Effective interventions and decline of antituberculosis drug resistance in Eastern Taiwan, 2004-2008

Background

The Taiwan health authority recently launched several tuberculosis (TB) control interventions, which may have an impact on the epidemic of drug-resistant TB. We conducted a population-based antituberculosis drug resistance surveillance program in Eastern Taiwan to measure the proportions of notified TB patients with anti-TB drug resistance and the trend from 2004 to 2008.

Methods and Findings

All culture-positive TB patients were enrolled. Drug susceptibility testing results of the first isolate of each TB patient in each treatment course were analyzed. In total, 2688 patients were included, of which 2176 (81.0%) were new TB cases and 512 (19.0%) were previously treated cases. Among the 2176 new TB cases, 97 (4.5%) were retreated after the first episode of TB treatment within the study period. The proportion of new patients with any resistance, isoniazid resistance but not multidrug-resistant TB (resistant to at least isoniazid and rifampin, MDR-TB), and MDR-TB was 16.4%, 7.5%, and 4.0%, respectively, and that among previously treated cases was 30.9%, 7.9%, and 17.6%, respectively. The combined proportion of any resistance decreased from 23.3% in 2004 to 14.3% in 2008, and that of MDR-TB from 11.5% to 2.4%.

Conclusions

The proportion of TB patients with drug-resistant TB in Eastern Taiwan remains substantial. However, an effective TB control program has successfully driven the proportion of drug resistance among TB patients downward.     

Control of (Multi)Drug Resistance and Tuberculosis Incidence over 23 Years in the Context of a Well-Supported Tuberculosis Programme in Rural Malawi

Background

The rise in tuberculosis (TB) incidence following generalized HIV epidemics can overwhelm TB control programmes in resource-limited settings, sometimes accompanied by rising rates of drug resistance. This has led to claims that DOTS-based TB control has failed in such settings. However, few studies have described the effect of a sustained and well-supported DOTS programme on TB incidence and drug resistance over a long period. We present long-term trends in incidence and drug resistance in rural Malawi.

Methods

Karonga District in northern Malawi has an adult HIV prevalence of ∼10%. A research group, the Karonga Prevention Study, collaborates with the National Tuberculosis Programme to support core TB control activities. Bacteriological, demographic and clinical (including HIV status) information from all patients starting TB treatment in the District have been recorded since 1988. During that period isolates from each culture-positive TB patient were exported for drug sensitivity testing. Antiretroviral therapy (ART) has been widely available since 2005.

Results

Incidence of new smear-positive adult TB peaked at 124/100,000/year in the mid-90s, but has since fallen to 87/100,000/year. Drug sensitivity information was available for 95% (3132/3307) of all culture-positive cases. Initial resistance to isoniazid was around 6% with no evidence of an increase. Fewer than 1% of episodes involved a multi-drug resistant strain.

Discussion

In this setting with a generalised HIV epidemic and medium TB burden, a well-supported DOTS programme enhanced by routine culture and drug sensitivity testing may well have reduced TB incidence and maintained drug resistance at low levels.     

Cytokine Kinetics in the First Week of Tuberculosis Therapy as a Tool to Confirm a Clinical Diagnosis and Guide Therapy

Background

Many patients treated for tuberculosis (TB) in low and middle income countries are treated based on clinical suspicion without bacteriological confirmation. This is often due to lack of rapid simple accurate diagnostics and low healthcare provider confidence in the predictive value of current tests. We previously reported in an animal TB model that levels of host markers rapidly change in response to treatment initiation.

Methods

We assessed the potential of host biomarker kinetics of TB patients during the first two weeks of therapy to identify patients responding to treatment. Adult patients clinically diagnosed with and treated for TB, 29 in Nigeria and 24 in Nepal, were analyzed.

Results

Changes in concentrations of non-specific host biomarkers, particularly IP-10, in response to the first week of anti-TB therapy were strongly associated with bacteriological confirmation of TB. A decrease in IP-10 level of >300pg/ml between 0 and 7 days of treatment identified 75% of both smear-positive and smear-negative culture positive patients and correctly excluded TB in all nine culture negative patients.

