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.

Objectives To understand the perspectives of adolescents (10–19 years old), their caregivers and healthcare providers regarding factors that impact adherence to tuberculosis (TB) treatment among adolescents. Design We conducted in-depth interviews using semistructured interview guides based on the World Health Organization (WHO)’s Five Dimensions of Adherence framework, which conceptualises adherence as being related to the health system, socioeconomic factors, patient, treatment and condition. We applied framework thematic analysis. Setting Between August 2018 and May 2019, at 32 public health centres operated by the Ministry of Health in Lima, Peru. Participants We interviewed 34 adolescents who completed or were lost to follow-up from treatment for drug-susceptible pulmonary TB disease in the preceding 12 months; their primary caregiver during treatment; and 15 nurses or nurse technicians who had ≥6 months’ experience supervising TB treatment. Results Participants reported numerous treatment barriers, the most common of which were the inconvenience of health facility-based directly observed therapy (DOT), long treatment duration, adverse treatment events and symptom resolution. The support of adult caregivers was critical for helping adolescents overcome these barriers and carry out the behavioural skills (eg, coping with the large pill burden, managing adverse treatment events and incorporating treatment into daily routines) needed to adhere to treatment. Conclusion Our findings support a three-pronged approach to improve TB treatment adherence among adolescents: (1) reduce barriers to adherence (eg, home-based or community-based DOT in lieu of facility-based DOT, reducing pill burden and treatment duration when appropriate), (2) teach adolescents the behavioural skills required for treatment adherence and (3) strengthen caregivers’ ability to support adolescents.

ObjectivesPatients with tuberculosis (TB) generally are instructed to isolate at the beginning of treatment in order to prevent disease transmission. The duration of isolation varies and may be prolonged (ie, lasting 1 month or more). Few studies have examined the impact of isolation during TB treatment on adolescents, who may be more vulnerable to its negative effects.MethodsThis study took place from 2018 through 2019 in Lima, Peru, where the Ministry of Health mandates the exclusion of patients with TB from educational institutions for at least 2 months. Using semi-structured guides, we conducted individual in-depth interviews with adolescents who received treatment for drug-susceptible TB, their primary caregivers and health providers. We performed thematic analysis of the transcribed interviews.ResultsWe interviewed 85 participants: 34 adolescents, 36 caregivers and 15 healthcare workers. At the time of their TB diagnoses, 28 adolescents were in secondary, postsecondary, vocational or military school. Adolescents with drug-susceptible TB were prescribed home isolation usually for 2 (and occasionally for 1) months. Consequently, they could neither attend school nor socialise with family members or friends. Two primary themes emerged from the interviews. First, as a result of their exclusion from school, most adolescents fell behind academically and had to repeat a semester or academic year. Second, absence from school, separation from friends and loved ones, and reinforcement of TB-related stigma (arising from fear of TB transmission) harmed adolescents’ mental health.ConclusionProlonged isolation led to educational setbacks and emotional trauma among adolescents with TB. Prolonged isolation is not supported by current evidence on TB transmission and is problematic from a human rights perspective, as it violates adolescents’ rights to education and freedom of movement. Isolation recommendations should be re-evaluated to align with data on TB transmission and the principles of patient-centred care.

Abstract We followed 35 children meeting a research definition for unconfirmed tuberculosis (TB) but in whom a pediatric pulmonologist did not diagnose or treat TB. After a median follow-up of 16.4 months, most children were not diagnosed with TB following a comprehensive evaluation. However, 2 were diagnosed with TB, demonstrating high TB risk (6%; exact 95% CI, 1%–19%). In some contexts, researchers may wish to supplement these research definitions with clinical decision data and longitudinal follow-up in order to improve specificity.

