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BACKGROUND: Diagnostic tools to identify incipient or subclinical TB stages will be helpful for preventive intervention. A simple biomarker to predict TB may be the monocytes to lymphocytes ratio (ML ratio) in peripheral blood.METHODS: We assessed the relationship between multiple time-updated ML ratio measurements and incidence of TB in people living with HIV (PLWH) after antiretroviral therapy (ART) was initiated. The ML ratio was updated at least every 6 months. TB incidence with corresponding 95% confidence intervals stratified according to time-updated ML ratio was calculated using ML ratio in quartiles.RESULTS: A total of 1305 PLWH were included in the analyses: 46 had incident TB and 1259 remained TB-free. The TB incidence rate was 10.3 (95% CI 7.1–14.9) cases/1000 patient-years (PYR) among participants with ML ratio ≥0.25 compared with 1.1/1000 PYR (95% CI 0.4–2.9) among those with ML ratio CONCLUSION: Increased ML ratio was predictive of incident TB among PLWH on or after ART. The ML ratio can be a simple tool to stratify the risk of TB in PLWH.

BACKGROUND: In high TB burden countries, delayed diagnosis remains a big challenge in TB control. The objective of this study is to assess the role of distance between residence and healthcare facility (HCF) on care-seeking among individuals with symptoms associated with pulmonary TB in Tanzania.METHODS: In this cross-sectional study, using data from a national TB survey, coordinates of 300 (residential) sites within 62 clusters were obtained through Google searches and average distances to HCF were calculated per cluster. Univariable and multivariable logistic regression analyses were conducted, with care-seeking behaviour being the primary outcome variable.RESULTS: Distance from residence to HCF had no effect on care-seeking behaviour of individuals with TB-related symptoms in this study (OR 1.00, 95% CI 1.00–1.00). Over 85% of HCFs where care has been sought lack TB diagnostic capacity, mostly comprising dispensaries with staff less educated in TB-related symptoms.CONCLUSION: Care-seeking behaviour among individuals with TB-related symptoms in Tanzania was not found to be associated with distance to HCF. First-line diagnostics should be improved 1) by equipping local dispensaries with basic TB diagnostic capacity, and 2) by educating staff of local dispensaries more thoroughly about basic TB symptoms and the importance of swift referrals.

Background Diagnosing urinary tract infections (UTIs) in nursing home residents is complex, as specific urinary symptoms are often absent and asymptomatic bacteriuria (ASB) is prevalent. The aim of this study was to assess the sensitivity of blood C-reactive protein (CRP) and procalcitonin (PCT), measured by point-of-care tests (PoCTs), to diagnose UTIs in this setting. Methods Elderly residents (≥65 years old) with a suspected UTI were recruited from psychogeriatric, somatic, or rehabilitation wards across 13 participating nursing homes. CRP and PCT were tested simultaneously in the same study participants. To assess the tests’ sensitivities, a stringent definition of “true” UTI was used that included the presence of symptoms, urinary leucocytes, a positive urine culture, and symptom resolution during antibiotic treatment covering isolated uropathogen(s). The original sample size was 440 suspected UTI episodes, in order to detect a clinically relevant sensitivity of at least 65% when calculated using the matched analysis approach to compare both PoCTs. Results After enrollment of 302 episodes (68.6% of the planned sample size), an unplanned and funder-mandated interim analysis was done, resulting in premature discontinuation of the study for futility. For 247 of 266 eligible episodes, all mandatory items required for the true UTI definition (92.9%) were available. In total, 49 episodes fulfilled our stringent UTI definition (19.8%). The sensitivities of CRP (cut-off, 6.5 mg/L) and PCT (cut-off, 0.025 ng/mL) were 52.3% (95% confidence interval [CI], 36.7–67.5%) and 37.0% (95% CI, 23.2–52.5%), respectively. Conclusions Our results indicate that CRP and PCT are not suitable tests for distinguishing UTI and ASB in nursing home residents. Clinical Trials Registration Netherlands Trial Registry NL6293., Blood C-reactive protein and procalcitonin measured by point-of-care tests are not suitable to distinguish urinary tract infection and asymptomatic bacteriuria in nursing home residents.

