S Tariq Sadiq

Missed opportunities for earlier HIV diagnosis within primary and secondary healthcare settings in the UK

Objective: To identify opportunities for earlier HIV diagnosis within primary and secondary care settings in the UK in Africans with newly diagnosed HIV infection. Methods: A survey of newly diagnosed HIV-positive Africans attending 15 HIV treatment centres across London was conducted between April 2004 and February 2006. The survey consisted of a confidential self-completed questionnaire linked to clinician-completed clinical records. Results: A total of 263 questionnaires were completed, representing an uptake rate of 79.5% of patients approached and 49.8% (131/263) of participants presented with advanced HIV disease (CD4 cell count < 200 cells/μl at diagnosis). In the year prior to HIV diagnosis 76.4% (181/237) had seen their GP, 38.3% (98/256) had attended outpatient services, and 15.2% (39/257) inpatient services, representing missed opportunities for earlier HIV diagnosis. Of those attending GP services the issue of HIV and/or HIV testing was raised for 17.6% (31/176) and 37.1% (78/210) had a previous negative HIV test, 32.5% of these within the UK. Medical attention was sought for wide ranging reasons, often not obviously connected to underlying HIV status. Despite the population predominantly coming from countries of high HIV prevalence personal appreciation of risk was comparatively low and knowledge of benefits of testing lacking. Conclusion: Africans are accessing health services but clinicians are failing to use these opportunities effectively for preventive and diagnostic purposes with regards to HIV infection. Comparatively low appreciation of personal risk and lack of perceived ill health within this community means clinicians need to be more proactive in addressing HIV.

Tenofovir-linked hyperparathyroidism is independently associated with the presence of vitamin D deficiency.

Background:To determine patient and treatment characteristics associated with vitamin D deficiency (VDD) in an UK inner city HIV-1-positive adult cohort. Methods:Two hundred twenty-seven HIV-positive patients attending prospectively for routine blood tests in winter had serum 25-hydroxyvitamin D and parathyroid hormone (PTH) concentrations and other routine chemistry measured. Those with and without VDD were defined as having serum 25-hydroxyvitamin D concentrations <50 nmol/L and >75 nmol/L, respectively. Characteristics were compared between patients with and without VDD. The effects of VDD, tenofovir use, and their interaction on chemical measures were investigated. Results:VDD was found in 57% (131 of 227) of patients. Independent associations included nonwhite ethnicity [adjusted odds ratio (95% confidence interval): 7.40 (2.52 to 21.7)], higher random blood glucose [2.38 (1.24 to 4.57) per mmol/L], higher estimated glomerular filtration rate [eGFR: 1.04 (1.01 to 1.06)], and higher PTH [1.19 (1.00 to 1.42)]. PTH was higher in those receiving tenofovir (median 7.2 pmol/L) than other patients (4.3; P < 0.001) overall, but high PTH with tenofovir occurred only in the context of VDD. Tenofovir use was not associated with serum creatinine or eGFR overall but interacted with vitamin D status (P = 0.05 and P = 0.08, respectively), being linked to somewhat higher creatinine and lower eGFR among patients without VDD but higher eGFR in VDD patients. Conclusions:25(OH) VDD is associated with tenofovir-linked hyperparathyroidism and also with higher eGFR.

Frequency and risk factors for prevalent, incident, and persistent genital carcinogenic human papillomavirus infection in sexually active women: community based cohort study

