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Tuberculosis case notification rates (CNRs) for young adults in Vietnam are increasing. To determine whether this finding could reflect emergence of Mycobacterium tuberculosis Beijing genotype, we studied all new sputum smear-positive pulmonary tuberculosis patients registered for treatment in 3 rural districts in Vietnam during 2003-2006. Beijing strain infections were more frequent in younger patients (15-24 years of age, 53%) than in older patients (31%; p<0.001). The increase in CNRs for youngest patients was larger for disease caused by the Beijing genotype than by other genotypes, but the difference was not significant. For patients 15-24 years of age, 85% of fluctuations in CNRs between years was caused by fluctuations in Beijing genotype infections compared with 53% and 23% in the groups 25-64 and >or=65 years of age, respectively (p<0.001). These findings suggest that young adults may be responsible for introducing Beijing strains into rural Vietnam. [ABSTRACT FROM AUTHOR]

Background: Tuberculous meningitis kills or disables more than half of those affected with the disease. Previous studies have been too small to determine whether adjunctive treatment with corticosteroids can reduce the risk of disability or death among adults with tuberculous meningitis, and the effect of coinfection with the human immunodeficiency virus (HIV) is unclear.Methods: We performed a randomized, double-blind, placebo-controlled trial in Vietnam in patients over 14 years of age who had tuberculous meningitis, with or without HIV infection, to determine whether adjunctive treatment with dexamethasone reduced the risk of death or severe disability after nine months of follow-up. We conducted prespecified subgroup analyses and intention-to-treat analyses.Results: A total of 545 patients were randomly assigned to groups that received either dexamethasone (274 patients) or placebo (271 patients). Only 10 patients (1.8 percent) had been lost to follow-up at nine months of treatment. Treatment with dexamethasone was associated with a reduced risk of death (relative risk, 0.69; 95 percent confidence interval, 0.52 to 0.92; P=0.01). It was not associated with a significant reduction in the proportion of severely disabled patients (34 of 187 patients [18.2 percent] among survivors in the dexamethasone group vs. 22 of 159 patients [13.8 percent] in the placebo group, P=0.27) or in the proportion of patients who had either died or were severely disabled after nine months (odds ratio, 0.81; 95 percent confidence interval, 0.58 to 1.13; P=0.22). The treatment effect was consistent across subgroups that were defined by disease-severity grade (stratified relative risk of death, 0.68; 95 percent confidence interval, 0.52 to 0.91; P=0.007) and by HIV status (stratified relative risk of death, 0.78; 95 percent confidence interval, 0.59 to 1.04; P=0.08). Significantly fewer serious adverse events occurred in the dexamethasone group than in the placebo group (26 of 274 patients vs. 45 of 271 patients, P=0.02).Conclusions: Adjunctive treatment with dexamethasone improves survival in patients over 14 years of age with tuberculous meningitis but probably does not prevent severe disability. [ABSTRACT FROM AUTHOR]

Background: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis., Methods: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated., Results: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%)., Conclusions: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Tuberculosis (TB) is the leading cause of death among people living with HIV and frequently transmitted among this susceptible group. Transmission can be reduced by infection control practices. Simple evidence-based methods to identify patients who should be isolated are not well described in the literature. We sought to identify a simple, sensitive symptom or symptom combination that healthcare providers in resource-limited settings can use to identify and isolate persons living with HIV with highly infectious TB., Methods: Participants from 8 outpatient facilities in Cambodia, Thailand, and Vietnam underwent an extensive evaluation for TB. Patients with ≥1 positive sputum smear and Mycobacterium tuberculosis culture growth from a pulmonary site were defined as having highly infectious TB. We calculated sensitivity and prevalence of individual symptoms and >1000 symptom combinations., Results: Of 1980 participants, 272 (14%) had TB. Forty percent (n = 109) were highly infectious. Sensitivity for detecting highly infectious TB was highest for having the following symptoms in the past month as follows: weight loss (84%), cough (83%), fever (81%), and fatigue (78%); however, these symptoms were found in 46%-54% of all participants. Having 2 or 3 of 4 symptoms (prevalence, 26%-47%)-weight loss, fever, current cough, and night sweats-was 72%-90% sensitive for highly infectious TB., Conclusions: The 2 or 3 of 4 symptom combinations of weight loss, fever, current cough, and night sweats, which are the same symptoms comprising the current World Health Organization-recommended TB diagnostic screen, are sensitive for detecting highly infectious TB in people living with HIV.

