Use of Topical and Systemic Retinoids in Solid Organ Transplant Recipients: Update and Review of the Current Literature.

BACKGROUND: Solid organ transplant recipients (SOTRs) are at an increased risk of epithelial malignancies, mainly squamous cell carcinoma, and its precursor lesions such as actinic keratoses, warts, and porokeratosis, which may respond to retinoid therapy. OBJECTIVE: To review the published evidence on the efficacy and safety of topical and systemic retinoids for the treatment and prophylaxis of malignant and premalignant conditions that mostly afflict SOTRs. MATERIALS AND METHODS: Systematic review of the literature to summarize the level of evidence and grade of recommendation for retinoid therapy with emphasis in the SOTR population. RESULTS: Acitretin has the highest strength of recommendation (Grade A) for prophylaxis of nonmelanoma skin cancer (NMSC) and treatment and prophylaxis of actinic keratoses in SOTR. In nonimmunosuppressed patients, acitretin and isotretinoin have a Grade B recommendation for treatment of recalcitrant warts. Topical retinoids have not shown efficacy in preventing NMSC in immunocompetent patients. CONCLUSION: Retinoids constitute a highly efficacious alternative for the management of the most common conditions that affect SOTRs. Acitretin has the most robust evidence for chemoprophylaxis in SOTRs. Knowledge about the specific indications and expected side effects of topical and systemic retinoids may help optimize their therapeutic potential.

New Insights into the Role of Human Papillomavirus in Anal Cancer and Anal Wart Development.

Human papillomavirus is associated with several anogenital and oropharyngeal lesions, including warts, premalignant lesions, and cancer. There are specific groups that were identified as high-risk groups for anal squamous cell carcinoma and anal human papillomavirus infection, namely HIV-positive patients, men who have sex with men, women with genital tract neoplasia, and solid organ transplant recipients. Condylomas have classically been considered to be a benign lesion, with an exception made for the Buschke-Loewenstein tumor, but several publications have shown that a high percentage of condylomas harbor high-grade lesions. Due to the similarities between anal and cervical carcinogenesis, anal cancer screening based on anal cytology and referral to high-resolution anoscopy, in case of abnormalities, have been advocated. Testing for anal human papillomavirus is not routinely done in anal cancer screening, because of the very high prevalence in high-risk populations. The large majority of anal cancers are squamous cell carcinomas (SCC), and around 90% are attributed to human papillomavirus. Human papillomavirus positivity in anal SCC seems to have a prognostic value, with better survival in those patients with positive tumors. Prophylactic vaccination has been shown to be important for prevention of anal human papillomavirus-related lesions.

The early impact of human papillomavirus vaccination on anogenital warts in Québec, Canada.

In Québec province in Canada, a public school-based and catch-up HPV vaccination programs with the quadrivalent vaccine have been introduced in September 2008 for girls aged 9-17 years. We assessed the early impact of the HPV vaccination program on the incidence of anogenital warts (AGW) in the Quebec general population. We used the provincial health administrative data of the Régie de l'assurance maladie du Québec (RAMQ). AGW were identified either through a prescription of podofilox, or a medical procedure code specific to AGW, or a diagnostic code for viral warts followed by a prescription of imiquimod or fluorouracil. Sex- and age-specific incidence rates were calculated for pre-vaccination (2004-2007) and vaccination (2009-2012) periods. We found a significant decline of 45% and 19% in the incidence of AGWs among females aged 15-19 and 20-24 years, respectively. A decline of 21% was also seen among males aged 15-19 years. The median age at an episode of AGW increased from 27 years in 2004 to 31 years in 2012 among females and remained stable in males. Our findings indicate that the HPV public vaccination program is associated with an important reduction in the incidence of AGW among young females and males. The benefit is more pronounced among females 15-19 years of age, who were eligible for the public vaccination program. The observed decline among young males could be due to herd immunity and/or privately paid vaccination.

Diez años de vacunación frente al virus del papiloma: nuevos retos y oportunidades / Ten years of papillomavirus vaccination: new challenges and opportunities

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Dicas em Saúde: Verrugas

Informações de utilidade pública sobre tratamento, prevenção e como se manifestam as verrugas.

