Detection and identification of human papillomavirus types isolated from Korean patients with flat warts

Flat warts, also called verruca planna (VP) or juvenile warts, are benign epithelial proliferations of the skin caused by infection with human papillomaviruses (HPV). Several HPV types are known to be associated with flat warts, and particularly HPV type 3 and 10 have been most frequently reported in other countries. In this study, for the detection and typing of human papillomavirus isolated from Korean patients with flat warts, polymerase chain reaction (PCR) and restriction endonuclease digestion were carried out with a set of restriction endonucleases, using the cloned HPV DNA and DNA from clinical specimens. A unique digestion pattern for HPV type 3 and 10, a form of miniature fingerprinting, enabled us to identify HPV type from the amplified fragments. A total of thirty clinical samples, as either frozen tissue or paraffin-embedded tissue, were investigated to verify the type. All the clinical samples except one were con-firmed to be type 3, one of the most frequently observed types in flat warts, and one sample was neither type 3 nor type 10. Further investigation of the unidentified sample by DNA sequencing and sequence alignment with other known HPV types revealed that the sample was a variant of HPV type 94, one of the EV-related HPVs, with the closest evolutionary distance to the HPV type 10 among the known flat wart-associated HPV types.     

Skin cancer and virus]

Human papillomaviruses (HPV) generally associated with benign skin and anogenital warts. Because several of skin cancers were found to contain HPV-DNA, it has been speculated that certain types of HPV could be specifically associated with cancers. Although HPV-DNAs are not isolated from most of skin cancers, they are often isolated from penile cancers, vulval cancers and anogenital Bowen's diseases. Patients with epidermodysplasia verruciformis start to suffer from disseminated incurable warts during their childhood, and some of these benign lesions often convert to skin cancer in adulthood. Although the disease is very rare, HPV may also play a role in malignant transformation in epidermodysplasia verruciformis. More than 60 types of HPVs distinguished by molecular hybridization techniques. The type of HPV determines the clinical picture of wart and natural fate of HPV-associated lesion. There are two groups of HPVs, which are benign types and malignant types. Viral DNA of malignant type of HPV transforms human keratinocytes in vitro, and the transforming activity has been mapped to the E6 and E7 genes.     

The interaction of high and low-risk human papillomavirus genotypes increases the risk of developing genital warts: A population-based cohort study

Cervical cancer is among the most common type of cancers in women and is associated with human papillomavirus (HPV) infection. Genital warts are also reported to be linked with HPV infection types 11 and 6. In turn, clinical characteristics and morphological features of warts may be useful in the prediction of prognosis and in making treatment decisions. Thus, we have investigated the association of high and low-risk HPVs genotype with genital wart risk, as well as pathological and cytological information in cases recruited from a population-based cohort study of 1380 patients. Patients infected with HPV genotype 6 or 11 had an increased risk of having warts, with OR of 2.34 (95% CI: 0.955-5.737, P = 0.06). Also, this association was enhanced in the presence of high plus low-risk HPV for having genital wart (OR: 2.814; 95%: 1.208-6.55, P = 0.017) and cases having high-risk HPV (OR: 2.329; 95% CI: 1.029-5.269, P = 0.042). Moreover, we observed patients with genital warts having CIN2/3, indicating the importance of informing the physician to the patient to prevent more severe lesions. Our data demonstrated that patients with both low/high-risk HPV types had an increased risk of developing genital warts and persistent infection with HPV was a necessary precursor for the increase in cervical lesions.     

Anogenital warts contain several distinct species of human papillomavirus.

Anogenital warts from 26 patients were examined for the presence of human papillomavirus (HPV). Although no whole, intact virus could be identified, varying amounts of nonintegrated HPV DNA were detected in 18 tissue specimens (70%) by employing both an agarose gel-ethidium bromide staining method and the Southern blot hybridization procedure. When hybridization analysis was performed under stringent conditions, six anogenital warts were observed to contain HPV genomic sequences related to either of the cutaneous viruses HPV type 1 (HPV-1) or HPV-2. In 12 tissue samples lacking sequence homology to either HPV-1 or HPV-2 under stringent conditions, HPV-related sequences were detected when the hybridization was performed under less stringent conditions, indicating that an HPV distinct from both HPV-1 and HPV-2 is also associated with these lesions. This anogenital HPV also appeared to be distinct from the other characterized types of HPV. These data indicate that at least three HPVs are associated with anogenital wart disease.     