Background: 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., Methods and Findings: 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., Conclusions: 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.

Background: The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-associated tuberculous meningitis is unknown., Methods: We conducted a randomized, double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to determine whether immediate ART reduced the risk of death. Antiretroviral drugs (zidovudine, lamivudine, and efavirenz) were started either at study entry or 2 months after randomization. All patients were treated with standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic co-trimoxazole and were followed up for 12 months. We conducted intention-to-treat, per-protocol, and prespecified subgroup analyses., Results: A total of 253 patients were randomized, 127 in the immediate ART group and 126 in the deferred ART group; 76 and 70 patients died within 9 months in the immediate and deferred ART groups, respectively. Immediate ART was not significantly associated with 9-month mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], .81-1.55; P = .50) or the time to new AIDS events or death (HR, 1.16; 95% CI, .87-1.55; P = .31). The percentage of patients with severe (grade 3 or 4) adverse events was high in both arms (90% in the immediate ART group and 89% in the deferred ART group; P = .84), but there were significantly more grade 4 adverse events in the immediate ART arm (102 in the immediate ART group vs 87 in the deferred ART group; P = .04)., Conclusions: Immediate ART initiation does not improve outcome in patients presenting with HIV-associated tuberculous meningitis. There were significantly more grade 4 adverse events in the immediate ART arm, supporting delayed initiation of ART in HIV-associated tuberculous meningitis. Clinical Trials Registration. ISRCTN63659091.

Background: Studies have suggested that the Mycobacterium tuberculosis Beijing genotype causes more severe clinical disease and higher treatment failure rates with standard regimens, possibly in association with an increased risk of acquiring drug resistance. We studied the effect of genotype on treatment failure in a rural area in Vietnam where multidrug resistance is strongly associated with the Beijing genotype., Methods: In a population-based prospective cohort study, patients with smear-positive tuberculosis were tested before and after treatment by spoligotyping and drug susceptibility analysis. Reinfections were excluded by DNA fingerprinting. The outcome was treatment failure based on culture., Results: Of 1106 patients eligible for analysis, 33 experienced treatment failure (3.0%; 95% confidence interval [CI], 2.1%-4.1%). The proportion of failure was 5.3% (95% CI, 0.3%-7.9%) among 380 patients with Beijing genotype infections. Multidrug-resistant tuberculosis strongly predicted failure (odds ratio [OR], 114; 95% CI, 30-430). After adjusting for multidrug-resistant tuberculosis, treatment failure was not associated with the Beijing genotype (adjusted OR, 0.7; 95% CI, 0.3-2.0). Amplification of drug resistance occurred in 3 patients (0.3%; 95% CI, 0.1%-0.7%) and was associated with multidrug resistance at baseline (P = .004) but not with the Beijing genotype. No multidrug resistance was created., Conclusion: The Beijing genotype was not associated with treatment failure in Vietnam; apparent associations were explained by the strong association of this genotype with multidrug resistance. Amplification of resistance in this patient population was rare.

Using population-based data from rural Vietnam, we assessed tuberculosis (TB) transmission within and outside of households. Eighty-three percent of persons with recent household TB were infected by different strains of Mycobacterium tuberculosis than were their household members. This result argues against the effectiveness of active TB case finding among household members.

Objective: To assess whether the increase in tuberculosis (TB) notification rates among young adults in Vietnam reflects increased transmission in the population at large., Method: Trends of case notification rates of new smear-positive TB were calculated from routinely reported data of district TB units over the period 1996-2005. Results from repeated tuberculin surveys among children aged 6-9 years were obtained to calculate the trend in annual risk of TB infection (ARTI)., Findings: From 1996 to 2006, notification rates in the age group 15-24 years increased by 4.3% per year, and more so in highly urbanised (6.7%) than in rural districts (1.7%). The ARTI in urban districts declined from 2.4% in 1992 to 1.2% in 1998 and 0.9% in 2005. In rural districts, the ARTI increased from 0.7% in 1991 to 1.2% in 1997, and then declined to 0.9% in 2006., Conclusion: The increase in TB notification rates among young adults in Ho Chi Minh Province is accompanied by a decrease in ARTI in children. This suggests that the trend in TB notification among young adults reflects increased rates of progression from infection to disease and/or increased transmission within this age group, rather than increased transmission in the population at large.

Background: Associations between multidrug resistance and the Mycobacterium tuberculosis Beijing genotype have been described mainly in populations with poor tuberculosis (TB) control such as prisons and inner cities, and may reflect shared risk factors rather than a biological association., Objective: To study the association between genotype and drug resistance among TB patients in a population with adequate TB control., Setting: Three rural districts in Vietnam. The study was performed at the Pham Ngoc Thach Tuberculosis and Lung Disease Hospital, Ho Chi Minh City, and the Tien Giang Provincial Tuberculosis and Lung Disease Hospital, My Tho, Vietnam., Methods: Pretreatment sputum specimens were collected for culture, drug susceptibility testing and spoligotyping of all sputum smear-positive pulmonary TB patients consecutively diagnosed over a 3-year period., Results: Beijing genotype infections were observed in 614 of 1744 (35%) patients. Beijing strains were more common among female (adjusted odds ratio [aOR] 1.4, P = 0.005), young (aOR 2.8, P < 0.001) and previously treated patients (aOR 2.4, P < 0.001). The Beijing genotype was associated with any resistance (aOR 3.7, P < 0.001) and multidrug resistance (aOR 6.8, P < 0.001) among new patients, and with any resistance (aOR 2.7, P = 0.005) but not with multidrug resistance (aOR 1.4, P = 0.545) among previously treated patients., Conclusion: In Vietnam, Beijing genotype is associated with young age and in new patients with multidrug resistance despite adequate TB control, suggesting a biological association. This potentially undermines the effectiveness of TB control in countries where Beijing genotype infections are common.

Setting: Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases, Ho Chi Minh City, Vietnam., Objective: Fluoroquinolones (FQs) are increasingly used in the treatment of tuberculosis (TB) and are the second-line drugs of choice for treatment of multidrug-resistant TB. We aimed to set up a polymerase chain reaction (PCR) based assay to detect the most common FQ-resistance-associated mutations in gyrase A (gyrA) of Mycobacterium tuberculosis., Design: A total of 42 FQ-resistant and 40 FQ-susceptible isolates were collected in 2005-2006 and sequenced in gyrA. Using sequencing results as gold standard, a real-time PCR using three locked nucleic acid probes (LNA-PCR) was designed to detect mutations at positions 90, 91 and 94 (97% of gyrA FQ-resistance-associated mutations) and evaluated., Results: Sequencing of 42 FQ-resistant isolates revealed no gyrA mutations in 10 isolates, 20 isolates had a single mutation and 12 isolates showed double peaks at resistance-associated alleles, suggesting a heterogeneous population. With LNA-PCR, all wild-type and 19/20 mutant isolates were correctly identified. Eleven of 12 heterogeneous isolates were correctly identified as resistant mutants. Overall, 71% ([19 + 11]/42) of phenotypically FQ-resistant isolates were detected. Specificity was 100% on 40 FQ-susceptible isolates., Conclusion: This assay provides a simple and rapid means to reliably detect FQ-resistance-associated gyrA mutations in M. tuberculosis.

The factors that govern the development of tuberculosis disease are incompletely understood. We hypothesized that some strains of Mycobacterium tuberculosis (M. tuberculosis) are more capable of causing disseminated disease than others and may be associated with polymorphisms in host genes responsible for the innate immune response to infection. We compared the host and bacterial genotype in 187 Vietnamese adults with tuberculous meningitis (TBM) and 237 Vietnamese adults with uncomplicated pulmonary tuberculosis. The host genotype of tuberculosis cases was also compared with the genotype of 392 cord blood controls from the same population. Isolates of M. tuberculosis were genotyped by large sequence polymorphisms. The hosts were defined by polymorphisms in genes encoding Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and Toll-like receptor-2 (TLR-2). We found a significant protective association between the Euro-American lineage of M. tuberculosis and pulmonary rather than meningeal tuberculosis (Odds ratio (OR) for causing TBM 0.395, 95% confidence intervals (C.I.) 0.193-0.806, P = 0.009), suggesting these strains are less capable of extra-pulmonary dissemination than others in the study population. We also found that individuals with the C allele of TLR-2 T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype (OR = 1.57 [95% C.I. 1.15-2.15]) than other individuals. The study provides evidence that M. tuberculosis genotype influences clinical disease phenotype and demonstrates, for the first time, a significant interaction between host and bacterial genotypes and the development of tuberculosis.

