High TB Burden Countries Research Articles

Geographical, Health Systems’ and Sociocultural Patterns of Tb/Hiv Co- Infected Patients’ Health Seeking Behavior in a Conflict Affected Setting: The Case of Eastern Democratic Republic of Congo

Background: The Democratic Republic of Congo (DRC) is one of the high burden TB countries. The country has been affected by a political conflict for more than 15 years now. HIV prevalence has been increasing in the country too. Detection and care of TB/HIV co-infected cases is a major problem in the country. Aim: This study aimed at describing patterns of health seeking behaviors among patients with TB/HIV regarding their choice of health facilities for integrated TB/HIV care in the Goma and surrounding health districts. Methods: The methods used included a cross-sectional descriptive survey with TB/HIV co-infected patients and qualitative interviews of health workers. Results: The study found that geographical residence did not play a major role in choice of facility for care by patients infected with TB and HIV. Many patients shun facilities which are close and seek care relatively far away. Instead of geographical proximity, availability of drugs and welcoming attitudes determined the choice of integrated care facilities. Also, fear for discrimination and stigmatization in the community result into patients in this area concealing their infection; rather, they claim being victim of empoisoning. Conclusion: Sustained decentralization of integrated TB/HIV services through better programs’ coordination and community involvement to address misconceptions about TB and HIV and stigmatization are essential to promote uptake of TB/HIV services and retain patients in treatment.

The Psychosocial Problems Of Pulmonary Tuberculosis Patients Undergoing DOTS Therapy (Direct Observed Treatment Short Course Therapy) in Selected Areas of Jalandhar District, Punjab.

Tuberculosis continues to be a major health problem in the world, particularly in the developing countries. The updated WHO report reveals that about 9.4 million new TB cases occurred in 2008 including 1.4 million cases among people living with HIV. The prevalence of the disease was about 11.1 million. There were about 1.3 million deaths from TB among HIV negative people and an additional 0.52 million TB deaths among HIV positive people. India is the highest TB burden country in the world, accounting for 21% of the global incidence and 2/3 of the cases in south-east Asia. In the year 2008, the incidence of tuberculosis was reported to be 1.9 million with prevalence of 2.186 million with mortality due to TB being 2, 76,512.

Ensuring tuberculosis infection control to support greater involvement of people living with HIV in health care

Health care workers (HCWs) in high TB burden countries bear significant risks of being infected with Mycobacterium tuberculosis and developing TB disease through their work. In recent years, an increasing number of people living with HIV (PLHIV) are taking part in delivering HIV and other health services in resource-limited settings with high TB burden. The greater involvement of PLHIV in health service delivery has many beneficial consequences on individuals and health systems, however, the involvement creates considerable opportunities for them to be exposed to patients with infectious TB disease. Due to their immunodeficiency, PLHIV are far more likely to develop active TB following the infection. Available evidence and recently revised WHO policy guidance on TB infection control suggest simple, predominantly administrative control measures are feasible and effective in reducing the infection. Nevertheless, many countries are still at the early stage of developing infection control policies. We call for evidence-based infection control measures in order to ensure a safe working environment for PLHIV in support of their greater involvement in health care. More research is needed to strengthen knowledge on TB infection risks amongst PLHIV through involvement in service delivery, and optimal interventions to reduce it.

The Forest behind the Tree: Phylogenetic Exploration of a Dominant Mycobacterium tuberculosis Strain Lineage from a High Tuberculosis Burden Country

