Risk of vaccine preventable diseases in UK migrants: A serosurvey and concordance analysis.

Background: Vaccine preventable diseases (VPDs) such as measles and rubella cause significant morbidity and mortality globally every year. The World Health Organization (WHO), reported vaccine coverage for both measles and rubella to be 71 % in 2019, indicating an immunity gap. Migrants in the EU/EEA may be at high risk of VPDs due to under-immunisation and poor living conditions. However, there are limited data on VPD seroprotection rates amongst migrants living in the United Kingdom (UK). Methods: We conducted an exploratory cross-sectional serosurvey amongst a sample of adult migrants living in Leicester, UK to: (a) determine seroprotection rates for measles, varicella zoster, and rubella in this group; (b) identify risk factors associated with seronegativity and, (c) understand if self-reported vaccine or diseases history is an effective measure of seroprotection. Participants gave a blood sample and completed a questionnaire asking basic demographic details and vaccine and disease history for the three VPDs. We summarised the data using median and interquartile range (IQR) for non-parametric continuous variables and count and percentage for categorical variables. We used logistic regression to establish predictors of seroprotection against these diseases. We examined the reliability of self-reported vaccination/disease history for prediction of seroprotection through a concordance analysis. Results: 149 migrants were included in the analysis. Seroprotection rates were: varicella zoster 98 %, rubella 92.6 % and measles 89.3 %. Increasing age was associated with seroprotection (OR 1.07 95 % CI 1.01-1.13 for each year increase in age). Migrants from Africa and the Middle East (aOR 15.16 95 % CI 1.31 - 175.06) and South/East Asia and Pacific regions (aOR 15.43 95 %CI 2.38 - 100.00) are significantly more likely to be seroprotected against measles as compared to migrants from Europe and Central Asia. The proportions of migrants unsure about their vaccination and disease history combined were 53.0 % for measles; 57.7 % for rubella; 43.0 % for varicella. There was no agreement between self-reported vaccination/disease history and serostatus. Conclusion: Our findings suggest lower levels of seroprotection against measles in migrants living in Leicester, UK, with younger migrants and those from Europe and Central Asia more likely to lack seroprotection. A high proportion of surveyed migrants were unaware of their vaccination/disease history and self-reported vaccine/disease was a poor predictor of seroprotection against VPDs which is important for clinical decision-making regarding catch-up vaccination in this population. Our results, although derived from a small sample, suggest that there may be gaps in seroimmunity for certain VPDs in particular migrant populations. These findings should inform future qualitative studies investigating barriers to vaccine uptake in migrants and population-level seroprevalence studies aimed at determining individualised risk profiles based on demographic and migration factors.

The impact, effectiveness and outcomes of targeted screening thresholds for programmatic latent tuberculosis infection testing in HIV.

BACKGROUND: Screening and treatment for latent tuberculosis infection (LTBI) are key for TB control. In the UK, the National Institute for Health and Care Excellence (NICE) and the British HIV Association (BHIVA) give conflicting guidance on which groups of people with HIV (PWH) should be screened, and previous national analysis demonstrated heterogeneity in how guidance is applied. There is an urgent need for a firmer clinical effectiveness evidence base on which to build screening policy. METHODS: We conducted a systematic, programmatic LTBI-screening intervention for all PWH receiving care in Leicester, UK. We compared yields (percentage IGRA positive) and number of tests required when applying the NICE and BHIVA testing strategies, as well as strategies targeting screening by TB incidence in patients' countries of birth. RESULTS: Of 1053 PWH tested, 118 were IGRA-positive (11.2%). Positivity was associated with higher TB incidence in country-of-birth [adjusted odds ratio, 50-149 cases compared with <50 cases/100 000: 11.6; 95% confidence interval (CI) 4.79-28.10)]. There was high testing uptake (1053/1069, 98.5%). Appropriate chemoprophylaxis was commenced in 100 of 117 (85.5%) patients diagnosed with LTBI, of whom 96 of 100 (96.0%) completed treatment. Delivering targeted testing to PWH from countries with TB incidence greater than 150 per 100 000 population or any sub-Saharan African country, would have correctly identified 89.8% of all LTBI cases while cutting tests required by 46.1% compared with NICE guidance, performing as well as BHIVA 2018 guidance. CONCLUSION: Targeting screening to higher risk PWH increases yield and reduces the number requiring testing. Our proposed 'PWH-LTBI streamlined guidance' offers a simplified approach, with the potential to improve national LTBI-screening implementation.