Toll-like receptors (TLR) are critical mediators of the immune response to pathogens and human polymorphisms in this gene family regulate inflammatory pathways and are associated with susceptibility to infection. Lipopeptides are present in a wide variety of microbes and stimulate immune responses through TLR1/2 or TLR2/6 heterodimers. It is not currently known whether polymorphisms in TLR1 regulate the innate immune response. We stimulated human whole blood with triacylated lipopeptide, a ligand for TLR1/2 heterodimers, and found substantial inter-individual variation in the immune response. We sequenced the coding region of TLR1 and found a non-synonymous polymorphism, I602S (base pair T1805G), that regulated signalling. In comparison to TLR1&#95;602S, the 602I variant mediated substantially greater basal and lipopeptide-induced NF-kappaB signalling in transfected HEK293 cells. These signalling differences among TLR1 variants were also found with stimulation by extracts of Mycobacterium tuberculosis. Furthermore, individuals with the 602II genotype produced substantially more IL-6 than those with the 602SS variant in a lipopeptide-stimulated whole-blood cytokine assay. Together, these observations demonstrate that variation in the inflammatory response to bacterial lipopeptides is regulated by a common TLR1 transmembrane domain polymorphism that could potentially impact the innate immune response and clinical susceptibility to a wide spectrum of pathogens.

Tuberculous meningitis (TBM) results from the haematogenous dissemination of Mycobacterium tuberculosis from the lung to the brain. Dissemination is believed to occur early during infection, before the development of adaptive immunity. Toll-like receptor 2 (TLR2) mediates recognition of M. tuberculosis and initiates the innate immune response to infection. We hypothesized that polymorphisms in the TLR2 gene influence bacterial dissemination and the development of TBM. A case-control study was designed to test the hypothesis. Cases of bacteriologically confirmed pulmonary tuberculosis (TB) (n=183) and TBM (n=175), and cord blood controls (n=389) were enrolled in Vietnam. TLR2 genotype 597CC was associated with susceptibility to TB (odds ratio (OR)=2.22, 95% confidence interval (CI): 1.23-3.99). The association was found with meningeal rather than pulmonary TB (TBM vs control, OR=3.26, 95% CI: 1.72-6.18), and was strongest when miliary TB was found on chest radiography (controls vs TBM with miliary TB, OR=5.28, 95% CI: 2.20-12.65). Furthermore, the association increased with the severity of neurologic symptoms (grade I TBM, OR=1.93, 95% CI: 0.54-6.92; grade II, OR=3.32, 95% CI: 0.84-13.2; and grade III, OR=5.70, 95% CI: 1.81-18.0). These results demonstrate a strong association of TLR2 SNP T597C with the development of TBM and miliary TB and indicate that TLR2 influences the dissemination of M. tuberculosis.

Background: Although meningitis is the most severe form of infection caused by Mycobacterium tuberculosis, the immunopathogenesis of this disease is poorly understood. We tested the hypothesis that polymorphisms in Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), an adaptor protein that mediates signals from Toll-like receptors activated by mycobacteria, are associated with susceptibility to tuberculosis (TB)., Methods: We used a case-population study design in Vietnam with cord-blood control samples (n = 392) and case patients (n = 358) who had either pulmonary (n = 183) or meningeal (n = 175) TB., Results: The TIRAP single-nucleotide polymorphism (SNP) C558T was associated with increased susceptibility to TB, with a 558T allele frequency of 0.035 in control samples versus 0.074 in case patients (odds ratio [OR], 2.25; P < .001). Subgroup analysis revealed that SNP 558T was more strongly associated with susceptibility to meningeal TB (OR, 3.02; P < .001) than to pulmonary TB (OR, 1.55; P = .22). In comparison to the 558CC genotype, the 558TT genotype was associated with decreased whole-blood interleukin-6 production, which suggests that TIRAP influences disease susceptibility by modulating the inflammatory response., Conclusions: These results provide the first evidence of an association of a TIRAP SNP with the risk of any disease and also suggest that the Toll-like receptor pathway influences susceptibility to meningeal and pulmonary TB by different immune mechanisms.