Conclusions

Monitoring of early IP-10 responses to treatment could form the basis of a simplified assay and could help identify patients who were erroneously clinically diagnosed with TB or those infected with drug resistant strains on inappropriate treatment. We believe this approach may be particularly appropriate for difficult to diagnose patients, e.g. smear-negative HIV-positive, or those with extra-pulmonary TB, often treated without bacterial confirmation.     

Pattern of Drug Resistance and Risk Factors Associated with Development of Drug Resistant Mycobacterium tuberculosis in Pakistan

Background

Drug resistant tuberculosis (DR-TB) is a major public health problem in developing countries such as Pakistan.

Objective

The current study was conducted to assess the frequency of drug resistant tuberculosis including multi drug resistance (MDR- TB) as well as risk factors for development of DR-TB, in Punjab, Pakistan.

Methodology

Drug susceptibility testing (DST) was performed, using proportion method, for 2367 culture positive Mycobacterium tuberculosis (MTB) cases that were enrolled from January 2012 to December 2013 in the province of Punjab, Pakistan, against first-line anti-tuberculosis drugs. The data was analyzed using statistical software; SPSS version 18.

Results

Out of 2367 isolates, 273 (11.5%) were resistant to at least one anti-TB drug, while 221 (9.3%) showed MDR- TB. Risk factors for development of MDR-TB were early age (ranges between 10–25 years) and previously treated TB patients.

Conclusion

DR-TB is a considerable problem in Pakistan. Major risk factors are previous history of TB treatment and younger age group. It emphasizes the need for effective TB control Program in the country.     

Characteristics and programme-defined treatment outcomes among childhood tuberculosis (TB) patients under the national TB programme in Delhi

Background

Childhood tuberculosis (TB) patients under India''s Revised National TB Control Programme (RNTCP) are managed using diagnostic algorithms and directly observed treatment with intermittent thrice-weekly short-course treatment regimens for 6–8 months. The assignment into pre-treatment weight bands leads to drug doses (milligram per kilogram) that are lower than current World Health Organization (WHO) guidelines for some patients.

Objectives

The main aim of our study was to describe the baseline characteristics and treatment outcomes reported under RNTCP for registered childhood (age <15 years) TB patients in Delhi. Additionally, we compared the reported programmatic treatment completion rates between children treated as per WHO recommended anti-TB drug doses with those children treated with anti-TB drug doses below that recommended in WHO guidelines.

Methods

For this cross-sectional retrospective study, we reviewed programme records of all 1089 TB patients aged <15 years registered for TB treatment from January to June, 2008 in 6 randomly selected districts of Delhi. WHO disease classification and treatment outcome definitions are used by RNTCP, and these were extracted as reported in programme records.

Results and Conclusions

Among 1074 patients with records available, 651 (61%) were females, 122 (11%) were <5 years of age, 1000 (93%) were new cases, and 680 (63%) had extra-pulmonary TB (EP-TB)—most commonly peripheral lymph node disease [310 (46%)]. Among 394 pulmonary TB (PTB) cases, 165 (42%) were sputum smear-positive. The overall reported treatment completion rate was 95%. Similar reported treatment completion rates were found in all subgroups assessed, including those patients whose drug dosages were lower than that currently recommended by WHO. Further studies are needed to assess the reasons for the low proportion of under-5 years of age TB case notifications, address challenges in reaching all childhood TB patients by RNTCP, the accuracy of diagnosis, and the clinical validity of reported programme defined treatment completion.     

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 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.     

Treatment of tuberculosis in a region with high drug resistance: outcomes, drug resistance amplification and re-infection

Introduction

Emerging antituberculosis drug resistance is a serious threat for tuberculosis (TB) control, especially in Eastern European countries.

