Tuberculosis resistance-conferring mutations with fitness cost among HIV-positive individuals in Uganda.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is considered to be less transmissible due to the fitness cost associated with drug resistance-conferring mutations in essential genes. OBJECTIVE: To test the hypothesis that TB drug resistance-conferring mutations with fitness cost are more frequent among human immunodeficiency virus (HIV) positive than among HIV-negative patients. DESIGN: We analysed all strains from the two TB drug resistance surveys conducted in Uganda between 2008 and 2011. Strains phenotypically susceptible to rifampicin and/or isoniazid were assumed to be wild-type; in all other cases, we performed whole-genome sequencing. Mutations at the rpoB531 and katG315 codons were considered without fitness loss, whereas other rpoB codons and non-katG were considered with fitness loss. RESULTS: Of the 897 TB patients, 286 (32.1%) were HIV-positive. Mutations with fitness loss in HIV-positive and HIV-negative patients were respectively as follows: non-531 rpoB: 1.03% (n = 3), 0.71% (n = 4) (OR 1.46, 95%CI 0.58-3.68); non-katG: 0.40% (n = 1), 1.0% (n = 6) (OR 0.40, 95%CI 0.07-2.20); rpoB531: 1.49% (n = 4), 0.69% (n = 4) (OR 2.29, 95%CI 0.83-5.77); katG315: 3.86% (n = 11), 2.55% (n = 15) (OR 1.54, 95%CI 0.81-2.90). The odds of mutations with and without fitness cost were higher for patients with a history of previous anti-tuberculosis treatment. CONCLUSIONS: Our data do not support the hypothesis that resistance-conferring mutations with fitness cost are likely to be often present in HIV-positive individuals.

Cost and cost-effectiveness of tuberculosis treatment shortening: a model-based analysis.

BACKGROUND: Despite improvements in treatment success rates for tuberculosis (TB), current six-month regimen duration remains a challenge for many National TB Programmes, health systems, and patients. There is increasing investment in the development of shortened regimens with a number of candidates in phase 3 trials. METHODS: We developed an individual-based decision analytic model to assess the cost-effectiveness of a hypothetical four-month regimen for first-line treatment of TB, assuming non-inferiority to current regimens of six-month duration. The model was populated using extensive, empirically-collected data to estimate the economic impact on both health systems and patients of regimen shortening for first-line TB treatment in South Africa, Brazil, Bangladesh, and Tanzania. We explicitly considered 'real world' constraints such as sub-optimal guideline adherence. RESULTS: From a societal perspective, a shortened regimen, priced at USD1 per day, could be a cost-saving option in South Africa, Brazil, and Tanzania, but would not be cost-effective in Bangladesh when compared to one gross domestic product (GDP) per capita. Incorporating 'real world' constraints reduces cost-effectiveness. Patient-incurred costs could be reduced in all settings. From a health service perspective, increased drug costs need to be balanced against decreased delivery costs. The new regimen would remain a cost-effective option, when compared to each countries' GDP per capita, even if new drugs cost up to USD7.5 and USD53.8 per day in South Africa and Brazil; this threshold was above USD1 in Tanzania and under USD1 in Bangladesh. CONCLUSION: Reducing the duration of first-line TB treatment has the potential for substantial economic gains from a patient perspective. The potential economic gains for health services may also be important, but will be context-specific and dependent on the appropriate pricing of any new regimen.

Characterisation of Mycobacterium tuberculosis isolates lacking IS6110 in Viet Nam.

SETTING: The molecular diagnosis of tuberculosis (TB) in Viet Nam is often based on the detection of insertion sequence (IS) 6110 in Mycobacterium tuberculosis. However, 8-11% of M. tuberculosis strains in South-East Asia do not contain this target and this undermines the validity of these molecular tests. OBJECTIVE: We quantified the frequency of M. tuberculosis strains lacking IS6110 in rural Viet Nam and studied their epidemiological and clinical characteristics. DESIGN: Consecutively diagnosed adult TB patients in rural Southern Viet Nam submitted two sputum samples for culture, IS6110 restriction fragment length polymorphism (RFLP) spoligotyping and 15-loci variable number tandem repeat typing. Polymerase chain reaction (PCR) was performed to confirm the absence of IS6110 elements in strains lacking IS6110 hybridisation in RFLP. RESULTS: Among 2664 TB patient isolates examined, 109 (4.1%) had no IS6110 element. Compared to other strains, these no-copy strains were less often resistant to anti-tuberculosis drugs, particularly to streptomycin (adjusted OR 0.2, 95%CI 0.1-0.5), and showed significant geographic variation. No associations with TB history or demographic factors were found. CONCLUSIONS: Strains without the IS6110 target pose a problem in Viet Nam as regards false-negative molecular TB diagnosis in PCR. Compared to other strains circulating in Viet Nam, no-copy strains are more susceptible to anti-tuberculosis drugs.

