scholarly journals Fanconi Syndrome Induced by Concomitant HIV PrEP and Tacrolimus

2021 ◽  
Vol 9 ◽  
pp. 232470962110502
Author(s):  
Becky S. Linn ◽  
Jeremy W. Vandiver ◽  
Dylan Ren ◽  
Joseph Shassetz
Keyword(s):  
Proximal Tubule ◽  
Fanconi Syndrome ◽  
Transcriptase Inhibitor ◽  
Related Phenomenon ◽  
Drug Induced ◽  
Preexposure Prophylaxis ◽  
Immunodeficiency Virus ◽  
Tacrolimus Therapy ◽  
Reverse Transcriptase Inhibitor ◽  
Severe Grade

Fanconi syndrome (FS) is a severe grade of drug-induced proximal tubule toxicity. There are numerous causes for acquired FS, and drug toxicity is one of the most common. FS is known to be associated with the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF). TDF is often used in combination with emtricitabine (FTC) for preexposure prophylaxis (PrEP) of human immunodeficiency virus (HIV) infection. TDF/FTC-induced FS has been observed as a dose-related phenomenon that is directly correlated to kidney function, high levels of absorption of the drug into the proximal tubule, and interactions with other medications. This case report describes a patient who acquired FS after starting TDF/FTC for PrEP in the setting of chronic kidney disease (CKD) with concomitant tacrolimus therapy, a known nephrotoxic agent.

scholarly journals Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1349
Author(s):  
Shrika G. Harjivan ◽  
Catarina Charneira ◽  
Inês L. Martins ◽  
Sofia A. Pereira ◽  
Guadalupe Espadas ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Imidazole Ring ◽  
Transcriptase Inhibitor ◽  
Drug Induced ◽  
Post Translational Modifications ◽  
Histidine Residues ◽  
Immunodeficiency Virus ◽  
Combined Antiretroviral Therapy ◽  
Reverse Transcriptase Inhibitor

Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor widely used in combined antiretroviral therapy and to prevent mother-to-child transmission of the human immunodeficiency virus type 1, is associated with several adverse side effects. Using 12-mesyloxy-nevirapine, a model electrophile of the reactive metabolites derived from the NVP Phase I metabolite, 12-hydroxy-NVP, we demonstrate that the nucleophilic core and C-terminal residues of histones are targets for covalent adduct formation. We identified multiple NVP-modification sites at lysine (e.g., H2BK47, H4K32), histidine (e.g., H2BH110, H4H76), and serine (e.g., H2BS33) residues of the four histones using a mass spectrometry-based bottom-up proteomic analysis. In particular, H2BK47, H2BH110, H2AH83, and H4H76 were found to be potential hot spots for NVP incorporation. Notably, a remarkable selectivity to the imidazole ring of histidine was observed, with modification by NVP detected in three out of the 11 histidine residues of histones. This suggests that NVP-modified histidine residues of histones are prospective markers of the drug’s bioactivation and/or toxicity. Importantly, NVP-derived modifications were identified at sites known to determine chromatin structure (e.g., H4H76) or that can undergo multiple types of post-translational modifications (e.g., H2BK47, H4H76). These results open new insights into the molecular mechanisms of drug-induced adverse reactions.

scholarly journals Impact of Next-generation Sequencing Defined Human Immunodeficiency Virus Pretreatment Drug Resistance on Virological Outcomes in the ANRS 12249 Treatment-as-Prevention Trial

2018 ◽  
Vol 69 (2) ◽  
pp. 207-214 ◽  
Author(s):  
Anne Derache ◽  
Collins C Iwuji ◽  
Kathy Baisley ◽  
Siva Danaviah ◽  
Anne-Geneviève Marcelin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Transcriptase Inhibitor ◽  
Hiv Positive ◽  
Treatment As Prevention ◽  
Kwazulu Natal ◽  
Immunodeficiency Virus ◽  
Virological Outcomes ◽  
Reverse Transcriptase Inhibitor ◽  
Generation Sequencing