Characterization of a New Type of Human Papillomavirus That Causes Skin Warts

A human papillomavirus (HPV) was isolated from the lesions of a patient (ML) bearing numerous hand common warts. This virus was compared with the well-characterized HPV found in typical plantar warts (plantar HPV). ML and plantar HPV DNAs have similar molecular weights (5.26 x 10(6) and 5.23 x 10(6), respectively) but were shown to be different by restriction enzyme analysis. When the cleavage products of both DNAs by endonuclease EcoRI, BamI, HpaI, or Hind were analyzed by electron microscopy, one, two, one, and four fragments were detected for ML HPV DNA instead of the two, one, two, and six fragments, respectively, detected for plantar HPV DNA. In contrast to plantar HPV DNA, a high proportion of ML HPV DNA molecules were resistant to these restriction enzymes. Most, if not all, of the molecules were either resistant to BamI and sensitive to EcoRI or sensitive to BamI and resistant to EcoRI. After denaturation and renaturation of the cleavage products of ML HPV DNA by a mixture of the two enzymes, the circular "heteroduplexes" formed showed one to three heterology loops corresponding to about 4 to 8% of the genome length. No sequence homology was detected between ML and plantar HPV DNAs by cRNA-DNA filter hybridization, by measuring the reassociation kinetics of an iodinated plantar HPV DNA in the presence of a 25-fold excess of ML HPV DNA, or by the heteroduplex technique. The two viruses had distinct electrophoretic polypeptide patterns and showed no antigenic cross-reaction by immunodiffusion or immunofluorescence techniques. Preliminary cRNA-DNA hybridization experiments, using viral DNAs from single or pooled plantar or hand warts, suggest that hand common warts are associated with viruses similar or related to ML HPV. The existence of at least two distinct types of HPVs that cause skin warts was demonstrated; they were provisionally called HPV type 1 and HPV type 2, with plantar HPV and ML HPV as prototypical viruses, respectively.     

Molecular cloning and characterization of the DNAs of human papillomaviruses 19, 20, and 25 from a patient with epidermodysplasia verruciformis.

Five human papillomavirus (HPV) DNAs from lesions of an epidermodysplasia verruciformis patient were cloned in lambda L 47: DNA of HPV 5, which predominated in the carcinoma; DNA of a variant type of HPV 8, which was not detected in the carcinoma DNA by Southern blot hybridization but only by cloning; and DNAs of three papillomaviruses that were isolated from warts. Southern blot and liquid phase DNA-DNA hybridization under stringent conditions showed that the three viruses from warts were new types, which we named HPVs 19, 20, and 25. These viruses cross-hybridized between 3 and 29% among themselves and with HPVs 5 and 8. After physical mapping with several restriction enzymes, the colinear genomes were aligned with HPV 8 DNA to define early and late regions. HPVs 8, 19, and 25 shared homology in different parts of their genomes.     

尖锐湿疣样本中HPV病毒的分子检测

调查男性和女性尖锐湿疣样本中人乳头瘤病毒（HPV）的检出率及病毒类型,为研发相关防治疫苗提供依据,以HPV 外壳蛋白DNA序列为模板设计特异引物,SSP－PCR扩增检测样本中HPV的感染率和病毒类型。收集了北京及邯郸市医院门诊尖锐湿疣样本22例,其中男性13例,女性9例。检测发现所有样本中存在着高浓度的HPV病毒DNA。男性样本中有5例感染HPV6型,6例感染HPV11型,2例为HPV6＋HPV11混合感染。女性样本中有3例感染HPV6型,2例感染HPV11型,4例为 HPV6＋HPV11混合感染。被诊断为宫颈湿疣的4位女性还在其含宫颈粘膜脱落细胞的样本中检出了HPV16、HPV18、HPV33、HPV35、HPV45、HPV54、HPV56或HPV58等高危险型病毒类型。所有检测到的HPV病毒DNA片段均TA克隆并将测定的DNA序列存入了国际基因数据库GenBank（DQ003066－DQ003079）。调查没有在单纯的男女尖锐湿疣组织块中检测到除HPV6和HPV11以外的其他HPV类型。该研究建立了灵敏可靠的HPV分子检测及分型方法,尖锐湿疣中HPV的检出率达100％。 本研究初步结果显示导致男女尖锐湿疣的HPV病毒类型没有显著差异,主要为HPV6及HPV11型。     

