Acceptability, feasibility and costs of universal offer of rapid point of care testing for HIV in an acute admissions unit: results of the RAPID project.

OBJECTIVES: UK guidance recommends that acute medical admissions are offered an HIV test. Our aim was to determine whether a dedicated staff member using a multimedia tool, a model found effective in the USA, is an acceptable, feasible, and cost-effective model when translated to a UK setting. METHODS: Over 4 months in 2010, a health advisor (HA) approached 19-65-year-olds at a central London acute medical admissions unit and offered a rapid HIV point of care test (POCT) with the aid of an educational video. Feasibility and acceptability were assessed through surveys and uptake rates. Costs per case of HIV infection identified were established. RESULTS: Of the 606 eligible people admitted during the pilot, 324 (53.5%) could not be approached or were individuals for whom testing was deemed inappropriate. In total, 23.0% of eligible admissions had an HIV POCT. Of the patients who watched the video and had not recently been tested for HIV, 93.6% (131 of 140) agreed to an HIV test; four further patients had an HIV test but did not watch the video. Three tests (2.2%; three of 135) were reactive and all were confirmed HIV positive on laboratory testing. HIV testing in this setting was felt to be appropriate by 97.5% of individuals. The cost per patient was £21, and the cost per case of HIV identified was £1083. CONCLUSIONS: Universal POCT HIV testing in an acute medical setting, facilitated by an educational video and dedicated staff, appears acceptable, feasible, effective, and low cost. These findings support the recommendation of HIV testing for all medical admissions in high-prevalence settings, although with this model a significant proportion remained untested.

Prognostic utility of pre-operative circulating osteopontin, carbonic anhydrase IX and CRP in renal cell carcinoma.

BACKGROUND: Objectively measured circulating biomarkers of prognosis complementing existing clinicopathological models are needed in renal cell carcinoma (RCC). METHODS: Blood samples collected from 216 RCC patients in Leeds before nephrectomy (median follow-up 7 years) were analysed for C-reactive protein (CRP), osteopontin (OPN) and carbonic anhydrase IX (CA9) and prognostic significance determined. RESULTS: CA9, OPN and CRP were univariately prognostic for overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) with CRP and CA9 being independently prognostic for OS/CSS and OS, respectively. Including CA9, OPN and CRP with other conventional prognostic factors gave a superior predictive capacity when compared with a previously published pre-operative clinical nomogram (Karakiewicz et al, 2009). Osteopontin outperformed this nomogram and the post-operative SSIGN score for OS but not for CSS, being significantly predictive for non-cancer deaths. Osteopontin, CRP and CA9 outperformed stage (c-index 76% compared with 70% for stage) and OPN or CA9 identified several subsets of poor prognosis patients including in T1 patients, who may benefit from adjuvant therapy and increased surveillance. CONCLUSION: Circulating CA9, OPN and CRP add value to existing clinicopathological prognostic factors/models and support further studies to investigate their potential use in improving the clinical management of RCC.

Improving the accuracy of pre-operative survival prediction in renal cell carcinoma with C-reactive protein.

BACKGROUND: Validated objective biomarkers are needed for patients with renal cell carcinoma (RCC) to guide patient management and define high-risk populations for follow-up or for therapeutic purposes. METHODS: Patients undergoing nephrectomy for RCC (n=286 all stages, 84% with conventional clear cell type) were included with a median duration follow-up of 5 years. The prognostic significance of pre-operative haematological and biochemical variables, including C-reactive protein (CRP) values were examined and whether they added additional information to a recently published pre-operative scoring system was determined. RESULTS: C-reactive protein was the most significant predictor of overall survival (OS; χ(2)=50.9, P<0.001). Five-year OS for patients with CRP ≤ 15 mg l(-1) vs >15 mg l(-1) was 72% (95% CI 65-78%) and 33% (95% CI 23-44%), respectively. Similar results were seen for cancer-specific survival (CSS) and disease-free survival. On multivariate analysis, CRP remained highly significant for CSS (χ(2)=17.3, P<0.0001) and OS (χ(2)=9.8, P<0.002), in addition to other pre-operative variables including log of neutrophil/lymphocyte ratio, red blood cell count and white cell count. C-reactive protein was significant in addition to the pre-operative nomogram score (χ(2)=12.5, P=0.0004 for OS, χ(2)=16.2, P=0.0001 for CSS and χ(2)=8.6, P=0.003 for DFS) and was still significant when other pre-operative variables were included. CONCLUSION: C-reactive protein and other haematological and biochemical variables have independent prognostic significance in RCC and may enhance pre-operative scoring systems.

