Recurrent Tuberculosis Cases Research Articles

Silicosis predicts drug resistance and retreatment among tuberculosis patients in India: a secondary data analysis from Khambhat, Gujarat (2006–2022)

BackgroundIndia, with the highest global burden of tuberculosis (TB) and drug-resistant TB, aims to eliminate TB by 2025. Yet, limited evidence exists on drug resistance patterns and retreatment among patients with silico-tuberculosis. This study explores these patterns and assesses the impact of silicosis on TB retreatment in India.MethodsThis secondary data analysis stems from a larger retrospective cohort study conducted in Khambhat, Gujarat, between January 2006 and February 2022. It included 138 patients with silico-tuberculosis and 2,610 TB patients without silicosis. Data from the Nikshay TB information portal were linked with silicosis diagnosis reports from the Pneumoconiosis Board using the unique Nikshay ID as the linking variable. Drug-resistant TB was defined as resistance to any anti-TB drug recorded in Nikshay. Retreatment refers to TB patients who have previously undergone anti-TB treatment for one month or more and need further treatment. Recurrent TB denotes patients who were previously declared cured or had completed treatment but later tested positive for microbiologically confirmed TB. Multivariable logistic regression was used to determine the impact of co-prevalent silicosis on drug resistance and retreatment.ResultsPatients with silico-tuberculosis showed a higher proportion of retreatment compared to those without silicosis (55% vs. 23%, p < 0.001). Notably, 28% of patients with silico-tuberculosis were recurrent TB cases, compared to 11% among those without silicosis. Regarding drug resistance, the silico-tuberculosis group exhibited a higher rate (6% vs. 3%), largely due to rifampicin resistance (5% vs. 2%, p = 0.022). Co-prevalent silicosis was associated with a 2.5 times greater risk of drug-resistant TB (adjusted OR 2.5, 95% CI, 1.1–5.3; p = 0.021). Additionally, patients with silico-tuberculosis had a fourfold increased risk of retreatment for TB (adjusted OR 4, 95% CI, 3–6; p < 0.001).ConclusionsCo-prevalent silicosis significantly elevates the risk of drug resistance, recurrence, and retreatment among TB patients in India. This study indicates a need for improved treatment protocols and suggests that future research should focus on randomized controlled trials to evaluate appropriate anti-TB regimen and duration of therapy for this high-risk group. Given India’s goal to eliminate TB by 2025, addressing the challenges posed by silico-tuberculosis is critical.

Utilizing whole genome sequencing to delineate relapse and reinfection tuberculosis on the Canadian prairies

RATIONALE Recurrent tuberculosis (TB) accounts for 5% of the Canadian TB burden. Recurrence can occur from relapse or reinfection. Identifying reinfection has implications for developing control policies. OBJECTIVE The objectives of this study were to quantify reinfection in recurrent TB using whole genome phylogenetic and single nucleotide polymorphism (SNP) and compare with epidemiological and clinical parameters from the Canadian prairies. METHODS DNA sequences of Mycobacterium tuberculosis isolates from recurrent TB cases along with epidemiological and clinical parameters were collected from Alberta and Saskatchewan. Inclusion criteria were two or more culture positive notifications age ≥17 years. SNP and phylogenetic tree scale differences (TIP) were used to determine the relapse and reinfection categories. RESULTS Of 7,627 notifications of TB disease, 533 were recurrent. 93 pairs (180 cases) were culture positive from which 26 (50 cases) were available for sequencing. 19 cases with SNP and TIP values ≤25 and ≤.001 were classified relapse. Seven SNP and TIP values >160 and >.001 were classified reinfection. Five of seven reinfections were Indigenous cases from high TB incidence areas. The non-sequenced and sequenced pairs differed only in age. CONCLUSIONS Recurrent culture positive TB is uncommon on the Canadian prairies and is more likely to be relapse. Reinfection is more likely in Indigenous persons living in high TB incidence communities. A limitation was the risk of selection bias since only 28% of eligible cases were sequenced. Since we did not know the non-sequenced reinfection risk, we could only conclude that the non-sequenced and sequenced categories were similar.

Advantages of analysing both pairwise SNV-distance and differing SNVs between Mycobacterium tuberculosis isolates for recurrent tuberculosis cause determination.

