Andrew Skingsley

High-Levels of Acquired Drug Resistance in Adult Patients Failing First-Line Antiretroviral Therapy in a Rural HIV Treatment Programme in KwaZulu-Natal, South Africa

Objective To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa. Design Cross-sectional study nested within HIV treatment programme. Methods Adult (≥18 years) HIV-infected individuals initially treated with a first-line stavudine- or zidovudine-based antiretroviral therapy (ART) regimen and with evidence of virological failure (one viral load >1000 copies/ml) were enrolled from 17 rural primary health care clinics. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS) for standard second-line regimens were calculated using the Stanford HIVDB 6.0.5 algorithms. Results A total of 222 adults were successfully genotyped for HIV drug resistance between December 2010 and March 2012. The most common regimens at time of genotype were stavudine, lamivudine and efavirenz (51%); and stavudine, lamivudine and nevirapine (24%). Median duration of ART was 42 months (interquartile range (IQR) 32–53) and median duration of antiretroviral failure was 27 months (IQR 17–40). One hundred and ninety one (86%) had at least one drug resistance mutation. For 34 individuals (15%), the GSS for the standard second-line regimen was <2, suggesting a significantly compromised regimen. In univariate analysis, individuals with a prior nucleoside reverse-transcriptase inhibitor (NRTI) substitution were more likely to have a GSS <2 than those on the same NRTIs throughout (odds ratio (OR) 5.70, 95% confidence interval (CI) 2.60–12.49). Conclusions There are high levels of drug resistance in adults with failure of first-line antiretroviral therapy in this rural primary health care programme. Standard second-line regimens could potentially have had reduced efficacy in about one in seven adults involved.

Weekend admissions as an independent predictor of mortality: an analysis of Scottish hospital admissions

Objectives Weekend admissions have been shown to be associated with an increased risk of mortality compared with weekday admissions for many diagnoses. We analysed emergency department admissions within the Scottish National Health Service to investigate whether mortality is increased in case of weekend emergency department admissions. Design A cohort study. Setting Scotland National Health Service (NHS) emergency departments. Participants 5 271 327 emergency department admissions between 1999 and 2009. We included all patients admitted via emergency departments recorded in the Scottish Morbidity Records (SMR01) in NHS, Scotland for whom complete demographic data were available. Primary outcome measures Death as recorded by the General Register Office (GRO). Results There was a significantly increased probability of death associated with a weekend emergency admission compared with admission on a weekday (unadjusted OR 1.27, 95% CI 1.26 to 1.28, p<0.0001; adjusted for year of admission, gender, age, deprivation quintile and number of comorbidities OR 1.42, 95% CI 1.40 to 1.43, p<0.0001). Conclusions Despite a general reduction in mortality over the last 11 years, there is still a significant excess mortality associated with weekend emergency admissions. Further research should be undertaken to identify the precise mechanisms underlying this effect so that measures can be put in place to reduce patient mortality.

Associations between selected immune-mediated diseases and tuberculosis: record-linkage studies

BackgroundPrevious studies have suggested that there may be an association between some immune-mediated diseases and risk of tuberculosis (TB).MethodsWe analyzed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999 to 2011), and a similar database (the Oxford Record Linkage Study (ORLS)) for a region of southern England in an earlier period. Rate ratios for TB were determined, comparing immune-mediated disease cohorts with comparison cohorts.ResultsIn the all-England dataset, there were significantly elevated risks of TB after hospital admission for the following individual immune-mediated diseases: Addisons disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, coeliac disease, Crohns disease, dermatomyositis, Goodpastures syndrome, Hashimotos thyroiditis, idiopathic thrombocytopenia purpura (ITP), myasthenia gravis, myxedema, pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögrens syndrome, systemic lupus erythematosus (SLE), thyrotoxicosis and ulcerative colitis. Particularly high levels of risk were found for Addison’s disease (rate ratio (RR) = 11.9 (95% CI 9.5 to 14.7)), Goodpasture’s syndrome (RR = 10.8 (95% CI 4.0 to 23.5)), SLE (RR = 9.4 (95% CI 7.9 to 11.1)), polymyositis (RR = 8.0 (95% CI 4.9 to 12.2)), polyarteritis nodosa (RR = 6.7 (95% CI 3.2 to 12.4)), dermatomyositis (RR = 6.6 (95% CI 3.0 to 12.5)), scleroderma (RR = 6.1 (95% CI 4.4 to 8.2)) and autoimmune hemolytic anemia (RR = 5.1 (95% CI 3.4 to 7.4)).ConclusionsThese two databases show that patients with some immune-mediated diseases have an increased risk of TB, although we cannot explicitly state the direction of risk or exclude confounding. Further study of these associations is warranted, and these findings may aid TB screening, control and treatment policies.

Prevalence of primary outcome changes in clinical trials registered on ClinicalTrials.gov: a cross-sectional study.

