Isoniazid Preventive Therapy and Risk for Resistant Tuberculosis

Preventive therapy may increase risk for drug resistance

Lymphocyte proliferation to mycobacterial antigens is detectable across a spectrum of HIV-associated tuberculosis

<p>Abstract</p> <p>Background</p> <p>Identifying novel TB diagnostics is a major public health priority. We explored the diagnostic characteristics of antimycobacterial lymphocyte proliferation assays (LPA) in HIV-infected subjects with latent or active TB.</p> <p>Methods</p> <p>HIV-infected subjects with bacille Calmette Guérin (BCG) scars and CD4 counts ≥ 200 cells/mm³entering a TB booster vaccine trial in Tanzania had baseline in vivo and in vitro immune tests performed: tuberculin skin tests (TST), LPA and five day assays of interferon gamma (IFN-γ) release. Assay antigens were early secreted antigenic target 6 (ESAT-6), antigen 85 (Ag85), and <it>Mycobacterium tuberculosis </it>whole cell lysate (WCL). Subjects were screened for active TB at enrollment by history, exam, sputum smear and culture. We compared antimycobacterial immune responses between subjects with and without latent or active TB at enrollment.</p> <p>Results</p> <p>Among 1885 subjects screened, 635 had latent TB and 13 had active TB. Subjects with latent TB were more likely than subjects without TB to have LPA responses to ESAT-6 (13.2% vs. 5.5%, P < 0.0001), Ag85 (18.7% vs. 3.1%, P < 0.0001), and WCL (45.7% vs. 17.1%, P < 0.0001). Subjects with active TB also were more likely than those without active TB to have detectable LPA responses to ESAT-6 (38.5% vs. 8.1%, P = 0.0001), Ag85 (46.2% vs. 8.5%, P < 0.0001), and WCL (61.5% vs. 27.0%, P = 0.0053). In subjects with a positive TST, LPA responses to ESAT-6, Ag85 and WCL were more common during active TB (p < 0.0001 for all tests). In diagnosing active TB, in vivo and in vitro tests of mycobacterial immune responses had sensitivity and specificity as follows: TST 84.6% and 65.5%, ESAT-6 LPA 38.5% and 92.0%, Ag85 LPA 46.2% and 91.5%, and WCL LPA 61.5% and 73.0%. Detectable LPA responses were more common in patients with higher CD4 counts, and higher HIV viral loads.</p> <p>Conclusion</p> <p>Lymphoproliferative responses to mycobacteria are detectable during HIV-associated active TB, and are less sensitive but more specific than TST.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier NCT00052195.</p

Risk Factors Associated with Positive QuantiFERON-TB Gold In-Tube and Tuberculin Skin Tests Results in Zambia and South Africa

INTRODUCTION: The utility of T-cell based interferon-gamma release assays for the diagnosis of latent tuberculosis infection remains unclear in settings with a high burden of tuberculosis. OBJECTIVES: To determine risk factors associated with positive QuantiFERON-TB Gold In-Tube (QFT-GIT) and tuberculin skin test (TST) results and the level of agreement between the tests; to explore the hypotheses that positivity in QFT-GIT is more related to recent infection and less affected by HIV than the TST. METHODS: Adult household contacts of tuberculosis patients were invited to participate in a cross-sectional study across 24 communities in Zambia and South Africa. HIV, QFT-GIT and TST tests were done. A questionnaire was used to assess risk factors. RESULTS: A total of 2,220 contacts were seen. 1,803 individuals had interpretable results for both tests, 1,147 (63.6%) were QFT-GIT positive while 725 (40.2%) were TST positive. Agreement between the tests was low (kappa = 0.24). QFT-GIT and TST results were associated with increasing age (adjusted OR [aOR] for each 10 year increase for QFT-GIT 1.15; 95% CI: 1.06-1.25, and for TST aOR: 1.10; 95% CI 1.01-1.20). HIV positivity was less common among those with positive results on QFT-GIT (aOR: 0.51; 95% CI: 0.39-0.67) and TST (aOR: 0.61; 95% CI: 0.46-0.82). Smear positivity of the index case was associated with QFT-GIT (aOR: 1.25; 95% CI: 0.90-1.74) and TST (aOR: 1.39; 95% CI: 0.98-1.98) results. We found little evidence in our data to support our hypotheses. CONCLUSION: QFT-GIT may not be more sensitive than the TST to detect risk factors associated with tuberculous infection. We found little evidence to support the hypotheses that positivity in QFT-GIT is more related to recent infection and less affected by HIV than the TST