Endogenous reactivation and exogenous reinfection are two possible causes of recurrent tuberculosis (TB). However, in some cases, precise cause determination can be challenging. In this study, we used whole genome sequencing to determine pairwise SNV distances and detect differing SNVs in initial and subsequent isolates for recurrent TB cases when the first and second episodes were caused by Mycobacterium tuberculosis (Mtb) strains with an identical spoligotype pattern. In total, 104 Mtb isolates from 36 recurrent TB and 16 single TB episode patients were included in the study. Most isolate pairs belonged to the SIT1 (n=21), SIT42 (n=9), SIT53 (n=9), and SIT254 (n=7) spoligotypes, and in 27 cases, resistance to at least one anti-TB drug was found in either isolate. Drug susceptibility was more common in the recurrent TB patient cohort, and longitudinal single TB episode isolates were more prone to be drug-resistant (p=0.03), while the association between patient cohort and spoligotype was not statistically significant (p=0.07). The pairwise SNV-distance between the longitudinal single TB episode isolates was small (0-7 SNVs). Among the recurrent TB isolates, based on the high SNV-distance (38-273 SNVs), six reinfection cases (16.7%) were identified. This distance was small (<10 SNVs) in the remaining 30 isolate pairs. Further analysis of differing SNVs revealed that 22 (61.1%) cases could be classified as possible reactivation. Notably, despite the small distance of 2-7 SNVs, initial isolates of eight patients (22.2%) had several SNVs that were not found in the second isolates; therefore, these cases were classified as reinfection with a closely related Mtb strain. No statistically significant difference in the time interval between specimen collection in the reactivation and reinfection Mtb sample groups (p=0.13) or an association between recurrence cause and drug resistance status (p=0.62) or spoligotype (p=0.79) could be detected. The mycobacterial median mutation rate of longitudinal single TB episodes and possible reactivation isolate pairs (n=37) was 0.12 SNVs/genome/year (IQR 0-0.39), and in 18 cases (48.6%), it was equal to zero. No statistically significant differences in mutation rate were found between recurrent TB and longitudinal single TB episode isolates (p=0.087), drug-susceptible and resistant isolates (p=0.37) or isolates of Beijing and other genotype families (p=0.33). Furthermore, four cases of fluoroquinolone resistance development through the acquired SNVs in the gyrA gene were identified. To conclude, this study highlighted the complexity of recurrent episode cause determination and showed the usefulness of differing SNV identification in both Mtb isolates in such cases. Expected drug susceptibility was the only discriminative factor for recurrent TB episode-causing mycobacterial strains, while no differences between reactivation and reinfection sample groups could be identified.

Estimation of the mutation rate of Mycobacterium tuberculosis in cases with recurrent tuberculosis using whole genome sequencing

The study of tuberculosis latency is problematic due to the difficulty of isolating the bacteria in the dormancy state. Despite this, several in vivo approaches have been taken to mimic the latency process. Our group has studied the evolution of the bacteria in 18 cases of recurrent tuberculosis. We found that HIV positive patients develop recurrent tuberculosis earlier, generally in the first two years (p value = 0.041). The genome of the 36 Mycobacterium tuberculosis paired isolates (first and relapsed isolates) showed that none of the SNPs found within each pair was observed more than once, indicating that they were not directly related to the recurrence process. Moreover, some IS6110 movements were found in the paired isolates, indicating the presence of different clones within the patient. Finally, our results suggest that the mutation rate remains constant during all the period as no correlation was found between the number of SNPs and the time to relapse.

Transition between Mycobacterium tuberculosis and nontuberculous mycobacteria in recurrent "tuberculosis" patients.

Recurrence of tuberculosis (TB) is still a key issue in the control of tuberculosis. The presence of nontuberculous mycobacteria (NTM) complicates the diagnosis of recurrent TB due to similarity in clinical presentation. Herein, we have used molecular genotyping methods to identify mycobacteria species, and analyzed the characteristics of patients with transition between MTB and NTM. Eighty-nine patients with recurrent tuberculosis over the past 12years were included in our analysis. We found that 9 patients had NTM infections during the study period. Six patients were infected with different mycobacterial strains, half of which were transformed from NTM to MTB, and the other half from MTB to NTM. In addition, the other 3 patients were infected with the same NTM species. Further WGS analysis showed that only one patient had a relapse and the remaining two were classified as reinfection. In conclusion, our results demonstrate that a proportion of previously diagnosed recurrent TB cases are attributed to the transition between MTB and NTM, highlighting the significance of species identification prior to initiation of treatment. The recurrence of mycobacterial diseases is majorly noted within 1year after treatment completion.

