein. Consequently, an antigen-specific immune response does not occur.23Initial infections of some types of HPV can be controlled by innate immunity, while clinically evident lesions require a local immune response involving CD8+ cytotoxic T lymphocytes and T helper 1 CD4+, which produce interleukin 2 (IL-2) and interferon-gamma (IFN-γ) and recognize the viral proteins E6, E7, and E2. The complete elimination of the virus may not take place, leading to its latency. HPV reactivation is often observed in immunosuppressed transplant patients and HIV patients. In mucosal infections, some other factors have been cited as capable of interfering in the immune response to HPV, such as the microbiota, mucosal secretion products, and hormonal responses.The first HPVs associated with cancer were HPVs 5 and 8 in patients with EV, a genetic disease that predisposes to infection by HPVs, mainly of the beta genus, and in which, due to a mechanism that is not fully understood, the body fails to eliminate the virus and warts are observed in various areas. In these patients, the HPVs are related to the appearance of non-melanoma skin cancers (NMSC) in areas exposed to the sun. β-HPVs also contribute to NMSC in immunosuppressed SOT patients, and doubts remain about their role in immunocompetent patients.Studies show that they target cell pathways involved in apoptosis, DNA repair, and cell differentiation. Cellular targets vary between different types of β-HPVs. The E6 protein of HPVs 5, 8, and 38, for example, allows the infected cell to accumulate genetic mutations necessary for the process of carcinogenesis by interfering with cellular defense mechanisms. It binds to the p300 protein, interferes with DNA repair in response to the damage produced by UVR, and contributes to the accumulation of mutations, chromosomal abnormalities, and cellular immortalization. Furthermore, it induces the degradation of Bak, a protein that repairs, through apoptosis, UVR-induced cellular DNA damage. The E7 protein of β-HPVs 23, 38, and 49 also has oncogenic properties, similar to the alpha genus, which involve inhibition of tumor suppressor proteins of the retinoblastoma family.Alpha genus HPVs, specifically 12 phylogenetically related types of sexual transmission, especially HPV 16, are related to cervical cancer and, with increasing evidence, to other cancers in the anogenital region  and oropharynx. Based mainly on studies on cervical cancer, the following are considered HR-HPVs: HPV 16, HPV 31, HPV 33, HPV 35, HPV 52, and HPV 58, of the alpha-9 species; HPV 18, HPV 39, HPV 45, and HPV 59 of the alpha-7 species; HPV 51, of the alpha-5 species; and HPV 56, of the alpha-6 species.This advance in knowledge was fundamental to establish primary and secondary prevention strategies: in 2014, vaccination to prevent HPV infection was introduced in the National Immunization Program of the Brazilian Ministry of Health and molecular tests for HPV DNA research have been introduced in some countries in order to identify high-risk types.The different clinical manifestations vary according to the type of HPV involved in the infection, the anatomical site of virus predilection, and the host’s immune response. HPV 1 and 63, of the Mu genus, for example, appear to target the eccrine ducts of the palmoplantar regions: HPV 1 causes myrmecia-like warts on the palms and plants, being rare elsewhere; HPV 63 produces punctate warts (0.5 to 2 mm) in the plantar region and is identified in the keratinocytes around the acrosyringia and in the upper portion of the eccrine duct. HPVs 4 and 65, of the gamma genus, produce pigmented warts in the palmoplantar region and lateral region of the hands and feet, while HPV 95, also of the gamma genus, produces non-pigmented papules in the plantar region. HPV 7, of the alpha genus, produces “butcher” warts, mainly on the hands. These considerations also apply to mucosal HPVs. For example, HPVs 6 and 11, belonging to the alpha genus, appear to have a more limited epithelial distribution: HPV 6 has a predilection for the genital region, while HPV 11 is more frequently observed in the oral region. These different epithelial tropisms reflect genetic differences of the virus, in addition to different patterns of gene expression and epithelial regulation in different anatomical sitesThe clinical manifestations on the skin include those common in medical practice, but there are also rarer manifestations, many of them related to genetic defects, which have an impact on the host's response to the virus infection. At the same time, the special situation of immunosuppression (whether acquired or not) is noteworthy, interfering with the natural history of the infection, leading to extensive conditions that are refractory to treatment and amplifying the oncogenicity of HPV.CWs are a benign condition and present spontaneous resolution in most cases. Nonetheless, they can grow, cause discomfort or embarrassment to patients, and persist for months or years, increasing viral transmission between individuals. The denomination of the warts, in general, takes into account the appearance of the lesion, such as flat and filiform wart; the location, such as palmoplantar, periungual, or genital; or the group of individuals in which the wart is mostly found, such as butcher’s wart. In relation to CWs, in general, three entities are considered: common wart, flat wart, and palmoplantar wart.28Clinically, common warts (CmWs) present as papules or raised nodules, with a rough surface, skin-colored or yellowish, single or multiple, of varying sizes, which can converge and form large plaques A. A typi29The HPVs most commonly found in CmWs are HPV 2, 4, 7, 26, 27, 28, 29, and 57.29Flat warts appear as flat, skin-colored, or yellowish erythematous papules, with a flat and smooth surface; they measure a few millimeters and have a tendency to coalesce. Koebner's phenomenon is observed relatively frequently. They usually occur on the face and back of the hands, and are found mainly in children and adolescents (hence the name juvenile flat wart), as well as in immunocompromised patients, such as those living with HIV and SOTs.28Palmoplantar warts (PPWs) appear as hyperkeratotic papules that, on pressure areas, show endophytic growth and, frequently, hemorrhage points. The lesions can be deep or superficial and, when located on the pressure areas, are very painful. They affect children and adolescents more frequently.The myrmecia wart is a deeper lesion that presents a rough surface, surrounded by a hyperkeratotic ring. They are compared to an iceberg, where only a small part is clinically visible, while most of the lesion is found in the deeper layers. They can be single or multiple, with an inflammatory and painful presentation. Myrmecia PPW is associated with HPV 1.29Mosaic warts are multiple lesions that converge and form keratotic plaques. They are present on the plantar region, with a more superficial and painless presentation, and are caused by HPV 2Periungual warts, which are usually painful, may show subungual growth resulting in partial onycholysisThe HPVS most commonly found in PPW lesions are types 1, 2, 4, 7, 63, 65, and 95.Regarding the differential diagnoses, the following should be considered: grooved and punctate plantar pitted keratolysis, punctate palmoplantar keratoderma, calluses, and SCC, especially the verrucous carcinoma subtype.29EV, described by Lewandoswsky and Lutz in 1922, is an autosomal recessive genetic disease characterized by a mutation in the TMC6 (EVER1) and TMC8 (EVER2) genes, which leads to chronic infection by specific types of HPVs, mainly of the beta genus.vs. host disease, atopic dermatitis, and systemic lupus erythematosus.Recently, new mutations have been described in patients with clinical features similar to those of EV, in which the previously reported mutations  had been ruled out. All of these patients have deficiencies in cellular immunity against HPV infections in common. Patients with these new mutations are also predisposed to other infections and tumors.Generalized verrucosity (GENV) was recently described as a chronic and progressive skin infection by HPV, in which patients present over 20 lesions located in more than one region of the body, with impairment of fingers and limited function. The clinical manifestations depend on the type of HPV involved, ranging from lesions such as flat wart, CmW, periungual wart, or genital wart, and are commonly found in several immunodeficiency syndromes. In WILD syndrome, the patient presents warts, immunodeficiency, lymphedema, and anogenital dysplasia B; in WHI34Verrucous carcinoma, described by Ackerman in 1948, is considered a variant of SCC with insidious evolution, slow-growing but recurring. The cutaneous form, epithelioma cuniculatum, is most commonly observed on the feet, predominates in men (2.3:1), and has a mean age of lesion onset of roughly 55 years. Its clinical presentation can vary from a small keratotic papule, similar to a common wart, to large, multilobulated tumors with a cauliflower aspect; differential diagnosis should include plantar warts, keratinocytic tumors such as keratoacanthoma, basal cell and squamous cell carcinoma, subcutaneous mycoses, and others A and B. in situ (CIN 3). Other epithelia may suffer the oncogenic action of the virus, originating vaginal intraepithelial neoplasia (VAIN), penile intraepithelial neoplasia (PIN), anal (AIN), and vulvar (VIN), currently called vulvar HSILs when related to HPVs and NIVd – differentiated, when linked to other precursor lesions. Flat lesions with basal atypia and koilocytosis due to HPV are called LSILs.38Most of the time, HPV infections are subclinical.Genital warts (GW) or condyloma acuminatum are the most common clinical manifestation of HPV infections in the anogenital region. They are related to LR-HPVs 6 and 11, although co-infection with HR-HPV  are described.in situ, as described in part II of this review. Clinically, it is characterized by flat, hyperchromic or erythematous, multiple, asymptomatic papules, located in the anogenital region, resembling seborrheic keratosis, common wart, lichen planus, or melanocytic nevus.40Bowenoid papulosis (BP) occurs in both sexes, preferentially affecting young people who are sexually active. Depending on its location and histopathological picture, it may correspond to LSILs or HSILs of the vulva and PIN or AIN. Histopathologically, it resembles SCC As in other locations, most HPV infections in the oral cavity are subclinical. The incidence of clinically defined lesions is estimated at around 3%. Lesions of the oral mucosa caused by HPV include CmW, condyloma acuminatum, squamous papilloma (SP), and focal epithelial hyperplasia (FEH). These lesions have many clinical and histopathological characteristics in common. HPVs 2 and 4 are considered to be related to CmWs of the oral mucosa, while in FEH, HPVs 13 and 32 were implicated; types 6 and 11 are common in SP and condyloma acuminatum. In the latter, HPVs 16 and 18 have also been described.FEH, or Heck's disease, is an uncommon asymptomatic condition that affects the mouth mucosa and predominates in children and young individuals. It was first described in Native Americans and