Intensive Case Finding and Isoniazid Preventative Therapy in HIV Infected Individuals in Africa: Economic Model and Value of Information Analysis

Background: Tuberculosis (TB) accounts of much of the morbidity and mortality associated with HIV. We evaluate the costeffectiveness of different strategies to actively screen for TB disease in HIV positive individuals, where isoniazid preventative therapy (IPT) is given to those screening negative, and use value of information analysis (VOI) to identify future research priorities. Methodology / Principal Findings: We built an individual sampling model to investigate the costs (2010 US Dollars) and consequences of screening for TB, and providing TB treatment or IPT in adults testing HIV positive in Sub-Saharan Africa. A systematic review and meta-analysis was conducted to assess performance of the nine different TB screening strategies evaluated. Probabilistic sensitivity analysis was conducted to incorporate decision uncertainty, and expected value of perfect information for the entire model and for groups of parameters was calculated. Screening all HIV infected individuals with sputum microscopy was the least costly strategy, with other strategies not cost-effective at WHO recommended thresholds. Screening those with TB symptoms with sputum microscopy and CXR would be cost-effective at a threshold ICER of $7,800 per quality-adjusted life year (QALY), but associated with significant uncertainty. VOI analysis suggests further information would be of value. Conclusions / Significance: Resource-constrained countries in sub-Saharan Africa wishing to scale up TB preventativ

Impact of DOTS expansion on tuberculosis related outcomes and costs in Haiti

BACKGROUND: Implementation of the World Health Organization's DOTS strategy (Directly Observed Treatment Short-course therapy) can result in significant reduction in tuberculosis incidence. We estimated potential costs and benefits of DOTS expansion in Haiti from the government, and societal perspectives. METHODS: Using decision analysis incorporating multiple Markov processes (Markov modelling), we compared expected tuberculosis morbidity, mortality and costs in Haiti with DOTS expansion to reach all of the country, and achieve WHO benchmarks, or if the current situation did not change. Probabilities of tuberculosis related outcomes were derived from the published literature. Government health expenditures, patient and family costs were measured in direct surveys in Haiti and expressed in 2003 US$. RESULTS: Starting in 2003, DOTS expansion in Haiti is anticipated to cost$4.2 million and result in 63,080 fewer tuberculosis cases, 53,120 fewer tuberculosis deaths, and net societal savings of $131 million, over 20 years. Current government spending for tuberculosis is high, relative to the per capita income, and would be only slightly lower with DOTS. Societal savings would begin within 4 years, and would be substantial in all scenarios considered, including higher HIV seroprevalence or drug resistance, unchanged incidence following DOTS expansion, or doubling of initial and ongoing costs for DOTS expansion. CONCLUSION: A modest investment for DOTS expansion in Haiti would provide considerable humanitarian benefit by reducing tuberculosis-related morbidity, mortality and costs for patients and their families. These benefits, together with projected minimal Haitian government savings, argue strongly for donor support for DOTS expansion

Cost-effectiveness of novel vaccines for tuberculosis control: a decision analysis study

<p>Abstract</p> <p>Background</p> <p>The development of a successful new tuberculosis (TB) vaccine would circumvent many limitations of current diagnostic and treatment practices. However, vaccine development is complex and costly. We aimed to assess the potential cost effectiveness of novel vaccines for TB control in a sub-Saharan African country - Zambia - relative to the existing strategy of directly observed treatment, short course (DOTS) and current level of bacille Calmette-Guérin (BCG) vaccination coverage.</p> <p>Methods</p> <p>We conducted a decision analysis model-based simulation from the societal perspective, with a 3% discount rate and all costs expressed in 2007 US dollars. Health outcomes and costs were projected over a 30-year period, for persons born in Zambia (population 11,478,000 in 2005) in year 1. Initial development costs for single vaccination and prime-boost strategies were prorated to the Zambian share (0.398%) of global BCG vaccine coverage for newborns. Main outcome measures were TB-related morbidity, mortality, and costs over a range of potential scenarios for vaccine efficacy.</p> <p>Results</p> <p>Relative to the status quo strategy, a BCG replacement vaccine administered at birth, with 70% efficacy in preventing rapid progression to TB disease after initial infection, is estimated to avert 932 TB cases and 422 TB-related deaths (prevention of 199 cases/100,000 vaccinated, and 90 deaths/100,000 vaccinated). This would result in estimated net savings of $3.6 million over 30 years for 468,073 Zambians born in year 1 of the simulation. The addition of a booster at age 10 results in estimated savings of$5.6 million compared to the status quo, averting 1,863 TB cases and 1,011 TB-related deaths (prevention of 398 cases/100,000 vaccinated, and of 216 deaths/100,000 vaccinated). With vaccination at birth alone, net savings would be realized within 1 year, whereas the prime-boost strategy would require an additional 5 years to realize savings, reflecting a greater initial development cost.</p> <p>Conclusions</p> <p>Investment in an improved TB vaccine is predicted to result in considerable cost savings, as well as a reduction in TB morbidity and TB-related mortality, when added to existing control strategies. For a vaccine with waning efficacy, a prime-boost strategy is more cost-effective in the long term.</p