Background: An important principle in the good conduct of clinical trials is that a summary of the trial protocol, with a pre-defined primary outcome, should be freely available before the study commences. The clinical trials registry ClinicalTrials.gov provides one method of doing this, and once the trial is registered, any changes made to the primary outcome are documented. The objectives of this study were: to assess the proportion of registered trials on ClinicalTrials.gov that had the primary outcome changed; to assess when the primary outcome was changed in relation to the listed study start and end dates and to assess whether the primary outcome change had any relation to the study sponsor. Methods: A cross-sectional analysis of all interventional clinical trials registered on ClinicalTrials.gov as of 25 October 2012 was performed. The main outcome was any change made to the initially listed primary outcome and the time of the change in relation to the trial start and end date. Findings: Our analysis showed that 28229 of 89204 (31.7%) registered studies had their primary outcome changed. Industry funding was associated with all primary outcome changes, odds ratio (OR)= 1.36, 95% confidence interval (CI)=1.31-1.41, p<0.001; with primary outcome changes after study start date OR=1.37, 95% CI=1.32-1.42, p<0.001; with primary outcome changes after primary completion date OR=1.84, 95% CI=1.75-1.94, p<0.001 and with primary outcome changes after study completion date OR=1.82, 95% CI=1.73-1.91, p<0.001. Conclusions A significant proportion of interventional trials registered on ClinicalTrials.gov have their primary outcomes altered after the listed study start and completion dates. These changes are associated with funding source.

Pediatric cholesteatoma surgery using a single-staged canal wall down approach: results of a 5-year longitudinal study.

Objective To present the results of a 5-year longitudinal study in a pediatric population undergoing surgery for extensive cholesteatoma using a canal wall down (CWD) approach with obliteration. Study Design Prospective longitudinal study. Patients Children (<16 years) undergoing surgery for cholesteatoma (58 ears) between 1999 and 2013. Interventions Therapeutic. Setting District general hospital. Main Outcome Measures (1) Residual, recurrence, and recidivist cholesteatoma rates at 5 years post-surgery; (2) postoperative hearing; (3) postoperative waterproofing of the ear; (4) number of subsequent ear surgery required. Results Fifty-five children (58 ears) contributed to the study. At 5 years, 16 of 58 (27.6%) had been lost to follow-up. Using Kaplan-Meier survival analysis, the residual rate after 5 years was 9.9% (95% CI: 3.8–24.4%), representing four residual cholesteatomas, and there were no recurrences detected. Using a cross-sectional analysis at 12 months of follow-up, the otorrhea risk was 0% and the risk of definitive waterproofing was 94.8%. There was a re-operation risk of 17.2% within 5 years which included second-stage ossiculoplasty. Regarding hearing, of the data available (n = 16), 10 children (62.5%) maintained their hearing (change between −10 and =10 dB), 2 (12.5%) had hearing gain (>10 dB), and 4 children (25%) had hearing reduction at 12 months postoperation. Four of 16 children (25%) had a postoperative hearing level of 30 dB or lower. Conclusion The use of a CWD approach with obliteration of the mastoid cavity to surgically treat extensive cholesteatoma in children results in a low recurrence rate and high rate of a trouble-free ear in the long term.

Southern African Treatment Resistance Network (SATuRN) RegaDB HIV drug resistance and clinical management database: supporting patient management, surveillance and research in southern Africa

Abstract Substantial amounts of data have been generated from patient management and academic exercises designed to better understand the human immunodeficiency virus (HIV) epidemic and design interventions to control it. A number of specialized databases have been designed to manage huge data sets from HIV cohort, vaccine, host genomic and drug resistance studies. Besides databases from cohort studies, most of the online databases contain limited curated data and are thus sequence repositories. HIV drug resistance has been shown to have a great potential to derail the progress made thus far through antiretroviral therapy. Thus, a lot of resources have been invested in generating drug resistance data for patient management and surveillance purposes. Unfortunately, most of the data currently available relate to subtype B even though >60% of the epidemic is caused by HIV-1 subtype C. A consortium of clinicians, scientists, public health experts and policy markers working in southern Africa came together and formed a network, the Southern African Treatment and Resistance Network (SATuRN), with the aim of increasing curated HIV-1 subtype C and tuberculosis drug resistance data. This article describes the HIV-1 data curation process using the SATuRN Rega database. The data curation is a manual and time-consuming process done by clinical, laboratory and data curation specialists. Access to the highly curated data sets is through applications that are reviewed by the SATuRN executive committee. Examples of research outputs from the analysis of the curated data include trends in the level of transmitted drug resistance in South Africa, analysis of the levels of acquired resistance among patients failing therapy and factors associated with the absence of genotypic evidence of drug resistance among patients failing therapy. All these studies have been important for informing first- and second-line therapy. This database is a free password-protected open source database available on www.bioafrica.net. Database URL: http://www.bioafrica.net/regadb/

Mastoid obliteration surgery for cholesteatoma in 183 adult ears--a 5-year prospective cohort study: Our Experience.

patient tolerance or anxiety related to the approach. Therefore, it is reasonable for the choice of technique to be dictated by surgeon training and comfort, patient preference and patient anatomy. While there was no difference in patient tolerance of the anaesthesia, transtracheal lidocaine injection prior to transcervical or transoral injection laryngoplasty may be considered to improve surgeon efficiency.

