Podofilotoxina 1, 5 mg/g e imiquimode 50 mg/g para condilomas acuminados decorrentes de infecção por papilomavírus humano (HPV) / Podofilotoxin 1. 5 mg / g and imiquimod 50 mg / g for condyloma acuminata due to human papillomavirus (HPV) infection

CONTEXTO: Condilomas acuminados, ou verrugas anogenitais, são lesões provocadas pela infecção por HPV. Trata-se de uma infecção sexualmente transmissível, de alto contágio. A maior parte dasinfecções por HPV são assintomáticas e o organismo elimina o vírus em poucos meses. Contudo, em alguns casos o vírus permanece nas genitálias, ânus ou na orofaringe e se observa o surgimento de lesões, como os condilomas acuminados, bem como o risco do desenvolvimento de diversas neoplasias. A transmissibilidade da infecção por HPV é maior quando há condilomas acuminados. Não há tratamentos que eliminem ou interfiram na história natural da infecção por HPV. No entanto, existem procedimentos e alternativas farmacológicas para a eliminação dos condilomas acuminados. Os procedimentos e alguns medicamentos são de administração exclusiva por profissionais médicos. Outros medicamentos podem ser aplicados pelo próprio paciente. No Brasil, há registro sanitário para podofilotoxina 1,5 mg/g (ou 0,15%) ou imiquimode 5% (ou 50 mg/g), ambos administráveis pelo paciente. No SUS, estão disponíveis o medicamento podofilina, em concentrações variando entre 100 mg/mL e 250 mg/mL (ou 10% a 25%), e os procedimentos de excisão cirúrgica e de tratamento geral de infecção sexualmente transmissível. TECNOLOGIAS: Podofilina 100 mg/mL a 250 mg/mL solução, podofilotoxina 1,5 mg/g creme e imiquimode 50 mg/g creme. PERGUNTAS: Podofilotoxina é mais eficaz/efetiva e segura em relação a podofilina para o tratamento de pacientes com condilomas acuminados associados à infecção por HPV? Para pacientes com verrugas anogenitais o uso de imiquimode comparado ao placebo ou a outro tratamento farmacológico há regressão completa ou parcial das verrugas após o tratamento? EVIDÊNCIAS CIENTÍFICAS: Evidências clínicas: foram elaborados dois Pareceres Técnico-Científicos, um para cada pergunta de pesquisa. Apenas um estudo comparou diretamente podofilotoxina 0,15% em relação a podofilina 25%. Neste estudo, não houve diferença significativa entre elas para a completa remissão de condilomas acuminados após quatro semanas de tratamento, com proporção de cura de, respectivamente, 44,8% e 44,9%. Este estudo também avaliou a utilização de podofilotoxina 0,5% e esta tecnologia foi significativamente mais eficaz, com 60,0% dos pacientes com remissão completa em quatro semanas. Em outro estudo, podofilotoxina 0,5% não foi significativamente mais eficaz que podofilina 20% na cura em quatro semanas, com eficácia em, respectivamente, 81,2% e 59,3% dos pacientes em seus grupos. Em outros estudos, observou-se que a eficácia de podofilotoxina é significativamente maior que placebo e semelhante a outrastecnologias. Podofilotoxina 0,5% proporciona maior risco para a ocorrência de eventos adversos locais. Já podofilotoxina 0,15% e as variadas concentrações de podofilina proporcionam perfil de segurança semelhante entre si. Sobre a eficácia e segurança de imiquimode 5%, observou-se que o medicamento é mais eficaz que placebo (RR: 4,03; IC 95%: 2,03 a 7,99). Um estudo de metanálise envolvendo comparações diretas e indiretas (Mixed Treatment Comparison), a eficácia de imiquimode 5% foi semelhante à de podofilina de 20% a 25% (OR: 1,07; ICr 95%: 0,15-3,45). Neste estudo, podofilotoxina 0,5% foi significativamente mais eficaz que podofilina ou imiquimode, contudo não avaliou podofilotoxina 0,15%. O perfil de segurança de imiquimode 5% foi considerado semelhante a podofilina e melhor que o de podofilotoxina 0,5%. Não houve comparação em relação a podofilotoxina 0,15%. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A avaliação de podofilotoxina 0,15% e de imiquimode 5% considerou o período entre os anos de 2018 e 2022, as projeções populacionais calculadas pelo IBGE, a prevalência de condilomas acuminados na população, a cobertura da atenção básica pelo SUS e a população sexualmente ativa nos últimos 12 meses. A estimativa de impacto orçamentário total em cinco anos para a potencial incorporação de podofilotoxina 0,15% foi de R$ 758.049,13 para novos casos e R$ 102.159.244,64 para os casos prevalentes. Para imiquimode 5% foi de, respectivamente, R$ 895.438,59 e R$ 120.674.671,98. Considerando os casos prevalentes, o impacto orçamentário médio por habitante para podofilotoxina 0,15% e imiquimode 5% foi de, respectivamente, R$ 0,48 e R$ 0,57. Análises de sensibilidade demonstraram maior que a variação na prevalência afeta mais o resultado do impacto orçamentário em relação ao preço dos tratamentos. As variações nas taxas de difusão das tecnologias proporcionam maior amplitude nas estimativas do impacto orçamentário. RECOMENDAÇÃO DA Conitec: Os membros da CONITEC presentes na 60ª reunião da CONITEC, realizada na data de 04/10/2017, consideraram que a podofilina 10 mg/mL a 250 mg/mL não deve ser excluída do SUS e que a podofilotoxina 1,5 mg/g creme e de imiquimode 50 mg/g creme devem ser incorporados ao SUS. CONSULTA PÚBLICA: A Consulta Pública nº 60/2017 foi realizada entre os dias 25/10/2017 e 13/11/2017. Foi recebida uma contribuição sobre experiência com os tratamentos. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 62ª reunião da CONITEC, 06/12/2017, deliberaram por recomendar a incorporação de podofilotoxina 1,5 mg/g creme, a incorporação do imiquimode 50mg/g creme e a não exclusão de podofilina 100 mg/mL para o tratamento de pacientes com verrugas anogenitais causadas pela infecção por vírus papiloma humano (HPV). Respectivamente, foram assinados os registros de deliberação nº 307/2017, nº 308/2017 e nº 321/2017. DECISÃO: A Portaria nº 64, de 28 de novembro de 2018, publicada no DOU nº 228,seção 1, página 142, tornou pública a decisão de incorporar a podofilotoxina 1,5 mg/g creme e imiquimode 50 mg/g creme e não excluir podofilina 100 mg/mL para o tratamento de pacientes com verrugas anogenitais causadas pela infecção por vírus papiloma humano (HPV), no âmbito do Sistema Único de Saúde - SUS.