Eskimos, but it exists in several other populations, including the elderly and AIDS patients. Clinically, multiple lesions are described, with predominance of papules, pink or white, flat and sessile; they can also be papillomatous, with a prominent rough surface. The latter are more rare and are located on the tongue and gums, while the former predominate on the labial and jugal mucosa. The lesions are asymptomatic and tend to spontaneous regression. Its manifestation in children should alert for the differential diagnosis with some syndromes such as type 1 neurofibromatosis, Cowden’s syndrome, and type 2B multiple endocrine neoplasia.39Recurrent respiratory papillomatosis (RRP) is a rare but potentially life-threatening disease that affects the respiratory tract, with a predilection for the larynx and trachea. The juvenile form manifests itself until the age of 20, and its diagnosis can be challenging since it shares symptoms with several common childhood respiratory diseases. It is attributed to infection by HPVs 6 and 11 in more than 90% of cases and, in childhood, it is assumed that the contamination for most cases occurs through the birth canal, with the possibility of infection through the placenta. Other HR-HPVs such as 16, 18, 31, and 33 may also be involved. It has an unpredictable course, and in rare cases evolve with malignancy. The diagnosis is made by histopathology of lesions in the bronchial tree sampled at bronchoscopy. In RRP forms with diffuse involvement of the bronchial tree, the differential diagnoses include Wegener's granulomatosis, recurrent polychondritis, amyloidosis, neurofibromatosis, tuberculosis, and sarcoidosis.in situ and can be associated with HR-HPVs, especially 16. BD is characterized by erythematous and desquamative plaques located in the keratinized areas of the anogenital region. EQ appears as shiny, erythematous plaques with a velvety appearance in areas of the mucosa of the vulva, glans, and internal aspect of the foreskin. Both can progress to invasive SCC.While the terminology is not consensual, Bowen’s disease (BD) and erythroplasia of Queyrat (EQ) correspond to SCCs Giant condyloma acuminatum, also called BLT, is a rare form of anogenital condyloma related to HPV, especially types 6 and 11, but occasionally HR-HPV can be found .43The classic description of BLT is a vegetative or verrucous tumor lesion, with exophytic and endophytic growth, sometimes with fistulas and bleeding . It grow43The diagnosis is confirmed by the typical histopathology, and must be complemented with imaging exams to define the treatment. FOP occurs preferentially on the cheeks, floor of the mouth, gums, and more rarely on the tongue, palate, and labial commissures. It is more common in men from the seventh decade of life onwards. The use of alcohol and tobacco, the latter both in the form of cigarettes and chewing tobacco, poor oral hygiene, repeated trauma due to inadequate prostheses, in addition to chronic inflammatory diseases such as lichen planus and lupus erythematosus, have been identified as risk factors. The related HPVs are types 2, 3, 6, and 11. Recurrences are frequent during follow-up of patients and, rarely, local metastases occur.vs. 13%). Although no cases of HSILs or carcinoma were found, the authors emphasized the need to monitor HPV infections in this group.It is assumed that the hormonal changes that occur during pregnancy temporarily interfere with the immune response, which could impact HPV replication/clearance. Thus, it is expected that there will be an increase in the frequency and progression of genital lesions caused by HPV during the gestational period.In relation to GWs, typical condylomatous lesions can be normochromatic, erythematous, or brownish with a rough surface, and can be flat, papulous, or pedunculated. They occur most frequently around the vaginal introitus, but can occur in multiple locations, such as the cervix, urethra, perineum, or intrarectal region. GWs can proliferate and become friable during pregnancy. In these patients, the lesions may be larger, more numerous, resistant to treatment, or recurrent.The incidence of anogenital warts in children has increased in recent decades.46The treatment of children with GW is a challenge in clinical practice, considering the possibility of sexual abuse, whose probability increases directly with increasing age. A retrospective study showed that the positive predictive value relating the presence of HPV infection in the anogenital region and possible sexual abuse increases from 36% between 4 and 8 years to 70% after 8 years of age.GWs in infants and children usually appear in the perineal region and, less frequently, in the vagina, vulva, and penis. Studies indicate that HPV 2, the causal agent of hand warts in humans, is commonly associated with anogenital warts in children, a finding that suggests autoinoculation and heteroinoculation as common ways of acquiring anogenital warts.Nonetheless, the presence of GWs in a child should alert the caregiver/health professional to the possibility of sexual abuse.The differential diagnoses of condyloma acuminatum in children include condyloma lata, molluscum contagiosum, achrocordon, pseudowarts, or infantile gluteal granuloma. Spontaneous resolution of GWs occurs in most cases in a few years or months; therefore, the therapeutic approach in childhood should be more conservative and less aggressive.Immunosuppressed individuals, especially those with HIV co-infection or immunosuppression due to SOT, have experienced better quality and longer life expectancy. The persistence of HPV infection is greater in these individuals than in the general population, which, combined with immunosuppression itself and the higher frequency of HR-HPV, may result in a higher incidence of neoplasms.19Common and benign diseases associated with HPV, such as GWs and extragenital warts, are also more prevalent in this population than in the general population.In renal transplant receptors (RTRs), the prevalence of CWs increases with the duration of immunosuppression; in the first year after transplantation, they are found in 15% of patients, reaching 92% after 15 years.In HIV patients, CWs are more numerous and aggressive; they may be associated with new types of HPV, including those more typically found in the genital mucosa.GWs are among the most common clinical manifestations of HPV infection in both immunosuppressed and immunocompetent individuals. HPVs 6 and 11 are the most common types found in GWs in both groups.Regarding RTR, in a prospective cohort conducted by Larsen et al. with 3,268 RTRs and 162,910 non-transplanted individuals, a three-fold greater risk of GWs was observed among the RTRs. Adjusted for age and sex, the risk was up to five times higher among RTR women.Individuals living with HIV are more susceptible to sexually transmitted infections, especially HPV. In these patients, there is a higher prevalence of co-infection with HR-HPV, especially HPV 16; the condyloma tend to be more extensive, aggressive, recurrent, and persistentNMSC is the most frequent cancer in Brazil, corresponding to about 30% of malignant tumors registered in the country, with an estimated incidence of almost 177,000 new cases for the year 2020.55The relationship between β-HPVs and NMSC is controversial and has been evaluated in recent years, and is better established for people with EV and immunosuppressed patients. In immunocompetent patients, this association is weak, impaired by the heterogeneity and omnipresence of this group of viruses in overall healthy skin, which makes it difficult to define infections that may be clinically relevant.25When compared with the general population, immunocompetent patients with SCC have a higher positivity for viral DNA from at least one type of β-HPV, on the skin and/or eyebrow hair, a common reservoir of viruses of the beta genus as well as for antibodies against the viral protein L1.Bernat-Garcia et al. detected the presence, mainly, of β-HPVs in NMSCs and in normal perilesional skin of RTR and immunocompetent individuals. The virus was detected more frequently in the former group and in normal skin.vs. 27%), and BCC (75% vs. 36%).In a review article, Sichero et al. reported a higher prevalence of β-HPVs in samples of premalignant and malignant lesions from immunosuppressed patients when compared with those immunocompetent: premalignant lesions (88% in the immunosuppressed and 54% in the immunocompetent), SCC  than in immunocompetent individuals (53.3%); the most prevalent genus was β-HPV in both populations and the occurrence of different types of HPV in one lesion was greater in immunocompromised patients.In SOT, the risk of NMSC increases 40-fold in the first five years after transplantation, and may reach 100-fold throughout life.Evidence showing an association between HPV and NMSC includes the presence of warts and SCCs in patients with EV,In immunocompromised patients, the fact that skin cancer develops at an earlier age, is more aggressive, and has a greater risk of metastasis implies the need to adopt effective preventive measures for this population. Therefore, the relevance of the dermatologist in prevention is emphasized, especially with guidance on measures for photoprotection, as well as identification and treatment of pre-neoplastic lesions and neoplasms in this population.In Brazil, cervical cancer is the third in incidence among women.The term vulvar carcinoma encompasses both SCC of the vulva and its precursor lesions. It is estimated that about 29% to 43% of these lesions are associated with HPV infection, particularly with types 16 and 18.Penile carcinoma is a rare entity and has a higher incidence in developing countries. HPV is responsible for approximately 50% of carcinomas in that site.Anal cancer is relatively uncommon in the general population. The persistence of HR-HPV infection is responsible for 88% of anal cancers, and a significant risk factor is co-infection with HR-HPV and HIV.HPV is detected in approximately 25% of oropharyngeal cancers.In a subsequent article, histopathological aspects, complementary diagnosis, treatment, and measures for the prevention of HPV infection will be addressed, including vaccination and health education.None declared.Geraldo Magela Magalhães: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; critical review of the literature; critical review of the manuscript.Érica Cristina Vieira: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; critical review of the literature; critical review of the manuscript.Lucas Campos Garcia: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; critical review of the literature; critical review of the manuscript.Maria de Lourdes Ribeiro de Carvalho Leite: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; critical review of the literature; critical review of the manuscript.Antônio Carlos Martins Guedes: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; critical review of the literature; critical review of the manuscript.Marcelo Grossi Araújo: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; critical review of the literature; critical review of the manuscript.None declared.ANSWERSDonovanosis. An Bras Dermatol. 2020;95(6): 675‐683.