A comparison of computed tomography and magnetic resonance brain imaging in HIV-positive patients with neurological symptoms.

We reviewed our practice in order to determine the optimum neuroimaging strategy for HIV-infected patients with acute neurological presentations between April 2007 and August 2008. Overall magnetic resonance imaging (MRI) detected cranial abnormalities in more than twice as many patients as did computed tomography (CT) (74% and 32%, n = 54 and 38, respectively). Replacement of CT by first-line MRI for all patients would have required an additional 16 MRI scans, although at a saving of 38 CT scans. Our study highlights the importance of first-line MRI brain imaging in HIV patients with neurological symptoms and reinforces the need for early transfer of patients from centres that do not have rapid access to (or expert interpretation of) MRI scanning, to an appropriate HIV specialist centre.

Pre-operative urinary cathepsin D is associated with survival in patients with renal cell carcinoma.

BACKGROUND: No circulating markers are routinely used for renal cancer. The objective of this pilot study was to investigate whether conditioned media (CM) from renal cancer cell lines contains potential biomarkers that, when measured in clinical fluids, have diagnostic or prognostic utility. METHODS: Comparative 2D PAGE profiling of CM from renal cell carcinoma (RCC) and normal renal cultures identified cathepsin D that was subsequently validated in urine samples from 239 patients and healthy and benign disease subjects. RESULTS: Urinary cathepsin D was found to be significantly associated with overall (OS) (hazard ratio, HR, 1.33, 95%CI [1.09-1.63], P=0.005) and cancer-specific survival (HR 1.36, 95%CI [1.07-1.74], P=0.013) in RCC patients on univariate analysis. An optimal cut point (211 ng ml(-1) micromolCr(-1)) around which to stratify patients by OS was determined. Five-year OS equal to/above and below this value was 47.0% (95%CI 35.4%, 62.4%) and 60.9% (48.8%, 76.0%), respectively. On multivariable analysis using pre-operative variables, cathepsin D showed some evidence of independent prognostic value for OS (likelihood ratio test P-value=0.056) although requiring further validation in larger patient numbers with sufficient statistical power to determine independent significance. CONCLUSION: These data establish an important proof of principle and show the potential of proteomics-based studies. Cathepsin D may be of value as a pre-operative urinary biomarker for RCC, alone or in combination.

Improvements in cheek volume in lipoatrophic individuals switching away from thymidine nucleoside reverse transcriptase inhibitors.

BACKGROUND: Thymidine nucleoside reverse transcriptase inhibitors (NRTIs) are associated with subcutaneous fat loss. Facial changes cannot be assessed by dual-energy X-ray absorptiometry (DEXA) scans. There are limited objective data on the reversibility of facial lipoatrophy. METHODS: We performed a facial volume substudy of a randomized thymidine NRTI replacement study carried out in HIV-infected subjects with moderate to severe lipoatrophy. Facial volume changes were assessed using validated 3D laser imaging. Changes in body composition were measured using DEXA scans. The association between changes in facial volume and body composition parameters at 48 weeks was measured using Spearman's rank correlation. RESULTS: Forty-seven individuals (46 male), 11 receiving zidovudine and 36 receiving stavudine, switched to either tenofovir disoproxil fumarate (DF) (n=23) or abacavir (ABC) (n=24). Thirty-nine of these 47 patients (84.8%) reported facial lipoatrophy at baseline. The median volume increase in both cheeks from baseline was 1857.3 mm(3). These volume changes and increases in limb fat at 48 weeks were similar in the two groups and correlated significantly (Spearman's r=0.41, P=0.004). CONCLUSIONS: Facial volume in lipoatrophic individuals was found to increase after thymidine NRTI replacement. We demonstrated a significant correlation between improvements in facial and limb fat parameters. Switching from thymidine NRTIs in patients with facial lipoatrophy could potentially reduce the need for cosmetic interventions.