Background The lifetime risk of tuberculosis (TB) among individuals with latent Mycobacterium tuberculosis infection (LTBI) is commonly estimated as 5–10%, but is highly variable between individuals. Validated estimates of personalised risk are needed to facilitate precise targeting of preventative treatment. We aimed to characterise population-level TB risk among people tested for LTBI, and to develop and validate a prognostic model to estimate personalised risk of disease. Methods We pooled individual-level data from 18 systematically-identified cohort studies conducted in 20 countries with low TB transmission (annual incidence ≤20/100,000 persons). We estimated population-level incident TB risk using flexible parametric survival models with random effect intercepts by source study. We then developed and validated a flexible parametric survival prediction model for incident TB using the internal-external cross-validation framework, iteratively discarding one contributing dataset from model development and using it for validation. Findings In pooled data including 80,468 individuals tested for LTBI and 803 TB cases, 5-year cumulative risk of incident TB among people with untreated LTBI was 15.6% (95% CI 8.0–29.2) for child contacts, 4.8% (3.0–7.7) for adult contacts, 5.0% (1.6–14.5) for migrants, and 4.8% (1.5–14.3) for immunocompromised groups. We found highly variable estimates within risk groups, necessitating a personalised approach to risk-stratification. We thus developed a prognostic model that combines a quantitative measure of T cell sensitisation and clinical covariates. These covariates included age, history of TB exposure (household contact of smear-positive index case, other contact, migration from high TB burden country or no exposure), HIV status and receipt of a solid organ or haematological transplant. Validation of this model achieved a random-effects meta-analysis C-statistic of 0.88 (0.82–0.93) for incident TB over 2 years. Decision curve analysis revealed that applying the model improved clinical decision-making for targeting LTBI treatment. Interpretation TB incidence rates are heterogeneous among people identified as having LTBI by current standards, even after stratification by indication for screening. We present a freely available and directly data-driven personalised risk predictor for incident TB (www.periskope.org). PERISKOPE-TB will facilitate a programmatic paradigm shift by allowing a fully evidence-based and patient-centred approach to TB risk stratification in settings aiming towards pre-elimination globally.

Background Diagnosing urinary tract infections (UTI) in nursing home residents is complex, due to frequent non-specific symptomatology and asymptomatic bacteriuria. The objective of this study was to explore health care professionals’ perceptions of the proposed use of inflammatory marker Point-Of-Care Testing (POCT) in this respect. Methods We conducted a qualitative inquiry (2018–2019) alongside the multicenter PROGRESS study (NL6293), which assessed the sensitivity of C-reactive protein and procalcitonin POCT in UTI. We used semi-structured face-to-face interviews. The participants were physicians (n = 12) and nurses (n = 6) from 13 nursing homes in the Netherlands. Most respondents were not familiar with inflammatory marker POCT, while some used POCT for respiratory tract infections. Both the interview guide and the analysis of the interview transcripts were based on the Consolidated Framework for Implementation Research. Results All respondents acknowledged that sufficiently sensitive POCT could decrease diagnostic uncertainty to some extent in residents presenting with non-specific symptoms. They primarily thought that negative test results would rule out UTI and justify withholding antibiotic treatment. Secondly, they described how positive test results could rule in UTI and justify antimicrobial treatment. However, most respondents also expected new diagnostic uncertainties to arise. Firstly, in case of negative test results, they were not sure how to deal with residents’ persisting non-specific symptoms. Secondly, in case of positive test results, they feared overlooking infections other than UTI. These new uncertainties could lead to inappropriate antibiotics use. Therefore, POCT was thought to create a false sense of confidence. Conclusions Our study suggests that inflammatory marker POCT will only improve UTI management in nursing homes to some extent. To realize the expected added value, any implementation of POCT requires thorough guidance to ensure appropriate use. Developing UTI markers with high negative and positive predictive values may offer greater potential to improve UTI management in nursing homes.

Background Trials to assess the efficacy of the radical cure of Plasmodium vivax malaria with 8-aminoquinolines require that most post-treatment relapses are identified, but there is no consensus on the optimal duration of follow-up in either symptomatic or asymptomatic vivax malaria. The efficacy of a 14-day course of primaquine on the cumulative incidence of recurrent asymptomatic P. vivax infections detected by ultrasensitive quantitative PCR (uPCR) as a primary endpoint was assessed. Methods A randomized, placebo-controlled, single-blind trial was conducted in four villages of the Lao PDR during 2016–2018 nested in a larger project evaluating mass drug administrations (MDA) with dihydroartemisinin-piperaquine (DP) and a single low-dose primaquine to clear Plasmodium falciparum infections. In the nested sub-study, eligible participants with mono- or mixed P. vivax infections detected by uPCR were randomized to receive either 14 days of primaquine (0.5 mg/kg/day) or placebo during the last round of MDA (round 3) through directly observed therapy. Participants were checked monthly for 12 months for parasitaemia using uPCR. The primary outcome was cumulative incidence of participants with at least one recurrent episode of P. vivax infection. Results 20 G6PD-normal participants were randomized in each arm. 5 (29%) of 20 participants in the placebo arm experienced asymptomatic, recurrent P. vivax infections, resulting in a cumulative incidence at month 12 of 29%. None of the 20 participants in the intervention arm had recurrent infections (p = 0.047 Fisher’s exact test). Participants with recurrent P. vivax infections were found to be parasitaemic for between one and five sequential monthly tests. The median time to recurrence of P. vivax parasitaemia was 178 days (range 62–243 days). Conclusions A 14-day course of primaquine in addition to a DP-MDA was safe, well-tolerated, and prevented recurrent asymptomatic P. vivax infections. Long follow-up for up to 12 months is required to capture all recurrences following the treatment of asymptomatic vivax infection. To eliminate all malarias in settings where P. vivax is endemic, a full-course of an 8-aminoquinolines should be added to MDA to eliminate all malarias. Trial registration This study was registered with ClinicalTrials.gov under NCT02802813 on 16th June 2016. https://clinicaltrials.gov/ct2/show/NCT02802813

