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Kara Wools-Kaloustian, Irene Marete, Samuel Ayaya, Annette H Sohn, Lam Van Nguyen, Shanshan Li, Valériane Leroy, Beverly S Musick, Jamie E Newman, Andrew Edmonds, Mary-Ann Davies, François Tanoh Eboua, Marie-Thérèse Obama, Marcel Yotebieng, Shobna Sawry, Lynne M Mofenson, Constantin T Yiannoutsos
BACKGROUND: Globally, 49% of the estimated 1.8 million children living with HIV are accessing antiretroviral therapy (ART). There are limited data concerning long-term durability of first-line ART regimens and time to transition to second-line. METHODS: Children initiating their first ART regimen between 2-14 years of age and enrolled in one of 208 sites in 30 Asia-Pacific and African countries participating in the Pediatric International Epidemiology Databases to Evaluate AIDS consortium were included in this analysis...
March 2, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Denise Kühnert, Roger Kouyos, George Shirreff, Jūlija Pečerska, Alexandra U Scherrer, Jürg Böni, Sabine Yerly, Thomas Klimkait, Vincent Aubert, Huldrych F Günthard, Tanja Stadler, Sebastian Bonhoeffer
Drug resistant HIV is a major threat to the long-term efficacy of antiretroviral treatment. Around 10% of ART-naïve patients in Europe are infected with drug-resistant HIV type 1. Hence it is important to understand the dynamics of transmitted drug resistance evolution. Thanks to routinely performed drug resistance tests, HIV sequence data is increasingly available and can be used to reconstruct the phylogenetic relationship among viral lineages. In this study we employ a phylodynamic approach to quantify the fitness costs of major resistance mutations in the Swiss HIV cohort...
February 20, 2018: PLoS Pathogens
James Demarest, Mark Underwood, Marty St Clair, David Dorey, Dannae Brown, Andrew Zolopa
Dolutegravir demonstrated superior virologic efficacy compared with raltegravir in treatment-experienced, integrase strand transfer inhibitor (INSTI)-naive patients with HIV-1 who harbored resistance to ≥2 classes of antiretroviral drugs. Significantly fewer dolutegravir-treated patients demonstrated virologic failure with treatment emergent resistance than raltegravir-treated patients through 48 weeks. Resistance analyses informed the design of investigator-selected background therapy (ISBT) that included at least 1 fully active agent...
February 14, 2018: AIDS Research and Human Retroviruses
Alexandre Storto, Benoit Visseaux, Mélanie Bertine, Quentin Le Hingrat, Gilles Collin, Florence Damond, Marie-Aude Khuong, Laurent Blum, Roland Tubiana, Marina Karmochkine, Charles Cazanave, Sophie Matheron, Diane Descamps, Charlotte Charpentier
Objectives: To assess the prevalence of minority resistant variants (MRV) and X4-tropic minority variants in ART-naive HIV-2-infected patients. Patients and methods: ART-naive HIV-2-infected patients with detectable plasma viral load (>100 copies/mL) included in the ANRS HIV-2 CO5 Cohort were assessed. We performed ultra-deep sequencing (UDS) of protease, RT, integrase and gp105 regions. Only mutations in the HIV-2 ANRS list >1% were considered. HIV-2 tropism was assessed by V3 loop region UDS, and each read was interpreted with determinants of CXCR4-coreceptor use...
February 3, 2018: Journal of Antimicrobial Chemotherapy
Prashant S Devrukhakar, M Shiva Shankar, G Shankar, R Srinivas
Zidvovudine (AZT) is a nucleoside analogue reverse transcriptase inhibitor (NRTI), a class of anti-retroviral drug. A stability-indicating assay method for AZT was developed in line with ICH guideline. Successful separation of AZT and its degradation products was achieved by gradient elution mode on reverse phase C18 column using 10 mM ammonium acetate: acetonitrile as the mobile phase at 0.8 mL/min flow rate, 25 µL injection volume, 30 °C column temperature and 285 nm detection wavelength. Two major acid degradation products were identified and characterized by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI/MS/MS) and accurate mass measurements...