Objective To investigate frequency and risk factors for prevalent, incident, and persistent carcinogenic human papillomavirus (HPV) in young women before the introduction of immunisation against HPV types 16 and 18 for schoolgirls. Design Cohort study Setting 20 London universities and further education colleges. Participants 2185 sexually active female students, mean age 21 years (range 16-27), 38% from ethnic minorities, who took part in the POPI (prevention of pelvic infection) chlamydia screening trial in 2004-08 and who provided duplicate, self taken vaginal swabs and completed questionnaires at baseline. At follow-up, a median of 16 months later, 821 women (38%) returned repeat vaginal swabs by post. In 2009-10, stored samples were tested for HPV. Results Samples from 404/2185 (18.5% (95% CI 16.9% to 20.2%)) of the cohort were positive for carcinogenic HPV at baseline, including 15.0% (327) positive for non-vaccine carcinogenic genotypes. Reporting two or more sexual partners in the previous year and concurrent Chlamydia trachomatis or bacterial vaginosis were independent risk factors for prevalent vaginal HPV infection. Infection with one or more new HPV types was found in 17.7% (145/821) of follow-up samples, giving an estimated annual incidence of carcinogenic HPV infection of 12.9% (95% CI 11.0% to 15.0%). Incident infection was more common in women reporting two or more partners in the previous year, aged<20, of black ethnicity, or with C trachomatis vaginosis at baseline. Multiple partners was the only independent risk factor for incident infection (adjusted relative risk 1.99 (95% CI 1.46 to 2.72)). Of 143 women with baseline carcinogenic HPV infection, 20 (14% (8.3% to 19.7%) had infection with the same carcinogenic HPV type(s) detected after 12-28 months. Of these women, 13 (65%) had redetected infection with HPV 16 or 18, and nine (45%) with non-vaccine carcinogenic HPV genotypes. Conclusion In the first UK cohort study of carcinogenic HPV in young women in the community, multiple sexual partners was an independent predictor of both prevalent and incident infection. Infection with non-vaccine carcinogenic genotypes was common. Although current HPV vaccines offer partial cross protection against some non-vaccine carcinogenic HPV types, immunised women will still need cervical screening.

Pooling serum samples may lead to loss of potential biomarkers in SELDI-ToF MS proteomic profiling

BackgroundHigh throughput proteomic technology offers promise for the detection of disease biomarkers and proteomic signature patterns but biomarker discovery studies can be limited by cost factors when large sample size numbers are required. Pooling sera or plasma samples from disease cases potentially offers a solution to cost implications by reducing the standard errors of mass to charge values. Surface enhanced laser desorption/ionization time of flight (SELDI-ToF) mass spectra obtained from individual and pooled sera from invasive aspergillosis cases and controls were compared.ResultsPooling resulted in 50% loss of peak clusters detected in individual samples. Overall, loss was greatest for low intensity clusters. Peak intensities and case:control intensity ratios, among clusters not lost, demonstrated good reproducibility.ConclusionPooling sera results in significant potential biomarker loss when using SELDI-ToF MS.

Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women

OBJECTIVES To describe the pharmacokinetics of darunavir in pregnant HIV-infected women in the third trimester and post-partum. PATIENTS AND METHODS This was a non-randomized, open-label, multicentre, Phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. HIV-infected pregnant women treated with darunavir (800/100 mg once daily or 600/100 mg twice daily) as part of their combination ART were included. Pharmacokinetic curves were recorded in the third trimester and post-partum. A cord blood sample and maternal sample were collected. The study is registered at ClinicalTrials.gov under number NCT00825929. RESULTS Twenty-four women were included in the analysis [darunavir/ritonavir: 600/100 mg twice daily (n=6); 800/100 mg once daily (n=17); and 600/100 mg once daily (n=1)]. Geometric mean ratios of third trimester versus post-partum (90% CI) were 0.78 (0.60-1.00) for total darunavir AUC0-tau after 600/100 mg twice-daily dosing and 0.67 (0.56-0.82) for total darunavir AUC0-tau after 800/100 mg once-daily dosing. The unbound fraction of darunavir was not different during pregnancy (12%) compared with post-partum (10%). The median (range) ratio of darunavir cord blood/maternal blood was 0.13 (0.08-0.35). Viral load close to delivery was <300 copies/mL in all but two patients. All children were tested HIV-negative and no congenital abnormalities were reported. CONCLUSIONS Darunavir AUC and Cmax were substantially decreased in pregnancy for both darunavir/ritonavir regimens. This decrease in exposure did not result in mother-to-child transmission. For antiretroviral-naive patients, who are adherent, take darunavir with food and are not using concomitant medication reducing darunavir concentrations, 800/100 mg of darunavir/ritonavir once daily is adequate in pregnancy. For all other patients 600/100 mg of darunavir/ritonavir twice daily is recommended during pregnancy.

The eSexual Health Clinic system for management, prevention, and control of sexually transmitted infections: exploratory studies in people testing for Chlamydia trachomatis

