Significant variation between SNP-based HLA imputations in diverse populations: the last mile is the hardest.

Four single nucleotide polymorphism (SNP)-based human leukocyte antigen (HLA) imputation methods (e-HLA, HIBAG, HLA*IMP:02 and MAGPrediction) were trained using 1000 Genomes SNP and HLA genotypes and assessed for their ability to accurately impute molecular HLA-A, -B, -C and -DRB1 genotypes in the Human Genome Diversity Project cell panel. Imputation concordance was high (>89%) across all methods for both HLA-A and HLA-C, but HLA-B and HLA-DRB1 proved generally difficult to impute. Overall, <27.8% of subjects were correctly imputed for all HLA loci by any method. Concordance across all loci was not enhanced via the application of confidence thresholds; reliance on confidence scores across methods only led to noticeable improvement (+3.2%) for HLA-DRB1. As the HLA complex is highly relevant to the study of human health and disease, a standardized assessment of SNP-based HLA imputation methods is crucial for advancing genomic research. Considerable room remains for the improvement of HLA-B and especially HLA-DRB1 imputation methods, and no imputation method is as accurate as molecular genotyping. The application of large, ancestrally diverse HLA and SNP reference data sets and multiple imputation methods has the potential to make SNP-based HLA imputation methods a tractable option for determining HLA genotypes.

Polyphenon E: a new treatment for external anogenital warts.

Background External genital warts (EGWs, condylomata acuminata) are a common, highly contagious disease caused by human papillomavirus (HPV), predominantly HPV 6 and HPV 11. Green tea catechins have been identified for their immunostimulatory, antiproliferative and antitumour properties. Two phase III trials evaluated treatment of EGWs with ointment containing a mixture of green tea catechins (Polyphenon E), U.S. adopted name: sinecatechins). Objectives To obtain additional data on the efficacy and safety of Polyphenon E ointment in the treatment of EGWs from two randomized, double-blind, vehicle-controlled trials. Methods Men and women aged > or = 18 years (n = 1005), with two to 30 EGWs (12-600 mm(2) total area) applied vehicle (G(Veh); n = 207), Polyphenon E ointment 10% (G(10%); n = 401) or Polyphenon E ointment 15% (G(15%); n = 397) three times daily until complete clearance of all EGWs (baseline + new EGWs) or for a maximum of 16 weeks. Results A total of 1004 patients were evaluable for safety and 986 for efficacy; 838 completed treatment after 16 weeks. Complete clearance of all EGWs was obtained in 53.6% (G(10%)) and 54.9% (G(15%)) of patients with Polyphenon E vs. vehicle (35.4%) (P < 0.001). Statistically significant differences in clearance rates appeared after 6 weeks of active treatment. Odds ratios vs. G(Veh) for G(10%) [2.10; 95% confidence interval (CI) 1.49-2.98] and G(15%) (2.22; 95% CI 1.57-3.14) indicated about a twofold higher chance of complete clearance under active treatment. Time to complete clearance was shorter with active treatment (hazard ratios 1.57 and 1.87, respectively, for G(10%) and G(15%) vs. G(Veh) groups; P < 0.001). Recurrence rates during follow-up were low and similar across groups: 5.8%, 6.8% and 6.5% (G(Veh), G(10%) and G(15%) groups, respectively). Adverse events were evenly distributed across groups ( approximately 30% of patients). Severe local signs were more frequent but moderate in the active treatment groups (1.5%, 9.2% and 13.5% for G(Veh), G(10%) and G(15%) groups, respectively). Conclusions Polyphenon E ointment is effective and well tolerated in the treatment of EGWs.

Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older.