The prophylactic vaccines available to protect against infections by HPV are well tolerated and highly immunogenic. People with HIV have a higher risk of developing HPV infection and HPV-associated cancers due to a lower immune response, and due to viral interactions. We performed a systematic review of RCTs to assess HPV vaccines efficacy and safety on HIV-infected people compared to placebo or no intervention in terms of seroconversion, infections, neoplasms, adverse events, CD4+ T-cell count and HIV viral load. The vaccine-group showed a seroconversion rate close to 100% for each vaccine and a significantly higher level of antibodies against HPV vaccine types, as compared to the placebo group . There were also no differences in terms of severe adverse events  and no severe adverse events  between vaccine and placebo groups. Secondary outcomes, such as CD4 + T-cell count and HIV viral load, did not differ between groups . Information on the remaining outcomes was scarce and that did not allow us to combine the data. The results support the use of the HPV vaccine in HIV-infected patients and highlight the need of further RCTs assessing the effectiveness of the HPV vaccine on infections and neoplasms. So far, over 200 virus types have been identified and of these, more than 40 types are sexually transmitted and can cause premalignant and malignant lesions of the cervix, anal, vulvar, vaginal, penile, oropharyngeal cancers as well as genital warts. Of these, HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 have been classified as oncogenic and HPV types 26, 30, 34, 53, 67, 69, 70, 73, 82 and 97 as probably/possibly carcinogenic. They are all defined as high risk. Types 16 and 18 cause 62.6% and 15.7% of cervical cancers worldwide respectively3. The HPV types classified as non-oncogenic (or low risk) include 6, 11, 32, 40, 42, 43, 44, 54, 55, 57, 61, 62, 64, 71, 72, 74, 81, 83, 84, 89, 90, 91 and they can develop benign tumours such as genital warts and respiratory papillomatosis. Among these, HPV 6 and 11 are the most frequent types5.Human papillomaviruses (HPV) are considered the most common causative agents of sexually transmitted diseases in the world6. Individuals infected with human immunodeficiency virus (HIV) have a higher risk of developing HPV incident and persistent infection, precancerous lesions and HPV-related cancers due to a lower immunological response, and due to viral interactions8. Each infection favours the acquisition and the amplification of the other ones9. HIV promotes initial infection through the destruction of the epithelial tight junctions10. People with HIV infections have a more rapid progression to malignancy12. Men who have Sex with Men (MSM) is the population with the highest risk of HPV anal infection13. Anal HPV infection, which contributes to the development of anal warts and anal cancers, is frequent amongst HIV + MSM, with risk of invasive anal cancer 37-fold greater than HIV + 14.Cervical cancer is the fourth most common cancer in women with estimated 528,000 new cases and 266,000 deaths annually16.Furthermore, HIV may reduce responsiveness to vaccines and their effectiveness due to immune deficits as the infection advancesThree types of prophylactic vaccines composed of virus-like particles are currently available: the bivalent , the quadrivalent  and the nonavalent  vaccines to prevent cervical cancer. The 2vHPV and 4vHPV ones are recombinant vaccines that protect against HPV types 16 and 18 persistent infections. In addition, the 4vHPV protects against HPV types 6 and 11 infections. Cervarix contains AS04, an adjuvant system that elicits a protective immune response for a longer period of time. 9vHPV vaccine to prevent infections and diseases related to nine HPV types .Cervarix was licensed in Australia, Philippines, EU in 2007, while in USA in 2009 and Gardasil was licensed in EU in 2007. The latter (Gardasil 9) was licensed in the USA in 2014, in Canada, in the EU and in Australia in 2015 and in other countries between 2015 and 2016.The body of evidence suggests that HPV vaccines are highly immunogenic and well tolerated and their immune response persists up to 10 years after vaccination. They induce excellent protection against vaccine-included genotypes, anogenital warts and high-grade intraepithelial neoplasia.All HPV vaccines are generally well tolerated with mild or self-limited injection site reactions being the most common adverse events. No serious effects have been found to be related to vaccination.20. Prophylactic HPV vaccines may also benefit HIV + patients, however, little is known about their safety and efficacy in this population.Several studies have described the impact and effectiveness of HPV vaccination, once it has been included in public health programsThis review seeks to evaluate the efficacy and safety of vaccines to prevent HPV infections and correlated lesions in cervical, vulvar, vaginal, penile, anal or oral districts in HIV-infected patients by meta-analysing the results of randomised controlled trials (RCTs).21 and of the Cochrane Handbook for Systematic Reviews of Interventions22. The full research protocol is available on Prospero Center for Reviews and Dissemination (PROSPERO) under the registration number of CRD42018084619. Ethical committee approval was not requested because this review used only published data.This systematic literature review was performed following the guidelines of the PRISMA StatementA comprehensive search strategy of all relevant studies regardless of language or publication status  was performed on the following electronic databases: EMBASE, PubMed (Medline) and Cochrane Database of Systematic Reviews up to 22-nd May, 2019. Details on the search strategy are reported in Supplemental Table The reference lists of the identified studies were also checked for additional studies. The clinical trials registry platform ClinicalTrials.gov was also searched for any ongoing trial.RCTs that compared the use of 2vHPV, 4vHPV or 9vHPV vaccines for HPV prevention against placebo or no intervention in HIV + individuals were evaluated for inclusion. Quasi-randomized trials and nonrandomized studies were not included.ofor HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58.HPV seroconversion:odue to HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58;oin the cervical, vulvar, vaginal, penile, anal or oral districts.Presence of infection:oCervical Intraepithelial Neoplasia (CIN);oVaginal Intraepithelial Neoplasia (VAIN);oVulvar Intraepithelial Neoplasia (VIN);oAnal Intraepithelial Neoplasia (AIN);oPenile Intraepithelial Neoplasia (PeIN);oOral Intraepithelial Neoplasia (OIN).Presence of grades 2 or 3 neoplasia:Efficacy:Adverse events (AEs);Mortality for all causes.Safety:HIV viral load (VL);CD4 + T-cell count;Completion rate of three doses of HPV vaccination series.After the removal of duplicates, the records were independently screened according to pre-specified criteria by four review authors  in two separate stages. First, titles, abstracts and descriptor terms were screened for eligibility followed by the full text. Disagreements on eligibility amongst the reviewers were resolved by discussion. Then, data was independently extracted, using a data extraction form, by four reviewers . Disagreements were solved by discussion amongst authors. The sources for data extraction were the original articles and the ClinicalTrials.gov registry.Data on study characteristics , patient features , baseline characteristics (CD4 + T-cell count and VL) and peculiarity of interventions  was extracted from each study. Primary outcomes of efficacy  and safety , as well as secondary outcomes  and the numbers of patients that were analysed by the authors, were also extracted.22, which includes the following criteria: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and outcome assessors (performance and detection biases), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias) and other biases. The RoB of each study was explicitly judged on each criterion and classified as ’low’, ’high’, or ’unclear’. An unclear RoB resulted from a lack of sufficient information about methods used in studies, making it impossible to judge whether or not the bias was present. In this review, risk of attrition bias was judged as ’low risk’ when the percentage of participants with missing data was low for primary outcomes, which was arbitrarily set at values lower than 15%, and when numbers and causes of losses to follow-up were balanced between arms.The Cochrane Risk of Bias (RoB) tool was usedTo summarize the overall RoB for a study, random sequence generation and allocation concealment, blinding of outcome assessors and incomplete outcome data were considered in order to classify each study as: ’low risk of bias’ when all four criteria were met; ’high risk of bias’ when all criteria were unmet; ’moderate risk of bias’ in the remaining cases.We also assessed RoB for AEs. We evaluated methods for monitoring and detecting an AE for each study: ‘low risk of bias for AEs’ was assigned when authors actively monitored for AEs, whereas a ‘high risk of bias’ was assigned in the case they simply provided spontaneous reporting of the occurring AEs. We also assessed whether the authors defined severe and not severe AEs according to a recognised international classification. The RoB of each study was assessed and discussed by all reviewers.23. The pooling method was inverse variance (IV) weighting for quantitative outcomes and Mantel–Haenszel (MH) weighting for dichotomous variables. For dichotomous outcomes, only studies with at least one observed event were considered for data