Recurrent Subclinical Tuberculosis Among Antiretroviral Therapy-Accessing Participants: Incidence, Clinical Course, and Outcomes.

Undiagnosed asymptomatic subclinical tuberculosis (TB) remains a significant threat to global TB control, accounting for a substantial proportion of cases among people living with human immunodeficiency virus (HIV)/AIDS (PLWHA). We determined incidence, progression, and outcomes of subclinical TB in antiretroviral therapy (ART)-accessing PLWHA with known previous TB in South Africa. A total of 402 adult PLWHA previously treated for TB were enrolled in the prospective Centre for the AIDS Programme of Research in South Africa TRuTH (TB Recurrence Upon TB and HIV treatment) Study. Participants were screened for TB with quarterly clinical and bacteriologic evaluation and biannual chest radiographs over 36 months. Those with suspected or confirmed TB were referred to the National TB Programme. Participants received HIV services, including ART. Incidence rate of TB was estimated using Poisson regression and descriptive statistical analyses summarized data. A total of 48 of 402 (11.9%) bacteriologically confirmed incident recurrent TB cases were identified, comprising 17 of 48 (35.4%) subclinical TB cases and 31 of 48 (64.5%) clinical TB cases. Age, sex, and body mass index were similar among subclinical, clinical, and no TB groups. Incidence rates (95% Confidence Interval [CI]) of recurrent TB overall, in clinical and subclinical TB groups were 2.3 (1.7-3.0), 1.5 (1.1-2.2), and 0.9 (0.5-1.4) per 100 person-years, respectively. In the subclinical TB group, 14 of 17 (82.4%) were diagnosed by TB culture only, 11 of 17 (64.7%) received TB treatment, and 6 of 17 (35.3%) resolved TB spontaneously. High incidence rates of recurrent subclinical TB in PLWHA highlight inadequacies of symptom-based TB screening in high TB-HIV burden settings.

Developing customized stepwise MIRU-VNTR typing for tuberculosis surveillance in Georgia.

IntroductionMycobacterial Interspersed Repetitive Units–Variable Tandem Repeats (MIRU-VNTR) typing has been widely used for molecular epidemiological studies of tuberculosis (TB). However, genotyping tools for Mycobacterium tuberculosis (Mtb) may be limiting in some settings due to high cost and workload. In this study developed a customized stepwise MIRU-VNTR typing that prioritizes high discriminatory loci and validated this method using penitentiary system cohort in the country of Georgia.MethodsWe used a previously generated MIRU-VNTR dataset from recurrent TB cases (32 cases) in Georgia and a new dataset of TB cases from the penitentiary system (102 cases) recruited from 2014 to 2015. A Hunter-Gaston Discriminatory Index (HGDI) was calculated utilizing a 24 standard loci panel, to select high discriminatory power loci, subsequently defined as the customized Georgia-specific set of loci for initial typing. The remaining loci were scored and hierarchically grouped for second and third step typing of the cohort. We then compared the processing time and costs of the customized stepwise method to the standard 24-loci method.ResultsFor the customized Georgia-specific set that was used for initial typing, 10 loci were selected with a minimum value of 0.32 to the highest HGDI score locus. Customized 10 loci (step 1) typing of 102 Mtb patient isolates revealed 35.7% clustered cases. This proportion was reduced to 19.5% after hierarchical application of 2nd and 3rd step typing with the corresponding groups of loci. Our customized stepwise MIRU-VNTR genotyping approach reduced the quantity of samples to be typed and therefore overall processing time and costs by 42.6% each.ConclusionOur study shows that our customized stepwise MIRU-VNTR typing approach is a valid alternative of standard MIRI-VNTR typing panels for molecular epidemiological investigation in Georgia that saves time, workload and costs. Similar approaches could be developed for other settings.