Significance of HPV-58 Infection in Women Who Are HPV-Positive,Cytology-Negative and Living in a Country with a High Prevalence of HPV-58 Infection

Purpose

Cervical cytology and human papillomavirus (HPV) DNA co-testing is recommended as a screening method for detecting cervical lesions. However, for women who are HPV-positive but cytology-negative, the appropriate management and significance of HPV-58 infection remain unknown.

Methods

This study of prevalent HPV detected at baseline with a median follow-up of 3.2 years evaluated the risk factors associated with cervical abnormalities and assessed the significance of HPV-58 infection. A total of 265 women were enrolled. All high-grade squamous intraepithelial lesions (HSIL) that were detected by cytology were confirmed by histology. Histological diagnoses of cervical intraepithelial neoplasia 2/3 were classified as HSIL. Women were classified into four groups according to the HPV genotype that was detected at their first visit: HPV-58 (n = 27), HPV-16 (n = 52; 3 women had HPV-58 co-infection), ten other high risk (HR) types (n = 79), or low/undetermined risk types (n = 107).

Results

Of 265 women, 20 (7.5%) had HSIL on their follow-up examinations. There were significant differences in the cumulative incidence of HSIL between the four groups (p<0.001). The 5-year cumulative incidence rates of HSIL were 34.0% (95% CI: 17.3–59.8%) in HPV-58 positive cases, 28.0% (95% CI: 13.8–51.6) in HPV-16 positive cases, 5.5% (95% CI: 2.1–14.0%) in one of the ten other types of HR-HPV positive cases, and 0% in women with low/undetermined risk HPV. When seen in women with HR-HPV (n = 158), persistent HPV infection was a significant factor associated with the development of HSIL (hazard ratio = 15.459, 95% CI: 2.042–117.045). Women with HPV-58 had a higher risk (hazard ratio = 5.260, 95% CI: 1.538–17.987) for the development of HSIL than women with HPV-16 (hazard ratio = 3.822, 95% CI: 1.176–12.424) in comparison with women with other types of HR-HPV.

Conclusion

HPV-58 has a high association with the development of HSIL in women who are HPV-positive and cytology-negative.     

Characterization of novel cutaneous human papillomavirus genotypes HPV-150 and HPV-151

DNA from two novel HPV genotypes, HPV-150 and HPV-151, isolated from hair follicles of immuno-competent individuals, was fully cloned, sequenced and characterized. The complete genomes of HPV-150 and HPV-151 are 7,436-bp and 7,386-bp in length, respectively. Both contain genes for at least six proteins, namely E6, E7, E1, E2, L2, L1, as well as a non-coding upstream regulatory region located between the L1 and E6 genes: spanning 416-bp in HPV-150 (genomic positions 7,371 to 350) and 322-bp in HPV-151 (genomic positions 7,213 to 148). HPV-150 and HPV-151 are phylogenetically placed within the Betapapillomavirus genus and are most closely related to HPV-96 and HPV-22, respectively. As in other members of this genus, the intergenic E2-L2 region is very short and does not encode for an E5 gene. Both genotypes contain typical zinc binding domains in their E6 and E7 proteins, but HPV-151 lacks the regular pRb-binding core sequence within its E7 protein. In order to assess the tissue predilection and clinical significance of the novel genotypes, quantitative type-specific real-time PCR assays were developed. The 95% detection limits of the HPV-150 and HPV-151 assays were 7.3 copies/reaction (range 5.6 to 11.4) and 3.4 copies/reaction (range 2.5 to 6.0), respectively. Testing of a representative collection of HPV-associated mucosal and cutaneous benign and malignant neoplasms and hair follicles (total of 540 samples) revealed that HPV-150 and HPV-151 are relatively rare genotypes with a cutaneous tropism. Both genotypes were found in sporadic cases of common warts and SCC and BCC of the skin as single or multiple infections usually with low viral loads. HPV-150 can establish persistent infection of hair follicles in immuno-competent individuals. A partial L1 sequence of a putative novel HPV genotype, related to HPV-150, was identified in a squamous cell carcinoma of the skin obtained from a 64-year old immuno-compromised male patient.     