BACKGROUND Self-directed and internet-based care are key elements of eHealth agendas. We developed a complex online clinical and public health intervention, the eSexual Health Clinic (eSHC), in which patients with genital chlamydia are diagnosed and medically managed via an automated online clinical consultation, leading to antibiotic collection from a pharmacy. Partner notification, health promotion, and capture of surveillance data are integral aspects of the eSHC. We aimed to assess the safety and feasibility of the eSHC as an alternative to routine care in non-randomised, exploratory proof-of-concept studies. METHODS Participants were untreated patients with chlamydia from genitourinary medicine clinics, untreated patients with chlamydia from six areas in England in the National Chlamydia Screening Programmes (NCSP) online postal testing service, or patients without chlamydia tested in the same six NCSP areas. All participants were aged 16 years or older. The primary outcome was the proportion of patients with chlamydia who consented to the online chlamydia pathway who then received appropriate clinical management either exclusively through online treatment or via a combination of online management and face-to-face care. We captured adverse treatment outcomes. FINDINGS Between July 21, 2014, and March 13, 2015, 2340 people used the eSHC. Of 197 eligible patients from genitourinary medicine clinics, 161 accessed results online. Of the 116 who consented to be included in the study, 112 (97%, 95% CI 91-99) received treatment, and 74 of those were treated exclusively online. Of the 146 eligible NCSP patients, 134 accessed their results online, and 105 consented to be included. 93 (89%, 95% CI 81-94) received treatment, and 60 were treated exclusively online. In both groups, median time to collection of treatment was within 1 day of receiving their diagnosis. 1776 (89%) of 1936 NCSP patients without chlamydia accessed results online. No adverse events were recorded. INTERPRETATION The eSHC is safe and feasible for management of patients with chlamydia, with preliminary evidence of similar treatment outcomes to those in traditional services. This innovative model could help to address growing clinical and public health needs. A definitive trial is needed to assess the efficacy, cost-effectiveness, and public health impact of this intervention. FUNDING UK Clinical Research Collaboration.

Positive Predictive Value of the Becton Dickinson VIPER system and the ProbeTec GC Qx assay, in extracted mode, for detection of Neisseria gonorrhoeae.

Objectives Performance of the new Becton Dickinson ProbeTec GC Qx assay on the BD VIPER platform was evaluated to ascertain whether confirmatory testing is required in our clinical setting. Methods Positive predictive value (PPV) was determined by comparison with culture and a confirmatory nucleic acid amplification test (NAAT)-based Neisseria gonorrhoeae assay from genital and extragenital samples (rectal and pharyngeal) collected from a genitourinary medicine (GUM) clinic. Results Among 14 223 clinical genital samples, 149 (1.0%) specimens were positive using the ProbeTec GC Qx assay, automated on the VIPER platform; 141 of these were confirmed by either culture or a real-time PCR targeting two gonococcal-specific targets (PPV 94.6%; 95% CI 90% to 98%). Among 840 pharyngeal samples, 26 (3.1%) were positive by the ProbeTec GC Qx assay; 13 were confirmed (PPV 50%; 95% CI 30% to 70%). Among 593 rectal samples, 17 tested positive by the ProbeTec GC Qx assay; all were confirmed (PPV 100%; 95% CI 80% to 100%). Conclusions The lower 95% CI of the PPV for the ProbeTec GC Qx assay for genital specimens was >90% in this GUM clinic population, and therefore confirmatory testing for genital specimens is not required. Confirmatory testing of pharyngeal and rectal samples should continue in line with national guidelines.

How likely is environmental or patient cross-contamination of Chlamydia trachomatis DNA to lead to false positive results in patients attending our clinic?

Objectives Environmental contamination with DNA from Chlamydia trachomatis (CT) has previously been found in Genitourinary Medicine (GUM) clinics. There are no known cases of cross-contamination of clinical samples and no known nosocomial infections. We investigated whether diagnostic samples could become contaminated from the environment by running dummy sample and carrying out a patient-throughput analysis. A total of 29 748 patients attended clinics over a year. Of these, 2860 (9.6%) had a positive Chlamydia test result. Method (1) A run of dummy samples (60 urine samples and 10 swabs) were processed as normal clinic specimens. (2) Patient-throughput analysis: Patient numbers attending the GUM clinic on a given day was categorised as low, moderate or high. χ2 Tests were used to look for associations between categorical variables and Chlamydia test positivity. A Poisson regression model was fitted to look at the effect of the number of people in the clinic on the number of positive results in a given day. As some clinics were only run on certain days of the week, a sensitivity analysis was later performed with attendances at non-daily clinics removed. Results All dummy samples tested negative and we did not find evidence of an association between daily Chlamydia positivity and clinic attendance. Conclusions It is unlikely that environmental or cross-contamination of CT has lead to significant numbers of false positive results. Laboratories check for possible cross-contamination routinely. The extension of this simple routine practice to all clinical areas could provide quality assurance, improving confidence in the results in clinics.