Study of Outcome After One Year Follow Up of Tuberculosis Patients After the Completion of Treatment in Tertiary Care Center in Western Maharashtra

Background: Tuberculosis (TB) still remains an important public health problem in India. After completion of treatment, we hardly know that what happened to these cases once they are declared as cured and released in community. Hence the study was conducted to find out the outcomes and factors associated with them. Material and methods: It was a longitudinal observational study. Patients were followed up for up to one year after completion of the treatment for weight gain, and adverse side effects. Results: In our study 91 % of the cases were cured, 1.7 % were treatment failure and 2.18 % died. All the cases of recurrent TB were cured. HIV and TB co-infection was found in 15.7 % cases. 85% of patients tolerated the anti-tubercular therapy (ATT) well. The incidence of extra pulmonary TB was 19.2 %. Out of 229 cases 16 failed to gain weight at the end of therapy. The gain in weight was statistically significant (p value &lt;0.001). The adverse outcome was seen in 20 cases. Conclusion: In our study, 91 % of the cases including 100% of recurrent Tb cases were cured because of newer RNTCP program. The incidence of extra pulmonary TB was higher than the national average. The majority (85%) of patients tolerated the anti-tubercular therapy (ATT) well. Out of 229 cases, only 16 patients failed to gain weight at the end of therapy. The gain in weight was significant predictor of good outcome in treating tuberculosis. The factors like weight gain, age, sex, place of stay or comorbidities were not associated as predictors of poor outcome. However, presence of co-morbidity like HIV and Diabetes may be associated with poor outcome but a higher sample size may be required to confirm it.

Recurrence and risk factors to the pulmonary tuberculosis patients after successful initial treatment in Beijing

Objective To analyze the recurrence and risk factors of pulmonary tuberculosis (TB) cases after successful initial treatment in Beijing. Methods A retrospective cohort study was conducted. The data of pulmonary TB cases with successful initial treatment in Beijing during 2015–2017 were collected from TB information management system. The medical records and infectious disease report cards registered or reported before December 31, 2020 were collected to find recurrent TB cases and survival analysis was performed. The recurrence of TB was estimated by using life-table method, Kaplan-Meier method was used for univariate analysis of recurrence, log-rank method was used for comparison between groups, and time-dependent Cox regression model was used for multivariate analysis. Results Of the 8 503 TB cases with successful initial treatment enrolled in Beijing, 253 (2.98%) had recurrence, with a recurrence rate density of 8.13/1000 person-years, in which 88.54% (224 cases) had recurrence within 3 years, and 3.57% had recurrence within 5 years. Multivariate analysis based on univariate analysis showed that, lung cavity (adjusted Hazard ratio, aHR =1.592, 95% CI: 1.166–2.172, P=0.003), time-dependent covariates such as age (aHR=1.004, 95% CI: 1.001–1.008, P=0.008), passive treatment (aHR=1.200, 95% CI: 1.008–1.428, P=0.040), being etiologically positive (aHR=1.154, 95% CI: 1.034–1.289, P=0.011) were the independent risk factors for TB recurrence. Conclusion We should strengthen the follow-up and management of pulmonary TB patients after successful treatment, and conduct targeted intervention for groups at high-risk for TB recurrence. Health education for the general people should be strengthened, and early detection and early treatment of TB cases should be performed to reduce TB recurrence.

Plasma Biomarkers of Risk of Tuberculosis Recurrence in HIV Co-Infected Patients From South Africa.

There is an urgent need to identify immunological markers of tuberculosis (TB) risk in HIV co-infected individuals. Previously we have shown that TB recurrence in HIV co-infected individuals on ART was associated with markers of systemic inflammation (IL-6, IL1β and IL-1Rα). Here we examined the effect of additional acute inflammation and microbial translocation marker expression on risk of TB recurrence. Stored plasma samples were drawn from the TB Recurrence upon Treatment with HAART (TRuTH) study, in which individuals with previously treated pulmonary TB were screened for recurrence quarterly for up to 4 years. Recurrent TB cases (n = 37) were matched to controls (n = 102) by original trial study arm assignment and ART start date. Additional subsets of HIV infected (n = 41) and HIV uninfected (n = 37) individuals from Improving Recurrence Success (IMPRESS) study were sampled at active TB and post successful treatment completion. Plasma concentrations of soluble adhesion molecules (sMAdCAM, sICAM and sVCAM), lipopolysaccharide binding protein (LBP) and transforming growth factor-beta (TGF-β1, TGF-β2, TGF-β3) were measured by multiplex immunoassays and ELISA. Cytokine data was square root transformed in order to reduce variability. Multivariable analysis adjusted for a number of potential confounders measured at sample time-point: age, BMI, CD4 count, viral load (VL) and measured at baseline: presence or absence of lung cavities, previous history of TB, and WHO disease stage (4 vs 3). The following analytes were associated with increased risk of TB recurrence in the multivariable model: sICAM (aOR 1.06, 95% CI: 1.02-1.12, p = 0.009), LBP (aOR 8.78, 95% CI: 1.23-62.66, p = 0.030) and TGF-β3 (aOR 1.44, 95% CI 1.01-2.05, p = 0.044). Additionally, we observed a positive correlation between LBP and sICAM (r= 0.347, p<0.0001), and LBP and IL-6, identified to be one of the strongest predictors of TB risk in our previous study (r=0.623, p=0.03). These data show that increased risk of TB recurrence in HIV infected individuals on ART is likely associated with HIV mediated translocation of microbial products and the resulting chronic immune activation.

