Pharmacokinetics, Safety, and Tolerability of Anti-SARS-CoV-2 Monoclonal Antibody, Sotrovimab, Delivered Intravenously or Intramuscularly in Japanese and Caucasian Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Sotrovimab 500 mg administered by a single intravenous (IV) infusion has been granted special approval for emergency use in Japan for treatment of SARS-CoV-2 infection in adults and children aged ≥ 12 years weighing ≥ 40 kg. This Phase 1, single-dose study investigated the pharmacokinetics, safety, and tolerability of IV or intramuscular (IM) sotrovimab 500 mg doses versus placebo in healthy Japanese and Caucasian volunteers. METHODS: This was a two-part, Phase 1, randomized, placebo-controlled, single-blind study. In Part 1, participants received a single sotrovimab 500 mg IV infusion or matching placebo on Day 1. In Part 2, participants received a single sotrovimab 500 mg IM dose or matching placebo on Day 1, administered as two 4 mL injections. RESULTS: There was no effect of ethnicity on the peak or total serum exposure of IV sotrovimab through Week 18; after adjusting for body weight, the point estimate and 90 % confidence interval for the ratio of total exposure between Japanese and Caucasian participants fell within conventional bioavailability bounds (80-125%). Geometric mean Cmax and AUClast following a single IM administration of sotrovimab were higher in Japanese participants compared with Caucasian participants, even after adjustment for body weight. Overall, a single IV or IM dose of sotrovimab was well tolerated by both Japanese and Caucasian participants. CONCLUSIONS: After adjusting for body weight, exposures following a single IV dose of sotrovimab 500 mg were similar between Japanese and Caucasian participants, and higher in Japanese participants following IM administration. Higher exposures were not associated with any safety signals. TRIAL REGISTRATION: ClinicalTrials.Gov: NCT04988152.

Real-world effectiveness of sotrovimab for the treatment of SARS-CoV-2 infection during Omicron BA.2 subvariant predominance: a systematic literature review.

PURPOSE: Emerging SARS-CoV-2 variants have impacted the in vitro activity of sotrovimab, with variable fold changes in neutralization potency for the Omicron BA.2 sublineage and onward. The correlation between reduced in vitro activity and clinical efficacy outcomes is unknown. A systematic literature review (SLR) evaluated the effectiveness of sotrovimab on severe clinical outcomes during Omicron BA.2 predominance. METHODS: Electronic databases were searched for peer-reviewed journals, preprint articles, and conference abstracts published from January 1-November 3, 2022. RESULTS: Five studies were included, which displayed heterogeneity in study design and population. Two UK studies had large samples of patients during BA.2 predominance: one demonstrated clinical effectiveness vs molnupiravir during BA.1 (adjusted hazard ratio [aHR] 0.54, 95% CI 0.33-0.88; p = 0.014) and BA.2 (aHR 0.44, 95% CI 0.27-0.71; p = 0.001); the other reported no difference in the clinical outcomes of sotrovimab-treated patients when directly comparing sequencing-confirmed BA.1 and BA.2 cases (HR 1.17, 95% CI 0.74-1.86). One US study showed a lower risk of 30-day all-cause hospitalization/mortality for sotrovimab compared with no treatment during the BA.2 surge in March (adjusted relative risk [aRR] 0.41, 95% CI 0.27-0.62) and April 2022 (aRR 0.54, 95% CI 0.08-3.54). Two studies from Italy and Qatar reported low progression rates but were either single-arm descriptive or not sufficiently powered to draw conclusions on the effectiveness of sotrovimab. CONCLUSION: This SLR showed that the effectiveness of sotrovimab was maintained against Omicron BA.2 in both ecological and sequencing-confirmed studies, by demonstrating low/comparable clinical outcomes between BA.1 and BA.2 periods or comparing against an active/untreated comparator.

Intramuscular vs Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Noninferiority Clinical Trial.