Additional file 1. Interview guide

Additional file 2. Coding tree

The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

Setting Tanzania is classified as one of the 22 high tuberculosis (TB) burden countries; however, the true burden of TB disease in the country remains unknown. Objective To assess the prevalence of bacteriologically confirmed pulmonary TB (PTB) in the adult population. Design This was a community-based cluster randomised survey with proportional-to-population-size selection of primary sampling units (districts). Participants were screened for TB using a symptom questionnaire and chest X-ray (CXR). Those with abnormal CXR and/or at least one symptom suggestive of TB were classified as individuals with presumptive TB, and asked to submit three sputum specimens for smear microscopy and culture. Results The weighted prevalence for sputum smear-positive TB cases was 249 per 100 000 adult population (95%CI 192-305) and that for bacteriologically confirmed TB cases was 293/100 000 (95%CI 228-358). Individuals aged ⩾45 years comprised 55% (71/129) of the identified smear-positive cases, but just 28% (6793/24 648) of the notified TB cases. CXR screening identified more TB cases than symptom screening. When weighted for human immunodeficiency virus prevalence among notified new smear-positive cases, the overall case detection of incident TB cases in 2012 was between 37% and 48%. Conclusions The prevalence of sputum smear-positive PTB and bacteriologically confirmed PTB in the adult population was higher than previous World Health Organization estimates. There is a potential underestimation of the number of bacteriologically confirmed PTB cases in the adult population. The age distribution of prevalent cases suggests an epidemiological shift towards the older generations, which has been a sign of successful TB control activities in the past. However, the survey shows that many infectious TB cases are currently missed by the National Tuberculosis Programme.

BACKGROUND: Excellent treatment outcomes have recently been reported for patients with multi/extensively drug-resistant tuberculosis (M/XDR-TB) in settings where optimal resources for individualised therapy are available. OBJECTIVE: To ascertain whether differences remain in treatment responses between patients with M/XDR-TB and those with non-M/XDR-TB. METHOD: Patients with TB were prospectively enrolled between March 2013 and March 2016 at five hospitals in Germany. Treatment was conducted following current guidelines and individualised on the basis of drug susceptibility testing. Two-month and 6-month sputum smear and sputum culture conversion rates were assessed. A clinical and radiological score were used to assess response to anti-tuberculosis treatment. RESULTS: Non-M/XDR-TB (n = 29) and M/XDR-TB (n = 46) patients showed similar rates of microbiological conversion: 2-month smear conversion rate, 90% vs. 78%; culture conversion rate, 67% vs. 61%; time to smear conversion, 19 days (IQR 10-32) vs. 31 days (IQR 14-56) (P = 0.066); time to culture conversion, 39 days (IQR 17-67) vs. 39 days (IQR 6-85) (P = 0.191). Both clinical and radiological scores decreased after the introduction of anti-tuberculosis treatment. CONCLUSION: There were no significant differences in scores between the two groups until 6 months of treatment. Under optimal clinical conditions, with the availability of novel diagnostics and a wide range of therapeutic options for individualised treatment, patients with M/XDR-TB achieved 6-month culture conversion rates that were compatible with those in patients with non-M/XDR-TB.

Setting The study was conducted within a nation-wide population-based tuberculosis (TB) prevalence survey in the adult population in Tanzania. Objective To assess the health care-seeking behaviour of coughers presumed to have TB. Design A survey in which participants were screened for TB using a symptom questionnaire and chest X-ray (CXR). Those with cough of ⩾ 2 weeks and/or who were coughing blood were interviewed about their health care-seeking behaviour and socio-demographic and clinical factors. Results Of 3388 people with presumptive TB, 31.0% (1051/3388) had sought treatment for their symptoms. Of these, about 42% (445/1051) sought care at sites with TB diagnostic capacity, where sputum examination was performed in 37.1% (165/445) and CXR in 28.1% (125/445). In sites with limited TB diagnostic capacity, fewer than 1% were referred for sputum examination or CXR. Individuals with additional symptoms were more likely to seek treatment. Knowledge about TB was significantly associated with care seeking at sites with TB diagnostic capacity. Conclusions A third of the persons with cough symptoms consistent with TB had sought health care. About 42% sought care in sites with TB diagnostic capacity, but most did not undergo TB diagnostic procedures, precluding a timely diagnosis.

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.

SUMMARY SETTING: Arusha, Mwanza, Mufindi and Kilosa in Tanzania. OBJECTIVE: To assess the test characteristics of three indirect adherence measures against a gold standard of direct measurements of drug intake for use in a resourceconstrained setting. METHODS: We assessed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), and the diagnostic odds ratio (dORs) of three indirect adherence measurement tools against direct measurement in urine using the IsoScreen assay. RESULTS: The single adherence question of missed doses in the last 2 days had the highest dOR (40.3) compared to the Morisky medication adherence scale (MMAS, 2.5) and pill counts (3.4). The sensitivities of these measures were respectively 97.9%, 92% and 89.6%. Specificity ranged from 46.4% (adherence question) to 17.9% (MMAS). The PPVs of adherence question, pill counts and MMAS were respectively 97.6%, 96.5% and 94.2%, while the NPVs ranged from 50% (adherence question) to 3.1% (MMAS). CONCLUSION: Among several instruments for indirect adherence measure in the routine setting of the Tanzanian National Tuberculosis and Leprosy Programme, a single adherence question was found to have the best discriminatory power. However, the single adherence question might not adequately identify patients who are non-adherent. Confirmatory studies are needed, especially in settings with low adherence rates. KEY WOR DS: tuberculosis; adherence; diagnostic odds ratio; IsoScreen