Factors associated with diagnostic delay in recurrent TB

BackgroundRecurrent tuberculosis (TB) contributes to the burden of TB. The study was designed to explore the time of diagnostic delay and risk of delay in patients with recurrent TB in China.MethodsA total of 13,334 patients with new and recurrent TB registered in Yulin a city in China were included. The Kaplan-Meier survival curve was employed to estimate the median delay time. The mixed-effects survival model was used to identify the correlates associated with diagnostic delay. The outcome of interest in the model was"being diagnosed".ResultsWe found that 6.5% of cases with TB were attributed to recurrence. The median delay time of recurrent TB cases (73 days) was more than twice as long as that of new TB (35 days). Individuals with recurrent TB had a higher risk of diagnostic delay than new TB (HR, 0.5, 95%CI, 0.5–0.6). Factors associated with diagnostic delay differed between new TB and recurrent TB cases. Immigrants (HR, 0.5, 95%CI, 0.3–0.9), cases notified by way of recommendation (HR, 0.6, 95%CI, 0.4–0.9) and diagnosed at TB dispensary (HR, 0.4, 95%CI, 0.3–0.6) were associated with a higher risk of a longer delay for recurrent TB cases.ConclusionsThe proportion of TB cases attributed to recurrence was high. Patients with recurrent TB had a longer delay time and a higher risk of diagnostic delay. Further interventions to improve diagnostic delay should focus on screening for TB in immigrants, improving public health services at the lowest healthcare level and update of TB diagnosis and management model.

Diagnostic Performance of Xpert MTB/RIF in Bronchoalveolar Lavage of Sputum-Scarce Recurrent Pulmonary Tuberculosis Cases

Abstract Introduction Xpert MTB/RIF has greater sensitivity and specificity than smear microscopy. Bronchoalveolar lavage (BAL) is safe and valuable tool in sputum-scarce and sputum-negative tuberculosis (TB) patients. Our study evaluated the performance of Xpert in BAL specimen of sputum-scarce recurrent TB cases exclusively. Materials and Methods Sputum-scarce recurrent TB patients who underwent BAL between July 2018 and July 2019 were included. The diagnostic performance of Xpert and acid-fast bacilli (AFB) smear examination in BAL specimen was compared with liquid culture Mycobacterium TB (MTB) and composite reference standard. Results A total of 126 patients were included in the study. MTB culture was positive in 70 cases and nontuberculous mycobacteria were seen in five cases. Xpert was positive was in 63 patients. Sensitivity of Xpert and AFB smear was 84.29% (95% confidence interval [CI]: 73.62–91.89) and 18.57% (95% CI: 10.28–29.66), respectively, with p &lt; 0.001 proving the superiority of Xpert. Xpert had a specificity of 97.96 (89.15–99.95), positive predictive value of 93.65% (95% CI 85.19–97.42), and negative predictive value of 80.36% (95% CI: 70.26–87.63). Smear had a specificity of 91.84% (95% CI: 80.21–97.58) against 97.96 (89.15–99.95) of Xpert, and smear was positive in nontuberculous mycobacterium cases as well. Xpert showed no cross-reactivity between mycobacterial species. Rifampicin resistance was seen in 8 (12.69%) cases, and 21 patients had other diagnoses. Conclusion Xpert has greater sensitivity in comparison to AFB smear in BAL specimen. Sputum-scarce recurrent TB cases have a similar chance of rifampicin resistance as sputum smear-positive cases should undergo BAL for Xpert analysis routinely.