First national tuberculin survey in Viet Nam: characteristics and association with tuberculosis prevalence.

OBJECTIVES: To estimate the prevalence of infection with Mycobacterium tuberculosis and the annual risk of tuberculous infection (ARTI) and to compare this with the prevalence of tuberculosis (TB) over study clusters and households. METHODS: A nationwide, stratified cluster sample survey was carried out in 2006-2007 in Viet Nam to assess the prevalence of infection with M. tuberculosis. A representative sample of children aged 6-14 years underwent a tuberculin skin test (TST) using the Mantoux method. RESULTS: Of 23,160 children registered, 21,487 (92.8%) were tested and read and available for analysis. Using a cut-off point of 10 mm, the estimated prevalence of TST positivity was 16.7%, and the ARTI was 1.7% (95%CI 1.5-1.8). Higher infection rates were found in urban than in rural and remote areas, and infection rates increased with age. There was significant association between the prevalence of TB disease and infection at the cluster level (regression coefficient 0.54, 95%CI 0.06-1.01, P = 0.027, correlation coefficient R(2) 0.120). Children with a (recent) case of TB in the household were 1.6 times more likely to be TST-positive than children in households with no recent cases (P < 0.05). CONCLUSION: The estimated nationwide ARTI was 1.7%. TST positivity was associated with the presence of a TB case in the household.

Suspected tuberculosis case detection and referral in private pharmacies in Viet Nam.

SETTINGS: Private pharmacies in Hanoi, Viet Nam. OBJECTIVES: To explore the response of health care providers (HCPs) in private pharmacies to suspected tuberculosis (TB) patients. METHODS: A simulated patient method combined with an interview in 128 randomly selected private pharmacies and 10 private pharmacies near TB hospitals. RESULTS: In the simulated patient method and interview, respectively 59 (46%) and 70 (55%) of HCPs referred the TB suspect to general health care. Only 11 (9%) referred the simulated patient to a TB care facility. Fifty-two (42%) of the HCPs identified suspected TB from a fictitious case described on paper; 34 (27%) were aware that free treatment was provided under the National Tuberculosis Programme (NTP). Knowledge about free NTP treatment predicted a higher rate of direct referrals to TB facilities (OR 5.80, 95%CI 1.88-19.62) and greater ability to identify suspected TB from a fictitious case on paper (OR 5.14, 95%CI 2.36-11.73). Pharmacies with Good Pharmacy Practice (GPP) certification were less likely to refer simulated patients to TB facilities than non-GPP pharmacies (OR 0.10, 95%CI ≤0.01-0.79). CONCLUSIONS: Nearly half of HCPs in private pharmacies do not refer TB suspects, possibly contributing to delays in diagnosis and treatment. Knowledge about free NTP treatment predicted better performance of HCPs.

Yield of interview screening and chest X-ray abnormalities in a tuberculosis prevalence survey.

BACKGROUND: Tuberculosis (TB) prevalence surveys generally rely on a combination of screening methods to identify suspects eligible for sputum culture. OBJECTIVE: To assess the yield of screening methods applied in a recent prevalence survey in Viet Nam and estimate the proportion of TB cases missed due to incomplete participation. METHODS: TB suspects were identified based on self-reported TB history or productive cough by interview and chest X-ray (CXR). We calculated the case yield of these two screening methods by dividing the number of cases detected per method by the total number of cases detected. As not all participants underwent the full screening procedure, we recalculated the maximum yield of the screening methods using multiple imputation methods. RESULTS: The yield from screening by interview and CXR were respectively 38% and 91%. Adjusting for missing data by multiple imputation, we estimated that we missed 9.9% (95%CI 6.8-14.2) of expected TB cases. CONCLUSION: In prevalence surveys, screening by pre-structured interview is insufficient, and should be supplemented with CXR to achieve sufficient identification of TB cases. The effect of incomplete participation in the full screening procedure may be substantial and should be adjusted for in the analysis.

Health-seeking behaviour among adults with prolonged cough in Vietnam.

