Tuberculosis (TB) remains a significant cause of morbidity and mortality in Vietnam. The current TB burden is unknown as not all individuals with TB are diagnosed, recorded and notified. The second ...national TB prevalence survey was conducted in 2017-2018 to assess the current burden of TB disease in the country.
Eighty-two clusters were selected using a multistage cluster sampling design. Adult (≥15 years of age) residents having lived for 2 weeks or more in the households of the selected clusters were invited to participate in the survey. The survey participants were screened for TB by a questionnaire and digital chest X-ray after providing written informed consent. Individuals with a positive symptom screen and/or chest X-ray suggestive of TB were asked to provide sputum samples to test for Mycobacterium tuberculosis by Ziehl-Neelsen direct light microscopy, Xpert MTB/RIF G4, BACTEC MGIT960 liquid culture and Löwenstein-Jensen solid culture. Bacteriologically confirmed TB cases were defined by an expert panel following a standard decision tree.
Of 87,207 eligible residents, 61,763 (70.8%) participated, and 4,738 (7.7%) screened positive for TB. Among these, 221 participants were defined as bacteriologically confirmed TB cases. The estimated prevalence of bacteriologically confirmed adult pulmonary TB was 322 (95% CI: 260-399) per 100,000, and the male-to-female ratio was 4.0 (2.8-5.8, p<0.001). In-depth interviews with the participants with TB disease showed that only 57.9% (95% CI: 51.3-64.3%) reported cough for 2 weeks or more and 32.1% (26.3-38.6%) did not report any symptom consistent with TB, while their chest X-ray results showed that 97.7% (95% CI: 94.6-99.1) had abnormal chest X-ray images suggesting TB.
With highly sensitive diagnostics applied, this survey showed that the TB burden in Vietnam remains high. Half of the TB cases were not picked up by general symptom-based screening and were identified by chest X-ray only. Our results indicate that improving TB diagnostic capacity and access to care, along with reducing TB stigma, need to be top priorities for TB control and elimination in Vietnam.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Retreatment tuberculosis (TB) disease is common in high-prevalence settings. The risk of repeated episodes of recurrent TB is unknown. We calculated the rate of recurrent TB per ...subsequent episode by matching individual treatment episodes over a period of 13 years.
Methods
All recorded TB episodes in Cape Town between 2003 and 2016 were matched by probabilistic linkage of personal identifiers. Among individuals with a first episode notified in Cape Town and who completed their prior treatment successfully we estimated the recurrence rate stratified by subsequent episode and HIV status. We adjusted person-time to background mortality by age, sex, and HIV status.
Results
A total of 292 915 TB episodes among 263 848 individuals were included. The rate of recurrent TB was 16.4 per 1000 person-years (95% CI, 16.2–16.6), and increased per subsequent episode (8.4-fold increase, from 14.6 to 122.7 per 1000 from episode 2 to 6, respectively). These increases were similar stratified by HIV status. Rates among HIV positives were higher than among HIV negatives for episodes 2 and 3 (2- and 1.5-fold higher, respectively), and the same thereafter.
Conclusions
TB recurrence rates were high and increased per subsequent episode, independent of HIV status. This suggests that HIV infection is insufficient to explain the high burden of recurrence; it is more likely due to a high annual risk of infection combined with an increased risk of infection or progression to disease associated with a previous TB episode. The very high recurrence rates would justify increased TB surveillance of patients with >1 episode.
Tuberculosis treatment episodes over a period of 13 years were linked. Rates of recurrence increased 9-fold between episode 2 and 5 and did not differ by HIV status or previous treatment outcome, suggesting an underlying mechanism not mediated by HIV infection.