Comparison of the structure and DNA-binding properties of the E2 proteins from an oncogenic and a non-oncogenic human papillomavirus

Human papillomaviruses (HPVS) that infect the genital tract can be divided into two groups: high-risk HPV types, such as HPV 16 and HPV 18, are associated with cancer, low-risk HPV types, such as HPV 6, are associated with benign warts. In both high-risk and low-risk HPV types, the papillomavirus E2 protein binds to four sites within the viral long control region (LCR) and regulates viral gene expression. Here, we present the crystal structure of the minimal DNA-binding domain (DBD) from the HPV 6 E2 protein. We show that the HPV 6 E2 DBD is structurally more similar to the HPV 18 and bovine papillomavirus type 1 (BPV1) E2 proteins than it is to the HPV 16 E2 protein. Using gel retardation assays, we show that the hierarchy of E2 sites within the HPV 16 and HPV 6 LCRs are different. However, despite these differences in structure and site preference, both the HPV 16 and 6 E2 DBDs recognise an extended version of the consensus E2 binding site derived from studies of the BPV1 E2 protein. In both cases, the preferred binding site is 5'AACCGN(4)CGGTT3', where the additional flanking base-pairs are in bold and N(4) represents a four base-pair central spacer. Both of these HPV proteins bind preferentially to E2 sites that contain an A:T-rich central spacer. We show that the preference for an A:T-rich central spacer is due, at least in part, to the need to adopt a DNA conformation that facilitates protein contacts with the flanking base-pairs.     

Characterization of Two Novel Gammapapillomaviruses,HPV179 and HPV184, Isolated from Common Warts of a Renal-Transplant Recipient

Gammapapillomavirus (Gamma-PV) is a diverse and rapidly expanding PV-genus, currently consisting of 76 fully characterized human papillomavirus (HPV) types. In this study, DNA genomes of two novel HPV types, HPV179 and HPV184, obtained from two distinct facial verrucae vulgares specimens of a 64 year-old renal-transplant recipient, were fully cloned, sequenced and characterized. HPV179 and HPV184 genomes comprise 7,228-bp and 7,324-bp, respectively, and contain four early (E1, E2, E6 and E7) and two late genes (L1 and L2); the non-coding region is typically positioned between L1 and E6 genes. Phylogenetic analysis of the L1 nucleotide sequence placed both novel types within the Gamma-PV genus: HPV179 was classified as a novel member of species Gamma-15, additionally containing HPV135 and HPV146, while HPV184 was classified as a single member of a novel species Gamma-25. HPV179 and HPV184 type-specific quantitative real-time PCRs were further developed and used in combination with human beta-globin gene quantitative real-time PCR to determine the prevalence and viral load of the novel types in the patient’s facial warts and several follow-up skin specimens, and in a representative collection, a total of 569 samples, of HPV-associated benign and malignant neoplasms, hair follicles and anal and oral mucosa specimens obtained from immunocompetent individuals. HPV179 and HPV184 viral loads in patients’ facial warts were estimated to be 2,463 and 3,200 genome copies per single cell, respectively, suggesting their active role in the development of common warts in organ-transplant recipients. In addition, in this particular patient, both novel types had established a persistent infection of the skin for more than four years. Among immunocompetent individuals, HPV179 was further detected in low-copy numbers in a few skin specimens, indicating its cutaneous tissue tropism, while HPV184 was further detected in low-copy numbers in one mucosal and a few skin specimens, suggesting its dual tissue tropism.     