Methods

We combined drug susceptibility results and molecular strain typing data with treatment outcome reports to assess the influence of drug resistance on TB treatment outcomes in a prospective cohort of patients from Abkhazia (Georgia). Patients received individualized treatment regimens based on drug susceptibility testing (DST) results. Definitions for antituberculosis drug resistance and treatment outcomes were in line with current WHO recommendations. First and second line DST, and molecular typing were performed in a supranational laboratory for Mycobacterium tuberculosis (MTB) strains from consecutive sputum smear-positive TB patients at baseline and during treatment.

Results

At baseline, MTB strains were fully drug-susceptible in 189/326 (58.0%) of patients. Resistance to at least H or R (PDR-TB) and multidrug-resistance (MDR-TB) were found in 69/326 (21.2%) and 68/326 (20.9%) of strains, respectively. Three MDR-TB strains were also extensively resistant (XDR-TB). During treatment, 3/189 (1.6%) fully susceptible patients at baseline were re-infected with a MDR-TB strain and 2/58 (3.4%) PDR-TB patients became MDR-TB due to resistance amplification. 5/47 (10.6%) MDR- patients became XDR-TB during treatment. Treatment success was observed in 161/189 (85.2%), 54/69 (78.3%) and 22/68 (32.3%) of patients with fully drug susceptible, PDR- and MDR-TB, respectively. Development of ofloxacin resistance was significantly associated with a negative treatment outcome.

Conclusion

In Abkhazia, a region with high prevalence of drug resistant TB, the use of individualized MDR-TB treatment regimens resulted in poor treatment outcomes and XDR-TB amplification. Nosocomial transmission of MDR-TB emphasizes the importance of infection control in hospitals.     

Alarming Levels of Drug-Resistant Tuberculosis in HIV-Infected Patients in Metropolitan Mumbai,India

Background

Drug-resistant tuberculosis (DR-TB) is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug) in patients attending public antiretroviral treatment (ART) centers in greater metropolitan Mumbai, India.

Methods

A cross-sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST) against all first and second-line TB-drugs using phenotypic liquid culture (MGIT) were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases.

Results

Between March 2013 and January 2014, ART-center attendees were screened during 14135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4%) were smear-positive and 202 (12%) had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%–40%) TB-patients. The proportions of DR-TB were 25% (29/114) and 44% (39/88) among new and previously treated cases respectively. The patterns of DR-TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR-TB), 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable), 6% extensively drug-resistant (XDR-TB) and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug). Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models.

Conclusion

The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing ongoing transmission in the community and health facilities. These data highlight the need to promptly diagnose drug-resistance among all HIV-infected patients by systematically offering access to first and second-line DST to all patients with ‘presumptive TB’ rather than ‘presumptive DR-TB’ and tailor the treatment regimen based on the resistance patterns.     

A predictive scoring instrument for tuberculosis lost to follow-up outcome

Background

Adherence to tuberculosis (TB) treatment is troublesome, due to long therapy duration, quick therapeutic response which allows the patient to disregard about the rest of their treatment and the lack of motivation on behalf of the patient for improved. The objective of this study was to develop and validate a scoring system to predict the probability of lost to follow-up outcome in TB patients as a way to identify patients suitable for directly observed treatments (DOT) and other interventions to improve adherence.

Methods

Two prospective cohorts, were used to develop and validate a logistic regression model. A scoring system was constructed, based on the coefficients of factors associated with a lost to follow-up outcome. The probability of lost to follow-up outcome associated with each score was calculated. Predictions in both cohorts were tested using receiver operating characteristic curves (ROC).

Results

The best model to predict lost to follow-up outcome included the following characteristics: immigration (1 point value), living alone (1 point) or in an institution (2 points), previous anti-TB treatment (2 points), poor patient understanding (2 points), intravenous drugs use (IDU) (4 points) or unknown IDU status (1 point). Scores of 0, 1, 2, 3, 4 and 5 points were associated with a lost to follow-up probability of 2,2% 5,4% 9,9%, 16,4%, 15%, and 28%, respectively. The ROC curve for the validation group demonstrated a good fit (AUC: 0,67 [95% CI; 0,65-0,70]).