Rifampin heteroresistance-where rifampin-resistant and -susceptible tuberculosis (TB) bacilli coexist-may result in failed standard TB treatment and potential spread of rifampin-resistant strains. ...The detection of rifampin heteroresistance in routine rapid diagnostic tests (RDTs) allows for patients to receive prompt and effective multidrug-resistant-TB treatment and may improve rifampin-resistant TB control. The limit of detection (LOD) of rifampin heteroresistance for phenotypic drug susceptibility testing by the proportion method is 1% and, yet, is insufficiently documented for RDTs. We, therefore, aimed to determine, for the four RDTs (XpertMTB/RIF, XpertMTB/RIF Ultra, GenoTypeMTBDR
v2.0, and GenoscholarNTM+MDRTBII), the LOD per probe and mutation, validated by CFU counting and targeted deep sequencing (Deeplex-MycTB). We selected one rifampin-susceptible and four rifampin-resistant strains, with mutations D435V, H445D, H445Y, and S450L, respectively, mixed them in various proportions in triplicate, tested them with each RDT, and determined the LODs per mutation type. Deeplex-MycTB revealed concordant proportions of the minority resistant variants in the mixtures. The Deeplex-MycTB-validated LODs ranged from 20% to 80% for XpertMTB/RIF, 20% to 70% for Xpert Ultra, 5% to 10% for GenoTypeMTBDRplusv2.0, and 1% to 10% for GenoscholarNTM+MDRTBII for the different mutations. Deeplex-MycTB, GenoTypeMTBDR
v2.0, and GenoscholarNTM+MDRTBII provide explicit information on rifampin heteroresistance for the most frequently detected mutations. Classic Xpert and Ultra report rifampin heteroresistance as rifampin resistance, while Ultra may denote rifampin heteroresistance through "mixed patterns" of wild-type and mutant melt probe, melt peak temperatures. Overall, our findings inform end users that the threshold for reporting resistance in the case of rifampin heteroresistance is the highest for Classic Xpert and Ultra to resolve phenotypic and genotypic discordant rifampin-resistant TB results.
Summary New tuberculosis drug regimens are creating new priorities for drug susceptibility testing (DST) and surveillance. To minimise turnaround time, rapid DST will need to be prioritised, but ...developers of these assays will need better data about the molecular mechanisms of resistance. Efforts are underway to link mutations with drug resistance and to develop strain collections to enable assessment of new diagnostic assays. In resource-limited settings, DST might not be appropriate for all patients with tuberculosis. Surveillance data and modelling will help country stakeholders to design appropriate DST algorithms and to decide whether to change drug regimens. Finally, development of practical DST assays is needed so that, in countries where surveillance and modelling show that DST is advisable, these assays can be used to guide clinical decisions for individual patients. If combined judiciously during both development and implementation, new tuberculosis regimens and new DST assays have enormous potential to improve patient outcomes and reduce the burden of disease.
Summary Unacceptable levels of Mycobacterium tuberculosis transmission are noted in high burden settings and a renewed focus on reducing person-to-person transmission in these communities is needed. ...We review recent developments in the understanding of airborne transmission. We outline approaches to measure transmission in populations and trials and describe the Wells–Riley equation, which is used to estimate transmission risk in indoor spaces. Present research priorities include the identification of effective strategies for tuberculosis infection control, improved understanding of where transmission occurs and the transmissibility of drug-resistant strains, and estimates of the effect of HIV and antiretroviral therapy on transmission dynamics. When research is planned and interventions are designed to interrupt transmission, resource constraints that are common in high burden settings—including shortages of health-care workers—must be considered.
Studies have shown that the Mycobacterium tuberculosis Beijing genotype is an emerging pathogen that is frequently associated with drug resistance. This suggests that drug resistant Beijing strains ...have a relatively high transmission fitness compared to other drug-resistant strains.
We studied the relative transmission fitness of the Beijing genotype in relation to anti-tuberculosis drug resistance in a population-based study of smear-positive tuberculosis patients prospectively recruited and studied over a 4-year period in rural Vietnam. Transmission fitness was analyzed by clustering of cases on basis of three DNA typing methods. Of 2531 included patients, 2207 (87%) were eligible for analysis of whom 936 (42%) were in a DNA fingerprint cluster. The clustering rate varied by genotype with 292/786 (37%) for the Beijing genotype, 527/802 (67%) for the East-African Indian (EAI) genotype, and 117/619 (19%) for other genotypes. Clustering was associated with the EAI compared to the Beijing genotype (adjusted odds ratio (OR(adj)) 3.4: 95% CI 2.8-4.4). Patients infected with streptomycin-resistant strains were less frequently clustered than patients infected with streptomycin-susceptible strains when these were of the EAI genotype (OR(adj) 0.6, 95% CI 0.4-0.9), while this pattern was reversed for strains of the Beijing genotype (OR(adj) 1.3, 95% CI 1.0-1.8, p for difference 0.002). The strong association between Beijing and MDR-TB (OR(adj) 7.2; 95% CI 4.2-12.3) existed only if streptomycin resistance was present.