OBJECTIVE: To compare the efficacy and safety of valacyclovir hydrochloride and famciclovir for the treatment of herpes zoster. DESIGN: A double-blind, randomized, controlled, multicenter clinical trial in which patients received 7 days of treatment and were followed up for 24 weeks. SETTINGS: Patients reported directly to specialist centers or were referred from primary care centers. PATIENTS: There were 597 otherwise healthy immunocompetent outpatients, aged 50 years and older, who presented within 72 hours of onset of zoster rash. INTERVENTIONS: Treatment with valacyclovir hydrochloride (1 g 3 times daily) or famciclovir (500 mg 3 times daily) for 7 days. MAIN OUTCOME MEASURES: Resolution of zoster-associated pain and postherpetic neuralgia, rash healing, and treatment safety. RESULTS: Intent-to-treat analysis did not detect statistically significant differences for valacyclovir vs famciclovir on resolution of zoster-associated pain (hazard ratio, 1. 02; 95% confidence interval, 0.84-1.23; P =.84). Furthermore, no differences were evident between treatments on rash healing rates and on a range of analyses of postherpetic neuralgia. Safety profiles for valacyclovir and famciclovir were similar, with headache and nausea being the more common adverse events. CONCLUSIONS: Valacyclovir treatment is comparable to famciclovir treatment in speeding the resolution of zoster-associated pain and postherpetic neuralgia. Current wholesale prices indicate that valacyclovir is the more cost-effective treatment for herpes zoster ($83.90 vs $140.70 per course).

Nongenital human papillomavirus infections.

Although genital HPV types produce a broad spectrum of disease, the nongenital types are a bit more predictive. Particularly in the immunocompromised patient, it appears as though when they become symptomatic they cause warts. These warts can be a particular problem with immunocompromised patients where the malignant potential can also be expressed. Additional understanding of the relationship between the papilloma viruses and cutaneous oncology is very important. There needs to be an application of seroepidemiologic techniques to understand better the epidemiology and further research on more effective and less painful therapies.

Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream.

BACKGROUND: Basal cell carcinoma (BCC) responds to interferon therapy. Imiquimod is a cytokine and interferon inducer. OBJECTIVE: This randomized, double-blind pilot trial evaluated the safety and efficacy of imiquimod 5% cream versus vehicle in the treatment of BCC. METHODS: In this population of 35 patients with BCC, 24 received imiquimod 5% cream and 11 received vehicle cream in 1 of 5 dosing regimens for up to 16 weeks. Six weeks after treatment, an excisional biopsy of the target site was performed. RESULTS: BCC cleared (on the basis of histologic examination) in all 15 patients (100%) dosed twice daily, once daily, and 3 times weekly; in 3 of 5 (60%) patients dosed twice weekly; 2 of 4 (50%) dosed once weekly; and in 1 of 11 (9%) treated with vehicle. Adverse events were predominantly local reactions at the target tumor site, with the incidence and severity of local skin reactions declining in groups dosed less frequently. CONCLUSION: Imiquimod 5% cream shows clinical efficacy in the treatment of BCC.

Genital warts and their treatment.

Genital warts are manifestations of a common viral sexually transmitted disease (STD) that are often diagnosed and treated with a variety of clinical specialties. Unlike for other STDs, there is a general lack of a well-established treatment algorithm for the management of external genital warts. This, coupled with a wide variety of treatments and clinical settings, makes the development of a simple algorithm virtually impossible. In this review what is known and not known about current treatments and case management will be discussed.

External genital warts: report of the American Medical Association Consensus Conference. AMA Expert Panel on External Genital Warts.

A consensus process was undertaken to describe and evaluate current information and practice regarding the diagnosis, treatment, and evaluation of patients with external genital warts (EGWs) and their sex partners. This process developed a number of key statements that were based on strong evidence in the literature or reasonable suppositions and opinions of experts. Key statements included the following. In most cases, EGWs can be diagnosed clinically by visual inspection. No one treatment is ideal for all patients or all warts. Women with EGWs and female sex partners of men with EGWs are at increased risk for human papillomavirus-related cervical disease and, like all women, should be screened for cervical cancer. The diagnosis of EGWs in children requires a sexual abuse evaluation. Clinicians who treat EGWs have a responsibility to counsel patients and to provide information about the infectivity, diagnosis, treatment, and natural history of EGWs and general information about sexual health and other sexually transmitted diseases.

Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts.

