Estimating long-term tuberculosis reactivation rates in Australian migrants

BACKGROUND: The risk of progression to tuberculosis (TB) disease is greatest soon after infection, yet disease may occur many years or decades later. However, rates of TB reactivation long after infection remain poorly quantified. Australia is a low-TB incidence setting and most cases occur among migrants. We explored how TB rates in Australian migrants varied with time from migration, age and gender. METHODS: We combined TB notifications in census years 2006, 2011 and 2016 with time and country-specific estimates oflatent TB prevalence in migrant cohorts to quantifypost-migration reactivation rates. RESULTS: During the census years 3,246 TB cases occurred among an estimated 2,084,000 migrants with latent-TB. There were consistent trends in post-migration reactivation rates, which appeared to be dependent on both time from migration and age. Rates were lower in cohorts with increasing time until at least twenty years from migration, and on this background there also appeared to be increasing rates during youth (15-24 years of age), and in those aged 70 years and above. Within five years of migration, annual reactivation rates were approximately 400 per 100,000 (uncertainty interval [UI]: 320-480), dropping to 170 (UI: 130-220) and 110 (UI: 70-160) from five-to-ten and ten-to-twenty, then sustaining at 60-70 per 100,000 up to sixty years from migration. Rates varied depending on age at migration. CONCLUSIONS: Post-migration reactivation rates appeared to show dependency on both time from migration and age. This approach to quantifying reactivation risk will enable evaluation of the potential impact of TB control and elimination strategies

Geospatial clustering and modelling provide policy guidance to distribute funding for active TB case finding in Ethiopia

Tuberculosis (TB) exhibits considerable spatial heterogeneity, occurring in clusters that may act as hubs of community transmission. We evaluated the impact of an intervention targeting spatial TB hotspots in a rural region of Ethiopia. To evaluate the impact of targeted active case finding (ACF), we used a spatially structured mathematical model that has previously been described. From model equilibrium, we simulated the impact of a hotspot-targeted strategy (HTS) on TB incidence ten years from intervention commencement and the associated cost-effectiveness. HTS was also compared with an untargeted strategy (UTS). We used logistic cost-coverage analysis to estimate cost-effectiveness of interventions. At a community screening coverage level of 95% in a hotspot region, which corresponds to screening 20% of the total population, HTS would reduce overall TB incidence by 52% compared with baseline. For UTS to achieve an equivalent effect, it would be necessary to screen more than 80% of the total population. Compared to the existing passive case detection strategy, the HTS at a CDR of 75 percent in hotspot regions is expected to avert 1,023 new TB cases over ten years saving USD 170 per averted case. Similarly, at the same CDR, the UTS will detect 1316 cases over the same period saving USD 3 per averted TB case. The incremental-cost effectiveness-ratio (ICER) of UTS compared with HTS is USD 582 per averted case corresponding to 293 more TB cases averted at an additional cost of USD 170,700. Where regional TB program spending was capped at current levels, maximum gains in incidence reduction were seen when the regional budget was shared between hotspots and non-hotspot regions in the ratio of 40% to 60%. Our analysis suggests that a spatially targeted strategy is efficient and cost-saving, with the potential for significant reduction in overall TB burden

The Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial

Objectives: To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection. Trial design: ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management. Participants: Participants will be recruited from >80 hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently

Preventive therapy for latent tuberculosis infection—the promise and the challenges

Around one third of the world's population may harbour latent tuberculosis infection (LTBI), an asymptomatic immunological state that confers a heightened risk of subsequently developing tuberculosis (TB). Effectively treating LTBI will be essential if the End TB Strategy is to be realized. This review evaluates the evidence in relation to the effectiveness of preventive antibiotic therapy to treat LTBI due to both drug-susceptible and drug-resistant bacteria. Current national and international preventive therapy guidelines are summarized, as well as ongoing randomized trials evaluating regimens to prevent drug-resistant TB. Populations that may benefit most from screening and treatment for LTBI include close contacts of patients with TB (particularly children under 5 years of age) and individuals with substantial immunological impairment. The risks and benefits of treatment must be carefully balanced for each individual. Electronic decision support tools offer one way in which clinicians can help patients to make informed decisions. Modelling studies indicate that the expanded use of preventive therapy will be essential to achieving substantial reductions in the global TB burden. However, the widespread scale-up of screening and treatment will require careful consideration of cost-effectiveness, while ensuring the drivers of ongoing disease transmission are also addressed