Setting: Six provinces in Vietnam where the DOTS strategy was introduced in 1989., Objective: To assess the impact of improved tuberculosis (TB) control on TB epidemiology in Vietnam., Methods: Data from the surveillance system in the period 1990-2003 were analysed to assess trends of notification rates and the mean ages of notified cases. Data from repeated tuberculin surveys in the period 1986-2002 were estimated to assess the prevalence of TB infection, the annual risk of infection and its trend using various cut-off points in those with and without bacille Calmette-Guérin (BCG) scar., Results: Age-standardised notification rates in the period 1996-2003 declined significantly, by 2.6% to 5.9% per year, in five provinces. However, in four provinces notification rates in the age group 15-24 years increased significantly, by 4.5% to 13.6% per year, during this period. The mean age of newly diagnosed patients with smear-positive TB increased up to 1995 but decreased thereafter. The annual risk of TB infection showed a significant annual decrease (4.9% per year) in one province in surveys performed between 1986 and 1997, and in two provinces (6.6% and 4.7%) in surveys conducted between 1993 and 2002., Conclusion: These data suggest limited impact to date of the DOTS strategy in Vietnam.

Tuberculous meningitis (TBM) is the most devastating form of tuberculosis. Both intracerebral and peripheral blood immune responses may be relevant to pathogenesis, diagnosis, and outcome. In this study, the relationship between pretreatment host response, disease phenotype, and outcome in Vietnamese adults with TBM was examined. Before treatment, peripheral blood IFN-gamma ELISPOT responses to the Mycobacterium tuberculosis Ags ESAT-6, CFP-10, and purified protein derivative (PPD) were a poor diagnostic predictor of TBM. Cerebrospinal fluid IL-6 concentrations at presentation were independently associated with severe disease presentation, suggesting an immunological correlate of neurological damage before treatment. Surprisingly however, elevated cerebrospinal fluid inflammatory cytokines were not associated with death or disability in HIV-negative TBM patients at presentation. HIV coinfection attenuated multiple cerebrospinal fluid inflammatory indices. Low cerebrospinal fluid IFN-gamma concentrations were independently associated with death in HIV-positive TBM patients, implying that IFN-gamma contributes to immunity and survival. Collectively, these results reveal the effect of HIV coinfection on the pathogenesis of TBM and suggest that intracerebral immune responses, at least in HIV-negative cases, may not be as intimately associated with disease outcome as previously thought.

Objectives: To assess the pattern of drug resistance among smear-positive tuberculosis (TB) patients in an inner city area in Vietnam., Methods: A random sample of patients diagnosed by the national TB programme (NTP) were offered HIV testing and submitted sputum for Mycobacterium tuberculosis drug sensitivity testing., Results: Of 1433 isolates from new patients, 360 (25%) were resistant to isoniazid (INH), 57 (4.0%) to rifampicin (RMP), 421 (29%) to streptomycin (SM) and 28 (2.0%) to ethambutol. Among 401 previously treated patients, this was 218 (54%), 109 (27%), 217 (54%) and 26 (7%), respectively. Multidrug resistance (MDR) was observed in 55 (3.8%) new and 102 (25%) previously treated patients. RMP resistance was strongly associated with resistance to INH (OR 46) and INH plus SM (OR 91, P = 0.004). Prevalence of drug resistance tended to decrease with age. Neither any resistance nor MDR was significantly associated with HIV infection., Conclusions: In this inner city area, levels of drug resistance, in particular of MDR among previously treated patients, are high. This may be related to the use of NTP regimens in the context of highly prevalent combined SM and INH resistance which may favour acquisition of RMP resistance.

