2012 European guideline for the management of anogenital warts.

BACKGROUND: Although new HPV vaccines have been developed and are in the process of implementation, anogenital warts remain a very frequent problem in clinical practice. OBJECTIVE: We wished to update previously published European guidelines for the management of anogenital warts. METHODS: We performed a systematic review of randomized controlled trials for anogenital warts. The primary data were analyzed and collated, and the findings were formulated within the structure of a clinical guideline. The IUSTI Europe Editorial Board reviewed the draft guideline which was also posted on the web for comments which we incorporated into the final version of the guideline. RESULTS: The data confirm that only surgical therapies have primary clearance rates approaching 100%. Recurrences, including new lesions at previously treated or new sites, occur after all therapies, and rates are often 20-30% or more. All therapies are associated with local skin reactions including itching, burning, erosions and pain. CONCLUSIONS: Physicians treating patients with genital warts should develop their own treatment algorithms which include local practice and recommendations. Such patient level management protocols should incorporate medical review of cases at least every 4 weeks, with switching of treatments if an inadequate response is observed. First episode patients should be offered sexually transmitted disease screening. Management should include partner notification and health promotion.

The impact of genital warts: loss of quality of life and cost of treatment in eight sexual health clinics in the UK.

OBJECTIVES: To estimate the loss of quality of life and cost of treatment associated with genital warts seen in sexual health clinics. METHODS: A cross-sectional questionnaire study and case note review of individuals with genital warts, carried out in eight sexual health clinics in England and Northern Ireland. Individuals with genital warts attending the participating clinics were invited to take part in the questionnaire study. 895 participants were recruited. A separate sample of 370 participants who had attended a participating clinic with a first visit for a first or recurrent episode of genital warts between April and June 2007 was included in the case note review. Quality of life was measured using the EQ-5D questionnaire and the cost of an episode of care was derived from the case note review. RESULTS: The weighted mean EQ-5D index score was 0.87 (95% CI 0.85 to 0.89). The weighted mean disutility was 0.056 (95% CI 0.038 to 0.074). The estimated mean loss of quality-adjusted life-years associated with an episode of genital warts was 0.018 (95% CI 0.0079 to 0.031), equivalent to 6.6 days of healthy life lost per episode. The weighted mean cost per episode of care was £94 (95% CI £84 to £104), not including the cost of a sexually transmitted infection screen. CONCLUSIONS: Genital warts have a substantial impact on the health service and the individual. This information can be utilised for economic evaluation of human papillomavirus vaccination.

Does the number of doses matter? A qualitative study of HPV vaccination acceptability nested in a dose reduction trial in Tanzania.

BACKGROUND: The multi-dose regimen is a known barrier to successful human papillomavirus (HPV) vaccination. Emerging evidence suggests that one vaccine dose could protect against HPV. While there are clear advantages to a single dose schedule, beliefs about vaccine dosage in low and middle income countries (LMICs) are poorly understood. We investigated acceptability of dose-reduction among girls, and parents/guardians of girls, randomised to receive one, two or three doses in an HPV vaccine dose-reduction and immunobridging study (DoRIS trial) in Tanzania. METHODS: Semi-structured interviews with girls (n = 19), and parents/guardians of girls (n = 18), enrolled in the study and completing their vaccine course. RESULTS: Most participants said they entrusted decisions about the number of HPV vaccine doses to experts. Random allocation to the different dose groups did not feature highly in the decision to participate in the trial. Given a hypothetical choice, girls generally said they would prefer fewer doses in order to avoid the pain of injections. Parental views were mixed, with most wanting whichever dose was most efficacious. Nonetheless, a few parents equated a higher number of doses with greater protection. CONCLUSION: Vaccine trials and programmes will need to employ careful messaging to explain that one dose offers sufficient protection against HPV should emerging evidence from ongoing dose-reduction clinical trials support this.

Hypothermia - an unusual initial presentation of human immunodeficiency virus infection.