Analysis of risk-structured vaccination model for the dynamics of oncogenic and warts-causing HPV types.

A new deterministic model is designed and used to assess the community-wide impact of mass vaccination of new sexually active individuals on the dynamics of the oncogenic and warts-causing HPV types. Rigorous qualitative analyses of the model, which incorporates the two currently available anti-HPV vaccines, reveal that it undergoes competitive exclusion when the reproduction of one HPV risk type (low/high) exceeds unity, while that of the other HPV risk type is less than unity. For the case when the reproduction numbers of the two HPV risk types (low/high) exceed unity, the two risk types co-exist. It is shown that the sub-model with the low-risk HPV types only has at least one endemic equilibrium whenever the associated reproduction threshold exceeds unity. Furthermore, this sub-model undergoes a re-infection-induced backward bifurcation under certain conditions. In the absence of the re-infection of recovered individuals and cancer-induced mortality in males, the associated disease-free equilibrium of the full (risk-structured) model is shown to be globally asymptotically stable whenever the reproduction number of the model is less than unity (that is, the full model does not undergo backward bifurcation under this setting). It is shown, via numerical simulations, that the use of the Gardasil vaccine could lead to the effective control of HPV in the community if the coverage rate is in the range of 73-95 % (84 %). If 70 % of the new sexually active susceptible females are vaccinated with the Gardasil vaccine, additionally vaccinating 34-56 % (45 %) of the new sexually active susceptible males can lead to the effective community-wide control (or elimination) of the HPV types.

Resolution of novel human papillomavirus-induced warts after HPV vaccination.

Human papillomavirus (HPV) XS2 was isolated from warts on an immunosuppressed patient. After HPV vaccination, the warts resolved. HPVXS2 was also found in warts and normal skin of HIV-positive patients and rarely in HIV-negative controls. Further studies should elucidate the mechanisms that lead to wart clearance.

HPV and HPV-associated diseases.

Human papillomavirus (HPV) is the most common sexually transmitted infection. HPV is associated with a significant burden of disease and cancer, including anogenital warts and recurrent respiratory papillomatosis, and anogenital and oropharyngeal cancers. Effective prevention is available, including primary prevention of cancers and anogenital warts through HPV vaccination, and secondary prevention of cervical cancer through screening and treatment of precancer. This article focuses on HPV infection and the clinical consequences of infection, with attention to cervical and anogenital squamous intraepithelial neoplasia and anogenital warts.

More on Hans Biberstein and his original ideas of vaccination against human warts and herpes infection.

This article presents less known aspects of Biberstein scientific activity. Biberstein pioneered the idea of producing a vaccine against human papillomavirus induced warts and he recognized the fact that there were different types of HPV induced lesions.

Virus-like particles and capsomeres are potent vaccines against cutaneous alpha HPVs.

The potential as prophylactic vaccines of L1-based particles from cutaneous genus alpha human papillomavirus (HPV) types has not been assessed so far. However, there is a high medical need for such vaccines since HPV-induced skin warts represent a major burden for children and for immunocompromised adults, such as organ transplant recipients. In this study, we have examined the immunogenicity of capsomeres and virus-like particles (VLPs) from HPV types 2, 27, and 57, the most frequent causative agents of skin warts. Immunization of mice induced immune responses resembling those observed upon vaccination with HPV 16 L1-based antigens. The antibody responses were cross-reactive but type-restricted in their neutralizing capacities. Application of adjuvant led to an enhanced potential to neutralize the respective immunogen type but did not improve cross-neutralization. Vaccination with capsomeres and VLPs from all four analyzed HPV types induced robust IFNgamma-associated T-cell activation. Immunization with mixed VLPs from HPV types 2, 27, and 57 triggered an antibody response similar to that after single-type immunization and capable of efficiently neutralizing all three types. Our results imply that vaccination with combinations of VLPs from cutaneous HPV types constitutes a promising strategy to prevent HPV-induced skin lesions.

Impact of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle vaccine in a sexually active population of North American women.