BackgroundGenotyping of Mycobacterium tuberculosis isolates is a powerful tool for epidemiological control of tuberculosis (TB) and phylogenetic exploration of the pathogen. Standardized PCR-based typing, based on 15 to 24 mycobacterial interspersed repetitive unit-variable number of tandem repeat (MIRU-VNTR) loci combined with spoligotyping, has been shown to have adequate resolution power for tracing TB transmission and to be useful for predicting diverse strain lineages in European settings. Its informative value needs to be tested in high TB-burden countries, where the use of genotyping is often complicated by dominance of geographically specific, genetically homogeneous strain lineages.Methodology/Principal FindingsWe tested this genotyping system for molecular epidemiological analysis of 369 M. tuberculosis isolates from 3 regions of Brazil, a high TB-burden country. Deligotyping, targeting 43 large sequence polymorphisms (LSPs), and the MIRU-VNTRplus identification database were used to assess phylogenetic predictions. High congruence between the different typing results consistently revealed the countrywide supremacy of the Latin-American-Mediterranean (LAM) lineage, comprised of three main branches. In addition to an already known RDRio branch, at least one other branch characterized by a phylogenetically informative LAM3 spoligo-signature seems to be globally distributed beyond Brazil. Nevertheless, by distinguishing 321 genotypes in this strain population, combined MIRU-VNTR typing and spoligotyping demonstrated the presence of multiple distinct clones. The use of 15 to 24 loci discriminated 21 to 25% more strains within the LAM lineage, compared to a restricted lineage-specific locus set suggested to be used after SNP analysis. Noteworthy, 23 of the 28 molecular clusters identified were exclusively composed of patient isolates from a same region, consistent with expected patterns of mostly local TB transmission.Conclusions/SignificanceStandard MIRU-VNTR typing combined with spoligotyping can reveal epidemiologically meaningful clonal diversity behind a dominant M. tuberculosis strain lineage in a high TB-burden country and is useful to explore international phylogenetical ramifications.

A first assessment of the genetic diversity of Mycobacterium tuberculosis complex in Cambodia

BackgroundCambodia is among the 22 high-burden TB countries, and has one of the highest rates of TB in South-East Asia. This study aimed to describe the genetic diversity among clinical Mycobacterium tuberculosis complex (MTC) isolates collected in Cambodia and to relate these findings to genetic diversity data from neighboring countries.MethodsWe characterized by 24 VNTR loci genotyping and spoligotyping 105 Mycobacterium tuberculosis clinical isolates collected between 2007 and 2008 in the region of Phnom-Penh, Cambodia, enriched in multidrug-resistant (MDR) isolates (n = 33).ResultsClassical spoligotyping confirmed that the East-African Indian (EAI) lineage is highly prevalent in this area (60%-68% respectively in whole sample and among non-MDR isolates). Beijing lineage is also largely represented (30% in whole sample, 21% among non-MDR isolates, OR = 4.51, CI95% [1.77, 11.51]) whereas CAS lineage was absent. The 24 loci MIRU-VNTR typing scheme distinguished 90 patterns with only 13 multi-isolates clusters covering 28 isolates. The clustering of EAI strains could be achieved with only 8 VNTR combined with spoligotyping, which could serve as a performing, easy and cheap genotyping standard for this family. Extended spoligotyping suggested relatedness of some unclassified "T1 ancestors" or "Manu" isolates with modern strains and provided finer resolution.ConclusionsThe genetic diversity of MTC in Cambodia is driven by the EAI and the Beijing families. We validate the usefulness of the extended spoligotyping format in combination with 8 VNTR for EAI isolates in this region.

S5 Prevalence of latent tuberculosis infection in immigrants to the UK: findings from a multi-centre study

