Pharmacogenomic associations with HIV-1 virologic suppression in TB/HIV patients

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Haas, Maria Arriaga, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5418156/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Human genetic variants can affect TB and HIV drug metabolism, which may lead to toxicity or treatment failure. We evaluated associations between genetic variants of antiretroviral therapy (ART) and HIV-1 outcomes among TB/HIV patients. Methods: We included RePORT-Brazil participants with TB/HIV who initiated standard TB treatment [2 months of isoniazid/rifampicin (or rifabutin)/pyrazinamide/ethambutol, then 4 months or more of isoniazid/rifampicin (or rifabutin)], and ART. The endpoint was HIV-1 virologic suppression (defined as <1,000 HIV-1 RNA copies/mL, for primary analysis, and <50 HIV-1 RNA copies/mL, for secondary analysis) after at least 2 weeks of ART. We compared non-nucleoside reverse transcriptase inhibitor (NNRTI)-based and integrase strand transfer inhibitor (INSTI)-based ART regimens. We genotyped CYP2B6 (rs3745274, rs28399499, rs4803419; affects efavirenz metabolism) and UGT1A1 (rs887829; affects dolutegravir and raltegravir metabolism); all have defined normal, intermediate, and slow genotypes. Genotyping was performed by MassARRAY iPLEX Gold. We compared outcome proportions (Fisher’s test) and time-to- virologic suppression (survival analysis, Wilcoxon-Gehan test). Results: Among 194 TB/HIV participants included, efavirenz was the most frequent NNRTI ([n=76], one participant received etravirine), and raltegravir was the most frequent INSTI (n=88). The overall virologic suppression was suboptimal, with 32% (n=62) of participants not achieving HIV-1 virologic suppression. Among them, 36% (n=28) used efavirenz-based ART and were more likely to be CYP2B6 normal metabolizers (n=8, 44%); and 30% (n=30) used INSTI-based ART and the UGT1A1 normal genotype was also the most common (n=13, 50%). The median time to virologic suppression for efavirenz-based ART was 184 days (95% Confidence Interval (CI)160-207), and for INSTI-based ART, 188 days (95% CI 144-231) (p=0.84). No significant associations were found comparing the proportions and time to virologic suppression among CYP2B6 and UGT1A1 genotypes. Conclusions : In this observational cohort of patients treated for TB/HIV, the proportion of participants achieving virologic suppression was low, and genetic variants affecting ART metabolism were not significantly associated with the likelihood of virologic suppression. TB/HIV genetic polymorphisms HIV-1 treatment virologic suppression pharmacogenetic Figures Figure 1 Figure 2 Figure 3 Introduction Human Immunodeficiency Virus (HIV) infection is a risk factor for the development of tuberculosis (TB) 1 – 4 and treatment of both disease is of high priority for TB/HIV co-infection management 5 , 6 . However, TB and HIV regimens have drug-drug interactions and are also associated with toxicity 7 , which can impact the outcome of TB/HIV treatment in two ways: subtherapeutic concentrations can result in treatment failure and drug resistance, and supratherapeutic concentrations may be associated with treatment toxicity 8 – 10 . Moreover, the serum levels of some TB and HIV drugs can be influenced by single nucleotide polymorphisms (SNPs) of genes involved in the metabolism of these drugs 11 – 13 . Of the 25 antiretroviral therapy (ART) drugs approved by the Food and Drug Administration, nine (36%) are known to have SNPs associated with plasma exposure and/or side effects 14 – 25 . The proposed mechanisms of TB and HIV drug interactions are mainly related to substrate activity, particularly inhibition or induction of the hepatic system of cytochrome P450. Considering non-nucleoside reverse transcriptase inhibitors and integrase strand transfer inhibitors, the inducers of the enzymatic system (e.g., normal metabolizers) decrease serum drug concentrations, while inhibitors (e.g., slow metabolizers) increase the concentration 8 . The dynamics between anti-TB drugs, ART, SNPs, and TB/HIV treatment outcomes are not yet fully understood. This study described the SNPs of the Brazilian population and evaluated the relationship between SNPs known to be associated with ART metabolism and HIV virologic suppression among TB/HIV participants in a large, prospective, cohort study in Brazil. Methods Study design and population The Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil study enrolled participants with newly diagnosed, culture-confirmed, pulmonary TB at five sites across three regions in Brazil, between June 2015 and June 2019, and followed participants for two years. Sites were in Rio de Janeiro (Instituto Nacional de Infectologia Evandro Chagas, Clínica de Saúde Rinaldo Delmare, Secretaria de Saúde de Duque de Caxias), Salvador (Instituto Brasileiro para Investigação da Tuberculose), and Manaus (Fundação Medicina Tropical Dr. Heitor Vieira Dourado). The RePORT-Brazil population is broadly representative of TB cases in Brazil, as described previously. 26 , 27 For this study, we included RePORT-Brazil participants with TB/HIV who initiated standard TB therapy and received ART during TB treatment. Variables and definitions Clinical, demographic, and socio-economic data were collected longitudinally at baseline, month 2, and end of TB treatment visits, and during the follow-up period; for the latter, participants were contacted by telephone to assess signs and symptoms of TB recurrence. The standard TB regimen was defined as a two-month intensive phase of isoniazid, rifampicin or rifabutin, pyrazinamide, and ethambutol, followed by a four-month (or more) continuation phase of isoniazid and rifampicin or rifabutin. 