OBJECTIVE: The purpose of this study was to inform policy regarding human papillomavirus (HPV) vaccination in North America. We measured the clinical impact of HPV-6/-11/-16/-18 vaccination in North American women. STUDY DESIGN: The study enrolled 21,954 women, the majority aged 16-25, across 5 studies of a quadrivalent HPV vaccine or its HPV-16 vaccine prototype. The North American subjects (n = 5996) were pooled from these trials, and the prevalence of HPV-6/-11/-16/-18 exposure was measured. The impact of vaccination on the burden of anogenital HPV lesions in an intention-to-treat population (regardless of enrollment HPV status) was calculated. RESULTS: At enrollment, the median age was 20 years; 13% of the women had had a Papanicolaou test abnormality, and 76% of the women had negative tests results for all 4 vaccine HPV types. With approximately 3 years of follow-up evaluations in the intention-to-treat population (regardless of enrollment HPV status), vaccination reduced the rate of HPV-16- and -18-related precancers and HPV-6/-11/-16/-18-related genital lesions by 66.4% (95% CI, 42.7%-81.1%) and 57.7% (95% CI, 27.3%-76.3%), respectively. CONCLUSION: The administration of HPV vaccine to sexually active North American women reduced the burden of HPV-6/-11/-16/-18-related disease. Catch-up vaccination programs in this population are warranted.

Podophyllin reaction mimicking Bowen's disease in a patient with delusions of verrucosis.

A 40-year-old woman presented with a delusion of warts on the forehead, for which she was applying podophyllin toxin. A skin biopsy was taken, which showed prominent mitotic figures in the basal and suprabasal layers of the epidermis and apoptotic keratinocytes. Histopathologically Bowen's disease was suspected, but was discounted after clinicopathological correlation was obtained and showed absence of epidermal atypia or disorganization. This case demonstrates the histological resemblance of podophyllin reaction to Bowen's disease. Differentiation of self-inflicted from organic skin disease may be difficult, especially where histopathological findings are confounded by cutaneous application of toxins.

Conversion to sirolimus: a useful strategy for recalcitrant cutaneous viral warts in liver transplant recipient.

Dermatological complications following transplantation are very common and the majority of immunosuppressed transplant recipients develop some to many warts due to human papillomavirus (HPV) infection. In the setting of immunosuppression, therapeutic management may be disappointing because of the extent of the lesions in patients unable to develop a sufficient immune response directed against HPV. We report here a case of a young liver transplant recipient who developed diffuse recalcitrant HPV-induced warts leading to an impairment of her quality of life. Taking into account the antiproliferative and cytostatic properties of the target-of-rapamycin (TOR) inhibitors, a new class of immunosuppressive drug, we significantly modified the immunosuppressive regimen. Conversion to sirolimus was followed by a rapid improvement of cutaneous state suggesting that this strategy may be useful for recalcitrant cutaneous viral warts in transplant recipient.

Topical photodynamic therapy for prevention of new skin lesions in renal transplant recipients.

Preclinical data suggest that topical methyl aminolevulinate photodynamic therapy may have potential in preventing new skin lesions in transplant recipients. An open intra-patient randomized study investigated the prevention potential of this treatment in 27 renal transplant patients with actinic keratoses and other skin lesions in two circular contralateral areas (5 cm diameter). The treatment area surface was debrided and methyl aminolevulinate cream (160 mg/g) was applied for 3 h prior to illumination by non-coherent red light (570-670 nm, light dose 75 J/cm2). The control area was not treated. The mean time to occurrence of the first new lesion was significantly longer in treated than control areas (9.6 vs 6.8 months, treatment difference 2.9 [95% confidence interval 0.2 to 5.5] months, p = 0.034). Over 12 months, 62% (16/26) of treated areas were free from new lesions compared with 35% (9/26) in control areas. These findings indicate that topical methyl aminolevulinate photodynamic therapy is a promising preventive treatment against new skin lesions in immunosuppressed patients.

Cottontail rabbit papillomavirus E8 protein is essential for wart formation and provides new insights into viral pathogenesis.