synthesis. The presence of statistical heterogeneity was assessed by Tau2 and I2 statistics. Data synthesis was not performed when I2 statistics > 90%.Our unit of data extraction, evaluation, and analysis was the primary randomized trial. The association between the intervention and dichotomous outcomes was measured by using the Risk Ratio (RR) with 95% confidence interval (95% CI), whereas for continuous variables it was measured by using the mean difference (MD) with 95% CI. In calculating the MD, equality of variances between the two groups was considered, unless evidence of not equal variances was present. All association measures were calculated considering the placebo group as the reference category. Meta-analyses were performed for all outcomes, provided that at least two studies were available, using a random effects modelStatistical analyses were carried out with R 3.6.3 statistical software  at p < 0.05 significance level.Gender ;Age ;Presence of risk factors (e.g. MSM);CD4 + T-cell count ;HIV VL .The effect of vaccines in the following subgroups were also sought:24 and was explicitly rated for each outcome on a four-levels scale . Since we have included only RCTs in this review, our rating started from a high level of certainty and then we eventually downgraded it by considering the following criteria: RoB of included studies, inconsistency and imprecision of relative effect estimates, indirectness of evidence and publication bias.The summary of findings was reported following the GRADE criteriaThere were fifty-six studies that were identified by our search strategy on 22-nd May, 2019. All of them were screened for inclusion by title and abstract assessment. Nine full-text articles were screened for eligibility and four of them met the inclusion criteria. A flow diagram describing the study selection process is reported in Fig. 28. The characteristics of these studies are reported in Supplemental Table Four randomised placebo-controlled trials were included in this review25; MSM ≥ 18 years with mean age of vaccine group of 37.3 ± 10.6 years and control group of 40.5 ± 10.0227; children aged 7–12 years with mean age of vaccine group of 10 years (95% CI 9.7–10.3) and placebo of 9.9 years (95% CI 9.4–10.4)26; MSM and women ≥ 27 years with median age of vaccine group of 47 (IQR 40–52) and placebo of 48 (IQR 42–53)28.The studies included people with HIV: women aged 18–25 years with mean age of vaccine group of 21.6 ± 2.21 years and placebo group of 22.7 ± 1.726. The four studies randomised a total of 950 participants. Overall, the vaccine groups consisted of 511 HIV + patients, ranging between 61 and 288 participants per study. The placebo groups consisted of 439 HIV + patients, ranging between 59 and 287 per study.The RCTs were carried out between 2008 and 2014 in South Africa, Spain, USA and Brazil. For one study the start and end dates were not reported28 and one evaluated the reactogenicity and safety of 2vHPV25. In one trial, participants have received the HPV-16/18 AS04-adjuvanted vaccine or the placebo at 0, 1, and 6 months25. In the other three trials, quadrivalent vaccine and placebo were administered at 0, 8, 24 weeks. None of the included studies reported the use of the 9vHPV.Three of the studies assessed immunogenicity and safety of the 4vHPVOutcomes in primary studies were reported at different time points as reported in Supplemental Table 26 and week 2827).Seroconversion outcomes were assessed after the end of the vaccination series 28.Abnormal Anal Cytology was assessed after the end of the vaccination series (week 52)25, month 626, week 2827 and week 4828).AEs outcomes were assessed after the end of the vaccination series .All-cause mortality outcome was assessed after the end of the vaccination series  and after the end of the vaccination series .CD4+ T-cell count outcome was assessed after the 2-nd vaccination (month 225 and week 827) and after the end of the vaccination series (month 625 and week 2827).HIV VL outcome was assessed after the 2-nd vaccination  as a continuous variable that measured the number of serum antibodies against HPV, expressed as the Geometric Mean antibody Titre (GMT) of enzyme-linked immunosorbent assay units per ml (EL.U./ml); (2) as a dichotomous variable that described the presence of serum antibodies against HPV.27. The data in Denny L et al. was available for HPV types 16 and 18 (2vHPV)25 whereas the data in Levin MJ et al. for HPV types 6, 11, 16, and 18 (4vHPV)27.Considering the continuous measurement, two studies included data on seroconversion for both vaccine and placebo groups after the end of the vaccination series27, whereas HPV types 16 and 18 were reported in both27.Considering the dichotomous measurement, two studies reported the data. HPV types 6 and 11 were reported in Levin MJ et al.27, did not include patients with protocol violations, unevaluable specimens, or the presence of type-specific antibodies at baseline27, whereas the data in Denny et al. were reported only for those subjects with available immunogenicity data at 7 months25.The data reported in Levin MJ et al.No study assessed seroconversion for HPV types 31, 33, 45, 52 and 58.28. None of the included studies have reported results concerning the presence of infections by HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58 in the cervical, vulvar, vaginal districts.One study reported the presence of anal and oral infections assessed in single detection at final visit or as confirmed persistent infections of any of HPV types 6, 11, 16, or 1828. None of the included studies reported results concerning the presence of grade 2 or 3 cervical, vaginal, vulvar, penile or oral intraepithelial neoplasia.One study reported data on high grade AIN and abnormal anal cytology28.There were three included studies that reported data on mortality for all causes after the vaccination seriesData on the number of patients with AEs for both vaccine and placebo groups after the end of the vaccination series were reported by all the four included studies. Overall, there was a high number of AEs for which data were reported. We decided to include in our review and data synthesis only the following two outcomes: 1) Severe AEs (SAEs); 2) not severe AEs.Data on SAEs were reported by all four included studies and their definitions were similar.28, but we did not consider the data by Wilkin TJ et al. because the reported time was not homogeneous with the other studies.Data on not severe AEs were reported in all four included studies and their definitions were similar28 used a table of grading to describe the severity of AEs. In Denny et al.25, SAEs were defined as AEs prompting emergency room or physician visits that were not related to common diseases or routine visits for physical examination or vaccination and as SAEs that were not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities. Instead, in Hidalgo-Tenorio C et al. a definition of AEs was not provided26.Two studiesFull details of AEs are reported in Supplemental Table 28 after the 2nd vaccination and after the end of the vaccination series. These data were reported only for those subjects with available CD4 + T-cell count results at the respective time points and were expressed using the same unit of measurement (number of CD4 + cells per µl).There were three included studies that reported data on CD4 + T-cell count27 after the 2nd vaccination and after the end of the vaccination series. These data were reported only for those subjects with available HIV VL results at the respective time points and were expressed using the same unit of measurement (log10 RNA copies/ml).There were two included studies that reported data on HIV VL or sheddingAll the included studies reported data on the number of patients who completed the vaccination series.25. The mean was approximated as the central value of the IQR and the standard deviation was approximated as the IQR divided by 1.35, based on the assumption of a Gaussian distribution.Data on CD4 + T-cell count and HIV VL outcomes in Denny L et al. were reported as median and inter-quartile range (IQR)26 were reported as group means and p-value from a t test for two independent samples. The standard deviations for the two groups were both set to the value of the pooled standard deviation.Data on CD4 + T-cell count and HIV VL outcomes in Hidalgo-Tenorio et al.27 for the placebo group were the same, due to decimal approximations. In this case, we added 0.5 to the upper limit.Lower and upper limits of the confidence interval for HPV type 18 immunogenicity in Levin MJ et al.26 and two at unclear risk28. RoB related to allocation concealment was judged unclear for three studies27 and low in the remaining one28. Performance bias (blinding of participants and personnel) and detection bias (blinding of outcome assessment) were rated at unclear risk for all the studies, since in all the RCTs the participants and the outcome assessors were blinded but none of the studies reported details on the methods of blinding. We found that three studies were at low risk of attrition bias, since participants with missing data were less than 15% and were balanced between arms. Conversely, one study25 was at high risk of attrition bias for the seroconversion outcome. Finally, as for the reporting bias and for other biases, we rated all studies at low risk.Assessment of RoB for each included study—using the Cochrane Collaboration criteria—is reported in Fig. Overall, we judged all studies to be at moderate RoB.28 defined AEs and SAEs according to an accepted international classification (Division of AIDS Table for Grading the Severity of Adult AEs) whereas the remaining