Determinants of non-adherence to anti-TB treatment in high income, low TB incidence settings: a scoping review.

BACKGROUND: Improving adherence to anti-TB treatment is a public health priority in high-income, low incidence (HILI) regions. We conducted a scoping review to identify reported determinants of non-adherence in HILI settings.METHODS: Key terms related to TB, treatment and adherence were used to search MEDLINE, EMBASE, Web of Science, PsycINFO and CINAHL in June 2019. Quantitative studies examining determinants (demographic, clinical, health systems or psychosocial) of non-adherence to anti-TB treatment in HILI settings were included.RESULTS: From 10,801 results, we identified 24 relevant studies from 10 countries. Definitions and methods of assessing adherence were highly variable, as were documented levels of non-adherence (0.9-89%). Demographic factors were assessed in all studies and clinical factors were frequently assessed (23/24). Determinants commonly associated with non-adherence were homelessness, incarceration, and alcohol or drug misuse. Health system (8/24) and psychosocial factors (6/24) were less commonly evaluated.CONCLUSION: Our review identified some key factors associated with non-adherence to anti-TB treatment in HILI settings. Modifiable determinants such as psychosocial factors are under-evidenced and should be further explored, as these may be better targeted by adherence support. There is an urgent need to standardise definitions and measurement of adherence to more accurately identify the strongest determinants.

An open label, randomised controlled trial of rifapentine versus rifampicin based short course regimens for the treatment of latent tuberculosis in England: the HALT LTBI pilot study.

BACKGROUND: Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks. METHODS: An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid ('intervention') or a daily combination of rifampicin/isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded. RESULTS: Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms. CONCLUSION: In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment. TRIAL REGISTRATION: The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ).

Discordance in latent tuberculosis (TB) test results in patients with end-stage renal disease.

OBJECTIVES: This natural experiment was designed to assess the impact of exposure to an active case of tuberculosis (TB) on a group of immunosuppressed individuals, with end-stage renal disease over an extended follow-up. STUDY DESIGN: Close contacts of people with sputum smear-positive Mycobacterium tuberculosis are at high risk of infection, particularly immunosuppressed individuals. An infectious TB healthcare worker worked in a renal dialysis unit for a month before diagnosis, with 104 renal dialysis patients, was exposed for ≥8 h. METHODS: Patients were informed and invited for screening 8-10 weeks postexposure. They either underwent standard two-step assessment with tuberculin skin test (TST) and QuantiFERON®-TB Gold (Cellestis GmbH; QFN) interferon-gamma release assay (IGRA) or after consent, enrolled in a study where these two tests were performed simultaneously with T-SPOT®-TB (Oxford Immunotec Ltd; TSPOT). Patients within the study were followed up for 2 years from exposure, with QFN and TSPOT repeated at months 3 and 6 from the first testing. RESULTS: Of 104 exposed individuals, 75 enrolled in the study. There was a high degree of discordance among QFN, TSPOT and TST. This was seen at both the first time point and also over time in subjects who were retested. No patients had active TB at the baseline testing. None received treatment for latent TB infection. Over the following 2 years, no one developed TB disease. CONCLUSION: This study suggests that there is a low risk of progression to active TB in low-incidence countries even in high-risk groups. This plus the degree of the test result discordance emphasises the complexities of managing TB in such settings as it is unclear which of these tests, if any, provides the best diagnostic accuracy.

Hepatitis C among vulnerable populations: A seroprevalence study of homeless, people who inject drugs and prisoners in London.