<h3>Background</h3> Notifications for tuberculosis (TB) in the United Kingdom (UK) increased by 30% between 1992 and 2007 with overseas-born migrants accounting for 72% of cases in 2007. Much of this increase is due to the synergy of migration from high-TB burden countries and the reactivation of pre-existing latent TB infection (LTBI). Since 2006, NICE guidance advocates screening for LTBI in all children from countries with a TB incidence &gt;40/100 000 and adults from Sub-Saharan Africa and countries with a TB incidence &gt;500/100 000. The rationale underpinning these guidelines remains unclear particularly as there are little data on the prevalence of LTBI in immigrants to the UK from regions with different TB incidence rates. <h3>Aims</h3> To quantify the prevalence of LTBI in immigrants, assess factors associated with IGRA positivity and to determine LTBI yield from current screening thresholds recommended by NICE. <h3>Methods</h3> Analysis of data prospectively obtained through IGRA testing (QuantiFERON-Gold/QuantiFERON-Gold-in-tube) of immigrants in three different centres in the UK during 2008–2010. Descriptive analyses were undertaken. Yields at different screening thresholds were calculated. Subsequent univariate and multivariate analyses were undertaken to assess independent factors associated with IGRA positivity; p&lt;0.05 considered significant. <h3>Results</h3> In total 915 immigrants were screened during the study period. Median age was 26.8 years (interquartile range 22–33), 50.6% were female and 72.5% had previously been BCG vaccinated. 48.9% and 28.5% of migrants screened originated from the Indian Subcontinent and Sub-Saharan Africa, respectively. Overall 911/915 individuals had determinate IGRA results—199 (21.7%) tested positive and 712 (77.8%) tested negative; 4 (0.4%) individuals had indeterminate results. Multivariate analysis revealed that increasing age (p&lt;0.0001) and increasing TB incidence of country of origin (p=0.0014) were independently associated with IGRA positivity. Applying current NICE guidance resulted in a yield of 76/311 (24.4%) but would miss 61.8% of the immigrant population with LTBI (Abstract S5 Table 1). <h3>Conclusions</h3> Immigrants have a high prevalence of LTBI but current NICE guidance detects only 38.2% of new entrants with LTBI. Given the high rates of reactivation of LTBI in new entrants, our findings suggest that consideration should be given to reducing the screening threshold to include those from the Indian Subcontinent (incidence 170/100 000) which would result in 67.8% of all LTBI cases being identified.

HIV-Associated Tuberculosis

The intersecting HIV and Tuberculosis epidemics in countries with a high disease burden of both infections pose many challenges and opportunities. For patients infected with HIV in high TB burden countries, the diagnosis of TB, ARV drug choices in treating HIV-TB coinfected patients, when to initiate ARV treatment in relation to TB treatment, managing immune reconstitution, minimising risk of getting infected with TB and/or managing recurrent TB, minimizing airborne transmission, and infection control are key issues. In addition, given the disproportionate burden of HIV in women in these settings, sexual reproductive health issues and particular high mortality rates associated with TB during pregnancy are important. The scaleup and resource allocation to access antiretroviral treatment in these high HIV and TB settings provide a unique opportunity to strengthen both services and impact positively in meeting Millennium Development Goal 6.

Retooling National TB Control Programmes (NTPs) with New Diagnostics: The NTP Perspective

BackgroundA delay is evident between the development of new policies on TB diagnostics and their implementation at country level. The Stop TB Partnership would benefit from information from national TB program (NTP) managers on progress towards implementation of new recommendations as well as the opportunities and challenges encountered in the process.Methods and FindingsTo solicit information on the introduction of new TB diagnostics at country level, questionnaires were sent out to NTP managers of high-burden TB countries and a subset of managers was interviewed. The results indicate that about 50% of high-burden TB countries are using the TB diagnostic tools newly recommended by the World Health Organization (WHO). Most NTP managers reported that new diagnostics would only be implemented when officially endorsed by the WHO. All countries have plans to adopt newly endorsed diagnostics at reference laboratory level, while approaches to optimize smear microscopy at lower levels of the health service are given less attention. NTP managers reported diverse challenges to the implementation of new diagnostics.ConclusionsMore information on the obstacles and advantages of introducing new diagnostic tools should be provided to NTP managers to ensure the rational adoption of new diagnostics. A single recommendation covering the introduction of a package of diagnostic tools might be preferable to NTP managers and facilitate implementation in high-burden TB countries.

Tuberculosis in Europe: a problem of drug resistance or much more?