We report an unusual case of human immunodeficiency virus (HIV) infection initially presenting with hypothermia and bradycardia associated with an HIV encephalitis. Searches reveal only five reported cases of spontaneous episodic hypothermia in the context of HIV infection. In our case, magnetic resonance imaging revealed the presence of a persistent cavum septum pellucidum (CSP), an anatomical and functional neuro-developmental abnormality, as well as changes compatible with an HIV encephalitis. Episodic hypothermia can occur in association with agenesis of the corpus callosum, known as Shapiro's syndrome, and the presence of a persistent CSP in our case suggests it may have contributed to the clinical presentation.

A multicentre, randomised, double-blind, placebo controlled study of cryotherapy versus cryotherapy and podophyllotoxin cream as treatment for external anogenital warts.

OBJECTIVES: To compare the efficacy and safety of combination therapy with cryotherapy and podophyllotoxin 0.15% cream versus cryotherapy alone in the treatment of anogenital warts. METHODS: A randomised, double-blind, multicentre controlled trial. Patients received podophyllotoxin cream or placebo twice daily for 3 days/week for up to 4 weeks, with weekly cryotherapy continued to week 12 if required. Further treatment from week 12 to 24 was discretionary. Patients were stratified by sex and history of warts. HIV positivity, warts treated in the past 4 months, or warts with a combined area of less than 10 mm(2) were exclusion criteria. Primary endpoints were clearance at weeks 4 and 12. RESULTS: 70 patients per group were randomly assigned and started treatment; 101 first-episode warts, 91 male. No treatment-related serious adverse events were reported. Follow-up at week 12 was 85%. By intention-to-treat analysis, clearances at 4 and 12 weeks were higher in the combination group (60.0% and 60.0%, respectively) than with cryotherapy alone (45.7%, 45.7%) although not statistically significant (RR 1.31, 95% CI 0.95 to 1.81). By week 24 there was no difference between the groups (68.6% and 64.3%, respectively; RR 1.07, CI 0.84 to 1.35). At week 4, wart clearance was higher in men (p = 0.001) and those with a past history of warts (p = 0.009), but these differences were not detected at week 12. There was some evidence for a higher relapse rate in the group receiving cryotherapy alone. CONCLUSIONS: Initial combination therapy with podophyllotoxin/cryotherapy was well tolerated and may have resulted in earlier clearance in some patients, compared with cryotherapy alone; however, overall differences in clearance rates were not statistically significant.

Estimation of the impact of genital warts on health-related quality of life.

OBJECTIVES: One of the two new human papillomavirus (HPV) vaccines protects against HPV types 6 and 11, which cause over 95% of genital warts, in addition to protecting against HPV types 16 and 18. In anticipation of HPV vaccine implementation, the impact of genital warts on health-related quality of life (HRQoL) was measured to assess the potential benefits of the quadrivalent over the bivalent vaccine. METHODS: Genitourinary medicine clinic patients aged 18 years and older with a current diagnosis of genital warts were eligible; 81 consented and were interviewed by a member of the research team. A generic HRQoL questionnaire, the EQ-5D (comprising EQ-5D index and EQ visual analogue scale (VAS) scores) and a disease-specific HRQoL instrument, the CECA10, were administered. Previously established UK population norms were used as a control group for EQ-5D comparisons. RESULTS: Cases (with genital warts) had lower EQ VAS and EQ-5D index scores than controls. After adjusting for age a mean difference between cases and controls 30 years of age and under (n = 70) of 13.9 points (95% CI 9.9 to 17.6, p<0.001) for the EQ VAS and 0.039 points (95% CI 0.005 to 0.068, p = 0.02) on the EQ-5D index (also adjusted for sex) was observed. The difference between cases and controls for the EQ VAS was especially notable in young women. CONCLUSIONS: Genital warts are associated with a significant detriment to HRQoL. The potential added benefit of preventing most cases of genital warts by HPV vaccination should be considered in decisions about which HPV vaccine to implement in the United Kingdom.

