Justin T. Denholm

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

BACKGROUND Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each days delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each days delay). INTERPRETATION We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING F Hoffmann-La Roche.

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 100 000 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 9 month isoniazid; 12 week rifapentine plus isoniazid; 3–4 month isoniazid plus rifampicin; or 3–4 month rifampicin alone. Guidelines on LTBI for low TB incidence countries – essential element of the @WHO #EndTB strategy and TB elimination http://ow.ly/RW8xn

Oseltamivir resistance in adult oncology and hematology patients infected with pandemic (H1N1) 2009 virus, Australia.

Resistance in virus-infected stem cell transplant recipients illustrates the need for surveillance.

Mannose-binding lectin and susceptibility to tuberculosis: a meta-analysis

It has been proposed that mannose‐binding lectin (MBL) levels may impact upon host susceptibility to tuberculosis (TB) infection; however, evidence to date has been conflicting. We performed a literature review and meta‐analysis of 17 human trials considering the effect of MBL2 genotype and/or MBL levels and TB infection. No significant association was demonstrated between MBL2 genotype and pulmonary TB infection. However, the majority of studies did not report MBL2 haplotype inclusive of promoter polymorphisms. Serum MBL levels were shown to be consistently elevated in the setting of TB infection. While this may indicate that high MBL levels protect against infection with TB, the increase was also of a degree consistent with the acute‐phase reaction. This analysis suggests that the relatively poorly characterized MBL2 genotypes reported are not associated significantly with susceptibility to pulmonary TB infection, but high MBL serum levels may be.

Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: A multicentre study

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents. 428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92–280) days and exposed to bedaquiline for 168 (86–180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively). Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30–60) days and 60 (33–90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related. Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions. Bedaquiline is safe and effective in treating MDR- and XDR-TB patients http://ow.ly/6MWK30adHkw

Construction of a mathematical model for tuberculosis transmission in highly endemic regions of the Asia-pacific

We present a mathematical model to simulate tuberculosis (TB) transmission in highly endemic regions of the Asia-Pacific, where epidemiology does not appear to be primarily driven by HIV-coinfection. The ten-compartment deterministic model captures many of the observed phenomena important to disease dynamics, including partial and temporary vaccine efficacy, declining risk of active disease following infection, the possibility of reinfection both during the infection latent period and after treatment, multidrug resistant TB (MDR-TB) and de novo resistance during treatment. We found that the model could not be calibrated to the estimated incidence rate without allowing for reinfection during latency, and that even in the presence of a moderate fitness cost and a lower value of R0, MDR-TB becomes the dominant strain at equilibrium. Of the modifiable programmatic parameters, the rate of detection and treatment commencement was the most important determinant of disease rates with each respective strain, while vaccination rates were less important. Improved treatment of drug-susceptible TB did not result in decreased rates of MDR-TB through prevention of de novo resistance, but rather resulted in a modest increase in MDR-TB through strain replacement. This was due to the considerably greater relative contribution of community transmission to MDR-TB incidence, by comparison to de novo amplification of resistance in previously susceptible strains.

Evaluation of the Cavidi ExaVir Load Assay (Version 3) for Plasma Human Immunodeficiency Virus Type 1 Load Monitoring

ABSTRACT We evaluated the new low-cost ExaVir Load (version 3) reverse transcriptase viral load assay against the Roche Cobas Amplicor assay. Results for samples tested using the reverse transcriptase assay correlated well with those obtained with the Roche assay (r = 0.85; n = 202). The version 3 reverse transcriptase assay shows improved sensitivity compared to the previous version.

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models.

Summary Background The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. Methods 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy. Findings Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31–62%) and a 72% reduction in mortality (range 64–82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. Interpretation Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level. Funding Bill and Melinda Gates Foundation

Cytokines for monitoring anti-tuberculous therapy: A systematic review

The ability to monitor response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The low reversion rate of interferon-gamma based assays means that they are unlikely to be useful for monitoring therapy. Several exploratory studies have evaluated the diagnostic potential of cytokine biomarkers other than interferon-gamma for monitoring anti-tuberculous therapy. A systematic review of these studies was performed to identify the most promising candidate biomarkers. TNF-α, IL-2, IL-6, IL-10 and IL-12 were the most extensively investigated cytokines. There was significant heterogeneity between studies in relation to study design and laboratory methodology, complicating direct comparisons. There was marked variation between studies in the observed changes during treatment for many of the biomarkers. Further longitudinal studies in sufficiently large patient cohorts with rigorous methodology are needed to determine the true potential of individual cytokine biomarkers, or combinations, for monitoring TB treatment.

Risk of active tuberculosis in immigrants: effects of age, region of origin and time since arrival in a low-exposure setting.

Objective: To estimate the risk of active tuberculosis (TB) in immigrants to Victoria, Australia, as a function of time since arrival and stratified by age group and region of origin.