August 2017: Journal of Pharmaceutical Analysis
Yoshiaki Yasutake, Shin-Ichiro Hattori, Hironori Hayashi, Kouki Matsuda, Noriko Tamura, Satoru Kohgo, Kenji Maeda, Hiroaki Mitsuya
Hepatitis B virus (HBV) reverse transcriptase (RT) is essential for viral replication and is an important drug target. Nonetheless, the notorious insolubility of HBV RT has hindered experimental structural studies and structure-based drug design. Here, we demonstrate that a Q151M substitution alone at the nucleotide-binding site (N-site) of human immunodeficiency virus type-1 (HIV-1) RT renders HIV-1 highly sensitive to entecavir (ETV), a potent nucleoside analogue RT inhibitor (NRTI) against HBV. The results suggest that Met151 forms a transient hydrophobic interaction with the cyclopentyl methylene of ETV, a characteristic hydrophobic moiety of ETV...
January 26, 2018: Scientific Reports
Erik Sörstedt, Christina Carlander, Leo Flamholc, Bo Hejdeman, Veronica Svedhem, Anders Sönnerborg, Magnus Gisslén, Aylin Yilmaz
BACKGROUND: Until the introduction of dolutegravir (DTG), people living with HIV who have developed nucleoside reverse transcriptase inhibitor (NRTI) mutations have had few other treatment options outside of regimens based on ritonavir-boosted protease inhibitors (PI/r). Here we report treatment results among people living with HIV in Sweden with pre-existing NRTI mutations on antiretroviral treatment (ART) with DTG and 1-2 NRTIs. METHODS: All people living with HIV on ART with DTG and 1-2 NRTIs with pre-existing NRTI mutations were retrospectively identified from the national InfCare HIV database...
January 22, 2018: International Journal of Antimicrobial Agents
Emmanuel Ndashimye, Mariano Avino, Fred Kyeyune, Immaculate Nankya, Richard M Gibson, Eva Nabulime, Art F Y Poon, Cissy Kityo, Peter Mugyenyi, Miguel E Quinones-Mateu, Eric Arts
OBJECTIVES: To screen for drug resistance and possible treatment with Dolutegravir (DTG) in treatment naïve patients and those experiencing virologic failure during first, second, and third line combined antiretroviral therapy (cART) in Uganda. DESIGN: Samples from 417 patients in Uganda were analyzed for predicted drug resistance upon failing a first (N=158), second (N=121), or third line (all 51 involving Raltegravir [RAL]) treatment regimen. METHOD: HIV-1 pol gene was amplified and sequenced from plasma samples...
January 21, 2018: AIDS Research and Human Retroviruses
Fuu-Jen Tsai, Chi-Fung Cheng, Chih-Ho Lai, Yang-Chang Wu, Mao-Wang Ho, Jen-Hsien Wang, Ni Tien, Xiang Liu, Hsinyi Tsang, Ting-Hsu Lin, Chiu-Chu Liao, Shao-Mei Huang, Ju-Pi Li, Jung-Chun Lin, Chih-Chien Lin, Jin-Hua Chen, Wen-Miin Liang, Ying-Ju Lin
HIV-infected patients exposed to antiretroviral therapy (ART) have an increased risk for hyperlipidemia and cardiovascular disease. We performed a longitudinal, comprehensive, and population-based study to investigate the cumulative effect of different types of ART regimens on hyperlipidemia risk in the Taiwanese HIV/ART cohort. A total of 13,370 HIV-infected patients (2,674 hyperlipidemia and 10,696 non-hyperlipidemia patients) were recruited after matching for age, gender, and the first diagnosis date of HIV infection by using the National Health Insurance Research Database in Taiwan...
December 5, 2017: Oncotarget
Mar Álvarez, Maria Nevot, Jesus Mendieta, Miguel A Martinez, Luis Menéndez-Arias
Nucleoside reverse transcriptase (RT) inhibitors (NRTIs) are the backbone of current antiretroviral treatments. However, emergence of viral resistance against NRTIs is a major threat to their therapeutic effectiveness. In HIV-1, NRTI resistance-associated mutations either reduce RT-mediated incorporation of NRTI triphosphates (discrimination mechanism) or confer an ATPmediated nucleotide excision activity that removes the inhibitor from the 3'-terminus of DNA primers, enabling further primer elongation (excision mechanism)...