Abstract Background Previous studies in human immunodeficiency virus (HIV)-positive individuals on thymidine analogue backbone antiretroviral therapy (ART) with either nevirapine or efavirenz have suggested poorer virological outcomes in the presence of pretreatment drug resistance (PDR). We assessed the impact of PDR on virological suppression (VS; <50 copies/mL) in individuals prescribed primarily tenofovir/emtricitabine/efavirenz in rural KwaZulu-Natal within a treatment-as-prevention trial. Methods Among 1557 HIV-positive individuals who reported no prior ART at study entry and provided plasma samples, 1328 individuals with entry viral load (VL) >1000 copies/mL had next-generation sequencing (NGS) of the HIV pol gene with MiSeq technology. Results were obtained for 1148 individuals, and the presence of PDR was assessed at 5% and 20% detection thresholds. Virological outcome was assessed using Cox regression in 837 of 920 ART initiators with at least 1 follow-up VL after ART initiation. Results PDR prevalence was 9.5% (109/1148) and 12.8% (147/1148) at 20% and 5% thresholds, respectively. After a median of 1.36 years (interquartile range, 0.91–2.13), mostly on fixed-dose combination tenofovir/emtricitabine/efavirenz, presence of both nonnucleoside reverse transcriptase inhibitor (NNRTI)/nucleoside reverse transcriptase inhibitor PDR vs no PDR was associated with longer time to VS (adjusted hazard ratio [aHR], 0.32; 95% confidence interval [CI], 0.12–0.86), while there was no difference between those with only NNRTI PDR vs no PDR (aHR, 1.05; 95% CI, 0.82–1.34) at the 5% threshold. Similar differences were observed for mutations detected at the 20% threshold, although without statistical significance. Conclusions NGS uncovered a high prevalence of PDR among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a mainly tenofovir/emtricitabine/efavirenz regimen was associated with poorer VS. However, there was no impact of NNRTI PDR alone. Clinical Trials Tegistration NCT01509508; South African National Clinical Trials Register: DOH-27-0512-3974.

scholarly journals Activity against Human Immunodeficiency Virus Type 1, Intracellular Metabolism, and Effects on Human DNA Polymerases of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine

2007 ◽  
Vol 51 (8) ◽  
pp. 2701-2708 ◽  
Author(s):  
Hirotomo Nakata ◽  
Masayuki Amano ◽  
Yasuhiro Koh ◽  
Eiichi Kodama ◽  
Guangwei Yang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Transcriptase Inhibitor ◽  
Multidrug Resistant ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 μM [3H]EFdA or [3H]3′-azido-2′,3′-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/109 cells, while that of AZT was 396.5 pmol/109 cells. When CEM cells were exposed to 10 μM [3H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/109 cells), while the amount of [3H]AZT-TP increased only moderately by 2.4-fold (970 pmol/109 cells). The intracellular half-life values of EFdA-TP and AZT-TP were ∼17 and ∼3 h, respectively. When MT-4 cells were cultured with 0.01 μM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1NL4-3, and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 μM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases α, β, and γ were >100 μM, >100 μM, and 10 μM, respectively, while those of ddA-TP were >100 μM, 0.2 μM, and 0.2 μM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.

scholarly journals Clinical Impact of Pretreatment Human Immunodeficiency Virus Drug Resistance in People Initiating Nonnucleoside Reverse Transcriptase Inhibitor–Containing Antiretroviral Therapy: A Systematic Review and Meta-analysis

2020 ◽  
Author(s):  
Silvia Bertagnolio ◽  
Lucas Hermans ◽  
Michael R Jordan ◽  
Santiago Avila-Rios ◽  
Collins Iwuji ◽  
...  
Keyword(s):  
Systematic Review ◽  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Treatment Outcomes ◽  
Meta Analysis ◽  
Transcriptase Inhibitor ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor

Abstract Background Increased access to antiretroviral therapy (ART) has resulted in rising levels of pretreatment human immunodeficiency virus drug resistance (PDR). This is the first systematic review and meta-analysis to assess the impact of PDR on treatment outcomes among people initiating nonnucleoside reverse transcriptase inhibitor (NNRTI)–based ART, including the combination of efavirenz (EFV), tenofovir (TDF), and lamivudine or emtricitabine (XTC). Methods We systematically reviewed studies and conference proceedings comparing treatment outcomes in populations initiating NNRTI-based ART with and without PDR. We conducted subgroup analyses by regimen: (1) NNRTIs + 2 nucleoside reverse transcriptase inhibitors (NRTIs), (2) EFV + 2 NRTIs, or (3) EFV/TDF/XTC; by population (children vs adults); and by definition of resistance (PDR vs NNRTI PDR). Results Among 6197 studies screened, 32 were analyzed (31 441 patients). We found that individuals with PDR initiating NNRTIs across all the subgroups had increased risk of virological failure compared to those without PDR. Risk of acquisition of new resistance mutations and ART switch was also higher in people with PDR. Conclusions This review shows poorer treatment outcomes in the presence of PDR, supporting the World Health Organization’s recommendation to avoid using NNRTIs in countries where levels of PDR are high.

P5335Effect of anthropometrics, serostatus, medication and cocaine use on quantified coronary plaque volumes in patients with human immunodeficiency virus

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Kolossvary ◽  
H Lai ◽  
D Bluemke ◽  
R N Mandler ◽  
E K Fishman ◽  
...  
Keyword(s):  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Coronary Plaque ◽  
Transcriptase Inhibitor ◽  
Plaque Volume ◽  
Hiv Patients ◽  
Cocaine Use ◽  
Calcified Plaque ◽  
Immunodeficiency Virus ◽  
Traditional Risk Factors ◽  
Reverse Transcriptase Inhibitor

Abstract Introduction The effect of human immunodeficiency virus (HIV) and its medications on coronary artery disease (CAD) is controversial. Furthermore, illicit drug use such as cocaine occurs more often in these populations, however its potential modulating impact on CAD poorly understood. Purpose We sought to assess the effect of anthropometrics, serostatus, HIV medications and cocaine use in HIV patients on coronary plaque volumes assessed using coronary CT angiography (CTA). Methods We randomly selected 100 HIV patients without known CAD, but with coronary CTA confirmed coronary stenosis. All major epicardial vessels were segmented. Total plaque volume, low-attenuation non-calcified plaque volume and calcified plaque volumes were quantified from vessel portions which contained coronary atherosclerosis. We used linear regression analysis to assess the association between anthropometric (age, sex, body mass index), traditional risk factors (hypertension, diabetes, positive family history, HDL, LDL, cholesterol, triglycerides levels, years of alcohol and smoking), HIV associated parameters (years of HIV infection, months of protease inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, antiretroviral therapy medication use, hepatitis virus C infection, endothelin 1 levels, CD4 levels and viral load), years of cocaine use and coronary plaque volumes. Results Among anthropometric and traditional risk factors age (β=10.35, p=0.006) and smoking years (β=2.72, p=0.044) showed a significant association with total plaque volume, while all other parameters did not. Among HIV related parameters non-showed a significant association with the total plaque volume. However, the years of cocaine use significantly increased the amount of plaque volume (β=4.51, p=0.024). The amount of low-attenuation non-calcified plaque volume was only associated with the years of cocaine use (β=0.30, p=0.031), while all other parameters were non-significant. The amount of calcified plaque volume was associated with age (β=2.82, p=0.047) and years of cocaine use (β=1.52=0.043). Conclusions Cocaine use significantly increases the amount of low-attenuation non-calcified plaque volume, calcified plaque volume and overall plaque volume in HIV patients. Our results suggest the importance of cocaine use prevention in HIV patients as it increases plaque volumes which have been shown to be associated with poor cardiovascular outcomes. Acknowledgement/Funding This study was supported by grants from the US National Institute on Drug Abuse, National Institutes of Health (U01DA040325).

scholarly journals A case of M184V mutant human immunodeficiency virus in a patient using daily pre-exposure prophylaxis

2019 ◽  
Vol 31 (1) ◽  
pp. 85-87 ◽  
Author(s):  
Sally Jewsbury ◽  
Chris Ward
Keyword(s):  
Human Immunodeficiency Virus ◽  
Transcriptase Inhibitor ◽  
Wild Type Virus ◽  
Development Of Resistance ◽  
Health Clinics ◽  
Immunodeficiency Virus ◽  
Sexual Health Clinics ◽  
Exposure Prophylaxis ◽  
Reverse Transcriptase Inhibitor ◽  
Optimal Adherence

