Abstract Background Understanding tuberculosis (TB) transmission dynamics is necessary to interrupt disease spread. We developed a model to estimate adjusted odds ratios (ORs) for factors associated with genetic relatedness, as proxy for transmission. Methods We build upon an existing iterative model that modifies genetically linked tuberculosis case data to better represent true transmission links. We incorporate bootstrapped logistic regression to calculate adjusted ORs with confidence intervals that account for correlation from individuals present across multiple transmission pairs. We assess model performance with simulation studies and apply the method to cohort data from Lima, Peru. Results Iterative algorithm estimates resembled those from logistic regression but had larger confidence intervals, reflecting the data correlation adjustment. Transmission pairs where at least one member was >34 years had decreased transmission odds. Pairs with at least one incarcerated or male member had increased adjusted transmission odds. Conclusions We produce adjusted ORs accounting for the correlation of pairwise genetic relatedness data. These ORs are an accurate proxy for the association between covariates and transmission and further our understanding of factors associated with tuberculosis transmission.

BACKGROUND:Tuberculosis (TB) causes major morbidity and mortality among children worldwide. Isoniazid preventive therapy (IPT) protects against progression to TB disease, but its effect on preventing new TB infection remains uncertain. METHODS:We conducted a longitudinal cohort study in Lima, Peru, enrolling adults with microbiologically confirmed pulmonary TB and their household contacts (HHCs). We assessed HHCs at baseline and 6 months for TB infection using tuberculin skin testing (TST) and for TB disease through clinical evaluation. We assessed two outcomes in relation to IPT initiation: TB infection among HHCs under 5 years of age, indicated by an increase in TST induration of ≥6 mm from baseline to 6 months, and progression to TB disease among HHCs of all ages, diagnosed between 15 days and 12 months after enrollment. RESULTS:Among 666 under-5-year-olds included assessed for TST conversion, 361 (54.2%) had initiated IPT. Overall, 103 (15.5%) converted at 6 months; IPT initiation was not associated with conversion (adjusted OR 1.01; 95% CI, 0.64-1.59). Index-participant cavitary disease was associated with an increased risk of conversion. In contrast, IPT initiation was associated with reduced risk of progression to TB disease among 14,032 HHCs of all ages (adjusted HR 0.45; 95% CI, 0.32-0.64) with more pronounced efficacy among under-5s (adjusted HR 0.19; 95% CI, 0.10-0.36). CONCLUSION:IPT was not associated with reduced TST conversion among children under 5 years, but it was strongly associated with reduced progression to TB disease among HHCs of all ages.

BACKGROUND:Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB) poses significant challenges to patients, providers, and programmes. We evaluated a 9-month, 5-drug all-oral regimen implemented under operational conditions in Peru. METHODS:Between February and September 2023, we enrolled 50 adults with confirmed pulmonary MDR/RR-TB in a prospective observational study conducted within Peru's National Tuberculosis Programme. The regimen consisted of bedaquiline, linezolid, levofloxacin, clofazimine, and delamanid, administered for 9 months and potentially extended to 12 months. We describe the frequency of clinically relevant adverse events of special interest, sputum culture conversion, end-of-treatment outcomes, and changes in dyspnoea and quality of life. RESULTS:Of 50 participants, 24 (48%) were women, and median age was 28.5 years (interquartile range [IQR]: 23-59 years); 38 (76%) had cavitary disease, and 29 (58%) had bilateral disease. Adverse events were infrequent and manageable; only one case of linezolid-associated myelosuppression led to permanent drug discontinuation. Of 33 participants with positive sputum culture, 100% experienced culture conversion (median: 39 days, IQR: 31-61). Favourable end-of-treatment outcomes were observed in 40 (85.1%) (95% confidence interval: 72.3%-92.6%). Quality-of-life and dyspnoea scores improved significantly in those with treatment success. CONCLUSION:This 9-month oral regimen was effective and safe and improved patient-reported outcomes. These results support broader adoption in national TB programmes across Latin America and beyond.

