Browsing by Author "Gupta, Amita"
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- ItemDrug susceptibility patterns of Mycobacterium tuberculosis from adults with multidrug-resistant tuberculosis and implications for a household contact preventive therapy trial(BMC (part of Springer Nature), 2021-02-24) Demers, Anne-Marie; Kim, Soyeon; McCallum, Sara; Eisenach, Kathleen; Hughes, Michael; Naini, Linda; Mendoza-Ticona, Alberto; Pradhan, Neeta; Narunsky, Kim; Poongulali, Selvamuthu; Badal-Faesen, Sharlaa; Upton, Caryn; Smith, Elizabeth; Shah, N. S.; Churchyard, Gavin; Gupta, Amita; Hesseling, Anneke; Swindells, SusanBackground: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs). Methods: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability. Results: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens. Conclusions: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.
- ItemEffects of pregnancy and isoniazid preventive therapy on mycobacterium tuberculosis interferon gamma response assays in women with HIV(Oxford University Press, 2020-07) Weinberg, Adriana; Aaron, Lisa; Montepiedra, Grace; Sterling, Timothy R.; Browning, Renee; Mmbaga, Blandina; Vhembo, Tichaona; Naik, Shilpa; Kabugho, Enid; Masheto, Gaerolwe; Pahwa, Savita; Mathad, Jyoti S.; LaCourse, Sylvia M.; McCarthy, Katie; Bradford, Sarah; Theron, Gerhard; Costello, Diane; Zimmer, Bonnie; Pierre, Marie F.; Gausi, Kamunkhwala; Denti, Paolo; Haas, David W.; Gupta, AmitaBackground Pregnancy is accompanied by immune suppression. We hypothesized that Mycobacterium tuberculosis-specific inflammatory responses used to identify latent tuberculosis infection (LTBI) lose positivity during pregnancy. We also hypothesized that isoniazid preventive therapy (IPT) may revert LTBI diagnoses because of its sterilizing activity. Methods 944 women with human immunodeficiency virus infection (HIV) participating in a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT antepartum versus postpartum, were tested by QuantiFERON-gold-in-tube (QGIT) antepartum and by QGIT and tuberculin skin test (TST) at delivery and postpartum. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations. Results From entry to delivery, 68 (24%) of 284 QGIT-positive women reverted to QGIT-negative or indeterminate. Of these, 42 (62%) recovered QGIT positivity postpartum. The loss of QGIT positivity during pregnancy was explained by decreased interferon gamma (IFNγ) production in response to TB antigen and/or mitogen. At delivery, LTBI was identified by QGIT in 205 women and by TST in 113 women. Corresponding numbers postpartum were 229 and 122 women. QGIT and TST kappa agreement coefficients were 0.4 and 0.5, respectively. Among QGIT-positive women antepartum or at delivery, 34 (12%) reverted to QGIT-negative after IPT. There were no differences between women who initiated IPT antepartum or postpartum. Conclusions Decreased IFNγ responses in pregnancy reduced QGIT positivity, suggesting that this test cannot reliably rule out LTBI during pregnancy. TST was less affected by pregnancy, but had lower positivity compared to QGIT at all time points. IPT was associated with loss of QGIT positivity, the potential clinical consequences of which need to be investigated.
- ItemFeasibility of identifying household contacts of rifampin-and multidrug-resistant tuberculosis cases at high risk of progression to tuberculosis disease(Oxford University Press, 2020-01) Gupta, Amita; Swindells, Susan; Kim, Soyeon; Hughes, Michael D.; Naini, Linda; Wu, Xingye; Dawson, Rodney; Mave, Vidya; Sanchez, Jorge; Mendoza, Alberto; Gonzales, Pedro; Kumarasamy, Nagalingeswaran; Comins, Kyla; Conradie, Francesca; Shenje, Justin; Fontain, Sandy Nerette; Garcia-Prats, Anthony; Asmelash, Aida; Nedsuwan, Supalert; Mohapi, Lerato; Lalloo, Umesh G.; Ferreira, Ana Cristina Garcia; Mugah, Christopher; Harrington, Mark; Jones, Lynne; Cox, Samyra R.; Smith, Betsy; Shah, N Sarita; Hesseling, Anneke C.; Churchyard, GavinBackground: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. Methods: We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing. Results: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy. Conclusions: The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.