Outpatient administration of BEAM conditioning prior to autologous stem cell transplantation for lymphoma is safe, feasible, and cost-effective.

High-dose BEAM chemotherapy (BCNU, etoposide, Ara-C, and melphalan) followed by autologous hematopoietic stem cell transplantation is frequently used as consolidative therapy for patients with recurrent or refractory Hodgkin or non-Hodgkin lymphoma. The BEAM regimen has traditionally been administered over 6 days in the hospital, with patients remaining hospitalized until hematologic recovery and clinical stability. In an effort to reduce the length of hospitalization for these patients, our institution has transitioned from inpatient (IP) to outpatient (OP) administration of BEAM conditioning. Here, we report the results of an analysis of the feasibility, cost, complications, and outcomes for the initial group of patients who received OP BEAM compared to a prior cohort of patients who received IP BEAM. Patient and disease characteristics were comparable for the two cohorts, as were engraftment kinetics. Length of hospital stay was reduced by 6 days for the OP cohort (P < 0.001), resulting in a cost savings of more than $17,000 per patient. Fewer complications occurred in the OP cohort, including severe enteritis (P = 0.01), organ toxicities (P = 0.01), and infections (P = 0.04). Overall survival rate up to 3 years posttransplant was better for the OP cohort (P = 0.02), likely due to differences in posttransplant therapies. We conclude that OP administration of BEAM conditioning is safe and may offer significant advantages, including decreased length of hospitalization, reduced costs, decreased risks for severe toxicities and infectious complications, and likely improvement in patient satisfaction and quality of life.

Clinical effectiveness and cost-effectiveness of interventions for the treatment of anogenital warts: systematic review and economic evaluation.

BACKGROUND: Typically occurring on the external genitalia, anogenital warts (AGWs) are benign epithelial skin lesions caused by human papillomavirus infection. AGWs are usually painless but can be unsightly and physically uncomfortable, and affected people might experience psychological distress. The evidence base on the clinical effectiveness and cost-effectiveness of treatments for AGWs is limited. OBJECTIVES: To systematically review the evidence on the clinical effectiveness of medical and surgical treatments for AGWs and to develop an economic model to estimate the cost-effectiveness of the treatments. DATA SOURCES: Electronic databases (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Web of Science) were searched from inception (or January 2000 for Web of Science) to September 2014. Bibliographies of relevant systematic reviews were hand-searched to identify potentially relevant studies. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were searched for ongoing and planned studies. REVIEW METHODS: A systematic review of the clinical effectiveness literature was carried out according to standard methods and a mixed-treatment comparison (MTC) undertaken. The model implemented for each outcome was that with the lowest deviance information criterion. A de novo economic model was developed to assess cost-effectiveness from the perspective of the UK NHS. The model structure was informed through a systematic review of the economic literature and in consultation with clinical experts. Effectiveness data were obtained from the MTC. Costs were obtained from the literature and standard UK sources. RESULTS: Of 4232 titles and abstracts screened for inclusion in the review of clinical effectiveness, 60 randomised controlled trials (RCTs) evaluating 19 interventions were included. Analysis by MTC indicated that ablative techniques were typically more effective than topical interventions at completely clearing AGWs at the end of treatment. Podophyllotoxin 0.5% solution (Condyline(®), Takeda Pharmaceutical Company Ltd; Warticon(®) solution, Stiefel Laboratories Ltd) was found to be the most effective topical treatment evaluated. Networks for other outcomes included fewer treatments, which restrict conclusions on the comparative effectiveness of interventions. In total, 84 treatment strategies were assessed using the economic model. Podophyllotoxin 0.5% solution first line followed by carbon dioxide (CO2) laser therapy second line if AGWs did not clear was most likely to be considered a cost-effective use of resources at a willingness to pay of £20,000-30,000 per additional quality-adjusted life-year gained. The result was robust to most sensitivity analyses conducted. LIMITATIONS: Limited reporting in identified studies of baseline characteristics for the enrolled population generates uncertainty around the comparability of the study populations and therefore the generalisability of the results to clinical practice. Subgroup analyses were planned based on type, number and size of AGWs, all of which are factors thought to influence treatment effect. Lack of data on clinical effectiveness based on these characteristics precluded analysis of the differential effects of treatments in the subgroups of interest. Despite identification of 60 studies, most comparisons in the MTC are informed by only one RCT. Additionally, lack of head-to-head RCTs comparing key treatments, together with minimal reporting of results in some studies, precluded comprehensive analysis of all treatments for AGWs. CONCLUSIONS: The results generated by the MTC are in agreement with consensus opinion that ablative techniques are clinically more effective at completely clearing AGWs after treatment. However, the evidence base informing the MTC is limited. A head-to-head RCT that evaluates the comparative effectiveness of interventions used in clinical practice would help to discern the potential advantages and disadvantages of the individual treatments. The results of the economic analysis suggest that podophyllotoxin 0.5% solution is likely to represent a cost-effective first-line treatment option. More expensive effective treatments, such as CO2 laser therapy or surgery, may represent cost-effective second-line treatment options. No treatment and podophyllin are unlikely to be considered cost-effective treatment options. There is uncertainty around the cost-effectiveness of treatment with imiquimod, trichloroacetic acid and cryotherapy. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005457. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Clinical assessment of 252Californium neutron intracavitary brachytherapy using a two-channel Y applicator combined with external beam radiotherapy for endometrial cancer.

OBJECTIVE: The aim of this study was to determine the efficacy of 252Californium neutron intracavitary brachytherapy using a two-channel Y applicator combined with external beam radiotherapy for the treatment of endometrial cancer. METHODS: Thirty-one patients with stage I-III endometrial cancer were recruited for this study. The stage I patients received only 252Californium neutron intracavitary brachytherapy with a two-channel applicator. The stage II and III patients received both 252Californium neutron intracavitary brachytherapy using a two-channel applicator and parallel-opposed whole pelvic radiotherapy. RESULTS: The five-year local control rate was 80.6% (25/31), the overall survival rate was 51.6% (16/31), and the disease-free survival rate was 54.8% (17/31). The incidence of serious late complications was 12.9% (4/31). CONCLUSIONS: 252Californium neutron intracavitary brachytherapy using a two-channel applicator combined with external beam radiotherapy was effective for treating endometrial cancer and the incidence of serious late complications related to this combination was within an acceptable range.

Clinical assessment of 252Californium neutron intracavitary brachytherapy using a two-channel Y applicator combined with external beam radiotherapy for endometrial cancer

OBJECTIVE: The aim of this study was to determine the efficacy of 252Californium neutron intracavitary brachytherapy using a two-channel Y applicator combined with external beam radiotherapy for the treatment of endometrial cancer. METHODS: Thirty-one patients with stage I-III endometrial cancer were recruited for this study. The stage I patients received only 252Californium neutron intracavitary brachytherapy with a two-channel applicator. The stage II and III patients received both 252Californium neutron intracavitary brachytherapy using a two-channel applicator and parallel-opposed whole pelvic radiotherapy. RESULTS: The five-year local control rate was 80.6% (25/31), the overall survival rate was 51.6% (16/31), and the disease-free survival rate was 54.8% (17/31). The incidence of serious late complications was 12.9% (4/31). CONCLUSIONS: 252Californium neutron intracavitary brachytherapy using a two-channel applicator combined with external beam radiotherapy was effective for treating endometrial cancer and the incidence of serious late complications related to this combination was within an acceptable range.

Temporal trends in genital warts among individuals covered by the public prescription drug insurance plan in the province of Quebec, Canada, from 1998 to 2007.

OBJECTIVE: We assessed temporal trend in the incidence and prevalence of genital warts (GWs) in the province of Quebec, Canada, between 1998 and 2007 as a baseline for future assessment of the impact of Quebec human papillomavirus vaccination program. MATERIALS AND METHODS: Data on GWs were obtained from the linkage of the physician service claims and the public insurance drug plan databases. Genital warts were identified through a prescription of podofilox, a medical procedure code specific to GWs or a diagnosis code for viral warts followed by a prescription of imiquimod or fluorouracil within 2 weeks. An episode was considered incident if it was preceded by a 12-month interval period free of GWs care. RESULTS: During the study period, a total of 27,138 episodes of GWs occurred among 24,267 individuals. The age-standardized incidence rate increased over time in men and women. The highest incidence was observed in women aged 20 to 24 years (391.9/100,000) and in men aged 25 to 29 years (383.3/100,000). Similar trends in prevalence were observed. CONCLUSIONS: The incidence and prevalence of GWs has increased among the population covered by the public insurance drug plan in Quebec.

Treatment outcome and cost-effectiveness analysis of two chemotherapeutic regimens (BEP vs. VIP) for poor-prognosis metastatic germ cell tumors.

BACKGROUND: In patients with small-volume disseminated disease of germ cell tumors, cure can be achieved with four cycles of bleomycin, etoposide, and cisplatin (BEP). However, around 20% of these cases are not curable. Strategies to improve cure rates have shown that none of the currently available modalities were superior to the others. Among the most used ones, BEP and VIP (etoposide, cisplatin, and ifosfamide) have been the most studied. However, there are no reports comparing the two, except for a few in abstract forms from southern India. Therefore, we did a treatment outcome and cost-effectiveness analysis of two chemotherapeutic regimens (BEP vs VIP) that are used in poor-prognosis metastatic germ cell tumors. MATERIALS AND METHODS: All male patients with germ cell tumors, diagnosed as having poor risk by IGCCCG, between January 2002 and December 2004 were included in the study. Clinical, laboratory, and other data were recorded. The patients were stratified into two categories on the basis of the type of chemotherapeutic regimen they received. RESULTS: In all, 46 patients were analyzed, with a median follow up of 26.6 months. The baseline characteristics (age, stage, PS, histology, and serum markers) were not different in the two treatment arms. There is no significant difference in the outcome with either of the chemotherapeutic modalities. VIP is less cost effective and more toxic compared to BEP. CONCLUSION: In view of the greater toxicity and cost of therapy, as well as lack of either overall or disease free survival advantage, VIP is not a preferred option for patients with high-risk germ cell tumors in the Indian setting and it is still advisable to treat patients with BEP.

[A model-based comparison of cost effectiveness of imiquimod versus podophyllotoxin for the treatment of external anogenital warts in France]. / Comparaison coût-efficacité par modélisation de l'imiquimod et de la podophyllotoxine dans le traitement du condylome acuminé externe en France.

OBJECTIVES: For the National health scheme, to compare the costs and the efficacy of treatment of external anogenital warts with imiquimod and podophyllotoxin and laser therapy in the case of failure or relapse. PATIENTS AND METHODS: A model simulating the two successive treatments was built. In the first phase, the two topical treatments applied by the patients: podophyllotoxin for 4 weeks and imiquimod for 16 weeks were compared. In the case of failure or relapse, laser therapy that is widely used in France in this indication and, was applied. The efficacy of the topical treatments was assessed after reanalysis of the results of two controlled clinical trials versus placebo. These two trials were retained because they were comparable in method and had been recently published at the same time. A review of the literature assessed the results of laser therapy. A survey was conducted to collect the medical resources consumed by the different treatments. RESULTS: Imiquimod provided a clearance rate of 49.5 p. 100, i.e., the disappearance of the lesions at 16 weeks, greater than that of podophyllotoxin (28.3 p. 100) at 4 weeks. The relapse rate was lowest with imiquimod (13.3 p. 100) than with podophyllotoxin (30.9 p. 100). The remission rate without relapse 3 months after the end of treatment was, including the laser, of 62 p. 100 following imiquimod and of 47 p. 100 following podophyllotoxin. The costs per patient cured was of 668 Euros for imiquimod and of 689 Euros for podophyllotoxin. CONCLUSION: Imiquimod, because of its greater initial efficacy, is at least as cost-effective as podophyllotoxin the treatment of external genital warts.

The cost-effectiveness of patient-applied treatments for anogenital warts.

A model was developed to estimate the cost-effectiveness of podophyllotoxin and imiquimod for self-treatment of anogenital warts. The effectiveness endpoint was sustained clearance after treatment and a subsequent follow-up period of approximately 12 weeks. Effectiveness of podophyllotoxin was estimated from a quantitative summary of nine placebo-controlled trials, while effectiveness of imiquimod was based on a quantitative summary of six placebo-controlled trials. Costs were considered from a UK health service provider perspective; drug acquisition costs were obtained from the British National Formulary and health service costs of clinic attendance were based on a recent survey of GUM clinics. The impact of uncertainty was explored in a wide range of one-way and probabilistic (multi-way) sensitivity analyses. The cost per sustained clearance was 313 for podophyllotoxin and 606 for imiquimod. The modest and statistically insignificant incremental effectiveness of imiquimod was purchased at high cost-2476 per additional sustained clearance. Sensitivity analyses showed the economic superiority of podophyllotoxin to be robust and statistically very significant.

[Incidence and management of condylomata acuminata by French general physicians]. / Incidence et prise en charge des condylomes acuminés externes en médecine générale.

OBJECTIVES: Condylomata acuminata (or genital warts) are sexually transmitted diseases caused by human papillomavirus. Until now, there has been no available epidemiologic data about this disease in France. We conducted a prospective study among French general practitioners (GPs) to estimate the incidence of consultations for external condylomata acuminata in general practice. We also assessed the management of patients with external condylomata acuminata by French GP's. DESIGN: A panel of French general practitioners, members of the Sentinel network, had to fill-in prospectively a questionnaire for each patient with condylomata acuminata diagnosed between July and November 2000. RESULTS: The annual number of consultations for external condylomata acuminata with French GP's was estimated at 23,000 (CI (95 p. 100) 21,000-25,000) including 15,000 new cases (CI (95 p. 100) 13,000-17,000). Taking into account the estimations we made at the same time in office-based private dermatologists, we estimated the annual incidence of external condylomata acuminata in France at 107/100 000 inhabitants. The management of patients with external condylomata acuminata by French GP's was in accordance with the European guidelines in 54 to 78 p. 100 of cases. French GP's mostly prescribed chemical treatment. DISCUSSION: A proportion of cases of condylomata acuminata may have not been diagnosed. Similarly, some lesions may have been wrongly diagnosed as condylomata acuminata, but these proportions of false positive and false negative remain unknown. The incidence of external condylomata acuminata in France is similar to those estimated in others developed countries.

The cost effectiveness of patient-applied versus provider-administered intervention strategies for the treatment of external genital warts.

OBJECTIVE: External genital warts are one of the fastest growing sexually transmitted diseases in the United States today. Two forms of therapy are available: provider-administered and patient-applied. In the most widely used provider-administered ablative therapies, sustained clearance rates range from 18.5% to 40.1%. With nonablative, patient-applied therapies, which are typically more acceptable to patients, sustained clearance rates range from 19.6% with podofilox gel to 44.0% with imiquimod cream. The purpose of this study, given the range of therapies available, their cost differences, and clinical trial-reported differences in rates of sustained clearance, is to determine which therapy modalities, from the providers' perspective, are the most cost effective and which are likely to be the most acceptable to the patient population. STUDY DESIGN: We consider the cost effectiveness of the two patient-applied therapies as first-line therapy followed by provider-administered ablative treatment as second-line therapy. A decision-analytic model framework is developed, with data drawn both from clinical trials and from previously published studies. RESULTS: When considering a two-stage therapy model, with an average sustained clearance rate of 30% assumed for provider-administered ablative therapies, estimated costs per sustained cleared patient are $1265 for patients initially treated with imiquimod and $1304 for patients initially treated with podofilox gel. CONCLUSIONS: Initial treatment with imiquimod is the preferred intervention option as it yields a 39% greater sustained clearance rate than podofilox gel while being 3% less costly per successful outcome.

The cost of treating genital warts.

BACKGROUND: Genital warts is a common sexually transmitted disease treated by a variety of medical specialists. Standard therapies offer symptomatic relief but cannot ensure lasting remission. Using the clinical literature, claims databases, and a panel of experienced practitioners, the relative efficacy, cost, and cost effectiveness of five common treatments for genital warts were assessed in this study. METHODS: We reviewed the clinical literature for the following genital wart therapies: podofilox, podophyllin, trichloroacetic acid, cryotherapy, and laser therapy, focusing on their relative efficacy. Physicians experienced in treating genital warts defined standard treatment protocols for men and women patients with moderate wart burdens. Using national claims data and protocols developed by physicians, we derived three economic models based on provider charges, third-party payments, and a resource-based relative value scale, respectively. RESULTS: The literature review demonstrated highly variable success and recurrence rates among treatment methods and failed to show that one treatment provides consistently superior efficacy. In the economic models, treating women generally proved more costly than treating men per episode of care. This was due to the need for more extensive follow-up visits in the treatment of women. Total costs were highest for cryotherapy and lowest for a patient-applied therapy that reduced the need for follow-up visits. CONCLUSIONS: Clinicians should consider both clinical and cost issues when choosing the appropriate treatment for patients with genital warts.

The cost effectiveness of treatment of genital warts with podophyllotoxin.

The cost effectiveness of 25% podophyllin resin and 0.5% podophyllotoxin solution in the treatment of genital warts in Genitourinary Medicine Clinic attenders was studied. Although the average treatment cost for a course of podophyllotoxin was more than that for podophyllin resin (20.75 pounds v. 14.95 pounds respectively) the overall cure rate with podophyllotoxin was 66% as opposed to 34.6% with podophyllin. When the costing of secondary treatment options was considered the cost per patient cured of warts with podophyllin resin was 27.15 pounds compared with 25.73 pounds for podophyllotoxin solution (not significant).