28 All participants underwent HIV testing at baseline unless already known to be a person living with HIV/AIDS. We collected data on ART, CD4 cell count, and HIV-1 RNA viral load (VL). We classified ART regimens according to the main antiretroviral class that composed the 3-drug regimen 29 : non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). We considered only ART used during TB treatment and our focus was on NNRTI (efavirenz) and INSTI (dolutegravir, raltegravir), as these regimens were recommended ART in Brazil for TB/HIV coinfection during the study period 29 . CD4 count was categorized as: <50 cells/µL, 50–200 cells/µL, and ≥ 200 cells/µL. We considered VL as a categorical variable and, for the primary analysis, we defined VL as suppressed (< 1000 HIV-1 RNA viral copies/µL) and as non-suppressed (≥ 1000 HIV-1 RNA viral copies/µL). For the secondary analysis, we considered HIV virologic suppression as < 50 HIV-1 RNA viral copies/µL. RePORT-Brazil genotyped 60 selected polymorphisms in 29 genes relevant to TB or HIV drug metabolism, and for this study, we selected CYP2B6 and UGT1A1 , which are associated with the metabolism of efavirenz and dolutegravir/raltegravir, respectively. Genotyping was done using MassARRAY® iPLEX Gold (Agena Bioscience™, California, USA) and Taqman (ThermoFisher Scientific, Massachusetts, USA). Statistical Analysis Participant characteristics were described in the full study population and according to HIV-1 virologic suppression, summarizing continuous variables with median and interquartile range (IQR) and categorical variables with frequency and percentages. Composite CYP2B6 metabolizer genotype was defined based on combinations of three polymorphisms as follows: normal (1: 15582CC-516GG-983TT or 2: 15582CT-516GG-983TT); intermediate (3: 15582TT-516GG-983TT; 4: 15582CC-516GT-983TT; 5: 15582CC-516GG-983CT; 6: 15582CT-516GT-983TT; or 7: 15582CT-516GG-983CT); and slow (8: 15582CC-516TT-983TT; 9: 15582CC-516GT-983CT; 10: 15582CC-516GG-983CC) 30 . And the UGTA1A metabolizer genotype was defined normal (887829CC), intermediate (887829CT), and slow (887829TT) 31 . The normal genotypes for CYP2B6 and UGTA1A are the inducers of the enzymatic system, and thus, metabolize ARV faster. 14 , 25 The outcome of interest was HIV-1 virologic suppression after at least two weeks of ART exposure. We used Fisher’s exact test, and Z-score test to compare the outcomes proportions, grouping by ART class and SNP categories. Additionally, we performed a survival analysis to compare time-to-virologic suppression (with two different VL cutpoints), by ART groups and by SNP categories using the Wilcoxon-Gehan statistics. For this analysis, we considered the time-to-suppression variable in days since TB treatment start for ART-experienced participants and time since ART start for ART-naïve participants until up to six months after TB treatment ended. All analyses were performed using SPSS version 25.0, with a significance level of 0.05. Results Among 1,189 participants with TB in RePORT-Brazil, 221 (18.5%) had HIV, and 194 (88%) were included in the analysis. Twelve participants (5%) used non-standard TB treatment, and 14 (6.5%) never started ART ( Figure 1 ). In the primary analysis, virologic suppression was achieved in 68% of the participants (n=132). Overall, most of the participants were male (n=150, 77%), median age was 35 years (IQR 28-42), and 57% (n=111) were ART-naïve. The ART class most used was INSTI (51%), followed by NNRTI (40%) and PI (8%). Raltegravir was the most frequent INSTI (88%), while efavirenz, the most frequent NNRTI (99%). There were 46 (27%) and 82 (49%) participants with CYP2B6 and UGT1A1 normal (i.e., fastest) metabolizer genotypes, respectively ( Table 1 ). Irrespectively of the ART regimen, the overall virologic suppression was suboptimal (68%). Among participants with efavirenz-based ART, 36% (n=28) did not achieved virologic suppression, while among INSTI-based ART, 30% (n=30) did not achieved virologic suppression, with no significant difference in these proportions (p=0.34). Among them, the ones that received efavirenz-based ART were more likely to be CYP2B6 normal metabolizers (n=8, 44%); and among persons treated with INSTI-based ART, the UGT1A1 normal was also the most common (n=13, 50%) ( Table 2 ). The overall median time-to-virologic suppression, irrespective of efavirenz- or INSTI based ART, was 188 days (95% CI 172-203). For efavirenz-based ART, the median time was 184 days (95% CI 160-207), and for INSTI-based ART, 188 days (95% CI 144-231) (p=0.84) ( Figure 2 ). Among efavirenz-based ART, considering the CYP2B6 genotypes,the median time-to-suppression for normal, intermediate, and slow metabolizer profiles was 282 days, 180 days, and 210 days respectively (p=0.68). Among the INSTI-based ART, the UGT1A1 normal metabolizer genotype had a median time-to-virologic suppression of 146 days, while intermediate of 253 days, and slow of 135 days (p=0.26) ( Figure 3A, and 3B, respectively). In the secondary analysis, lowering the VL cutpoint to <50 HIV-1 RNA viral copies/mL to define virologic suppression, more participants did not achieve the desire outcome. And among them, the proportion of normal metabolizers for CYP2B6 and UGT1A1 were again higher, although with no significance difference. The time-to-virologic suppression did not differ statistically among efavirenz-based and INSTI-based ART regimens and among CYP2B6 and UGT1A1 metabolizers genotypes ( Supplemental Table 1 , Supplemental Figure 1 , and Supplemental Figure 2A and 2B ). Discussion We evaluated HIV-1 virologic suppression according to the genetic variants that affect NNRTI and INSTI metabolism among TB/HIV participants in Brazil. The virologic suppression was suboptimal, irrespective of efavirenz- vs INSTI-based ART regimens. Different from the literature, 32 the time-to-virologic suppression between efavirenz- and INSTI-based regimens was similar, as well as between their metabolizer genotypes. However, among the ones not achieving virologic suppression, there was a higher proportion of CYP2B6 and UGT1A1 normal metabolizer genotypes, which is an expected finding. 30 , 33 , 34 Moreover, we were expecting to find faster time-to-virologic suppression and higher rates of virologic suppression among INSTI-based regimens, compared to efavirenz-based regimens 32 , 35 , 36 , but no significant differences were found. INSTI-based regimens were more commonly used than efavirenz-based regimens. This may be explained by a trend in recommendation for primary ART regimen for treatment-naïve TB/HIV patients in Brazil in 2017. Moreover, rates of resistance to efavirenz in the world and in Brazil is high – ranging from 3.4–5.5% and could exceed 10% 37 . This precludes using efavirenz-based regimens as a first line ART without baseline HIV-1 genotyping. 38 , 39 For that reason, since 2017, for TB/HIV patients meeting the criteria of severe disease – i.e., CD4 cell count < 100 cells/µL, disseminated TB, other concomitant opportunistic infection, and hospitalized patients –, the recommended ART regimen was to include raltegravir; and efavirenz-based treatment was recommended for TB/HIV without severe disease. However, since 2019, the first- line ART regimen recommended for TB/HIV participants has been a double dose dolutegravir-based ART regimen, expecting to increase effectiveness as dolutegravir is a safe and well tolerated drug, with a higher genetic barrier to resistance. 40 Raltegravir is no longer recommended as an option for TB/HIV patients. 9 , 41 Efavirenz-based regimens are also well-tolerated, but neuropsychiatric adverse reactions, and primary and acquired resistance, can limit its use. 42 , 43 Regarding the genetic variants, we found higher proportions of UGT1A1 and CYP2B6 normal metabolizer genotypes among participants not achieving virologic suppression. And this is expected as the faster the ART is metabolized, the lower will be its bioavailability, leading to lower drug exposure, and ultimately not suppressing the HIV-1 VL. This finding suggests an association, that could be stronger if there were a larger sample size. Our study had limitations. We were unable to handle the VL as a continuous variable because not all participants had VL measured at the same timepoint during the follow up. Not all participants had SNPs available, and we did not evaluate HIV-1 treatment toxicity. Conversely, we highlight that we had a prospective cohort study that is representative of the Brazilian population 26 , with important data on human genetic variants and ART, as well as treatment outcomes, and UGT1A1 and CYP2B6 metabolizer profiles. In this observational cohort of patients treated for TB/HIV, the proportion of participants achieving virologic suppression was low, and genetic variants affecting ART metabolism were not significantly associated with the likelihood of virologic suppression. Declarations Ethics approval and consent to participate The RePORT-Brazil study was approved by the institutional review board of the Instituto Nacional de Infectologia Evandro Chagas (CAAE: 25102412.3.1001.5262), by the institutional review boards of the other study sites, and Vanderbilt University Medical Center. Written informed consent was obtained from all participants and all clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki. Consent for publication - not applicable Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was funded by the Departamento de Ciência e Tecnologia (DECIT) - Secretaria de Ciência e Tecnologia (SCTIE) – Ministério da Saúde (MS), Brazil (25029.000507/2013-07 to V. C. R.), the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID): (U01 AI069923; R01 A1120790; F31 AI152614 to T.R.S.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. And this study was also financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES) – Finance Code 001, CAPES-PrInt 88887.694717/2022-00 to F.R. Authors' contributions F.R., T.R.S., and V.C.R. conceptualized the research question and drafted the initial manuscript. F.R. and G.A. conducted the analysis. V.R. and T.R.S. provided thorough feedback on the research design and analysis interpretation, supervised the analysis, and revised successive drafts of the manuscript. B.A., M.A., and D.W.H. provided valuable feedback and comments on successive manuscript drafts. 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Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS Lond Engl. 2013 Jun 1;27(9):1403–12. Tables Tables 1 to 2 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files BMCIDSupplementaryMaterial.docx Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5418156","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":377340544,"identity":"cb0418ed-54d6-4677-8757-6dd57cdd8971","order_by":0,"name":"Felipe Ridolfi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIie3RsQrCMBCA4SuFdomd46KvcOAkiL6KpeAk2NFBJS76Cn0MH8DhSkAX0c0lS12cFVcRUxRBMLWjYP4pBD4uRwBsth/MF66g/OBB16Ehtr4TRs6LAG2wV448jzkBWYL406mMhzAI/IiI4l242MsMzsuxmbBUyGQDzRk7dolQhQvVQyc5ro2kw0MhKzNAj/dRnlA1UPXBZbQyT6kfNLk9iJ6yLUG4o4l4Eao9yahgF/2wZMXRe+wS1ap6lzQhMhNfyks8amF9HqUZXdssUNEhO9HESPJcAP5+o0cUf5D76bJ4is1ms/1Vd+gqXQbn4OmjAAAAAElFTkSuQmCC","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Felipe","middleName":"","lastName":"Ridolfi","suffix":""},{"id":377340545,"identity":"59626ffa-c12f-4d7f-8326-718278008ae5","order_by":1,"name":"Gustavo Amorim","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Gustavo","middleName":"","lastName":"Amorim","suffix":""},{"id":377340546,"identity":"0a4229c4-1215-47e9-b94b-1add3d5598c7","order_by":2,"name":"David W. Haas","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"W.","lastName":"Haas","suffix":""},{"id":377340548,"identity":"355d9423-14b9-4795-81a0-c1382b1bf8d9","order_by":3,"name":"Maria Arriaga","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Arriaga","suffix":""},{"id":377340549,"identity":"57820ade-9247-4bcb-8719-4754edf9a1cb","order_by":4,"name":"Cody Staats","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Cody","middleName":"","lastName":"Staats","suffix":""},{"id":377340550,"identity":"7034be58-fed7-4fc4-a776-75967e17fbff","order_by":5,"name":"Marcelo Cordeiro-Santos","email":"","orcid":"","institution":"Fundação Medicina Tropical Dr. Heitor Vieira Dourado","correspondingAuthor":false,"prefix":"","firstName":"Marcelo","middleName":"","lastName":"Cordeiro-Santos","suffix":""},{"id":377340551,"identity":"fbe52d3e-85fc-4025-a75a-c0eef2709e28","order_by":6,"name":"Afrânio L. Kritski","email":"","orcid":"","institution":"Universidade Federal do Rio de Janeiro","correspondingAuthor":false,"prefix":"","firstName":"Afrânio","middleName":"L.","lastName":"Kritski","suffix":""},{"id":377340552,"identity":"2d093f2c-956d-4824-932b-04302553ddec","order_by":7,"name":"Marina C. Figueiredo","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Marina","middleName":"C.","lastName":"Figueiredo","suffix":""},{"id":377340553,"identity":"4729ff5b-092b-43c6-ac46-236530a95e7d","order_by":8,"name":"Bruno B. Andrade","email":"","orcid":"","institution":"Instituto Gonçalo Moniz, Fundação Oswaldo