Genital human papillomavirus infection is one of the most common sexually transmitted diseases. Imiquimod is a new agent, an immune-response modifier, that has been demonstrated to have potent in vivo antiviral and antitumor effects in animal models. The present prospective, multicenter, double-blind, randomized, vehicle-controlled trial evaluated the efficacy and safety of daily patient-applied imiquimod for up to 16 weeks for the treatment of external genital warts. Wart recurrence was investigated during a 12-week treatment-free follow-up period. In the intent-to-treat analysis, baseline warts cleared from 49 of 94 (52%) patients treated with 5% imiquimod cream, 13 of 90 (14%) patients treated with 1% imiquimod cream, and 3 of 95 (4%) vehicle-treated patients; the differences between the groups treated with vehicle and imiquimod were significant (P < 0.0001). For subjects who completed the follow-up period, recurrence rates after a complete response were 19% (9 of 48 patients) in the 5% imiquimod cream group, 17% (2 of 12) in the 1% imiquimod cream group, and 0% (0 of 3) in the vehicle-treated group. There were no systemic reactions, although local skin reactions (generally of mild or moderate severity) were common, particularly in the 5% imiquimod cream group. Local reactions caused two patients to discontinue treatment. The most frequently reported local skin reactions were erythema, excoriation or flaking, and erosion. Patient-applied 5% imiquimod cream is effective for the treatment of external genital warts and has a favorable safety profile.

Treatment of genital warts with an immune-response modifier (imiquimod).

BACKGROUND: Genital warts are a common sexually transmitted disease caused by human papillomavirus. Imiquimod is a novel immune-response modifier capable of inducing a variety of cytokines, including interferon alfa, tumor necrosis factor-alpha, as well as interleukins 1, 6, and 8. In animal models imiquimod has demonstrated antiviral, antitumor, and adjuvant activity. In vitro, imiquimod has no antiviral or antitumor activity. OBJECTIVE: Our purpose was to determine the safety and efficacy of topical imiquimod for the treatment of external genital warts. METHODS: This prospective double-blind, placebo-controlled, parallel design clinical trial was performed in three outpatient centers, a public health clinic, a university-based clinic, and a private practice. One hundred eight patients with external genital warts (predominantly white men) were entered into the trial. Fifty-one patients were randomly selected to receive 5% imiquimod cream; 57 patients were randomly chosen to receive placebo cream. Study medication was applied three times weekly for up to 8 weeks. Patients whose warts cleared completely were observed for up to 10 weeks to determine recurrence rates. RESULTS: In the intent-to-treat analysis, the warts of 37% (19 of 51) of the imiquimod-treated patients and 0% (0 of 57) of the placebo group cleared completely (p < 0.001). In addition, many patients experienced a partial response. A reduction in baseline wart area of 80% or more was observed in 62% of imiquimod-treated patients (28 of 45) and 4% of the placebo group (2 of 50) (p < 0.001); a 50% reduction or more in wart area was noted in 76% of imiquimod-treated patients (34 of 45) and 8% of placebo recipients (4 of 50) (p < 0.001). Of imiquimod-treated patients whose warts cleared completely and who finished the 10-week follow-up period, 19% (3 of 16) experienced recurrences of warts. Imiquimod-treated patients experienced a significantly greater number of local inflammatory reactions than the placebo group. Symptoms and signs associated with the local inflammatory reactions included itching (54.2%), erythema (33.3%), burning (31.3%), irritation (16.7%), tenderness (12.5%), ulceration (10.4%), erosion (10.4%), and pain (8.3%). There were no differences in systemic reactions or laboratory abnormalities between treatment groups. CONCLUSION: Topical 5% imiquimod cream appears to have a significant therapeutic effect in the treatment of external genital warts.

Human papillomavirus and human disease.

Human papillomaviruses (HPVs) are associated with a spectrum of different diseases in humans, including common warts and genital warts. Of more serious concern is the connection between certain HPV types and some malignancies, particularly cervical and anal cancer. DNA from HPV-16 and HPV-18, two types frequently found in cervical cancer tissue, can immortalize cells in laboratory cultures, unlike DNA from HPV types associated with benign genital lesions. Although it is unclear how high-risk HPV types cause cancer, studies indicate that malignant transformation involves the viral E6 and E7 gene products, which may exert their effect by interfering with the cellular proteins that regulate cell growth. The vast majority of those infected do not develop malignancies, indicating that HPV infection alone is not enough to cause cancer. Cofactors such as cigarette smoking, may be required before neoplasia can occur. The potential seriousness of HPV infections is suggested by the observations that the number of genital HPV infections diagnosed is increasing and that cervical cancer is the second leading cause of cancer deaths in women throughout the world.

Therapeutic approaches to genital warts.