Injecting drugs substantially increases the risk of hepatitis C virus (HCV) infection and is common in the homeless and prisoners. Capturing accurate data on disease prevalence within these groups is challenging but is essential to inform strategies to reduce HCV transmission. The aim of this study was to estimate the prevalence of HCV in these populations. We conducted a cross-sectional study between May 2011 and June 2013 in London and, using convenience sampling, recruited participants from hostels for the homeless, drug treatment services and a prison. A questionnaire was administered and blood samples were tested for hepatitis C. We recruited 491 individuals who were homeless (40.7%), 205 drug users (17%) and 511 prisoners (42.3%). Eight per cent of patients (98/1207, 95% CI: 6.7%-9.8%) had active HCV infection and 3% (38/1207, 95% CI: 2.3%-4.3%) past HCV infection. Overall, one quarter (51/205) of people recruited in drug treatment services, 13% (65/491) of people from homeless residential sites and 4% (20/511) prisoners in this study were anti-HCV positive. Seventy-seven of the 136 (56.6%, 95% CI: 47.9%-65%) of HCV infected participants identified had a history of all three risk factors (homelessness, imprisonment and drug use), 27.3% (95% CI: 20.1%-35.6%) had 2 overlapping risk factors, and 15.4% (95% CI: 10.6%-23.7%) one risk factor. Drug treatment services, prisons and homelessness services provide good opportunities for identifying hepatitis C-infected individuals. Effective models need to be developed to ensure case identification in these settings that can lead to an effective treatment and an efficient HCV prevention.

Active case finding and treatment adherence in risk groups in the tuberculosis pre-elimination era.

Vulnerable populations, including homeless persons, high-risk drug and alcohol users, prison inmates and other marginalised populations, contribute a disproportionate burden of tuberculosis (TB) cases in low-incidence settings. Drivers of this disease burden include an increased risk of both TB transmission in congregate settings, and progression from infection to active disease. Late diagnosis and poor treatment completion further propagate the epidemic and fuel the acquisition of drug resistance. These groups are therefore a major priority for TB control programmes in low-incidence settings. Targeted strategies include active case finding (ACF) initiatives and interventions to improve treatment completion, both of which should be tailored to local populations. ACF usually deploys mobile X-ray unit screening, which allows sensitive, high-throughput screening with immediate availability of results. Such initiatives have been found to be effective and cost-effective, and associated with reductions in proxy measures of transmission in hard-to-reach groups. The addition of point-of-care molecular diagnostics and automated X-ray readers may further streamline the screening pathway. There is little evidence to support interventions to improve adherence among these risk groups. Such approaches include enhanced case management and directly observed treatment, while video-observed therapy (currently under evaluation) appears to be a promising tool for the future. Integrating outreach services to include both case detection and case-management interventions that share a resource infrastructure may allow cost-effectiveness to be maximised. Integrating screening and treatment for other diseases that are prevalent among targeted risk groups into TB outreach interventions may further improve cost-effectiveness. This article reviews the existing literature, and highlights priorities for further research.

The challenge of estimating tuberculosis mortality accurately in England and Wales.

BACKGROUND: Accurate estimates of tuberculosis (TB) mortality are required to monitor progress towards the World Health Organization End TB goal of reducing TB deaths by 95% by 2035. We compared TB death data for England and Wales from the national surveillance system (Enhanced Tuberculosis Surveillance System [ETS]) and the vital registration system from the Office for National Statistics (ONS). METHODS: TB cases notified in ETS were matched to deaths in ONS (dONS) with International Classification of Diseases, Tenth Revision (ICD-10) codes indicating that TB caused/contributed to the death (A15-A19). Deaths captured in one but not both systems were assessed to identify if ONS captured all TB deaths and if there was under-notification of TB in ETS. We stratified deaths into active TB, TB sequelae, incidental deaths and not TB. RESULTS: Between 2005 and 2015, there were fewer deaths in ETS (dETS) than dONS with ICD-10 codes A15-A19 (n = 4207 vs. n = 6560); 57% of dETS were recorded as dONS and 53% of dONS were notified to ETS. A total of 9289 deaths were identified from dETS and dONS: 64% were due to active TB, 23% were TB sequelae, 6% were incidental and 7% were not TB. CONCLUSIONS: TB deaths in ETS and ONS differ substantially. Almost one third of TB deaths recorded by ONS are not due to active TB; this can be amended through coding changes.

Increasing incidence of HIV- associated tuberculosis in Romanian injecting drug users.

