RESUMO
Like cervical cancer, anal cancer is caused by human papillomavirus (HPV). HPV is the most common sexually transmitted agent and is found in the anal canal of almost all HIV-positive men who have sex with men (MSM). Rates of HPV anal cancer are disproportionately higher in this population. Although the nanovalent HPV vaccine is efficacious in protecting against oncogenic HPV types, a substantial proportion of MSM remains unvaccinated and anal HPV infection continues to be an important public health burden. Therefore, it is important to identify strategies to prevent HPV infection. We report on two promising and interlinked strategies: (1) the development of a cell-based Renilla luminescence reporter assay using HPV-16 pseudovirions that encapsidate SV40-driven Renilla luminescence reporter expression plasmid and (2) use of this assay for high-throughput screening (HTS) of FDA- and internationally approved drugs to identify those that could be repurposed to prevent HPV infection. We conducted a screen of 1906 drugs. The assay was valid with a Z' of 0.67 ± 0.04, percent coefficient of variance of 10.0, and signal-to-background noise window of 424.0 ± 8.0. Five drugs were chosen for further analyses based on selection parameters of ≥77.0% infection of HPV-16 pseudovirion-driven Renilla expression with <20.0% cytotoxicity. Of these, the antifungal pentamidine and a gamma-amino butyric acid receptor agonist securinine exhibited ≥90.0% infection with <10.0% cytotoxicity. This luminescent cell-based reporter expression plasmid assay for HTS is a valid method to identify FDA- and internationally approved drugs with the potential to be repurposed into prevention modalities for HPV infection.
Assuntos
Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos , Genes Reporter , Papillomavirus Humano 16/efeitos dos fármacos , Proteínas Luminescentes/genética , Plasmídeos/genética , Linhagem Celular , Aprovação de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Reprodutibilidade dos Testes , Estados Unidos , United States Food and Drug AdministrationRESUMO
BACKGROUND: Anal high-grade squamous intraepithelial lesions (HSILs) ablation may reduce the incidence of invasive cancer, but few data exist on treatment efficacy and natural regression without treatment. METHODS: An open-label, randomized, multisite clinical trial of human immunodeficiency virus (HIV)-infected adults aged ≥27 years with 1-3 biopsy-proven anal HSILs (index HSILs) without prior history of HSIL treatment with infrared coagulation (IRC). Participants were randomized 1:1 to HSIL ablation with IRC (treatment) or no treatment (active monitoring [AM]). Participants were followed every 3 months with high-resolution anoscopy. Treatment participants underwent anal biopsies of suspected new or recurrent HSILs. The AM participants underwent biopsies only at month 12. The primary end point was complete clearance of index HSIL at month 12. RESULTS: We randomized 120 participants. Complete index HSIL clearance occurred more frequently in the treatment group than in the AM (62% vs 30%; risk difference, 32%; 95% confidence interval [CI], 13%-48%; P < .001). Complete or partial clearance (clearance of ≥1 index HSIL) occurred more commonly in the treatment group (82% vs 47%; risk difference, 35%; 95% CI, 16%-50%; P < .001). Having a single index lesion, compared with having 2-3 lesions, was significantly associated with complete clearance (relative risk, 1.96; 95% CI, 1.22-3.10). The most common adverse events related to treatment were mild or moderate anal pain and bleeding. No serious adverse events were deemed related to treatment or study participation. CONCLUSION: IRC ablation of anal HSILs results in more clearance of HSILs than observation alone.
Assuntos
Técnicas de Ablação/métodos , Síndrome da Imunodeficiência Adquirida/complicações , Neoplasias do Ânus/diagnóstico , Neoplasias do Ânus/cirurgia , Hipertermia Induzida/métodos , Lesões Intraepiteliais Escamosas/diagnóstico , Lesões Intraepiteliais Escamosas/cirurgia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proctoscopia , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate prospectively the safety of the infrared coagulator (IRC) as a treatment for anal high-grade squamous intraepithelial lesions (HSILs) in HIV-infected individuals and to seek preliminary evidence for efficacy. METHODS: HIV-infected patients with =3 biopsy-proven internal anal HSILs received office-based treatment with the IRC at participating AIDS Malignancy Consortium sites. Treatments were performed during high-resolution anoscopy (HRA) under local anesthesia. Patients were reevaluated at 3 months, and persistent lesions could be retreated. Patients were evaluated every 3 months for a year with anal cytology and HRA with biopsy. Human papillomavirus (HPV) DNA was measured at baseline and at follow-up using MY09/MY11 L1 polymerase chain reaction. RESULTS: A total of 44 HSILs were treated from 16 men and 2 women. HPV 16 was the most common HPV type identified. There was no consistent change in HPV type or viral load in patients before and after treatment with the IRC. No procedure-related severe adverse events were reported. Twelve patients reported mild or moderate anal/rectal pain or bleeding. CONCLUSIONS: The IRC is a well-tolerated method of treating discrete anal canal HSILs in HIV-infected patients. A larger study to characterize its efficacy better in the management of HSILs in HIV-infected individuals is warranted.