Outcome from treatment of Pneumocystis jirovecii pneumonia with co-trimoxazole.

A retrospective case-notes audit of 359 HIV-1-infected adult patients with first-episode laboratory-confirmed Pneumocystis jirovecii pneumonia treated with co-trimoxazole (from 1987 adjuvant steroids were used if PaO(2) <9.3 kPa) showed that only 230/359 (64%) patients completed treatment; 104 (29%) patients had treatment-limiting toxicity; rash occurred in 4/60 (6.7%) patients in 1985-1988 and in 15/47 (31.9%) in 2005-2008. Twenty-five patients (7%) failed co-trimoxazole treatment. Overall mortality was 13.6% (49/359); mortality among patients who failed co-trimoxazole treatment was 48% (12/25) and by contrast mortality was 4.8% (5/104) among patients with treatment-limiting toxicity.

Tackling STI epidemics through the HIV clinic: is sex high enough on the agenda?

Sexually transmitted infection (STI) rates among men having sex with men continue to increase. HIV services may operate independently to genitourinary medicine clinics and the sexual health of HIV-positive patients may be of low priority in the context of medical problems related to HIV. A prospective study of HIV-positive gay men was conducted in a London outpatient clinic over a three-month period. Data were available for 90 men. Forty-five percent had STI screens in the preceding six months. These revealed a high rate of infections; 26 infections diagnosed in 14 men in the study period. Fifty-seven percent of the 90 men in the study had more than one partner in the past three months and approximately one-third had unprotected sexual activity. A significant proportion of men were unaware of recent outbreaks of hepatitis C and lymphogranuloma venereum and of HIV postexposure prophylaxis. We therefore recommend that sexual history-taking, STI screens and health promotion should become a routine feature of HIV outpatient consultations in this group.

Immune reconstitution sarcoidosis presenting with hypercalcaemia and renal failure in HIV infection.

An HIV-positive white man developed hypercalcaemia and renal failure 15 months after starting highly active antiretroviral therapy. Investigations showed systemic sarcoidosis affecting parotids, skin and kidneys. This presentation was thought to be a manifestation of immune reconstitution inflammatory syndrome, and the patient was successfully treated with corticosteroid therapy.

Dissemination of Strongyloides stercoralis as an immune restoration phenomenon in an HIV-1-infected man on antiretroviral therapy.

We present a case of Strongyloides stercoralis infection in an HIV-infected man, resulting in Escherichia coli meningitis after initiation of antiretroviral therapy. Recent evidence from studies of strongyloides development supports the concept that strongyloides dissemination in this case is an example of an immune reconstitution inflammatory syndrome.

Significant benefit of a targeted HIV testing module on medical students' knowledge and confidence.

The objective was to evaluate the efficacy of a HIV targeted-testing teaching session in improving knowledge and confidence at a London medical school. A survey assessing knowledge of HIV testing guidelines, confidence to offer testing and outcomes of targeted-testing teaching was developed and distributed to fifth year medical students. Results were compared for students who had completed GU/HIV modules (GU+) and those who had not (GU-) and chi-squared testing was performed; 100 and 119 questionnaires were returned by GU+ and GU- students (response rate of 92.6% and 97.5%), respectively. For the three knowledge-based questions, GU+ students were significantly more likely to provide correct answers for two (p < 0.001). Similarly, they were significantly more likely to feel confident in offering an HIV test (p < 0.001). After targeted-testing teaching 92%, 98% and 62% felt more confident about when to test, how to discuss testing and more knowledgeable about testing, respectively. Most students were happy to offer HIV testing in different medical settings; significantly fewer reported this for an acute admissions unit compared with antenatal clinic (79% vs 96%). Students who had received targeted-testing teaching demonstrated better knowledge and confidence about HIV testing. We hope this study raises awareness of the need to include HIV testing teaching in medical school curricula.

