The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

https://erj.ersjournals.com/content/erj/38/3/516.full.pdf

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update

In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P = 0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001). Conclusions The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.)

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Three Months of Rifapentine and Isoniazid for Latent Tuberculosis Infection

Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines.

We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB.

After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2–4.4%, I2=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9–1.8%, I2=95.9%), and latent TB infection was 51.5% (95% CI 47.1–55.8%, I2=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1–4.5%, I2=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8–12.6%, I2=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1–1.8%, I2=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2–32.4%, I2=99.5%). There was substantial heterogeneity among published studies.

Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.

https://erj.ersjournals.com/content/erj/41/1/140.full.pdf

Contact investigation for tuberculosis: a systematic review and meta-analysis.

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.

https://erj.ersjournals.com/content/erj/46/6/1563.full.pdf

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

Summary Investigation of people exposed to cases of infectious tuberculosis (contact investigation) is key to tuberculosis control in countries with low tuberculosis incidence. However, in countries in which the incidence of tuberculosis is high, contact investigation is not commonly done. Increasing concerns about the failure to meet case-detection targets and about the spread of drug-resistant Mycobacterium tuberculosis have prompted a reassessment of the potential benefits of contact investigation. We did a systematic review to determine the yield of household contact investigation. The yield for all tuberculosis (bacteriologically confirmed and clinically diagnosed) was 4·5% (95% CI 4·3–4·8, I 2 =95·5%) of contacts investigated; for cases with bacteriological confirmation the yield was 2·3% (95% CI 2·1–2·5, I 2 =96·6%). Latent tuberculosis infection was found in 51·4% (95% CI 50·6–52·2, I 2 =99·4%) of contacts investigated. The substantial heterogeneity in all analyses indicated high variability among studies that was not accounted for by subgroup analyses. These results suggest that contact investigation merits serious consideration as a means to improve early case detection and decrease transmission of M tuberculosis in high-incidence areas.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(08)70071-9.pdf

Tuberculosis and latent tuberculosis infection in close contacts of people with pulmonary tuberculosis in low-income and middle-income countries: a systematic review and meta-analysis

Multidrug-resistant tuberculosis (MDRTB) has emerged as a major public health problem worldwide. To determine the incidence and risk factors associated with tuberculosis among contacts of MDRTB index cases, we studied human immunodeficiency virus-seronegative close contacts of 64 culture-confirmed MDRTB patients in Rio de Janeiro, Brazil. Between March 1988 and July 1992, tuberculosis developed in 17 (7.8%) of 218 previously healthy close contacts of 64 MDRTB index cases (1.6 cases per 1,000-person-months of contact). Among strains of Mycobacterium tuberculosis isolated from 13 contacts of 12 index cases, six (46%) had susceptibility patterns identical to those of their index cases, four (31%) had different patterns of resistance, and three (23%) were susceptible to all drugs. Tuberculosis developed more frequently in male contacts (p or = 15 yr of age (p < 0.05), nonwhites (p < 0.001), and persons not previously vaccinated with bacillus Calmette-Guerin (BCG) (p < 0.05). The association...

M J Marques

Papers

Transmission of tuberculosis to close contacts of patients with multidrug-resistant tuberculosis.