Objective: To assess the combined effects of drug resistance, HIV infection and treatment regimen on treatment outcomes of smear-positive tuberculosis patients in Ho Chi Minh City, Vietnam., Methods: A representative sample of patients diagnosed in 1998-2000 in 12 urban districts was offered HIV testing and submitted sputum for Mycobacterium tuberculosis culture and drug susceptibility testing. New patients were treated with 2SHRZ/6HE in nine districts and with 2SHRZ/4RH in three districts., Results: The cure rate was 87% (1240/1430) among new patients compared to only 73% (287/391) among previously treated patients. Failure was associated with multidrug resistance (adjusted odds ratios [aOR] 49.6 and 16.6, respectively) and combined resistance to isoniazid (INH) and streptomycin (SM) (aOR 13.4 and 4.8), but not with HIV infection. New patients had an increased risk of failure on treatment with 2SHRZ/4RH compared to 2SHRZ/6HE if the isolate was resistant to INH and SM (aOR 2.8, P = 0.016). Death during treatment occurred in 15 of 50 HIV-infected patients (30%). Mortality was significantly associated with HIV infection (aOR 29.9), multidrug resistance (aOR 4.7) and other resistance to two or more drugs (aOR 2.1)., Conclusion: In Vietnam, adaptation of treatment regimens should be considered, and interventions are needed to reduce the high mortality among HIV-infected patients.

Background: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to 1 or more antituberculosis drugs is an increasingly common clinical problem, although the impact on outcome is uncertain., Methods: We performed a prospective study of 180 Vietnamese adults admitted consecutively for TBM. M. tuberculosis was cultured from the cerebrospinal fluid (CSF) of all patients and was tested for susceptibility to first-line antituberculosis drugs. Presenting clinical features, time to CSF bacterial clearance, clinical response to treatment, and 9-month morbidity and mortality were compared between adults infected with susceptible and those infected with drug-resistant organisms., Results: Of 180 isolates, 72 (40.0%) were resistant to at least 1 antituberculosis drug, and 10 (5.6%) were resistant to at least isoniazid and rifampicin. Isoniazid and/or streptomycin resistance was associated with slower CSF bacterial clearance but not with any differences in clinical response or outcome. Combined isoniazid and rifampicin resistance was strongly predictive of death (relative risk of death, 11.63 [95% confidence interval, 5.21-26.32]) and was independently associated with human immunodeficiency virus infection., Conclusions: Isoniazid and/or streptomycin resistance probably has no detrimental effect on the outcome of TBM when patients are treated with first-line antituberculosis drugs, but combined isoniazid and rifampicin resistance is strongly predictive of death.

Objective: To describe the establishment and development of the National Tuberculosis Control Programme (NTP) of Vietnam., Methods: Data were obtained from the surveillance system established by the new NTP in 1986 and based on the principles now described as the WHO DOTS strategy., Results: The proportion of districts covered by the NTP increased from 40% in 1986 to almost 100% in 2000. The proportion of communes applying NTP guidelines increased from 18% in 1986 to 99.8% in 2000. The total number of tuberculosis cases notified increased from 8737 in 1986 to 89 792 in 2000. Most of these are new smear-positive cases. Based on WHO estimations of the incidence rate, the proportion of new smear-positive cases detected and put on short-course treatment has been over 70% since 1996. Reported cure rates with short-course chemotherapy are consistently over 85%., Conclusions: DOTS is feasible in a low-income, high-burden country. The main reasons for success were political commitment, a well-functioning health network, integration of tuberculosis control into the general health service at district level, a continuous supply of drugs and effective external support. Major challenges are long-term financial support, expansion to remote areas and vulnerable groups, definition of the role of the private sector, and future developments of the HIV epidemic and multidrug resistance.

Setting: Ho Chi Minh City, Vietnam., Objectives: To determine treatment outcome among patients treated by private lung specialists in a public-private mix (PPM) project for improved TB control., Methods: Cohorts of patients treated by private lung specialists within the PPM project and in National Tuberculosis Programme (NTP) facilities were followed for up to 12 months. The quality of case management and treatment outcome was determined based on information in treatment cards. As a complement, questionnaire surveys of private providers (PPs) and patients and focus group discussions with PPs were conducted., Results: Among 400 patients treated by PPs, 36 different treatment regimens were used. Directly observed treatment was not used at all, and treatment evaluation with sputum smear microscopy and health education was inadequate. Overall treatment success was 60% and the default rate was 37%, which was considerably worse than in NTP facilities., Conclusion: This PPM project, which used a combination of training, supervision, standardised referral and information system and financial incentives, did not achieve sufficiently good treatment outcome by PPs. Possible reasons for the poor outcome include absence of subsidisation of drug costs and lack of regulatory enforcement.