Experts recommend exclusive breastfeeding from birth to six months because it protects against deadly childhood illness, including respiratory tract infections and diarrhea. We hypothesized that exclusive breastfeeding would decrease the risk of active tuberculosis (TB) in children. We analyzed cross-sectional data from 279 children in Lima, Peru aged 6 to 59 months with TB symptoms and a close adult contact with TB. Mothers self-reported breastfeeding, and children were evaluated for TB per national guidelines. To quantify the association between exclusive breastfeeding and TB, we estimated prevalence ratios using a generalized linear model with a log link, binomial distribution, and robust variance. Twenty-two percent of children were diagnosed with TB and 72% were exclusively breastfed for six months. We found no evidence that six months of exclusive breastfeeding was associated with TB disease in either bivariate analyses (prevalence ratio [PR] = 1.5; 95%CI = 0.8-2.5) or multivariable analyses adjusting for sex and socioeconomic status (adjusted PR = 1.6; 95%[CI] = 0.9-2.7). In post hoc analyses among children whose close TB contact was their mother, we found evidence of a weak positive association between breastfeeding and TB (aPR = 2.1; 95%[CI] = 0.9-4.9). This association was not apparent among children whose close contact was not the mother (aPR = 1.2; 95%[CI] = 0.6-2.4). Our results raise the possibility that children who are breastfed by mothers with TB may be at increased risk for TB, given the close contact. Due to the cross-sectional study design, these results should be interpreted with caution. If these findings are confirmed in longitudinal analyses, future interventions could aim to minimize TB transmission from mothers with TB to breastfeeding infants.

On average, Peruvian individuals are among the shortest in the world 1 . Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.

Introduction Sleep quality and physical activity can affect the mental and physical health of pregnant women and their babies in utero. Methods We investigated the feasibility of objectively assessing sleep quality and physical activity among resource-constrained, pregnant women in urban Lima, Peru. Twenty pregnant women were asked to complete written sleep logs and wear ActiSleep, a wristwatch-like device that records sleep quality (consecutive minutes of uninterrupted sleep) and physical activity (steps), for seven consecutive days. Sociodemographic data and pregnancy characteristics were also collected. Results Of twenty women, 13 (65%) had sufficient data collected for analysis. The mean age of study participants was 26.3 years (SD = 3.9), with a mean sleep duration of 6.9 h (SD = 1.4). The median time for sleep onset was 21:15. The mean time for sleep latency was 17.3 min; and wake after sleep onset was 116 min. The mean number of awakenings was 20.4 (SD = 6.7); and sleep efficiency was 77.9%. For physical activity, participants averaged of 6,029 steps per day (SD = 3,087). Discussion Objective assessment of sleep quality and physical activity among pregnant women in a resource-constrained setting was promising, despite modest data collection completeness. Wearable technology could be used in health interventions to improve sleep quality and physical activity among this population.

Tuberculosis (TB) diagnosis relies on a sputum sample, which cannot be easily obtained from all symptomatic patients. Mycobacterium tuberculosis DNA can be detected from oral swabs, a noninvasive, safe alternative sample type; however, reported sensitivities have been variable and likely depend on sample collection, processing procedures and host characteristics. We analyzed three buccal swab samples from 123 adults with culture-confirmed TB in Lima, Peru. We compared the sensitivity and specificity of two sample collection devices (OmniSwab and EasiCollect FTA cards) and examined factors associated with detection. DNA was extracted with a commercially available kit and detected via real-time PCR IS6110 amplification. Overall sensitivity for buccal samples was 51% (95% Confidence Interval [CI] 42–60%). Specificity from a single sample among healthy controls was 96.7% (95% CI 83–99.9%). Positive sputum smear and cavitary disease, correlates of disease burden, were associated with detection via buccal swab. Although we observed higher sensitivities with the Omniswab samples, this appeared to be due primarily to differences in patient characteristics (e.g., cavitary disease). Overall, our findings support the potential for a buccal sample-based TB assay. Future work should focus on assay optimization and streamlining the assay workflow.