Latent tuberculosis screening and treatment in HIV: highly acceptable in a prospective cohort study.

Background: People living with HIV (PLWH) are at increased risk of re-activation of latent tuberculosis infection (LTBI). Although UK and international guidelines identify this group as a priority for LTBI screening and treatment, data on attitudes of PLWH to this policy recommendation are lacking. Methods: A five-point, Likert-style questionnaire was administered to PLWH to assess views and intentions towards accepting LTBI screening and treatment. Subsequent interferon-γ release assay (IGRA) testing was offered, and chemoprophylaxis if required. Influencing demographic and psychological associations with planned, and actual, testing and treatment uptake were assessed using multivariable logistic regression. Results: 444 out of 716 (62%) patients responded. 417 out of 437 (95.4%) expressed intention to accept LTBI testing. The only significant association was the perceived importance of testing to the individual (adjusted odds ratio (aOR) 8.98, 95% CI 2.55-31.67). 390 out of 393 (99.2%) accepted appropriate IGRA screening; 41 out of 390 (10.5%) were positive. 397 out of 431 (92.1%) expressed intention to accept chemoprophylaxis, associated with perceived importance of treatment (aOR 3.52, 95% CI 1.46-8.51), a desire to have treatment for LTBI (aOR 1.77, 95% CI 0.99-3.15) and confidence in taking treatment (aOR 3.77, 95% CI 1.84-7.72). Of those offered chemoprophylaxis, 36 out of 37 (97.3%) accepted and 34 out of 36 (94.4%) completed treatment. There were no correlates with actual screening acceptance. Conclusions: LTBI is common amongst PLWH, highlighting the importance of robust screening and treatment programmes. This study shows that screening and treatment for LTBI is highly acceptable to PLWH and provides strong, objective evidence for policy-makers developing guidelines in this cohort.

Clinical outcomes of patients with and without HIV hospitalized with COVID-19 in England during the early stages of the pandemic: a matched retrospective multi-centre analysis (RECEDE-C19 study).

BACKGROUND: The contribution of HIV to COVID-19 outcomes in hospitalized inpatients remains unclear. We conducted a multi-centre, retrospective matched cohort study of SARS-CoV-2 PCR-positive hospital inpatients analysed by HIV status. METHODS: HIV-negative patients were matched to people living with HIV (PLWH) admitted from 1 February 2020 to 31 May 2020 up to a 3:1 ratio by the following: hospital site, SARS-CoV-2 test date ± 7 days, age ± 5 years, gender, and index of multiple deprivation decile ± 1. The primary objective was clinical improvement (two-point improvement or better on a seven-point ordinal scale) or hospital discharge by day 28, whichever was earlier. RESULTS: A total of 68 PLWH and 181 HIV-negative comparators were included. In unadjusted analyses, PLWH had a reduced hazard of achieving clinical improvement or discharge [adjusted hazard ratio (aHR) = 0.57, 95% confidence interval (CI): 0.39-0.85, p = 0.005], but this association was ameliorated (aHR = 0.70, 95% CI: 0.43-1.17, p = 0.18) after additional adjustment for ethnicity, frailty, baseline hypoxaemia, duration of symptoms prior to baseline, body mass index (BMI) categories and comorbidities. Baseline frailty (aHR = 0.79, 95% CI: 0.65-0.95, p = 0.011), malignancy (aHR = 0.37, 95% CI 0.17, 0.82, p = 0.014) remained associated with poorer outcomes. The PLWH were more likely to be of black, Asian and minority ethnic background (75.0% vs 48.6%, p = 0.0002), higher median clinical frailty score [3 × interquartile range (IQR): 2-5 vs, 2 × IQR: 1-4, p = 0.0069), and to have a non-significantly higher proportion of active malignancy (14.4% vs 9.9%, p = 0.29). CONCLUSIONS: Adjusting for confounding comorbidities and demographics in a matched cohort ameliorated differences in outcomes of PLWH hospitalized with COVID-19, highlighting the importance of an appropriate comparison group when assessing outcomes of PLWH hospitalized with COVID-19.

