Erlina Burhan

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

Isoniazid, Rifampin, and Pyrazinamide Plasma Concentrations in Relation to Treatment Response in Indonesian Pulmonary Tuberculosis Patients

ABSTRACT Numerous studies have reported low concentrations of antituberculosis drugs in tuberculosis (TB) patients, but few studies have examined whether low drug concentrations affect TB treatment response. We examined steady-state plasma concentrations of isoniazid, rifampin, and pyrazinamide at 2 h after the administration of drugs (C2 h) among 181 patients with pulmonary tuberculosis in Indonesia and related these to bacteriological response during treatment. C2 h values below reference values for either isoniazid, rifampin, or pyrazinamide were found in 91% of patients; 60% had at least two low C2 h concentrations. The isoniazid C2 h was noticeably lower in fast versus slow acetylators (0.9 mg/liter versus 2.2 mg/liter, P < 0.001). At the end of treatment, 82% of the patients were cured, whereas 30 patients (17%) had dropped out during the study, and 2 patients (1%) failed treatment. No association was found between C2 h concentrations and sputum culture results at 8 weeks of treatment. Post hoc analysis showed that patients with low pyrazinamide C2 h (P = 0.01) and patients with large extensive lung lesions (P = 0.01) were at risk of at least one positive culture at week 4, 8, or 24/32. Antituberculosis drug concentrations were often low, but treatment response was nevertheless good. No association was found between drug concentrations and 8 weeks culture conversion, but low pyrazinamide drug concentrations may be associated with a less favorable bacteriological response. The use of higher doses of pyrazinamide may warrant further investigation.

Effects of Introducing Xpert MTB/RIF on Diagnosis and Treatment of Drug-Resistant Tuberculosis Patients in Indonesia: A Pre-Post Intervention Study

Background In March 2012, the Xpert MTB/RIF assay (Xpert) was introduced in three provincial public hospitals in Indonesia as a novel diagnostic to detect tuberculosis and rifampicin resistance among high risk individuals. Objective This study assessed the effects of using Xpert in place of conventional solid and liquid culture and drug-susceptibility testing on case detection rates, treatment initiation rates, and health system delays among drug-resistant tuberculosis (TB) patients. Methods Cohort data on registration, test results and treatment initiation were collected from routine presumptive patient registers one year before and one year after Xpert was introduced. Proportions of case detection and treatment initiation were compared using the Pearson Chi square test and median time delays using the Mood’s Median test. Results A total of 975 individuals at risk of drug-resistant TB were registered in the pre-intervention year and 1,442 in the post-intervention year. After Xpert introduction, TB positivity rate increased by 15%, while rifampicin resistance rate reduced by 23% among TB positive cases and by 9% among all tested. Second-line TB treatment initiation rate among rifampicin resistant patients increased by 19%. Time from client registration to diagnosis was reduced by 74 days to a median of a single day (IQR 0–4) and time from diagnosis to treatment start was reduced by 27 days to a median of 15 days (IQR 7–51). All findings were significant with p<0.001. Conclusion Compared to solid and liquid culture and drug-susceptibility testing, Xpert detected more TB and less rifampicin resistance, increased second-line treatment initiation rates and shortened time to diagnosis and treatment. This test holds promise to improve rapid case finding and management of drug-resistant TB patients in Indonesia.

Clinical Course of Avian Influenza A(H5N1) in Patients at the Persahabatan Hospital, Jakarta, Indonesia, 2005-2008

Background Limited understanding of the presentation and course of influenza A(H5N1) infection in humans hinders evidence-based management. Methods We reviewed the case records of patients admitted to the Persahabatan Hospital (RSP), Jakarta, Indonesia, with influenza A(H5N1) confirmed by real-time polymerase chain reaction. Results Twenty-two previously well patients, aged 3 to 47 years (median 24.5 years), were identified. All attended a clinic or hospital after a median of 2 days of illness (range 0–7). Times to first dose of oseltamivir (three died before receiving oseltamivir) were 2 to 12 days (median 7 days), administered mostly (n = 15) at RSP. Nineteen patients required mechanical ventilation. Deaths numbered 18 (case fatality = 82%) occurring within hours to 6 days of RSP admission, corresponding to 6 to 16 days of illness. Admission hyperglycemia (≥ 140 mg/dL), unrelated to steroids or known underlying diabetes mellitus, and elevated D-dimer levels (0.81–5.2 mg/L, upper limit of normal < 0.5 mg/L) were present in 14/21 (67%) and 20/21 (95%) patients, respectively. Fibrinogen concentrations were mostly low/normal at 129.9 to 517.9 mg/dL (median 241.1, normal 200–400 mg/dL), whereas C-reactive protein (9/11) and ferritin (6/8) levels were increased. Risk factors for death (univariate analysis) included: (1) increased D-dimers, (2) hyperglycema, (3) increased urea, (4) more extensive chest radiograph shadowing, and (5) lower admission oxygen saturation. Conclusions Early diagnosis and effective treatment of human influenza A(H5N1) infection remains challenging. Most patients were referred late with advanced disease. Oseltamivir had limited clinical impact. Elevated D-dimer levels, consistent with fibrinolysis, and hyperglycemia warrant more research to determine their underlying mechanisms and optimal treatment.

