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.

Canterbury Health, Ageing and Life Course (CHALICE) study: rationale, design and methodology.

AIMS: New Zealand's ageing population threatens the financial sustainability of our current model of health service delivery. The Canterbury Health, Ageing and Life Course (CHALICE) study aims to develop a comprehensive and flexible database of important determinants of health to inform new models. This paper describes the design, methodology, and first 300 participants of CHALICE. METHODS: Commencing August 2010, CHALICE is a multidisciplinary prospective random cohort study and biobank of 1,000 Canterbury adults aged 49-51 years at inception, stratified by self-identified Maori (n=200) and non-Maori (n=800) ethnicity. Assessment covers sociodemographic, physical, cognition, mental health, clinical history, family and social, cardiovascular, and lifestyle domains. Detailed follow-up assessment occurs every 5 years, with a brief postal follow-up assessment undertaken annually. RESULTS: For the first 300 participants (44 Maori, 256 non-Maori), the participation rate is 63.7%. Overall, 53.3% of participants are female, 75.3% are living in married or de facto relationships, and 19.0% have university degrees. These sociodemographic profiles are comparable with the 2006 Census, Canterbury region, 50-54 years age group percentages (50.7%, 77.2%, and 14.3%, respectively). CONCLUSIONS: CHALICE has been designed to provide quality data that will inform policy development and programme implementation across a broad spectrum of health indicators.

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.

Sweet's syndrome in a patient with haemophilia, HIV and hepatitis C infection.

Sweet's syndrome is a rare skin condition associated with both drug treatment and a number of different disease processes including haematological malignancies, inflammatory conditions and HIV infection. In this case report, we present a patient with HIV, haemophilia and hepatitis C who presented to our team with significant thrombocytopaenia and Sweet's syndrome. We discuss the difficulties with diagnosis and management in the context of multiple co-morbidities and suggest that both hepatitis C and HIV may have been aetiologically involved by suppressing platelet production and also causing bone marrow-driven neutrophilic disease.

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.

Unacceptable side-effects associated with a hyperosmolar vaginal microbicide in a phase 1 trial.

We carried out a phase 1 trial of a candidate vaginal microbicide gel against HIV-1 and other sexually transmitted diseases, which contained cellulose acetate 1,2-benzenedicarboxylate (also known as cellulose acetate phthalate) in a glycerol-based vehicle. We had to terminate the study after five women had completed dosing, due to all women experiencing unacceptable vulvo-vaginal side-effects. Further investigations showed that the gel had a very high osmolality, which we believe led to excessive fluid transudation across the vaginal mucosa and acute mucosal dysfunction. We also showed that the rheology of the gel changed dramatically on fluid dilution. The osmolality and rheology of candidate microbicides and other genital mucosal products should therefore be analysed and considered at an early stage of product development.

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.

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.

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.

The interrelation of demographic and geospatial risk factors between four common sexually transmitted diseases.

OBJECTIVES: To examine the interrelation between demographic and geospatial risk factors for gonorrhoea, chlamydia, genital warts, and genital herpes. DESIGN: We analysed age, sex, ethnicity, socioeconomic status, and area of residence for Leeds residents aged 15-54 with Neisseria gonorrhoeae, genital Chlamydia trachomatis, first episode genital herpes, and first episode genital warts during 1994-5. The 1991 UK census provided denominator population information. RESULTS: Regression analysis showed that young age (15-24 years), ethnicity (with a gradient of risk black >white >Asian), and residence in inner city areas of deprivation were independent risk factors for all STDs. There were highly significant correlations in the geospatial distribution of incidence rates between the four infections. However, there was variation in the degree of central urban clustering, with gonorrhoea having the most restricted, and genital warts and chlamydia the widest distribution. 31% of all disease occurred in the four inner city census wards, representing 15% of the population. CONCLUSION: These results are in keeping with core group theory applying in a unified manner to the four most common UK sexually transmitted diseases in this urban area. Population based studies are needed to clarify whether ethnicity is associated with differing sexual behavioural or mixing patterns. Our data suggest that chlamydia screening in women <25 years of age could detect 70% of cases in the community, that such programmes should give particular emphasis to implementation in core group areas, and that they could function as unifying strategies for the control of most common STDs within urban areas.

Concurrent granulomatous Pneumocystis carinii and Mycobacterium xenopi pneumonia: an unusual manifestation of HIV immune reconstitution disease.

This report of concurrent granulomatous Pneumocystis carinii pneumonia (GPCP) and Mycobacterium xenopi pneumonia (MXIP) in a patient with advanced HIV disease 3-5 weeks after commencing antiretroviral therapy (ART) fits the syndrome of HIV immune reconstitution/restoration disease (IRD). It may also be a unique window into the immunology of granulomatous inflammation.

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.

Labial tuberculosis: a unique cause of lip swelling complicating HIV infection.

BACKGROUND: HIV disease has many oral manifestations including tuberculosis, which most commonly presents as irregular ulceration of the tongue or the palate. We detail an HIV-infected patient found to have tuberculosis of the lip. CONCLUSIONS: To our knowledge tuberculosis of the lips has never been reported in conjunction with HIV infection, and in this case establishing the oral diagnosis resulted in the diagnosis of disseminated disease.

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.