Tuberculosis incidence in country of origin is a key determinant of the risk of active tuberculosis in people living with HIV: Data from a 30-year observational cohort study.

INTRODUCTION: People living with HIV (PLWH) are at high risk of active tuberculosis (TB) but this risk in the era of antiretroviral treatment (ART) remains unclear. It is critical to identify the groups who should be prioritised for latent TB (LTBI) screening. In this study we identified the risk factors associated with developing incident TB disease, by analysing a 30-year observational cohort. METHODS: We evaluated PLWH in Leicester, UK, between 1983 and 2017 to ascertain those who developed active TB and the timing of this in relation to HIV diagnosis; whether before, concurrently with, or more than 3 months after the diagnosis of HIV (incident TB). Predictors of incident TB were ascertained using Cox proportional hazards models. RESULTS: In all, 325 out of 2158 (15.1%) PLWH under care had had active TB; 64/325 (19.7%) prior to HIV diagnosis, 161/325 (49.5%) concurrently with/within 3 months of HIV diagnosis and 100/325 (30.8%) had incident TB. Incident TB risk was 4.57/1000 person-years. Increased TB incidence in the country of birth was associated with an increased risk of developing incident TB [50-149/100 000 population, adjusted hazard ratio (AHR) = 3.10, 95% CI: 0.94-10.20; 150-249/100 000 population, AHR = 7.14, 95% CI: 3.46-14.74; 250-349/100 000 population, AHR = 5.90, 95% CI: 2.32-14.99; ≥ 350/100 000 population, AHR = 3.96, 95% CI: 1.39-11.26]. CONCLUSIONS: Tuberculosis risk remains high among PLWH and is related to TB incidence in the country of birth. Further work is required to determine whether specific groups of PLWH should be targeted for programmatic LTBI screening, and whether it will result in high uptake and completion of chemoprophylaxis and is cost-effective for widespread implementation.

Strategic treatment optimization for HCV (STOPHCV1): a randomised controlled trial of ultrashort duration therapy for chronic hepatitis C.

Background: The world health organization (WHO) has identified the need for a better understanding of which patients with hepatitis C virus (HCV) can be cured with ultrashort course HCV therapy. Methods: A total of 202 individuals with chronic HCV were randomised to fixed-duration shortened therapy (8 weeks) vs variable-duration ultrashort strategies (VUS1/2). Participants not cured following first-line treatment were retreated with 12 weeks' sofosbuvir/ledipasvir/ribavirin. The primary outcome was sustained virological response 12 weeks (SVR12) after first-line treatment and retreatment. Participants were factorially randomised to receive ribavirin with first-line treatment. Results: All evaluable participants achieved SVR12 overall (197/197, 100% [95% CI 98-100]) demonstrating non-inferiority between fixed-duration and variable-duration strategies (difference 0% [95% CI -3.8%, +3.7%], 4% pre-specified non-inferiority margin). First-line SVR12 was 91% [86%-97%] (92/101) for fixed-duration vs 48% [39%-57%] (47/98) for variable-duration, but was significantly higher for VUS2 (72% [56%-87%] (23/32)) than VUS1 (36% [25%-48%] (24/66)). Overall, first-line SVR12 was 72% [65%-78%] (70/101) without ribavirin and 68% [61%-76%] (69/98) with ribavirin (p=0.48). At treatment failure, the emergence of viral resistance was lower with ribavirin (12% [2%-30%] (3/26)) than without (38% [21%-58%] (11/29), p=0.01). Conclusions: Unsuccessful first-line short-course therapy did not compromise retreatment with sofosbuvir/ledipasvir/ribavirin (100% SVR12). SVR12 rates were significantly increased when ultrashort treatment varied between 4-7 weeks rather than 4-6 weeks. Ribavirin significantly reduced resistance emergence in those failing first-line therapy. ISRCTN Registration: 37915093 (11/04/2016).