Frequency and severity of potential drug interactions in a cohort of HIV-infected patients Identified through a Multidisciplinary team

OBJECTIVES: Interactions between antiretroviral treatment (ART) and comedications are a concern in HIV-infected patients. This study aimed to determine the frequency and severity of potential drug-drug interactions (PDDIs) with ART in our setting. METHODS: Observational study by a multidisciplinary team in 1259 consecutive HIV patients (March 2015-September 2016). Data on demographics, toxic habits, comorbidities, and current ART were collected. A structured questionnaire recorded concomitant medications (including occasional and over-the-counter drugs). PDDIs were classified into four categories: (1) no interactions, (2) mild (clinically non-significant), (3) moderate (requiring close monitoring or drug modification/dose adjustment), and (4) severe (contraindicated). STATISTICAL ANALYSIS: chi-square test, logistic regression analysis. RESULTS: In total, 881 (70%) patients took comedication, and 563 (44.7%) had ≥ PDDI. Forty-one comedicated patients (4.6%) had severe and 522 (59.2%) moderate PDDIs. Moderate PDDIs mainly involved cardiovascular (53.8%) and central nervous system (40.2%) drugs. Independent risk factors for PDDIs were ART containing a boosted protease inhibitor (odds ratio [OR]=9.11, 95% confidence interval [CI] 5.15-16.11; p = 0.0001) and/or non-nucleoside reverse transcriptase (NNRTI) (OR = 4.34, 95%CI 2.49-7.55; p = 0.0001), HCV co-infection (OR = 3.26, 95%CI 2.15-4.93; p = 0.0001), and use of two or more comedications (OR = 3.36, 95%CI 2.27-4.97; p = 0.0001). Adherence and effectiveness of ART were similar in patients with and without PDDIs. The team made 133 recommendations related to comedications (drug change or dose adjustment) or ART (drug switch or change in administration schedule). CONCLUSIONS: Systematic evaluation detected a significant percentage of PDDIs requiring an intervention in HIV patients on ART. Monitoring and advice about drug-drug interactions should be part of routine practice

Impact of probiotic Saccharomyces boulardii on the gut microbiome composition in HIV-treated patients: a double-blind, randomised, placebo-controlled trial

Dysbalance in gut microbiota has been linked to increased microbial translocation, leading to chronic inflammation in HIV-patients, even under effective HAART. Moreover, microbial translocation is associated with insufficient reconstitution of CD4+T cells, and contributes to the pathogenesis of immunologic non-response. In a double-blind, randomised, placebo-controlled trial, we recently showed that, compared to placebo, 12 weeks treatment with probiotic Saccharomyces boulardii significantly reduced plasma levels of bacterial translocation (Lipopolysaccharide-binding protein or LBP) and systemic inflammation (IL-6) in 44 HIV virologically suppressed patients, half of whom (n = 22) had immunologic non-response to antiretroviral therapy (<270 CD4+Tcells/μL despite long-term suppressed viral load). The aim of the present study was to investigate if this beneficial effect of the probiotic Saccharomyces boulardii is due to modified gut microbiome composition, with a decrease of some species associated with higher systemic levels of microbial translocation and inflammation. In this study, we used 16S rDNA gene amplification and parallel sequencing to analyze the probiotic impact on the composition of the gut microbiome (faecal samples) in these 44 patients randomized to receive oral supplementation with probiotic or placebo for 12 weeks. Compared to the placebo group, in individuals treated with probiotic we observed lower concentrations of some gut species, such as those of the Clostridiaceae family, which were correlated with systemic levels of bacterial translocation and inflammation markers. In a sub-study of these patients, we observed significantly higher parameters of microbial translocation (LBP, soluble CD14) and systemic inflammation in immunologic non-responders than in immunologic responders, which was correlated with a relative abundance of specific gut bacterial groups (Lachnospiraceae genus and Proteobacteria). Thus, in this work, we propose a new therapeutic strategy using the probiotic yeast S. boulardii to modify gut microbiome composition. Identifying pro-inflammatory species in the gut microbiome could also be a useful new marker of poor immune response and a new therapeutic target