- ItemInclusion of key populations in clinical trials of new antituberculosis treatments : current barriers and recommendations for pregnant and lactating women, children, and HIV-infected persons(Public Library of Science, 2019) Gupta, Amita; Hughes, Michael D.; Garcia-Prats, Anthony J.; McIntire, Katherine; Hesseling, Anneke C.ENGLISH ABSTRACT: Pregnant women, children < 15 years old and, HIV-infected persons contribute approximately 20% of the global tuberculosis (TB) burden, with an estimated 216,000, 1,000,000, and 1,040,000 cases each year, respectively, yet these populations are currently largely excluded from TB clinical trials, leading to suboptimal treatment and poor access to new therapeutics. • Special considerations in these populations include specific TB disease spectrum and severity, lower sensitivity of commonly used TB diagnostic tests, potential differential drug dosing and treatment responses, drug–drug interactions, and challenges in acquiring high-quality data through clinical trials. • To counter the automatic exclusion of pregnant and lactating women that currently pervades the TB trial landscape, early discussions among trialists, pharmaceutical companies, maternal–child clinical experts, ethicists, and regulatory bodies are needed to address risks, benefits, and compelling rationale for inclusion. Reconsenting women when pregnancy occurs on a trial to allow continuation of study drug by informed choice is a practical and valuable approach to expand the currently limited evidence base. • Children tend to have less severe, often paucibacillary TB disease and may respond better to treatment than adults. Consequently, trials of shorter, less intense TB treatment regimens in children are needed; pharmacokinetic and safety studies should be initiated earlier and involve age groups in parallel rather than in an age-de-escalation approach. More rapid development of child-friendly drug formulations is needed. • All HIV-infected populations, including those with advanced disease, who are likely to be the intended population of the TB therapy, should be involved in Phase IIb and/or Phase III trials, as appropriate, to maximize knowledge of treatment, toxicities, drug– drug interactions, and outcomes.
- ItemIndividual and composite adverse pregnancy outcomes in a randomized trial on isoniazid preventative therapy among women living with human immunodeficiency virus(Oxford University Press, 2021-06-01) Theron, Gerhard; Montepiedra, Grace; Aaron, Lisa; McCarthy, Katie; Chakhtoura, Nahida; Jean-Philippe, Patrick; Zimmer, Bonnie; Loftis, Amy James; Chipato, Tsungai; Nematadzira, Teacler; Nyati, Mandisa; Onyango-Makumbi, Carolyne; Masheto, Gaerolwe; Ngocho, James; Tongprasert, Fuanglada; Patil, Sandesh; Lespinasse, Dominique; Weinberg, Adriana; Gupta, AmitaBackground: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1078, a randomized noninferiority study designed to compare the safety of starting isoniazid preventive therapy (IPT) in women living with human immunodeficiency virus (HIV) either during pregnancy or after delivery, showed that IPT during pregnancy increased the risk of composite adverse pregnancy outcomes, but not individual outcomes. Many known factors are associated with adverse pregnancy outcomes: these factors' associations and effect modifications with IPT and pregnancy outcomes were examined. Methods: Pregnant women living with HIV from 8 countries with tuberculosis incidences >60/100 000 were randomly assigned to initiate 28 weeks of IPT either during pregnancy or at 12 weeks after delivery. Using univariable and multivariable logistic regression and adjusting for factors associated with pregnancy outcomes, composite and individual adverse pregnancy outcome measures were analyzed. Results: This secondary analysis included 925 mother-infant pairs. All mothers were receiving antiretrovirals. The adjusted odds of fetal demise, preterm delivery (PTD), low birth weight (LBW), or a congenital anomaly (composite outcome 1) were 1.63 times higher among women on immediate compared to deferred IPT (95% confidence interval [CI], 1.15-2.31). The odds of fetal demise, PTD, LBW, or neonatal death within 28 days (composite outcome 2) were 1.62 times higher among women on immediate IPT (95% CI, 1.14-2.30). The odds of early neonatal death within 7 days, fetal demise, PTD, or LBW (composite outcome 3) were 1.74 times higher among women on immediate IPT (95% CI, 1.22-2.49). Conclusions: We confirmed higher risks of adverse pregnancy outcomes associated with the initiation of IPT during pregnancy, after adjusting for known risk factors for adverse pregnancy outcomes.
- ItemIsoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women(Massachusetts Medical Society, 2019-10-03) Gupta, Amita; Montepiedra, Grace; Aaron, Lisa; Theron, Gerhard; McCarthy, Katie; Bradford, Sarah; Chipato, Tsungai; Vhembo, Tichaona; Stranix-Chibanda, Lynda; Onyango-Makumbi, Carolyne; Masheto, Gaerolwe R.; Mmbaga, Blandina T.; Aurpibul, Linda; Bhosale, Ramesh; Mave, Vidya; Rouzier, Vanessa; Hesseling, Anneke; Shin, Katherine; Zimmer, Bonnie; Costello, Diane; Sterling, Timothy R.; Chakhtoura, Nahida; Jean-Philippe, Patrick; Weinberg, AdrianaBACKGROUND: The safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown. METHODS: In this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years. RESULTS: A total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], −4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, −0.39; 95% CI, −1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 person-years in the deferred group (rate difference, 0.01; 95% CI, −0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9). CONCLUSIONS: The risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, NCT01494038. opens in new tab.)
- ItemLow vitamin-D levels combined with PKP3-SIGIRR-TMEM16J host variants is associated with tuberculosis and death in HIV-infected and -exposed infants(Public Library of Science, 2016) Gupta, Amita; Montepiedra, Grace; Gupte, Akshay; Zeldow, Bret; Jubulis, Jennifer; Detrick, Barbara; Violari, Avy; Madhi, Shabir; Bobat, Raziya; Cotton, Mark; Mitchell, Charles; Spector, Stephen; IMPAACT NWCS113 and P1041 Study TeamBackground: This study examined the associations of 25-hydroxyvitamin D and specific host genetic variants that affect vitamin D levels or its effects on immune function, with the risk of TB or mortality in children. Methods: A case-cohort sample of 466 South African infants enrolled in P1041 trial (NCT00080119) underwent 25-hydroxyvitamin D testing by chemiluminescent immunoassay. Single nucleotide polymorphisms (SNPs) that alter the effect of vitamin D [e.g. vitamin D receptor (VDR)], vitamin D levels [e.g. vitamin D binding protein (VDBP)], or toll like receptor (TLR) expression (SIGIRR including adjacent genes PKP3 and TMEM16J) were identified by real-time PCR. Outcomes were time to TB, and to the composite of TB or death by 192 weeks of follow-up. Effect modification between vitamin D status and SNPs for outcomes was assessed. Findings: Median age at 25-hydroxyvitamin D determination was 8 months; 11% were breastfed, 51% were HIV-infected and 26% had low 25-hydroxyvitamin D (<32ng/mL). By 192 weeks, 138 incident TB cases (43 definite/probable, and 95 possible) and 26 deaths occurred. Adjusting for HIV status and potential confounders, low 25-hydroxyvitamin D was associated with any TB (adjusted hazard ratio [aHR] 1.76, 95% CI 1.01–3.05; p = 0.046) and any TB or death (aHR 1.76, 95% CI 1.03–3.00; p = 0.038). Children with low 25-hydroxyvitamin D and TMEM 16J rs7111432-AA or PKP3 rs10902158-GG were at increased risk for probable/definite TB or death (aHR 8.12 and 4.83, p<0.05) and any TB or death (aHR 4.78 and 3.26, p<0.005) respectively; SNPs in VDBP, VDR, and vitamin D precursor or hydroxylation genes were not. There was significant interaction between low 25-hydroxyvitamin D and, TMEM 16J rs7111432-AA (p = 0.04) and PKP3 rs10902158-GG (p = 0.02) SNPs. Conclusions: Two novel SNPs, thought to be associated with innate immunity, in combination with low vitamin D levels were identified as increasing a young child’s risk of developing TB disease or death. Identifying high-risk children and providing targeted interventions such as vitamin D supplementation may be beneficial.
