Risk Factors for Acquired Rifamycin and Isoniazid resistance: A systematic review and meta-analysis

BACKGROUND: Studies looking at acquired drug resistance (ADR) are diverse with respect to geographical distribution, HIV co-infection rates, retreatment status and programmatic factors such as regimens administered and directly observed therapy. Our objective was to examine and consolidate evidence from clinical studies of the multifactorial aetiology of acquired rifamycin and/or isoniazid resistance within the scope of a single systematic review. This is important to inform policy and identify key areas for further studies. METHODS: Case-control and cohort studies and randomised controlled trials that reported ADR as an outcome during antitubercular treatment regimens including a rifamycin and examined the association of at least 1 risk factor were included. Post hoc, we carried out random effects Mantel-Haenszel weighted meta-analyses of the impact of 2 key risk factors 1) HIV and 2) baseline drug resistance on the binary outcome of ADR. Heterogeneity was assessed used I 2 statistic. As a secondary outcome, we calculated median cumulative incidence of ADR, weighted by the sample size of the studies. RESULTS: Meta-analysis of 15 studies showed increased risk of ADR with baseline mono- or polyresistance (RR 4.85 95% CI 3.26 to 7.23, heterogeneity I 2 58%, 95% CI 26 to 76%). Meta-analysis of 8 studies showed that HIV co-infection was associated with increased risk of ADR (RR 3.02, 95% CI 1.28 to 7.11); there was considerable heterogeneity amongst these studies (I 2 81%, 95% CI 64 to 90%). Non-adherence, extrapulmonary/disseminated disease and advanced immunosuppression in HIV co-infection were other risk factors noted. The weighted median cumulative incidence of acquired multi drug resistance calculated in 24 studies (assuming whole cohort as denominator, regardless of follow up DST) was 0.1% (5 th to 95 th percentile 0.07 to 3.2%). CONCLUSION: Baseline drug resistance and HIV co-infection were significant risk factors for ADR. There was a trend of positive association with non-adherence which is likely to contribute to the outcome of ADR. The multifactorial aetiology of ADR in a programmatic setting should be further evaluated via appropriately designed studies

Transcriptomic Characterization of Tuberculous Sputum Reveals a Host Warburg Effect and Microbial Cholesterol Catabolism.

The crucial transmission phase of tuberculosis (TB) relies on infectious sputum and yet cannot easily be modeled. We applied one-step RNA sequencing (RNA-Seq) to sputum from infectious TB patients to investigate the host and microbial environments underlying transmission of Mycobacterium tuberculosis. In such TB sputa, compared to non-TB controls, transcriptional upregulation of inflammatory responses, including an interferon-driven proinflammatory response and a metabolic shift toward glycolysis, was observed in the host. Among all bacterial sequences in the sputum, approximately 1.5% originated from M. tuberculosis, and its transcript abundance was lower in HIV-1-coinfected patients. Commensal bacterial abundance was reduced in the presence of M. tuberculosis infection. Direct alignment to the genomes of the predominant microbiota species also reveals differential adaptation, whereby firmicutes (e.g., streptococci) displayed a nonreplicating phenotype with reduced transcription of ribosomal proteins and reduced activities of ATP synthases, while Neisseria and Prevotella spp. were less affected. The transcriptome of sputum M. tuberculosis more closely resembled aerobic replication and shared similarity in carbon metabolism to in vitro and in vivo models with significant upregulation of genes associated with cholesterol metabolism and downstream propionate detoxification pathways. In addition, and counter to previous reports on intracellular M. tuberculosis infection in vitro, M. tuberculosis in sputum was zinc, but not iron, deprived, and the phoP loci were also significantly downregulated, suggesting that the pathogen is likely extracellular in location. IMPORTANCE Although a few studies have described the microbiome composition of TB sputa based on 16S ribosomal DNA, these studies did not compare to non-TB samples and the nature of the method does not allow any functional inference. This is the first study to apply such technology using clinical specimens and obtained functional transcriptional data on all three aspects simultaneously. We anticipate that an improved understanding on the biological interactions in the respiratory tract may also allow novel interventions, such as those involving microbiome manipulation or inhibitor targeting disease-specific metabolic pathways

Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

11 páginas, 2 figuras, 1 tablaInappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance.I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038)Peer reviewe