Background: Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19. Method: This multicenter phase 3 study based on a randomized open-label design tested the noninferiority of IM to IV administration according to an absolute noninferiority margin of 3.5%. From June to August 2021, patients aged ≥12 years with COVID-19, who were neither hospitalized nor receiving supplemental oxygen but were at high risk for progression, were randomized 1:1:1 to receive sotrovimab as a single 500-mg IV infusion or a 500- or 250-mg IM injection. The primary composite endpoint was progression to (1) all-cause hospitalization for >24 hours for acute management of illness or (2) all-cause death through day 29. Results: Sotrovimab 500 mg IM was noninferior to 500 mg IV: 10 (2.7%) of 376 participants vs 5 (1.3%) of 378 met the primary endpoint, respectively (absolute adjusted risk difference, 1.06%; 95% CI, -1.15% to 3.26%). The 95% CI upper limit was lower than the prespecified noninferiority margin of 3.5%. The 250-mg IM group was discontinued early because of the greater proportion of hospitalizations vs the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease-related events and died (500 mg IM, 2/393, <1%; 250 mg IM, 2/195, 1%). Conclusions: Sotrovimab 500-mg IM injection was well tolerated and noninferior to IV administration. IM administration could expand outpatient treatment access for COVID-19. Clinical Trials Registration: ClinicalTrials.gov: NCT04913675.

Safety, Virology, Pharmacokinetics, and Clinical Experience of High-Dose Intravenous Sotrovimab for the Treatment of Mild to Moderate COVID-19: An Open-Label Clinical Trial.

Background: Five hundred milligrams of intravenous (IV) sotrovimab has been shown to be well tolerated and efficacious against pre-Omicron strains in treating patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk for disease progression. Methods: This was an open-label, single-arm substudy of phase 3 COMET-TAIL (NCT04913675) assessing the safety and tolerability of a 2000 mg IV dose of sotrovimab. Symptomatic patients (aged ≥18 years) with COVID-19 at high risk for progression were enrolled from June 30 through July 11, 2022, when Omicron BA.5, BA.2.12.1, and BA.4 were the predominant circulating variants in the United States. The primary end point was the occurrence of adverse events (AEs), serious AEs (SAEs), AEs of special interest, and COVID-19 disease-related events (DREs) through day 8. Safety, pharmacokinetics, viral load, and hospitalization >24 hours for acute management of illness or death through day 29 were assessed. Results: All participants (n = 81) were Hispanic, 58% were female, and 51% were aged ≥55 years. Through day 8, no AEs, including infusion-related reactions or hypersensitivity, were reported; 2 participants reported DREs (mild cough, n = 2). One SAE (acute myocardial infarction), which was considered unrelated to sotrovimab or COVID-19 by the investigator, occurred on day 27 and was the only hospitalization reported. Maximum serum concentration (geometric mean) was 745.9 µg/mL. Viral load decreased from baseline through day 29; only 2 (3%) participants had a persistently high viral load (≥4.1 log10 copies/mL) at day 8. Conclusions: Two thousand milligrams of IV sotrovimab was well tolerated, with no safety signals observed. Trial registration: ClinicalTrials.gov Identifier: NCT04913675.

Population pharmacokinetics and exposure-response analysis of a single dose of sotrovimab in the early treatment of patients with mild to moderate COVID-19.

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death in non-hospitalized high-risk patients with mild to moderate coronavirus disease 2019 following either intravenous (i.v.) or intramuscular (i.m.) administration. Population pharmacokinetic (PopPK) and exposure-response (ER) analyses were performed to characterize single dose sotrovimab pharmacokinetics (PK) and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between-participant variability in sotrovimab PK and efficacy following i.v. or i.m. administration. Sotrovimab PK was described by a two-compartment model with linear elimination; i.m. absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on i.m. bioavailability and first-order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final PopPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 h that described the relationship between exposure and probability of progression within the ER dataset for COMET-TAIL. The number of risk factors (≤1 vs. >1) was incorporated as an additive shift on the model-estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure-progression relationship across severe acute respiratory syndrome-coronavirus 2 variants.

Surveillance of HIV-1 transmitted integrase strand transfer inhibitor resistance in the UK.