- ItemUsing a composite maternal-infant outcome measure in tuberculosis prevention studies among pregnant women(Oxford University Press, 2021-08-02) Montepiedra, Grace; Kim, Soyeon; Weinberg, Adriana; Theron, Gerhard; Sterling, Timothy R.; LaCourse, Sylvia M.; Bradford, Sarah; Chakhtoura, Nahida; Jean-Philippe, Patrick; Evans, Scott; Gupta, AmitaBackground: Tuberculosis (TB-)-preventive therapy (TPT) among pregnant women reduces risk of TB in mothers and infants, but timing of initiation should consider potential adverse effects. We propose an analytical approach to evaluate the risk-benefit of interventions. Methods: A novel outcome measure that prioritizes maternal and infant events was developed with a 2-stage Delphi survey, where a panel of stakeholders assigned scores from 0 (best) to 100 (worst) based on perceived desirability. Using data from TB APPRISE, a trial among pregnant women living with human immunodeficiency virus (WLWH) that randomized the timing of initiation of isoniazid, antepartum versus postpartum, was evaluated. Results: The composite outcome scoring/ranking system categorized mother-infant paired outcomes into 8 groups assigned identical median scores by stakeholders. Maternal/infant TB and nonsevere adverse pregnancy outcomes were assigned similar scores. Mean (SD) composite outcome scores were 43.7 (33.0) and 41.2 (33.7) in the antepartum and postpartum TPT initiation arms, respectively. However, a modifying effect of baseline antiretroviral regimen was detected (P = .049). When women received nevirapine, composite scores were higher (worse outcomes) in the antepartum versus postpartum arms (adjusted difference, 14.3; 95% confidence interval [CI], 2.4-26.2; P = .02), whereas when women received efavirenz there was no difference by timing of TPT (adjusted difference, .62; 95% CI, -3.2-6.2; P = .53). Conclusions: For TPT, when used by otherwise healthy persons, preventing adverse events is paramount from the perspective of stakeholders. Among pregnant WLWH in high-TB-burden regions, it is important to consider the antepartum antiretroviral regimen taken when deciding when to initiate TPT. Clinical Trials Registration. NCT01494038 (IMPAACT P1078).
- ItemWillingness to take multidrug-resistant tuberculosis (MDR-TB) preventive therapy among adult and adolescent household contacts of MDR-TB index cases : an international multisite cross-sectional study(Oxford University Press, 2020-02) Suryavanshi, Nishi; Murrill, Matthew; Gupta, Amita; Hughes, Michael; Hesseling, Anneke; Kim, Soyeon; Naini, Linda; Jones, Lynne; Smith, Betsy; Gupte, Nikhil; Dawson, Rodney; Mave, Vidya; Meshram, Sushant; Mendoza-Ticona, Alberto; Sanchez, Jorge; Kumarasamy, Nagalingeswaran; Comins, Kyla; Conradie, Francesca; Shenje, Justin; Fontain, Sandy Nerette; Garcia-Prats, Anthony; Asmelash, Aida; Nedsuwan, Supalert; Mohapi, Lerato; Lalloo, Umesh; Ferreira, Ana Cristina Garcia; Okeyo, Elisha; Swindells, Susan; Churchyard, Gavin; Shah, N. SaritaBackground. Household contacts (HHCs) of individuals with multidrug-resistant tuberculosis (MDR-TB) are at high risk of infection and subsequent disease. There is limited evidence on the willingness of MDR-TB HHCs to take MDR-TB preventive therapy (MDR TPT) to decrease their risk of TB disease. Methods. In this cross-sectional study of HHCs of MDR-TB and rifampicin-resistant tuberculosis (RR-TB) index cases from 16 clinical research sites in 8 countries, enrollees were interviewed to assess willingness to take a hypothetical, newly developed MDR TPT if offered. To identify factors associated with willingness to take MDR TPT, a marginal logistic model was fitted using generalized estimating equations to account for household-level clustering. Results. From 278 MDR-TB/RR-TB index case households, 743 HHCs were enrolled; the median age of HHCs was 33 (interquartile range, 22-49) years, and 62% were women. HHC willingness to take hypothetical MDR TPT was high (79%) and remained high even with the potential for mild side effects (70%). Increased willingness was significantly associated with current employment or schooling (adjusted odds ratio [aOR], 1.83 [95% confidence interval {CI}, 1.07-3.13]), appropriate TB-related knowledge (aOR, 2.22 [95% CI, 1.23-3.99]), confidence in taking MDR TPT (aOR, 7.16 [95% CI, 3.33-15.42]), and being comfortable telling others about taking MDR TPT (aOR, 2.29 [95% CI, 1.29-4.06]). Conclusions. The high percentage of HHCs of MDR-TB/RR-TB index cases willing to take hypothetical MDR TPT provides important evidence for the potential uptake of effective MDR TPT when implemented. Identified HHC-level variables associated with willingness may inform education and counseling efforts to increase HHC confidence in and uptake of MDR TPT.