Conclusion

This model has a good capacity to predict a lost to follow-up outcome. Its use could help TB Programs to determine which patients are good candidates for DOT and other strategies to improve TB treatment adherence.     

Impact of Community-Based DOT on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis

Background

Poor adherence to tuberculosis (TB) treatment can lead to prolonged infectivity and poor treatment outcomes. Directly observed treatment (DOT) seeks to improve adherence to TB treatment by observing patients while they take their anti-TB medication. Although community-based DOT (CB-DOT) programs have been widely studied and promoted, their effectiveness has been inconsistent. The aim of this study was to critical appraise and summarize evidence of the effects of CB-DOT on TB treatment outcomes.

Methods

Studies published up to the end of February 2015 were identified from three major international literature databases: Medline/PubMed, EBSCO, and EMBASE. Unpublished data from the grey literature were identified through Google and Google Scholar searches.

Results

Seventeen studies involving 12,839 pulmonary TB patients (PTB) in eight randomized controlled trials (RCTs) and nine cohort studies from 12 countries met the criteria for inclusion in this review and 14 studies were included in meta-analysis. Compared with clinic-based DOT, pooled results of RCTs for all PTB cases (including smear-negative or -positive, new or retreated TB cases) and smear-positive PTB cases indicated that CB-DOT promoted successful treatment [pooled RRs (95%CIs): 1.11 (1.02–1.19) for all PTB cases and 1.11 (1.02–1.19) for smear-positive PTB cases], and completed treatment [pooled RRs (95%CIs): 1.74(1.05, 2.90) for all PTB cases and 2.22(1.16, 4.23) for smear-positive PTB cases], reduced death [pooled RRs (95%CIs): 0.44 (0.26–0.72) for all PTB cases and 0.39 (0.23–0.66) for smear-positive PTB cases], and transfer out [pooled RRs (95%CIs): 0.37 (0.23–0.61) for all PTB cases and 0.42 (0.25–0.70) for smear-positive PTB cases]. Pooled results of all studies (RCTs and cohort studies) with all PTB cases demonstrated that CB-DOT promoted successful treatment [pooled RR (95%CI): 1.13 (1.03–1.24)] and curative treatment [pooled RR (95%CI): 1.24 (1.04–1.48)] compared with self-administered treatment.

Conclusions

CB-DOT did improved TB treatment outcomes according to the pooled results of included studies in this review. Studies on strategies for implementation of patient-centered and community-centered CB-DOT deserve further attention.     

Multidrug-resistant tuberculosis treatment outcomes in Karakalpakstan, Uzbekistan: treatment complexity and XDR-TB among treatment failures

Background

A pilot programme to treat multidrug-resistant TB (MDR-TB) was implemented in Karakalpakstan, Uzbekistan in 2003. This region has particularly high levels of MDR-TB, with 13% and 40% among new and previously treated cases, respectively.

Methodology

This study describes the treatment process and outcomes for the first cohort of patients enrolled in the programme, between October 2003 and January 2005. Confirmed MDR-TB cases were treated with an individualised, second-line drug regimen based on drug susceptibility test results, while suspected MDR-TB cases were treated with a standardised regimen pending susceptibility results.

Principal Findings

Of 108 MDR-TB patients, 87 were started on treatment during the study period. Of these, 33 (38%) were infected with strains resistant to at least one second-line drug at baseline, but none had initial ofloxacin resistance. Treatment was successful for 54 (62%) patients, with 13 (15%) dying during treatment, 12 (14%) defaulting and 8 (8%) failing treatment. Poor clinical condition and baseline second-line resistance contributed to treatment failure or death. Treatment regimens were changed in 71 (82%) patients due to severe adverse events or drug resistance. Adverse events were most commonly attributed to cycloserine, ethionamide and p-aminosalicylic acid. Extensively drug resistant TB (XDR-TB) was found among 4 of the 6 patients who failed treatment and were still alive in November 2006.