Setting: Ho Chi Minh City, Vietnam., Aim: To determine the extent of initial default in the NTP, the reasons for initial default, health seeking after initial default and treatment received at other health facilities., Method: Questionnaire-based interviews of patients who were diagnosed with sputum-positive TB in the NTP during 2000 and who did not register for treatment in the NTP., Results: The initial default rate was 8.3%; 79% gave reasons related to the NTP working procedures or treatment strategy, while 17.5% gave reasons related to insufficient knowledge among patients about TB and/or the need for treatment. Sixty-five per cent had been treated with anti-tuberculosis drugs at other health facilities after default, of which 74% had been treated at fully private facilities., Conclusion: Initial default is mainly caused by some patients' negative perceptions of working procedures and/or treatment strategy in the NTP. The majority of these patients are treated in private clinics after default from the NTP. The NTP needs to improve patients' perceptions of the treatment strategy and develop more user-friendly services that enable more patients to access treatment and reduce the risk of patients receiving substandard treatment in the private sector.

Objective: To determine acquired drug resistance among failure and relapse cases after treatment of new smear-positive tuberculosis., Methods: A cohort of 2901 patients with new smear-positive tuberculosis was enrolled in Vietnam. Sputum samples were stored at enrolment. Upon failure or relapse, another sputum sample was collected. Both were cultured and underwent drug susceptibility testing and restriction fragment length polymorphism (RFLP) typing., Results: Of 40 failure cases, 17 had multidrug resistance (MDR) at enrolment. At failure, 15 of the 23 (65%) patients without primary MDR had acquired MDR. Of 39 relapse cases and 143 controls, none had primary MDR., Conclusion: Primary drug resistance was a strong risk factor for failure and relapse and for acquiring further resistance. As 80% of failure cases had MDR, the standard re-treatment regimen appears inadequate for failure cases in this control programme with a very high cure rate among new cases.

Setting: Ho Chi Minh City (HCMC), Vietnam., Objective: To assess the impact on case detection of a public-private mix (PPM) project linking private providers (PPs) to the National Tuberculosis Programme (NTP)., Method: Nine-month monitoring of referral and diagnostic data recorded in new referral forms and treatment cards for PPs and upgraded NTP registers., Results: A total of 1549 TB suspects were referred, of whom 1090 (70%) actually went to the NTP for sputum examination. A total of 569 cases were detected through referrals or notification, of whom 45% were new sputum smear-positive cases. The case detection of new sputum smear-positive cases in PPM districts increased by 18% (21/100,000, 95%CI 0-42) compared to the previous year, while a slight decrease occurred in control districts. In HCMC as a whole, case detection increased by 7% (7/100,000, 95%CI 2-11/100,000). Among sputum smear-positive cases detected in NTP through referrals from PPs, 58% defaulted before initiating treatment., Conclusions: The tendency towards increased case detection associated with this PPM indicates a potential for utilising PPs to improve case detection. However, the NTP and PPs should jointly address the problem of initial default before considering expansion of this PPM model.

Setting: Ho Chi Minh City, Vietnam., Objective: To compare tuberculosis case management and treatment outcome between a semi-private chest clinic and a publicly run national tuberculosis programme (NTP)., Method: Prospective, non-randomised, comparative cohort study. Case-management and treatment outcome was determined for 176 patients treated in the semi-private clinic and 326 patients treated in the NTP., Results: In the semi-private clinic cohort, significantly fewer patients completed treatment and/or were cured than in the NTP cohort (48.9% vs. 85.0%, P < 0.001). Among patients with sputum-positive pulmonary TB, significantly fewer were cured in the semi-private clinic cohort compared to the NTP cohort (22.2% vs. 79.2%, P < 0.001), and treatment success was significantly lower (35.2% vs. 79.7%. P < 0.001). Adjustment for a number of potential confounders did not change these findings significantly., Conclusions: Treatment outcome was considerably better in the NTP than in the semi-private clinic. The difference is not likely to be due to differences in patient characteristics or in provider knowledge. Different financial incentives for the providers in the two settings and ways of paying for services by patients are possible reasons for the observed difference in the quality of case management and treatment outcome.