We examined Mycobacterium tuberculosis DNA detection from buccal swab samples collected from children in Lima, Peru. DNA was extracted and amplified via real-time polymerase chain reaction. Sensitivity was 21% (95% confidence interval [CI]: 7%-42%) in 24 culture-confirmed tuberculosis cases and 4.6% (95% CI: 1%-13%) in 65 clinically diagnosed unconfirmed cases. Sensitivity was highest for smear-positive tuberculosis. Specificity was 99% in the 199 controls (95% CI: 96%-100%).

1. Velásquez GE, Brooks MB, Coit JM, Pertinez H, Vargas Vásquez D, Sánchez Garavito E, et al. Efficacy and safety of high-dose rifampin in pulmonary tuberculosis: a randomized controlled trial. Am J Respir Crit Care Med 2018;198:657–666. 2. Aarnoutse RE, Kibiki GS, Reither K, Semvua HH, Haraka F, Mtabho CM, et al. Pharmacokinetics, tolerability, and bacteriological response of rifampin administered at 600, 900, and 1,200 milligrams daily in patients with pulmonary tuberculosis. Antimicrob Agents Chemother 2017; 61:e01054-17. 3. Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter A, et al.; PanACEA Consortium. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med 2015;191:1058–1065. 4. Svensson RJ, Svensson EM, Aarnoutse RE, Diacon AH, Dawson R, Gillespie SH, et al. Greater early bactericidal activity at higher rifampicin doses revealed by modeling and clinical trial simulations. J Infect Dis 2018;218:991–999. 5. Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, et al.; PanACEA Consortium. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis 2017;17: 39–49. 6. Svensson EM, Svensson RJ, Te Brake LHM, Boeree MJ, Heinrich N, Konsten S, et al. The potential for treatment shortening with higher rifampicin doses: relating drug exposure to treatment response in patients with pulmonary tuberculosis. Clin Infect Dis 2018;67:34–41.

BACKGROUND:Stool is a promising specimen option to diagnose pediatric tuberculosis (TB), but studies have reported a wide range of test sensitivities. We conducted a meta-analysis to assess the accuracy of Xpert MTB/RIF or 'in-house' molecular tests on stool samples against culture or Xpert MTB/RIF on respiratory samples or clinically-diagnosed unconfirmed TB and aimed to identify factors that contribute to the heterogeneity of reported sensitivity.METHODS:We searched EMBASE and Pubmed databases and conference abstract books for studies reporting molecular stool testing against a clinical or microbiological reference standard among children.RESULTS:We identified 16 studies that included 2,481 children in stool test analyses. Pooled specificity was 98% [95%CI: 96-99], pooled sensitivity was 57% [95%CI: 40-72] against culture and 3% [95%CI: 2-6] among children with clinically-diagnosed, unconfirmed TB. There was much heterogeneity. Sensitivity was higher among children with a smear-positive sputum test. Rifampin resistance in stool was reported in two studies and detected in 5/14 children (36%).CONCLUSION:Our results suggest molecular stool tests have potential as diagnostic rule-in tests, but it is challenging to optimize sensitivity due to between-study variation in methodology and test procedures. Therefore, we recommend future research with rigorous study design and standardized results reporting.

Diagnostic testing for tuberculosis depends on microbiological detection of Mycobacterium tuberculosis (Mtb) in sputum. For patients unable to expectorate sputum, such as children and individuals living with HIV, this poses barriers to rapid diagnosis and treatment initiation. Therefore, this study aimed to use oral swabs as an alternative sample type for Mtb detection via molecular testing. In a pilot study, we aimed to evaluate sensitivity of Mtb detection via oral swabs using Xpert MTB/RIF ULTRA. We enrolled 33 TB cases and 30 controls from Lima, Peru, and detected Mtb from oral swabs with a sensitivity of 45% (95% confidence interval (CI) 29–62%) and specificity of 100% (95% CI 89–100%) using liquid culture of sputum as reference test. Our current protocol will need optimization, but these results support future exploration of the use of oral swabs for Mtb detection.