Conclusions

While acceptable treatment success was achieved, the complexity of treatment and the development of XDR-TB among treatment failures are important issues to be addressed when considering scaling up MDR-TB treatment.     

Molecular Epidemiology and Clinical Characteristics of Drug-Resistant Mycobacterium tuberculosis in a Tuberculosis Referral Hospital in China

Background

Despite the large number of drug-resistant tuberculosis (TB) cases in China, few studies have comprehensively analyzed the drug resistance-associated gene mutations and genotypes in relation to the clinical characteristics of M. tuberculosis (Mtb) isolates.

Methodology/Principal Findings

We thus analyzed the phenotypic and genotypic drug resistance profiles of 115 Mtb clinical isolates recovered from a tuberculosis referral hospital in Beijing, China. We also performed genotyping by 28 loci MIRU-VNTR analysis. Socio-demographic and clinical data were retrieved from medical records and analyzed. In total, 78 types of mutations (including 42 previously reported and 36 newly identified ones) were identified in 115 Mtb clinical isolates. There was significant correlation between phenotypic and genotypic drug resistance rates for first-line anti-TB drugs (P<0.001). Genotyping revealed 101 MIRU-VNTR types, with 20 isolates (17.4%) being clustered and 95 isolates (82.6%) having unique genotypes. Higher proportion of re-treatment cases was observed among patients with clustered isolates than those with unique MIRU-VNTR genotypes (75.0% vs. 41.1%). Moreover, clinical epidemiological links were identified among patients infected by Mtb strains belonging to the same clusters, suggesting a potential of transmission among patients.

Conclusions/Significance

Our study provided information on novel potential drug resistance-associated mutations in Mtb. In addition, the genotyping data from our study suggested that enforcement of the implementation of genotyping in diagnostic routines would provide important information for better monitor and control of TB transmission.     

Use of Anti-Retroviral Therapy in Tuberculosis Patients on Second-Line Anti-TB Regimens: A Systematic Review

Introduction

Use of antiretroviral therapy (ART) during treatment of drug susceptible tuberculosis (TB) improves survival. However, data from HIV infected individuals with drug resistant TB are lacking. Second line TB drugs when combined with ART may increase drug interactions and lead to higher rates of toxicity and greater noncompliance. This systematic review sought to determine the benefit of ART in the setting of second line drug therapy for drug resistant TB.

Methods

We included individual patient data from studies that evaluated treatment of drug-resistant tuberculosis in HIV-1 infected individuals published between January 1980 and December of 2009. We evaluated the effect of ART on treatment outcomes, time to smear and culture conversion, and adverse events.

Results

Ten observational studies, including data from 217 subjects, were analyzed. Patients using ART during TB treatment had increased likelihood of cure (hazard ratio (HR) 3.4, 95% CI 1.6–7.4) and decreased likelihood of death (HR 0.4, 95% CI 0.3–0.6) during treatment for drug resistant TB. These associations remained significant in patients with a CD4 less than 200 cells/mm³ and less than 50 cells/mm³, and when correcting for drug resistance pattern.

Limitations

We identified only observational studies from which individual patient data could be drawn. Limitations in study design, and heterogeneity in a number of the outcomes of interest had the potential to introduce bias.

Discussion

While there are insufficient data to determine if ART use increases adverse drug interactions when used with second line TB drugs, ART use during treatment of drug resistant TB appears to improve cure rates and decrease risk of death. All individuals with HIV appear to benefit from ART use during treatment for TB.     

Directly Observed Therapy Reduces Tuberculosis-Specific Mortality: A Population-Based Follow-Up Study in Taipei,Taiwan

Objectives

To determine the effect of directly observed therapy (DOT) on tuberculosis-specific mortality and non-TB-specific mortality and identify prognostic factors associated with mortality among adults with culture-positive pulmonary TB (PTB).