The cottontail rabbit papillomavirus (CRPV) a and b subtypes display a conserved E8 open reading frame encoding a 50-amino-acid hydrophobic protein, with structural similarities to the E5 transmembrane oncoprotein of genital human PVs (HPVs). CRPV E8 has been reported to play a role in papilloma growth but not to be essential in papilloma formation. Here we report that the knockout of E8 start codon almost prevented wart induction upon biobalistic inoculation of viral DNA onto rabbit skin. The scarce warts induced showed very slow growth, despite sustained expression of E6 and E7 oncogenes. This points to an essential role of E8 in disturbing epidermal homeostasis. Using a yeast two-hybrid screen, we found that E8 interacted with the zinc transporter ZnT1, protocadherin 1 (PCDH1), and AHNAK/desmoyokin, three proteins as yet unrelated to viral pathogenesis or cell transformation. HPV16 E5 also interacted with these proteins in two-hybrid assay. CRPV E8 mainly localized to the Golgi apparatus and the early endosomes of transfected keratinocytes and colocalized with ZnT1, PCDH1, and AHNAK. We showed that ZnT1 and PCDH1 formed a complex and that E8 disrupted this complex. CRPV E8, like HPV16 E5, increased epidermal growth factor (EGF)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and both the EGF-dependent and the EGF-independent activity of activating protein-1 (AP-1). Competition experiments with a nonfunctional truncated ZnT1 protein showed that E8-ZnT1 interaction was required for AP-1 activation. Our data identify CRPV E8 as a key player in papilloma induction and unravel novel cellular targets for inducing the proliferation of keratinocytes.

Therapeutic vaccination with papillomavirus E6 and E7 long peptides results in the control of both established virus-induced lesions and latently infected sites in a pre-clinical cottontail rabbit papillomavirus model.

This study was performed to test the therapeutic efficacy of overlapping long E6 and E7 peptides, containing both CD4+ T-helper and CD8+ CTL epitopes, on CRPV-induced lesions, which is an appropriate pre-clinical model for HPV diseases, including recurrent respiratory papillomatosis (RRP). Therapeutic peptide vaccination was able to significantly control wart growth (p < 0.01) and abrogate latent CRPV infection (p = 0.0006) compared to controls. Vaccination was associated with a T(H)1 T cell response, as suggested by a strong DTH skin test, antigen-specific proliferation of PBMC and a minimal IgG antibody response. Thus, this study shows promise for treatment of RRP by vaccination with long peptides.

Management of cutaneous warts: an evidence-based approach.

Cutaneous warts are benign epidermal proliferations caused by human papillomavirus infection. Treatment aims to cure the patient's physical and psychological discomfort, and to prevent the spread of infection by contact with other body areas or with other individuals. Among the available medical and destructive therapeutic options for cutaneous warts, none is uniformly effective or virucidal. Moreover, in most cases the safety and efficacy of these treatment options has not been assessed in randomized controlled trials, so that the reproducibility of many of the listed treatments is difficult to evaluate and a possible placebo effect cannot be ruled out. This article provides indications for the management of patients with cutaneous warts through an evidence-based approach, considering a first-, second-, and third-line therapy for each clinical form. The first line includes medical treatments useful to cure single, or few, and/or small common warts of short duration (<1 year). If these treatments have failed or are contraindicated, cryotherapy may be considered as second-line therapy. For recurrent or difficult-to-treat lesions, a third-line of therapy includes a variety of alternative therapeutic options that are in clinical use but are not necessarily approved by the US FDA, and their use may be further limited by adverse effects.

Incidence of oral lesions in HIV-1-infected women: reduction with HAART.

Few studies assess the effectiveness of HAART on reducing the incidence and recurrence of oral lesions. We investigated such changes among 503 HIV+ women over six years in the Women's Interagency HIV Study. The incidence of erythematous candidiasis (EC), pseudomembranous candidiasis (PC), hairy leukoplakia (HL), and warts was computed over follow-up visits after HAART initiation compared with before HAART initiation. Analysis of our data demonstrates a strong decrease in candidiasis after HAART initiation. The incidence of EC fell to 2.99% from 5.48% (RR 0.545); PC fell to 2.85% from 6.70% (RR 0.425); and EC or PC fell to 3.43% from 7.35% (RR 0.466). No changes were seen in HL or warts. Higher HIV-RNA was associated with greater incidence of candidiasis and HL, but not warts. Analysis of these data indicates that recurrence and incidence of candidiasis are reduced by HAART, and that recurrence is reduced independently of CD4 and HIV-RNA.