Tuberculosis has re-emerged as a public health concern in high-income countries in the last few decades. The European region accounts for only 5% of world TB cases. The incidence of new TB cases in Europe varies from very low rates in Scandinavian countries (six to eight cases/100,000 population) to rates as high as 231 cases/100,000 population in Tajikistan; the Russian Federation is eleventh among the 22 high-burden TB countries. The estimated detection rate of new sputum smear-positive pulmonary cases and the treatment success rate in 2007 were poor compared with other WHO regions: 51% of cases were diagnosed and 70% of them completed a full course of anti-TB therapy, which is still a long way from the World Health Assembly targets (detection of 70% of infectious cases and successful treatment of 85% of them). The low success rate is largely attributable to the increasing number of drug-resistant TB cases: Eastern European countries are among those with the highest rates of multidrug-resistant (MDR)-TB (TB resistant to rifampicin and isoniazid) in the world. By the end of September 2009, at least one case of extensively drug-resistant TB (named XDR-TB and defined as a MDR-TB strain with additional resistance to any fluoroquinolone, and to at least one of three injectable drugs used in anti-TB treatment) had been reported by 25 countries in the WHO European Region. In Western Europe, TB continues to cause disease among elderly native-born individuals, although high-risk groups including immigrants, prisoners, HIV-infected persons and drug addicts significantly contribute to the overall burden. Improved TB control in Europe requires a large coordinated effort by all stakeholders, including governments, governmental and non-governmental institutions, as well as the academic and private sectors and affected communities.

Tuberculosis: vaccines in the pipeline

TB is presenting new challenges as a global health problem, especially with new threats of HIV coinfection and multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis. The current TB vaccine, Mycobacterium bovis bacillus Calmette–Guerin (BCG), is the most widely used vaccine worldwide but its efficacy against pulmonary TB in adults in many high-burden countries is limited. Different vaccine strategies will probably be required for the various needs that exist within a population in which some individuals have been previously immunized with BCG, coinfected with HIV and/or latently infected with M. tuberculosis. In the last 15 years, new strategies to improve or replace BCG in the laboratory have led to several promising vaccine candidates that are actively being evaluated in human clinical trials. Some of these new vaccines may eventually be recommended for travelers to TB high-burden countries. This paper summarizes the progress of vaccine candidates in animal models to improve, replace or augment BCG vaccination.

Tuberculosis Among Foreign-born Persons in Taiwan, 2002–2005

The foreign-born population has been growing in Taiwan. Most foreign-born persons come from countries with a high burden of tuberculosis (TB). Monitoring the trend and characteristics of TB in this population is essential for TB control in Taiwan. Information about foreign-born persons residing in Taiwan and data of all foreign-born TB cases notified during 2002-2005 were obtained from the national authorities and analyzed. A total of 2,444 foreign-born TB cases were notified during 2002-2005, which accounted for 3.6% of all notified TB cases during that period in Taiwan. The proportion of foreign-born TB cases was constant, without any significant yearly variation. The average annual TB notification rate in the foreign-born population was higher than that in the Taiwan-born population (94.0/100,000 vs. 72.0/100,000). There were significant differences in age, sex and regional distribution between foreign-born and Taiwan-born TB cases (p < 0.001). Foreign-born cases were predominantly female (65.4%) and aged 25-44 years (70.9%), whereas the majority of cases among the Taiwan-born population were male (69.4%) and aged > or = 65 years (49.6%). Most foreign-born TB patients (62.7%) lived in northern Taiwan but only about one-third (36.1%) of Taiwan-born TB cases were notified from that region. Among foreign-born TB cases whose original countries were recorded, the majority came from Mainland China and Vietnam, which accounted for 73.0% of all cases, followed by the Philippines (7.4%), Thailand (7.3%) and Indonesia (6.0%). Foreign-born TB patients have different profiles and a higher case rate compared to Taiwan-born patients. Monitoring the epidemiologic trend of TB among foreign-born persons, especially those who come from high TB-burden countries, is essential in the fight against TB in Taiwan.