Beijing genotype strains showed less overall transmissibility than EAI strains, but when comparisons were made within genotypes, Beijing strains showed increased transmission fitness when streptomycin-resistant, while the reverse was observed for EAI strains. The association between MDR-TB and Beijing genotype in this population was strongly dependent on resistance to streptomycin. Streptomycin resistance may provide Beijing strains with a fitness advantage over other genotypes and predispose to multidrug resistance in patients infected with Beijing strains.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epidemiological evidence supports vitamin D deficiency as a risk factor for tuberculosis. Differences in solar ultraviolet B (UV-B) exposure, the major source of vitamin D, might therefore partially ...explain global variation in tuberculosis incidence.In a global country-based ecological study, we explored the correlation between vitamin D-proxies, such as solar UV-B exposure, and other relevant variables with tuberculosis incidence, averaged over the period 2004-2013.Across 154 countries, annual solar UV-B exposure was associated with tuberculosis incidence. Tuberculosis incidence in countries in the highest quartile of UV-B exposure was 78% (95% CI 57-88%, p<0.001) lower than that in countries in the lowest quartile, taking into account other vitamin D-proxies and covariates. Of the explained global variation in tuberculosis incidence, 6.3% could be attributed to variations in annual UV-B exposure. Exposure to UV-B had a similar, but weaker association with tuberculosis notification rates in the multilevel analysis with sub-national level data for large countries (highest
lowest quartile 29% lower incidence; p=0.057).The potential preventive applications of vitamin D supplementation in high-risk groups for tuberculosis merits further investigation.
Xpert MTB/Rif, a molecular test to detect tuberculosis (TB), has been proven to have high sensitivity and specificity when compared with liquid culture in clinical settings. However, little is known ...about its performance in community TB screening.
In Vietnam, a national TB prevalence survey was conducted in 2017. Survey participants who screened positive by chest X-ray, cough symptoms and/or recent history of tuberculosis were requested to provide at least two sputum samples that were tested for Mycobacterium tuberculosis by Xpert MTB/Rif G4 (Xpert) and BACTEC MGIT960 culture (MGIT).
There were 4,649 eligible participants provided both samples for testing. Among them, 236 (5.1%) participants tested positive for TB by Xpert, 244 (5.3%) tested positive by MGIT and 317 tested positive by at least one test; 163 (51.4%) had discordant test results. Of the positive Xpert, 162 (68.6%) showed a low or very low bacterial load. In multivariate logistic regression comparing discordant with Xpert-MGIT concordant positive results, discordant Xpert-positive results occurred more often among participants who had low sputum bacterial load, male sex, a history of TB treatment, or night sweats. The associated factors were male sex, abnormal chest X-ray and having night sweats when the logistic model was against those with both Xpert and MGIT negative.
We found high rates of discordance in the performance of Xpert and MGIT for community-based TB case finding. In situations where the majority of TB cases are expected to have a low bacterial load, multiple diagnostic tests and/or multiple samples are required to reach sufficient sensitivity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
New drugs for the treatment of tuberculosis (TB) are becoming available for the first time in over 40 y. Optimal strategies for introducing these drugs have not yet been established. The objective of ...this study was to compare different strategies for introducing the new TB drug bedaquiline based on patients' resistance patterns.
We created a Markov decision model to follow a hypothetical cohort of multidrug-resistant (MDR) TB patients under different bedaquiline use strategies. The explored strategies included making bedaquiline available to all patients with MDR TB, restricting bedaquiline usage to patients with MDR plus additional resistance and withholding bedaquiline introduction completely. We compared these strategies according to life expectancy, risks of acquired resistance, and the expected number and health outcomes of secondary cases. For our simulated cohort, the mean (2.5th, 97.5th percentile) life expectancy from time of initiation of MDR TB treatment at age 30 was 36.0 y (33.5, 38.7) assuming all patients with MDR TB received bedaquiline, 35.1 y (34.4, 35.8) assuming patients with pre-extensively drug-resistant (PreXDR) and extensively drug-resistant (XDR) TB received bedaquiline, and 34.9 y (34.6, 35.2) assuming only patients with XDR TB received bedaquiline. Although providing bedaquiline to all MDR patients resulted in the highest life expectancy for our initial cohort averaged across all parameter sets, for parameter sets in which bedaquiline conferred high risks of added mortality and only small reductions in median time to culture conversion, the optimal strategy would be to withhold use even from patients with the most extensive resistance. Across all parameter sets, the most liberal bedaquiline use strategies consistently increased the risk of bedaquiline resistance but decreased the risk of resistance to other MDR drugs. In almost all cases, more liberal bedaquiline use strategies reduced the expected number of secondary cases and resulting life years lost. The generalizability of our results is limited by the lack of available data about drug effects among individuals with HIV co-infection, drug interactions, and other sources of heterogeneity, as well as changing recommendations for MDR TB treatment.
If mortality benefits can be empirically verified, our results provide support for expanding bedaquiline access to all patients with MDR TB. Such expansion could improve patients' health, protect background MDR TB drugs, and decrease transmission, but would likely result in greater resistance to bedaquiline.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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