Undernourished Household Contacts Are at Increased Risk of Tuberculosis (TB) Disease, but not TB Infection- a Multicenter Prospective Cohort Analysis.

Undernutrition is the leading risk factor for tuberculosis (TB) globally and in India. This multicenter prospective cohort analysis from India suggests that undernutrition is associated with increased risk of TB disease but not TB infection among household contacts of persons with TB.

Glycated Hemoglobin Trajectories and Their Association With Treatment Outcomes Among Patients With Pulmonary TB in India: A Prospective Cohort Study.

BACKGROUND: Transient hyperglycemia is seen commonly during TB treatment, yet its association with unfavorable treatment outcomes is unclear. RESEARCH QUESTION: Does an association exist between glycated hemoglobin (HbA1c) trajectories and TB treatment outcomes? STUDY DESIGN AND METHODS: Adults with pulmonary TB were evaluated prospectively for 18 months after the second HbA1c measurement. HbA1c trajectories during the initial 3 months of treatment were defined as follows: persistent euglycemia, HbA1c < 6.5% at baseline and 3-month follow-up; persistent hyperglycemia, HbA1c ≥ 6.5% at baseline and 3-month follow-up; transient hyperglycemia, HbA1c ≥ 6.5% at baseline and < 6.5% at 3-month follow-up; incident hyperglycemia, HbA1c < 6.5% at baseline and ≥ 6.5% at 3-month follow-up. Multivariable Poisson regression was used to measure the association between HbA1c trajectories and unfavorable treatment outcomes of failure, recurrence, and all-cause mortality. RESULTS: Of the 587 participants, 443 participants (76%) had persistent euglycemia, 118 participants (20%) had persistent hyperglycemia, and 26 participants (4%) had transient hyperglycemia. One participant had incident hyperglycemia and was excluded. Compared with participants with persistent euglycemia, those with transient hyperglycemia showed a twofold higher risk of experiencing an unfavorable treatment outcome (adjusted incidence rate ratio [aIRR], 2.07; 95% CI, 1.04-4.15) after adjusting for confounders including diabetes treatment, and BMI; we did not find a significant association with persistent hyperglycemia (aIRR, 1.64; 95% CI, 0.71-3.79). Diabetes treatment was associated with a significantly lower risk of unfavorable treatment outcomes (aIRR, 0.38; 95% CI, 0.15-0.95). INTERPRETATION: Transient hyperglycemia and lack of diabetes treatment was associated with a higher risk of unfavorable treatment outcomes in adults with pulmonary TB.

Early Microbiologic Markers of Pulmonary Tuberculosis Treatment Outcomes.

Rationale: Earlier biomarkers of pulmonary tuberculosis (PTB) treatment outcomes are critical to monitor shortened anti-TB treatment (ATT). Objectives: To identify early microbiologic markers of unfavorable TB treatment outcomes. Methods: We performed a subanalysis of 2 prospective TB cohort studies conducted from 2013 to 2019 in India. We included participants aged ⩾18 years who initiated 6-month ATT for clinically or microbiologically diagnosed drug-sensitive PTB and completed at least one follow-up visit. Sputum specimens were subjected to a baseline Xpert Mycobacterium tuberculosis/rifampin (MTB/RIF) assay, acid-fast bacilli (AFB) microscopy and liquid and solid cultures, and serial AFB microscopy and liquid and solid cultures at weeks 2, 4, and 8. Poisson regression was used to assess the impact of available microbiologic markers (test positivity, smear grade, time to detection, and time to conversion) on a composite outcome of failure, recurrence, or death by 18 months after the end of treatment. Models were adjusted for age, sex, nutritional status, diabetes, smoking, alcohol consumption, and regimen type. Results: Among 1,098 eligible cases, there were 251 (22%) adverse TB treatment outcomes: 127 (51%) treatment failures, 73 (29%) recurrences, and 51 (20%) deaths. The primary outcome was independently associated with the Xpert MTB/RIF assay (medium-positive adjusted incidence rate ratio [aIRR], 1.91; 95% confidence interval [CI], 1.07-3.40; high-positive aIRR, 2.51; 95% CI, 1.41-4.46), positive AFB smear (aIRR, 1.48; 95% CI, 1.06-2.06), and positive liquid culture (aIRR, 1.98; 95% CI, 1.21-3.23) at baseline; Week 2 positive liquid culture (aIRR, 1.47; 95% CI, 1.04-2.09); and Week 8 positive AFB smear (aIRR, 1.63; 95% CI, 1.06-2.50) and positive liquid culture (aIRR, 1.54; 95% CI, 1.07-2.22). There was no evidence of Mycobacterium tuberculosis growth in the Mycobacterium Growth Indicator Tube at Week 4 conferring a higher risk of adverse outcomes (aIRR, 1.25; 95% CI, 0.89-1.75). Conclusions: Our analysis identifies Week 2 respiratory mycobacterial culture as the earliest microbiologic marker of unfavorable PTB treatment outcomes.