December 22, 2017: Journal of Biological Chemistry
Matthew J Young
Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs used to treat human immunodeficiency virus (HIV) the cause of acquired immunodeficiency syndrome. Development of severe mitochondrial toxicity has been well documented in patients infected with HIV and administered NRTIs. In vitro biochemical experiments have demonstrated that the replicative mitochondrial DNA (mtDNA) polymerase gamma, Polg, is a sensitive target for inhibition by metabolically active forms of NRTIs, nucleotide reverse transcriptase inhibitors (NtRTIs)...
2017: Frontiers in Molecular Biosciences
Isabella Bon, Leonardo Calza, Giuseppina Musumeci, Serena Longo, Alessia Bertoldi, Vanessa D'Urbano, Davide Gibellini, Eleonora Magistrelli, Pier Luigi Viale, Maria Carla Re
BACKGROUND: Total HIV-DNA load in peripheral blood cell (PBMCs) reflects the global viral reservoir that seems not to be affected by antiretroviral treatment. However, some studies reported a different permeability of different drugs in cellular compartments. OBJECTIVE: To investigate the relation between the amount of total HIV-1 DNA and different treatment strategies. METHODS: Total HIV-1 DNA was quantified by real time PCR in PBMCs collected from 161 patients with long-term undetectable HIV-RNA receiving different therapy schedules (3-drug regimens or 2-drug regimen containing Raltegravir as integrase inhibitor)...
2017: Current HIV Research
Heather Sevinsky, Luna Zaru, Reena Wang, Xiaohui Xu, Cheryl Pikora, Todd A Correll, Timothy Eley
BACKGROUND: Two clinical studies (PRINCE-1 and -2) in HIV-1-infected children assessed the safety, efficacy, and pharmacokinetics of dual nucleos(t)ide reverse transcriptase inhibitor (NRTI) background therapy plus once-daily atazanavir powder formulation boosted with ritonavir (ATV+RTV). Here, we present a combined analysis of ATV pharmacokinetics and pharmacodynamics across these studies. METHODS: Intensive 24-hour pharmacokinetic profiles at steady state compared ATV exposures (area under the concentration-time curve in one dosing interval [AUCτ]) in 5 ATV+RTV baseline weight-band dosing categories with historic data in adults receiving ATV+RTV 300/100-mg capsules...
December 4, 2017: Pediatric Infectious Disease Journal
Mark F Cotton, Afaaf Liberty, Indiana Torres-Escobar, Maria Isabel Gonzalez-Tome, Jurgen Lissens, Luna Zaru, Isabelle Klauck, Daniela Cambilargiu, Cheryl Pikora, Todd A Correll
BACKGROUND: Novel antiretroviral formulations that are palatable, safe, and effective are needed for infants and children. METHODS: PRINCE-2 is an ongoing clinical trial assessing safety, efficacy, and palatability of once-daily atazanavir powder formulation boosted with ritonavir (ATV+RTV) plus optimized dual NRTI therapy in ARV-naïve/experienced children with screening HIV-1 RNA ≥1000 copies/mL. Children aged 3 months to <11 years received ATV+RTV by 5 baseline weight bands: 5 to <10kg=150/80mg; 5 to <10kg=200/80mg; 10 to <15kg=200/80mg; 15 to <25kg=250/80mg; and 25 to <35kg=300/100mg...
December 4, 2017: Pediatric Infectious Disease Journal
Julia K Rohr, Prudence Ive, Charles Robert Horsburgh, Rebecca Berhanu, Christopher J Hoffmann, Robin Wood, Andrew Boulle, Janet Giddy, Hans Prozesky, Michael Vinikoor, Mwanza Wa Mwanza, Gilles Wandeler, Mary-Ann Davies, Matthew P Fox
BACKGROUND: After first-line antiretroviral therapy failure, the importance of change in nucleoside reverse transcriptase inhibitor (NRTI) in second line is uncertain due to the high potency of protease inhibitors used in second line. SETTING: We used clinical data from 6290 adult patients in South Africa and Zambia from the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Southern Africa cohort. METHODS: We included patients who initiated on standard first-line antiretroviral therapy and had evidence of first-line failure...
