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Host Transcriptomic Signature As Alternative Test-Of-Cure in Visceral Leishmaniasis Patients Coinfected with HIV

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Host Transcriptomic Signature As Alternative Test-Of-Cure in Visceral Leishmaniasis Patients Coinfected with HIV View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by White Rose Research Online This is a repository copy of Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients coinfected with HIV. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/158875/ Version: Accepted Version Article: Kaye, Paul orcid.org/0000-0002-8796-4755, Adriaensen, Wim, Cuypers, Bart et al. (7 more authors) (2020) Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients coinfected with HIV. EBioMedicine. ISSN 2352-3964 (In Press) Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ 1 Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis 2 patients coinfected with HIV 3 4 Wim Adriaensen1*, Bart Cuypers2,3, Carlota F. Cordero1, Bewketu Mengasha4, Séverine 5 Blesson5, Lieselotte Cnops1, Paul M. Kaye6, Fabiana Alves5, Ermias Diro4, Johan van 6 Griensven1 7 *corresponding author ([email protected], +3232470807) 8 9 1 Unit of Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical 10 Medicine, Nationalestraat 122, 2000 Antwerp, Belgium 11 2 Unit of Molecular Parasitology, Department of Biomedical Sciences, Institute of Tropical 12 Medicine, Nationalestraat 122, 2000 Antwerp, Belgium 13 3 Adrem Data Lab, Department of Mathematics and Computer Science, University of 14 Antwerp, Middelheim 1, 2020 Antwerp, Belgium 15 4 Leishmaniasis Research and Treatment Centre, University of Gondar, Gondar, Ethiopia 16 5 Drugs for Neglected Diseases initiative, 15 Chemin Louis-Dunant, 1202 Geneva, 17 Switzerland 18 6 York Biomedical Research Institute, University of York, UK 19 20 Keywords: Visceral leishmaniasis, HIV, RNA signature, treatment efficacy, blood signature 21 22 23 24 25 26 1 27 Abstract: 28 Background 29 Visceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high 30 relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on 31 invasive organ aspiration for parasite detection. In the search of a less-invasive alternative and 32 because the host immune response is pivotal for treatment outcome in immunocompromised 33 VL patients, we studied changes in the whole blood transcriptional profile of VL-HIV patients 34 during treatment. 35 Methods: 36 Embedded in a clinical trial in Northwest Ethiopia, RNA-Seq was performed on whole blood 37 samples of 28 VL-HIV patients before and after completion of a 29-day treatment regimen of 38 AmBisome or AmBisome/miltefosine. Pathway analyses were combined with a machine 39 learning approach to establish a clinically-useful 4-gene set. 40 Findings: 41 Distinct signatures of differentially expressed genes between D0 and D29 were identified for 42 patients who failed treatment and were successfully treated. Pathway analyses in the latter 43 highlighted a downregulation of genes associated with host cellular activity and immunity, and 44 upregulation of antimicrobial peptide activity in phagolysosomes. No signs of disease 45 remission nor pathway enrichment were observed in treatment failure patients. Next, we 46 identified a 4-gene pre-post signature (PRSS33, IL10, SLFN14, HRH4) that could accurately 47 discriminate treatment outcome at end of treatment (D29), displaying an average area-under- 48 the-ROC-curve of 0.95 (CI: 0.75–1.00). 49 Interpretation: 2 50 A simple blood-based signature thus holds significant promise to facilitate treatment efficacy 51 monitoring and provide an alternative test-of-cure to guide patient management in VL-HIV 52 patients. 53 Funding: 54 Project funding was provided by the AfricoLeish project, supported by the European Union 55 Seventh Framework Programme (EU FP7). 56 57 Research in context 58 Evidence before this study 59 Human immunodeficiency virus (HIV) infection has been identified as a significant challenge 60 facing visceral leishmaniasis (VL) control. VL treatment in HIV patients very often fails and 61 results in extended treatment time followed by high relapse and case-fatality rates. In addition 62 to limited and toxic treatment options, the treatment outcome assessment thus becomes 63 imperative in VL-HIV patients to guide decisions on treatment extension, treatment adjustment 64 or secondary prophylaxis initiation. However, with no alternatives to assess treatment efficacy, 65 repeated invasive and painful aspiration from infected organs for microscopical detection of 66 the parasite remains the only approach. Chronic patients thus undergo repeated tissue aspirates 67 or empirical optimization of treatment regimens. Hence, the development of a less-invasive 68 alternative to assess treatment efficacy represents an urgent and important unmet clinical need 69 to achieve VL control. 