The E7 proteins of the nononcogenic human papillomavirus type 6b (HPV-6b) and of the oncogenic HPV-16 differ in retinoblastoma protein binding and other properties.

The E7 early viral protein of the oncogenic human papillomavirus type 16 (HPV-16) has been strongly implicated in the maintenance of the malignant phenotype in cervical cancers and cancer-derived cell lines. HPV-16 E7 is a nuclear phosphoprotein that can cooperate with ras to transform baby rat kidney cells, transactivates the adenovirus E2 promoter, and binds to the retinoblastoma (RB) protein. The E7 phosphoprotein of the nononcogenic HPV-6b, which is generally associated with benign genital warts, is similar to the HPV-16 E7 in amino acid sequence but differs dramatically in migration in sodium dodecyl sulfate-polyacrylamide gels, sedimentation in nondenaturing glycerol gradients, and the ability to bind the RB protein. Our results indicate that the RB protein preferentially binds the phosphorylated form of HPV-6b E7, which comprises a minor fraction of the total E7 expressed in transiently transfected COS-7 cells. These characteristics may help to explain the difference in the oncogenic potential of the oncogenic and nononcogenic types of genital papillomaviruses.     

HPV-16 E2 contributes to induction of HPV-16 late gene expression by inhibiting early polyadenylation

We provide evidence that the human papillomavirus (HPV) E2 protein regulates HPV late gene expression. High levels of E2 caused a read-through at the early polyadenylation signal pAE into the late region of the HPV genome, thereby inducing expression of L1 and L2 mRNAs. This is a conserved property of E2 of both mucosal and cutaneous HPV types. Induction could be reversed by high levels of HPV-16 E1 protein, or by the polyadenylation factor CPSF30. HPV-16 E2 inhibited polyadenylation in vitro by preventing the assembly of the CPSF complex. Both the N-terminal and hinge domains of E2 were required for induction of HPV late gene expression in transfected cells as well as for inhibition of polyadenylation in vitro. Finally, overexpression of HPV-16 E2 induced late gene expression from a full-length genomic clone of HPV-16. We speculate that the accumulation of high levels of E2 during the viral life cycle, not only turns off the expression of the pro-mitotic viral E6 and E7 genes, but also induces the expression of the late HPV genes L1 and L2.     

Chimeric human papillomavirus type 16 (HPV-16) L1 particles presenting the common neutralizing epitope for the L2 minor capsid protein of HPV-6 and HPV-16

Both the Human papillomavirus (HPV) major (L1) and minor (L2) capsid proteins have been well investigated as potential vaccine candidates. The L1 protein first oligomerizes into pentamers, and these capsomers assemble into virus-like particles (VLPs) that are highly immunogenic. Here we examine the potential of using HPV type 16 (HPV-16) L1 subunits to display a well-characterized HPV-16 L2 epitope (LVEETSFIDAGAP), which is a common-neutralizing epitope for HPV types 6 and 16, in various regions of the L1 structure. The L2 sequence was introduced by PCR (by replacing 13 codons) into sequences coding for L1 surface loops D-E (chideltaC-L2), E-F (chideltaA-L2), and an internal loop C-D (chideltaH-L2); into the h4 helix (chideltaF-L2); and between h4 and beta-J structural regions (chideltaE-L2). The chimeric protein product was characterized using a panel of monoclonal antibodies (MAbs) that bind to conformational and linear epitopes, as well as a polyclonal antiserum raised to the L2 epitope. All five chimeras reacted with the L2 serum. ChideltaA-L2, chideltaE-L2, and chideltaF-L2 reacted with all the L1 antibodies, chideltaC-L2 did not bind H16:V5 and H16:E70, and chideltaH-L2 did not bind any conformation-dependent MAb. The chimeric particles elicited high-titer anti-L1 immune responses in BALB/c mice. Of the five chimeras tested only chideltaH-L2 did not elicit an L2 response, while chideltaF-L2 elicited the highest L2 response. This study provides support for the use of PV particles as vectors to deliver various epitopes in a number of locations internal to the L1 protein and for the potential of using chimeric PV particles as multivalent vaccines. Moreover, it contributes to knowledge of the structure of HPV-16 L1 VLPs and their derivatives.     