BACKGROUND: HIV treatment guidelines have traditionally recommended that all HIV-positive individuals are tested for evidence of drug resistance prior to starting ART. Testing for resistance to reverse transcriptase inhibitors and PIs is well established in routine care. However, testing for integrase strand transfer inhibitor (InSTI) resistance is less consistent. OBJECTIVES: To inform treatment guidelines by determining the prevalence of InSTI resistance in a national cohort of recently infected individuals. PATIENTS AND METHODS: Recent (within 4 months) HIV-1 infections were identified using a Recent Infection Testing Algorithm of new HIV-1 diagnoses in the UK. Resistance-associated mutations (RAMs) in integrase, protease and reverse transcriptase were detected by ultradeep sequencing, which allows for the sensitive estimation of the frequency of each resistant variant in a sample. RESULTS: The analysis included 655 randomly selected individuals (median age = 33 years, 95% male, 83% MSM, 78% white) sampled in the period 2014 to 2016 and determined to have a recent infection. These comprised 320, 138 and 197 samples from 2014, 2015 and 2016, respectively. None of the samples had major InSTI RAMs occurring at high variant frequency (≥20%). A subset (25/640, 3.9%) had major InSTI RAMs occurring only as low-frequency variants (2%-20%). In contrast, 47/588 (8.0%) had major reverse transcriptase inhibitor and PI RAMs at high frequency. CONCLUSIONS: Between 2014 and 2016, major InSTI RAMs were uncommon in adults with recent HIV-1 infection, only occurring as low-frequency variants of doubtful clinical significance. Continued surveillance of newly diagnosed patients for evidence of transmitted InSTI resistance is recommended to inform clinical practice.

First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment.

This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0-τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0-14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.).

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.

Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: an analysis of a national observational cohort.

BACKGROUND: Deaths in HIV-positive people have decreased since the introduction of highly active antiretroviral therapy (HAART) in 1996. Fewer AIDS-related deaths and an ageing cohort have resulted in an increase in the proportion of HIV patients dying from non-AIDS-related disorders. Here we describe mortality and causes of death in people diagnosed with HIV in the HAART era compared with the general population. METHODS: In this observational analysis, we linked cohort data collected by Public Health England (PHE) for individuals aged 15 years and older, diagnosed with HIV in England and Wales from 1997 to 2012, to the Office for National Statistics (ONS) national mortality register. Cohort inclusion began at diagnosis with follow-up clinical information collected every year from all 220 National Health Service (NHS) HIV outpatient clinics nationwide. To classify causes of death we used a modified Coding Causes of Death in HIV (CoDe) protocol, which uses death certificate data and clinical markers. We applied Kaplan-Meier analysis for survival curves and mortality rate estimation and Cox regression to establish independent predictors of all-cause mortality, adjusting for sex, infection route, age at diagnosis, region of birth, year of diagnosis, late diagnosis, and history of HAART. We used standardised mortality ratios (SMRs) to make comparisons with the general population. FINDINGS: Between 1997 and 2012, 88 994 people were diagnosed with HIV, contributing 448 839 person-years of follow up. By the end of 2012, 5302 (6%) patients had died (all-cause mortality 118 per 10 000 person-years, 95% CI 115-121). In multivariable analysis, late diagnosis was a strong predictor of death (hazard ratio [HR] 3·50, 95% CI 3·13-3·92). People diagnosed more recently had a lower risk of death (2003-07: HR 0·66, 95% CI 0·62-0·70; 2008-12: HR 0·65, 95% CI 0·60-0·71). Cause of death was determinable for 4808 (91%) of 5302 patients; most deaths (2791 [58%] of 4808) were attributable to AIDS-defining illnesses. Cohort mortality was significantly higher than the general population for all causes (SMR 5·7, 95% CI 5·5-5·8), particularly non-AIDS infections (10·8, 9·8-12·0) and liver disease (3·7, 3·3-4·2). All-cause mortality was highest in the year after diagnosis (SMR 24·3, 95% CI 23·4-25·2). INTERPRETATION: Despite the availability of free treatment and care in the UK, AIDS continues to account for the majority of deaths in HIV-positive people, and mortality remains higher in HIV-positive people than in the general population. These findings highlight the importance of prompt diagnosis, care engagement, and optimum management of comorbidities in reducing mortality in people with HIV. FUNDING: Public Health England.