OBJECTIVES To assess the prevalence of tuberculous infection and the annual risk of tuberculous infection (ARTI) for 2007-2009 in Bangladesh, approximately 45 years after the first tuberculin survey in 1964-1966. METHODS A tuberculin survey was conducted along with the National Tuberculosis Disease Prevalence Survey in 2007-2009. This was a multistaged community-based, cross-sectional survey, including 17,718 children aged 5-14 years. The prevalence of tuberculous infection was estimated using the mixture method and a cut-off point of ≥ 8 mm. RESULTS The prevalence of infection was 10.0% (interquartile range [IQR] 8.6-12.2) in children aged 5-9 years and 17.9% (IQR 15.4-20.2) in those aged 10-14 years using the mixture analysis. Prevalence was 12.4% (95% confidence interval [CI] 11.7-13.1) in children aged 5-9 years and 22.6% (95%CI 21.6-23.4) in those aged 10-14 years using a cut-off point of ≥ 8 mm. The estimated ARTI was respectively 1.5% and 1.7% in 5-9 and 10-14 year olds using the mixture method and respectively 1.9% and 2.1% using the cut-off method. CONCLUSIONS The moderate reduction in the prevalence of infection and slow decline of the ARTI after two decades of DOTS implementation indicates considerable ongoing transmission.

SETTING: Tanzania has an estimated tuberculosis (TB) prevalence of 295 per 100 000 adult population. There is currently no nationally representative information on factors associated with TB in Tanzania. OBJECTIVE: To determine the demographic and clinical factors associated with bacteriologically confirmed TB in the adult general population of Tanzania. DESIGN: A case-control study nested in a nationally representative TB prevalence survey. All patients with bacteriologically confirmed pulmonary TB (PTB) constituted cases and a representative sample of people without bacteriologically confirmed PTB constituted controls. We calculated adjusted odds ratios (aORs) to identify factors associated with TB. RESULTS: Age groups 25–34 years (aOR 3.7, 95%CI 1.5–8.8) and 55–64 years (aOR 2.5, 95%CI 1.1–5.5), male sex (aOR 1.6, 95%CI 1.1–2.3) and low body mass index (BMI) (aOR 1.7, 95%CI 1.1–2.8) were significantly associated with TB. Association with human immunodeficiency virus (HIV) and diabetes mellitus (DM) was not statistically significant. The population attributable fraction (PAF) was 2% (95%CI −2 to 5) for DM and 3% (95%CI −2 to 8) for HIV. CONCLUSION: Being in an older age group, being male and having a low BMI were associated with bacteriologically confirmed PTB. On the population level, classic risk factors for TB have no major effect on prevalent TB from which future transmission may occur. acceptedVersion

This study aimed to estimate the risk of progression to active tuberculosis (TB) within 2 yrs after entry in newly arriving immigrants who were screened with the QuantiFERON®-TB Gold In-Tube assay (QFT-GIT; Cellestis, Carnegie, Australia). In a case–base design, we determined the prevalence QFT-GIT-positive subjects among a representative sample of immigrants aged ≥18 yrs who arrived between April 2009 and March 2011 (the base cohort). Active TB patients (cases) within 2 yrs post-arrival in 2005, 2006 or 2007 were extracted from the Netherlands Tuberculosis Register. The risk of progression to active TB was estimated using Bayesian analyses to adjust for the sensitivity of QFT-GIT. Among the base cohort, 20% of 1,468 immigrants were QFT-GIT positive. Stratified by TB incidence in the person's country of origin as low (

Objectives High early mortality after antiretroviral therapy (ART) initiation in resource-limited settings is associated with low baseline CD4 cell counts and a high burden of opportunistic infections. Our large urban HIV clinic in Uganda has made concerted efforts to initiate ART at higher CD4 cell counts and to improve diagnosis and care of patients coinfected with tuberculosis (TB). We sought to determine associated treatment outcomes. Methods Routinely collected data for all patients who initiated ART from 2005 to 2009 were analysed. Median baseline CD4 cell counts by year of ART initiation were compared using the Cuzick test for trend. Mortality and TB incidence rates in the first year of ART were computed. Hazard ratios (HRs) were calculated using multivariable Cox proportional hazards models. Results First-line ART was initiated in 7659 patients; 64% were women, and the mean age was 37 years (standard deviation 9 years). Median baseline CD4 counts increased from 2005 to 2009 [82 cells/μL (interquartile range (IQR) 24, 153) to 148 cells/μL (IQR 61, 197), respectively; P