A multicentre surveillance study on the characteristics, bacterial aetiologies and in vitro antibiotic susceptibilities in patients with acute exacerbations of chronic bronchitis

Background and objective:  Antimicrobial resistance is a global problem and the prevalence is high in many Asian countries.

The path to impact of operational research on tuberculosis control policies and practices in Indonesia

Background Operational research is currently one of the pillars of the global strategy to control tuberculosis. Indonesia initiated capacity building for operational research on tuberculosis over the last decade. Although publication of the research in peer-reviewed journals is an important indicator for measuring the success of this endeavor, the influence of operational research on policy and practices is considered even more important. However, little is known about the process by which operational research influences tuberculosis control policy and practices. Objective We aimed to investigate the influence of operational research on tuberculosis control policy and practice in Indonesia between 2004 and 2014. Design Using a qualitative study design, we conducted in-depth interviews of 50 researchers and 30 policy makers/program managers and performed document reviews. Transcripts of these interviews were evaluated while applying content analysis. Results Operational research contributed to tuberculosis control policy and practice improvements, including development of new policies, introduction of new practices, and reinforcement of current program policies and practices. However, most of these developments had limited sustainability. The path from the dissemination of research results and recommendations to policy and practice changes was long and complex. The skills, interests, and political power of researchers and policy makers, as well as health system response, could influence the process. Conclusions Operational research contributed to improving tuberculosis control policy and practices. A systematic approach to improve the sustainability of the impact of operational research should be explored.Background Operational research is currently one of the pillars of the global strategy to control tuberculosis. Indonesia initiated capacity building for operational research on tuberculosis over the last decade. Although publication of the research in peer-reviewed journals is an important indicator for measuring the success of this endeavor, the influence of operational research on policy and practices is considered even more important. However, little is known about the process by which operational research influences tuberculosis control policy and practices. Objective We aimed to investigate the influence of operational research on tuberculosis control policy and practice in Indonesia between 2004 and 2014. Design Using a qualitative study design, we conducted in-depth interviews of 50 researchers and 30 policy makers/program managers and performed document reviews. Transcripts of these interviews were evaluated while applying content analysis. Results Operational research contributed to tuberculosis control policy and practice improvements, including development of new policies, introduction of new practices, and reinforcement of current program policies and practices. However, most of these developments had limited sustainability. The path from the dissemination of research results and recommendations to policy and practice changes was long and complex. The skills, interests, and political power of researchers and policy makers, as well as health system response, could influence the process. Conclusions Operational research contributed to improving tuberculosis control policy and practices. A systematic approach to improve the sustainability of the impact of operational research should be explored.

Adjunctive dexamethasone for the treatment of HIV-infected adults with tuberculous meningitis (ACT HIV): Study protocol for a randomised controlled trial

Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20% of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and investigate alternative management strategies in a subset of patients who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT). Discussion: Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis chemotherapy is a risk factor for death from TBM. Alternative management strategies in DILI may allow the safe continuation of rifampicin and isoniazid therapy.

Molecular Diagnosis of Tuberculosis

Tuberculosis (TB) is one of the leading causes of adult death in the Asia-Pacific Region, including Indonesia. As an infectious disease caused by Mycobacterium tuberculosis (MTB), TB remains a major public health issue especially in developing nations due to the lack of adequate diagnostic testing facilities. Diagnosis of TB has entered an era of molecular detection that provides faster and more cost-effective methods to diagnose and confirm drug resistance in TB cases, meanwhile, diagnosis by conventional culture systems requires several weeks. New advances in the molecular detection of TB, including the faster and simpler nucleic acid amplification test (NAAT) and whole-genome sequencing (WGS), have resulted in a shorter time for diagnosis and, therefore, faster TB treatments. In this review, we explored the current findings on molecular diagnosis of TB and drug-resistant TB to see how this advancement could be integrated into public health systems in order to control TB.

Supporting progress towards the post-2015 targets and regional tuberculosis elimination: a statement of intent from the third meeting of the Asian TB Experts Community

The World Health Organization (WHO) is challenging all countries, both high- and low-incidence, to dramatically intensify efforts to meet bold new goals of reducing global tuberculosis (TB) deaths by 95% and the incidence by 90% (<10 cases per 100 000 population) by 2035 [1]. This radical strategic change came from the recognition that the current strategy of passive case finding and directly observed therapy (DOT) is not sufficiently curbing the incidence of TB. The new strategy calls for a synergy of interventions to enable early case detection, systematic screening and prevention of TB in contacts (adults and children) and high-risk groups, such as people living with HIV or other immune depressing conditions, people with diabetes, patients receiving dialysis, patients preparing for organ or haematological transplantation, patients with silicosis, prisoners, healthcare workers, homeless individuals, illicit drug users and individuals in communal settings. At the end of 2014, the WHO released the first guidelines on the management of latent tuberculosis infection (LTBI). The guidelines provide evidence based guidance on practices for testing, treating and managing LTBI in infected individuals with the highest likelihood of progression to active disease [2]. Although primarily aimed at high-income or upper middle-income countries, with an estimated TB incidence rate of <100 per 100 000 population, they represent an unprecedented gear change in the scaling up of TB prevention as a component of TB control programmes [2]. In the first concerted Asian reaction to the post-2015 strategy the significance of TB screening was recognised http://ow.ly/LnWPW