Comparative immune responses to Mycobacterium tuberculosis in people with latent infection or sterilizing protection.

There is great need for vaccines against tuberculosis (TB) more efficacious than the licensed BCG. Our goal was to identify new vaccine benchmarks by identifying immune responses that distinguish individuals able to eradicate the infection (TB-resisters) from individuals with latent infection (LTBI-participants). TB-resisters had higher frequencies of circulating CD8+ glucose monomycolate (GMM)+ Granzyme-B+ T cells than LTBI-participants and higher proportions of polyfunctional conventional and nonconventional T cells expressing Granzyme-B and/or PD-1 after ex vivo M. tuberculosis stimulation of blood mononuclear cells. LTBI-participants had higher expression of activation markers and cytokines, including IL10, and IFNγ. An exploratory analysis of BCG-recipients with minimal exposure to TB showed absence of CD8+GMM+Granzyme-B+ T cells, lower or equal proportions of Granzyme-B+PD-1+ polyfunctional T cells than TB-resisters and higher or equal than LTBI-participants. In conclusion, high Granzyme-B+PD-1+ T cell responses to M. tuberculosis and, possibly, of CD8+GMM+Granzyme-B+ T cells may be desirable for new TB vaccines.

A Cross-Sectional Analysis of the Nicotine Metabolite Ratio and Its Association with Sociodemographic and Smoking Characteristics among People with HIV Who Smoke in South Africa.

The nicotine metabolite ratio (NMR) is associated with race/ethnicity but has not been evaluated among smokers in the African region. We conducted a cross-sectional analysis of baseline data from a large randomized, controlled trial for smoking cessation among people with HIV (PWH) in South Africa. Urine samples were analyzed for the NMR and evaluated as a binary variable using a cutoff value of the fourth quartile to determine the fastest metabolizers. The median NMR was 0.31 (IQR: 0.31, 0.32; range: 0.29, 0.57); the cut-point for fast metabolizers was ≥0.3174 ng/mL. A high NMR was not associated with the number of cigarettes per day (OR = 1.10, 95% CI: 0.71, 1.70, p = 0.66) but was associated with 40% lower odds of a quit attempt in the past year (OR = 0.69; 95% CI: 0.44, 1.07, p = 0.09) and alcohol use (OR = 0.59, 95% CI: 0.32, 1.06, p = 0.07). No association was seen with marijuana or HIV clinical characteristics. As we found only minimal variability in the NMR and minimal associations with intensity of smoking, NMR may be of limited clinical value in this population, although it may inform which individuals are less likely to make a quit attempt.

Assessing Pretomanid for Tuberculosis (APT), a Randomized Phase 2 Trial of Pretomanid-Containing Regimens for Drug-Sensitive Tuberculosis: 12-Week Results.