Tuberculosis relapse is more common than reinfection in Beijing, China

Background Recurrent tuberculosis (TB) is a major health problem in countries with a high TB burden. It is very necessary to elucidate the situation of recurrent TB in Beijing, capital of China. Objective To determine the proportion of recurrent tuberculosis (TB) cases and to identify relapsed or reinfected cases, as well as risk factors associated with recurrence in Beijing. Methods We conducted a retrospective study that included all TB cases in Beijing that were successfully treated from 2013 to 2015. Recurrence due to relapse or reinfection was determined using the variable number of tandem repeats (VNTR) method. Risk factors associated with recurrence were analysed. Results Tuberculosis recurred in 275 of the 4043 successfully treated TB patients, giving a recurrence rate of 6.8% (275/4043). 190 of the 275 cases were culture positive in both instances, and genotyping results for both episodes were available for 58 of these patients. The cultured isolates from 40 of the 58 recurrent cases (69%) had identical genotypic patterns in both episodes, indicating a relapse. 31% (18/58) had different genotypes, indicating reinfection by a new strain and suggested recent transmission. Those people in the 30–59 age group (p < .001), and those retreated for pulmonary TB (p < .001) were more likely to have TB recurrence. Conclusion Our results indicate that relapse was more common than reinfection in recurrent TB cases in Beijing from 2013 to 2015. Age and retreatment were found to be risk factors for TB recurrence.

Melioidosis In Suspected Recurrent Tuberculosis: A disease in disguise

Melioidosis, caused by the soil saprophyte B. pseudomallei, is a 'neglected' infectious disease in many Asian countries. It remained undiagnosed or misdiagnosed in India for long due to a lack of awareness and facilities to diagnose the disease; however, it is slowly gaining the status of an emerging disease recently. The disease is well known as a great mimicker, as the presentations are very similar to many other tropical diseases, and more importantly, to tuberculosis . A prospective observational study was conducted from January 2016 - December 2018 to find the occurance of melioidosis in patients with 'recurrent' tuberculosis infection in a tertiary health care hospital from southern India. All suspected cases of recurrent tuberculosis were simultaneously tested for the presence of B. pseudomallei, and basic demographics and clinical details were documented. Among 11,138 patients admitted with suspected tuberculosis infection, 586 (5.2%) patients were confirmed. There was recurrent Mycobacterium tuberculosis infection in 11/586 (1.8%) cases, and 7/586 (1.2%) had growth of B. pseudomallei in culture. Patients with melioidosis had either pulmonary involvement, or bone and joint infections and deep abscesses. Uncontrolled diabetes mellitus was the major risk factor. The study foreshadows the need for prompt and accurate microbiological diagnosis along with a high index of suspicion from the clinicians in countries which are endemic for both melioidosis and tuberculosis, thus ameliorating the irrational anti-tuberculosis treatment.

Urban-rural disparities in treatment outcomes among recurrent TB cases in Southern Province, Zambia

BackgroundAt least 13–20% of all Tuberculosis (TB) cases are recurrent TB. Recurrent TB has critical public health importance because recurrent TB patients have high risk of Multi-Drug Resistant TB (MDR-TB). It is critical to understand variations in the prevalence and treatment outcomes of recurrent TB between different geographical settings.The objective of our study was to estimate the prevalence of recurrent TB among TB cases and compare risk of unfavorable treatment outcomes between rural and urban settings.MethodsIn a retrospective cohort study conducted in southern province of Zambia, we used mixed effects logistic regression to asses associations between explanatory and outcome variables. Primary outcome was all-cause mortality and exposure was setting (rural/urban). Data was abstracted from the facility TB registers.ResultsOverall 3566 recurrent TB cases were diagnosed among 25,533 TB patients. The prevalence of recurrent TB was 15.3% (95% CI: 14.8 15.9) in urban and 11.3% (95% CI: 10.7 12.0) in rural areas. Death occurred in 197 (5.5%), 103 (2.9%) were lost to follow-up, and 113 (3.2%) failed treatment. Rural settings had 70% higher risk of death (adjusted OR: 1.7; 95% CI: 1.2 2.7). Risk of lost to follow-up was twice higher in rural than urban (adjusted OR: 2.0 95% CI: 1.3 3.0). Compared to HIV-uninfected, HIV-infected individuals on Antiretroviral Treatment (ART) were 70% more likely to die (adjusted OR: 1.7; 95% CI: 1.2 3.1).ConclusionRecurrent TB prevalence was generally high in both urban and rural settings. The risk of mortality and lost to follow-up was higher among rural patients. We recommend a well-organized Directly Observed Therapy strategy adapted to setting where heightened TB control activities are focused on areas with poor treatment outcomes.