BACKGROUND: A high prevalence of tuberculosis (TB) among HIV-positive injecting drug users (IDUs) may fuel the TB epidemic in the general population of Romania. We determined the frequency and characteristics of TB in HIV-infected IDUs referred to a national centre. METHODS: Prospective observational cohort study of all newly-diagnosed HIV-positive IDUs admitted to Victor Babes Hospital, Bucharest, between January 2009 and December 2014. Socio-demographics, clinical characteristics and outcomes of HIV/TB co-infected IDUs were compared to HIV-positive IDUs without TB. RESULTS: 170/598 (28.5%) HIV-infected IDUs were diagnosed with TB. The prevalence increased from 12.5% in 2009 to 32.1% in 2014 (P < 0.001). HIV/TB co-infected individuals had lower median CD4 cell counts 75 (vs. 450/mm3 , P < 0.0001) and higher median HIV viral loads 5.6 log10 (vs. 4.9 log10 , P < 0.0001) when presenting to healthcare services. 103/170 (60.6%) HIV/TB co-infected IDUs were diagnosed with pulmonary TB. Resistant Mycobacterium tuberculosis strains were common, with 18/105 (17.1%) of patients having Multi-Drug Resistant (MDR) disease. Higher mortality rate was associated with TB co-infection (P < 0.0001), extra-pulmonary TB (P = 0.0026) and extensively drug resistant TB (P = 0.024). CONCLUSIONS: Tuberculosis (TB) is an increasing problem in HIV-infected IDUs in Romania. Presentation is often with advanced HIV, significant TB drug resistance and consequent outcomes are poor.

Mycobacterium tuberculosis and whole-genome sequencing: how close are we to unleashing its full potential?

BACKGROUND: Nearly two decades after completion of the genome sequence of Mycobacterium tuberculosis (MTB), and with the advent of next generation sequencing technologies (NGS), whole-genome sequencing (WGS) has been applied to a wide range of clinical scenarios. Starting in 2017, England is the first country in the world to pioneer its use on a national scale for the diagnosis of tuberculosis, detection of drug resistance, and typing of MTB. AIMS: This narrative review critically analyses the current applications of WGS for MTB and explains how close we are to realizing its full potential as a diagnostic, epidemiologic, and research tool. SOURCES: We searched for reports (both original articles and reviews) published in English up to 31 May 2017, with combinations of the following keywords: whole-genome sequencing, Mycobacterium, and tuberculosis. MEDLINE, Embase, and Scopus were used as search engines. We included articles that covered different aspects of whole-genome sequencing in relation to MTB. CONTENT: This review focuses on three main themes: the role of WGS for the prediction of drug susceptibility, MTB outbreak investigation and genetic diversity, and research applications of NGS. IMPLICATIONS: Many of the original expectations have been accomplished, and we believe that with its unprecedented sensitivity and power, WGS has the potential to address many unanswered questions in the near future. However, caution is still needed when interpreting WGS data as there are some important limitations to be aware of, from correct interpretation of drug susceptibilities to the bioinformatic support needed.

Tuberculosis treatment outcomes among disadvantaged patients in India.

Setting: Urban slums and poor rural areas in India, 2012-2014. Objective: To describe the characteristics of tuberculosis (TB) patients enrolled in treatment through Operation ASHA, a non-governmental organisation serving disadvantaged populations in India, and to identify risk factors for unfavourable treatment outcomes. Design: This was a retrospective cohort study. Patient characteristics were assessed for their relationship with treatment outcomes using mixed effects logistic regression, adjusting for clustering by treatment centre and Indian state. Outcomes were considered favourable (cured/treatment completed) or unfavourable (treatment failure, loss to follow-up, death, switch to multidrug-resistant TB treatment, transfer out). Results: Of 8415 patients, 7148 (84.9%) had a favourable outcome. On multivariable analysis, unfavourable outcomes were more common among men (OR 1.31, 95%CI 1.15-1.51), older patients (OR 1.12, 95%CI 1.04-1.21) and previously treated patients (OR 2.05, 95%CI 1.79-2.36). Compared to pulmonary smear-negative patients, those with extra-pulmonary disease were less likely to have unfavourable outcomes (OR 0.72, 95%CI 0.60-0.87), while smear-positive pulmonary patients were more likely to have unfavourable outcomes (OR 1.38, 95%CI 1.15-1.66 for low [scanty/1+] and OR 1.71, 95%CI 1.44-2.04 for high [2+/3+] positive smears). Conclusion: The treatment success rate within Operation ASHA is comparable to that reported nationally for India. Men, older patients, retreatment cases and smear-positive pulmonary TB patients may need additional interventions to ensure a favourable outcome.