Cruz","correspondingAuthor":false,"prefix":"","firstName":"Bruno","middleName":"B.","lastName":"Andrade","suffix":""},{"id":377340554,"identity":"4bdc1506-c98f-4289-b99c-38464ad46c67","order_by":9,"name":"Timothy R. Sterling","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Timothy","middleName":"R.","lastName":"Sterling","suffix":""},{"id":377340555,"identity":"dda82424-8cb1-464c-84a9-514ad51ef9ca","order_by":10,"name":"Valeria C. Rolla","email":"","orcid":"","institution":"Instituto Nacional de Infectologia Evandro Chagas","correspondingAuthor":false,"prefix":"","firstName":"Valeria","middleName":"C.","lastName":"Rolla","suffix":""},{"id":377340556,"identity":"f1857787-c6aa-44fe-8922-50cdda93d1b4","order_by":11,"name":"Regional Prospective Observational Research in Tuberculosis Brazil consortium (RePORT-Brazil)","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Regional","middleName":"Prospective Observational Research in Tuberculosis Brazil consortium","lastName":"(RePORT-Brazil)","suffix":""}],"badges":[],"createdAt":"2024-11-08 17:23:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5418156/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5418156/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71563054,"identity":"70907290-a971-4117-89f3-aa7452bbbbcb","added_by":"auto","created_at":"2024-12-16 17:15:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31045,"visible":true,"origin":"","legend":"\u003cp\u003eStudy diagram\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5418156/v1/866a1ab90aa3e52a1d6e8017.png"},{"id":71563056,"identity":"603beba4-4b85-4409-b051-da056d1d11b8","added_by":"auto","created_at":"2024-12-16 17:15:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":42888,"visible":true,"origin":"","legend":"\u003cp\u003eTime-to-HIV-1 virologic suppression (\u0026lt;1,000 viral copies/mL) in days, according to ART regimen (Efavirenz vs INSTI)\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFootnote:\u003c/u\u003e ART: antiretroviral therapy; INSTI: integrase strand transfer inhibitors: raltegravir or dolutegravir. Statistical test: Wilcoxon-Gehan test (survival analysis), significance level .05.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5418156/v1/168367834429c42d90563b28.png"},{"id":71563055,"identity":"e6e8f326-7f0c-42bc-a67e-d8a584c42e30","added_by":"auto","created_at":"2024-12-16 17:15:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":94496,"visible":true,"origin":"","legend":"\u003cp\u003eTime-to-HIV-1 virologic suppression (\u0026lt;1,000 viral copies/mL), according to \u003cstrong\u003e(A)\u003c/strong\u003e \u003cem\u003eCYP2B6\u003c/em\u003e (Efavirenz) genotypes and\u003cem\u003e \u003c/em\u003e\u003cstrong\u003e(B) \u003c/strong\u003e\u003cem\u003eUGT1A1\u003c/em\u003e (INSTI)\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFootnote:\u003c/u\u003e ART: antiretroviral therapy; EFZ: efavirenz (a non-nucleoside reverse transcriptase inhibitor [NNRTI]); INSTI: integrase strand transfer inhibitors: raltegravir or dolutegravir. Statistical test: Wilcoxon-Gehan test (survival analysis), significance level .05.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5418156/v1/84cbf29f09d2c2f7c6c0133b.png"},{"id":71565069,"identity":"67194c23-625c-44ba-9ca1-a97e26df1f8d","added_by":"auto","created_at":"2024-12-16 17:31:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":542157,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5418156/v1/e723423d-b73f-4c88-97c7-99e6c3bd9964.pdf"},{"id":71563058,"identity":"3348b40e-68b8-42d6-9c9f-3b256a9b07f3","added_by":"auto","created_at":"2024-12-16 17:15:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1905336,"visible":true,"origin":"","legend":"","description":"","filename":"BMCIDSupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-5418156/v1/bbb0946f6094e36807ebfbdb.docx"},{"id":71563933,"identity":"dd2edd9c-3d38-4b8a-994f-10e1a6fb851e","added_by":"auto","created_at":"2024-12-16 17:23:09","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":40540,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5418156/v1/ec89bec72ded6684a2074984.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pharmacogenomic associations with HIV-1 virologic suppression in TB/HIV patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHuman Immunodeficiency Virus (HIV) infection is a risk factor for the development of tuberculosis (TB)\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e and treatment of both disease is of high priority for TB/HIV co-infection management \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, TB and HIV regimens have drug-drug interactions and are also associated with toxicity\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, which can impact the outcome of TB/HIV treatment in two ways: subtherapeutic concentrations can result in treatment failure and drug resistance, and supratherapeutic concentrations may be associated with treatment toxicity\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Moreover, the serum levels of some TB and HIV drugs can be influenced by single nucleotide polymorphisms (SNPs) of genes involved in the metabolism of these drugs\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Of the 25 antiretroviral therapy (ART) drugs approved by the Food and Drug Administration, nine (36%) are known to have SNPs associated with plasma exposure and/or side effects\u003csup\u003e\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. The proposed mechanisms of TB and HIV drug interactions are mainly related to substrate activity, particularly inhibition or induction of the hepatic system of cytochrome P450. Considering non-nucleoside reverse transcriptase inhibitors and integrase strand transfer inhibitors, the inducers of the enzymatic system (e.g., normal metabolizers) decrease serum drug concentrations, while inhibitors (e.g., slow metabolizers) increase the concentration\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe dynamics between anti-TB drugs, ART, SNPs, and TB/HIV treatment outcomes are not yet fully understood. This study described the SNPs of the Brazilian population and evaluated the relationship between SNPs known to be associated with ART metabolism and HIV virologic suppression among TB/HIV participants in a large, prospective, cohort study in Brazil.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003e The Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil study enrolled participants with newly diagnosed, culture-confirmed, pulmonary TB at five sites across three regions in Brazil, between June 2015 and June 2019, and followed participants for two years. Sites were in Rio de Janeiro (Instituto Nacional de Infectologia Evandro Chagas, Cl\u0026iacute;nica de Sa\u0026uacute;de Rinaldo Delmare, Secretaria de Sa\u0026uacute;de de Duque de Caxias), Salvador (Instituto Brasileiro para Investiga\u0026ccedil;\u0026atilde;o da Tuberculose), and Manaus (Funda\u0026ccedil;\u0026atilde;o Medicina Tropical Dr. Heitor Vieira Dourado). The RePORT-Brazil population is broadly representative of TB cases in Brazil, as described previously.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e For this study, we included RePORT-Brazil participants with TB/HIV who initiated standard TB therapy and received ART during TB treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eVariables and definitions\u003c/h2\u003e \u003cp\u003eClinical, demographic, and socio-economic data were collected longitudinally at baseline, month 2, and end of TB treatment visits, and during the follow-up period; for the latter, participants were contacted by telephone to assess signs and symptoms of TB recurrence.\u003c/p\u003e \u003cp\u003eThe standard TB regimen was defined as a two-month intensive phase of isoniazid, rifampicin or rifabutin, pyrazinamide, and ethambutol, followed by a four-month (or more) continuation phase of isoniazid and rifampicin or rifabutin.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAll participants underwent HIV testing at baseline unless already known to be a person living with HIV/AIDS. We collected data on ART, CD4 cell count, and HIV-1 RNA viral load (VL). We classified ART regimens according to the main antiretroviral class that composed the 3-drug regimen\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e: non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). We considered only ART used during TB treatment and our focus was on NNRTI (efavirenz) and INSTI (dolutegravir, raltegravir), as these regimens were recommended ART in Brazil for TB/HIV coinfection during the study period\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. CD4 count was categorized as: \u0026lt;50 cells/\u0026micro;L, 50\u0026ndash;200 cells/\u0026micro;L, and \u0026ge;\u0026thinsp;200 cells/\u0026micro;L. We considered VL as a categorical variable and, for the primary analysis, we defined VL as suppressed (\u0026lt;\u0026thinsp;1000 HIV-1 RNA viral copies/\u0026micro;L) and as non-suppressed (\u0026ge;\u0026thinsp;1000 HIV-1 RNA viral copies/\u0026micro;L). For the secondary analysis, we considered HIV virologic suppression as \u0026lt;\u0026thinsp;50 HIV-1 RNA viral copies/\u0026micro;L.\u003c/p\u003e \u003cp\u003eRePORT-Brazil genotyped 60 selected polymorphisms in 29 genes relevant to TB or HIV drug metabolism, and for this study, we selected \u003cem\u003eCYP2B6\u003c/em\u003e and \u003cem\u003eUGT1A1\u003c/em\u003e, which are associated with the metabolism of efavirenz and dolutegravir/raltegravir, respectively. Genotyping was done using MassARRAY\u0026reg; iPLEX Gold (Agena Bioscience\u0026trade;, California, USA) and Taqman (ThermoFisher Scientific, Massachusetts, USA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eParticipant characteristics were described in the full study population and according to HIV-1 virologic suppression, summarizing continuous variables with median and interquartile range (IQR) and categorical variables with frequency and percentages.\u003c/p\u003e \u003cp\u003eComposite \u003cem\u003eCYP2B6\u003c/em\u003e metabolizer genotype was defined based on combinations of three polymorphisms as follows: normal (1: 15582CC-516GG-983TT or 2: 15582CT-516GG-983TT); intermediate (3: 15582TT-516GG-983TT; 4: 15582CC-516GT-983TT; 5: 15582CC-516GG-983CT; 6: 15582CT-516GT-983TT; or 7: 15582CT-516GG-983CT); and slow (8: 15582CC-516TT-983TT; 9: 15582CC-516GT-983CT; 10: 15582CC-516GG-983CC) \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. And the \u003cem\u003eUGTA1A\u003c/em\u003e metabolizer genotype was defined normal (887829CC), intermediate (887829CT), and slow (887829TT) \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. The normal genotypes for \u003cem\u003eCYP2B6\u003c/em\u003e and \u003cem\u003eUGTA1A\u003c/em\u003e are the inducers of the enzymatic system, and thus, metabolize ARV faster. \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e The outcome of interest was HIV-1 virologic suppression after at least two weeks of ART exposure.\u003c/p\u003e \u003cp\u003eWe used Fisher\u0026rsquo;s exact test, and Z-score test to compare the outcomes proportions, grouping by ART class and SNP categories. Additionally, we performed a survival analysis to compare time-to-virologic suppression (with two different VL cutpoints), by ART groups and by SNP categories using the Wilcoxon-Gehan statistics. For this analysis, we considered the time-to-suppression variable in days since TB treatment start for ART-experienced participants and time since ART start for ART-na\u0026iuml;ve participants until up to six months after TB treatment ended. All analyses were performed using SPSS version 25.0, with a significance level of 0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAmong 1,189 participants with TB in RePORT-Brazil, 221 (18.5%) had HIV, and 194 (88%) were included in the analysis. Twelve participants (5%) used non-standard TB treatment, and 14 (6.5%) never started ART (\u003cstrong\u003eFigure 1\u003c/strong\u003e). In the primary analysis, virologic suppression was achieved in 68% of the participants (n=132). Overall, most of the participants were male (n=150, 77%), median age was 35 years (IQR 28-42), and 57% (n=111) were ART-naïve. The ART class most used was INSTI (51%), followed by NNRTI (40%) and PI (8%). Raltegravir was the most frequent INSTI (88%), while efavirenz, the most frequent NNRTI (99%). There were 46 (27%) and 82 (49%) participants with \u003cem\u003eCYP2B6\u0026nbsp;\u003c/em\u003eand \u003cem\u003eUGT1A1\u003c/em\u003e normal (i.e., fastest) metabolizer genotypes, respectively (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eIrrespectively of the ART regimen, the overall virologic suppression was suboptimal (68%). Among participants with efavirenz-based ART, 36% (n=28) did not achieved virologic suppression, while among INSTI-based ART, 30% (n=30) did not achieved virologic suppression, with no significant difference in these proportions (p=0.34). \u0026nbsp;Among them, the ones that received efavirenz-based ART were more likely to be \u003cem\u003eCYP2B6\u003c/em\u003e normal metabolizers (n=8, 44%); and among persons treated with INSTI-based ART, the \u003cem\u003eUGT1A1\u003c/em\u003e normal was also the most common (n=13, 50%) (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eThe overall median time-to-virologic suppression, irrespective of efavirenz- or INSTI based ART, was 188 days (95% CI 172-203). For efavirenz-based ART, the median time was 184 days (95% CI 160-207), and for INSTI-based ART, 188 days (95% CI 144-231) (p=0.84) (\u003cstrong\u003eFigure 2\u003c/strong\u003e). Among efavirenz-based ART, considering the \u003cem\u003eCYP2B6\u003c/em\u003e genotypes,the median time-to-suppression for normal, intermediate, and slow metabolizer profiles was 282 days, 180 days, and 210 days respectively (p=0.68). Among the INSTI-based ART, the \u003cem\u003eUGT1A1\u003c/em\u003e normal metabolizer genotype had a median time-to-virologic suppression of 146 days, while intermediate of 253 days, and slow of 135 days (p=0.26) (\u003cstrong\u003eFigure 3A, and 3B,\u0026nbsp;\u003c/strong\u003erespectively).\u003c/p\u003e\n\u003cp\u003eIn the secondary analysis, lowering the VL cutpoint to \u0026lt;50 HIV-1 RNA viral copies/mL to define virologic suppression, more participants did not achieve the desire outcome. And among them, the proportion of normal metabolizers for \u003cem\u003eCYP2B6\u003c/em\u003e and \u003cem\u003eUGT1A1\u003c/em\u003e were again higher, although with no significance difference. The time-to-virologic suppression did not differ statistically among efavirenz-based and INSTI-based ART regimens and among \u003cem\u003eCYP2B6\u003c/em\u003e and \u003cem\u003eUGT1A1\u003c/em\u003e metabolizers genotypes (\u003cstrong\u003eSupplemental Table 1\u003c/strong\u003e, \u003cstrong\u003eSupplemental Figure 1\u003c/strong\u003e, and\u003cstrong\u003e\u0026nbsp;Supplemental Figure 2A\u0026nbsp;\u003c/strong\u003eand\u0026nbsp;\u003cstrong\u003e2B\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e We evaluated HIV-1 virologic suppression according to the genetic variants that affect NNRTI and INSTI metabolism among TB/HIV participants in Brazil. The virologic suppression was suboptimal, irrespective of efavirenz- vs INSTI-based ART regimens. Different from the literature,\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e the time-to-virologic suppression between efavirenz- and INSTI-based regimens was similar, as well as between their metabolizer genotypes. However, among the ones not achieving virologic suppression, there was a higher proportion of \u003cem\u003eCYP2B6\u003c/em\u003e and \u003cem\u003eUGT1A1\u003c/em\u003e normal metabolizer genotypes, which is an expected finding.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e Moreover, we were expecting to find faster time-to-virologic suppression and higher rates of virologic suppression among INSTI-based regimens, compared to efavirenz-based regimens\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, but no significant differences were found.\u003c/p\u003e \u003cp\u003eINSTI-based regimens were more commonly used than efavirenz-based regimens. This may be explained by a trend in recommendation for primary ART regimen for treatment-na\u0026iuml;ve TB/HIV patients in Brazil in 2017. Moreover, rates of resistance to efavirenz in the world and in Brazil is high \u0026ndash; ranging from 3.4\u0026ndash;5.5% and could exceed 10%\u003csup\u003e37\u003c/sup\u003e. This precludes using efavirenz-based regimens as a first line ART without baseline HIV-1 genotyping. \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e For that reason, since 2017, for TB/HIV patients meeting the criteria of severe disease \u0026ndash; i.e., CD4 cell count\u0026thinsp;\u0026lt;\u0026thinsp;100 cells/\u0026micro;L, disseminated TB, other concomitant opportunistic infection, and hospitalized patients \u0026ndash;, the recommended ART regimen was to include raltegravir; and efavirenz-based treatment was recommended for TB/HIV without severe disease. However, since 2019, the first- line ART regimen recommended for TB/HIV participants has been a double dose dolutegravir-based ART regimen, expecting to increase effectiveness as dolutegravir is a safe and well tolerated drug, with a higher genetic barrier to resistance.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e Raltegravir is no longer recommended as an option for TB/HIV patients.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e Efavirenz-based regimens are also well-tolerated, but neuropsychiatric adverse reactions, and primary and acquired resistance, can limit its use.\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRegarding the genetic variants, we found higher proportions of \u003cem\u003eUGT1A1\u003c/em\u003e and \u003cem\u003eCYP2B6\u003c/em\u003e normal metabolizer genotypes among participants not achieving virologic suppression. And this is expected as the faster the ART is metabolized, the lower will be its bioavailability, leading to lower drug exposure, and ultimately not suppressing the HIV-1 VL. This finding suggests an association, that could be stronger if there were a larger sample size.\u003c/p\u003e \u003cp\u003eOur study had limitations. We were unable to handle the VL as a continuous variable because not all participants had VL measured at the same timepoint during the follow up. Not all participants had SNPs available, and we did not evaluate HIV-1 treatment toxicity. Conversely, we highlight that we had a prospective cohort study that is representative of the Brazilian population\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, with important data on human genetic variants and ART, as well as treatment outcomes, and \u003cem\u003eUGT1A1\u003c/em\u003e and \u003cem\u003eCYP2B6\u003c/em\u003e metabolizer profiles.