Modulation of retino-collicular transmission by Group III metabotropic glutamate receptors at different ages during development.

Group III metabotropic glutamate receptors (especially mGlu4, mGlu7, mGlu8) are thought to be involved in modulating visual processing in the adult superior colliculus, a major termination site of retinal input in the rodent brain. We have investigated this role by making field EPSP recordings in response to optic tract stimulation in superior colliculus slices taken from rats aged from P14 to P180. Application of the Group III agonist L-AP4 at a concentration (10 microM) effective to activate mGlu4 and mGlu8 receptors, but not mGlu7 receptors, resulted in reductions of the field EPSP in all ages, although the effect was greatest in slices taken from P14 rats. Increasing the L-AP4 concentration to 100 microM so as to also activate mGlu7 receptors resulted in further field EPSP reductions. Similar reductions were seen in the combined presence of the GABA antagonists picrotoxin and CGP55845A, indicating a lack of involvement of GABAergic mechanisms in the action of L-AP4. Pairing of optic tract stimuli (20 ms separation) resulted in paired-pulse depression at all ages. L-AP4 was found to reduce paired-pulse depression at both 10 microM and 100 microM in slices from all ages of rat. The results of this study suggest that mGlu4/mGlu8 and mGlu7 receptors modulate retino-tectal transmission via a presynaptic mechanism, and that these effects are greatest in young animals. This is the first demonstration of a functional change in Group III receptor effect with aging, and this would be consistent with developmental regulation of these receptors.

GABA(B) receptors at glutamatergic synapses in the rat striatum.

Although multiple effects of GABA(B) receptor activation on synaptic transmission in the striatum have been described, the precise locations of the receptors mediating these effects have not been determined. To address this issue, we carried out pre-embedding immunogold electron microscopy in the rat using antibodies against the GABA(B) receptor subunits, GABA(B1) and GABA(B2). In addition, to investigate the relationship between GABA(B) receptors and glutamatergic striatal afferents, we used antibodies against the vesicular glutamate transporters, vesicular glutamate transporter 1 and vesicular glutamate transporter 2, as markers for glutamatergic terminals. Immunolabeling for GABA(B1) and GABA(B2) was widely and similarly distributed in the striatum, with immunogold particles localized at both presynaptic and postsynaptic sites. The most commonly labeled structures were dendritic shafts and spines, as well as terminals forming asymmetric and symmetric synapses. In postsynaptic structures, the majority of labeling associated with the plasma membrane was localized at extrasynaptic sites, although immunogold particles were also found at the postsynaptic specialization of some symmetric, putative GABAergic synapses. Labeling in axon terminals was located within, or at the edge of, the presynaptic active zone, as well as at extrasynaptic sites. Double labeling for GABA(B) receptor subunits and vesicular glutamate transporters revealed that labeling for both GABA(B1) and GABA(B2) was localized on glutamatergic axon terminals that expressed either vesicular glutamate transporter 1 or vesicular glutamate transporter 2. The patterns of innervation of striatal neurons by the vesicular glutamate transporter 1- and vesicular glutamate transporter 2-positive terminals suggest that they are selective markers of corticostriatal and thalamostriatal afferents, respectively. These results thus provide evidence that presynaptic GABA(B) heteroreceptors are in a position to modulate the two major excitatory inputs to striatal spiny projection neurons arising in the cortex and thalamus. In addition, presynaptic GABA(B) autoreceptors are present on the terminals of spiny projection neurons and/or striatal GABAergic interneurons. Furthermore, the data indicate that GABA may also affect the excitability of striatal neurons via postsynaptic GABA(B) receptors.

Hepatitis B virus reactivation or reinfection associated with HIV-1 infection.