Implementing antiretroviral resistance testing in a primary health care HIV treatment programme in rural KwaZulu-Natal, South Africa: early experiences, achievements and challenges

BackgroundAntiretroviral drug resistance is becoming increasingly common with the expansion of human immunodeficiency virus (HIV) treatment programmes in high prevalence settings. Genotypic resistance testing could have benefit in guiding individual-level treatment decisions but successful models for delivering resistance testing in low- and middle-income countries have not been reported.MethodsAn HIV Treatment Failure Clinic model was implemented within a large primary health care HIV treatment programme in northern KwaZulu-Natal, South Africa. Genotypic resistance testing was offered to adults (≥16 years) with virological failure on first-line antiretroviral therapy (one viral load >1000 copies/ml after at least 12 months on a standard first-line regimen). A genotypic resistance test report was generated with treatment recommendations from a specialist HIV clinician and sent to medical officers at the clinics who were responsible for patient management. A quantitative process evaluation was conducted to determine how the model was implemented and to provide feedback regarding barriers and challenges to delivery.ResultsA total of 508 specimens were submitted for genotyping between 8 April 2011 and 31 January 2013; in 438 cases (86.2%) a complete genotype report with recommendations from the specialist clinician was sent to the medical officer. The median turnaround time from specimen collection to receipt of final report was 18 days (interquartile range (IQR) 13–29). In 114 (26.0%) cases the recommended treatment differed from what would be given in the absence of drug resistance testing. In the majority of cases (n = 315, 71.9%), the subsequent treatment prescribed was in line with the recommendations of the report.ConclusionsGenotypic resistance testing was successfully implemented in this large primary health care HIV programme and the system functioned well enough for the results to influence clinical management decisions in real time. Further research will explore the impact and cost-effectiveness of different implementation models in different settings.

Funding source and primary outcome changes in clinical trials registered on ClinicalTrials.gov are associated with the reporting of a statistically significant primary outcome: a cross-sectional study

Background: We and others have shown a significant proportion of interventional trials registered on ClinicalTrials.gov have their primary outcomes altered after the listed study start and completion dates. The objectives of this study were to investigate whether changes made to primary outcomes are associated with the likelihood of reporting a statistically significant primary outcome on ClinicalTrials.gov. Methods: A cross-sectional analysis of all interventional clinical trials registered on ClinicalTrials.gov as of 20 November 2014 was performed. The main outcome was any change made to the initially listed primary outcome and the time of the change in relation to the trial start and end date. Findings: 13,238 completed interventional trials were registered with ClinicalTrials.gov that also had study results posted on the website. 2555 (19.3%) had one or more statistically significant primary outcomes. Statistical analysis showed that registration year, funding source and primary outcome change after trial completion were associated with reporting a statistically significant primary outcome . Conclusions: Funding source and primary outcome change after trial completion are associated with a statistically significant primary outcome report on clinicaltrials.gov.

Linkage to HIV care following diagnosis in the WHO European Region: A systematic review and meta-analysis, 2006-2017

Background Timely linkage to care after HIV diagnosis is crucial as delayed access can result in poor patient outcomes. The aim of this systematic review was to synthesise the evidence to achieve a better understanding of what proportion of patients are linked to care and what factors impact linkage. Methods Systematic searches were run in six databases up to the end of February 2017. The grey literature was also reviewed. Inclusion criteria were: sample size ≥50 people (aged ≥15), from the WHO European Region, published 2006–2017 and in English. Linkage to care was defined as a patient seen for HIV care after diagnosis. Study selection, data extraction and quality assurance were performed by two independent reviewers. Random-effects meta-analysis was carried out to summarise linkage to care within three months of diagnosis. Results Twenty-four studies were included; 22 presented linkage to care data and seven examined factors for linkage. Linkage among 89,006 people in 19 countries was captured. Meta-analysis, restricted to 12 studies and measuring prompt linkage within three months, gave a pooled estimate of 85% (95% CI: 75%-93%). Prompt linkage was higher in studies including only people in care (94%; 95% CI: 91%-97%) than in those of all new diagnoses (71%; 95% CI: 50%-87%). Heterogeneity was high across and within strata (>99%). Factors associated with delaying or not linking to care included: acquiring HIV through heterosexual contact/injecting drug use, younger age at diagnosis, lower levels of education, feeling well at diagnosis and diagnosis outside an STI clinic. Conclusion Overall, linkage to care was high, though estimates were lower in studies with a high proportion of people who inject drugs. The high heterogeneity between studies made it challenging to synthesise findings. Studies should adopt a standardised definition with a three month cut-off to measure prompt linkage to care to ensure comparability.