Peruvians are among the shortest people in the world. To understand the genetic basis of short stature in Peru, we examined an ethnically diverse group of Peruvians and identified a novel, population-specific, missense variant in FBN1 (E1297G) that is significantly associated with lower height in the Peruvian population. Each copy of the minor allele (frequency = 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). This is the largest effect size known for a common height-associated variant. This variant shows strong evidence of positive selection within the Peruvian population and is significantly more frequent in Native American populations from coastal regions of Peru compared to populations from the Andes or the Amazon, suggesting that short stature in Peruvians is the result of adaptation to the coastal environment.

Following publication of the original article [1]. The authors reported that there is a mistake in Fig. 1: the number of patients in the control group its 449 patients, instead of 455.

Rationale: We examined whether increased rifampin doses could shorten standard therapy for tuberculosis without increased toxicity. Objectives: To assess the differences across three daily oral doses of rifampin in change in elimination rate of Mycobacterium tuberculosis in sputum and frequency of rifampin-related adverse events. Methods: We conducted a blinded, randomized, controlled phase 2 clinical trial of 180 adults with new smear-positive pulmonary tuberculosis, susceptible to isoniazid and rifampin. We randomized 1:1:1 to rifampin at 10, 15, and 20 mg/kg/d during the intensive phase. We report the primary efficacy and safety endpoints: change in elimination rate of M. tuberculosis log(10) colony-forming units and frequency of grade 2 or higher rifampin-related adverse events. We report efficacy by treatment arm and by primary (area under the plasma concentration-time curve [AUC]/minimum inhibitory concentration [MIC]) and secondary (AUC) pharmacokinetic exposure. Measurements and Main Results: Each 5-mg/kg/d increase in rifampin dose resulted in differences of -0.011 (95% confidence interval, -0.025 to +0.002; P = 0.230) and -0.022 (95% confidence interval, -0.046 to -0.002; P = 0.022) log(10) cfu/ml/d in the modified intention-to-treat and per-protocol analyses, respectively. The elimination rate in the per-protocol population increased significantly with rifampin AUC(0-6) (P = 0.011) but not with AUC(0-6)/MIC99.9 (P = 0.053). Grade 2 or higher rifampin-related adverse events occurred with similar frequency across the three treatment arms: 26, 31, and 23 participants (43.3%, 51.7%, and 38.3%, respectively) had at least one event (P = 0.7092) up to 4 weeks after the intensive phase. Treatment failed or disease recurred in 11 participants (6.1%). Conclusions: Our findings of more rapid sputum sterilization and similar toxicity with higher rifampin doses support investigation of increased rifampin doses to shorten tuberculosis treatment.

The enteric string test can be used to obtain a specimen for microbiological confirmation of tuberculosis in children, but it is not widely used for this. The aim of this analysis to evaluate this approach in children with tuberculosis symptoms.

Evidence has existed for decades that higher doses of rifampin may be more effective, but potentially more toxic, than standard doses used in tuberculosis treatment. Whether increased doses of rifampin could safely shorten treatment remains an open question.

BACKGROUND:Introducing solids foods to infants before 6 months has been associated with adverse long-term health outcomes. Studies and surveys frequently use maternal report to identify the age when infants start solid foods.OBJECTIVE:To address the accuracy of maternal report at 1 year postpartum regarding introduction of solid foods.METHODS:Between 2008 and 2009, the authors enrolled mothers of healthy term singletons at an urban Boston hospital within 72 hours of giving birth. We called mothers monthly for 6 months and asked if they had given their baby solid foods in the previous month. At 1 year, we contacted mothers again and asked when they first gave solid foods; answers at 1 year were compared with the data collected monthly.RESULTS:The authors analyzed data on 157 women, all of whom had, according to monthly responses, started solid foods before 6 months. At 1 year, only 14% (22/157) of reports matched data recorded monthly. Although 100% of women introduced solids before 6 months, at 1 year, 41.4% reported starting solids at 6 months.CONCLUSIONS:Among women who started feeding solids before 6 months, most did not give an accurate response at 1 year. Most said they started giving solids later than they did. Maternal report may not be the best way to collect such data, and health outcomes based on such data may be biased toward the null.