Whole genome sequencing provides additional insights into recurrent tuberculosis classified as endogenous reactivation by IS6110 DNA fingerprinting

Recurrent tuberculosis (TB) after successful TB treatment occurs due to endogenous reactivation (relapse) or exogenous reinfection. We revisited the conclusions of relapse in a high TB incidence setting that were drawn on the basis of IS6110 restriction fragment length polymorphism (RFLP) analysis in a large retrospective cohort study in suburban Cape Town, South Africa. Using whole genome sequencing (WGS), we undertook pair-wise genome comparison of Mycobacterium tuberculosis strains cultured from diagnostic sputum samples collected at the index and recurrent TB episode for 25 recurrent TB cases who had been classified as relapse based on identical DNA fingerprint patterns in the earlier study. We found that paired strain genome sequences were identical or showed minimal variant differences in 22 of 25 recurrent TB cases, consistent with relapse. One showed 20 variant differences, suggestive of exogenous reinfection. Two of the 25 had mixed infections, each with the index episode strain detected as the dominant strain at recurrence in one of these patients, the minority strain harboured drug-resistance conferring mutations (rpoB, katG). In conclusion, our study highlights the additional value of WGS for investigating recurrent TB in settings with high infection pressure and closely related circulating strains, where the extent of re- and mixed infection may be underestimated.

3166 Association between HIV and early weight loss and the impact on subsequent treatment outcomes among patients with tuberculosis

OBJECTIVES/SPECIFIC AIMS: Previous research suggests that weight loss during early TB treatment (first two months of anti-TB therapy) is a predictor of poor tuberculosis (TB) treatment outcomes among HIV-negative populations, but the relationship has not been well studied in the context of HIV. We examined the association between HIV and weight change during the first two months of anti-tuberculosis treatment, and also assessed the effects of HIV and early weight change on tuberculosis (TB) treatment outcomes. METHODS/STUDY POPULATION: Adults with culture-confirmed, drug-susceptible, pulmonary TB, regardless of HIV status, were enrolled into the Regional Prospective Observational Research for Tuberculosis (RePORT)-Brazil cohort and followed on standard anti-TB therapy. For the primary analysis, we compared weight change in persons living with HIV (PLWH) and HIV-negative patients between baseline and two months using multivariable bootstrapped quantile regression and modified Poisson regression. For secondary analysis, we examined the separate effects of HIV and weight change on poor TB treatment outcome (treatment failure, TB recurrence, or death) using Cox proportional hazards regression. RESULTS/ANTICIPATED RESULTS: Among 323 participants, 45 (14%) were HIV-positive. On average, PLWH lost 0.7% (interquartile range (IQR): −5.1%, 4.4%) of their baseline body weight between baseline and two months; those without HIV gained 3.5% (IQR: 0.8%, 6.7%). After adjusting for age, sex, and baseline BMI, PLWH lost 4.1% (95% confidence interval (CI): −6.5%, −1.6%) more weight during the first two months of anti-TB treatment than HIV-negative individuals. HIV infection was associated with weight loss ≥5% (adjusted odds ratio = 9.3; 95% CI: 4.2-20.6). Regarding the secondary analysis, 14 patients had a poor TB treatment outcome: 2 treatment failures, 4 cases of recurrent TB, and 8 deaths. PLWH and patients who lost ≥5% weight had significantly increased risk of poor TB treatment outcome with hazard ratios of 8.77 (95% CI: 2.96-25.94) and 4.09 (95% CI: 1.11-15.14), respectively. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results suggest that HIV is associated with weight loss during early TB treatment, and both HIV and early weight loss were associated with poor treatment outcome. Future research should examine the potential etiologies of these findings and identify the types of interventions that would best promote weight gain during TB treatment, especially among PLWH, in order to prevent poor TB treatment outcomes.

Recurrent tuberculosis among HIV-coinfected patients: a case series from KwaZulu-Natal.