This study presents a case report of a 31-year-old gay man who acquired human immunodeficiency virus while using daily emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis (PrEP). He had an M184V nucleoside reverse-transcriptase inhibitor mutation at diagnosis. Either he acquired a pre-existing M184V mutation or he acquired a wild-type virus but then suboptimal use of FTC/TDF led to the development of resistance. For PrEP to be safely managed and seroconvertors to be identified quickly, PrEP should be commissioned by the NHS and managed within sexual health clinics. Notwithstanding the current provision of PrEP, those accessing it must be reminded about the importance of regular testing and optimal adherence.

scholarly journals Maintenance of Viral Suppression after Optimization Therapy from Etravirine Plus Raltegravir to Rilpivirine Plus Dolutegravir in HIV-1-Infected Patients

2019 ◽  
Vol 18 ◽  
pp. 232595821882165 ◽  
Author(s):  
Niccolò Riccardi ◽  
Filippo Del Puente ◽  
Lucia Taramasso ◽  
Antonio Di Biagio
Keyword(s):  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Viral Suppression ◽  
Real Life ◽  
Transcriptase Inhibitor ◽  
Strand Transfer ◽  
Immunodeficiency Virus ◽  
Transfer Inhibitor ◽  
Reverse Transcriptase Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Non-nucleoside reverse-transcriptase inhibitor plus integrase strand transfer inhibitor–based dual therapies are an attractive simplification, nucleoside reverse transcriptase inhibitor-sparing strategy for experienced human immunodeficiency virus-infected patients. Thus, we performed a 24-week real-life observational study to assess efficacy and safety of switching from raltegravir plus etravirine to dolutegravir plus rilpivirine in 7 previously heavily treated patients. This simplification strategy reduced pill burden and preserved viral suppression in treatment-experienced patients with no major mutations to rilpivirine at historical genotyping.

scholarly journals Safety, tolerance, and efficacy of atevirdine in asymptomatic human immunodeficiency virus-infected individuals.

1996 ◽  
Vol 40 (11) ◽  
pp. 2664-2668 ◽  
Author(s):  
A M Been-Tiktak ◽  
I Williams ◽  
H M Vrehen ◽  
J Richens ◽  
D Aldam ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Transcriptase Inhibitor ◽  
Viral Loads ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Cell Counts ◽  
Cd4 Cell Counts ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Cd4 Cell ◽  
Hiv 1

Atevirdine is a nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). In this study we investigated the effect of atevirdine in asymptomatic antiretroviral naive HIV-infected patients with CD4+ cell counts of between 200 and 750 cells per mm3. Patients were randomized to receive 600 mg of atevirdine (n = 15) or a placebo (n = 15) three times a day for 12 weeks. There was no statistically significant effect of atevirdine on viral loads (HIV p24 antigen and HIV-1 RNA levels by PCR) or CD4+ cell counts. The data do not support the use of atevirdine as a monotherapy in the treatment of HIV-infected patients.

scholarly journals Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Sauzanne G. Khalilieh ◽  
Ka Lai Yee ◽  
Rosa I. Sanchez ◽  
Li Fan ◽  
Matt S. Anderson ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Ethinyl Estradiol ◽  
Safety Data ◽  
Transcriptase Inhibitor ◽  
Cytochrome P450 3A ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Initial Reduction ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor

ABSTRACT Identifying and understanding potential drug-drug interactions (DDIs) are vital for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), and cytochrome P450 3A (CYP3A) substrates and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with the CYP3A substrates midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Coadministration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that coadministered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (K. L. Yee, S. G. Khalilieh, R. I. Sanchez, R. Liu, et al., Clin Drug Investig 37:659–667, 2017 [https://doi.org/10.1007/s40261-017-0513-4]; S. G. Khalilieh, K. L. Yee, R. I. Sanchez, R. Liu, et al., J Clin Pharmacol 58:1044–1052, 2018 [https://doi.org/10.1002/jcph.1103]), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but the reduction became less pronounced with time (K. L. Yee, R. I. Sanchez, P. Auger, R. Liu, et al., Antimicrob Agents Chemother 61:e01757-16, 2017 [https://doi.org/10.1128/AAC.01757-16]). Overall, the coadministration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while coadministration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a CYP3A inducer less potent than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.

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