Injecting drug use predicts active tuberculosis in a national cohort of people living with HIV.

OBJECTIVES: Tuberculosis (TB) is common in people living with HIV, leading to worse clinical outcomes including increased mortality. We investigated risk factors for developing TB following HIV diagnosis. DESIGN: Adults aged at least 15 years first presenting to health services for HIV care in England, Wales or Northern Ireland from 2000 to 2014 were identified from national HIV surveillance data and linked to TB surveillance data. METHODS: We calculated incidence rates for TB occurring more than 91 days after HIV diagnosis and investigated risk factors using multivariable Poisson regression. RESULTS: A total of 95 003 adults diagnosed with HIV were followed for 635 591 person-years; overall incidence of TB was 344 per 100 000 person-years (95% confidence interval 330-359). TB incidence was high for people who acquired HIV through injecting drugs [PWID; men 876 (696-1104), women 605 (365-945)] and black Africans born in high TB incidence countries [644 (612-677)]. The adjusted incidence rate ratio for TB amongst PWID was 4.79 (3.35-6.85) for men and 6.18 (3.49-10.93) for women, compared with MSM. The adjusted incidence rate ratio for TB in black Africans from high-TB countries was 4.27 (3.42-5.33), compared with white UK-born individuals. Lower time-updated CD4 cell count was associated with increased rates of TB. CONCLUSION: PWID had the greatest risk of TB; incidence rates were comparable with those in black Africans from high TB incidence countries. Most TB cases in PWID were UK-born, and likely acquired TB through transmission within the United Kingdom. Earlier HIV diagnosis and quicker initiation of antiretroviral therapy should reduce TB incidence in these populations.

Insidious Risk of Severe Mycobacterium chimaera Infection in Cardiac Surgery Patients.

BACKGROUND: An urgent UK investigation was launched to assess risk of invasive Mycobacterium chimaera infection in cardiothoracic surgery and a possible association with cardiopulmonary bypass heater-cooler units following alerts in Switzerland and The Netherlands. METHODS: Parallel investigations were pursued: (1) identification of cardiopulmonary bypass-associated M. chimaera infection through national laboratory and hospital admissions data linkage; (2) cohort study to assess patient risk; (3) microbiological and aerobiological investigations of heater-coolers in situ and under controlled laboratory conditions; and (4) whole-genome sequencing of clinical and environmental isolates. RESULTS: Eighteen probable cases of cardiopulmonary bypass-associated M. chimaera infection were identified; all except one occurred in adults. Patients had undergone valve replacement in 11 hospitals between 2007 and 2015, a median of 19 months prior to onset (range, 3 months to 5 years). Risk to patients increased after 2010 from <0.2 to 1.65 per 10000 person-years in 2013, a 9-fold rise for infections within 2 years of surgery (rate ratio, 9.08 [95% CI, 1.81-87.76]). Endocarditis was the most common presentation (n = 11). To date, 9 patients have died. Investigations identified aerosol release through breaches in heater-cooler tanks. Mycobacterium chimaera and other pathogens were recovered from water and air samples. Phylogenetic analysis found close clustering of strains from probable cases. CONCLUSIONS: We identified low but escalating risk of severe M. chimaera infection associated with heater-coolers with cases in a quarter of cardiothoracic centers. Our investigations strengthen etiological evidence for the role of heater-coolers in transmission and raise the possibility of an ongoing, international point-source outbreak. Active management of heater-coolers and heightened clinical awareness are imperative given the consequences of infection.

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.

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.

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.

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

BACKGROUND: Antiretroviral 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. METHODS: An 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. RESULTS: A 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. CONCLUSIONS: Genotypic 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.

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

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/

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.

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

BACKGROUND: Previous studies have suggested that there may be an association between some immune-mediated diseases and risk of tuberculosis (TB). METHODS: We 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. RESULTS: In the all-England dataset, there were significantly elevated risks of TB after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, coeliac disease, Crohn's disease, dermatomyositis, Goodpasture's syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), myasthenia gravis, myxedema, pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren's 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)). CONCLUSIONS: These 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.

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.