SETTING: An increasing proportion of tuberculosis (TB) patients in low-incidence countries are immigrants. It is unclear whether contact investigations among immigrant patients are adequate. OBJECTIVE: To determine whether ethnicity of pulmonary TB patients was associated with coverage and yield of contact investigations in the Netherlands. DESIGN: Contact investigation results were extracted from records of patients reported in the nationwide surveillance register in 2006 and 2007. Prevalence odds ratios (PORs) with 95% confidence intervals (CIs) were calculated to determine the association between patient ethnicity and coverage of contact investigations and the yield of individuals with Mycobacterium tuberculosis infection or TB. RESULTS: Of the 1040 pulmonary TB patients reported, 642 (62%) were eligible for analysis. Compared to close contacts of Dutch patients, close contacts of immigrant patients were significantly less likely to be examined for TB (89% vs. 93%, POR 0.6, 95%CI 0.5-0.7) and infection (50% vs. 75%, POR 0.3, 95%CI 0.3-0.4), whereas the yield was significantly higher for disease (1.5% vs. 0.4%, POR 3.4, 95%CI 1.8-6.4) and infection (13% vs. 10%, POR 1.2, 95%CI 1.0-1.5). CONCLUSION: The effectiveness of contact investigations in the Netherlands can be optimised by expanding the investigation of contacts of immigrant patients

SETTING: A national tuberculosis (TB) drug resistance survey in Tanzania. OBJECTIVE: To compare the performance of the Genotype ® MTBDRplus line-probe assay (LPA) on smear-positive sputum specimens with conventional culture and isoniazid (INH) plus rifampicin (RMP) drug susceptibility testing (DST). DESIGN: Mycobacterium tuberculosis isolates tested at the Tanzanian Central TB Reference Laboratory (CTRL) were submitted for quality assurance of phenotypic DST to its supranational reference laboratory (SRL), together with ethanol-preserved sputum specimens for LPA DST. RESULTS: Only 321 samples could be tested using LPA; of these, three were identified as being non-tuberculous mycobacteria using CTRL DST. Both tests had 269 sets with interpretable results. CTRL DST yielded almost the same number of interpretable results as LPA, with 90% concordance (κ = 0.612, P < 0.001). Five (1.9%) multidrug-resistant (MDR) strains, 46 (17.1%) resistant to INH only and 0 RMP only, were found by CTRL DST. For the LPA, these results were respectively 5 (1.9%), 26 (9.7%) and 2 (0.7%). With SRL DST as the gold standard, LPA was more accurate than CTRL DST for RMP, but missed almost half the INH-resistant samples. CONCLUSION: LPA applied directly on ethanol-preserved sputum specimens was similar to phenotypic DST in terms of yield of interpretable results. Although probably more accurate for RMP and MDR-TB, it appears to seriously underestimate INH resistance. Considering speed, easy and safe specimen transportation and low infrastructure requirements, LPA DST from sputum can be recommended for surveys in resource-poor settings.

The targets for tuberculosis control, framed within the United Nations' Millennium Development Goals, are to ensure that the incidence per head of tuberculosis is falling by 2015, and that the 1990 prevalence and mortality per head are halved by 2015. In monitoring progress in tuberculosis control, the ultimate aim for all countries is to count tuberculosis cases (incidence) accurately through routine surveillance. Disease prevalence surveys are costly and laborious, but give unbiased measures of tuberculosis burden and trends, and are justified in high-burden countries where many cases and deaths are missed by surveillance systems. Most countries in which tuberculosis is highly endemic do not yet have reliable death registration systems. Verbal autopsy, used in cause-of-death surveys, is an alternative, interim method of assessing tuberculosis mortality, but needs further validation. Although several new assays for Mycobacterium tuberculosis infection have recently been devised, the tuberculin skin test remains the only practical method of measuring infection in populations. However, this test typically has low specificity and is therefore best used comparatively to assess geographical and temporal variation in risk of infection. By 2015, every country should be able to assess progress in tuberculosis control by estimating the time trend in incidence, and the magnitude of reductions in either prevalence or deaths.

Setting District and urban health care facilities in three provinces (Manica, Sofala, Tete) in central Mozambique. Objective To assess the level of implementation of selected tuberculosis infection prevention and control (TB-IPC) measures. Design In a cross-sectional study of TB-IPC implementation in 29 health care facilities, we assessed TB clinics, laboratories, out-patient departments and medical and TB wards. Assessment included selected managerial, administrative and environmental measures and the availability and use of respiratory protective equipment (N95 respirators). Results Guidelines for diagnosis and treatment of (presumptive) TB patients were not present in all facilities. Staff instructed patients on sputum collection in 91%, but only 4% observed it. Using a pragmatic '20% rule', 52% of the rooms assessed had adequate ventilation. Potentially, this could be increased to 76%. Three quarters of the health care workers had N95 respirators. Only 36% knew how to use it correctly. Conclusion Implementation of TB-IPC measures showed wide variations within health care facilities. Relatively simple measures to improve TB-IPC include the availability of guidelines, opening doors and windows to improve ventilation, and training and support on correct N95 respirator use. However, even relatively simple measures are challenging to implement, and require careful attention in and evaluation of the implementation process.