BACKGROUND:Hepatotoxicity is frequent in the standard-of-care regimen for drug-susceptible tuberculosis, yet the association of each companion drug with hepatotoxicity has not been fully characterized. We examined the association between hepatotoxicity and the pharmacokinetics of rifampin and its companion drugs in standard therapy, as well as N-acetyltransferase 2 (NAT2) genotype. METHODS:We evaluated HIRIF trial participants who were randomized to receive rifampin 10, 15, or 20 mg/kg/day during the intensive phase of tuberculosis treatment. We fitted Cox proportional hazards models to identify risk factors for grade 2 or higher (grade 2+) alanine transaminase (ALT) or aspartate transaminase (AST) elevation, and considered pharmacokinetic exposure of each antituberculosis drug and NAT2 genotype as potential covariates. RESULTS:Among 168 participants with pharmacokinetic data, neither rifampin dose nor exposure were associated with the risk of grade 2+ ALT or AST elevation. Higher pyrazinamide exposure (hazard ratio [HR] 1.85 for every 50 mg*h/L AUC0-6h increase), higher isoniazid exposure (HR 1.40 for every 5 mg*h/L AUC0-6h increase), and among a subset with known NAT2 genotype, slow NAT2 acetylator status (HR 9.32 relative to fast, n=90) were associated with grade 2+ ALT or AST elevation in univariable analysis. In multivariable analysis, only pyrazinamide exposure was associated with hepatotoxicity. CONCLUSIONS:While higher pyrazinamide and isoniazid exposures and slow NAT2 acetylator status were each associated with increased hepatotoxicity, only pyrazinamide exposure was associated when considering pharmacokinetic variables together. Rifampin exposure was not associated with hepatotoxicity, supporting further evaluation of doses up to 20 mg/kg/day in a larger trial.

People who experience incarceration face a markedly elevated risk of tuberculosis (TB), yet the extent to which this vulnerability persists after release remains incompletely characterized. We analyze data from a prospective cohort study conducted in Lima, Peru, including 3,658 adults with newly diagnosed pulmonary TB and 6,335 household contacts aged 15-60. Recent incarceration (within the preceding five years) is reported by 187 (5%) index patients and 112 household contacts (1.7%). Compared with those without incarceration history, formerly incarcerated individuals are more likely to present with more severe TB disease at diagnosis and experience a higher likelihood of adverse treatment outcomes. Among individuals with available incarceration timing data, TB diagnoses cluster after release, with nearly three-quarters occurring within two years. At the household level, TB infection prevalence at enrollment is higher among contacts with a history of incarceration and among those exposed to an index patient with prior incarceration, including among those with relatively short incarceration histories. These associations persist after adjustment for demographic, clinical, and socioeconomic factors. Together, these findings indicate that TB-related vulnerability extends beyond incarceration and into the post-release period, underscoring the importance of timely diagnosis and continuity of care post release.

BACKGROUND:Youth aged 15-24 years are significantly impacted by tuberculosis globally. Their expanding social networks heighten exposure risks, potentially amplifying tuberculosis transmission, but their role in within-household transmission remains poorly understood. METHODS:A household contact cohort study in Lima, Peru (2009-2012) enrolled individuals (>15 years) with incident tuberculosis (index patients) and their household contacts (HHCs), following them for 12 months. We evaluated whether the age of index patients and HHCs modified the risk of tuberculosis infection among HHCs. Study outcomes included: (1) prevalent tuberculosis infection among child contacts (<15 years) at enrollment and (2) incident tuberculosis infection among HHCs. Whole-genome sequencing of Mycobacterium tuberculosis (Mtb) isolates from index-HHC pairs assessed whether index patient age modified the likelihood of within-household transmission, defined as ≤12 single-nucleotide polymorphism differences. RESULTS:Child contacts of youth index patients had a lower risk of prevalent tuberculosis infection than those with adult index patients (aRR = 0.77; 95% CI: .67-.87). Among index-secondary patient pairs, 62% (26/42) of pairs with a youth index patient were genetically linked, compared to 72% (48/67) of pairs with an adult index patient (P = .3). Child and youth contacts had lower incident tuberculosis infection risk at 12-month follow-up compared to adult contacts (child vs adult: HR = 0.33; 95% CI: .28-.38; youth vs adult: HR = 0.61; 95% CI: .52-.71). CONCLUSIONS:Youth play a limited role in household tuberculosis transmission. Compared to adults, youth transmitted less TB as index patients and were less likely to be infected as HHCs. Research should explore youth social interactions and community-based transmission to inform targeted prevention strategies.