Contexte: Bidonvilles urbains et zones rurales pauvres, Inde, 2012­2014.Objectif: Décrire les caractéristiques des patients atteints de tuberculose (TB) enrôlés dans un traitement à travers l'Opération ASHA, une organisation non-gouvernementale au service des populations désavantagées en Inde, et identifier les facteurs de risque de résultat défavorable du traitement.Schéma: Etude rétrospective de cohorte. Les caractéristiques des patients ont été évaluées en fonction de leur relation avec les résultats du traitement grâce à une régression logistique à effets mixtes ajustée sur le regroupement par centre de traitement et par l'état d'Inde. Le résultat a été considéré comme favorable (guéri/traitement achevé) ou défavorable (échec du traitement, perte de vue, décès, évolution vers un traitement de TB multirésistante, transfert).Résultats: De 8415 patients, 7148 (84,9%) ont eu un résultat favorable. En analyse multi-variable, les résultats défavorables ont été plus fréquents parmi les hommes (OR 1,31 ; IC 95% 1,15­1,51), les patients plus âgés (OR 1,12 ; IC95% 1,04­1,21) et les patients déjà traités (OR 2,05 ; IC95% 1,79­2,36). Comparés aux patients atteints de TB pulmonaire à frottis négatif, les patients atteints de TB extra-pulmonaire ont été moins susceptibles d'avoir un résultat défavorable (OR 0,72 ; IC95% 0,60­0,87), tandis que les patients atteints de TB pulmonaire à frottis positif ont été plus susceptibles d'avoir un résultat défavorable (OR 1,38 ; IC95% 1,15­1,66 pour les frottis positifs faibles [rares/1+] et OR 1,71 ; IC95% 1,44­2,04 pour les frottis élevés [2+/3+]).Conclusion: Le taux de succès du traitement dans le cadre de l'Opération ASHA est comparable à celui rapporté au niveau national en Inde. Les hommes, les patients plus âgés, les cas en retraitement et les patients atteints de TB pulmonaire à frottis positif pourraient avoir besoin d'interventions supplémentaires afin d'assurer un résultat favorable.

Marco de referencia: Barriadas urbanas y zonas rurales pobres en la India del 2012 al 2014.Objetivo: Describir las características de los pacientes con tuberculosis (TB) inscritos en tratamiento en el marco de la Operación ASHA, que es una organización no gubernamental que atiende a las poblaciones desfavorecidas en la India, y determinar los factores de riesgo de obtener desenlaces terapéuticos desfavorables.Método: Un estudio retrospectivo de cohortes. Las características de los pacientes se evaluaron con respecto a los desenlaces terapéuticos, mediante un análisis de regresión logística de efectos mixtos y ajuste con relación a los conglomerados, según el centro de tratamiento y el estado de la India. Los desenlaces se consideraron favorables (curación o tratamiento completo) o desfavorables (fracaso terapéutico, pérdida durante el seguimiento, muerte, cambio de tratamiento por TB multirresistente o transferencia a otro centro).Resultados: De los 8415 pacientes, en 7148 el desenlace fue favorable (84,9%). El análisis multivariante reveló que los desenlaces desfavorables eran más frecuentes en los hombres (OR 1,31; IC95% 1,15­1,51), los ancianos (OR 1,12; IC95% 1,04­1,21) y en los pacientes con antecedente de tratamiento antituberculoso (OR 2,05; IC95% 1,79­2,36). Tomando como referencia a los pacientes con baciloscopia negativa, los desenlaces desfavorables fueron menos probables en los pacientes con TB extrapulmonar (OR 0,72; IC95% 0,60­0,87) y más probables en los pacientes con TB pulmonar y baciloscopia positiva (OR 1,38; IC95% 1,15­1,66 para las baciloscopias bajas, de escasos bacilos a 1+ y OR 1,71; IC95% 1,44­2,04 para las baciloscopia altas, de 2+ o 3+).Conclusión: La tasa de éxito del tratamiento antituberculoso en el marco de la Operación ASHA es equivalente a la notificada a escala nacional en la India. Los pacientes de sexo masculino, los ancianos, los casos en retratamiento y los que presentan una TB pulmonar con baciloscopia positiva pueden necesitar intervenciones complementarias a fin de fomentar los desenlaces favorables.