Optimal adherence is essential for successful antiretroviral therapy. We analyzed the relation between minimum plasma drug concentration (Cmin) and total drug exposure over 24 hr (AUC24) with virologic failure for therapy-adherent patients in the nevirapine (NVP) and efavirenz (EFV) groups of the double nonnucleoside study (2NN), which compared the efficacy of NVP and/or EFV together with stavudine and lamivudine. The objective was to find cutoff values of the Cmin and AUC24 below which the risk of virologic failure increased. The relation between Cmin and AUC24 with virologic failure (never a plasma viral load [pVL] < 50 copies/ml or a rebound to two consecutive pVL > 50 copies/ml) was analyzed with proportional hazard analyses. Data were censored at end of study or change of allocated treatment. The risk of virologic failure with NVP (n = 511) started to increase at a Cmin < 3.1 mg/L (hazard ratio [HR], 1.33; 95% confidence interval [CI], 0.89-1.97), but there was no cutoff value below which a statistically significant increased risk occurred. Neither was such a cutoff point identified for the AUC24. The risk of virologic failure with EFV (n = 312) was significantly increased at a Cmin < 1.1 mg/L (HR, 1.95; 95% CI, 1.08-3.54) and an AUC24 < 40 mg x hr x L1 (HR, 1.95; 95% CI, 1.07-3.54). Both cutoff values represent the median values for adherent patients. These associations were driven by patients from Thailand. Adjusting for geographical region made the association between Cmin and AUC24 with virologic failure statistically nonsignificant. The sensitivity of the Cmin values was too low (29% for NVP, 64% for EFV) to be an adequate predictor for virologic failure. We conclude that identifying the Cmin value for the sole purpose of predicting virologic failure in patients who report to be adherent to NVP or EFV is questionable because of the absence of a concentration-response relation (NVP) or the low sensitivity for such a cutoff value (NVP and EFV)

Levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c), as well as the TC:HDL-c ratio, were compared in patients receiving different antiretroviral therapy regimens. Patients receiving first-line regimens including protease inhibitors (PIs) had higher TC and TG levels and TC : HDL-c ratios than did antiretroviral-naive patients; patients receiving 2 PIs had higher levels of each lipid. Ritonavir-containing regimens were associated with higher TC and TG levels and TC : HDL-c ratios than were indinavir-containing regimens; however, receipt of nelfinavir was associated with reduced risk of lower HDL-c levels, and receipt of saquinavir was associated with lower TC : HDL-c ratios. Patients receiving nonnucleoside reverse-transcriptase inhibitors had higher levels of TC and LDL-c than did antiretroviral-naive patients, although the risk of having lower HDL-c levels was lower than that in patients receiving a single PI. Efavirenz was associated with higher levels of TC and TG than was nevirapine.

High early mortality after antiretroviral therapy (ART) initiation in resource-limited settings is associated with low baseline CD4 cell counts and a high burden of opportunistic infections. Our large urban HIV clinic in Uganda has made concerted efforts to initiate ART at higher CD4 cell counts and to improve diagnosis and care of patients coinfected with tuberculosis (TB). We sought to determine associated treatment outcomes.Routinely collected data for all patients who initiated ART from 2005 to 2009 were analysed. Median baseline CD4 cell counts by year of ART initiation were compared using the Cuzick test for trend. Mortality and TB incidence rates in the first year of ART were computed. Hazard ratios (HRs) were calculated using multivariable Cox proportional hazards models.First-line ART was initiated in 7659 patients; 64% were women, and the mean age was 37 years (standard deviation 9 years). Median baseline CD4 counts increased from 2005 to 2009 [82 cells/μL (interquartile range (IQR) 24, 153) to 148 cells/μL (IQR 61, 197), respectively; P0.001]. The mortality rate fell from 6.5/100 person-years at risk (PYAR) [95% confidence interval (CI) 5.5-7.6 PYAR] to 3.6/100 PYAR (95% CI 2.2-5.8 PYAR). TB incidence rates increased from 8.2/100 PYAR (95% CI 7.1-9.5 PYAR) to 15.6/100 PYAR (95% CI 12.4-19.7 PYAR). A later year of ART initiation was independently associated with decreased mortality (HR 0.91; 95% CI 0.83-1.00; P=0.04).Baseline CD4 cell counts have increased over time and are associated with decreased mortality. Additional reductions in mortality might be a result of a better standard of care and increased TB case finding. Further efforts to initiate ART earlier should be prioritized even in a setting of capped or reduced funding for ART programmes.

SUMMARYThe aim of this study was to determine the nationwide prevalence of smear-positive tuberculosis (TB) in Bangladesh. A multi-stage cluster survey of a random sample of persons aged ⩾15 years was included in 40 clusters (20 urban, 20 rural). Two sputum samples were collected from study participants and tested initially by fluorescence microscopy and confirmed by the Ziehl–Neelsen method. The crude and adjusted prevalence rates and 95% confidence intervals (CIs) were calculated using standard methods. A total of 33 new smear-positive TB cases were detected among 52 098 individuals who participated in the study. The average participation rate was over 80%. The overall crude prevalence of new smear-positive TB in persons aged ⩾15 years was estimated as 63·3/100 000 (95% CI 43·6–88·9) and the adjusted prevalence was 79·4/100 000 (95% CI 47·1–133·8). TB prevalence was higher in males (n=24) and in rural areas (n=20). The prevalence was highest in the 55–64 years age group (201/100 000) and lowest in 15–24 years age group (43·0/100 000). The prevalence was higher in persons with no education (138·6/100 000, 95% CI 78·4–245·0). The overall prevalence of smear-positive TB was significantly lower than the prevalence estimate of the previous nationwide survey in Bangladesh in 1987–1988 (870/100 000).

