Ross Harris

Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100u200a000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9u2005month isoniazid; 12u2005week rifapentine plus isoniazid; 3–4u2005month isoniazid plus rifampicin; or 3–4u2005month rifampicin alone. Guidelines on LTBI for low TB incidence countries – essential element of the @WHO #EndTB strategy and TB elimination http://ow.ly/RW8xn

Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis

Objectives To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon γ release assays (IGRA) in children. Design Systematic review and meta-analysis. Searches of electronic databases 1950 to November 2013, checking of reference lists, hand searching of journals, and contact with experts. Setting Community congregate settings and households. Inclusion criteria Vaccinated and unvaccinated children aged under 16 with known recent exposure to patients with pulmonary tuberculosis. Children were screened for infection with M tuberculosis with interferon γ release assays. Data extraction Study results relating to diagnostic accuracy were extracted and risk estimates were combined with random effects meta-analysis. Results The primary analysis included 14 studies and 3855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon γ release assays (ELISpot or QuantiFERON). Restriction of the analysis to the six studies (n=1745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77). Conclusions BCG protects against M tuberculosis infection as well as progression from infection to disease. Trial registration PROSPERO registration No CRD42011001698 (www.crd.york.ac.uk/prospero/).

Increased uptake and new therapies are needed to avert rising hepatitis C-related end stage liver disease in England: Modelling the predicted impact of treatment under different scenarios

BACKGROUND & AIMSnHepatitis C (HCV) related disease in England is predicted to rise, and it is unclear whether treatment at current levels will be able to avert this. The aim of this study was to estimate the number of people with chronic HCV infection in England that are treated and assess the impact and costs of increasing treatment uptake.nnnMETHODSnNumbers treated were estimated using national data sources for pegylated interferon supplied, dispensed, or purchased from 2006 to 2011. A back-calculation approach was used to project disease burden over the next 30 years and determine outcomes under various scenarios of treatment uptake.nnnRESULTSn5000 patients were estimated to have been treated in 2011 and 28,000 in total from 2006 to 2011; approximately 3.1% and 17% respectively of estimated chronic infections. Without treatment, incident cases of decompensated cirrhosis and hepatocellular carcinoma were predicted to increase until 2035 and reach 2290 cases per year. Treatment at current levels should reduce incidence by 600 cases per year, with a peak around 2030. Large increases in treatment are needed to halt the rise; and with more effective treatment the best case scenario predicts incidence of around 500 cases in 2030, although treatment uptake must still be increased considerably to achieve this.nnnCONCLUSIONSnIf the infected population is left untreated, the number of patients with severe HCV-related disease will continue to increase and represent a substantial future burden on healthcare resources. This can be mitigated by increasing treatment uptake, which will have the greatest impact if implemented quickly.

New treatments for hepatitis C virus (HCV): scope for preventing liver disease and HCV transmission in England

New direct‐acting antivirals have the potential to transform the hepatitis C (HCV) treatment landscape, with rates of sustained viral response in excess of 90%. As these new agents are expensive, an important question is whether to focus on minimizing the consequences of severe liver disease, or reducing transmission via ‘treatment as prevention’. A back‐calculation model was used to estimate the impact of treatment of mild, moderate and compensated cirrhosis on incident cases of HCV‐related end‐stage liver disease/hepatocellular carcinoma (ESLD/HCC). In addition, a dynamic model was used to determine the impact on incidence and prevalence of chronic infection in people who inject drugs (PWID), the main risk group in England. Treating 3500 cirrhotics per year was predicted to reduce ESLD/HCC incidence from 1100 (95% CrI 970–1240) cases per year in 2015 to 630 (95% CrI 530–770) in 2020, around half that currently expected, although treating moderate‐stage disease will also be needed to sustain this reduction. Treating mild‐stage PWID was required to make a substantial impact on transmission: with 2500 treated per year, chronic prevalence/annual incidence in PWID was reduced from 34%/4.8% in 2015 to 11%/1.4% in 2030. There was little overlap between the two goals: treating mild stage had virtually no impact on ESLD/HCC within 15 years, but the long timescale of liver disease means relatively few PWID reach cirrhosis before cessation of injecting. Strategies focussing on treating advanced disease have the potential for dramatic reductions in severe morbidity, but virtually no preventative impact.

Multiple parameter evidence synthesis-a potential solution for when information on drug use and harm is in conflict

The quality of the evidence on estimating drug-related harm is not yet as advanced as that for intervention effectiveness. Multiple parameter evidence synthesis offers a potential solution, in which all available evidence is combined into a single coherent model.We present a case study of estimating the number of people infected with hepatitis C.