OBJECTIVE: To assess health-seeking behaviour among adults with prolonged cough in a population-based, nationally representative sample in Vietnam. METHODS: Cross-sectional survey conducted from September 2006 to July 2007. All inhabitants aged ≥15 years were invited for screening for cough, history of tuberculosis (TB) treatment and chest X-ray (CXR) examination. TB suspects, defined as any survey participant with CXR abnormalities consistent with TB, or productive cough for more than 2 weeks or TB treatment either currently or in the preceding 2 years submitted sputum specimens for smear examination and culture and provided information on health-seeking behaviour in an in-depth interview. RESULTS: Of 94 179 persons participating in the survey, 4.6% had prolonged productive cough. Forty-four percentage of those had sought health care and reported pharmacies (35%), commune health posts (29%), public hospitals (24%) and private physicians (10%) as first point of contact. Only 7% had undergone sputum smear examination. Of TB suspects with prolonged productive cough, 2.9% were diagnosed with TB; 10.2% of these reported smear and 21.9% reported X-ray examination when visiting a health care facility. The average patient delay was 4.1 weeks (95% CI: 3.9-4.4) among cough suspects and 4.0 weeks (95% CI: 3.1-4.9) among TB cases. CONCLUSIONS: In this Vietnamese survey, nearly half of persons with cough for more than 2 weeks had visited a health care provider. The commonest first health facility contacted was the pharmacy. Sputum smears were rarely examined, except in the provincial TB hospital. Our findings highlight the need to improve diagnostic practices by retraining health staff on the performance of sputum examination for TB suspects.

Operational research for improved tuberculosis control: the scope, the needs and the way forward.

The promotion of research is one of the main components of the World Health Organizations Stop TB Strategy, which includes 'programme-based operational research (OR)' and 'research on introducing new tools into practice'. The importance of OR in improving tuberculosis (TB) control was recognised a long time ago, and historical OR studies have been instrumental in the development of major strategies for TB control. Although a growing number of OR projects are being conducted in the world today, little is known about their results or their likely impact on TB control programmes. As funding organisations increasingly recognise the need for OR, we propose a rational framework to conduct OR, which covers a spectrum from local setting-oriented to international policy guiding research, and determines the relevance, replicability and generalisability of the results. OR in TB control is aimed at 1) improving programme performance; 2) assessing the feasibility, effectiveness and impact of new strategies or interventions on TB control; and 3) collecting evidence to guide policy recommendations on specific interventions. This requires strengthened capacity to plan and conduct OR in low-income countries and appropriate support to conduct both nationally and internationally led OR projects. Suggestions are made for potential steps for improved purpose-driven OR, which may help to improve TB control locally and inform policy recommendations internationally.

Household expenditure and tuberculosis prevalence in VietNam: prediction by a set of household indicators.

OBJECTIVE: To study the association between TB and household expenditure in a nationwide TB prevalence survey in Viet Nam using nine household characteristics. METHOD: To assess the prevalence of TB in Viet Nam, a nationwide stratified cluster sample survey was conducted from 2006 to 2007. Nine household characteristics used in the second Viet Nam Living Standards Survey (VLSS) were scored per household. In the VLSS dataset, we regressed these nine characteristics against household expenditure per capita, and used the coefficients to predict household expenditure level (in quintiles) in our survey and assess its relation with TB prevalence. RESULTS: The prevalence of bacteriologically confirmed TB was 307 per 100,000 population in persons aged ≥ 15 years (95%CI 249-366). After adjustment for confounders, prevalence was found to be associated with household expenditure level: the rate was 2.5 times higher for those in the lowest household expenditure quintile (95%CI 1.6-3.9) than those in the highest quintile. CONCLUSION: With a set of nine household characteristics, we were able to predict household expenditure level fairly accurately. There was a significant association between TB prevalence rates and estimated household expenditure level, showing that TB is related to poverty in Viet Nam.

Risk of travelling to the country of origin for tuberculosis among immigrants living in a low-incidence country.

SETTING: Two thirds of tuberculosis (TB) patients in the Netherlands are foreign-born. OBJECTIVE: To determine if travelling to the country of origin is a risk factor for TB among two different immigrant groups that have lived in the Netherlands for at least 2 years. DESIGN: In this unmatched case-control study, the frequency and duration of travel to the country of origin in the preceding 12 months were compared between adult Moroccan and Turkish TB patients and community controls. RESULTS: Moroccan patients had travelled more often (26/32 = 81%) in the preceding year than Moroccan controls (472/816 = 58%). The travel-associated odds ratio (OR) for TB among Moroccans was 3.2 (95%CI 1.3-7.7), and increased to 17.2 (95%CI 3.7-79) when the cumulative duration of travel exceeded 3 months. The corresponding population fraction of Moroccan TB cases attributable to recent travel was 56% (95%CI 19-71). Among Turkish immigrants TB was not associated with travel (OR 0.9, 95%CI 0.3-2.4). CONCLUSION: Travel to the country of origin was a risk factor for TB among Moroccans, but not among Turkish people living in the Netherlands. The difference in travel-associated OR between these two immigrant groups is probably related to differences in TB incidence in these countries.