Addressing social determinants in the field of tuberculosis (TB) has received great attention in the past years, mainly due to the fact that worldwide TB incidence has not declined as much as expected, despite highly curative control strategies. One of the objectives of the World Health Organization Global Task Force on TB Impact Measurement is to assess the prevalence of TB disease in 22 high-burden countries by active screening of a random sample of the general population. These surveys provide a unique opportunity to assess socio-economic determinants in relation to prevalent TB and its risk factors. This article describes methods of measuring the socio-economic position in the context of a TB prevalence survey. An indirect measurement using an assets score is the most feasible way of doing this. Several examples are given from recently conducted prevalence surveys of the use of an assets score, its construction, and the analyses of the obtained data.

A national tuberculosis (TB) drug resistance survey in Tanzania.To compare the performance of the Genotype® MTBDRplus line-probe assay (LPA) on smear-positive sputum specimens with conventional culture and isoniazid (INH) plus rifampicin (RMP) drug susceptibility testing (DST).Mycobacterium tuberculosis isolates tested at the Tanzanian Central TB Reference Laboratory (CTRL) were submitted for quality assurance of phenotypic DST to its supranational reference laboratory (SRL), together with ethanol-preserved sputum specimens for LPA DST.Only 321 samples could be tested using LPA; of these, three were identified as being non-tuberculous mycobacteria using CTRL DST. Both tests had 269 sets with interpretable results. CTRL DST yielded almost the same number of interpretable results as LPA, with 90% concordance (κ = 0.612, P0.001). Five (1.9%) multidrug-resistant (MDR) strains, 46 (17.1%) resistant to INH only and 0 RMP only, were found by CTRL DST. For the LPA, these results were respectively 5 (1.9%), 26 (9.7%) and 2 (0.7%). With SRL DST as the gold standard, LPA was more accurate than CTRL DST for RMP, but missed almost half the INH-resistant samples.LPA applied directly on ethanol-preserved sputum specimens was similar to phenotypic DST in terms of yield of interpretable results. Although probably more accurate for RMP and MDR-TB, it appears to seriously underestimate INH resistance. Considering speed, easy and safe specimen transportation and low infrastructure requirements, LPA DST from sputum can be recommended for surveys in resource-poor settings.

Setting A passive case-finding strategy as present in the DOTS strategy presupposes a patient's willingness to seek care. This requires awareness of tuberculosis (TB) symptoms and the diagnostic process, and positive attitudes towards access and probability of cure. Objective To measure parameters of health-seeking intention in Southern Angola and to inform the design of context-specific interventions to improve case detection. Design A survey in four communities based on the cough-to-cure pathway represented by five domains with either one or two proxy measures. These were assessed for association with appropriate health-seeking behaviour (visiting a medical institution or service). Results In total, 805 individuals were included in the study. Appropriate health-seeking behaviour was positively associated with knowing the disease (OR 3.1, 95%CI 1.4-6.8), knowing key symptoms (OR 1.4, 95%CI 1.0-1.9), perceived curability (OR 1.3, 95%CI 1.0-1.6), and the perception that TB services were free of charge (OR 1.9, 95%CI 1.4-2.7). Respondents who perceived a personal risk for TB were less likely to have an appropriate intended health-seeking behaviour (OR 0.7, 95%CI 0.5-0.9). Conclusion Knowledge about TB should include key symptoms, perceived curability and information on access to services when designing interventions to improve case detection. The study highlights the importance of advocacy, social mobilisation and communication strategies.

To assess the prevalence of anti-tuberculosis drug resistance in a national representative sample of tuberculosis (TB) patients in Tanzania according to recommended methodology.Cluster survey, with 40 clusters sampled proportional to size, of notified TB patients from all diagnostic centres in the country.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.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.

Data on socio-economic status, exposure to risk factors for tuberculosis (TB) and previous health-seeking for TB may be included in a TB prevalence survey to gain better knowledge about the distribution of TB in the population as well as a better understanding of what factors are driving the TB epidemic in a given setting. This article provides an overview of how such additional information may be collected. The article highlights the need to carefully consider the risk of jeopardising the quality of the overall survey by overburdening it with additional data collection, and concludes that additional time and resources for planning, training, logistics and supervision are required to safeguard quality. The article also discusses special considerations regarding sampling, sample size and data interpretation when including such information in a TB 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.