Although many treatments are available for genital warts caused by human papillomavirus (HPV), none are uniformly successful in the treatment of this disease. Most current treatment options work by destroying affected tissue, either by a cytotoxic or a physically ablative mode of action. Interferons have antiviral, antiproliferative, and immunomodulatory activities, but these have not translated into a high level of cure rates against warts. With all current treatments, recurrent warts are common. Therapies currently being investigated include a 5-fluorouracil/epinephrine collagen gel that achieves high concentrations of 5-fluorouracil at the site of injection. Other new treatment modalities focus on activating the host's immune system or improving the delivery of therapeutic compounds to the affected site. Imiquimod, a novel immune-response modifier, induces interferon and a number of other endogenous cytokines. A cream formulation containing 5% imiquimod resulted in good total clearance rates and generally tolerable side effects in controlled clinical trials of patients with external genital warts. Perhaps the most effective means for managing HPV disease would be a vaccine that prevents the occurrence of genital warts. Although it is unlikely that such a vaccine will be introduced in the near future, preliminary studies indicate that it may be possible to develop suitable prophylactic and therapeutic vaccines.

Human papilloma virus infection of the vulva.

The relationship between human papilloma virus (HPV) and cervical cancer is in the process of being defined. This potential opportunity to understand a human oncogenic virus has drawn significant attention to HPV. While cervical cancer is a potentially fatal outcome of HPV infection, genital warts are the most common manifestation of genital HPV infection. In addition to knowledge of etiology, natural history, and therapeutic options, patients and providers need to consider emotional impact to successfully manage the care of patients with this common infection. This article summarizes current knowledge of recent advances of HPV infection of the vulva.

Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy.

Oral administration of the prodrug valacyclovir results in enhanced bioavailability and significantly greater plasma concentrations of acyclovir than can be achieved with oral doses of acyclovir itself. The results of clinical trials with valacyclovir have demonstrated significant benefits in the resolution of pain associated with herpes zoster infection. Efficacy parameters were similar for valacyclovir and acyclovir in the treatment of herpes simplex; however the results were achieved with lower and less-frequent doses of valacyclovir. The cost of a course of therapy with valacyclovir is expected to be similar to that of other antivirals. The potential clinical benefits of valacyclovir will likely be apparent in the case of acyclovir-resistant herpesvirus infections, where high-dose intravenous treatment with acyclovir has been necessary. Most of these resistant viruses have been encountered in immunocompromised patients, and the resistance has been attributed to inadequate exposure to the drug. Because optimal levels of acyclovir are achieved with a simpler dosing regimen of valacyclovir, compliance may be improved in many patients, thus reducing the incidence of resistant virus.

Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults.

Acyclovir treatment of acute herpes zoster speeds rash healing and decreases pain and ocular complications. The limited oral bioavailability of acyclovir necessitates frequent dosing. Valaciclovir, the l-valyl ester of acyclovir, is rapidly and almost completely converted to acyclovir in vivo and gives three- to fivefold increases in acyclovir bioavailability. In a randomized, double-blind, multicenter study, the safety and efficacy of oral valaciclovir given at a dosage of 1,000 mg three times daily for 7 or 14 days and oral acyclovir given at a dosage of 800 mg five times daily for 7 days were compared in immunocompetent adults aged > or = 50 years with herpes zoster. Patients were evaluated for 6 months. The intent-to-treat analysis (1,141 patients) showed that valaciclovir for 7 or 14 days significantly accelerated the resolution of herpes zoster-associated pain (P = 0.001 and P = 0.03, respectively) compared with acyclovir; median pain durations were 38 and 44 days, respectively, versus 51 days for acyclovir. Treatment with valaciclovir also significantly reduced the duration of postherpetic neuralgia and decreased the proportion of patients with pain persisting for 6 months (19.3 versus 25.7%). However, there were no differences between treatments in pain intensity or quality-of-life measures. Cutaneous manifestations resolved at similar rates in all groups. Adverse events were similar in nature and prevalence among groups, and no clinically important changes occurred in hematology or clinical chemistry parameters. Thus, in the management of immunocompetent patients > or = 50 years of age with localized herpes zoster, valaciclovir given at 1,000 mg three times daily for 7 days accelerates the resolution of pain and offers simpler dosing, while it maintains the favorable safety profile of acyclovir.