two studies measured AEs using an ad hoc developed questionnaire.RoB for AEs was rated as low for all studies since all researchers provided active monitoring for AEs. Data on AEs were ranked by all studies according to a 4 levels severity scale. Two studies25 comprised a population of women aged 18–25, whereas the other two studies27 comprised two populations of MSM and children aged 7–12 respectively.The combined MDs in the immunogenicity outcome, considering unequal variances between groups, were 4333.3 GMT EL. U./ml (95% CI 2701.4–5965.1) for HPV 16 and 1404.8 GMT EL.U./ml (95% CI 414.8–2394.7) for HPV 18 Fig. . One stuThe results concerning the presence of anal and oral infections, as well as high grade AIN and abnormal anal cytology are reported in Supplemental Fig. The results concerning the AEs and mortality outcomes (dichotomous outcomes) are reported in Fig. The results concerning CD4 + T-cell count outcome (continuous outcome) are reported in Fig. 10 RNA copies/ml (95% CI − 0.3 to 0.3) after the end of the vaccination series.The results concerning HIV VL outcome (continuous outcome) are reported in Fig. The results concerning the completion rate outcome are reported in Supplemental Fig. No subgroup analysis was performed due to lack of the minimum number of studies.As reported in Table The purpose of this systematic review is to summarize available data on the efficacy and safety of any types of HPV prophylactic vaccines in HIV + patients. Four RCTs conducted between 2008 and 2014 in Europe, America and Africa comprehending 950 participants living with HIV were included, 511 in the intervention group and 439 in the control group. Overall, we judged all the studies to be at moderate RoB.As for the vaccine assessed, the immunogenicity and safety of the 4vHPV was tested in three trials, whereas only one evaluated the reactogenicity and safety of 2vHPV and none of the included studies reported the use of the 9vHPV.There were no differences in the average CD4 + T-cell count and HIV VL, both after the 2-nd vaccination and after the end of the vaccination series.Furthermore, no differences in the risk of AEs were observed.Information on the remaining outcomes was scarce and that did not allow us to combine data.EMBASE, PubMed and Cochrane Database of Systematic Reviewswere used to search for studies and data was extracted from the manuscripts and from the ClinicalTrials.gov registry.The RCTs included were conducted among women, MSM and children, which represent the most vulnerable populations. However, HIV-infected men who have sex exclusively with women, injection drug users and transgender individuals were not considered as no RCTs including them were found.Among the primary outcomes, HPV seroconversion and incidence of AEs were evaluated in all included studies, while other outcomes were analysed only in some of them: GMTs for all HPV vaccine types in two studies, persistent anal and oral HPV infection of any HPV type in one study. No data were available on the efficacy of vaccine against CIN of grades 2 or 3. Regarding secondary outcomes, HIV VL and CD4 + T-cell count were reported in two studies.29.As yet, no studies on second-generation 9vHPV in HIV patients have been published, although it is assumed that the 9vHPV will elicit an immune response. Clinical trials are currently underway to provide more extensive data on the efficacy and safety of the 9vHPV vaccine in the prevention of HPV disease in individuals with HIV30 is assessing immunogenicity and safety of 9vHPV vaccine among 158 adult HIV + women. Another RCT31 in the USA is assessing the immunogenicity of the 9vHPV vaccine in MSM infected by HIV. Furthermore, the COVENANT trial32 is evaluating the effect of HPV vaccine in reducing lesions in HIV + women with high-grade cervical lesions.In Spain, a clinical trialFor all the outcomes that were analysed, we found a high degree of certainty of the evidence of the efficacy and safety of HPV vaccine in HIV + patients.With regards to AEs, there was high heterogeneity in their definitions, nor were the time-points of assessment equal across studies. This latter issue was also present for other outcomes, as reported in Supplemental Table We are aware of some main limitations that could affect the results of this review. Firstly, the populations considered in the studies were heterogeneous. Secondly, the clinical outcomes of the HPV vaccination, such as infections and high grade lesions or neoplasms, were assessed in only one study and the long term outcomes were not assessed in any RCT. As minor limitations, the time-points used were decided after seeing the time-points reported in the primary studies and small approximations on summary measures of some outcomes, as described in the previous sections, were made.The development of 2vHPV, 4vHPV e 9vHPV vaccines against HPV represents an opportunity to control and possibly eradicate the cancers associated to infection.33. In addition to high incidence, multiple HPV infections are more common among HIV + patients; a higher risk of multiple HPV types was found among HIV + MSM as compared to HIV- MSM34. In comparison to HIV- subjects, they have an increased HPV persistence, higher risk of HPV-related tumours and faster disease progression. Thus, HPV prevention is very important in HIV + patients35. Currently HPV vaccination is recommended for use among adult females and males up to 26 years, as well as MSM and subjects with immunocompromising conditions including those with HIV infection37.People HIV-infected are at increased risk of acquisition of HPV infection leading on to the development of cervical cancer and other genital illness38. The availability of limited information about the efficacy of HPV vaccines in people living with HIV has recently been highlighted both by WHO and in a systematic review39.The World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) recommend HPV vaccination with a three-dose schedule  for all HIV + up to 26 years of age if they have not already been vaccinated40 did not consider HIV + patients, while Bergman et al.39 included both HIV- and HIV + subjects, but they did not consider some outcomes of our interest. In particular, HIV VL and CD4 + T-cell count were not analysed in Bergman et al.39.Two Cochrane systematic reviews have been conducted to assess the efficacy of HPV vaccines. However, Arbyn et al.39. We both observed that vaccines are effective and safe but there is still limited evidence in people living with HIV. The authors suggested that further studies on the duration of protection and on the effect of declining immunity are needed.The results of this systematic review agreed with those obtained by Bergman et al. on common outcomes41. As for the seroconversion rates, the antibodies levels and occurrence of AEs, the results of our study agree with those of Zhan et al.41. An important difference concerns instead the level of CD4 + T-cell count in the vaccine group which in our analysis does not show significant differences when compared with placebo group.A systematic review and meta-analysis was recently published on the safety and efficacy of vaccination for people living with HIV that considered 24 studies, which included RCTs and non-RCT. In this review, studies reporting the difference between HIV + and HIV- people after HPV vaccination were also consideredFew RCTs on HIV + patients comparing efficacy and safety of HPV vaccination against placebo were carried out. Their results suggested that after the HPV vaccination, seroconversion rates were nearly 100% in women, men and children and a high antibody titers was observed for all HPV genotypes included in the vaccines. Vaccination in patients with HIV infection is safe as the number of serious AEs is similar between HIV + subjects treated with vaccines and placebo. Moreover, vaccines did not cause variations in CD4 + T-cell count and HIV VL. There is evidence on the benefit of HPV vaccine in HIV + patients, although efficacy on prevention of infections and HPV-related neoplasia still remains unknown. The results of our meta-analyses, despite being based on a few studies, suggest that HPV vaccine can be safely used in HIV + patients. Evidence on the efficacy and safety profile is available for 2vHPV, and 4vHPV vaccines. Regarding 9vHPV vaccine, no RCT in HIV + individuals is currently available. The compliance of the vaccination for the HIV + population represents a relevant issue that can be addressed by providing direct access to vaccination programs in hospital departments were HIV patients are cared for and by implementation effective communication campaigns on the importance of primary prevention.As AEs were reported in all RCTs in a heterogeneous manner, we believe that there is a need to standardise the way the information is collected and reported.Another important aspect which is worth considering for future research concerns the lack of information on some important outcomes. For example, the prevention of anogenital warts was only addressed in one study, whereas no study considered cervical intraepithelial neoplasia and cancer as outcomes.Further studies are needed to assess the effectiveness of the HPV vaccines in preventing infections and neoplasms in people living with HIV.Supplementary Figure LegendSupplementary FigureS1Supplementary FigureS2Supplementary Figure S3Supplementary Table S1Supplementary Table S2SupplementaryTable S3SupplementaryTable S4