\u003c/p\u003e \u003cp\u003eIn this observational cohort of patients treated for TB/HIV, the proportion of participants achieving virologic suppression was low, and genetic variants affecting ART metabolism were not significantly associated with the likelihood of virologic suppression.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe RePORT-Brazil study was approved by the institutional review board of the Instituto Nacional de Infectologia Evandro Chagas (CAAE: 25102412.3.1001.5262), by the institutional review boards of the other study sites, and Vanderbilt University Medical Center. Written informed consent was obtained from all participants and all clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication -\u0026nbsp;\u003c/strong\u003enot applicable\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by the Departamento de Ci\u0026ecirc;ncia e Tecnologia (DECIT) - Secretaria de Ci\u0026ecirc;ncia e Tecnologia (SCTIE) \u0026ndash; Minist\u0026eacute;rio da Sa\u0026uacute;de (MS), Brazil (25029.000507/2013-07 to V. C. R.), the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID): (U01 AI069923; R01 A1120790; F31 AI152614 to T.R.S.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. And this study was also financed in part by the Coordena\u0026ccedil;\u0026atilde;o de Aperfei\u0026ccedil;oamento de Pessoal de N\u0026iacute;vel Superior \u0026ndash; Brazil (CAPES) \u0026ndash; Finance Code 001, CAPES-PrInt 88887.694717/2022-00 to F.R.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eF.R., T.R.S., and V.C.R. conceptualized the research question and drafted the initial manuscript. F.R. and G.A. conducted the analysis. V.R. and T.R.S. provided thorough feedback on the research design and analysis interpretation, supervised the analysis, and revised successive drafts of the manuscript. B.A., M.A., and D.W.H. provided valuable feedback and comments on successive manuscript drafts. B.A., M.C.S., A.K., C.S., T.R.S., V.R., and M.C.F. played pivotal roles in the conceptualization of the RePORT-Brazil cohort, project administration, data and funding acquisition, and revised successive drafts of the manuscript. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the study participants, the teams of clinical and laboratory platforms of all RePORT Brazil consortium sites.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePai M, Behr MA, Dowdy D, Dheda K, Divangahi M, Boehme CC, et al. Tuberculosis. 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Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial. Lancet Infect Dis. 2021 Jun;21(6):813\u0026ndash;22.\u003c/li\u003e\n\u003cli\u003eDalal B, Shankarkumar A, Ghosh K. Individualization of antiretroviral therapy - Pharmacogenomic aspect. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26831415/\u003c/li\u003e\n\u003cli\u003eSwaminathan S, Ramachandran G. Role of pharmacogenomics in the treatment of tuberculosis: a review. Pharmacogenomics Pers Med [Internet]. 2012 Sep 1; Available from: https://doi.org/10.2147%2Fpgpm.s15454\u003c/li\u003e\n\u003cli\u003eAzuma J, Ohno M, Kubota R, Yokota S, Nagai T, Tsuyuguchi K, et al. 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Antimicrob Agents Chemother. 2014 Jul 12;58(7):4145\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003eBertrand J, Verstuyft C, Chou M, Borand L, Chea P, Nay KH, et al. Dependence of efavirenz- and rifampicin-isoniazid-based antituberculosis treatment drug-drug interaction on CYP2B6 and NAT2 genetic polymorphisms: ANRS 12154 study in Cambodia.: ANRS 12154 Study in Cambodia. J Infect Dis. 2014 Feb 1;209(3):399\u0026ndash;408.\u003c/li\u003e\n\u003cli\u003eLuetkemeyer AF, Rosenkranz SL, Lu D, Grinsztejn B, Sanchez J, Ssemmanda M, et al. Combined effect of CYP2B6 and NAT2 genotype on plasma efavirenz exposure during rifampin-based antituberculosis therapy in the STRIDE study. Clin Infect Dis Off Publ Infect Dis Soc Am. 2015 Jun 15;60(12):1860\u0026ndash;3.\u003c/li\u003e\n\u003cli\u003eChen S, St Jean P, Borland J, Song I, Yeo AJ, Piscitelli S, et al. Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics. Pharmacogenomics. 2014 Jan 1;15(1):9\u0026ndash;16. \u003c/li\u003e\n\u003cli\u003eArriaga M, Amorim G, Queiroz A, Rodrigues M, Pereira M, Nogueira B, et al. Novel Stepwise Approach to Assess Representativeness of a Large Multicenter Observational Cohort of Tuberculosis Patients: The Example of RePORT Brazil. Int J Infect Dis. 2020 Nov 14;11:140. \u003c/li\u003e\n\u003cli\u003ePeetluk LS, Rebeiro PF, Ridolfi FM, Andrade BB, Cordeiro-Santos M, Kritski A, et al. A clinical prediction model for unsuccessful pulmonary tuberculosis treatment outcomes. Clin Infect Dis. 2021 Jul 2;(ciab598).\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient care: 2017 update. Geneva, Switzerland; 2017. \u003c/li\u003e\n\u003cli\u003eSecretaria de Vigil\u0026acirc;ncia em Sa\u0026uacute;de. Departamento de Vigil\u0026acirc;ncia, Preven\u0026ccedil;\u0026atilde;o e Controle das Infec\u0026ccedil;\u0026otilde;es Sexualmente Transmiss\u0026iacute;veis, do HIV/Aids e das Hepatites Virais, Minist\u0026eacute;rio da Sa\u0026uacute;de. Protocolo Cl\u0026iacute;nico e Diretrizes Terap\u0026ecirc;uticas para Manejo da Infec\u0026ccedil;\u0026atilde;o pelo HIV em Adultos. Bras\u0026iacute;lia; 2018. 412 p. \u003c/li\u003e\n\u003cli\u003eHolzinger ER, Grady B, Ritchie MD, Ribaudo HJ, Acosta EP, Morse GD, et al. Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants. Pharmacogenet Genomics. 2012 Dec;22(12):858\u0026ndash;67.\u003c/li\u003e\n\u003cli\u003eCindi Z, Kawuma AN, Maartens G, Bradford Y, Venter F, Sokhela S, et al. Pharmacogenetics of Dolutegravir Plasma Exposure Among Southern Africans With Human Immunodeficiency Virus. J Infect Dis. 2022 Nov 1;226(9):1616\u0026ndash;25.\u003c/li\u003e\n\u003cli\u003eMahale PR, Patel BS, Kasmani N. Treatment Outcomes of Dolutegravir- Versus Efavirenz-Based Highly Active Antiretroviral Therapy Regimens Among Treatment-Naive People Living With HIV. Cureus. 15(6):e40139.\u003c/li\u003e\n\u003cli\u003eChen S, St Jean P, Borland J, Song I, Yeo AJ, Piscitelli S, et al. Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics. Pharmacogenomics. 2014 Jan;15(1):9\u0026ndash;16.\u003c/li\u003e\n\u003cli\u003eLuetkemeyer AF, Rosenkranz SL, Lu D, Grinsztejn B, Sanchez J, Ssemmanda M, et al. Combined effect of CYP2B6 and NAT2 genotype on plasma efavirenz exposure during rifampin-based antituberculosis therapy in the STRIDE study. Clin Infect Dis Off Publ Infect Dis Soc Am. 2015 Jun 15;60(12):1860\u0026ndash;3.