Rationale: Pretomanid is a new nitroimidazole with proven treatment-shortening efficacy in drug-resistant tuberculosis. Pretomanid-rifamycin-pyrazinamide combinations are potent in mice but have not been tested clinically. Rifampicin, but not rifabutin, reduces pretomanid exposures. Objectives: To evaluate the safety and efficacy of regimens containing pretomanid-rifamycin-pyrazinamide among participants with drug-sensitive pulmonary tuberculosis. Methods: A phase 2, 12-week, open-label randomized trial was conducted of isoniazid and pyrazinamide plus 1) pretomanid and rifampicin (arm 1), 2) pretomanid and rifabutin (arm 2), or 3) rifampicin and ethambutol (standard of care; arm 3). Laboratory values of safety and sputum cultures were collected at Weeks 1, 2, 3, 4, 6, 8, 10, and 12. Time to culture conversion on liquid medium was the primary outcome. Measurements and Main Results: Among 157 participants, 125 (80%) had cavitary disease. Median time to liquid culture negativity in the modified intention-to-treat population (n = 150) was 42 (arm 1), 28 (arm 2), and 56 (arm 3) days (P = 0.01) (adjusted hazard ratio for arm 1 vs. arm 3, 1.41 [95% confidence interval (CI), 0.93-2.12; P = 0.10]; adjusted hazard ratio for arm 2 vs. arm 3, 1.89 [95% CI, 1.24-2.87; P = 0.003]). Eight-week liquid culture conversion was 79%, 89%, and 69%, respectively. Grade ≥3 adverse events occurred in 3 of 56 (5%), 5 of 53 (9%), and 2 of 56 (4%) participants. Six participants were withdrawn because of elevated transaminase concentrations (five in arm 2, one in arm 1). There were three serious adverse events (arm 2) and no deaths. Conclusions: Pretomanid enhanced the microbiologic activity of regimens containing a rifamycin and pyrazinamide. Efficacy and hepatic adverse events appeared highest with the pretomanid and rifabutin-containing regimen. Whether this is due to higher pretomanid concentrations merits exploration. Clinical trial registered with www.clinicaltrials.gov (NCT02256696).

Impact of Undernutrition on Tuberculosis Treatment Outcomes in India: A Multicenter, Prospective, Cohort Analysis.

BACKGROUND: Undernutrition is the leading risk factor for tuberculosis (TB) globally. Its impact on treatment outcomes is poorly defined. METHODS: We conducted a prospective cohort analysis of adults with drug-sensitive pulmonary TB at 5 sites from 2015-2019. Using multivariable Poisson regression, we assessed associations between unfavorable outcomes and nutritional status based on body mass index (BMI) nutritional status at treatment initiation, BMI prior to TB disease, stunting, and stagnant or declining BMI after 2 months of TB treatment. Unfavorable outcome was defined as a composite of treatment failure, death, or relapse within 6 months of treatment completion. RESULTS: Severe undernutrition (BMI <16 kg/m2) at treatment initiation and severe undernutrition before the onset of TB disease were both associated with unfavorable outcomes (adjusted incidence rate ratio [aIRR], 2.05; 95% confidence interval [CI], 1.42-2.91 and aIRR, 2.20; 95% CI, 1.16-3.94, respectively). Additionally, lack of BMI increase after treatment initiation was associated with increased unfavorable outcomes (aIRR, 1.81; 95% CI, 1.27-2.61). Severe stunting (height-for-age z score <-3) was associated with unfavorable outcomes (aIRR, 1.52; 95% CI, 1.00-2.24). Severe undernutrition at treatment initiation and lack of BMI increase during treatment were associated with a 4- and 5-fold higher rate of death, respectively. CONCLUSIONS: Premorbid undernutrition, undernutrition at treatment initiation, lack of BMI increase after intensive therapy, and severe stunting are associated with unfavorable TB treatment outcomes. These data highlight the need to address this widely prevalent TB comorbidity. Nutritional assessment should be integrated into standard TB care.

Amniotic membrane attenuates heterotopic ossification following high-dose bone morphogenetic protein-2 treatment of segmental bone defects.

Treatment of large bone defects with supraphysiological doses of bone morphogenetic protein-2 (BMP-2) has been associated with complications including heterotopic ossification (HO), inflammation, and pain, presumably due to poor spatiotemporal control of BMP-2. We have previously recapitulated extensive HO in our rat femoral segmental defect model by treatment with high-dose BMP-2 (30 µg). Using this model and BMP-2 dose, our objective was to evaluate the utility of a clinically available human amniotic membrane (AM) around the defect space for guided bone regeneration and reduction of HO. We hypothesized that AM surrounding collagen sponge would attenuate heterotopic ossification compared with collagen sponge alone. In vitro, AM retained more BMP-2 than a synthetic poly(ε-caprolactone) membrane through 21 days. In vivo, as hypothesized, the collagen + AM resulted in significantly less heterotopic ossification and correspondingly, lower total bone volume (BV), compared with collagen sponge alone. Although bone formation within the defect was delayed with AM around the defect, by 12 weeks, defect BVs were equivalent. Torsional stiffness was significantly reduced with AM but was equivalent to that of intact bone. Collagen + AM resulted in the formation of dense fibrous tissue and mineralized tissue, while the collagen group contained primarily mineralized tissue surrounded by marrow-like structures. Especially in conjunction with high doses of growth factor delivered via collagen sponge, these findings suggest AM may be effective as an overlay adjacent to bone healing sites to spatially direct bone regeneration and minimize heterotopic ossification.