Genomic Diversity among Beijing and non-Beijing Mycobacterium tuberculosis Isolates from Myanmar

BackgroundThe Beijing family of Mycobacterium tuberculosis is dominant in countries in East Asia. Genomic polymorphisms are a source of diversity within the M. tuberculosis genome and may account for the variation of virulence among M. tuberculosis isolates. Till date there are no studies that have examined the genomic composition of M. tuberculosis isolates from the high TB-burden country, Myanmar.Methodology/Principle FindingsTwenty-two M. tuberculosis isolates from Myanmar were screened on whole-genome arrays containing genes from M. tuberculosis H37Rv, M. tuberculosis CDC1551 and M. bovis AF22197. Screening identified 198 deletions or extra regions in the clinical isolates compared to H37Rv. Twenty-two regions differentiated between Beijing and non-Beijing isolates and were verified by PCR on an additional 40 isolates. Six regions (Rv0071-0074 [RD105], Rv1572-1576c [RD149], Rv1585c-1587c [RD149], MT1798-Rv1755c [RD152], Rv1761c [RD152] and Rv0279c) were deleted in Beijing isolates, of which 4 (Rv1572-1576c, Rv1585c-1587c, MT1798-Rv1755c and Rv1761c) were variably deleted among ST42 isolates, indicating a closer relationship between the Beijing and ST42 lineages. The TbD1 region, Mb1582-Mb1583 was deleted in Beijing and ST42 isolates. One M. bovis gene of unknown function, Mb3184c was present in all isolates, except 11 of 13 ST42 isolates. The CDC1551 gene, MT1360 coding for a putative adenylate cyclase, was present in all Beijing and ST42 isolates (except 1). The pks15/1 gene, coding for a putative virulence factor, was intact in all Beijing and non-Beijing isolates, except in ST42 and ST53 isolates.ConclusionThis study describes previously unreported deletions/extra regions in Beijing and non-Beijing M. tuberculosis isolates. The modern and highly frequent ST42 lineage showed a closer relationship to the hypervirulent Beijing lineage than to the ancient non-Beijing lineages. The pks15/1 gene was disrupted only in modern non-Beijing isolates. This is the first report of an in-depth analysis on the genomic diversity of M. tuberculosis isolates from Myanmar.

Drug susceptibility pattern of Mycobacterium tuberculosis in adult patients with miliary tuberculosis

Miliary tuberculosis (TB) is a fatal form of TB. Although drug resistance in TB patients has increased worldwide, there is limited information on drug resistance in miliary TB. This study from Pakistan evaluated drug susceptibility pattern among miliary TB patients of a high TB-burden country. All adult patients with miliary TB, admitted between 1994 and 2001, were identified using a computerized database. Culture-positive isolates were evaluated for drug susceptibility using middle brook 7H10 agar according to National Committee for Clinical Laboratories Standard criteria. Of 110 patients diagnosed with miliary TB, 32 (30%) were culture positive (yielding 35 culture isolates). The sources of positive cultures were sputum (37%), cerebrospinal fluid (18%), lymph nodes (12%), bone marrow (9%), bronchial wash (9%), urine (6%), lungs (6%) and liver (3%). Isoniazid resistance was found in three (9%) isolates. All the isolates were sensitive to rifampicin, ethambutol, pyrazinamide and streptomycin. Despite a worldwide increase in TB drug resistance, patients with miliary TB have infection with drug-sensitive mycobacterium. First-line anti-TB drugs should be used as initial therapy in miliary TB patients.

ESAT-6 and CFP-10 can be combined to reduce the cost of testing for Mycobacterium tuberculosis infection, but CFP-10 responses associate with active disease

Commercial tests measuring IFN-gamma responses to ESAT-6 and CFP-10 are available for diagnosing Mycobacterium tuberculosis infection. Measures that minimize cost and complexity will facilitate their application in less-developed countries. We investigated whether overlapping peptides representing both ESAT-6 and CFP-10 are required to detect M. tuberculosis infection in a high TB-burden country, and whether they can be combined in a single pool. ESAT-6 and CFP-10 peptides were compared in IFN-gamma enzyme-linked immunospot (ELISPOT) in 183 HIV-negative smear-positive TB cases and 1673 HIV-negative household contacts. Separate peptide pools for each antigen were compared with a combined pool in 498 contacts. Forty per cent of responsive contacts recognized both antigens, 51% only ESAT-6 and 10% only CFP-10, whereas 56% of responsive cases recognized both antigens, 30% only ESAT-6 and 13% only CFP-10. Accordingly, CFP-10 response rates were higher for TB cases (odds ratio 2.409, P<0.001). Low purified protein derivative response rates indicated that responses to CFP-10 only were non-specific in contacts. Agreement between peptides in separate versus combined pools was good (kappa=0.758, r=0.840). Therefore a combined ESAT-6/CFP-10 peptide pool provided maximum sensitivity and efficiency, but CFP-10 was mainly required to detect active disease.

