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Boshi Huang, Xinhao Liu, Ye Tian, Dongwei Kang, Zhongxia Zhou, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
In the present work, we described the synthesis, antiviral profiles and metabolic stability in human plasma of compound 6, a potential carbonate prodrug of HIV-1 NNRTI drug candidate RDEA427. Compound 6 was found to inhibit the wild-type (WT) and K103N/Y181C double mutant HIV-1 strains at nano- and submicromolar concentrations, respectively. Moreover, it displayed potent HIV-1 reverse transcriptase inhibitory activity (IC50  = 0.264 μM). Further stability test in human plasma showed that 6 could release its active form RDEA427 in a linearly time-independent manner, possibly acting as a potential prodrug...
March 5, 2018: Bioorganic & Medicinal Chemistry Letters
Xavier Tchetnya, Calypse Asangbe Ngwasiri, Tiayah Munge, Leopold Ndemnge Aminde
BACKGROUND: Toxic epidermal necrolysis (TEN) is a rare life threatening dermatological disorder characterized by extensive epidermal detachment and erosion of mucous membranes. It is typically a side effect of some medications. Nevirapine, a nonnucleoside reverse transcriptase inhibitor (NNRTI) is one of the frequently used components of highly active antiretroviral therapy (HAART). Skin rash is its common adverse reaction, usually mild and rarely progressing to TEN. Ophthalmic involvement is common as well but rarely progresses to blindness especially in the pediatric population...
March 13, 2018: BMC Pediatrics
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
Wassim Chehadeh, Osama Albaksami, Sonia Elezebeth John, Widad Al-Nakib
OBJECTIVES: To investigate the prevalence of non-polymorphic resistance-associated mutations (RAMs) in HIV-1 patients on first-line antiretroviral therapy in Kuwait. SUBJECTS AND METHODS: Total ribonucleic acid (RNA) was isolated from plasma samples of 42 patients who received first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. HIV-1 protease and reverse transcriptase genetic regions were then amplified by nested reverse-transcription polymerase chain reaction (RT-PCR), and directly sequenced...
March 5, 2018: Medical Principles and Practice: International Journal of the Kuwait University, Health Science Centre
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
Nadia Galizzi, Laura Galli, Andrea Poli, Nicola Gianotti, Elisabetta Carini, Alba Bigoloni, Giuseppe Tambussi, Silvia Nozza, Adriano Lazzarin, Antonella Castagna, Daniela Mancusi, Roberta Termini
INTRODUCTION: A regimen with rilpivirine (RPV), abacavir (ABC) and lamivudine (3TC) is simple and may allow the sparing of tenofovir and protease inhibitors. However, data on use of this combination as a strategy of switch are limited. Aims of the study were to assess the long-term efficacy and safety of this regimen. METHODS: Retrospective study on HIV-1 infected patients followed at the Infectious Disease Department of the San Raffaele Scientific Institute, HBsAg-negative, HLA B5701-negative, with no documented resistance to RPV, ABC and 3TC, with HIV-RNA<50 copies/mL who started RPV plus ABC/3TC from March 2013 to September 2015...
2018: PloS One
Shenghan Lai, Christopher M Heaphy, Anthony J Rizzo, David D Celentano, Gary Gerstenblith, Ji Li, Richard D Moore, Glenn Treisman, Shaoguang Chen, Parker Foster, Thomas Kickler, Hong Lai
BACKGROUND: Although cocaine use may induce/accelerate HIV-associated comorbidities in HIV-infected individuals on antiretroviral therapy (ART), and that HIV itself may accelerate aging, the issue of whether cocaine use plays a role in HIV-associated aging in HIV-infected cocaine users has not been reported. The goals of this study were (1) to explore factor(s) associated with peripheral blood leukocyte telomere length, a marker of cellular replicative history, and telomere shortening in HIV-infected individuals, and (2) to assess whether cocaine use plays a role in accelerating telomere shortening in cocaine users with HIV infection...