HPV-2E2蛋白(A338V)突变体对E2蛋白DNA结合能力增强的研究

HPV-2是引起皮肤寻常疣的常见HPV型别,病毒E2蛋白可抑制病毒早期启动子的活性。我们曾经报道来自一例巨大寻常疣患者的HPV-2突变E2蛋白对病毒早期启动子活性的抑制作用明显减弱,该E2蛋白在其C末端的DNA结合区域带有A338V的点突变。本研究利用原核表达系统表达纯化了突变E2(A338V)和HPV-2原毒株的羧基端和全长蛋白。电泳迁移率实验结果显示,E2蛋白可与带有E2蛋白特异性结合位点的寡核苷酸探针形成复合物,突变E2蛋白比原毒株E2蛋白的DNA结合能力强。这提示DNA结合能力的增强可能为E2蛋白对病毒启动子活性影响的分子基础,与患者出现罕见巨大寻常疣这一临床表型关联。     

Biochemical characterization of two types of human papillomaviruses associated with epidermodysplasia verruciformis.

The DNAs of the human papillomaviruses (HPVs) associated with the benign lesions of two patients suffering from epidermodysplasia verruciformis (patients JD and JK) were analyzed by using 12 restriction endonucleases. None of the restriction endonucleases were one-cut enzymes for the HPV DNA obtained from patient JD, referred to as the prototypical HPV-5, whereas five of them were one-cut enzymes for the DNA of the major virus found in patient JK, referred to as HPV-9. The molecular cloning of the two fragments resulting from the cleavage of HPV-5 DNA by endonuclease HindIII and of the single fragment obtained after treatment of HPV-9 DNA with endonuclease BamHI was performed in Escherichia coli after the fragments were inserted in plasmid pBR322. A cleavage map of the two cloned genomes was constructed. Little sequence homology (4 to 5%) was detected between HPV-5 and HPV-9 DNAs by DNA-DNA hybridization experiments in liquid phase at saturation; this homology was reproducibly higher than that (2 to 3%) detected under the same conditions between these DNAs and HPV-1a DNA. In addition, blot hybridization experiments performed under stringent conditions showed no or little sequence homology between the DNAs of HPV-5 and HPV-9 and those of HPV prototypes of types 1, 2, 3, 4, and 7 associated with skin warts. These results confirm that HPV-5 and HPV-9 are two distinct HPV types.     

男性人乳头瘤病毒感染研究进展*

人乳头瘤病毒(human papillomavirus,HPV)感染是全球最常见的性传播性疾病(STD)之一,与生殖系统肿瘤和生殖器疣密切相关。HPV感染与女性生殖健康之间的病因学关系已经有了较多的研究,近年来越来越多的学者开始关注男性HPV感染。本文就男性HPV感染与男性生殖健康的研究进展进行综述。     

The E1circumflexE4 protein of human papillomavirus interacts with the serine-arginine-specific protein kinase SRPK1