In Vietnam the spread of HIV infection is thought to be limited. In 12 urban districts of Ho Chi Minh City representative samples of tuberculosis patients have undergone HIV testing since 1995. HIV prevalence increased steeply from 0.5% in 1995 to 4% in 2000, with a doubling time of approximately 21 months. This study highlights the need to intensify HIV/AIDS prevention and control in Vietnam.

Few data address the outcomes of patients who have multidrug-resistant tuberculosis (MDR-TB), defined as resistance to at least isoniazid and rifampin, and who receive a standard World Health Organization (WHO) recommended retreatment regimen after relapse or failure with initial treatment. In this case series, we examined treatment outcomes of a convenience sample of 42 relapse or failure patients who had documented MDR-TB and who had received a standard WHO retreatment regimen (2SHRZE/1HRZE/5H3R3E3). One patient died of tuberculosis in the last month of treatment; the remaining 41 patients completed retreatment. Of the 42, 14 (33%) were sputum smear-negative on completion of therapy. The proportion of patients cured of MDR-TB with the WHO retreatment regimen was similar to historic outcomes when no chemotherapy for TB was given.

Vietnam has a well-organised National TB Control Programme (NTP) with outstanding treatment results. Excellent prospect of cure is provided free of charge. Still, some people prefer to pay for their TB treatment themselves in private clinics. This is a potential threat to TB control since no notification of cases treated in the private sector occurs, and there is no control of the effectiveness of treatment provided in private clinics. Using a qualitative approach within a grounded theory framework, this study explores health-seeking behaviour among people with TB, applying a specific focus on reasons for choices of private versus pubic health care providers. The study identifies a number of characteristics of private TB care, which both seem attractive to patients and at the same time contrast sharply with the structure of the NTP strategy. These include flexible diagnostic procedures, no administrative procedures to establish eligibility for treatment, flexible choices of drug regimens, non-supervised treatment (no DOT), no tracing of defaulters in the household, no official registration of TB cases and thus less threat to personal integrity. A possibility to demand individualised service through the use of fee-for-service payments directly to physicians also seems attractive to many patients. A number of the components of the NTP strategy that have been put in place in order to secure optimal public health outcomes are lacking in the private sector. A dilemma for TB control is that this seems to be an important reason for why many people with TB opt for private providers where quality of care is virtually uncontrolled. The global threat of TB has led to calls for forceful measures to control TB. However, based on the findings in this study it is argued that the use of rigid approaches to TB control that do not encompass a strong component of responsiveness towards the needs of individuals may be counterproductive for public health.

Setting: Ho Chi Minh City (HCMC), Vietnam., Objectives: To assess knowledge about tuberculosis, to describe self-reported dispensing practices and to estimate the magnitude of anti-tuberculosis drug dispensing in private pharmacies., Design: Survey of a random sample of 147 private pharmacies out of a total of 1814 registered pharmacies. Interviews were carried out based on a structured questionnaire., Results: Eighteen per cent of interviewees identified TB as a possible diagnosis for a fictitious case with fever and cough for 4 weeks. Fifty-eight per cent reported selling anti-tuberculosis drugs often or sometimes. Interviewees estimated that 1.3 persons on average (95%CI 0.6-1.9) had bought anti-tuberculosis drugs during the last 4-week period, and that 24% of them had bought anti-tuberculosis drugs without a prescription., Conclusion: We have estimated that between 1100 and 3400 persons buy anti-tuberculosis drugs each month in the 1814 registered private pharmacies in HCMC, that about a quarter of them do so without a prescription, and that at least 40% of all anti-tuberculosis drug dispensing in HCMC occurs in the private sector. Regulations need to be put in place urgently and collaboration strengthened between the strong National Tuberculosis Programme and the unorganised private sector in HCMC.