\u003c/li\u003e\n\u003cli\u003eRutherford GW, Horvath H. Dolutegravir Plus Two Nucleoside Reverse Transcriptase Inhibitors versus Efavirenz Plus Two Nucleoside Reverse Transcriptase Inhibitors As Initial Antiretroviral Therapy for People with HIV: A Systematic Review. PloS One. 2016;11(10):e0162775. \u003c/li\u003e\n\u003cli\u003eDooley KE, Kaplan R, Mwelase N, Grinsztejn B, Ticona E, Lacerda M, et al. Dolutegravir-based Antiretroviral Therapy for Patients Coinfected With Tuberculosis and Human Immunodeficiency Virus: A Multicenter, Noncomparative, Open-label, Randomized Trial. Clin Infect Dis Off Publ Infect Dis Soc Am. 2020 Feb 3;70(4):549\u0026ndash;56.\u003c/li\u003e\n\u003cli\u003eGupta RK, Gregson J, Parkin N, Haile-Selassie H, Tanuri A, Andrade Forero L, et al. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect Dis. 2018 Mar;18(3):346\u0026ndash;55. \u003c/li\u003e\n\u003cli\u003eFerreira ACG, Coelho LE, Grinsztejn E, Jesus CS de, Guimar\u0026atilde;es ML, Veloso VG, et al. Transmitted drug resistance in patients with acute/recent HIV infection in Brazil. Braz J Infect Dis Off Publ Braz Soc Infect Dis. 2017;21(4):396\u0026ndash;401.\u003c/li\u003e\n\u003cli\u003eArruda MB, Boullosa LT, Cardoso CC, da Costa CM, Alves CR, de Lima ST, et al. Brazilian network for HIV Drug Resistance Surveillance (HIV-BresNet): a survey of treatment-naive individuals. J Int AIDS Soc. 2018 Mar;21(3):e25032. \u003c/li\u003e\n\u003cli\u003eSecretaria de Vigil\u0026acirc;ncia em Sa\u0026uacute;de. Departamento de Vigil\u0026acirc;ncia, Preven\u0026ccedil;\u0026atilde;o e Controle das Infec\u0026ccedil;\u0026otilde;es Sexualmente Transmiss\u0026iacute;veis, do HIV/Aids e das Hepatites Virais M da. Protocolo Cl\u0026iacute;nico e Diretrizes Terap\u0026ecirc;uticas para Manejo da Infec\u0026ccedil;\u0026atilde;o pelo HIV em Adultos M\u0026oacute;dulo 1: Tratamento. Bras\u0026iacute;lia (DF), Brasil; 2023. \u003c/li\u003e\n\u003cli\u003eGrinsztejn B, De Castro N, Arnold V, Veloso VG, Morgado M, Pilotto JH, et al. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis. 2014 Jun;14(6):459\u0026ndash;67.\u003c/li\u003e\n\u003cli\u003eP\u0026eacute;rez-Molina JA. Safety and tolerance of efavirenz in different antiretroviral regimens: results from a national multicenter prospective study in 1,033 HIV-infected patients. HIV Clin Trials. 2002;3(4):279\u0026ndash;86.\u003c/li\u003e\n\u003cli\u003eShubber Z, Calmy A, Andrieux-Meyer I, Vitoria M, Renaud-Th\u0026eacute;ry F, Shaffer N, et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS Lond Engl. 2013 Jun 1;27(9):1403\u0026ndash;12. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 2 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"TB/HIV, genetic polymorphisms, HIV-1 treatment, virologic suppression, pharmacogenetic","lastPublishedDoi":"10.21203/rs.3.rs-5418156/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5418156/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Human genetic variants can affect TB and HIV drug metabolism, which may lead to toxicity or treatment failure. We evaluated associations between genetic variants of antiretroviral therapy (ART) and HIV-1 outcomes among TB/HIV patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe included RePORT-Brazil participants with TB/HIV who initiated standard TB treatment [2 months of isoniazid/rifampicin (or rifabutin)/pyrazinamide/ethambutol, then 4 months or more of isoniazid/rifampicin (or rifabutin)], and ART. The endpoint was HIV-1 virologic suppression (defined as \u0026lt;1,000 HIV-1 RNA copies/mL, for primary analysis, and \u0026lt;50 HIV-1 RNA copies/mL, for secondary analysis) after at least 2 weeks of ART. We compared non-nucleoside reverse transcriptase inhibitor (NNRTI)-based and integrase strand transfer inhibitor (INSTI)-based ART regimens. We genotyped \u003cem\u003eCYP2B6\u003c/em\u003e (rs3745274, rs28399499, rs4803419; affects efavirenz metabolism) and \u003cem\u003eUGT1A1\u003c/em\u003e (rs887829; affects dolutegravir and raltegravir metabolism); all have defined normal, intermediate, and slow genotypes. Genotyping was performed by MassARRAY iPLEX Gold. We compared outcome proportions (Fisher’s test) and time-to- virologic suppression (survival analysis, Wilcoxon-Gehan test).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong 194 TB/HIV participants included, efavirenz was the most frequent NNRTI ([n=76], one participant received etravirine), and raltegravir was the most frequent INSTI (n=88). The overall virologic suppression was suboptimal, with 32% (n=62) of participants not achieving HIV-1 virologic suppression. Among them, 36% (n=28) used efavirenz-based ART and were more likely to be \u003cem\u003eCYP2B6\u003c/em\u003e normal metabolizers (n=8, 44%); and 30% (n=30) used INSTI-based ART and the \u003cem\u003eUGT1A1\u003c/em\u003e normal genotype was also the most common (n=13, 50%). The median time to virologic suppression for efavirenz-based ART was 184 days (95% Confidence Interval (CI)160-207), and for INSTI-based ART, 188 days (95% CI 144-231) (p=0.84). No significant associations were found comparing the proportions and time to virologic suppression among \u003cem\u003eCYP2B6\u003c/em\u003e and \u003cem\u003eUGT1A1\u003c/em\u003egenotypes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: In this observational cohort of patients treated for TB/HIV, the proportion of participants achieving virologic suppression was low, and genetic variants affecting ART metabolism were not significantly associated with the likelihood of virologic suppression.\u003c/p\u003e","manuscriptTitle":"Pharmacogenomic associations with HIV-1 virologic suppression in TB/HIV patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-16 17:15:04","doi":"10.21203/rs.3.rs-5418156/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cb858238-2685-4ae5-8764-f72fe21cc1ba","owner":[],"postedDate":"December 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-16T17:15:06+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-16 17:15:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5418156","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5418156","identity":"rs-5418156","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}