Assessing transmissibility of HIV-1 drug resistance mutations from treated and from drug-naive individuals (AIDS (2015) 29 (2045-2052))

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Results from a European multi-cohort study

Publisher Copyright: © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.Background: INSTIs have become a pillar of first-line ART. Real-world data are needed to assess their effectiveness in routine care. Objectives: We analysed ART-naive patients who started INSTI-based regimens in 2012-19 whose data were collected by INTEGRATE, a European collaborative study including seven national cohorts. Methods: Kaplan-Meier analyses assessed time to virological failure (VF), defined as one viral load (VL) ≥1000 copies/mL, two consecutive VLs ≥50 copies/mL, or one VL ≥50 copies/mL followed by treatment change after ≥24 weeks of follow-up, and time to INSTIs discontinuation (INSTI-DC) for any reason. Factors associated with VF and INSTI-DC were explored by logistic regression analysis. Results: Of 2976 regimens started, 1901 (63.9%) contained dolutegravir, 631 (21.2%) elvitegravir and 444 (14.9%) raltegravir. The 1 year estimated probabilities of VF and INSTI-DC were 5.6% (95% CI 4.5-6.7) and 16.2% (95% CI 14.9-17.6), respectively, and were higher for raltegravir versus both elvitegravir and dolutegravir. A baseline VL ≥100 000 copies/mL [adjusted HR (aHR) 2.17, 95% CI 1.55-3.04, P 3 drugs versus 3 drugs (aHR 2.73, 95% CI 1.55-4.79, P < 0.001) and starting ART following availability of dolutegravir (aHR 0.64, 95% CI 0.48-0.83, P = 0.001). Major INSTI mutations indicative of transmitted drug resistance occurred in 2/1114 (0.2%) individuals. Conclusions: This large multi-cohort study indicates high effectiveness of elvitegravir- or dolutegravir-based first-line ART in routine practice across Europe.publishersversionpublishe

Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration.

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Effectiveness of integrase strand transfer inhibitors in HIV-infected treatment-experienced individuals across Europe

Funding Information: The INTEGRATE project received an unconditioned grant from Gilead Sciences Europe Ltd. This study was also funded by the Swedish Research Council (2016‐01675, to AS), the European Union by the CARE H2020 project (under grant agreement no. 825673) and Stockholm County Council (ALF 20190451 and CIMED 20200645; to AS), and the Fundação para a Ciência e Tecnologia, Portugal (INTEGRIV Project PTDC/SAU‐INF/31990/20170 and GHTM‐UID/Multi/04413/2013; to AA). Funding Information: The INTEGRATE project received an unconditioned grant from Gilead Sciences Europe Ltd. This study was also funded by the Swedish Research Council (2016-01675, to AS), the European Union by the CARE H2020 project (under grant agreement no. 825673) and Stockholm County Council (ALF 20190451 and CIMED 20200645; to AS), and the Fundação para a Ciência e Tecnologia, Portugal (INTEGRIV Project PTDC/SAU-INF/31990/20170 and GHTM-UID/Multi/04413/2013; to AA). The INTEGRATE study group: A. Abecasis, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical - Universidade Nova de Lisboa, Lisbon, Portugal M. Bobkova, Gamaleya Federal Center for Epidemiology and Microbiology of Russia C. Seguin-Devaux, Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg M. Fabbiani, University Hospital of Siena, Siena, Italy F. Garcia, Hospital Universitario San Cecilio, Granada, Spain A. M. Geretti, University of Liverpool, UK P. Gomes, Laboratório de Biologia Molecular (LMCBM, SPC, CHLO-HEM), Lisbon, Portugal and Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Universitário Egas Moniz, Caparica, Portugal F. Incardona, EuResist Network, Roma, Italy – IPRO, Roma, Italy R. Kaiser, University of Cologne, Cologne, Germany R. Paredes, Irsicaixa, Spain B. Rossetti, University Hospital of Siena, Siena, Italy M. Sayan, Kocaeli University, Medical Faculty, Turkey A. Sönnerborg, Karolinska Institutet, Stockholm, Sweden A. M. Vandamme, REGA Institut KU Leuven, Belgium M. Zazzi, University of Siena, Siena, Italy. Publisher Copyright: © 2022 British HIV Association.Objectives: To explore the effectiveness and durability of integrase strand transfer inhibitor (INSTI)-based regimens in pre-treated subjects. Methods: Treatment-experienced individuals starting an INSTI-based regimen during 2012–2019 were selected from the INTEGRATE collaborative study. The time to virological failure [VF: one measurement of viral load (VL) ≥ 1000 copies/mL or two ≥ 50 copies/ml or one VL measurement ≥ 50 copies/mL followed by treatment change] and to INSTI discontinuation were evaluated. Results: Of 13 560 treatments analysed, 4284 were from INSTI-naïve, non-viraemic (IN-NV) individuals, 1465 were from INSTI-naïve, viraemic (IN-V) individuals, 6016 were from INSTI-experienced, non-viraemic (IE-NV) individuals and 1795 were from INSTI-experienced, viraemic (IE-V) individuals. Major INSTI drug resistance mutations (DRMs) were previously detected in 4/519 (0.8%) IN-NV, 3/394 (0.8%) IN-V, 7/1510 (0.5%) IE-NV and 25/935 (2.7%) IE-V individuals. The 1-year estimated probabilities of VF were 3.1% [95% confidence interval (CI): 2.5–3.8] in IN-NV, 18.4% (95% CI: 15.8–21.2) in IN-V, 4.2% (95% CI: 3.6–4.9) in IE-NV and 23.9% (95% CI: 20.9–26.9) in IE-V subjects. The 1-year estimated probabilities of INSTI discontinuation were 12.1% (95% CI: 11.1–13.0) in IN-NV, 19.6% (95% CI: 17.5–21.6) in IN-V, 10.8% (95% CI: 10.0–11.6) in IE-NV and 21.7% (95% CI: 19.7–23.5) in IE-V subjects. Conclusions: Both VF and INSTI discontinuation occur at substantial rates in viraemic subjects. Detection of DRMs in a proportion of INSTI-experienced individuals makes INSTI resistance testing mandatory after failure.publishersversionpublishe