Centre Hospitalier Régional of Orléans, France, were prospectively subjected to endocervical swabs for HPV DNA PCR and Pap smear. Fifty women  living in France  were enrolled, including 26.0% of HIV-negative women from general population and 74.0% of women with known HIV infection. Cervical HPV prevalence was 68.0%, with 56.0% of HR-HPV. HR-HPV -68 and -58 were the predominant genotypes . HR-HPV-16 and HR-HPV-18 were infrequently detected. HIV-infected women showed a trend to be more frequently infected by HPV than HIV-negative women (70.3% versus 61.5%). Most women (84.0%) showed normal cytology, while the remaining (16.0%) exhibited cervical abnormalities and were frequently HIV-infected (87.5%). These observations highlight the unsuspected high burden of cervical HR-HPV infections mostly associated with atypical genotypes, HIV infection and cervical abnormalities in first-generation immigrant African women living in France.Human papillomavirus (HPV)-related cervical lesions in first-generation immigrant African women in France should reflect the epidemiology of high-risk (HR)-human papillomavirus (HPV) infection in sub-Saharan Africa. First-generation immigrant African women attending the The online version of this article (10.1007/s10903-020-01074-7) contains supplementary material, which is available to authorized users. High-risk (HR)-human papillomavirus (HPV) genotypes are responsible for 5.2% of all cancers worldwide, 2.2% of cancers in developed countries and 7.7% of all cancers in developing countries –3. In suSub-Saharan African adult female population harbors high rates of cervical HR-HPV infections that can reach 46.2% in HIV-negative and 79.1% in HIV-positive women, with frequent variations from one region to another –10. LikeAround 300,000 immigrant women originating from sub-Saharan Africa are living in France . Most fiCentre Hospitalier Régional of Orléans, France.The aim of the present cross-sectional study was to assess the prevalence and genotypes distribution of cervical HR-HPV infection and associated risk factors in HIV-positive and HIV-negative immigrant African women living in France and attending the Centre Hospitalier Régional d'Orléans  attending the ans Fig. . This stNo data is available concerning HPV prevalence in African immigrant women living in France. To estimate the minimum sample size for this study we have used the minimum HPV prevalence reported for immigrant women living in Italy , a neighCentre Gratuit d’Information, de Dépistage et de Diagnostic (CeGIDD) of the Centre Hospitalier Régional d'Orléans were prospectively included in 2018. The CeGIDD is an outpatient consultation service providing HIV, STIs, hepatitis and HPV prevention, screening and care for the general adult population as well as HIV-treatment and medical follow-up for HIV-infected individuals. The CeGIDD is regularly attended by women of various origins wishing to be screened and cared for infectious diseases, mainly STIs, and also to have contraception. Furthermore, primary molecular testing for HPV screening is systematically offered to all women aged between 25 to 65 years attending CeGIDD centers [First-generation immigrant African women attending the  centers . The CeGCentre Hospitalier Régional d'Orléans for known HIV infection.The main inclusion criteria were originating from sub-Saharan Africa and, never having undergone molecular or cytological screening for HPV infection and precancerous lesions. The included women have signed informed consent, were aged between 25 and 65 years, were sexually active, had no genital troubles at physical examination and had completed the study questionnaire. Exclusion criteria included age less than 25 years and more than 65 years, having previously undergone molecular or cytological screening for cervical HPV infection and precancerous lesions since the arrival in France, not willing to participate to the study or to answer the face-to-face sociodemographic and medical data questionnaire. All women from general population reaching these inclusion criteria were included in the study. Knowing that our inclusion criteria were particularly specific and selective, the recruitment of women was extended to African immigrant women followed-up at the Chlamydia trachomatis, Neisseria gonorrhoeae, genital herpes and Trichomonas vaginalis. All women received an information session on HIV, STIs and cervical cancer, and completed a face-to-face questionnaire that included socio-demographic characteristics and behavioral data such as age, marital status, social occupation, education level, past-history of STIs, HIV status and also sexual behavioral characteristics such as the number of lifetime sexual partners, frequency of condom use and the age at first sexual intercourse. Women diagnosed positive for any STI received adequate care and those negative for HBV were vaccinated against HBV.After signed the informed consent form, the included women benefited from free STIs screening including HIV, hepatitis B (HBV) and hepatitis C (HCV) viruses, Hôpital européen Georges Pompidou, Paris, France, for molecular analyses.After completing the medical and socio-demographic data collection questionnaire, a nurse performed cervicovaginal sampling using a flocked swab , frozen at − 80 °C. Cervicovaginal swab were transported in frozen ice packs, to the virology laboratory of the After the sample procedure, included women were referred to the gynecologist to undergo Pap smear cytology. Cytological results were classified according to the Bethesda system 2001 . SamplesHPV detection and genotyping were assessed using the real-time PCR assay Anyplex™ II HPV28 , as described previously .2 or Fisher's exact tests were used for categorical variables and the non-parametric Mann–Whitney U-test for quantitative variables.Means and standard deviations (SD) were calculated for quantitative variables and proportions for categorical variables. The results were presented as a 95% confidence interval (CI). Pearson’s χHospitalier Régional d’Orléans formally approved the study. All included women gave their informed signed consent to participate to the study. For each included woman, the record of the consent to participate in the study was documented on each questionnaire. The Ethical Committee formally approved this consent procedure. Feedback of medical results and particularly all results of HPV detection and genotyping were given to each participant. Women infected with any STI, those harboring cervical HR-HPV and women with HPV-related lesions received adequate treatment and therapeutic follow up.The Scientific Committee of the Centre A total of 50 women  living in Orléans, France, for an average of 10.7 years  were prospectively included (Table Single women (46.0%) were a little more represented than women living in life-couple with a male partner (38.0%). Although the majority of these African immigrant women were unemployed (58.0%), a relatively high number of them (36.0%) reported having a regular paid job in France, while only 3 women (6.0%) were students. Sexual intercourse onset occurred generally (74.0%) between 16 and 20 years. The majority (68.0%) of study women had one regular sexual partner during the last 12 months. Unprotected sexual intercourse was particularly frequent, as only 12.0% of study participants declared to systematically use condom during sex, while the large majority (60.0%) of them reported condom use inconsistently during sex. Unexpectedly, 28.0% of participants reported never using condom with their sexual partner.Chlamydia infection. No past history of any other STIs such as syphilis, gonorrhea and genital condyloma was declared. In addition, none of the women included in the study had been vaccinated against HPV infection and had ever undergone molecular and cytological screening for HPV infection and precancerous lesions, both in their country of origin, and also since their arrival in France.Finally, two (4.0%) women declared having had previous acute genital herpes and another one (2.0%) reported past history of genital Table Overall, more than two-thirds of study women were shedding genital HPV DNA, corresponding to a prevalence of HPV detection of 68.0% (34/50), with 56.0% (28/50) of HR-HPV genotypes Table . Genitalversus 61.5%; P = 0.73). Similarly, HIV-infected women were almost twice more infected by HR-HPV than HIV-negative women, but the difference was not significant . However, the prevalence of HPV-68 was higher in HIV-uninfected women  than in HIV-infected women , but this difference was not statistically significant (P = 0.70).HIV-infected women showed a trend to be more frequently infected by HPV than HIV-negative women, but without statistical significance  and corresponded to women with genital HR-HPV infection. These women already infected with HR-HPV genotypes could be a priori poorly eligible for catch-up HPV vaccination.The second category included women exclusively infected with low-risk genotypes . These women could be a priori eligible for possible catch-up prophylactic HPV vaccination against the seven high-risk genotypes targeted by the Gardasil-9® vaccine .Finally, the third category comprised one-third of the study women , without detectable genital HPV DNA. These women could be a priori likely eligible for possible catch-up prophylactic HPV vaccination.We herein report unsuspected high burden of cervical HR-HPV infection in a consecutive series of non-vaccinated and never screened first-generation adult immigrant women originating from sub-Saharan Africa and living in France. Genital HPV and HR-HPV were highly frequent both in HIV-infected and uninfected African immigrant women. Unexpectedly, the non-vaccine HPV-68, a genotype rarely found within the French female population, was the most frequently detected. These findings point to the remarkable and atypical epidemiological