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.

BACKGROUND: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials. METHODS: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality. RESULTS: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. CONCLUSIONS: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.).

Socio-demographic heterogeneity in the prevalence of COVID-19 during lockdown is associated with ethnicity and household size: Results from an observational cohort study.

BACKGROUND: Accumulating evidence indicates that COVID-19 causes adverse outcomes in ethnic minority groups. However, little is known about the impact of ethnicity and household size on acquiring infection with SARS-CoV-2. METHODS: We undertook a retrospective cohort study, in Leicester (UK), of all individuals assessed for COVID-19 with polymerase chain reaction (PCR) testing at University Hospitals of Leicester NHS Trust between 1st March and 28th April 2020. We used logistic regression to identify sociodemographic, clinical and temporal factors associated with SARS-CoV-2 PCR positivity before/after lockdown. FINDINGS: 971/4051 (24.0%) patients with suspected COVID-19 were found to be PCR positive for SARS-CoV-2. PCR positivity was more common amongst individuals from ethnic minortiy backgrounds than their White counterparts (White 20.0%, South Asian 37.5%, Black 36.1%, Other 32.2%; p<0.001 for all ethnic minority groups vs White). After adjustment, compared to White ethnicity, South Asian (aOR 2.44 95%CI 2.01, 2.97), Black (aOR 2.56 95%CI 1.71, 3.84) and Other (aOR 2.53 95%CI 1.74, 3.70) ethnicities were more likely to test positive, as were those with a larger estimated household size (aOR 1.06 95%CI 1.02, 1.11). We saw increasing proportions of positive tests in the three weeks post-lockdown amongst the ethnic minority , but not the White, cohort. Estimated household size was associated with PCR positivity after, but not before, lockdown (aOR 1.10 95%CI 1.03, 1.16). INTERPRETATION: In individuals presenting with suspected COVID-19, those from ethnic minority communities and larger households had an increased likelihood of SARS-CoV-2 PCR positivity. Pandemic control measures may have more rapid impact on slowing viral transmission amongst those of White ethnicity compared to ethnic minority groups, Research is urgently required to understand the mechanisms underlying these disparities and whether public health interventions have differential effects on individuals from ethnic minority groups. FUNDING: 10.13039/100006662 NIHR.

Clinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study.

BACKGROUND: The clinical utility of interferon-γ release assays (IGRAs) for diagnosis of active tuberculosis is unclear, although they are commonly used in countries with a low incidence of tuberculosis. We aimed to resolve this clinical uncertainty by determining the accuracy and utility of commercially available and second-generation IGRAs in the diagnostic assessment of suspected tuberculosis in a low-incidence setting. METHODS: We did a prospective cohort study of adults with suspected tuberculosis in routine secondary care in England. Patients were tested for Mycobacterium tuberculosis infection at baseline with commercially available (T-SPOT.TB and QuantiFERON-TB Gold In-Tube [QFT-GIT]) and second-generation (incorporating novel M tuberculosis antigens) IGRAs and followed up for 6-12 months to establish definitive diagnoses. Sensitivity, specificity, positive and negative likelihood ratios, and predictive values of the tests were determined. FINDINGS: Of the 1060 adults enrolled in the study, 845 were included in the analyses and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for all tuberculosis diagnosis, including culture-confirmed and highly probable cases, was 81·4% (95% CI 76·6-85·3), which was higher than QFT-GIT (67·3% [62·0-72·1]). Second-generation IGRAs had a sensitivity of 94·0% (90·0-96·4) for culture-confirmed tuberculosis and 89·2% (85·2-92·2) when including highly probable tuberculosis, giving a negative likelihood ratio for all tuberculosis cases of 0·13 (95% CI 0·10-0·19). Specificity ranged from 86·2% (95% CI 82·3-89·4) for T-SPOT.TB to 80·0% (75·6-83·8) for second-generation IGRAs. INTERPRETATION: Commercially available IGRAs do not have sufficient accuracy for diagnostic evaluation of suspected tuberculosis. Second-generation tests, however, might have sufficiently high sensitivity, low negative likelihood ratio, and correspondingly high negative predictive value in low-incidence settings to facilitate prompt rule-out of tuberculosis. FUNDING: National Institute for Health Research.

