Predictors of multidrug- and extensively drug-resistant tuberculosis in a high HIV prevalence community

Background

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) have emerged in high-HIV-prevalence settings, which generally lack laboratory infrastructure for diagnosing TB drug resistance. Even where available, inherent delays with current drug-susceptibility testing (DST) methods result in clinical deterioration and ongoing transmission of MDR and XDR-TB. Identifying clinical predictors of drug resistance may aid in risk stratification for earlier treatment and infection control.

Methods

We performed a retrospective case-control study of patients with MDR (cases), XDR (cases) and drug-susceptible (controls) TB in a high-HIV-prevalence setting in South Africa to identify clinical and demographic risk factors for drug-resistant TB. Controls were selected in a 1∶1∶1 ratio and were not matched. We calculated odds ratios (OR) and performed multivariate logistic regression to identify independent predictors.

Results

We enrolled 116, 123 and 139 patients with drug-susceptible, MDR, and XDR-TB. More than 85% in all three patient groups were HIV-infected. In multivariate analysis, MDR and XDR-TB were each strongly associated with history of TB treatment failure (adjusted OR 51.7 [CI 6.6-403.7] and 51.5 [CI 6.4–414.0], respectively) and hospitalization more than 14 days (aOR 3.8 [CI 1.1–13.3] and 6.1 [CI 1.8–21.0], respectively). Prior default from TB treatment was not a risk factor for MDR or XDR-TB. HIV was a risk factor for XDR (aOR 8.2, CI 1.3–52.6), but not MDR-TB. Comparing XDR with MDR-TB patients, the only significant risk factor for XDR-TB was HIV infection (aOR 5.3, CI 1.0–27.6).

Discussion

In this high-HIV-prevalence and drug-resistant TB setting, a history of prolonged hospitalization and previous TB treatment failure were strong risk factors for both MDR and XDR-TB. Given high mortality observed among patients with HIV and drug-resistant TB co-infection, previously treated and hospitalized patients should be considered for empiric second-line TB therapy while awaiting confirmatory DST results in settings with a high-burden of MDR/XDR-TB.     

Drug-Resistant Tuberculosis among HIV-Infected Patients Starting Antiretroviral Therapy in Durban, South Africa

Objective

To estimate the prevalence of drug-resistant tuberculosis (TB) and describe the resistance patterns in patients commencing antiretroviral therapy (ART) in an HIV clinic in Durban, South Africa.

Design

Cross-sectional cohort study.

Methods

Consecutive HIV-infected adults (≥18y/o) initiating HIV care were enrolled from May 2007–May 2008, regardless of signs or symptoms of active TB. Prior TB history and current TB treatment status were self-reported. Subjects expectorated sputum for culture (MGIT liquid and 7H11 solid medium). Positive cultures were tested for susceptibility to first- and second-line anti-tuberculous drugs. The prevalence of drug-resistant TB, stratified by prior TB history and current TB treatment status, was assessed.

Results

1,035 subjects had complete culture results. Median CD4 count was 92/µl (IQR 42–150/µl). 267 subjects (26%) reported a prior history of TB and 210 (20%) were receiving TB treatment at enrollment; 191 (18%) subjects had positive sputum cultures, among whom the estimated prevalence of resistance to any antituberculous drug was 7.4% (95% CI 4.0–12.4). Among those with prior TB, the prevalence of resistance was 15.4% (95% CI 5.9–30.5) compared to 5.2% (95% CI 2.1–8.9) among those with no prior TB. 5.1% (95% CI 2.4–9.5) had rifampin or rifampin plus INH resistance.

Conclusions

The prevalence of TB resistance to at least one drug was 7.4% among adults with positive TB cultures initiating ART in Durban, South Africa, with 5.1% having rifampin or rifampin plus INH resistance. Improved tools for diagnosing TB and drug resistance are urgently needed in areas of high HIV/TB prevalence.     

Evaluation of the 2007 WHO guideline to improve the diagnosis of tuberculosis in ambulatory HIV-positive adults

Background

In 2007 WHO issued a guideline to improve the diagnosis of smear-negative and extrapulmonary tuberculosis (EPTB) in HIV-positive patients. This guideline relies heavily on the acceptance of HIV-testing and availability of chest X-rays.