Respiratory health status is impaired in UK HIV-positive adults with virologically suppressed HIV infection.

OBJECTIVES: We sought to evaluate whether people living with HIV (PLWH) using effective antiretroviral therapy (ART) have worse respiratory health status than similar HIV-negative individuals. METHODS: We recruited 197 HIV-positive and 93 HIV-negative adults from HIV and sexual health clinics. They completed a questionnaire regarding risk factors for respiratory illness. Respiratory health status was assessed using the St George's Respiratory Questionnaire (SGRQ) and the Medical Research Council (MRC) breathlessness scale. Subjects underwent spirometry without bronchodilation. RESULTS: PLWH had worse respiratory health status: the median SGRQ Total score was 12 [interquartile range (IQR) 6-25] in HIV-positive subjects vs. 6 (IQR 2-14) in HIV-negative subjects (P < 0.001); breathlessness was common in the HIV-positive group, where 47% compared with 24% had an MRC breathlessness score ≥ 2 (P = 0.001). Eighteen (11%) HIV-positive and seven (9%) HIV-negative participants had airflow obstruction. In multivariable analyses (adjusted for age, gender, smoking, body mass index and depression), HIV infection remained associated with higher SGRQ and MRC scores, with an adjusted fold-change in SGRQ Total score of 1.54 [95% confidence interval (CI) 1.14-2.09; P = 0.005] and adjusted odds ratio of having an MRC score of ≥ 2 of 2.45 (95% CI 1.15-5.20; P = 0.02). Similar findings were obtained when analyses were repeated including only HIV-positive participants with a viral load < 40 HIV-1 RNA copies/mL. CONCLUSIONS: Despite effective ART, impaired respiratory health appears more common in HIV-positive adults, and has a significant impact on health-related quality of life.

Isoniazid-resistant tuberculosis: a cause for concern?

The drug isoniazid (INH) is a key component of global tuberculosis (TB) control programmes. It is estimated, however, that 16.1% of TB disease cases in the former Soviet Union countries and 7.5% of cases outside of these settings have non-multidrug-resistant (MDR) INH resistance. Resistance has been linked to poorer treatment outcomes, post-treatment relapse and death, at least for specific sites of disease. Multiple genetic loci are associated with phenotypic resistance; however, the relationship between genotype and phenotype is complex, and restricts the use of rapid sequencing techniques as part of the diagnostic process to determine the most appropriate treatment regimens for patients. The burden of resistance also influences the usefulness of INH preventive therapy. Despite seven decades of INH use, our knowledge in key areas such as the epidemiology of resistant strains, their clinical consequences, whether tailored treatment regimens are required and the role of INH resistance in fuelling the MDR-TB epidemic is limited. The importance of non-MDR INH resistance needs to be re-evaluated both globally and by national TB control programmes.

What are the most efficacious treatment regimens for isoniazid-resistant tuberculosis? A systematic review and network meta-analysis.