February 2, 2018: Progress in Neuro-psychopharmacology & Biological Psychiatry
Ali Judd, Elizabeth Chappell, Anna Turkova, Sophie Le Coeur, Antoni Noguera-Julian, Tessa Goetghebuer, Katja Doerholt, Luisa Galli, Dasja Pajkrt, Laura Marques, Intira J Collins, Diana M Gibb, Maria Isabel González Tome, Marisa Navarro, Josiane Warszawski, Christoph Königs, Vana Spoulou, Filipa Prata, Elena Chiappini, Lars Naver, Carlo Giaquinto, Claire Thorne, Magdalena Marczynska, Liubov Okhonskaia, Klara Posfay-Barbe, Pradthana Ounchanum, Pornchai Techakunakorn, Galina Kiseleva, Ruslan Malyuta, Alla Volokha, Luminita Ene, Ruth Goodall
BACKGROUND: Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand. METHODS AND FINDINGS: Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013...
January 2018: PLoS Medicine
Emmi Andersson, Agnes Nordquist, Joakim Esbjörnsson, Leo Flamholc, Magnus Gisslén, Bo Hejdeman, Gaetano Marrone, Hans Norrgren, Veronica Svedhem, Suzanne Wendahl, Jan Albert, Anders Sönnerborg
OBJECTIVE: To study the trends of transmitted drug resistance (TDR) in HIV-1 patients newly diagnosed in Sweden, 2010-2016. DESIGN: Register-based study including all antiretroviral therapy-naïve patients ≥18 years diagnosed with HIV-1 in Sweden 2010-2016. METHODS: Patient data and viral pol sequences were extracted from the national InfCareHIV database. TDR was defined as the presence of surveillance drug resistance mutations (SDRMs). A CD4 T-cell decline trajectory model estimated time of infection...
January 24, 2018: AIDS
Meytal Galilee, Akram Alian
Reverse transcriptase (RT) is the target for the majority of anti-HIV-1 drugs. As with all anti-AIDS treatments, continued success of RT inhibitors is persistently disrupted by the occurrence of resistance mutations. To explore latent resistance mechanisms potentially accessible to therapeutically challenged HIV-1 viruses, we examined RT from the related feline immunodeficiency virus (FIV). FIV closely parallels HIV-1 in its replication and pathogenicity, however, is resistant to all non-nucleoside inhibitors (NNRTI)...
January 24, 2018: PLoS Pathogens
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
Zhongxia Zhou, Tao Liu, Dongwei Kang, Zhipeng Huo, Gaochan Wu, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
A new series of diarylpyrimidines (DAPYs) were designed, synthesized and evaluated as novel HIV-1 NNRTIs to further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), guided by the comprehensive analysis of X-ray structural biology data of HIV-1 RT/NNRTI complexes and molecular modeling. Encouragingly, most of the synthesized DAPYs were found to be active against the HIV-1 wild-type (WT) strain with EC50 values ranging from 3 nM to 63 nM, and displayed significantly reduced cytotoxicity compared with etravirine (ETV) and rilpivirine (RPV)...
January 19, 2018: Organic & Biomolecular Chemistry
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
Jia-Mei Guo, Ming-Yu Ba, Ying Yang, Chun-Suo Yao, Miao Yu, Jian-Gong Shi, Ying Guo
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection. In this study, we identified (+)-(7'S,8S,8'S)-3',4,4',5,5'-pentamethoxy-2,7'-cyclolignan (SG-1), a cyclolignan semi-synthesized from Machilus robusta and M. wangchiana extracts, as a potent NNRTI. SG-1 displayed anti-HIV-1 activity with an IC50 of 0.77 μmol/L by inhibiting reverse transcriptase (RT) RNA-dependent DNA polymerase activity through a direct binding...
December 27, 2017: Journal of Asian Natural Products Research
Jenny Coetzee, Gillian Hunt, Maya Jaffer, Kennedy Otwombe, Lesley Scott, Asiashu Bongwe, Johanna Ledwaba, Sephonono Molema, Rachel Jewkes, Glenda E Gray
BACKGROUND: HIV drug resistance (HIVDR) poses a threat to future antiretroviral therapy success. Monitoring HIVDR patterns is of particular importance in populations such as sex workers (SWs), where documented HIV prevalence is between 34-89%, and in countries with limited therapeutic options. Currently in South Africa, there is a dearth in evidence and no ongoing surveillance of HIVDR amongst sex work populations. This study aims to describe the prevalence of HIVDR amongst a sample of female sex workers (FSWs) from Soweto, South Africa...