In vitro evaluation of novel reverse transcriptase inhibitors TAF (tenofovir alafenamide) and OBP-601 (2,3-didehydro-3-deoxy-4-ethynylthymidine) against multi-drug resistant primary isolates of HIV-2

New antiretroviral drugs are needed to treat HIV-2 infected patients failing therapy. Herein, we evaluate the activity of novel reverse transcriptase inhibitors tenofovir alafenamide (TAF) and OBP-601(2,3-didehydro-3-deoxy-4-ethynylthymidine) against primary isolates from HIV-2 infected patients experiencing virologic failure. TAF and OBP-601 were tested against twelve primary isolates obtained from nine drug-experienced patients failing therapy and three drug naïve patients using a single-round infectivity assay in TZM-bl cells. The RT-coding region of pol was sequenced and the GRADE algorithm was used to identify resistance profiles and mutations. TAF and OBP-601 inhibited the replication of almost all isolates at a median EC50 of 0.27 nM and 6.83 nM, respectively. Two isolates showed moderate-level resistance to OBP-601 or TAF and two other isolates showed high-level resistance to OBP-601 or to both drugs. With one exception, all resistant viruses had canonical nucleoside reverse transcriptase inhibitors (NRTIs)-associated resistance mutations (K65R, N69S, V111I, Y115F, Q151M and M184V). Our results show that TAF has potent activity against most multi-drug resistant HIV-2 isolates and should be considered for the treatment of HIV-2 infected patients failing therapy.Financial support for this research was provided by the Fundação para a Ciência e a Tecnologia (FCT), Portugal (project VIH/SAU/0029/2011) and by the LIFE project of the European and Developing Countries Clinical Trials Partnership (EDCTP) program supported by the European Union. Inês Bártolo is supported by a post-doc fellowship (SFRH/BPD/76225/2011) from Fundação para a Ciência e a Tecnologia (FCT).info:eu-repo/semantics/publishedVersio

A retrospective observational study of low-level viraemia and its immunological and virological significance: which outcome to expect