Human papillomavirus (HPV) infections of the squamous epithelium are associated with high-level expression of the E1circumflexE4 protein during the productive phase of infection. However, the precise mechanisms of how E1circumflexE4 contributes to the replication cycle of the virus are poorly understood. Here, we show that the serine-arginine (SR)-specific protein kinase SRPK1 is a novel binding partner of HPV type 1 (HPV1) E1circumflexE4. We map critical residues within an arginine-rich domain of HPV1 E1circumflexE4, and in a region known to facilitate E1circumflexE4 oligomerization, that are requisite for SRPK1 binding. In vitro kinase assays show that SRPK1 binding is associated with phosphorylation of an HPV1 E1circumflexE4 polypeptide and modulates autophosphorylation of the kinase. We show that SRPK1 is sequestered into E4 inclusion bodies in terminally differentiated cells within HPV1 warts and that colocalization between E1circumflexE4 and SRPK1 is not dependent on additional HPV1 factors. Moreover, we also identify SRPK1 binding of E1circumflexE4 proteins of HPV16 and HPV18. Our findings indicate that SRPK1 binding is a conserved function of E1circumflexE4 proteins of diverse virus types. SRPK1 influences important biochemical processes within the cell, including nuclear organization and RNA metabolism. While phosphorylation of HPV1 E4 by SRPK1 may directly influence HPV1 E4 function during the infectious cycle, the modulation and sequestration of SRPK1 by E1circumflexE4 may affect the ability of SRPK1 to phosphorylate its cellular targets, thereby facilitating the productive phase of the HPV replication cycle.     

Detection of human papillomavirus DNA in skin warts from immunocompromised patients but not in semen from men whose wives have abnormal cervical cytology.

The epidemiology of human papillomaviruses (HPV) was studied in 61 immunocompromised patients (e.g. renal and cardiac transplants; Bowen's disease; genital cancer) undergoing therapy at the University Hospital of Wales at Cardiff U.K. Warts from various sites of these patients were studied for the presence of HPV types 6, 11, 16 and 18 using the dot-blot DNA hybridization technique. Four HPV-16 and one HPV-11 was detected. The presence of HPV-16 in our study is quite significant since it suggests the potential occurrence of genital HPV types in skin warts in immunocompromised patients and hence the need for screening such patients against HPV types. HPV, mainly types 16 and 18 are usually associated with genital cancer, cervical malignancies and cervical intraepithelial neoplasia. The semen of the husband of 30 women with cervical abnormalities and the semen of 30 husbands (control) of wives with normal cervix were tested for HPV-6, 11, 16 and 18. No HPV-DNA could be detected in all of the 60 specimen. This suggests that specimens were either truly negative for any of those types or because virus DNA could present in a small amount less than 5 pg/microliters in some patients. Whether semen plays a role in transmitting HPV is still controversial.     

Cost of Preventing,Managing, and Treating Human Papillomavirus (HPV)-Related Diseases in Sweden before the Introduction of Quadrivalent HPV Vaccination

Objective

Costs associated with HPV-related diseases such as cervical dysplasia, cervical cancer, and genital warts have not been evaluated in Sweden. These costs must be estimated in order to determine the potential savings if these diseases were eradicated and to assess the combined cost-effectiveness of HPV vaccination and cervical cancer screening. The present study aimed to estimate prevention, management, and treatment costs associated with cervical dysplasia, cervical cancer, and genital warts from a societal perspective in Sweden in 2009, 1 year before the quadrivalent HPV vaccination program was implemented.

Methods and Materials

Data from the Swedish cervical cancer screening program was used to calculate the costs associated with prevention (cytological cervical cancer screening), management (colposcopy and biopsy following inadequate/abnormal cytological results), and treatment of CIN. Swedish official statistics were used to estimate treatment costs associated with cervical cancer. Published epidemiological data were used to estimate the number of incident, recurrent, and persistent cases of genital warts; a clinical expert panel assessed management and treatment procedures. Estimated visits, procedures, and use of medications were used to calculate the annual cost associated with genital warts.

Results

From a societal perspective, total estimated costs associated with cervical cancer and genital warts in 2009 were €106.6 million, of which €81.4 million (76%) were direct medical costs. Costs associated with prevention, management, and treatment of CIN were €74 million; screening and management costs for women with normal and inadequate cytology alone accounted for 76% of this sum. The treatment costs associated with incident and prevalent cervical cancer and palliative care were €23 million. Estimated costs for incident, recurrent and persistent cases of genital warts were €9.8 million.

Conclusion

Prevention, management, and treatment costs associated with cervical dysplasia, cervical cancer, and genital warts are substantial. Defining these costs is important for future cost-effectiveness analyses of the quadrivalent HPV vaccination program in Sweden.