BackgroundRecurrent tuberculosis (TB) following TB treatment completion in HIV-infected individuals remains a major public health burden. We assessed the role of various risk factors in mediating the development of recurrent TB and subsequent resistance to antiretroviral therapy and anti-TB drugs.Patients and methodsWe analyzed secondary demographic, clinical, and laboratory data from medical records of five HIV-infected TB patients enrolled between 2009 and 2014 in a prospective observational study investigating TB recurrence. Paired clinical isolates of Myco-bacterium tuberculosis were typed by IS6110 restriction fragment length polymorphism analysis to determine the mechanism of TB recurrence. Plasma samples were genotyped to determine acquisition of HIV drug resistance mutations on antiretroviral treatment (ART).ResultsAll five patients were HIV-coinfected, with a previous history of TB infection and prior exposure to anti-TB treatment, and residual lung damage, and demonstrated poor treatment adherence – significant risk factors linked to the development of recurrent TB disease. Furthermore, three of the five patients had multiple episodes of drug-susceptible TB infection with subsequent drug-resistant TB infection. Genotyping of the initial and recurrent M. tuberculosis isolates demonstrated three cases of recurrent TB because of relapse and two because of reinfection. All five patients had no mutations at ART initiation; however, by the end of the study follow-up, all patients developed dual class resistance.ConclusionThis series demonstrates the complexity of recurrent TB in HIV coinfection. We highlight the challenges of managing coinfected patients and the increased propensity for the development of drug resistance. We report on the role of various risk factors mediating the development of resistance and subsequent clinical impact. This report underscores the need for structural clinical and adherence interventions for the management of complex treatment and dosing.

Relapse Versus Reinfection of Recurrent Tuberculosis Patients in a National Tuberculosis Specialized Hospital in Beijing, China.

Tuberculosis (TB) recurrence can result from either relapse of an original infection or exogenous reinfection with a new strain of Mycobacterium tuberculosis (MTB). The aim of this study was to assess the roles of relapse and reinfection among recurrent TB cases characterized by a high prevalence rate of drug-resistant TB within a hospital setting. After 58 paired recurrent TB cases were genotyped to distinguish relapse from reinfection, 37 (63.8%) were demonstrated to be relapse cases, while the remaining 21 were classified as reinfection cases. Statistical analysis revealed that male gender was a risk factor for TB reinfection, odds ratios and 95% confidence interval (OR [95% CI]: 4.188[1.012–17.392], P = 0.049). Of MTB isolates obtained from the 37 relapse cases, 11 exhibited conversion from susceptible to resistance to at least one antibiotic, with the most frequent emergence of drug resistance observed to be levofloxacin. For reinfection cases, reemergence of rifampicin-resistant isolates harboring double gene mutations, of codon 531 of rpoB and codon 306 of embB, were observed. In conclusion, our data demonstrate that relapse is a major mechanism leading to TB recurrence in Beijing Chest Hospital, a national hospital specialized in TB treatment. Moreover, male patients are at higher risk for reinfection. The extremely high rate of multidrug-resistant tuberculosis (MDR-TB) among reinfection cases reflects more successful transmission of MDR-TB strains versus non-resistant strains overall.

Recurrence of tuberculosis in a low-incidence setting: a retrospective cross-sectional study augmented by whole genome sequencing

BackgroundThe recurrence of tuberculosis (TB) disease in treated patients can serve as a marker of the efficacy of TB control programs. Recurrent disease represents either endogenous reactivation with the same strain of Mycobacterium tuberculosis due to non-compliance or inadequate therapy or exogenous reinfection with a new strain. Genotyping or whole genome sequencing (WGS) of M. tuberculosis isolates from initial and recurrent cases can differentiate between reinfection and reactivation. This study examined cases of recurrent TB in New South Wales, Australia, using genotyping and WGS.MethodsCulture-confirmed TB cases diagnosed at least 12 months apart between January 2011 and December 2016 were included. Isolates of M. tuberculosis from patients were compared using 24-locus Mycobacterial Interspersed Repetitive Unit Variable Number Tandem Repeat (MIRU-24) typing and WGS.ResultsEighteen cases of recurrent disease were identified but isolates from only 15 (83%) were available for study. MIRU-24 findings classified 13 (13/15; 87%) as reactivation and two (13%), as reinfection. Sequencing 13 cultivable paired isolates demonstrated 11 reactivations and two reinfections. There was genomic similarity in 10 out of 13 pairs while one case (1/13; 8%) had 12 SNPS differences. Two other cases (2/13;15%) had > 200 SNPs differences and were classified as reinfection. No phenotypic or genomic evidence of drug resistance was observed.ConclusionTB control programs can achieve consistently low rates of recurrent disease in low incidence settings. WGS of implicated isolates augments the differentiation between reactivation and reinfection and indicates that the majority of recurrences are due to reactivation rather than reinfection. Predominance of reactivation over reinfection indicates high-quality public health practices and a low risk of local transmission.Trial registrationThis study was approved by the Western Sydney Local Health District (WSLHD) Human Research Ethics Committee (HREC Ref: AU RED LNR/17/WMEAD/190; SSA Ref: LNR SSA/17/WMEAD/191).