April 1, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Max Lataillade, Nannan Zhou, Samit R Joshi, Sangil Lee, David A Stock, George J Hanna, Mark Krystal
BACKGROUND: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 T-cells. The phase 2b trial AI438011 investigated the safety, efficacy, and dose-response of fostemsavir vs ritonavir-boosted atazanavir (ATV/r) in treatment-experienced, HIV-1-infected subjects. METHODS: Two hundred fifty-one treatment-experienced subjects with baseline (BL) susceptibility to study drugs [temsavir half-maximal inhibitory concentration (IC50) <100 nM, PhenoSense Entry assay] received fostemsavir or ATV/r, each with tenofovir disoproxil fumarate + raltegravir...
March 1, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Mira Hleyhel, Stéphanie Goujon, Jeanne Sibiude, Roland Tubiana, Catherine Dollfus, Albert Faye, Laurent Mandelbrot, Jacqueline Clavel, Josiane Warszawski, Stéphane Blanche
All nucleoside analogues for treating HIV infection, due to their capacity to integrate into and alter human DNA, are experimentally genotoxic to some extent. The long-term oncogenic risk after in utero exposure remains to be determined. Cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) was evaluated, by cross-checking against the National Cancer Registry, in the French perinatal study of children born to HIV+ mothers. Twenty-one cancers were identified in 15,163 children (median age: 9...
December 5, 2017: Environmental and Molecular Mutagenesis
Bethany Corrigan, Irene Mukui, Lloyd Mulenga, Nobuhle Mthethwa, Mosilinyane Letsie, Stephanie Bruno, Natella Rakhmanina
BACKGROUND: Data are limited on the selection and sequencing of second and third-line pediatric antiretroviral treatment (ART) in resource-limited settings. This study aimed to evaluate characteristics of African pediatric patients initiated on darunavir (DRV) and/or etravirine (ETR) through a specific drug donation program. METHODS: This was a cross-sectional study of baseline immunologic, virologic and demographic characteristics of children and adolescents initiating DRV- and/or ETR-based ART...
November 14, 2017: Pediatric Infectious Disease Journal
P P Xiao, J Lu, H Y Hu, X Q Xu, P Ding, G F Fu, X P Huan, Y Zhou, H T Yang
Objective: To understand the incidence and related factors of HIV-1 drug resistance among HIV/AIDS patients experiencing treatment failure in Jiangsu province, China. Methods: The HIV/AIDS integrated prevention and control data information management system of China were used to collect the basic data of patients, blood specimens were collected from patients who had antiretroviral therapy (ART) failure with ≥12 months and older than 18 years in 2016 in Jiangsu, excluding cases with missing information, 713 cases were enrolled in this study...
November 6, 2017: Zhonghua Yu Fang Yi Xue za Zhi [Chinese Journal of Preventive Medicine]
Alexander J Szubert, Andrew J Prendergast, Moira J Spyer, Victor Musiime, Philippa Musoke, Mutsa Bwakura-Dangarembizi, Patricia Nahirya-Ntege, Margaret J Thomason, Emmanuel Ndashimye, Immaculate Nkanya, Oscar Senfuma, Boniface Mudenge, Nigel Klein, Diana M Gibb, A Sarah Walker
BACKGROUND: Although WHO recommends viral load (VL) monitoring for those on antiretroviral therapy (ART), availability in low-income countries remains limited. We investigated long-term VL and resistance in HIV-infected children managed without real-time VL monitoring. METHODS AND FINDINGS: In the ARROW factorial trial, 1,206 children initiating ART in Uganda and Zimbabwe between 15 March 2007 and 18 November 2008, aged a median 6 years old, with median CD4% of 12%, were randomised to monitoring with or without 12-weekly CD4 counts and to receive 2 nucleoside reverse transcriptase inhibitors (2NRTI, mainly abacavir+lamivudine) with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or 3 NRTIs as long-term ART...
November 2017: PLoS Medicine
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