Sex Differences in TB Clinical Presentation, Drug Exposure, and Treatment Outcomes in India.

BACKGROUND: The role of sex differences in clinical presentation, TB drug pharmacokinetic variables, and treatment outcomes is unclear. RESEARCH QUESTION: What is the effect of sex on TB disease severity, drug exposure, and treatment outcome? STUDY DESIGN AND METHODS: This study was a prospective cohort study conducted in India. It assessed TB disease severity; risk of unfavorable treatment outcomes (failure, recurrence, and death) according to sex; and risk factors for unfavorable outcomes stratified according to sex. Effects of sex on the pharmacokinetic variables (maximum concentration and area under the curve) of rifampicin, isoniazid, and pyrazinamide were estimated by using noncompartmental analyses. RESULTS: Of 1,541 people with microbiologically confirmed TB, 567 (37%) were women. Women had a lower risk of high mycobacterial burden (smear grade ≥ 2 and/or time to detection < 7 days) with an adjusted OR of 0.70 (95% CI, 0.56-0.87). Among the 744 participants who were followed up prospectively, 261 (35%) were women. Women had a lower risk of unfavorable treatment outcomes (adjusted incidence risk ratio, 0.60; 95% CI, 0.43-0.85), mostly because recurrence was lower (adjusted incidence risk ratio, 0.45; 95% CI, 0.23-0.86). Isoniazid (but not rifampicin and pyrazinamide) maximum concentration and area under the curve were significantly higher among women (P < .01) than men. Among women, unfavorable outcomes were more likely among those with cavitary disease, but among men, increased risk of unfavorable outcomes was associated with alcohol use, higher BMI, and lower glycated hemoglobin level. INTERPRETATION: Women present with lower mycobacterial burden, achieve higher TB drug exposure, and are less likely to have unfavorable treatment outcomes than men. Strategies to improve TB treatment success should take into account sex differences in risk factors for unfavorable outcomes.

Virological failure among people living with HIV receiving second-line antiretroviral therapy in Pune, India.

BACKGROUND: The number of people receiving second-line antiretroviral therapy (ART) has increased as global access to ART has expanded. Data on the burden and factors associated with second-line ART virologic failure (VF) from India remain limited. METHODS: We conducted cross-sectional viral load (VL) testing among adults (≥ 18 years) who were registered at a publicly funded ART center in western India between 2014 and 2015 and had received second-line ART for at least 6 months. Sociodemographic and clinical characteristics were abstracted from routinely collected programmatic data. Logistic regression evaluated factors associated with VF (defined as VL > 1000 copies/mL). RESULTS: Among 400 participants, median age was 40 years (IQR 34-44), 71% (285/400) were male, and 15% (59/400) had VF. Relative to participants without VF, those with VF had lower median CD4 counts (230 vs 406 cells/mm3, p < 0.0001), lower weight at first-line failure (49 vs 52 kg, p = 0.003), were more likely to have an opportunistic infection (17% vs 3%, p < 0.0001) and less likely to have optimal ART adherence (71% vs 87%, p = 0.005). In multivariable analysis, VF was associated with opportunistic infection (aOR, 4.84; 95% CI, 1.77-13.24), lower CD4 count (aOR 4.15; 95% CI, 1.98-8.71) and lower weight at first-line failure (aOR, 2.67; 95% CI, 1.33-5.34). CONCLUSIONS: We found second-line VF in about a sixth of participants in our setting, which was associated with nearly fivefold increased odds in the context of opportunistic infection. Weight could be a useful clinical indicator for second-line VF.

The Association of Gestational Diabetes with HIV Infection and Tuberculosis in Indian Women.

Infection of HIV is associated with an increased diabetes risk, which also increases tuberculosis risk. It is unknown if similar associations exist with gestational diabetes (GDM). We screened pregnant women living with and without HIV for GDM using oral glucose tolerance testing. In a subgroup of women with latent tuberculosis (positive interferon-gamma [IFN-γ] release assay), we used supernatants from tuberculosis antigen tubes to compare cytokine levels from women with and without GDM, matched by age and HIV status. Of 234 women, 21 (9%) had GDM, 13.9% living with HIV, and 6.5% without HIV (P = 0.06). Compared with women without GDM, women with GDM had lower median IFN-γ (19.1 versus 141.9 pg/mL, P = 0.03) and interleukin-2 (18.7 versus 249 pg/mL, P < 0.01). Our study suggests that HIV infection is associated with an increased risk of GDM, which is associated with decreased Mycobacterium tuberculosis immune responses. Gestational diabetes screening should be prioritized in tuberculosis-endemic countries, especially in women living with HIV.

Tuberculosis (TB) Aftermath: study protocol for a hybrid type I effectiveness-implementation non-inferiority randomized trial in India comparing two active case finding (ACF) strategies among individuals treated for TB and their household contacts.

BACKGROUND: Approximately 7% of all reported tuberculosis (TB) cases each year are recurrent, occurring among people who have had TB in the recent or distant past. TB recurrence is particularly common in India, which has the largest TB burden worldwide. Although patients recently treated for TB are at high risk of developing TB again, evidence around effective active case finding (ACF) strategies in this population is scarce. We will conduct a hybrid type I effectiveness-implementation non-inferiority randomized trial to compare the effectiveness, cost-effectiveness, and feasibility of two ACF strategies among individuals who have completed TB treatment and their household contacts (HHCs). METHODS: We will enroll 1076 adults (≥ 18 years) who have completed TB treatment at a public TB unit (TU) in Pune, India, along with their HHCs (averaging two per patient, n = 2152). Participants will undergo symptom-based ACF by existing healthcare workers (HCWs) at 6-month intervals and will be randomized to either home-based ACF (HACF) or telephonic ACF (TACF). Symptomatic participants will undergo microbiologic testing through the program. Asymptomatic HHCs will be referred for TB preventive treatment (TPT) per national guidelines. The primary outcome is rate per 100 person-years of people diagnosed with new or recurrent TB by study arm, within 12 months following treatment completion. The secondary outcome is proportion of HHCs < 6 years, by study arm, initiated on TPT after ruling out TB disease. Study staff will collect socio-demographic and clinical data to identify risk factors for TB recurrence and will measure post-TB lung impairment. In both arms, an 18-month "mop-up" visit will be conducted to ascertain outcomes. We will use the RE-AIM framework to characterize implementation processes and explore acceptability through in-depth interviews with index patients, HHCs and HCWs (n = 100). Cost-effectiveness will be assessed by calculating the incremental cost per TB case detected within 12 months and projected for disability-adjusted life years averted based on modeled estimates of morbidity, mortality, and time with infectious TB. DISCUSSION: This novel trial will guide India's scale-up of post-treatment ACF and provide an evidence base for designing strategies to detect recurrent and new TB in other high burden settings. TRIAL REGISTRATION: NCT04333485 , registered April 3, 2020. CTRI/2020/05/025059 [Clinical Trials Registry of India], registered May 6 2020.

Virological failure and treatment switch after ART initiation among people living with HIV with and without routine viral load monitoring in Asia.

INTRODUCTION: Viral load (VL) testing is still challenging to monitor treatment responses of antiretroviral therapy (ART) for HIV treatment programme in Asia. We assessed the association between routine VL testing and virological failure (VF) and determine factors associated with switching to second-line regimen. METHODS: Among 21 sites from the TREAT Asia HIV Observational Database (TAHOD), people living with HIV (PLHIV) aged ≥18 years initiating ART from 2003 to 2021 were included. We calculated the average number of VL tests per patient per year between the date of ART initiation and the most recent visit. If the median average number of VL tests was ≥ 0.80 per patient per year, the site was classified as a routine VL site. A site with a median < 0.80 was classified into the non-routine VL sites. VF was defined as VL ≥1000 copies/ml during first-line therapy. Factors associated with VF were analysed using generalized estimating equations with Poisson distribution. RESULTS: Of 6277 PLHIV starting ART after 2003, 3030 (48%) were from 11 routine VL testing sites and 3247 (52%) were from 10 non-routine VL testing sites. The median follow-up was 9 years (IQR 5-13). The median age was 35 (30-42) years; 68% were male and 5729 (91%) started non-nucleoside reverse-transcriptase inhibitor-based regimen. The median pre-ART CD4 count in PLHIV from routine VL sites was lower compared to non-routine VL sites (144 vs. 156 cells/mm3 , p <0.001). Overall, 1021 subsequent VF at a rate of 2.15 (95% CI 2.02-2.29) per 100 person-years (PY). VF was more frequent at non-routine VL sites (adjusted incidence rate ratio 2.85 [95% CI 2.27-3.59]) compared to routine VL sites. Other factors associated with an increased rate of VF were age <50 years and CD4 count <350 cells/mm3 . A total of 817 (13%) patients switched to second-line regimen at a rate of 1.44 (95% CI 1.35-1.54) per 100 PY. PLHIV at routine VL monitoring sites were at higher risk of switching than those at non-routine VL sites (adjusted sub-hazard ratio 1.78 95% CI [1.17-2.71]). CONCLUSIONS: PLHIV from non-routine VL sites had a higher incidence of persistent VF and a low switching regimen rate, reflecting possible under-utilized VL testing.