BACKGROUND:Household-based studies are commonly used to investigate tuberculosis (TB) transmission and evaluate preventive interventions. These studies typically assume that household contacts (HHCs) who develop TB disease were infected by the identified index patient. However, community-acquired infections may challenge this assumption, potentially biasing findings. Here, we evaluated the proportion of genetically linked index-HHC pairs and examined whether this proportion varied based on the TB burden in the community. METHODS:We conducted a prospective cohort study in Lima, Peru, enrolling microbiologically confirmed pulmonary TB index patients and their HHCs who were followed for 1 year. Mycobacterium tuberculosis (Mtb) isolates from culture-positive index patients and HHCs underwent whole-genome sequencing (WGS). We defined index-HHC patient pairs as resulting from within-household transmission when the genetic distance between their Mtb isolates was ≤12 single nucleotide polymorphisms. To contextualize our findings, we conducted a systematic review of Mtb genotyping studies that used spoligotyping, restriction fragment length polymorphisms , mycobacterial interspersed repetitive units-variable number tandem repeats, or WGS to assess within-household TB infection transmission among index-HHC patient pairs. RESULTS:In our Lima study, among 175 index-HHC patient pairs, 109 (62%) were classified as within-household transmission. The systematic review identified 22 qualifying studies from settings with TB burdens ranging from 6.7 to 845 cases per 100 000 person-years. Studies in settings with TB incidence of ≤250 per 100 000 person-years consistently reported linkage proportions of ≥61%, whereas high-burden settings exhibited greater variability. CONCLUSIONS:Our findings suggest that, among individuals exposed to TB at home, within-household transmission predominates in moderate- or low-TB-burden settings. However, its relative contribution in high-incidence settings remains unclear.

Estimating the transmissibility of asymptomatic Mycobacterium tuberculosis infection can clarify its contribution to tuberculosis (TB) spread. We conducted a prospective cohort study in Lima, Peru, enrolling index TB patients and their household contacts (HHCs) and classifying patients by the presence of symptoms including cough, night sweats, weight loss, or fever. We followed HHCs with serial tuberculin skin testing and clinical evaluations. Among 4,296 child HHCs, adjusted estimates for baseline infection (prevalence ratio 0.62 [95%CI 0.37-1.03]), incident infection at 6 months (hazard ratio (aHR) 0.63 [95% CI 0.27-1.49]), and TB disease during 1 year of follow-up (aHR 0.74 [95% CI 0.35-1.56]) were all consistent with lower risk for infection and disease progression among HHCs of asymptomatic compared with symptomatic index patients. Although asymptomatic infections may be less transmissible than symptomatic infections, the high prevalence of asymptomatic patients in national surveys suggest that they may contribute substantially to transmission.

BACKGROUND:Diabetes mellitus (DM) increases the risk of tuberculosis (TB) progression and poor treatment outcomes. Rising global DM prevalence presents an emerging threat to TB control. We sought to determine whether DM affects TB transmissibility. METHODS:From 2009 to 2012, we enrolled 3109 microbiologically confirmed pulmonary TB patients and their 12 767 household contacts (HHCs) whom we followed for 1 year for the occurrence of TB infection as measured by a tuberculin skin test and for TB disease. We assessed the association between index patient DM and TB infection and disease occurrence in HHCs. RESULTS:The DM status of index patients was not associated with TB infection among child HHCs (adjusted prevalence rate ratio [aPRR], 1.05; 95% CI: 0.78-1.42) or with incident TB infection at 6 months among HHCs uninfected at baseline (adjusted cumulative rate ratio [aCRR], 0.85; 95% CI: 0.66-1.09). Among the 12 442 HHCs without TB disease at baseline, 368 (3.0%) developed TB during the 12-month follow-up. HHCs exposed to an index TB patient with DM had a reduced incidence of TB disease (aCRR = 0.33, 95% CI: 0.13-0.85). CONCLUSIONS:In this cohort study, diabetes mellitus in index patients did not increase the risk of TB infection among HHCs and was instead associated with a substantially lower risk of incident TB disease. These findings challenge the prevailing assumption that DM uniformly amplifies transmission due to its association with smear positivity and cavitary disease, suggesting that its influence on TB dynamics may be more complex than previously understood.

Community-based tuberculosis screening using mobile X-ray units can effectively increase case detection rates by reducing barriers to accessing services. This study evaluated the multi-armed bandit (MAB) framework, a machine learning approach, for optimizing mobile screening locations. Using simulations, we compared two MAB algorithms-Exp3 and LinUCB-with strategies based on historical case rates and random placement. The MAB algorithms continually updated site selection based on observed screening yields, and LinUCB additionally incorporated local socioeconomic indicators associated with tuberculosis rates. Over three years, assuming two mobile units serving 95 sites in Lima, Peru, 1,000 simulations demonstrated the MAB algorithms significantly reduced the average number of screenings needed to detect one individual with tuberculosis: 112 (standard deviation [SD]: 10) for Exp3 and 79 (SD: 12) for LinUCB, versus 152 (SD: 11) for random placement and 143 (SD: 11) for historic case-rate-driven placement. LinUCB performed best, achieving a 20% increase in detection efficiency by week 16 and 50% by week 40 compared to case-rate-driven placement. Overall, both MAB algorithms improved tuberculosis screening yields, emphasizing the value of data-driven approaches for optimizing mobile screening interventions. Incorporating adaptive models into screening programs may enhance targeting efficiency and offers a promising direction for policymakers and implementers seeking to optimize resource allocation in high-burden setting.

Incarcerated populations face an extremely high risk of tuberculosis (TB), yet little is known about whether this elevated risk persists after release into the community. Among 3,666 TB patients aged ≤ 60 years enrolled in a prospective cohort study in Lima, Peru, 188 (5%) reported a history of incarceration. These individuals presented with more severe disease (mean score difference = 0.25) and had a higher risk of a poor treatment outcome compared to those who had not been incarcerated (risk ratio [RR] = 2.17). Among 138 with known incarceration dates, nearly three-quarters (73%) were diagnosed within two years of release, suggesting that infections were acquired while in prison. Among 7,101 household contacts aged 15-60 years, 121 (1.7%) had a history of incarceration and these had a higher prevalence of TB infection (prevalence risk ratio [PRR] = 1.33). The prevalence risk was similarly elevated in the subset who were incarcerated for only ≤ 3 months (PRR = 1.37). Incarceration leaves a lasting imprint on TB dynamics, driving more severe disease, poorer outcomes, and elevated household infection risk after release. Prisons act as reservoirs that amplify TB epidemics, underscoring the urgent need for control strategies that bridge prison and community health systems.

Household-based studies are widely used to assess tuberculosis (TB) transmission and evaluate preventive strategies. These studies typically assume that household contacts (HHCs) who develop TB are infected by their index patient, but community-acquired infections may introduce misclassification, potentially biasing results. We aimed to quantify the extent of within-household TB transmission using genetic linkage data. We first analyzed a prospective cohort study conducted in Lima, Peru, where we enrolled microbiologically confirmed TB index patients and their HHCs, following them for one year. We applied whole-genome sequencing (WGS) and 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) genotyping to determine genetic relatedness between index-HHC pairs. We then conducted a systematic review of household TB transmission studies that applied genotyping methods to assess the proportion of genetically linked index-HHC pairs across diverse settings. In Lima, we analyzed 175 index-HHC pairs with high-quality WGS data. We classified 62% as genetically linked, suggesting household transmission. Matching proportions were higher for secondary HHC cases (68%) than co-prevalent cases (52%). Our systematic review identified 13 studies across various epidemiological settings. Among statistically robust studies, household transmission predominated in moderate TB incidence settings (<250 cases per 100,000 person-years), with genetic linkage exceeding 68%. However, in high-burden settings, within-household transmission varied widely, likely due to community-acquired infections and methodological differences. In summary, our findings suggest that in settings with ≤250 TB cases per 100,000 person-years, 20–35% of household TB cases may be misclassified due to community transmission, with lower misclassification among child and female contacts. The extent of this issue in high-burden settings remains unclear.

BACKGROUND:Variability in the pharmacokinetics (PK) of first-line antituberculosis drugs (rifampicin [RIF], isoniazid [INH], and pyrazinamide [PZA]) is high and may be influenced by pharmacogenetic polymorphism. We performed a pharmacogenetic substudy in 90 participants with PK data from the HIRIF trial in Peru. METHODS:Relevant single-nucleotide polymorphisms (SNPs) in the NAT2, SLCO1B1, AADAC, and AOX1 loci were genotyped using real-time polymerase chain reaction (PCR). RESULTS:The proportions of slow, intermediate, and fast acetylators predicted by a conventional 6-SNP NAT2 panel were 32.5%, 48.2%, and 19.2%, respectively. A single NAT2 tag SNP (rs1495741) agreed with the panel-predicted phenotype in 91% and was a better predictor of INH area under the curve (AUC). Accounting for discrepancies possibly caused by rare alleles not represented in the panel or that could be unequivocally resolved using observed AUC, sensitivity of the tag SNP was 97.7%. A previously described SNP in SLCO1B1 (rs4149032) was present at an allele frequency of 0.31 and appeared to influence RIF AUC and maximum concentration (Cmax) at a dose of 20 mg/kg, despite an extreme distribution of alleles across the randomized arms. The AADAC SNP (rs1803155) predominated in the study population and was not linked to RIF PK, although an effect could have been missed due to sample size and allele frequency. There was no association between PZA PK and a common SNP in AOX1 (rs55754655). CONCLUSIONS:A tag SNP approach may offer simpler and cheaper prediction of INH PK. Further exploration of the impact of SLCO1B1 SNPs on RIF PK is required in this and other populations. Clinical Trials Registration. NCT01408914.

Tuberculosis (TB) infectiousness decreases significantly with only a few days of treatment, but delayed diagnosis often leads to late treatment initiation. We conducted a sequential explanatory mixed methods study to understand the barriers and facilitators to prompt diagnosis among people with TB. We enrolled 100 adults who started TB treatment in the Carabayllo district of Lima, Peru, between November 2020 and February 2022 and administered a survey about their symptoms and healthcare encounters. We calculated total diagnostic delay as time from symptom onset to diagnosis. We conducted semi-structured interviews of 26 participants who had a range of delays investigating their experience navigating the health system. Interview transcripts were inductively coded for concepts related to diagnostic barriers and facilitators. Overall, 38