Prospective evaluation of the cost of diagnosis and treatment of invasive fungal disease in a cohort of adult haematology patients in the UK

OBJECTIVESnThe direct cost of invasive fungal disease (IFD) includes antifungal drugs as well as diagnostic tests. The aim of this study was to determine these costs.nnnMETHODSnA total of 203 haematology patients were enrolled into the study and followed for a median of 556 days. Data were prospectively collected on antifungal drugs, diagnostic tests, length of stay and antibiotic usage.nnnRESULTSnThe overall mean (IQR) cost of care per patient (using UK-based reference costs) was £88u200a911 (45u200a339-121u200a594), £61u200a509 (39u200a748-78u200a383), £50u200a332 (23u200a037-72u200a057) and £34u200a075 (19u200a928-43u200a900) for proven/probable IFD, possible IFD, not classified and no evidence of IFD, respectively (P<0.001). The attributable cost of IFD was £54u200a836. Inpatient hospital stay accounted for nearly 74% of costs. In proven/probable IFD inpatient care, antifungals, antibiotics and IFD status accounted for 68%, 25%, 5% and 2%, respectively, compared with 85%, 11%, 2% and 2%, respectively, for no IFD (P<0.001). Among the allogeneic transplant patients, £36u200a914 (60%) of the total cost (£60u200a917) was used during the first 100 days.nnnCONCLUSIONSnIFD was associated with longer length of stay and higher total overall cost of care, with attributable costs greater than £50u200a000 per case of IFD. Costs for inpatient stay far outstrip the cost of antifungal agents.

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 12u2005604 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 4u2005months, in which rifampicin was protected by another effective drug at 6u2005months, and rifampicin was taken for 6u2005months), extending the duration of rifampicin and increasing the number of effective drugs at 4u2005months 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.

Two decades of successes and failures in controlling the transmission of HIV through injecting drug use in England and Wales, 1990 to 2011

Responses to injecting drug use have changed focus over the last 20 years. Prevalence and incidence of human immunodeficiency virus (HIV) among people who inject drugs (PWID) in England and Wales were examined in relation to these changes. A voluntary unlinked-anonymous surveillance study obtained a biological sample and questionnaire data from PWID through annual surveys since 1990. Prevalence and incidence trends were estimated via generalised linear models, and compared with a policy time-line. Overall HIV prevalence among 38,539 participations was 1.15%. Prevalence was highest among those who started injecting before 1985; throughout the 1990s, prevalence fell in this group and was stable among those who started injecting later. Prevalence was higher in 2005 than 2000 (odds ratio: 3.56 (95% confidence interval (CI) 1.40–9.03) in London, 3.40 (95% CI 2.31–5.02) elsewhere). Estimated HIV incidence peaked twice, around 1983 and 2005. HIV was an important focus of policy concerning PWID from 1984 until 1998. This focus shifted at a time when drug use and risk were changing. The increased incidence in 2005 cannot be ascribed to the policy changes, but these appeared to be temporally aligned. Policy related to PWID should be continually reviewed to ensure rapid responses to increased risk.

Evaluating 17 years of latent tuberculosis infection screening in north-west England: a retrospective cohort study of reactivation

Approximately 72% of tuberculosis (TB) cases in England occur among non-UK born individuals, mostly as a result of reactivation of latent TB infection (LTBI). Programmatic LTBI screening is a key intervention of the TB strategy for England. This article reviews the results of a long-standing LTBI screening initiative in England. A retrospective cohort was created through probabilistic linkage between LTBI screening data and national TB case notifications. Screened persons were followed until they died, became a case, emigrated or until cohort-end. TB incidence rates and rate ratios (IRR) were calculated. 97 out of 1820 individuals screened for LTBI were reported to have active TB. Crude incidence rates among LTBI-positive, treatment-naïve individuals were 4.1 and 2.3 per 100u2005person-years in the QuantiFERON and tuberculin skin test cohorts, respectively. Among the QuantiFERON cohort, Poisson regression showed that LTBI positivity (IRR 22.6, 95% CI 6.8–74.6) and no chemoprophylaxis increased the probability of becoming a TB case (IRR 0.17, 95% CI 0.05–0.6). We found high TB rates in LTBI-positive, treatment-naïve individuals and a strong association between no treatment and becoming a TB case, demonstrating feasibility and effectiveness of LTBI screening and providing important policy lessons for LTBI screening in England and beyond. Screening follow-up showed high TB rates in LTBI-positive, treatment-naïve individuals and treatment protection http://ow.ly/IUaW30bggkH

Respiratory symptoms in people living with HIV and the effect of antiretroviral therapy: a systematic review and meta-analysis

Background Antiretroviral therapy (ART) has significantly altered the pattern of acute and chronic HIV-related disease. However, it is not clear what this means in terms of respiratory symptoms. We sought to investigate the association between HIV status and respiratory symptoms and how these have changed with the availability of ART. Methods We searched Cochrane, Medline and Embase databases for studies published between 1946 and August 2015 comparing the prevalence of respiratory symptoms in populations with and without HIV infection. We undertook random effects meta-analysis of the main symptoms reported. We studied heterogeneity and completed sensitivity analyses and funnel plots. Results From 5788 unique references identified, 24 papers provided relevant data: 18 documented the prevalence of cough and 11 examined the prevalence of breathlessness among other symptoms reported. Compared with the HIV negative, people living with HIV (PLWH) were more likely to have respiratory symptoms with pooled ORs for the prevalence of cough of 3.05 (95% CI 2.24 to 4.16) in resource-limited populations without access to ART; 2.18 (1.56 to 3.18) in resource-rich populations without access to ART and 1.11 (0.99 to 1.24) in resource-rich populations with access to ART. In resource-rich settings, although the availability of ART was associated with a reduction in the difference between HIV-positive and HIV-negative individuals, PLWH were more likely to report breathlessness, OR 1.39 (95% CI 1.11 to 1.73). Conclusions Respiratory symptoms are more common in PLWH than controls. This association persists although at a reduced level in populations with access to ART.