The Hepatitis C Awareness Through to Treatment (HepCATT) study: improving the cascade of care for hepatitis C virus-infected people who inject drugs in England.

BACKGROUND AND AIMS: Previous studies have shown low rates of diagnosis and treatment of hepatitis C virus (HCV) infection in people who inject drugs (PWID). Our aims were to test the effect of a complex intervention [Hepatitis C Awareness Through to Treatment (HepCATT)] in drug and alcohol clinics-primarily, on engagement of HCV-positive PWID with therapy and, secondarily, on testing for HCV, referral to hepatology services and start of HCV treatment. DESIGN AND SETTING: A non-randomized pilot study in three specialist addiction clinics in England comparing an intervention year (starting between September 2015 and February 2016) with a baseline year (2014), together with three control clinics. PARTICIPANTS: Analysis included all attendees at the intervention and control specialist addiction clinics identified as PWID. INTERVENTION: The intervention comprised the placement of a half-time facilitator in each clinic for 12 months with the brief to increase diagnosis of HCV infection within clients at those services and the engagement of diagnosed individuals with an appropriate care pathway. The facilitator undertook various activities, which could include training of key workers, direct interaction with clients, streamlining and support for hepatology appointments and introduction of dried blood-spot testing. MEASUREMENTS: For each clinic and period, we obtained the total number of clients and, as relevant, their status as PWID, tested for HCV, known HCV-positive, engaged with HCV therapy or treated. FINDINGS: Compared with baseline, there was strong evidence that engagement with HCV therapy in the intervention year increased (P < 0.001) more in the HepCATT centres than controls, up + 31 percentage points [95% confidence interval (CI) = 19-43] versus -12 (CI = -31 to + 6) and odds ratio (OR) = 9.99 (CI = 4.42-22.6) versus 0.35 (CI = 0.08-1.56). HepCATT centres also had greater increases in HCV testing (OR = 3.06 versus 0.78, P < 0.001), referral to hepatology (OR = 9.60 versus 0.56, P < 0.001) and treatment initiation (OR = 9.5 versus 0.74, P < 0.001). CONCLUSIONS: Introducing a half-time facilitator into drug and alcohol clinics in England increased engagement of HCV-positive people who inject drugs with hepatitis C virus care pathways, with increased uptake also of testing, referral to hepatology and initiation of treatment.

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. OBJECTIVES: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. DESIGN: Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. SETTING: UK NHS trust hospitals. PARTICIPANTS: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. INTERVENTIONS: Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). MAIN OUTCOME MEASURES: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. RESULTS: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50-76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). CONCLUSIONS: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. FUTURE WORK: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. TRIAL REGISTRATIONS: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.

A nested case-control study of predictors for tuberculosis recurrence in a large UK Centre.