Is IPT more effective in high-burden settings? Modelling the effect of tuberculosis incidence on IPT impact

Setting: Isoniazid preventive therapy (IPT) is effective for preventing active tuberculosis (TB), although its mechanism of action is poorly understood and the optimal disease burden for IPT use has not been defined. Objective: To describe the relationship between TB incidence and IPT effectiveness. Methods: We constructed a model of TB transmission dynamics to investigate IPT effectiveness under various epidemiological settings. The model structure was intended to be highly adaptable to uncertainty in both input parameters and the mechanism of action of IPT. To determine the optimal setting for IPT use, we identified the lowest number needed to treat (NNT) with IPT to prevent one case of active TB. Results: We found that the NNT as a function of TB incidence shows a ‘U-shape’, whereby IPT impact is greatest at an intermediate incidence and attenuated at both lower and higher incidence levels. This U-shape was observed over a broad range of parameter values; the optimal TB incidence was between 500 and 900 cases per 100 000 per year. Conclusions: TB burden is a critical factor to consider when making decisions about communitywide implementation of IPT. We believe that the total disease burden should not preclude programmatic application of IPT

What's in a name? Brand name confusion and generic medicines

We need an urgent review of medicines labelling in Australia and New Zealand.Shane L Carney, Madlen Gazarian, Justin T Denholm, David M Reith, Robert K Penhall, Christine R Jenkins, Kay A Wilhelm, Paul A Komesaroff, Mary M Osborn and Richard O Da

Long-term follow-up of contacts exposed to multidrug-resistant tuberculosis in Victoria, Australia, 1995–2010

Setting: The effectiveness of public health strategies following exposure to multidrug-resistant tuberculosis (MDR-TB) is not clear. Objective: To perform long-term follow-up of MDR-TB contacts and review individual outcomes and management approaches. Design: Retrospective review of MDR-TB contacts identified by the Victorian Department of Health from 1995 to 2010. Health records, including personal medical and pharmacy records and statewide clinical and laboratory TB databases, were searched to identify management strategies and individual outcomes. Results: A total of 570 contacts of 47 MDR-TB cases were identified, with a total follow-up period of 3093 person-years of observation (PYO) since exposure. Of 570 contacts, 49 (8.6%) were considered likely to have been infected with Mycobacterium tuberculosis from index cases, and 11/49 (22.5%) of these were prescribed preventive therapy tailored to isolate susceptibility. No MDR-TB cases occurred in those receiving preventive treatment, while two cases were observed in those not treated (incidence 2878/100 000 PYO during the first 2 years post exposure). Conclusions: The risk of MDR-TB transmission to close contacts in this low-prevalence setting highlights the potential for public health strategies involving preventive treatment

The prevalence of tuberculosis infection among foreign-born Canadians: a modelling study

Background: The prevalence of tuberculosis infection is critical to the design of tuberculosis prevention strategies, yet is unknown in Canada. We estimated the prevalence of tuberculosis infection among Canadian residents born abroad. Methods: We estimated the prevalence of tuberculosis infection by age and year of migration to Canada for people from each of 168 countries by constructing country-specific and calendar year-specific trends for annual risk of infection using a previously developed model. We combined country-specific prevalence estimates with Canadian Census data from 2001, 2006, 2011, 2016 and 2021 to estimate the overall prevalence of tuberculosis infection among foreign-born Canadian residents. Results: The estimated overall prevalence of tuberculosis infection among foreign-born people in Canada was 25% (95% uncertainty interval [UI] 20%- 35%) for census year 2001, 24% (95% UI 20%-33%) for 2006, 23% (95% UI 19%- 30%) for 2011, 22% (95% UI 19%-28%) for 2016 and 22% (95% UI 19%-27%) for 2021. The prevalence increased with age at migration and incidence of tuberculosis in the country of origin. In 2021, the estimated prevalence of infection among foreign-born residents was lowest in Quebec (19%, 95% UI 16%- 24%) and highest in Alberta (24%, 95% UI 21%-28%) and British Columbia (24%, 95% UI 20%-30%). Among all foreign- born Canadian residents with tuberculosis infection in 2021, we estimated that only 1 in 488 (95% UI 185- 1039) had become infected within the 2 preceding years. Interpretation: About 1 in 4 foreign-born Canadian residents has tuberculosis infection, but very few were infected within the 2 preceding years (the highest risk period for progression to tuberculosis disease). These data may inform future tuberculosis infection screening policies