Methods and Findings

Cohort study of TB suspects in four tuberculosis (TB) clinics in Phnom Penh, Cambodia. We assessed the operational performance of the guideline, the incremental yield of investigations, and the diagnostic accuracy for smear-negative tuberculosis in HIV-positive patients using culture positivity as reference standard. 1,147 (68.9%) of 1,665 TB suspects presented with unknown HIV status, 1,124 (98.0%) agreed to be tested, 79 (7.0%) were HIV-positive. Compliance with the guideline for chest X-rays and sputum culture requests was 97.1% and 98.3% respectively. Only 35 of 79 HIV-positive patients (44.3%) with a chest X-ray suggestive of TB started TB treatment within 10 days. 105 of 442 HIV-positive TB suspects started TB treatment (56.2% smear-negative pulmonary TB (PTB), 28.6% smear-positive PTB, 15.2% EPTB). The median time to TB treatment initiation was 5 days (IQR: 2–13 days), ranging from 2 days (IQR: 1–11.5 days) for EPTB, over 2.5 days (IQR: 1–4 days) for smear-positive PTB to 9 days (IQR: 3–17 days) for smear-negative PTB. Among the 34 smear-negative TB patients with a confirmed diagnosis, the incremental yield of chest X-ray, clinical suspicion or abdominal ultrasound, and culture was 41.2%, 17.6% and 41.2% respectively. The sensitivity and specificity of the algorithm to diagnose smear-negative TB in HIV-positive TB suspects was 58.8% (95%CI: 42.2%–73.6%) and 79.4% (95%CI: 74.8%–82.4%) respectively.

Conclusions

Pending point-of-care rapid diagnostic tests for TB disease, diagnostic algorithms are needed. The diagnostic accuracy of the 2007 WHO guideline to diagnose smear-negative TB is acceptable. There is, however, reluctance to comply with the guideline in terms of immediate treatment initiation.     

Prevalence of drug-resistant tuberculosis in mainland China: systematic review and meta-analysis

Background

The spread of drug-resistant tuberculosis (TB) is one of the major public health problems in the world. Surveillance of anti-TB drug resistance is important for monitoring TB control strategies. However, the status of drug-resistant TB in China has been reported inconsistently.

Methods

We systematically reviewed published studies on drug-resistant TB in China until March 31, 2011, and quantitatively summarized prevalence and patterns of anti-TB drug resistance among new cases and previously treated cases, respectively.

Results

Ninety-five eligible articles, published during 1993–2011, were included in this review. The meta-analyses showed that the prevalence of drug-resistant TB in new cases was 27.9% (95% CI, 25.6%–30.2%) (n/N = 27360/104356) and in previously treated cases was 60.3% (95% CI, 56.2%–64.2%) (n/N = 30350/45858). Furthermore, in these two study populations, the prevalence of multiple drug resistance was found to be 5.3% (95% CI, 4.4%–6.4%) (n/N = 8810/101718) and 27.4% (95% CI, 24.1%–30.9%) (n/N = 10486/44530) respectively. However, the results were found to be frequently heterogeneous (p for Q tests <0.001). The most common resistance was observed for isoniazid among both study populations. Different patterns of drug resistance were observed in the subgroup analysis with respect to geographic areas, drug susceptibility testing methods and subject enrollment time.

Conclusions

Results of meta-analyses indicated a severe status of drug-resistant TB in China, which attaches an importance to strength TB prevention and control.     

Longitudinal analysis of QuantiFERON-TB Gold In-Tube in children with adult household tuberculosis contact in South Africa: a prospective cohort study

Background

QuantiFERON-TB Gold In Tube (QFT-GIT) is a tool for detecting M. tuberculosis infection. However, interpretation and utility of serial QFT-GIT testing of pediatric tuberculosis (TB) contacts is not well understood. We compared TB prevalence between baseline and 6 months follow-up using QFT-GIT and tuberculin skin testing (TST) in children who were household contacts of adults with pulmonary TB in South Africa, and explored factors associated with QFT-GIT conversions and reversions.

Method

Prospective study with six month longitudinal follow-up.

Results

Among 270 enrolled pediatric contacts, 196 (73%) underwent 6-month follow-up testing. The 6-month prevalence estimate of MTB infection in pediatric contacts increased significantly from a baseline of 29% (79/270, 95%CI [24–35]) to 38% (103/270, 95% CI [32–44], p<0.001) using QFT-GIT; prevalence increased from a baseline of 28% (71/254, 95%CI [23–34]) to 33% (88/263, 95%CI [21–32], p = 0.002) using TST. Prevalence estimates were influenced by thresholds for positivity for TST, but not for QFT-GIT. Among 134 children with a negative or indeterminate baseline QFT-GIT, 24 (18%) converted to positive at follow-up; conversion rates did not differ significantly when using more stringent thresholds to define QFT-GIT conversion. Older age >10 years (AOR 8.9 95%CI [1.1–72]) and baseline TST positivity ≥5 mm (AOR 5.2 95%CI [1.2–23]) were associated with QFT-GIT conversion. Among 62 children with a positive baseline QFT-GIT, 9 (15%) reverted to negative; female gender (AOR 18.5 95%CI [1.1–321]; p = 0.04] was associated with reversion, while children with baseline positive TST were less likely to have QFT-GIT reversion (AOR 0.01 95%CI [0.001–0.24]).