Smokeless tobacco use and oral potentially malignant disorders among people living with HIV (PLHIV) in Pune, India: Implications for oral cancer screening in PLHIV.

INTRODUCTION: In India, smokeless tobacco (SLT) is a predominant form of tobacco used among people living with HIV (PLHIV). Despite SLT being a risk factor for oral potentially malignant disorders (OPMDs), no prior studies have quantified the association of OPMDs with SLT use among PLHIV. This limits the planning of preventive and control strategies for oral cancer among PLHIV, who are at higher risk for the disease. METHODS: We enrolled 601 PLHIV and 633 HIV-uninfected individuals in an oral cancer screening study at BJ Government Medical College, Pune, India. Oral cavity images were collected using an m-Health application and reviewed by three clinicians. Participants with two clinician positive diagnoses were deemed to have suspected OPMDs. Prevalence ratios (PRs) were used to quantify the association between suspected OPMDs and SLT use among PLHIV. PRs for current SLT users, across HIV status and use duration were also estimated. Corrected PRs were obtained by modifying the maximum likelihood estimation. Models were adjusted for age, smoking, alcohol use and CD4 counts. RESULTS: Of those enrolled, 61% were men, median age was 36 years (IQR: 28-44), and 33% currently use SLT. Proportion of current SLT users was similar across PLHIV and HIV-uninfected groups but use duration for current SLT use was higher among PLHIV(p<0.05). Among PLHIV, current SLT users had a 5-times (95% CI:3.1-7.0) higher prevalence of suspected OPMDs, compared to non-users. Relative to HIV uninfected individuals with the same SLT use duration, significant associations with suspected OPMDs were seen for PLHIV with<10 use years (PR: 3.5, 95% CI: 1.5-8.1) but not for PLHIV with≥10 use years (PR: 1.3, 95% CI: 0.9-1.8). CONCLUSION: PLHIV that are current SLT users are at high risk of OPMDs and potentially oral cancer. The development of strategies for screening, early detection, and management of OPMDs must be considered for this group.

Burden of COVID-19 and case fatality rate in Pune, India: an analysis of the first and second wave of the pandemic.

Objective: To assess trends in case incidence and fatality rate between the first and second waves, we analyzed programmatic COVID-19 data from Pune city, an epicenter of COVID-19 cases in India. Method: The trends of cases incidence, time-to-death and case fatality rate (CFR) were analyzed. Poisson regression models adjusted for age and gender were used to determine the independent effect of pandemic waves on mortality. Results: Of 465 192 COVID-19 cases, 162 182 (35%) were reported in the first wave and 4146 (2.5%) deaths, and 275 493 (59%) in the second wave and 3184 (1.1%) deaths (P<0.01). The overall CFR was 1.16 per 1000 person-days (PD), which declined from 1.80 per 1000 PD during the first wave to 0.77 per 1000 PD in the second. The risk of death was 1.49 times higher during the first wave (adjusted CFR ratio (aCFRR)1.49; 95% CI: 1.37-1.62) and 35% lower in the second wave (aCFRR 0.65; 95% CI: 0.59-0.70). Conclusion: The burden of COVID-19 cases and deaths was more significant in the second wave; however, the CFR declined as the pandemic progressed. Nevertheless, investigating new therapies and implementing mass vaccination against COVID-19 are urgently needed.