A survey of how and why medical students and junior doctors choose a career in ENT surgery.

OBJECTIVE: To ascertain determinants of an interest in a career in ENT surgery through a survey of medical students and junior doctors. METHODS: A survey was administered, comprising Likert scales, forced response and single option questions, and free text responses, at five different courses or events for those interested in a career in ENT. RESULTS: The survey had an 87 per cent response rate; respondents consisted of 43 applicants for national selection, 15 foundation doctors and 23 medical students. The most important factors that encourage ENT as a career included: the variety of operative procedures, work-life balance, inherent interest in this clinical area and inspirational senior role models. Exposure to ENT in undergraduate or post-graduate training is critical in deciding to pursue this specialty. CONCLUSION: It is important to promote those aspects of ENT surgery that attract people to it, and to argue for greater exposure to ENT during undergraduate and post-graduate training.

Itraconazole cyclodextrin solution: the role of in vitro susceptibility testing in predicting successful treatment of HIV-related fluconazole-resistant and fluconazole-susceptible oral candidosis.

OBJECTIVES: This study assessed the ability of in vitro susceptibility testing of clinical Candida isolates to predict in vivo response to itraconazole cyclodextrin solution. METHODS: One hundred specimens were obtained from HIV-positive patients with oral thrush, of which 72 speciments were from patients who were clinically unresponsive to fluconazole at standard doses and had fluconazole-resistant isolates in vitro. Susceptibility to itraconazole was assessed by measuring the relative growth of an isolate in liquid medium containing a single concentration of itraconazole and then expressing growth in itraconazole as a percentage of growth in antifungal-free medium. RESULTS AND CONCLUSIONS: Where specimens yielded only one isolate, a cut-off relative growth in itraconazole of 68% discriminated between isolates from patients failing to respond clinically to itraconazole solution and those from patients successfully treated with the preparation (specificity 100%; sensitivity 88%). The presence of mixed infection reduced the predictive accuracy of the test. Only 30% of fluconazole-resistant isolates were cross-resistant to itraconazole. No isolates were resistant to itraconazole but susceptible to fluconazole. Non-response to itraconazole solution was attributed to resistant yeast infection in the majority of cases, and this susceptibility method accurately identified specimens from patients unlikely to respond to the drug.

Clinically significant azole cross-resistance in Candida isolates from HIV-positive patients with oral candidosis.

OBJECTIVES: To determine the proportion of fluconazole-resistant Candida albicans isolates that have clinically significant cross-resistance to itraconazole or ketoconazole, that is sufficient to result in failure of these agents at their standard doses (200 and 400 mg daily for 7 days, respectively). METHODS: Seven hundred C. albicans isolates from HIV-positive patients with oral candidosis underwent susceptibility testing using a relative growth method, for which cut-off values corresponding to clinical drug failure have been established. RESULTS: A total of 431 isolates were fully azole-susceptible and three main resistance patterns were detected: isolates resistant to fluconazole alone (n = 100); isolates resistant to fluconazole and ketoconazole but susceptible to itraconazole (n = 94); and isolates resistant to all three drugs (n = 50). No isolates were consistently resistant to ketoconazole without being fluconazole-resistant, and no itraconazole resistance was detected without ketoconazole resistance. Resistance to fluconazole alone was more common in specimens obtained soon after first clinical fluconazole failure, whereas specimens from patients with a longer history of fluconazole-unresponsive candidosis were more likely to be infected with cross-resistant isolates. Median days of prior azole exposure and cumulative fluconazole dose were significantly less for those with isolates resistant to fluconazole alone than for those with ketoconazole cross-resistant isolates, who had received less azole therapy and smaller cumulative fluconazole doses than those with isolates cross-resistant to all three drugs (although not statistically significant). After the diagnosis of fluconazole-unresponsive candidosis, increasing cumulative doses of itraconazole solution were associated with increasing likelihood of cross-resistance. CONCLUSIONS: Clinically significant cross-resistance to other azoles may occur in fluconazole-resistant isolates of C. albicans, although initially most isolates are not cross-resistant and the detection of cross-resistant isolates is associated with a history of greater prior azole exposure. Patients who have been treated for fluconazole-resistant candidosis for longer and with greater cumulative doses of itraconazole solution tend to become infected with increasingly cross-resistant isolates of C. albicans.