Following acute hepatitis B virus (HBV) infection, most individuals develop antibodies to HBV surface (anti-HBs) and core antigen (anti-HBc). Prevalence studies have shown that 10-18% develop anti-HBc in the absence of detectable anti-HBs. We report four such cases, all with persistence of serum anti-HBc, who had evidence of a second period of active HBV replication as demonstrated by the reappearance of serum hepatitis B surface antigen (HBsAg). In one patient, an HBsAg subtype difference indicated that the second period of HBsAg-positivity was due to a reinfection. In the other cases, reactivation may also explain the findings. All cases were anti-HIV-1 seropositive at the time of reappearance of HBsAg. There is experimental evidence that anti-HBc has a protective effect against HBV infection; however, this may require intact cell-mediated immunity to be effective. HIV-1 infection may render such patients susceptible to reinfection. Alternatively, some patients with anti-HBc, but without detectable anti-HBs may have latent HBV infection. Immunosuppression associated with HIV-1 infection may allow reactivation.

New rapid latex agglutination test for diagnosing Trichomonas vaginalis infection.

A newly developed latex agglutination test for Trichomonas vaginalis infection was compared for sensitivity, specificity, efficiency, and positive and negative predictive values with microscopy, culture, and an enzyme linked immunosorbent assay (ELISA) in the diagnosis of 395 women attending a genitourinary medicine clinic. T vaginalis infection was diagnosed in 42 (11%) women. The sensitivities of both the latex agglutination test and the ELISA were 95% compared with 74% for microscopy and 76% for culture. The latex test was specific and showed no cross reaction with a wide range of other genital tract infections. The latex agglutination test can detect antigen in both soluble and insoluble forms, and as it is simple to perform, can be undertaken during routine examination without recourse to special equipment or training. Further evaluation is required.

Microsporidial keratoconjunctivitis in a patient with AIDS.

A male patient is described with acquired immune deficiency syndrome (AIDS) who developed chronic keratoconjunctivitis and chronic sinusitis due to infection with the microsporidian Encephalitozoon cuniculi. Diagnosis was confirmed by electron microscopic examination of conjunctival epithelial cells and nasal polypectomy specimens. Treatment with propamidine isethionate 0.1% (Brolene) eye drops six times daily led to a prompt resolution of the keratoconjunctivitis.

Laboratory indices of prognosis in HIV infection.

The progression of a HIV seropositive patient from an asymptomatic infection or persistent generalised lymphadenopathy to AIDS is dependent on many factors. The most useful prognostic indicators appear to be CD4 + lymphocyte count, beta 2-microglobulin level, anti-p24 antibody titre and p24 antigenaemia. The use of a combination of prognostic indices can enhance the accuracy of the prediction.

The treatment of human papillomavirus lesions of the lower genital tract.

Anogenital warts are caused by human papillomavirus types 6 and 11 infection, and are the most common clinical manifestation of lower genital tract human papillomavirus infection. They are the most frequently recognized sexually transmitted disease in the developed world, occurring at an incidence rate of 0.5-1.2% in young men and women aged 18-25 years. Many therapies for genital warts have been described, none being ideal in that all therapeutic modalities fail to clear the warts in a proportion of patients, and the recurrence of warts after successful treatment is seen with all treatments. The current knowledge base of the therapy of genital warts is flawed by a lack of good natural history data either with treatment or without treatment over longer periods of time, in that most trials report comparisons of monotherapies over a short time and there is a lack of structured trials addressing consecutive therapies over longer durations, as occurs in real-life clinical situations.

Human papillomavirus type 31 infection of the uterine cervix in England.

A total of 452 uterine cervical scrapes, from two centres in England, has been examined by dot blot hybridisation for the presence of human papilloma virus (HPV) types 6, 11, 16, 18 and 31. HPV DNA was found in 36.5% samples. Twenty-nine of the women were infected with more than one type. Of those with detectable HPV, 14.5% had HPV type 31 infections. This type appears to cause significant infection of the genital tract in England.

The oncogenic potential of Candida in the female genital tract.