OBJECTIVE: To evaluate the validity of the fixed mathematical relationship between the annual risk of tuberculous infection (ARTI), the prevalence of smear-positive tuberculosis (TB) and the incidence of smear-positive TB specified as the Styblo rule, which TB control programmes use to estimate the incidence of TB disease at a population level and the case detection rate. METHODS: Population-based tuberculin surveys and surveys on prevalence of smear-positive TB since 1975 were identified through a literature search. For these surveys, the ratio between the number of tuberculous infections (based on ARTI estimates) and the number of smear-positive TB cases was calculated and compared to the ratio of 8 to 12 tuberculous infections per prevalent smear- positive TB case as part of the Styblo rule. FINDINGS: Three countries had national population-based data on both ARTI and prevalence of smear-positive TB for more than one point in time. In China the ratio ranged from 3.4 to 5.8, in the Philippines from 2.6 to 4.4, and in the Republic of Korea, from 3.2 to 4.7. All ratios were markedly lower than the ratio that is part of the Styblo rule. CONCLUSION: According to recent country data, there are typically fewer than 8 to 12 tuberculous infections per prevalent smear-positive TB case, and it remains unclear whether this ratio varies significantly among countries. The decrease in the ratio compared to the Styblo rule probably relates to improvements in the prompt treatment of TB disease (by national TB programmes). A change in the number of tuberculous infections per prevalent smear-positive TB case in population-based surveys makes the assumed fixed mathematical relationship between ARTI and incidence of smear-positive TB no longer valid.

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important group ofantiretroviral drugs in the treatment of a chronic HIV-I infection. The risk of viral resistance to NNRTIs is strongly diminished when they are used as part of a highly active antiretroviral combination therapy (HAART). Randomised trials have shown that nevirapine and efavirenz have a comparable antiretroviral efficacy. While rash and hepatotoxicity are associated with the use of nevirapine, the use of efavirenz is associated with neuropsychiatric abnormalities. The increase in HDL-cholesterol, which may be associated with a lower risk of cardiovascular disease, is greater with nevirapine than with efavirenz. The choice between the two drugs can be tailored to the needs of the patient. The rapid selection ofNNRTI-resistant HIV-I strains during the sub-optimal use of nevirapine and efavirenz demands the development of new NNRTIs.

Objectives To assess long-term changes in lipids and lipoproteins concentrations associated with exposure to non-nucleoside reverse transcriptase inhibitors. Methods Long-term analysis of plasma lipid concentrations was performed in patients starting first-line antiretroviral therapy with stavudine (d4T) and lamivudine, and either nevirapine or efavirenz. Results Concentrations of total cholesterol, low-density lipoprotein cholesterol and triglycerides continued to increase, while high-density lipoprotein cholesterol showed a slight decrease compared with earlier reported increases after 48 weeks. Conclusions Changes in body fat distribution expected to occur with continued exposure to d4T could offer a potential explanation for these findings.

Background The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. Methods In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma. HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. Findings Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. Interpretation Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events

Objectives To study the dynamics of CD4 T-lymphocyte counts (CD4 counts) after the initiation of either protease inhibitor (PI)-based or nevirapine (NVP)-based first-line highly active antiretroviral therapy (HAART). Design and methods A retrospective cohort study of 1029 HIV-infected antiretroviral therapy-naive patients initiating either PI-based or NVP-based HAART was carried out. Patients were censored as soon as they experienced virological failure, or changed their original antiretroviral regimen for any reason. Results In total, 920 and 109 patients initiated PI- and NVP-based HAART, respectively. The patients in the PI group more often had AIDS (15 vs. 6% in the NVP group), had a lower median baseline CD4 count (234 vs. 250 cells/μL in the NVP group) and had higher median baseline plasma HIV-1 RNA levels (pVL) (5.0 vs. 4.7 log10 HIV-1 RNA copies/mL in the NVP group). After 96 weeks of follow-up, the mean increase from baseline in CD4 count, adjusted for baseline CD4 count, age, gender and baseline pVL, was 310 cells/μL in the PI group and 212 cells/μL in the NVP group (P=0.003). This difference was mainly attributable to the patients in the NVP group initiating HAART with a baseline CD4 count below 200 cells/μL. There were no differences between the PI and NVP groups with respect to the change in the number of CD4 cells as a proportion of the total number of lymphocytes. Conclusion Patients successfully treated with NVP-based HAART have a smaller increase in absolute CD4 cells compared with those treated with PI-based HAART.

Backgound: A substantial number of patients start their first-line antiretroviral therapy at an advanced stage of an HIV-1 infection. Potential differences between specific drug regimens in antiviral efficacy and safety in these patients are of major importance. Methods: A post-hoc analysis within the randomized controlled 2NN trial comparing efficacy between regimes containing nevirapine (NVP), efavirenz (EFV), or both, in addition to stavudine and lamivudine. Primary outcome: risk of virologic failure in different strata of baseline CD4 T-lymphocyte counts and plasma HIV-1 RNA concentrations (pVL). Virologic failure: never reaching a pVL 400 copies/ml. Results: The risk of virologic failure was increased at very low CD4 counts ( 200 x 10(6) cells/l [hazard ratio (HR), 1.28; 95% confidence interval (CI), 0.93-1.77]. The same was seen for a pVL >= 100 000 copies/ml compared to a lower pVL (HR, 1.20; CI, 0.96-1.50). There were no statistically significant differences between NVP and EFV in risk of virologic failure within any of the CD4 or pVL strata, although EFV performed slightly better in the low CD4 stratum. The incidence of rash in the NVP group was significantly higher in female patients with higher CD4 cell counts, while adverse events in the EFV group were not associated with CD4 cell count. Conclusions: Initial antiretroviral therapy including NVP or EFV is effective in patients with an advanced HIV-1 infection. A high baseline CD4 cell count is associated with the occurrence of rash in female patients using NVP. (c) 2005 Lippincott Williams C Wilkins