Association of national and regional lockdowns with COVID-19 infection rates in Pune, India.

Assessing the impact of lockdowns on COVID-19 incidence may provide important lessons for management of pandemic in resource-limited settings. We examined growth of incident confirmed COVID-19 patients before, during and after lockdowns during the first wave in Pune city that reported the largest COVID-19 burden at the peak of the pandemic. Using anonymized individual-level data captured by Pune's public health surveillance program between February 1st and September 15th 2020, we assessed weekly incident COVID-19 patients, infection rates, and epidemic curves by lockdown status (overall and by sex, age, and population density) and modelled the natural epidemic using the compartmental model. Effect of lockdown on incident patients was assessed using multilevel Poisson regression. We used geospatial mapping to characterize regional spread. Of 241,629 persons tested for SARS-CoV-2, 64,526 (26%) were positive, contributing to an overall rate of COVID-19 disease of 267·0 (95% CI 265·3-268·8) per 1000 persons. The median age of COVID-19 patients was 36 (interquartile range [IQR] 25-50) years, 36,180 (56%) were male, and 9414 (15%) were children < 18 years. Epidemic curves and geospatial mapping showed delayed peak of the patients by approximately 8 weeks during the lockdowns as compared to modelled natural epidemic. Compared to a subsequent unlocking period, incident COVID-19 patients were 43% lower (IRR 0·57, 95% CI 0·53-0·62) during India's nationwide lockdown and were 22% lower (IRR 0·78, 95% CI 0.73-0.84) during Pune's regional lockdown and was uniform across age groups and population densities. Both national and regional lockdowns slowed the COVID-19 infection rates in population dense, urban region in India, underscoring its impact on COVID-19 control efforts.

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial.

BACKGROUND: Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. METHODS: TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). RESULTS: Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). CONCLUSIONS: In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. CLINICAL TRIALS REGISTRATION: NCT02958709.

Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial.

Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain. Objectives: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin. Methods: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBACFU0-14) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13. Measurements and Main Results: Sixty participants enrolled. Median EBACFU0-14 counts (2.5th-97.5th percentiles) were 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-0.37), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log10 h), for arms C-F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events. Conclusions: Bactericidal activity was greater with the World Health Organization-recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens. Clinical trial registered with www.clinicaltrials.gov (NCT03174184).

Whole Genome Sequencing Assessing Impact of Diabetes Mellitus on Tuberculosis Mutations and Type of Recurrence in India.

BACKGROUND: Evidence describing the impact of diabetes mellitus (DM) on the recurrence and mutation rate of Mycobacterium tuberculosis (Mtb) is limited. METHODS: This study was nested in 3 cohort studies of tuberculosis (TB) patients with and without DM in India. Paired Mtb isolates recovered at baseline and treatment failure/recurrence underwent whole genome sequencing. We compared acquisition of single-nucleotide polymorphisms (SNPs), TB drug resistance mutations, and type of recurrence (endogenous reactivation [<8 SNPs] or exogenous reinfection [≥8 SNPs]) by DM status. RESULTS: Of 1633 enrolled in the 3 parent cohorts, 236 (14.5%) had microbiologically confirmed TB treatment failure/recurrence; 76 Mtb isolate pairs were available for sequencing (22 in TB-DM and 54 in TB-only). The SNP acquisition rate was overall was 0.43 (95% confidence interval [CI], .25-.64) per 1 person-year (PY); 0.77 (95% CI, .40-1.35) per 1 PY, and 0.44 (95% CI, .19-.86) per 1 PY at treatment failure and recurrence, respectively. Significant difference in SNP rates by DM status was seen at recurrence (0.21 [95% CI, .04-.61]) per 1 PY for TB-only vs 1.28 (95% CI, .41-2.98) per 1 PY for TB-DM; P = .02). No significant difference in SNP rates by DM status was observed at treatment failure. Acquired TB drug resistance was seen in 4 of 18 (22%) in TB-DM vs 4 of 45 (9%) in TB-only (P = .21). Thirteen (17%) participants had exogenous reinfection; the reinfection rate at recurrence was 25% (3/12) for TB-DM vs 17% (4/24) in TB-only (P = .66). CONCLUSIONS: Considerable intrahost Mtb mutation rates were present at recurrence among patients with DM in India. One-fourth of patients with DM had exogenous reinfection at recurrence.