Determinants of tuberculosis Treatment Outcomes

Background: Despite 6 months of standardised tuberculosis treatment, unsuccessful treatment outcomes (acquired drug resistance, failure, relapse) may occur in a subset of patients with drug-susceptible tuberculosis. The aim of this thesis was to study determinants of treatment outcomes in rifampicin susceptible pulmonary tuberculosis in a setting with a high prevalence of HIV-1 co-infection. Methods: A prospective cohort study was carried out to determine the frequency and determinants of acquired drug resistance. The minimum inhibitory concentration (MIC) of sputum TB isolates was determined in a sub-set (BACTEC 960 system). The clinical utility of MTBDRplus performed directly on 2-month sputum for treatment monitoring was assessed. Expression of 12 MTB-specific messenger (m) and small (s) RNAs was quantified in RNA extracted from sputum before tuberculosis treatment and compared to expression in exponential and stationary phase H37Rv cultures. Intensive pharmacokinetic studies were carried out for rifampicin, isoniazid and pyrazinamide and non-linear mixed effects modeling was used to derive individual pharmacokinetic parameters. Multivariate logistic regression and multivariate adaptive regression splines (MARS) analyses were used to evaluate utility of pharmacokinetic/pharmacodynamics measures (AUC0-24:MIC, Cmax,:MIC, % time above MIC) to predict 2-month culture conversion. A panel of analytes measured by ELISA and Luminex in plasma/serum taken pre-trearment and at 2 and 5-6 months on treatment was evaluated to determine correlates of HIV-1 co-infection, disease severity and unsuccessful outcomes. Results: 0.3- 1% of patients treated for rifampicin susceptible-tuberculosis (n=306) acquired drug resistance during or subsequent to treatment. None of the 17 cases of isoniazid monoresistance had unsuccessful outcomes. There were no differences in baseline MIC profiles (n=109) when analysed by retreatment, 2-month culture conversion or HIV-1 status and there was no evidence of increase in MIC during treatment comparing baseline and 2-month isolates (n=20). Direct MTBDRplus (n=289) on 2-month sputa had a sensitivity of 78%(95%CI 65-87) and specificity of 80%(95%CI 74-84) for predicting culture conversion with a negative predictive value of 93%(95%CI 89-96). This was in comparison to a gold standard of MTBDRplus on positive 2-month cultures. The transcriptomic signature (here limited to 11 selected mRNAs/sRNAs) of sputum (n=19) more closely resembled H37Rv in exponential phase culture than stationary phase culture. There was evidence of biological variation and a trend towards an increased hspXhi atpAlo nuoGlo signal in the sub-group who were culture positive at 2 months. Ambulant HIV-1-tuberculosis co-infected patients (n=100), the majority of whom were co-prescribed ART, did not have reduced anti-tuberculosis drug concentrations compared with HIV-1 uninfected tuberculosis patients. No relationship was found between pharmacokinetic exposures and 2-month culture conversion using logistic regression, after adjusting for MIC and clinical factors. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was below 4.6 mg/L and rifampicin Cmax /MIC below 28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax>4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion. We found significant differences in the majority of blood analytes over the course of treatment (n=133). Within the HIV-1 co-infected sub-group, there were marked differences comparing subjects with and without advanced immunosuppression and with and without virological suppression. We found an association between Type 1 interferon response, neutrophil-associated cytokines (IL-17 and IL-8), neutrophil-associated MMPs (MMP-8 and MMP-9) and the presence of cavitatory disease. On multivariate analyses, receiver operator curve-derived thresholds at baseline for IL-8, IL-6, IL-1RA, MMP-3 and ferritin and thresholds for IL-8. IL-6, IL-1RA, MMP-3, MMP-8, TIMP-1, TIMP-3, GM-CSF and VEGF at 2 months were able to predict unfavourable outcomes with reasonable performance characteristics. Conclusion: Although rare, in this high burden setting, acquired drug resistance does contribute to the growing drug-resistant tuberculosis epidemic. Emphasis should be on prevention of transmission to others. Ambulant HIV-1 co-infected patients, the majority of whom were co-prescribed antiretroviral therapy, did not have reduced anti-tuberculosis drug concentrations compared with HIV-1 uninfected patients. The majority of patients had plasma drug exposures well below accepted thresholds, but nevertheless had good treatment outcomes. Further clinical studies are required to investigate the potential role of nonlinear pharmacokinetic/pharmacodynamic relationships such as concentration-dependent antagonism. A deeper understanding of host and mycobacterial factors influencing treatment outcomes is required in the search for biomarkers and surrogate endpoints predicting long-term outcomes.Open Acces

Primary central nervous system lymphoma presenting as multiple space-occupying lesions in advanced human immunodeficiency virus infection

A 31-year-old man presented with seizures and cerebellar symptoms on a background of weight loss and lethargy. He was found to be infected with human immunodeficiency virus (HIV) and following radiological imaging, was commenced on treatment for presumed cerebral toxoplasmosis. Due to a lack of response, both clinically and on interval imaging, a positron-emission tomography-computed tomography and brain biopsy were undertaken, which demonstrated high-grade primary central nervous system lymphoma (PCNSL). Awareness amongst both clinicians and radiologists of the multifarious patterns of intra-cranial involvement in patients with HIV is, therefore, of utmost importance, as the treatment and prognosis of these entities are entirely different

Unusual complication and successful high-dose chemotherapy treatment of advanced Burkitt’s lymphoma in an adult HIV-positive patient

Adult Burkitt’s lymphoma emerged as an AIDS-defining condition in the 1980s. We describe a case of HIV-associated adult Burkitt’s lymphoma diagnosed and treated with high-dose chemotherapy in our institution, complicated by unusual bilateral renal vein tumour thrombi and tumour lysis syndrome. We believe this unique case highlights the need for early recognition of current and potential complications on staging computed tomography imaging, as well as successful use of a high-dose chemotherapy regimen

Summary of literature search and study selection.

<p>Summary of literature search and study selection.</p

Forest plot of comparison: 1) HIV status, outcome of ADR. 1.2) ADR by region.

<p>Only 8/10 studies which examined HIV as a risk factor for ADR were included as we were unable to obtain the exact proportion of those HIV seropositive among the patients that developed ADR from either the paper or by contacting the authors in the other 2 studies. The end point for 5 studies was acquisition of isoniazid/rifamycin/multidrug resistance [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139017#pone.0139017.ref013" target="_blank">13</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139017#pone.0139017.ref014" target="_blank">14</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139017#pone.0139017.ref021" target="_blank">21</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139017#pone.0139017.ref030" target="_blank">30</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139017#pone.0139017.ref033" target="_blank">33</a>] and the end point for 3 studies was acquisition of rifamycin resistance [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139017#pone.0139017.ref022" target="_blank">22</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139017#pone.0139017.ref028" target="_blank">28</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139017#pone.0139017.ref035" target="_blank">35</a>], based on data available.</p

RCTS- ADR and associated risk factors.

<p>RCTS- ADR and associated risk factors.</p

Prospective cohorts- ADR and associated risk factors.

<p>Prospective cohorts- ADR and associated risk factors.</p