Methods

All adult Taiwanese with PTB in Taipei, Taiwan were included in a retrospective cohort study in 2006–2010. Backward stepwise multinomial logistic regression was used to identify risk factors associated with each mortality outcome.

Results

Mean age of the 3,487 patients was 64.2 years and 70.4% were male. Among 2471 patients on DOT, 4.2% (105) died of TB-specific causes and 15.4% (381) died of non-TB-specific causes. Among 1016 patients on SAT, 4.4% (45) died of TB-specific causes and 11.8% (120) died of non-TB-specific causes. , After adjustment for potential confounders, the odds ratio for TB-specific mortality was 0.45 (95% CI: 0.30–0.69) among patients treated with DOT as compared with those on self-administered treatment. Independent predictors of TB-specific and non-TB-specific mortality included older age (ie, 65–79 and ≥80 years vs. 18–49 years), being unemployed, a positive sputum smear for acid-fast bacilli, and TB notification from a general ward or intensive care unit (reference: outpatient services). Male sex, end-stage renal disease requiring dialysis, malignancy, and pleural effusion on chest radiography were associated with increased risk of non-TB-specific mortality, while presence of lung cavities on chest radiography was associated with lower risk.

Conclusions

DOT reduced TB-specific mortality by 55% among patients with PTB, after controlling for confounders. DOT should be given to all TB patients to further reduce TB-specific mortality.     

Directly observed therapy and improved tuberculosis treatment outcomes in Thailand

Background

The World Health Organization (WHO) recommends that tuberculosis (TB) patients receive directly observed therapy (DOT). Randomized controlled trials have not consistently shown that this practice improves TB treatment success rates. In Thailand, one of 22 WHO-designated high burden TB countries, patients may have TB treatment observed by a health care worker (HCW), family member, or no one. We studied whether DOT improved TB treatment outcomes in a prospective, observational cohort.

Methods and Findings

We prospectively collected epidemiologic data about TB patients treated at public and private facilities in four provinces in Thailand and the national infectious diseases hospital from 2004–2006. Public health staff recorded the type of observed therapy that patients received during the first two months of TB treatment. We limited our analysis to pulmonary TB patients never previously treated for TB and not known to have multidrug-resistant TB. We analyzed the proportion of patients still on treatment at the end of two months and with treatment success at the end of treatment according to DOT type. We used propensity score analysis to control for factors associated with DOT and treatment outcome. Of 8,031 patients eligible for analysis, 24% received HCW DOT, 59% family DOT, and 18% self-administered therapy (SAT). Smear-positive TB was diagnosed in 63%, and 21% were HIV-infected. Of patients either on treatment or that defaulted at two months, 1601/1636 (98%) patients that received HCW DOT remained on treatment at two months compared with 1096/1268 (86%) patients that received SAT (adjusted OR [aOR] 3.8; 95% confidence interval [CI] 2.4–6.0) and 3782/3987 (95%) patients that received family DOT (aOR 2.1; CI, 1.4–3.1). Of patients that had treatment success or that defaulted at the end of treatment, 1369/1477 (93%) patients that received HCW DOT completed treatment compared with 744/1074 (69%) patients that received SAT (aOR 3.3; CI, 2.4–4.5) and 3130/3529 (89%) patients that received family DOT (aOR 1.5; 1.2–1.9). The benefit of HCW DOT compared with SAT was similar, but smaller, when comparing patients with treatment success to those with death, default, or failure.

Conclusions

In Thailand, two months of DOT was associated with lower odds of default during treatment. The magnitude of benefit was greater for DOT provided by a HCW compared with a family member. Thailand should consider increasing its use of HCW DOT during TB treatment.     

Anti-tuberculosis therapy-induced hepatotoxicity among Ethiopian HIV-positive and negative patients

Background

To assess and compare the prevalence, severity and prognosis of anti-TB drug induced hepatotoxicity (DIH) in HIV positive and HIV negative tuberculosis (TB) patients in Ethiopia.