INTRODUCTION: Consensus on the best treatment regimens for patients with isoniazid-resistant TB is limited; global treatment guidelines differ. We undertook a systematic review and meta-analysis using mixed-treatment comparisons methodology to provide an up-to-date summary of randomised controlled trials (RCTs) and relative regimen efficacy. METHODS: Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Extracted data were inputted into fixed-effects and random-effects models. ORs for all possible network comparisons and hierarchical rankings for different regimens were obtained. RESULTS: 12 604 records were retrieved and 118 remained postextraction, representing 59 studies-27 standalone and 32 with multiple papers. In comparison to a baseline category that included the WHO-recommended regimen for countries with high levels of isoniazid resistance (rifampicin-containing regimens using fewer than three effective drugs at 4 months, in which rifampicin was protected by another effective drug at 6 months, and rifampicin was taken for 6 months), extending the duration of rifampicin and increasing the number of effective drugs at 4 months lowered the odds of unfavourable outcomes (treatment failure or the lack of microbiological cure; relapse post-treatment; death due to TB) in a fixed-effects model (OR 0.31 (95% credible interval 0.12-0.81)). In a random-effects model all estimates crossed the null. CONCLUSIONS: Our systematic review and network meta-analysis highlight a regimen category that may be more efficacious than the WHO population level recommendation, and identify knowledge gaps where data are sparse. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42014015025.

Treatment regimens for rifampicin-resistant tuberculosis: highlighting a research gap.

Treatment guidance for non-multidrug-resistant (MDR) rifampicin-resistant (RMP-R) tuberculosis (TB) is variable. We aimed to undertake a systematic review and meta-analysis of the randomised controlled trial (RCT) data behind such guidelines to identify the most efficacious treatment regimens. Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Despite 12 604 records being retrieved, only three studies reported treatment outcomes by regimen for patients with non-MDR RMP-R disease, preventing meta-analysis. Our systematic review highlights a substantial gap in the literature regarding evidence-based treatment regimens for RMP-R TB.

Waist-to-height ratio as a measure of abdominal obesity in southern Chinese and European children and adolescents.

BACKGROUND: Waist-to-height ratio (WHtR), with a 0.5 threshold (WHtR0.5), is regarded as a simple age- and gender-independent criterion of abdominal obesity (AO) and a better predictor than the 90th percentile of waist circumference (WCP90). OBJECTIVE: An analysis of gender and ethnic differences of WHtR and other AO indices between children and adolescents from southern China (HK: Hong-Kong, China) and Europe (LD: Lódz, Poland). SUBJECTS: Two large cross-sectional surveys of children and adolescents aged 7-19 years, one from LD (13 172) and one from HK (14 566). METHODS: The percentile and standardized values of WHtR and other parameters (WC, body mass index (BMI)) were assessed using the LMS method. The WHtR values corresponding to WCP90 and to the BMI definition of global obesity (BMIP95) were evaluated with the polynomial regression model. The compliance of the AO prevalence data, obtained with two criteria (WCP90 vs WHtR0.5) was analyzed using Cohen's kappa index (κC). RESULTS: The WHtR data of Polish subjects were generally higher than those of their HK peers, and the ethic differences increased with age. The WHtR values of HK boys showed a stronger relationship with BMI z-score. WHtR corresponding to WCP90 assumed values <0.5. An application of Cohen's kappa coefficient (κC) to Polish subjects showed either 'substantial' (κC>0.6) or 'almost perfect' (κC>0.8) agreement in the AO prevalence for both criteria (WCP90 and WHtR0.5). For these criteria, either 'fair' (κC <0.4) or 'moderate' (κC<0.6) AO consistency ratings were observed among HK girls. In HK boys, a significant difference in the prevalence of AO was observed, independent of the criterion used. CONCLUSIONS: Our results provide further evidence of the need for developing ethnic-specific WC charts and for recommending that a WHtR cutoff of 0.5 may not be appropriate to predict cardiometabolic risk in children of different ethnic groups.

Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance.

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.