BACKGROUND: Tuberculosis (TB) recurrence represents a challenge to control programs. In low incidence countries, the prevailing risk factors leading to recurrence are poorly characterised. METHODS: We conducted a nested case-control study using the Leicester TB service TBIT database. Cases were identified from database notifications between 1994 and 2014. Controls had one episode and were matched to cases on a ratio of two to one by the date of notification. Multiple imputation was used to account for missing data. Multivariate conditional logistic regression analysis was employed to identify clinical, sociodemographic and TB specific risk factors for recurrence. RESULTS: From a cohort of 4628 patients, 82 TB recurrences occurred (1.8%). Nineteen of 82 patients had paired isolates with MIRU-VNTR strain type profiles available, of which 84% were relapses and 16% reinfections. On multivariate analysis, smoking (OR 3.8; p = 0.04), grade 3/4 adverse drug reactions (OR 5.6; p = 0.02), ethnicity 'Indian subcontinent' (OR 8.5; p = <0.01), ethnicity 'other' (OR 31.2; p = 0.01) and receipt of immunosuppressants (OR 6.8; p = <0.01) were independent predictors of TB recurrence. CONCLUSIONS: Within this UK setting, the rate of TB recurrence was low, predominantly due to relapse. The identification of an elevated recurrence risk amongst the ethnic group contributing most cases to the national TB burden presents an opportunity to improve individual and population health.

Which HIV-infected adults with high CD4 T-cell counts benefit most from immediate initiation of antiretroviral therapy? A post-hoc subgroup analysis of the START trial.

BACKGROUND: Immediate initiation of antiretroviral therapy (ART) in asymptomatic adults with CD4 counts higher than 500 cells per µL, as recommended, might not always be possible in resource-limited settings. We aimed to identify subgroups of individuals who would benefit most from immediate treatment. METHODS: The START trial was a randomised controlled trial in asymptomatic, HIV-positive adults previously untreated with ART. Participants with CD4 counts higher than 500 cells per µL were randomly assigned to receive immediate ART or to defer ART until CD4 counts were lower than 350 cells per µL. The primary endpoint of the study was serious AIDS-defining illnesses or death from AIDS and serious non-AIDS illnesses or non-AIDS-related death. In this post-hoc analysis, we estimated event rates and absolute risk reduction with immediate versus deferred ART, overall and by subgroup. Subgroups were prespecified in the study protocol or formed post hoc on the basis of baseline characteristics associated with morbidity and mortality in people with HIV. For continuous characteristics, approximate terciles were chosen as subgroup cutoff points, unless different cutoffs were clinically meaningful (eg, age ≥50 years). We estimated the number needed to treat immediately with ART for 1 year to prevent one primary event. Heterogeneity in the absolute risk reduction between subgroups was assessed with bootstrap tests. The START trial is registered with ClinicalTrials.gov, number NCT00867048. FINDINGS: Between April 15, 2009, and Dec 23, 2013, we enrolled 4684 participants from 35 countries across five continents, of whom 2325 were assigned to immediate ART and 2359 were assigned to deferred ART. The primary endpoint occurred in 42 participants in the immediate ART group (0·58 events per 100 person-years) and 100 participants in the deferred ART group (1·37 events per 100 person-years). The absolute risk reduction was 0·80 (95% CI 0·48-1·13) per 100 person-years with immediate treatment, and the number needed to treat immediately to prevent one event was 126 (95% CI 89-208). Significant heterogeneity in absolute risk reduction with immediate ART was found across subgroups according to age (p=0·0022), CD4 to CD8 ratio (p=0·0007), and plasma HIV RNA viral load (p=0·033) at baseline. The highest absolute risk reductions and the lowest numbers needed to treat were found in participants aged 50 years or older, those with CD4 to CD8 ratios of less than 0·5, and those with plasma HIV RNA viral loads of 50 000 copies per mL or higher. INTERPRETATION: Asymptomatic, ART-naive adults with CD4 counts higher than 500 cells per µL who are older, have a low CD4 to CD8 ratio, or a high plasma HIV RNA viral load benefit most from immediate initiation of ART and should be prioritised for treatment. FUNDING: US National Institute of Allergy and Infectious Diseases.