profile of cervical HPV infection in first-generation African immigrants living in France, with a rare and non-vaccine high-risk genotype being the most frequently detected. Furthermore, despite their advanced age, nearly half of study women , including those only infected with low-risk HPV genotypes and those without detectable genital HPV DNA, could be eligible for catch-up HPV prophylactic vaccination with the nonavalent Gardasil-9® vaccine.In these African immigrant women, we found a particularly high prevalence of cervical HPV 68.0%), frequently associated with HR-HPV genotypes (56.0%) found in 61.5% of HIV-negative and 70.3% of HIV-positive women. It is difficult to compare our observations with the few previously published studies on HPV cervical infection among immigrant women living in Europe. Moreover, the published studies are heterogeneous with each other, especially concerning the origin and selection of immigrant women (regular or clandestine), and the types of methodology used. However, some points can be debated. Firstly, such high prevalences of cervical HR-HPV in study women appear uncommon and higher than the HPV prevalences previously reported in the French female general population with cervical HR-HPV infection rates ranging from 8 to 22.8% in HIV-negative adult women with normal cytology –26 and 2.0%, freqAs a consequence, adult first-generation African immigrant women living in France, especially those infected with HIV, should be at very high risk for developing cervical cancer. In Italy, a neighboring country of France, the estimated risk for high grade cervical lesions and cancers was effectively higher in immigrant women from high HPV prevalence regions, especially sub-Saharan African countries, as compared to native women living in Italy as well as in other high-income European countries . HoweverThe distribution of HPV genotypes in women, with a majority harboring the non-vaccine HPV-68, was different to that previously reported in French women born to French parents with HR-HPV-16 as the most detected genotype . This unThe wide heterogeneity of the HPV genotypes distribution in our study female immigrant population was previously reported in Africa , 10, 11.For immigrant women at risk for cervical cancer, regular HPV molecular testing, cytological screening for precancerous cervical lesions and adequate treatment remain the best suitable preventive approach to avoid the occurrence of cervical cancer , 39–42. Finally, in our series of first-generation African immigrant women living in France and who underwent cervical cancer screening for the first time, we found a large proportion (84.0%) of normal cytological results, and only a minority exhibited pathological Pap smear test, including ASCUS (6.0%) observed both in one HIV-infected and one HIV-negative woman, and also low-grade (6.0%) and high-grade (4.0%) cervical lesions only observed in HIV-positive women. Although there was no statistically difference between HIV-infected and HIV-negative women in regards to Pap smear results, our findings show that worst cervical lesions are mostly found in HIV-positive women than in HIV-negative. Further large studies are needed to have a more precise evaluation of the burden of HPV-related cervical lesions and cancers in the African immigrant women living in France, which constitute a population in which the coverage of cervical cancer screening remains very low. Indeed, in France, foreign women born to parents coming from a foreign country were more than five times more likely to have never been screened for cervical cancer in their lifetime than French women born to French parents . FurtherOur study has some limitations. Firstly, the inclusion sites in Orléans limited to outpatient consultation services for HIV and STIs may have introduced a recruitment bias in favor of HIV- and STI- infected women. Secondly, women who consulted for the management of STI could clearly be more at risk of carrying HPV. Therefore, healthy African immigrant women are under-represented in our study. Thirdly, the high frequency of HIV-infected women in our study may have resulted in overestimating the prevalences of cervical HPV molecular detection. Fourth, the small sample size of our study population makes these results not fully representative of the first-generation immigrant women originating from sub-Saharan Africa and living in France. Finally, our conclusions on a high HPV infection rate among immigrants from sub-Saharan Africa living in France should be conditional and call for other studies on larger samples.Our study highlights for the first time the high prevalence of cervical HPV infection with original genotypes distribution frequently associated with HIV infection in never-screened immigrant women originating from sub-Saharan Africa and living in France. There is an urgent need to implement adapted screening interventions specific for sub-Saharan African immigrant women who appear to be at very high risk for cervical cancer. Regular access to HPV molecular screening and Pap smear triage constitutes likely the necessary condition to allow preventing genital cancers in immigrant African women living in France. New strategies using genital self-sampling have proven to be as suitable for HPV molecular testing as the usual clinician-administered vaginal sampling , 63–65. Supplementary File 1 (XLSX 32 kb)Below is the link to the electronic supplementary material.


E6™ Cervical Test and compare the HPV16 and/or HPV18 E6 detection rates with the HPV DNA testing. Paired urine, vaginal self-collected and cervical specimens were collected from 124 women who participated in cervical cancer screening or treatment in this proof-of-concept study and underwent to HPV16/18-E6 testing and high-risk HPV DNA testing prior to treatment of cervical neoplasia or cancer. Concordance between urinary, vaginal and cervical HPV16/18-E6 and HPV-DNA testing was evaluated for patients classified as negative group (<CIN2) and histological positive group . Overall, HPV16/18-E6 oncoprotein was detected in 30.6% of cervical samples, 20.3% of self-collected vaginal samples and 21% of urine samples. Regarding the clinical sensitivity, the HPV16/18-E6 oncoprotein was not detected in CIN2 cases, and was detected at low rates in CIN3 cases. The clinical sensitivity of the HPV16/18-E6 oncoprotein for detecting invasive cervical cancer was 70% for cervical scrapes, 55% for self-collected vaginal samples and 52% for urine samples. This study reports the urinary detection of E6 oncoprotein in vivo for the first time and our results suggest that this detection is only for invasive/microinvasive lesions. Then, further protocol development and standardization to achieve a clinical sensitivity for CIN2/3 detection close to what can be achieved for invasive lesions using the physician collected cervical is needed.Cervical cancer is a significant public health problem, especially in low- and middle-income countries, where women have little access to cervical cancer screening; consequently 80% of cervical cancer related mortality occurs in these regions. The development of screening methods that need less infrastructure thus represents an urgent medical need. The study aims to compare the detection rates of high-risk human papillomavirus 16 and 18 E6 oncoprotein in urine, vaginal self-collected, and cervical scrapes of women using the Onco Cervical cancer is the fourth most common cancer in women worldwide, with an estimated 567,847 new cases and 311,365 deaths occurring annually. Approximately 85% of the global burden is registered in less developed regions, highlighting a major public health problem . This hiThe implementation of organized screening programs based on cervical cytology (Pap test) has led to a significant reduction of cervical cancer incidence and mortality in high-income countries –5. Such The presence of HPV E6 oncoprotein is necessary for oncogenic transformation, and its detection in self-collected biological specimens might be an attractive approach in resource-limited settings with a high prevalence of cervical cancer. The detection of the E6 oncoprotein of HPV16/18 from physician-collected cervical samples –31 showeThis study was conducted between January and September of 2017 among 124 non-pregnant women, aged 25–64, who attended the Cancer Prevention or the Gynecologic Oncology Departments of Barretos Cancer Hospital (HCB), Brazil. None of the participants had received HPV vaccination, were hysterectomized or had treated an HPV infection before.Women with invasive cervical cancer were enrolled during the first visit at the outpatient clinic of the Gynecologic Oncology Department, and specimens were collected prior to treatment. Women with histology confirmed CIN2 or 3 were enrolled in the Outpatient Surgical Center, prior to a loop electrosurgical excision (LEEP) procedure, and women with normal cytology were enrolled in the Prevention Department during cervical cancer screening.The local Research Ethics Committee and the Brazilian National Research Ethics Commission (CONEP) approved the study (CAAE 62057316.8.0000.5437). All participants provided written informed consent, and all the personal information was maintained encrypted in a database to ensure participants’ data confidentiality.Prior to a pelvic examination, women provided a random urine sample in a 80 mL polypropylene container, and a self-collected vaginal sample was obtained via the Viba-Brush® . Women then underwent pelvic examination by a gynecologist, and a physician-collected cervical scraping was obtained via the Cervex-Brush Combi® . Self-collected vaginal and physician-collected