Measurement of exhaled nitric oxide as a potential screening tool for pulmonary tuberculosis.

BACKGROUND: There is a need for low-technology, inexpensive screening tools for active tuberculosis (TB) case finding. OBJECTIVE: to assess the potential usefulness of measuring exhaled nitric oxide (eNO). DESIGN: Cross-sectional comparison in Hanoi, Viet Nam, comparing 90 consecutive smear-positive, culture-confirmed TB patients presenting at a referral hospital with office workers (no X-ray confirming TB) at this hospital (n = 52) and at a construction firm (n = 84). eNO levels were analysed using a validated handheld analyser. RESULTS: eNO levels among TB patients (median 15 parts per billion [ppb], interquartile range [IQR] 10-20) were equal to those among construction firm workers (15 ppb, IQR 12-19, P = 0.517) but higher than those among hospital workers (8.5 ppb, IQR 5-12.5, P < 0.001). Taking the hospital workers as the comparison group, best performance as a diagnostic tool was at a cut-off of 10 ppb, with sensitivity 78% (95%CI 68-86) and specificity 62% (95%CI 47-75). Test characteristics could be optimised to 84% vs. 67% by excluding individuals who had recently smoked or consumed alcohol. CONCLUSION: While eNO measurement has limited value in the direct diagnosis of pulmonary TB, it may be worth developing and evaluating as a cost-effective replacement of chest X-ray in screening algorithms of pulmonary TB where X-ray is not available.

National anti-tuberculosis drug resistance study in Tanzania.

OBJECTIVE: To assess the prevalence of anti-tuberculosis drug resistance in a national representative sample of tuberculosis (TB) patients in Tanzania according to recommended methodology. DESIGN: Cluster survey, with 40 clusters sampled proportional to size, of notified TB patients from all diagnostic centres in the country. RESULTS: The survey enrolled 1019 new and 148 retreatment patients. The adjusted prevalence of Mycobacterium tuberculosis strains resistant to any of the four first-line drugs in new patients was 8.3%, while the prevalence of multidrug-resistant TB (MDR-TB) was 1.1%. In retreatment patients, the crude prevalence for any resistance and for MDR-TB was respectively 20.6% and 3.9%. The prevalence of drug resistance did not differ in relapse patients compared to failure patients. These estimates are among the lowest in those African countries with an estimated level of drug resistance in the last 5 years. CONCLUSION: The low levels of drug resistance in Tanzania are likely due to a well performing TB control programme and the absence of noticeable involvement of the private sector in TB treatment.

Decrease in risk of tuberculosis infection despite increase in tuberculosis among young adults in urban Vietnam.

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.

Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts.

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-gamma release assays (IGRAs), QuantiFERON-TB Gold In-tube (QFT-GIT) and T-SPOT.TB, and the tuberculin skin test (TST) in immigrants contacts. Immigrant close contacts of sputum smear-positive TB patients were included when aged > or =16 yrs and their TST result was > or =5 mm 0 or 3 months after diagnosis of the index patient. Contacts were followed for the next 2 yrs for development of TB disease. Of 339 immigrant contacts with TST > or =5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB. The PPV for progression to TB during this period was 9/288 = 3.1% (95% CI 1.3-5.0%) for TST > or =10 mm, 7/184 = 3.8% (95% CI 1.7-5.9%) for TST > or =15 mm, 5/178 = 2.8% (95% CI 1.0-4.6%) for QFT-GIT and 6/181 = 3.3% (95% CI 1.3-5.3%) for T-SPOT.TB. Sensitivity was 100%, 88%, 63% and 75%, respectively. The predictive values of QFT-GIT, T-SPOT.TB and TST for progression to TB disease among immigrant close contacts were comparable.

Liquid culture for Mycobacterium tuberculosis: proceed, but with caution.

Attempts to improve the diagnosis of tuberculosis (TB) in high-burden countries has resulted in significant funding and initiatives to change the method of diagnosis of TB from light microscopy supplemented with X-ray to a sophisticated diagnostic algorithm based on the latest technological innovations. Such activities are overdue and should be welcomed, but the lack of skills and support available to interpret and use the results represents a danger. The introduction of new diagnostic methods, particularly liquid culture, should be carefully structured according to the local situation, failing which frustration and the disruption of previously underdeveloped but adequately functioning laboratories may result.

Interferon-gamma release assays in immigrant contacts and effect of remote exposure to Mycobacterium tuberculosis.