The possible role of Candida species in carcinogenesis at the uterine cervix was investigated in 226 females attending a colposcopy clinic. Approximately 34% of the 226 subjects harbored Candida species in cervical/vaginal secretions, but there was no association with any particular histologic abnormality. Two independent analytical procedures were used for strain discrimination of the isolates of C. albicans, but again no relationship was found between individual strains and histologic diagnoses. Only three C. glabrata strains were isolated, but they were all in association with cervical intraepithelial neoplasia (CIN) II or III. A total of 18 strains of C. albicans, one C. glabrata and one C. parapsilosis all inhibited the formation of the nitrosamine nitrosodimethylamine (NDMA) from precursors. Furthermore, C. albicans strains did not convert NDMA to carcinogenic metabolites. The results of this study do not suggest that C. albicans has a role in cervical carcinogenesis.

Expression of cytochrome P450 enzymes in the cervix. An immunohistochemical study.

The expression of cytochrome P450 isoenzymes (subfamilies) CYP1A, CYP2B, CYP2C, CYP3A and CYP4A in the histologically normal cervix was explored using a panel of polyclonal antibodies. There was variation in the intensity of immunohistochemical reaction between the isoenzymes and between the various components of the cervix. Half the subjects tested were smokers and had increased urinary cotinine levels. Statistical analysis revealed no significant differences between smokers and nonsmokers in the expression of these isoenzymes. The implications of these observations in relation to cervical carcinogenesis are discussed.

A study to estimate the prevalence of upper respiratory tract papillomatosis in patients with genital warts.

Respiratory tract papillomas are associated with human papillomavirus (HPV) types 6 and 11; these HPV types are also commonly associated with genital warts (condyloma acuminata). Although most commonly seen in young children, the incidence of respiratory tract papillomas in young adults is increasing. It has been postulated that orogenital contact is the means of transmission in this age group. We performed a survey of adults with genital warts to assess the prevalence of respiratory tract papillomatosis in relation to sexual behaviour and other factors. Fifty-three adult patients (35 male, 18 female) with genital warts attending a genitourinary medicine clinic agreed to examination of the mouth and throat, including indirect laryngoscopy. Seventy per cent of the group had participated in oral sex. Two patients (3.8%) had lesions attributable to HPV infection of the oropharynx and larynx (one with laryngeal keratosis, one with papilloma of the pharynx). There was no specific risk factor identified to predict respiratory tract disease. In view of the high infectivity of genital warts, it is interesting to note the low prevalence of oropharyngeal warts in adults indulging in orogenital contact. Since malignant transformation is known in respiratory tract papillomas, we would recommend that any patient with genital warts who develops unexplained hoarseness has a specialist examination of the upper respiratory tract.

Audits of the treatment of genital warts: closing the feedback loop.

An initial audit of the treatment of patients presenting to the GUM Department at Leeds General Infirmary with a first episode of anogenital warts was reported in 1993. Treatment was found to be unselective and poorly monitored and the results of treatment were disappointing. As a consequence, guidelines for the management of new patients presenting with genital warts were devised. In order to establish whether these guidelines had produced any improvements in outcome, a second audit was performed looking at the results of treatment in patients with new genital warts who attended 6 months or more after the new guidelines were introduced. Progress was documented for 6 months after presentation. There was a significant fall in the numbers of patients receiving podophyllin 25% solution as first-line treatment, and corresponding increases in the initial use of cryotherapy, trichloracetic acid and, in men, podophyllotoxin solution. (Podophyllotoxin was not licensed for use in women at the time of the second audit.) There were significant improvements in the outcome of treatment. Originally 44% of men had warts despite receiving treatment for 3 months, and 32% were still attending for treatment 6 months after presentation. After the introduction of treatment guidelines, these figures had fallen to 8% and 3% respectively. In the first audit 38% of women still had warts after 3 months' treatment but in the second audit this figure was reduced to 18%. At 6 months, the percentage of women still attending for treatment was halved from 12% in the first audit to 6% in the second audit. The mean number of clinic visits fell from 5 to 3 in men and from 9 to 6 in women. The treatment protocols have been modified and now include the use of podophyllotoxin cream and solution in both men and women.