The role of azoles in the treatment and prophylaxis of cryptococcal disease in HIV infection.

OBJECTIVE: To assess the role of azole therapy in the treatment and prophylaxis of cryptococcosis in HIV-seropositive individuals. STUDY DESIGN: Retrospective case review. SETTING: A dedicated HIV unit in London, UK. PATIENTS: Fifty individuals with a positive cryptococcal antigen or culture from any site between 1 January 1985 and 31 December 1992. RESULTS: Thirty-eight patients initially presented with meningitis and 12 with alternative disease, five of whom subsequently developed meningeal disease. The 12 patients who presented without meningitis received chronic suppressive therapy after the diagnosis of cryptococcal disease. Two patients receiving itraconazole developed meningitis as did three out of four treated with 200 mg fluconazole daily, but none of the six receiving 400 mg fluconazole daily. Treatment of cryptococcal meningitis was successful in 17 of the 19 patients given fluconazole but only three of the six receiving itraconazole. Following successful treatment of meningitis five out of seven patients given itraconazole and five out of seven given 200 mg fluconazole daily relapsed compared with three out of 25 receiving 400 mg fluconazole daily. CONCLUSION: Fluconazole is an effective treatment for cryptococcal meningitis. For prophylaxis following meningitis, a dose of 400 mg fluconazole is the preferred treatment; lower doses are associated with a higher relapse rate.

A dose comparison study of a new triazole antifungal (D0870) in HIV-positive patients with oral candidiasis.

OBJECTIVE: This multicentre study evaluated the clinical efficacy and tolerability of D0870 in treating oropharyngeal candidiasis in HIV-positive patients who had no history of clinical resistance to fluconazole. METHODS: Three regimens were evaluated in two phases. In phase I a 50 mg initial dose was followed by 10 mg for 4 days (Group 1). In phase II a 100 mg initial dose was followed by 25 mg for 4 days (Group 2), or 10 mg for 5 days (Group 3). RESULTS: Clinical cure was obtained in 27 patients of a total of 35 (77%) and six other patients improved (17%). Two patients at the lowest dose failed and both had very low plasma concentration of D0870. No association was found between clinical outcome; minimum inhibitory concentration of D0870 pre-therapy for Candida albicans, maximum recorded plasma D0870 concentration, cfu of culture or CD4 cell count at entry. Overall, 37% of the patients experienced relapse during the 2 weeks post therapy. Tolerance was excellent. Mild adverse events possibly related to the study drug were recorded in five patients. CONCLUSION: D0870 demonstrates excellent efficacy at low doses in the treatment of HIV-related OPC and exhibits a favourable safety profile.

Treatment of HIV-related fluconazole-resistant oral candidosis with D0870, a new triazole antifungal.

OBJECTIVES: To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal candidosis. DESIGN: Multicentre open study. PATIENTS: HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more. METHODS: Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 days. Symptoms and signs of candidosis were compared at entry and on days 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates. Limited pharmacokinetic samples were taken on days 1 and 7. RESULTS: Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, three of whom were receiving concomitant therapy known to suppress bone marrow. Three patients reported headaches as adverse events that were attributed to study medication, but D0870 was well tolerated overall. CONCLUSIONS: D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal candidosis and was well tolerated, although efficacy in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered.

Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis.

AIMS: To compare the serum concentrations of itraconazole and hydroxyitraconazole after treatment with itraconazole cyclodextrin solution and itraconazole capsules in human immunodeficiency virus (HIV) positive patients with oral candidosis. METHODS: The pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole were assessed on days 1 and 7 of therapy in acquired immunodeficiency syndrome (AIDS) patients with oral candidosis taking either itraconazole solution or capsules and the serum concentrations (measured by high performance liquid chromatography) correlated with the clinical response to therapy. In addition, the in vitro susceptibility of Candida spp isolates taken from patients at the start of the therapy was assessed. RESULTS: Nine of 16 patients treated with itraconazole capsules and eight of 15 treated with the solution responded to treatment. Three of the non-responders in each treatment group were infected with isolates resistant to itraconazole in vitro. Although with both preparations there was considerable inter-patient variability in the maximum recorded serum concentrations of itraconazole, they were significantly lower on day 1 and day 7 in those receiving capsules compared with those taking the solution. Patients unresponsive to therapy, but infected with susceptible isolates, had significantly lower concentrations of itraconazole and hydroxyitraconazole levels on days 1 and 7 than patients responding to treatment. However, patients infected with itraconazole resistant isolates (tested in vitro) failed to respond to treatment despite achieving similar serum concentrations of itraconazole and hydroxy-itraconazole to the responsive patients. For patients with in vitro susceptible isolates a serum itraconazole concentration of < 1000 ng/ml on day 7 was predictive of therapeutic failure (specificity 71%, sensitivity 100%). CONCLUSIONS: Itraconazole cyclodextrin solution achieves higher serum itraconazole and hydroxy-itraconazole concentrations than the capsule formulation in AIDS patients, and this is associated with improved efficacy.

Management of pulmonary aspergillosis in AIDS: an emerging clinical problem.

AIMS: To review the clinical, radiographic, and therapeutic features of 11 cases of respiratory Aspergillus infection in patients with AIDS. METHODS: All induced sputum and bronchoalveolar lavage samples obtained from HIV seropositive patients between January 1985 and March 1993 were analysed for Aspergillus species. Additionally, where appropriate, bronchial or renal biopsy specimens, or both, were taken before treatment had started. RESULTS: In 11 patients Aspergillus fumigatus was identified in alveolar samples obtained by sputum induction. This was confirmed by bronchoalveolar lavage in eight. Three patients had Aspergillus plaques in the trachea and bronchus, while a fourth patient had an aspergilloma. Risk factors for Aspergillus infection were present in all patients, including corticosteroid treatment in three cases and neutropenia in four, three of whom had received chemotherapy for Kaposi's sarcoma. Four patients had concomitant cytomegalovirus infection. Ten patients had a CD4 count of less than 50 cells/mm3 while one patient had a disseminated T cell lymphoma with a CD4 count of 242 cells/mm3. Of the three patients with samples obtained by sputum induction who did not undergo bronchoscopy, two had a normal chest x ray picture and the third had a right lobar pneumonia complicating an aggressive lymphoma. All three were treated with itraconazole 200 mg twice a day without further investigation. Survival from the time of diagnosis of Aspergillus infection was short: seven patients died within six weeks, although only one death was directly attributed to pulmonary aspergillosis. At six monthly follow up, one patient, who initially had a positive Aspergillus culture from bronchial washings and a normal chest radiograph, developed a renal aspergilloma despite the disappearance of Aspergillus sp from the sputum. CONCLUSION: Pulmonary aspergillosis is an important clinical problem in patients with AIDS with a CD4 count of less than 50 cells/mm. Furthermore, patients with Aspergillus sp in sputum induction or bronchial washings may develop disseminated disease despite adequate treatment of the primary infection.