70 Added value of this study 71 Our study is the first to investigate whole transcriptome changes in the severly neglected group 72 of visceral leishmaniasis patients with a concurrent HIV infection, where the host immune 73 response is largely uncharted but believed to be pivotal for treatment outcome. In a translational 3 74 effort, the findings were biologically interpreted and systemically reduced to a 4-gene 75 biomarker that could accurately discriminate treatment outcome. 76 Implications of the all the available evidence 77 This signature holds significant promise to facilitate treatment efficacy monitoring in R&D and 78 could provide an alternative test-of-cure to guide patient management in VL-HIV patients. 79 80 Introduction 81 Visceral leishmaniasis (VL) is a potentially fatal, yet neglected, vector-borne disseminated 82 infection caused by protozoans of the Leishmania donovani spp. complex (1). Typical 83 symptoms include fever spikes, substantial weight loss, splenomegaly and alterations of 84 haematopoiesis. With a global estimate of 90,000 cases annually, Ethiopia together with Brazil, 85 India, Kenya, Somalia, South Sudan and Sudan host more than 90% of all VL cases (2). 86 87 Compared to varying cure rates of around 90-95% in VL patients, treatment of patients with a 88 concurrent Human Immunodeficiency Virus-1 (HIV) infection (referred to herein as ‘VL-HIV 89 patients’) in endemic regions of East-Africa, Brazil and India frequently fails. Treatment failure 90 results in extended treatments and case-fatality rates up to 25% (3,4). This is particularly true 91 for East Africa where antileishmanial drugs show lower efficacy rates and HIV prevalence 92 rates of 10-20% are reported among VL patients (3). Even if apparent parasitological clearance 93 at end of treatment and viral suppression with ART is achieved, up to 60% of VL-HIV patients 94 will develop recurrent relapse, typically within 3-6 months after initial cure (compared to 1- 95 5% in immunocompetent VL patients) (3,5). Hence, treatment outcome assessment is 96 imperative in VL-HIV patients to guide decisions on treatment extension, treatment adjustment 97 or secondary prophylaxis initiation. 98 4 99 To date, a repeated invasive and painful aspiration for microscopical detection of the parasite 100 from infected organs (spleen, bone marrow or lymph nodes) remains the only approach for test- 101 of-cure. Although spleen aspiration shows the highest sensitivity (6), it has a life-threatening 102 risk of splenic haemorrhage that renders it unsuitable in patients with severe thrombocytopenia. 103 In addition, these techniques require a great level of expertise, training of personnel and 104 appropriate facilities where blood transfusion and management of intraabdominal bleeding is 105 possible. Due to these reasons, chronic patients often undergo repeated tissue aspirates or 106 empirical optimization of treatment regimens. Hence, the development of a less-invasive 107 alternative to assess treatment efficacy represents an urgent and important unmet clinical need. 108 109 Molecular techniques for parasite detection seem promising, but could be less suitable as the 110 parasitic load in blood decreases steeply after two days of treatment and gives no information 111 on the host’s immunological recovery (7). In immunocompromised individuals in particular, 112 host immune response restoration has been shown to be pivotal in the efficacy of VL treatment 113 (8). Therefore, transcriptomic signatures in peripheral blood may reflect immunological 114 responses underpinning clearance or persistence of parasites. In recent years, gene signatures 115 derived from blood transcriptomic profiling have shown great promise in treatment monitoring 116 for a number of infectious diseases (9–11). With a 5-gene signature, robust prediction of 117 treatment failure in tuberculosis patients could be achieved after 1 or 4 weeks of therapy (11). 118 Similarly, Liu et al. identified and validated a 10-gene signature that predicted Ebola treatment
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