OBJECTIVE: To assess the association between remote exposure to tuberculosis (TB) and results of the tuberculin skin test (TST), and two interferon-gamma release assays (IGRAs)-QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB-in immigrant contacts of sputum smear-positive TB patients. METHODS: Immigrants aged >or=16 years in close contact with smear-positive TB patients were included. QFT-GIT and T-SPOT.TB were performed if the TST induration size was >or=5 mm. Associations between test results and origin from an endemic country were assessed. RESULTS: Of 433 close contacts, 322 (74%) had TST >or=5 mm, of whom, 282 (88%) had valid test results for all assays. Positive QFT-GIT results were obtained for 152/282 (54%) and positive T-SPOT.TB for 168/282 (60%). After adjustment for age, sex and recent contact, positive IGRA results and TST results >/=10 mm were found to be more frequent among immigrants who originated from Africa, in particular sub-Saharan Africa. CONCLUSION: When IGRAs are used to determine latent TB infection in foreign-born individuals, positive findings not only relate to recent TB infection, but also reflect prior TB exposure in the country of origin. This late reactivity will limit their usefulness in contact investigations among immigrants originating from endemic areas.

Organisation of a tuberculosis prevalence survey.

Measuring tuberculosis (TB) prevalence trends provides information on progress towards the Millennium Development Goals. The World Health Organization recently published guidelines on assessing TB prevalence through population-based surveys. The current manuscript describes in detail the organisation of the field activities in such a survey. These activities need to be embedded in a strong organisational framework where the steering committee has the overall responsibility and the survey coordinator the day-to-day supervision. Field activities need to be tailored to the community, with respect to both time and place and direct involvement of community members. Frequent and well-described monitoring procedures need to be in place to be able to identify systematic and non-systematic errors at the earliest opportunity.

High tuberculosis prevalence in a psychiatric hospital in Vietnam.

Little is known about tuberculosis (TB) prevalence in psychiatric hospitals in Vietnam, but prevalence may be higher than in the general population. We assessed the TB prevalence among in-patients of a psychiatric hospital in 2005 in Danang City, Vietnam. Of 300 in-patients, 70 had an abnormal X-ray or prolonged cough, and underwent sputum smear examinations. The prevalence of smear-positive TB was 0.33% (1/300, 95%CI 0.008-1.9). Twenty-three (7.7%) patients had X-ray lesions suggesting active TB and 22 (7.3%) had a history of TB treatment. TB prevalence was high in this psychiatric hospital, and TB infection control needs strengthening.

HIV-related mortality among tuberculosis patients in The Netherlands, 1993-2001.

Human immunodeficiency virus (HIV) infection in tuberculosis (TB) patients in The Netherlands during the period 1993-2001 was associated with an increased risk of death (adjusted odds ratio 4.71, P < 0.002). Age and sex-standardised mortality rates among HIV-infected TB patients decreased significantly over time, from 22.9% in 1993-1995 to 11.8% in 1999-2001 (P < 0.001). No such change was observed for HIV-negative patients. The decrease in mortality is likely due to the more widespread use of highly active antiretroviral therapy (HAART).

Low tuberculosis notification in mountainous Vietnam is not due to low case detection: a cross-sectional survey.

BACKGROUND: Studies show that tuberculosis notification declines with increasing altitude. This can be due to declining incidence or declining case detection. In Vietnam notification rates of new smear-positive tuberculosis in the central mountainous provinces (26/100,000 population) are considerably lower than in Vietnam in general (69/100,000 population). In order to clarify whether this is explained by low incidence or low case detection, we aimed to assess the prevalence of new smear-positive tuberculosis among adults with prolonged cough in three mountainous provinces in central Vietnam. METHODS: A house-to-house survey of persons (> or = 15 years) was carried out in twelve randomly selected districts in 2003. Three sputum specimens were microscopically examined of persons reporting a prolonged cough (> or = 3 weeks). Case detection was assessed by the ratio between notification and prevalence. RESULTS: Of 68,946 included persons (95% response), 1,298 (1.9% 95%CI 1.8-2.2) reported a prolonged cough. Of these, eighteen were sputum smear-positive of whom two had had anti-tuberculosis treatment. The prevalence of new smear-positive tuberculosis was 27/100,000 (95%CI 11-44/100,000) and the notification rate was 44/100,000 among persons > or = 15 years. The estimated case detection rate was 76%. CONCLUSION: Low tuberculosis notification in this mountainous setting is probably a true reflection of low tuberculosis incidence. Possible causes for low incidence in mountainous areas include low transmission rates or altitude-related differences in pathology.