Introduction: Low-level viraemia (LLV) is observed in some patients with HIV-1 infection on stable antiretroviral therapy (ART). The significance of these findings remains controversial as it conflicts with traditional optimal clinic outcome. This study aims to evaluate the effect of LLV on the establishment of virological failure (VF) and immune deterioration. Methods: Retrospective observational study of a cohort of HIV-1 infected patients of an Infectious Diseases Clinic, who presented an HIV-1 viral load of 20 to 200 cp/mL, during the year 2012. Patients who were not on ART or non-adherent in the previous 6 months were excluded. Compliance was quantified by clinical and pharmaceutical records. Adherence was defined as ≥95% compliance rate. Demographic, clinical, immunological and therapeutic data were collected from clinical records. LLV was defined as a range of 20–200 cp/mL and stratified as transient (T-LLV): only one measurement, persistent (P-LLV): 2 consecutive measurements with an interval ≥3 months and recurrent (R-LLV): ≥1 T-LLV during an 18-month follow-up. Statistical analysis was performed with Microsoft Office® – Excel 2012. Kolmogorov–Smirnov test, t-test and chi-square test were performed for a significant p value <0.05. Results: During 2012, 2161 HIV-1 infected patients were evaluated at our Clinic, 93% of which were on ART. LLV was documented in 378 (19%), adherence was verified in 151 (52%). The analysis of this cohort (n=151) revealed: 77 (51%) T-LLV, 13 (8.6%) R-LLV and 61 (40%) P-LLV. Mean viral load was 46 cp/mL. Mean TCD4 count was 665 cells/µL with a variation of +63 cells/µL during the study period. There was no VF documented. ART regimens were switched in 16 (11%) patients. Gastrointestinal disturbance was found in 13 (9%). Analysis showed no statistical differences between the analyzed variables (CD4 variation, time of diagnosis and treatment, duration of LLV persistence (less than or more than one year), number of ART regimens, ART regimen and type of NRTI backbone) for all groups (T-LLV, R-LLV, P-LLV), except for mean viral load that showed significant superiority in the T-LLV(38 cp/mL) and R-LLV(36 cp/mL) vs P-LLV(58 cp/mL) (p=0.01 and p<0.01, respectively). Conclusions: The absence of significant differences in immunological and virological outcomes in this cohort and the absence of VF in all groups, suggests a scarce impact of LLV in patient's prognosis. Prospective studies, with longer follow-up could bring more accurate information

Origin and epidemiological history of HIV-1 CRF14_BG

Background CRF14_BG isolates, originally found in Spain, are characterized by CXCR4 tropism and rapid disease progression. This study aimed to identify the origin of CRF14_BG and reconstruct its epidemiological history based on new isolates from Portugal. Methodology/Principal Findings C2V3C3 env gene sequences were obtained from 62 samples collected in 1993–1998 from Portuguese HIV-1 patients. Full-length genomic sequences were obtained from three patients. Viral subtypes, diversity, divergence rate and positive selection were investigated by phylogenetic analysis. The molecular structure of the genomes was determined by bootscanning. A relaxed molecular clock model was used to date the origin of CRF14_BG. Geno2pheno was used to predict viral tropism. Subtype B was the most prevalent subtype (45 sequences; 73%) followed by CRF14_BG (8; 13%), G (4; 6%), F1 (2; 3%), C (2; 3%) and CRF02_AG (1; 2%). Three CRF14_BG sequences were derived from 1993 samples. Near full-length genomic sequences were strongly related to the CRF14_BG isolates from Spain. Genetic diversity of the Portuguese isolates was significantly higher than the Spanish isolates (0.044 vs 0.014, P<0.0001). The mean date of origin of the CRF14_BG cluster was estimated to be 1992 (range, 1989 and 1996) based on the subtype G genomic region and 1989 (range, 1984–1993) based on the subtype B genomic region. Most CRF14_BG strains (78.9%) were predicted to be CXCR4. Finally, up to five amino acids were under selective pressure in subtype B V3 loop whereas only one was found in the CRF14_BG cluster. Conclusions CRF14_BG emerged in Portugal in the early 1990 s soon after the beginning of the HIV-1 epidemics, spread to Spain in late 1990 s as a consequence of IVDUs migration and then to the rest of Europe. CXCR4 tropism is a general characteristic of this CRF that may have been selected for by escape from neutralizing antibody response.This work was supported by grant PTDC/SAU-FCF/67673/2006 from Fundação para a Ciência e Tecnologia Portugal, and by CHAIN (Collaborative HIV and Anti-HIV Drug Resistance Network), European Union. Inês Bártolo and Pedro Borrego are recipients of PhD scholarships from Fundação para a Ciência e Tecnologia (FCT), Portugal. Ana Abecasis is supported by a Post-Doc grant from the Fundação para a Ciência e Tecnologia (FCT), Portugal (SFRH/BPD/65605/2009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio