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.

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.

Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts.

OBJECTIVES: To evaluate the efficacy and cost effectiveness of self applied podophyllotoxin 0.5% solution and podophyllotoxin 0.15% cream, compared to clinic applied 25% podophyllin in the treatment of genital warts over 4 weeks. METHODS: We conducted a randomised controlled trial in 358 immunocompetent men and women with genital warts of 3 months' duration or less. RESULTS: In the principal analysis both podophyllotoxin solution (OR 2.93, 95% CI 1.56 to 5.50) and podophyllotoxin cream (OR 1.97, 95% CI 1.04 to 3.70) were associated with significantly increased odds of remission of all warts compared to podophyllin. We performed two further analyses. When subjects defaulting from follow up were assumed to have been cured odds of remission of all warts were also significantly increased both for podophyllotoxin solution (OR 3.04, 95% CI 1.68 to 5.49) and for podophyllotoxin cream (OR 2.46, 95% CI 1.38 to 4.40). When subjects defaulting from follow up were assumed not to have been cured odds of remission of all warts were significantly increased for podophyllotoxin solution (OR 1.92, 95% CI 1.13 to 3.27), but not for podophyllotoxin cream (OR 1.17, 95% CI 0.69 to 2.00). Local side effects were seen in 24% of subjects, and recurrence of warts within 12 weeks of study entry in 43% of all initially cleared subjects, without statistically significant differences between the treatment groups. Direct, indirect, and total costs were similar across the three treatment groups. Podophyllotoxin solution was the most cost effective treatment, followed by podophyllotoxin cream, with podophyllin treatment being the least cost effective. CONCLUSIONS: Self treatment of anogenital warts with podophyllotoxin showed greater efficacy and cost effectiveness than clinic based treatment with podophyllin.

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.

Facile and efficient one-pot synthesis of 4beta-arylaminopodophyllotoxins: synthesis of DNA topoisomerase II inhibitors (NPF and W-68).

A series of 4beta-arylamino-4'-O-demethylepipodophyllotoxins and 4beta-arylaminoepipodophyllotoxins have been synthesized with significant stereoselectivity and improved yields by employing the methanesulphonic acid/sodium iodide reagent system. Compounds NPF. W-68 and other DNA topoisomerase II inhibitors are prepared in good to excellent yields by this method and these are active or more active than etoposide in their inhibition of the human DNA topoisomerase II.

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).