Conclusion

Among pediatric contacts of adult household TB cases in South Africa, prevalence estimates of TB infection increased significantly from baseline to 6 months. Conversions and reversions occurred among pediatric TB contacts using QFT-GIT, but QFT-GIT conversion rates were less influenced by thresholds used for conversions than were TST conversion rates.     

Predictors on delay of initial health-seeking in new pulmonary tuberculosis cases among migrants population in East China

Objectives

To determine the length of delay in initial health-seeking in new pulmonary tuberculosis (PTB) cases among migrant population in the eastern part of China, and factors associated with it.

Methods

A cross-sectional study was conducted using a structured questionnaire in six counties in Shanghai, Guangdong and Jiangsu from May to October, 2008, to estimate the extent and factors responsible for delayed initial health-seeking of the new PTB cases. The interval between self-reported onset of TB symptoms and date of first attendance at any medical institution was determined. More than the median duration was defined as delayed health-seeking.

Results

A total of 323 new migrant PTB patients participated in the study. Only 6.5% had medical insurance. The median and mean durations to initial health-seeking were respectively 10 and 31 days. There was no significant association between socio-demographic factors and delayed initial health-seeking. Average monthly working days >24 (AOR, 1.61; 95% CI, 1.03–2.51), and hemoptysis or bloody sputum (AOR, 0.48; 95% CI, 0.28–0.85) were significantly associated with delayed initial health-seeking.

Conclusions

Interventions to improve health seeking behavior among the migrant population in China must focus on strengthening their labor, medical security and health education.     

Microscopic-Observation Drug-Susceptibility Assay for the Diagnosis of Drug-Resistant Tuberculosis in Harare,Zimbabwe

Introduction

Limited data exist on use of the microscopic-observation drug-susceptibility (MODS) assay among persons suspected of MDR-TB living in high HIV-prevalence settings.

Methods

We retrospectively reviewed available clinical and drug susceptibility data for drug-resistant TB suspects referred for culture and drug-susceptibility testing between April 1, 2011 and March 1, 2012. The diagnostic accuracy of MODS was estimated against a reference standard including Löwenstein-Jensen (LJ) media and manual liquid (BACTEC MGIT) culture. The accuracy of MODS drug-susceptibility testing (DST) was assessed against a reference standard absolute concentration method.

Results

One hundred thirty-eight sputum samples were collected from 99 drug-resistant TB suspects; in addition, six previously cultured MDR isolates were included for assessment of DST accuracy. Among persons with known HIV infection status, 39/59 (66%) were HIV-infected. Eighty-six percent of patients had a history of prior TB treatment, and 80% of individuals were on antituberculous treatment at the time of sample collection. M. tuberculosis was identified by reference standard culture among 34/98 (35%) MDR-TB suspects. Overall MODS sensitivity for M. tuberculosis detection was 85% (95% CI, 69–95%) and specificity was 93% (95% CI, 84–98%); diagnostic accuracy did not significantly differ by HIV infection status. Median time to positivity was significantly shorter for MODS (7 days; IQR 7–15 days) than MGIT (12 days; IQR 6–16 days) or LJ (28 days; IQR 21–35 days; p<0.001). Of 33 specimens with concurrent DST results, sensitivity of the MODS assay for detection of resistance to isoniazid, rifampin, and MDR-TB was 88% (95% CI, 68–97%), 96% (95% CI, 79–100%), and 91% (95% CI, 72–99%), respectively; specificity was 89% (95% CI, 52–100%), 89% (95% CI, 52–100%), and 90% (95% CI, 56–100%), respectively.

Conclusion

In a high HIV-prevalence setting, MODS diagnosed TB and drug-resistant TB with high sensitivity and shorter turnaround time compared with standard culture and DST methods.     

Factors associated with delays in treatment initiation after tuberculosis diagnosis in two districts of India

Background

Excessive time between diagnosis and initiation of tuberculosis (TB) treatment contributes to ongoing TB transmission and should be minimized. In India, Revised National TB Control Programme (RNTCP) focuses on indicator start of treatment within 7 days of diagnosis for patients with sputum smear-positive PTB for monitoring DOTS implementation.

Objectives

To determine length of time between diagnosis and initiation of treatment and factors associated with delays of more than 7 days in smear-positive pulmonary TB.

Methods

Using existing programme records such as the TB Register, treatment cards, and the laboratory register, we conducted a retrospective cohort study of all patients with smear-positive pulmonary TB registered from July-September 2010 in two districts in India. A random sample of patients with pulmonary TB who experienced treatment delay of more than 7 days was interviewed using structured questionnaire.