Detection of Chlamydia trachomatis in rectal specimens in women and its association with anal intercourse: a systematic review and meta-analysis.

Objectives Chlamydia trachomatis is the most commonly diagnosed bacterial STI. Lack of prevalence and risk factor data for rectal chlamydia in women has testing and treatment implications, as azithromycin (a first-line urogenital chlamydia treatment) may be less effective for rectal chlamydia. We conducted a systematic review of studies on women in high-income countries to estimate rectal chlamydia prevalence, concurrency with urogenital chlamydia and associations with reported anal intercourse (AI). Design Systematic review and four meta-analyses conducted using random-effects modelling. Data sources Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO and the Cochrane Database were searched for articles published between January 1997 and October 2017. Eligibility criteria Studies reporting rectal chlamydia positivity in heterosexual women aged ≥15 years old in high-income countries were included. Studies must have used nucleic acid amplification tests and reported both the total number of women tested for rectal chlamydia and the number of rectal chlamydia infections detected. Conference abstracts, case reports and studies with self-reported diagnoses were excluded. Data extracted included setting, rectal and urogenital chlamydia testing results, AI history, and demographics. Results Fourteen eligible studies were identified, all among diverse populations attending sexual health services. Among routine clinic-attending women, summary rectal chlamydia positivity was 6.0% (95% CI 3.2% to 8.9%); summary concurrent rectal chlamydia infection was 68.1% in those who tested positive for urogenital chlamydia (95% CI 56.6% to 79.6%); and of those who tested negative for urogenital chlamydia, 2.2% (95% CI 0% to 5.2%) were positive for rectal chlamydia. Reported AI was not associated with rectal chlamydia (summary risk ratio 0.90; 95% CI 0.75 to 1.10). Conclusions High levels of rectal chlamydia infection have been shown in women with urogenital chlamydia infection. The absence of association between reported AI and rectal chlamydia suggests AI is not an adequate indicator for rectal testing. Further work is needed to determine policy and practice for routine rectal testing in women.

Chlamydia testing: Reaching high-risk sexually active young people in the community

Falasinnu et al. found strong evidence highlighting the importance of age, number of sexual partners and ethnicity in identifying at-risk populations for chlamydia and gonorrhoea. We aimed to explore if offering on the spot, rapid sexually transmitted infections (STI) tests might be an acceptable way of accessing sexually experienced people aged <25. In September 2014, as part of improving clinical outreach in the community, we conducted the first UK one-day service evaluation pilot of the Cepheid GeneXpert rapidChlamydia trachomatis/Neisseria gonorrhoeae testing system in an inner London further education college. Consecutive students in public areas were invited to provide urine samples for ‘on-the-spot’ chlamydia/gonorrhoea testing, and to give telephone feedback in the next two weeks. The mean age of 52 eligible students was 19 years (range 16 to 24), 65% were female and 37% were smokers. Reported ethnicity was AfroCaribbean 67%, white 22% or other 11%. Mean number of sexual partners in the last 12 months was three (range 0–18), with most students (64%) never having been tested for STIs. Of 39 participants with a new sexual partner in the last six months only seven had been tested for chlamydia during this period. Seven urine samples (13%, 95% confidence interval 4% to 22%) were positive: six for chlamydia and one for gonorrhoea. Negative results were sent by text in a mean time of 2 h 12min after providing the sample (range 1 h 30min–5 hr 50min). Students with infections were telephoned and given advice about obtaining treatment. Six were given their result in a mean time of 3 h 18min (range 1 h 40min–5 h 40min). The final student was contacted 55 h later. Five students were confirmed treated by two weeks of whom four had notified partners. None of the seven infected students had planned to get tested. A total of 42 students (81%) provided feedback: all were happy to be tested and liked the rapid results. Comments included: ‘it is good to be safe’, ‘helps people – makes them aware’, ‘easy’, ‘reliable’, ‘less technical’, ‘in college so right there’, ‘good so you don’t get worried a lot’, ‘sooner you know the better’, ‘other clinics should do that’, ‘couldn’t believe I got the result the same day’. As this was the first STI test for most students, this level of engagement is encouraging. They also suggested advertising testing; making it less obvious the testing was for STIs; testing for a range of infections including HIV and providing same day treatment. We provided same day results to a group shown by Falasinnu et al. to be at high risk of STIs. Most students would not otherwise have been tested, including all those who had positive results. Our pilot could inform commissioning of future community-based service delivery of chlamydia/gonorrhoea testing in this high-risk group.