2017: PloS One
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
Ravindra K Gupta, John Gregson, Neil Parkin, Hiwot Haile-Selassie, Amilcar Tanuri, Liliana Andrade Forero, Pontiano Kaleebu, Christine Watera, Avelin Aghokeng, Nicholus Mutenda, Janet Dzangare, San Hone, Zaw Zaw Hang, Judith Garcia, Zully Garcia, Paola Marchorro, Enrique Beteta, Amalia Giron, Raph Hamers, Seth Inzaule, Lisa M Frenkel, Michael H Chung, Tulio de Oliveira, Deenan Pillay, Kogie Naidoo, Ayesha Kharsany, Ruthiran Kugathasan, Teresa Cutino, Gillian Hunt, Santiago Avila Rios, Meg Doherty, Michael R Jordan, Silvia Bertagnolio
BACKGROUND: Pretreatment drug resistance in people initiating or re-initiating antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) might compromise HIV control in low-income and middle-income countries (LMICs). We aimed to assess the scale of this problem and whether it is associated with the intiation or re-initiation of ART in people who have had previous exposure to antiretroviral drugs. METHODS: This study was a systematic review and meta-regression analysis...
March 2018: Lancet Infectious Diseases
Joseph Rwagitinywa, Maryse Lapeyre-Mestre, Robert Bourrel, Agnès Sommet
OBJECTIVE: This study aimed to estimate the rate of generic users among HIV-infected patients treated by antiretroviral (ARV) drugs potentially substitutable and to determine factors associated with switch from brand to generic ARV in real-life settings in a French region. METHODS: Cohort of HIV-infected patients aged of ≥18 years, exposed to at least one of the generic of lamivudine (3TC-150mg/300mg), zidovudine/lamivudine (AZT-200mg/3TC-150mg), nevirapine (NVP-200mg), efavirenz (EFV-600mg) and those exposed to brand 3TC, AZT/3TC, NVP, EFV, the fixed-dose combination abacavir/lamivudine (ABC/3TC) or the single-tablet regimen efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF) as recorded in the French health insurance database between January 2012 and May 2015 were included...
November 2, 2017: Thérapie
Ellen F Eaton, Ashutosh Tamhane, Thibaut Davy-Mendez, William C Mathews, Richard D Moore, Michael S Saag, Michael J Mugavero
OBJECTIVE: To evaluate the real world durability of contemporary ART for treatment-naïve people living with HIV (PLWH). DESIGN: A retrospective follow-up study in a multisite cohort. METHODS: This study of the CNICS (CFAR Network of Integrated Clinical Systems) cohort integrates data from eight Center for AIDS Research (CFARs). PLWH initiating ART between 2007 and 2014 were included. Durability was defined as time from the initiation until discontinuation/modification using Kaplan-Meier survival curves...
January 28, 2018: AIDS
Zhimi Tan, Xiaofang Jia, Fang Ma, Yanling Feng, Hongzhou Lu, Jun-O Jin, Dage Wu, Lin Yin, Li Liu, Lijun Zhang
BACKGROUND: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), has been widely used in the therapy of human immunodeficiency virus (HIV) infection. Some of its toxic effects on hepatic cells have been reported to display features of mitochondrial dysfunction through bioenergetic stress and autophagy, etc. However, alteration of protein levels, especially mitochondrial protein levels, in hepatic cells during treatment of EFV has not been fully investigated. METHODS: We built a cell model of EFV-induced liver toxicity through treating Huh-7 cells with different concentrations of EFV for different time followed by the analysis of cell viability using cell counting kit -8 (CCK8) and reactive oxygen species (ROS) using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSox dye...
2017: PloS One
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