Results

2027 of 3411 patients registered with pulmonary TB were smear-positive. 711(35%) patients had >7 days between diagnosis and treatment and 262(13%) had delays >15 days. Mean duration between TB diagnosis and treatment initiation was 8 days (range = 0–128 days). Odds of treatment delay >7 days was 1.8 times more likely among those who had been previously treated (95% confidence interval [CI] 1.5–2.3) and 1.6 (95% CI 1.3–1.8) times more likely among those diagnosed in health facilities without microscopy centers. The main factors associated with a delay >7 days were: patient reluctance to start a re-treatment regimen, patients seeking second opinions, delay in transportation of drugs to the DOT centers and delay in initial home visits. To conclude, treatment delay >7 days was associated with a number of factors that included history of previous treatment and absence of TB diagnostic services in the local health facility. Decentralized diagnostic facilities and improved referral procedures may reduce such treatment delays.     

Prevalence and impact of minority variant drug resistance mutations in primary HIV-1 infection

Objective

To evaluate minority variant drug resistance mutations detected by the oligonucleotide ligation assay (OLA) but not consensus sequencing among subjects with primary HIV-1 infection.

Design/Methods

Observational, longitudinal cohort study. Consensus sequencing and OLA were performed on the first available specimens from 99 subjects enrolled after 1996. Survival analyses, adjusted for HIV-1 RNA levels at the start of antiretroviral (ARV) therapy, evaluated the time to virologic suppression (HIV-1 RNA<50 copies/mL) among subjects with minority variants conferring intermediate or high-level resistance.

Results

Consensus sequencing and OLA detected resistance mutations in 5% and 27% of subjects, respectively, in specimens obtained a median of 30 days after infection. Median time to virologic suppression was 110 (IQR 62–147) days for 63 treated subjects without detectable mutations, 84 (IQR 56–109) days for ten subjects with minority variant mutations treated with ≥3 active ARVs, and 104 (IQR 60–162) days for nine subjects with minority variant mutations treated with <3 active ARVs (p = .9). Compared to subjects without mutations, time to virologic suppression was similar for subjects with minority variant mutations treated with ≥3 active ARVs (aHR 1.2, 95% CI 0.6–2.4, p = .6) and subjects with minority variant mutations treated with <3 active ARVs (aHR 1.0, 95% CI 0.4–2.4, p = .9). Two subjects with drug resistance and two subjects without detectable resistance experienced virologic failure.

Conclusions

Consensus sequencing significantly underestimated the prevalence of drug resistance mutations in ARV-naïve subjects with primary HIV-1 infection. Minority variants were not associated with impaired ARV response, possibly due to the small sample size. It is also possible that, with highly-potent ARVs, minority variant mutations may be relevant only at certain critical codons.     

Self-reported risks for multiple-drug resistance among new tuberculosis cases: implications for drug susceptibility screening and treatment

Background

Multiple drug-resistance in new tuberculosis (TB) cases accounts for the majority of all multiple drug-resistant TB (MDR-TB) worldwide. Effective control requires determining which new TB patients should be tested for MDR disease, yet the effectiveness of global screening recommendations of high-risk groups is unknown.

Methods

Sixty MDR-TB cases with no history of previous TB treatment, 80 drug-sensitive TB and 80 community-based controls were recruited in Lima, Peru between August and December, 2008 to investigate whether recommended screening practices identify individuals presenting with MDR-TB. Odd ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression to study the association of potential risk factors with case/control variables.

Results

MDR-TB cases did not differ from drug-sensitive TB and community controls in rates of human immunodeficiency virus infection, reported hospital or prison visits in the 3 years prior to diagnosis. MDR-TB cases were more likely than drug-sensitive TB controls to have had a recent MDR-TB household contact (OR 4.66, (95% CI 1.56–13.87)); however, only 15 cases (28.3%) reported this exposure. In multivariate modeling, recent TB household contact, but not contact with an MDR-TB case, remained predictive of MDR-TB, OR 7.47, (95% CI 1.91–29.3). Living with a partner rather than parents was associated with a lower risk of MDR-TB, OR 0.15, (95% CI 0.04–0.51).

Conclusion

Targeted drug susceptibility testing (DST) linked to reported MDR-TB contact or other high-risk exposures does not identify the majority of new TB cases with MDR disease in Lima where it is endemic. All new TB cases should be screened with DST to identify MDR patients. These findings are likely applicable to other regions with endemic MDR-TB.     

Characteristics and treatment outcomes of patients with MDR and XDR tuberculosis in a TB referral hospital in Beijing: a 13-year experience

Background

Information on treatment outcomes among hospitalized patients with multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are scarce in China.