Update on the Treatment of Tuberculosis and Latent Tuberculosis Infection

Tuberculosis (TB) has emerged as a global public health epidemic. Despite decreasing numbers of cases in the United States since 1992, TB remains a serious public health problem among certain patient populations and is highly prevalent in many urban areas. The responsibility for prescribing an appropriate drug regimen and ensuring that treatment is completed is assigned to the public health program or the clinician not to the patient. The initial prescribed regimen for the treatment of TB usually consists of 4 drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. The minimum length for the treatment of drug-susceptible TB with a rifampin-based regimen is 6 to 9 months. Providing medications directly to the patient and watching him/her swallow the anti-TB drugs, which is termed directly observed therapy, is recommended for all patients diagnosed with TB and can help ensure higher completion rates, prevent the emergence of drug resistant TB, and enhance TB control. There has been renewed interest in the treatment of those with latent TB infection as a TB-control strategy in the United States for eliminating the large reservoir of individuals at risk for progression to TB. The 2 broad categories of persons who should be tested for latent TB infection are those who are likely to have been recently infected (such as contacts to infectious TB cases) and persons who are at increased risk of progression to TB disease following infection with Mycobacterium tuberculosis (eg, human immunodeficiency virus infection and selected medical conditions; recent immigrants to the United States from high TB-burden countries). The preferred regimen for the treatment of latent TB infection is 9 months of isoniazid. There is now renewed interest in and great need for the development of new drugs to treat TB and latent TB infection.

S9.4 DOTS-Plus: Country experiences

Multidrug-resistant tuberculosis (MDR-TB), the prevalence of which has increased across the globe in recent years, is a serious threat to public health. Timely diagnosis of MDR-TB, especially among new TB cases, is essential to facilitate appropriate treatment, which can prevent further emergence of drug resistance and its spread in the population. The present case report from India aims to address some operational challenges in diagnosing MDR-TB among new cases and potential measures to overcome them. It argues that even after seven years of implementing the DOTS-Plus program for controlling MDR-TB, India still lacks the technical capacity for rapid MDR-TB diagnosis. The case report underscores an urgent need to explore the use of WHO-endorsed techniques such as Xpert MTB/Rif and commercial assays such as Genotype MTBDR for rapid diagnosis of MDR-TB among new cases. Suitable applications may be found for other TB high-burden countries where MDR-TB is a major concern.

Tuberculosis problems in the Asia-Pacific region.

Tuberculosis (TB) is the top killer of the productive age group in developing countries. More than half of cases in the world occur in Asia-Pacific region. The number of cases will increase in the next decades due to increase in urban poor population and HIV incidence, and poor access to health services and poor TB programme. The mainstay of effective strategy is to promote DOTS. DOTS population coverage is high, 58% in the Western Pacific Region but low; 29% in the southeast Asia region. Even among intermediate TB-burden countries in Asia, reduction of incidence has stagnated in recent years because of aging population, health problems in the urban poor population and influx of populations from high endemic areas. Indicators of successful TB programmes are high cure rate and low drug resistance rate. There is a strong correlation between the overall quality of TB control in the past and the current primary drug-resistant rate. To solve these problems, priority should be given to nationwide implementation of DOTS in high TB-burden countries with emphasis on ensuring availability of free anti-TB drugs and strengthening primary health care. General hospitals and private sector should be involved in control programmes to prevent drug resistant cases.