In Latin America, little is known about the involvement of private health-care providers in tuberculosis (TB) detection and management. We sought to gain a better understanding of current and potential roles of the private sector in delivering TB services in Peru. We conducted a mixed-methods study in North Lima, Peru. The quantitative component comprised a patient pathway analysis assessing the alignment of TB services with patient care-seeking behavior. The qualitative component comprised in-depth interviews with 18 private health-care providers and 5 key informants. We estimated that 77% of patients sought care initially at a facility with TB diagnostic capacity and 59% at a facility with TB treatment capacity. Among private facilities, 43% offered smear microscopy, 13% offered radiography, and none provided TB treatment. Among public-sector facilities, 100% offered smear microscopy, 26% offered radiography, and 99% provided TB treatment. Private providers believed they offered shorter wait times and a faster diagnosis, but they struggled with a lack of referral systems and communication with the public sector. Nonrecognition of private-sector tests by the public sector led to duplicate testing of referred patients. Although expressing willingness to collaborate with public-sector programs for diagnosis and referral, private providers had limited interest in treating TB. This study highlights the role of private providers in Peru as an entry point for TB care. Public-private collaboration is necessary to harness the potential of the private sector as an ally for early diagnosis.

Rationale: The persistent burden of tuberculosis (TB) disease emphasizes the need to identify individuals with TB for treatment and those at a high risk of incident TB for prevention. Targeting interventions toward those at high risk of developing and transmitting TB is a public health priority. Objectives: We aimed to identify characteristics of individuals involved in TB transmission in a community setting, which may guide the prioritization of targeted interventions. Methods: We collected clinical and sociodemographic data from a cohort of patients with TB in Lima, Peru. We used wholegenome sequencing data to assess the genetic distance between all possible pairs of patients; we considered pairs to be the result of a direct transmission event if they differed by three or fewer SNPs, and we assumed that the first diagnosed patient in a pair was the transmitter and the second was the recipient. We used logistic regression to examine the association between host factors and the likelihood of direct TB transmission. Measurements and Main Results: Analyzing data from 2,518 index patients with TB, we identified 1,447 direct transmission pairs. Regardless of recipient attributes, individuals less than 34 years old, males, and those with a history of incarceration had a higher likelihood of being transmitters in direct transmission pairs. Direct transmission was more likely when both patients were drinkers or smokers. Conclusions: This study identifies men, young adults, former prisoners, alcohol consumers, and smokers as priority groups for targeted interventions. Innovative strategies are needed to extend TB screening to social groups such as young adults and prisoners with limited access to routine preventive care.

This study aimed to describe the rate of tuberculosis (TB) found by using the active search strategy in teenagers and youths in three youth detention centers. TB was screened through the active search algorithm with chest X-ray, the automated reading was carried out by artificial intelligence software, the GeneXpert Ultra MTB/RIF molecular test, and clinical evaluation. A total of 640 individuals were screened, 94 (14.6%) had an abnormal chest X-ray. Of those screened, we obtained 105 GeneXpert tests of which 94 had abnormal X-rays, 9 were respiratory symptomatic and 2 were on antiretroviral treatment with TB clinical picture. We obtained 8 (8.5%) cases of TB detected with GeneXpert, 7 with abnormal radiography and 1 with normal radiography. Finally, of these 8 cases, 3 were cases of rifampicin-resistant tuberculosis (RR-TB) (42.8%). The rate of screening by active search was 1250 per 100,000 screened, 10 times higher than the rate in the general population. We recommend the inclusion of youth detention centers as target groups for systematic screening and the development of interventions to reduce the risk of TB infection.

The World Health Organization's end TB strategy promotes the use of symptom and chest radiograph screening for tuberculosis (TB) disease. However, asymptomatic early states of TB beyond latent TB infection and active disease can go unrecognized using current screening criteria. We conducted a longitudinal cohort study enrolling household contacts initially free of TB disease and followed them for the occurrence of incident TB over 1 year. Among 1,747 screened contacts, 27 (52%) of the 52 persons in whom TB subsequently developed during follow-up had a baseline abnormal radiograph. Of contacts without TB symptoms, persons with an abnormal radiograph were at higher risk for subsequent TB than persons with an unremarkable radiograph (adjusted hazard ratio 15.62 [95% CI 7.74-31.54]). In young adults, we found a strong linear relationship between radiograph severity and time to TB diagnosis. Our findings suggest chest radiograph screening can extend to detecting early TB states, thereby enabling timely intervention.