Methodology/Principal Findings

We conducted this retrospective study to analyze the characteristics and treatment outcomes in MDR- and XDR-TB patients in the 309 Hospital in Beijing, China during 1996–2009. Socio-demographic and clinical data were retrieved from medical records and analyzed. Logistic regression analysis was performed to identify risk factors associated with poor treatment outcomes and Cox proportional hazards regression model was further used to determine risk factors associated with death in TB patients. Among the 3,551 non-repetitive hospitalized TB patients who had drug susceptibility testing (DST) results, 716 (20.2%) had MDR-TB and 51 (1.4%) had XDR-TB. A total of 3,270 patients who had medical records available were used for further analyses. Treatment success rates (cured and treatment completed) were 90.9%, 53.4% and 29.2% for patients with non-MDR-TB, patients with MDR-TB excluding XDR-TB and patients with XDR-TB, respectively. Independent risk factors associated with poor treatment outcomes in MDR-TB patients included being a migrant (adjusted OR = 1.77), smear-positivity at treatment onset (adjusted OR = 1.94) and not receiving 3 or more potentially effective drugs (adjusted OR = 3.87). Independent risk factors associated with poor treatment outcomes in XDR-TB patients were smear-positivity at treatment onset (adjusted OR = 10.42) and not receiving 3 or more potentially effective drugs (adjusted OR = 14.90). The independent risk factors associated with death in TB patients were having chronic obstructive pulmonary disease (adjusted HR = 5.25) and having hypertension (adjusted HR = 4.31).

Conclusions/Significance

While overall satisfactory treatment success for non-MDR-TB patients was achieved, more intensive efforts should be made to better manage MDR- and XDR-TB cases in order to improve their treatment outcomes and to minimize further emergence of so-called totally drug-resistant TB cases.     

Treatment interruption and variation in tablet taking behaviour result in viral failure: a case-control study from Cape Town, South Africa

Background

Understanding of the impact of non-structured treatment interruption (TI) and variation in tablet-taking on failure of first-line antiretroviral therapy (ART) is limited in a resource-poor setting.

Methods

A retrospective matched case-control analysis. Individuals failing ART were matched by time on ART with 4 controls. Viral load (VL) and CD4 count were completed 4-monthly. Adherence percentages, from tablet returns, were calculated 4-monthly (interval) and from ART start (cumulative). Variation between intervals and TI (>27 days off ART) were recorded. Conditional multivariate logistic regression analysis was performed to estimate the effect of cumulative adherence <90%, at least one episode of adherence variation >10% and TI on virological failure. Age, gender, baseline log VL and CD4 were included as possible confounders in the multivariate model.

Results

244 patients (44 cases, 200 controls) were included. Median age was 32 years (IQR28–37), baseline CD4 108 cells/mm3 (IQR56–151), VL 4.82 log (IQR4.48–5.23). 94% (96% controls, 86% failures) had cumulative adherence >90%. The odds of failure increased 3 times (aOR 3.01, 95%CI 0.81–11.21) in individuals with cumulative adherence <90%, 2.2 times (aOR 2.20, 95%CI 1.04–4.64) in individuals with at least one episode of fluctuating adherence of >10% and 4.01 times (aOR 4.01, 95%CI 1.45–11.10) in individuals with TIs. For individuals with TI and cumulative adherence >95%, the odds of failing were 5.65 (CI 1.40–22.85).

Conclusion

It is well known that poor cumulative adherence increases risk of virological failure, but less well understood that TI and variations in tablet-taking also play a key role, despite otherwise excellent adherence.     

Spread of extensively drug-resistant tuberculosis in KwaZulu-Natal province, South Africa

Background

In 2005 a cluster of 53 HIV-infected patients with extensively drug-resistant tuberculosis (XDR-TB) was detected in the Msinga sub-district, the catchment area for the Church of Scotland Hospital (CoSH) in Tugela Ferry, in KwaZulu-Natal province (KZN), South Africa. KZN is divided into 11 healthcare districts. We sought to determine the distribution of XDR TB cases in the province in relation to population density.

Methods

In this cross-sectional study, the KZN tuberculosis laboratory database was analysed. Results of all patients with a sputum culture positive for Mycobacterium tuberculosis from January 2006 to June 2007 were included. Drug-susceptibility test results for isoniazid, rifampicin, ethambutol, streptomycin, kanamycin and ofloxacin were available for all patients as well as the location of the hospital where their clinical diagnosis was made.

Findings

In total, 20858 patients attending one of 73 hospitals or their adjacent clinics had cultures positive for M. tuberculosis. Of these, 4170 (20%) were MDR-TB cases. Four hundred and forty three (11%) of the MDR tuberculosis cases displayed the XDR tuberculosis susceptibility profile. Only 1429 (34%) of the MDR-TB patients were seen at the provincial referral hospital for treatment. The proportion of XDR-TB amongst culture-confirmed cases was highest in the Msinga sub-district (19.6%), followed by the remaining part of the Umzinyati district (5.9%) and the other 10 districts (1.1%). The number of hospitals with at least one XDR-TB case increased from 18 (25%) to 58 (80%) during the study period.

Interpretation

XDR-TB is present throughout KZN. More than 65% of all diagnosed MDR-TB cases, including XDR-TB patients, were left untreated and likely remained in the community as a source of infection.     

Impact of Xpert MTB/RIF Testing on Tuberculosis Management and Outcomes in Hospitalized Patients in Uganda

Rationale

The clinical impact of Xpert MTB/RIF for tuberculosis (TB) diagnosis in high HIV-prevalence settings is unknown.

Objective

To determine the diagnostic accuracy and impact of Xpert MTB/RIF among high-risk TB suspects.

Methods

We prospectively enrolled consecutive, hospitalized, Ugandan TB suspects in two phases: baseline phase in which Xpert MTB/RIF results were not reported to clinicians and an implementation phase in which results were reported. We determined the diagnostic accuracy of Xpert MTB/RIF in reference to culture (solid and liquid) and compared patient outcomes by study phase.

Results

477 patients were included (baseline phase 287, implementation phase 190). Xpert MTB/RIF had high sensitivity (187/237, 79%, 95% CI: 73–84%) and specificity (190/199, 96%, 95% CI: 92–98%) for culture-positive TB overall, but sensitivity was lower (34/81, 42%, 95% CI: 31–54%) among smear-negative TB cases. Xpert MTB/RIF reduced median days-to-TB detection for all TB cases (1 [IQR 0–26] vs. 0 [IQR 0–1], p<0.001), and for smear-negative TB (35 [IQR 22–55] vs. 22 [IQR 0–33], p = 0.001). However, median days-to-TB treatment was similar for all TB cases (1 [IQR 0–5] vs. 0 [IQR 0–2], p = 0.06) and for smear-negative TB (7 [IQR 3–53] vs. 6 [IQR 1–61], p = 0.78). Two-month mortality was also similar between study phases among 252 TB cases (17% vs. 14%, difference +3%, 95% CI: −21% to +27%, p = 0.80), and among 87 smear-negative TB cases (28% vs. 22%, difference +6%, 95% CI: −34 to +46%, p = 0.77).

Conclusions

Xpert MTB/RIF facilitated more accurate and earlier TB diagnosis, leading to a higher proportion of TB suspects with a confirmed TB diagnosis prior to hospital discharge in a high HIV/low MDR TB prevalence setting. However, our study did not detect a decrease in two-month mortality following implementation of Xpert MTB/RIF possibly because of insufficient powering, differences in empiric TB treatment rates, and disease severity between study phases.     

Predictors of death among patients who completed tuberculosis treatment: a population-based cohort study

Background

Mortality among patients who complete tuberculosis (TB) treatment is still high among vulnerable populations. The objective of the study was to identify the probability of death and its predictive factors in a cohort of successfully treated TB patients.

Methods

A population-based retrospective longitudinal study was performed in Barcelona, Spain. All patients who successfully completed TB treatment with culture-confirmation and available drug susceptibility testing between 1995–1997 were retrospectively followed-up until December 31, 2005 by the Barcelona TB Control Program. Socio-demographic, clinical, microbiological and treatment variables were examined. Mortality, TB Program and AIDS registries were reviewed. Kaplan-Meier and a Cox regression methods with time-dependent covariates were used for the survival analysis, calculating the hazard ratio (HR) with 95% confidence intervals (CI).

Results

Among the 762 included patients, the median age was 36 years, 520 (68.2%) were male, 178 (23.4%) HIV-infected, and 208 (27.3%) were alcohol abusers. Of the 134 (17.6%) injecting drug users (IDU), 123 (91.8%) were HIV-infected. A total of 30 (3.9%) recurrences and 173 deaths (22.7%) occurred (mortality rate: 3.4/100 person-years of follow-up). The predictors of death were: age between 41–60 years old (HR: 3.5; CI:2.1–5.7), age greater than 60 years (HR: 14.6; CI:8.9–24), alcohol abuse (HR: 1.7; CI:1.2–2.4) and HIV-infected IDU (HR: 7.9; CI:4.7–13.3).

Conclusions

The mortality rate among TB patients who completed treatment is associated with vulnerable populations such as the elderly, alcohol abusers, and HIV-infected IDU. We therefore need to fight against poverty, and promote and develop interventions and social policies directed towards these populations to improve their survival.     

Multidrug-resistant and extensively drug-resistant tuberculosis in multi-ethnic region, Xinjiang Uygur Autonomous Region, China

Background

The multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has emerged as a global threat. Xinjiang is a multi-ethnic region and suffered second highest incidence of TB in China. However, epidemiological information on MDR and XDR TB is scarcely investigated.

Methodology/Principal Findings

A prospective study was conducted to analyze the prevalence of MDR and XDR TB and the differences of drug resistance TB between Chinese Han and other nationalities population at Chest Hospital of Xinjiang Uygur Autonomous Region, China. We performed in vitro drug susceptibility testing of Mycobacterium tuberculosis to first- and second-line anti-tuberculosis drugs for all 1893 culture confirmed positive TB cases that were diagnosed between June 2009 and June 2011. Totally 1117 (59.0%, 95% CI, 56.8%–61.2%) clinical isolates were resistant to ≥1 first-line drugs; the prevalence of MDR TB was 13.2% (95% CI, 11.7%–14.7%), of which, 77 (30.8%; 95% CI, 25.0%–36.6%) and 31 (12.8%; 95% CI, 8.6%–17.0%) isolates were pre-XDR and XDR TB respectively. Among the MDR/XDR TB, Chinese Han patients were significantly less likely to be younger with an odds ratio 0.42 for age 20–29 years and 0.52 for age 40–49 years; P _trend = 0.004), and Chinese Han patients has a lower prevalence of XDR TB (9.6%) than all the other nationality (14.9%).

Conclusions/Significance

The burden of drug resistance TB cases is sizeable, which highlights an urgent need to reinforce the control, detection and treatment strategies for drug resistance TB. However, the difference of MDR and XDR TB between Chinese Han and other nationalities was not observed.     

Incidence and risk factors of serious adverse events during antituberculous treatment in Rwanda: a prospective cohort study

Background

Tuberculosis (TB) and TB-human immunodeficiency virus infection (HIV) coinfection is a major public health concern in resource-limited settings. Although TB treatment is challenging in HIV-infected patients because of treatment interactions, immunopathological reactions, and concurrent infections, few prospective studies have addressed this in sub-Saharan Africa.In this study we aimed to determine incidence, causes of, and risk factors for serious adverse events among patients on first-line antituberculous treatment, as well as its impact on antituberculous treatment outcome.

Methods and findings

Prospective observational cohort study of adults treated for TB at the Internal Medicine department of the Kigali University Hospital from May 2008 through August 2009.Of 263 patients enrolled, 253 were retained for analysis: median age 35 (Interquartile range, IQR 28–40), 55% male, 66% HIV-positive with a median CD4 count 104 cells/mm³ (IQR 44–248 cells/mm³). Forty percent had pulmonary TB, 43% extrapulmonary TB and 17% a mixed form. Sixty-four (26%) developed a serious adverse event; 58/167 (35%) HIV-infected vs. 6/86 (7%) HIV-uninfected individuals. Commonest events were concurrent infection (n = 32), drug-induced hepatitis (n = 24) and paradoxical reactions/TB-IRIS (n = 23).HIV-infection (adjusted Hazard Ratio, aHR 3.4, 95% Confidence Interval, CI 1.4–8.7) and extrapulmonary TB (aHR 2, 95%CI 1.1–3.7) were associated with an increased risk of serious adverse events. For TB/HIV co-infected patients, extrapulmonary TB (aHR 2.0, 95%CI 1.1–3.9) and CD4 count <100 cells/mm3 at TB diagnosis (aHR 1.7, 95%CI 1.0–2.9) were independent predictors. Adverse events were associated with an almost two-fold higher risk of unsuccessful treatment outcome at 6 months (HR 1.89, 95%CI 1.3–3.0).

Conclusion

Adverse events frequently complicate the course of antituberculous treatment and worsen treatment outcome, particularly in patients with extrapulmonary TB and advanced immunodeficiency. Concurrent infection accounts for most events. Our data suggest that deterioration in a patient already receiving antituberculous treatment should prompt an aggressive search for additional infections.     

Factors associated with HIV infection in married or cohabitating couples in Kenya: results from a nationally representative study

Background

In order to inform prevention programming, we analyzed HIV discordance and concordance within couples in the Kenya AIDS Indicator Survey (KAIS) 2007.

Methods

KAIS was a nationally representative population-based sero-survey that examined demographic and behavioral indicators and serologic testing for HIV, HSV-2, syphilis, and CD4 cell counts in 15,853 consenting adults aged 15–64 years. We analyzed interview and blood testing data at the sexual partnership level from married or cohabitating couples. Multivariable regression models were used to identify factors independently associated with HIV discordant and concordant status.

Results

Of 3256 couples identified in the survey, 2748 (84.4%) had interview and blood testing data. Overall, 3.8% of couples were concordantly infected with HIV, and in 5.8% one partner was infected, translating to 338,000 discordant couples in Kenya. In 83.6% of HIV-infected Kenyans living in married or cohabitating couples neither partner knew their HIV status. Factors independently associated with HIV-discordance included young age in women (AOR 1.5, 95% CI: 1.2–1.8; p<0.0001), increasing number of lifetime sexual partners in women (AOR 1.5, 95% CI: 1.3–1.8; p<0.0001), HSV-2 infection in either or both partners (AOR 4.1, 95% CI: 2.3–7.2; p<0.0001), and lack of male circumcision (AOR 1.6, 95% CI: 1.0–2.5; p = 0.032). Independent factors for HIV-concordance included HSV-2 infection in both partners (AOR 6.5, 95% CI: 2.3–18.7; p = 0.001) and lack of male circumcision (AOR 1.8, 95% CI: 1.0–3.3; p = 0.043).

Conclusions

Couple prevention interventions should begin early in relationships and include mutual knowledge of HIV status, reduction of outside sexual partners, and promotion of male circumcision among HIV-uninfected men. Mechanisms for effective prevention or suppression of HSV-2 infection are also needed.     

Long delays and missed opportunities in diagnosing smear-positive pulmonary tuberculosis in Kampala, Uganda: a cross-sectional study

Background

Early detection and treatment of tuberculosis cases are the hallmark of successful tuberculosis control. We conducted a cross-sectional study at public primary health facilities in Kampala city, Uganda to quantify diagnostic delay among pulmonary tuberculosis (PTB) patients, assess associated factors, and describe trajectories of patients'' health care seeking.

Methodology/Principal Findings

Semi-structured interviews with new smear-positive PTB patients (≥15 years) registered for treatment. Between April 2007 and April 2008, 253 patients were studied. The median total delay was 8 weeks (IQR 4–12), median patient delay was 4 weeks (inter-quartile range [IQR] 1–8) and median health service delay was 4 weeks (IQR 2–8). Long total delay (>14 weeks) was observed for 61/253 (24.1%) of patients, long health service delay (>6 weeks) for 71/242 (29.3%) and long patient delay (>8 weeks) for 47/242 (19.4%). Patients who knew that TB was curable were less likely to have long total delay (adjusted Odds Ratio [aOR] 0.28; 95%CI 0.11–0.73) and long patient delay (aOR 0.36; 95%CI 0.13–0.97). Being female (aOR 1.98; 95%CI 1.06–3.71), staying for more than 5 years at current residence (aOR 2.24 95%CI 1.18–4.27) and having been tested for HIV before (aOR 3.72; 95%CI 1.42–9.75) was associated with long health service delay. Health service delay contributed 50% of the total delay. Ninety-one percent (231) of patients had visited one or more health care providers before they were diagnosed, for an average (median) of 4 visits (range 1–30). All but four patients had systemic symptoms by the time the diagnosis of TB was made.

Conclusions/Significance

Diagnostic delay among tuberculosis patients in Kampala is common and long. This reflects patients waiting too long before seeking care and health services waiting until systemic symptoms are present before examining sputum smears; this results in missed opportunities for diagnosis.     

Interferon-gamma release assays for the diagnosis of active tuberculosis in HIV-infected patients: a systematic review and meta-analysis

Background

Interferon-gamma release assays (IGRAs) have provided a new method for the diagnosis of Mycobacterium tuberculosis infection. However, the role of IGRAs for the diagnosis of active tuberculosis (TB), especially in HIV-infected patients remains unclear.

Methods

We searched PubMed, EMBASE and Cochrane databases to identify studies published in January 2001–July 2011 that evaluated the evidence of using QuantiFERON-TB Gold in-tube (QFT-GIT) and T-SPOT.TB (T-SPOT) on blood for the diagnosis of active TB in HIV-infected patients.

Results

The search identified 16 eligible studies that included 2801 HIV-infected individuals (637 culture confirmed TB cases). The pooled sensitivity for the diagnosis of active TB was 76.7% (95%CI, 71.6–80.5%) and 77.4% (95%CI, 71.4–82.6%) for QFT-GIT and T-SPOT, respectively, while the specificity was 76.1% (95%CI, 74.0–78.0%) and 63.1% (95%CI, 57.6–68.3%) after excluding the indeterminate results. Studies conducted in low/middle income countries showed slightly lower sensitivity and specificity when compared to that in high-income countries. The proportion of indeterminate results was as high as 10% (95%CI, 8.8–11.3%) and 13.2% (95%CI, 10.6–16.0%) for QFT-GIT and T-SPOT, respectively.

Conclusion

IGRAs in their current formulations have limited accuracy in diagnosing active TB in HIV-infected patients, and should not be used alone to rule out or rule in active TB cases in HIV-infected patients. Further modification is needed to improve their accuracy.