Methodology/Principal Findings

In this study, 103 HIV positive and 94 HIV negative TB patients were enrolled. All patients were evaluated for different risk factors and monitored biochemically and clinically for development of DIH. Sub-clinical hepatotoxicity was observed in 17.3% of the patients and 8 out of the 197 (4.1%) developed clinical hepatotoxicity. Seven of the 8 were HIV positive and 2 were positive for HBsAg.

Conclusions/Significance

Sub-clinical hepatotoxicity was significantly associated with HIV co-infection (p = 0.002), concomitant drug intake (p = 0.008), and decrease in CD4 count (p = 0.001). Stepwise restarting of anti TB treatment was also successful in almost all the patients who developed clinical DIH. We therefore conclude that anti-TB DIH is a major problem in HIV-associated TB with a decline in immune status and that there is a need for a regular biochemical and clinical follow up for those patients who are at risk.     

Comparison of Treatment Outcomes of New Smear-Positive Pulmonary Tuberculosis Patients by HIV and Antiretroviral Status in a TB/HIV Clinic,Malawi

Background

Smear-positive pulmonary TB is the most infectious form of TB. Previous studies on the effect of HIV and antiretroviral therapy on TB treatment outcomes among these highly infectious patients demonstrated conflicting results, reducing understanding of important issues.

Methods

All adult smear-positive pulmonary TB patients diagnosed between 2008 and 2010 in Malawi’s largest public, integrated TB/HIV clinic were included in the study to assess treatment outcomes by HIV and antiretroviral therapy status using logistic regression.

Results

Of 2,361 new smear-positive pulmonary TB patients, 86% had successful treatment outcome (were cured or completed treatment), 5% died, 6% were lost to follow-up, 1% failed treatment, and 2% transferred-out. Overall HIV prevalence was 56%. After adjusting for gender, age and TB registration year, treatment success was higher among HIV-negative than HIV-positive patients (adjusted odds ratio 1.49; 95% CI: 1.14–1.94). Of 1,275 HIV-infected pulmonary TB patients, 492 (38%) received antiretroviral therapy during the study. Pulmonary TB patients on antiretroviral therapy were more likely to have successful treatment outcomes than those not on ART (adjusted odds ratio : 1.83; 95% CI: 1.29–2.60).

Conclusion

HIV co-infection was associated with poor TB treatment outcomes. Despite high HIV prevalence and the integrated TB/HIV setting, only a minority of patients started antiretroviral therapy. Intensified patient education and provider training on the benefits of antiretroviral therapy could increase antiretroviral therapy uptake and improve TB treatment success among these most infectious patients.     

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.     

Transmission of MDR and XDR Tuberculosis in Shanghai,China

Background

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are global health problems. We sought to determine the characteristics, prevalence, and relative frequency of transmission of MDR and XDR TB in Shanghai, one of the largest cities in Asia.

Methods

TB is diagnosed in district TB hospitals in Shanghai, China. Drug susceptibility testing for first-line drugs was performed for all culture positive TB cases, and tests for second-line drugs were performed for MDR cases. VNTR-7 and VNTR-16 were used to genotype the strains, and prior treatment history and treatment outcomes were determined for each patient.

Results

There were 4,379 culture positive TB cases diagnosed with drug susceptibility test results available during March 2004 through November 2007. 247 (5.6%) were infected with a MDR strain of M. tuberculosis and 11 (6.3%) of the 175 MDR patients whose isolate was tested for susceptibility to second-line drugs, were XDR. More than half of the patients with MDR and XDR were newly diagnosed and had no prior history of TB treatment. Nearly 57% of the patients with MDR were successfully treated.

Discussion

Transmission of MDR and XDR strains is a serious problem in Shanghai. While a history of prior anti-TB treatment indicates which individuals may have acquired MDR or XDR TB, it does not accurately predict which TB patients have disease caused by transmission of MDR and XDR strains. Therefore, universal drug susceptibility testing is recommended for new and retreatment TB cases.