samples were preserved in a methanol-based liquid medium .E6™ Cervical Test and were stored at 4°C. Six milliliters of urine were added to a 50mM solution of EDTA and used to perform HPV DNA testing. The remaining urine was used to perform the OncoE6™ Cervical Test without solution of EDTA. Self-collected vaginal samples, physician-collected samples and urine samples that were designated for HPV DNA testing were stored at 4°C; urine aliquots designed to conduct the OncoE6™ Cervical Test were stored at -20°C. Testing for HPV DNA and E6 oncoprotein were performed on each physician collected sample, vaginal self-collected sample and urine self-collected sample.Within two hours of sample collection, specimens were sent to the Molecular Oncology Research Center of the Barretos Cancer Hospital for processing. Five milliliters of each vaginal self- and physician-collected sample were retrieved from the preservative medium to perform the OncoE6™ Cervical Test were performed on each of the following specimens: urine sample, self-collected vaginal sample, and physician-collected cervical sample.For each participant, HPV DNA testing and OncoDetection of HPV DNA was performed using the Cobas® 4800 HPV platform  which is a multiplex real-time PCR assay that provides specific genotyping information for HPV16 and 18, while concurrently detecting 12 other high-risk types  in a pooled result. Vaginal self-collected and the physician-collected samples were performed according to the manufacturer’s instructions. An aliquot of six milliliters of urine added to a 50mM solution of EDTA was used to perform the HPV DNA testing according to the Cobas® 4800 HPV standard protocol.E6™ Cervical Test , an immunochromatographic assay that detects elevated levels of HPV16/18-E6 oncoproteins using a lateral flow format and high-affinity monoclonal antibodies to capture / detect the E6 oncoprotein from cell lysates generated from cervical specimens. Five milliliters each of the self-collected vaginal and the physician-collected cervical samples were centrifuged. The resulting pellet was suspended in 930μL of Rinse Solution and transferred to a test tube, both provided with the OncoE6™ Cervical Test kit. The E6 test was performed according to the manufacturer’s instructions [The detection of the HPV E6 oncoprotein was performed using the Oncoructions . Urine sWomen were divided in two groups: negative  or positive  for disease according to the histological analysis of the biopsy or LEEP by pathologists blinded to the clinical exam and medical history. Women with visible cervical lesions observed upon colposcopy underwent biopsy or endocervical curettage as clinically indicated by the gynecologist performing colposcopy. Women without an apparent abnormality did not undergo cervical biopsy and were categorized as negative (<CIN2).http://www.R-project.org/), and the significance level was set at 5% for all tests. All reported p-values are two-sided.Statistical analyses were performed using R . Of those, 44 (35.5%) had invasive carcinoma, 26 (21.0%) CIN3, 9 (7.2%) CIN2, 2 (1.6%) CIN1 and 43 (34.7%) without precursor or neoplastic lesion of the cervix. Therefore, 79 cases were classified as positive (CIN2+) and 45 as negative (<CIN2). The three specimens  for all women were submitted to Cobas® 4800 HPV e OncoE6Among the HPV positive cases for any hr-HPV of the physician collected samples , HPV16 was the most frequent type detected , followed by others hr-HPV , and HPV18 . In self-collected vaginal samples, HPV16 DNA was the most detected type , as well as in the urine samples . Co-infection rates on cervical sample was 12.2%, whereas in vaginal self-collected samples was 14.8% and in urine samples 14.5%. No case of HPV16 and HPV18 co-infection was detected.Using the cervical sample collected by the physician as the gold standard, the positivity rate of HPV-DNA was similar to the obtained by the vaginal self-collection , nevertheless it was significantly higher than the urine samples  .Thirty-eight physician collected specimens were positive on HPV16/18-E6 test, being 31 positive for HPV16-E6 and 7 positive for HPV18-E6. Among the self-collected vaginal samples, 20 were positive for HPV16-E6 and 5 for HPV18-E6. In urine samples, HPV16-E6 was detected in 22 specimens and HPV18-E6 in 4.Using the cervical sample collected by the physician as the reference, the positivity rate of HPV16/18-E6 test was significantly higher than the vaginal self-collection  and the urine  .In the HPV DNA test (Cobas), rates were progressively higher according to the severity of the diagnosis . High-grThe E6-HPV test used in this study is specific for HPV16 and HPV18 E6 oncoprotein, then comparative analysis with the HPV DNA test was performed only for these specific HPV types. The HPV16/18-E6 positivity rate was significantly lower (<0.01) than the HPV DNA positivity rate for HPV types 16 and 18 when the analysis was stratified by specimen type  . CompariAccuracy analyzes of the HPV16/18-E6 and HPV-DNA tests were performed stratified for CIN2, CIN3 and invasive carcinomas, and are shown in Tables The HPV16/18-E6 HPV test had a significantly lower sensitivity rate than the HPV-DNA test for both CIN2 and CIN3 detection, regardless of the type of specimen . On the other hand, it presented higher specificity rate than the HPV-DNA test.Concerning the diagnosis of invasive cervical carcinoma, the HPV16/18-E6 test had a lower sensitivity rate than the HPV-DNA test in all samples , but achieved higher specificity rates. The only situation in which the HPV16/18-E6 test had similar sensitivity to the HPV-DNA test was only when HPV16 and 18 HPV DNA were evaluated.E6™ Cervical Test and the Cobas® 4800 HPV Test to physician collected cervical samples, to self-collected vaginal samples, and to urine samples. Our results showed that the E6 oncoproteins of HPV16 and/or 18 were present in urine specimens from women with cervical cancer and were detected at similar rates as the vaginal self-collected samples. Sensitivity for CIN2/3 detection, however, was lower than what was observed by the HPV DNA test.Cervical cancer remains an urgent problem of public health, especially in low- and middle-income countries ; reasonsThe HPV DNA test’s sensitivity for CIN2/3 detection using urine samples in the current study is higher than reported by previous studies that used Cobas HPV test , 22, butThe hr-HPV prevalence in cervical samples based on the Cobas HPV test outcome was high due to an intended selective bias: almost 64% of the selected women had CIN2/3 or invasive cervical cancer. The hr-HPV prevalence in the Brazilian population is around 12% , 35.The HPV DNA test exhibits a higher sensitivity for detection of CIN2/3 than the HPV16/18-E6 test; this is true for all three types of specimens; for all types of specimens, however, the specificity was higher for the HPV16/18-E6 test than for the HPV DNA test. This result was expected, partly because Cobas HPV Test detects 14 hr-HPV types and the OncoE6 test detects the E6 oncoprotein of only HPV16 and HPV18; Fifty-seven per cent of the CIN2/3 cases were either HPV negative or positive only for hr-HPV other than HPV16 or 18, while this number decreased to 25% for invasive carcinoma. It has been shown that elevated expression of the E6 oncoprotein is also an indicator of persistence of viral infection , thus soE6™ Cervical Test), and the other was a case of normal cytology testing positive for HPV18 E6.Using the HPV16/18-E6 test, similar rates of detection of high-grade lesions were seen for the self-collected vaginal samples and the urine samples, and both these sample types had a lower detection rate than the physician-collected sample. Previous studies evaluating the HPV16/18-E6 test with clinician-collected samples showed lower sensitivity and specificity for detection of high-grade lesion than we observed in our study. Zhao et al. conducted a study in rural areas of China using the OncoE6 Test and obtained 42.4% of sensitivity and 99.1% of specificity with CIN2+ as an endpoint . In a stGiven the importance of improving the adherence to cervical cancer screening, researchers are trying to validate sampling options that are more acceptable to the target population, like the self-collected vaginal samples and urine specimens that can be collected at home –17. In FUrine sampling is a non-invasive self-collection method, and, it is highly accepted by women , 39. It This study was developed as a proof of concept for detecting the HPV E6 oncoprotein in urine samples and was submitted to a bias on the samples’ selection because we preferred to work with more invasive/microinvasive lesions than non-invasive cases which will increase our changes of detecting the E6 oncoprotein in the urine samples. The true value of detecting E6 oncoprotein for cervical cancer screening purposes should be addressed in other studies enrolling a large number of specimens with an appropriate sample size calculation.This study shows that the detection of HPV16/18 E6 oncoprotein is feasible in urine samples of invasive lesions. While it may seem surprising and encouraging that a majority of cervical cancer related to HPV16 and/or 18 could be readily detected via E6 oncoprotein present in the urine, further protocol development and standardization to achieve a clinical sensitivity for CIN2/3 detection close to what can be achieved for invasive lesions using the physician collected cervical is needed. We believe that the outcome of our study warrants such further development. Large population-based studies with more HPV types included are essential in future.S1 Table(XLS)Click here for additional data file.