nucleoside reverse transcriptase inhibitor
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2022 ◽  
Vol 23 (2) ◽  
pp. 944
Author(s):  
Thanh Truong Giang Ly ◽  
Jisoo Yun ◽  
Jong-Seong Ha ◽  
Yeon-Ju Kim ◽  
Woong-Bi Jang ◽  
...  

Anterior gradient protein 2 homolog (AGR2), an endoplasmic reticulum protein, is secreted in the tumor microenvironment. AGR2 is a member of the disulfide isomerase family, is highly expressed in multiple cancers, and promotes cancer metastasis. In this study, we found that etravirine, which is a non-nucleoside reverse transcriptase inhibitor, could induce AGR2 degradation via autophagy. Moreover, etravirine diminished proliferation, migration, and invasion in vitro. Moreover, in an orthotopic xenograft mouse model, the combination of etravirine and paclitaxel significantly suppressed cancer progression and metastasis. This drug may be a promising therapeutic agent for the treatment of ovarian cancer.


2021 ◽  
Vol 12 (4) ◽  
pp. 847-861
Author(s):  
Raphael Z. Sangeda ◽  
Perpétua Gómes ◽  
Soo-Yon Rhee ◽  
Fausta Mosha ◽  
Ricardo J. Camacho ◽  
...  

As more HIV patients start combination antiretroviral therapy (cART), the emergence of HIV drug resistance (HIVDR) is inevitable. This will have consequences for the transmission of HIVDR, the success of ART, and the nature and trend of the epidemic. We recruited a cohort of 223 patients starting or continuing their first-line cART in Tanzania towards the end of the stavudine era in 2010. Patients were then followed for one year. Of those with a viral load test at baseline and follow-up time, 34% had a detectable viral load at the one-year endpoint. For 41 patients, protease and reverse transcriptase genotyping were successful. Eighteen samples were from cART-naïve patients, and 23 samples were taken under therapy either at baseline for cART-experienced patients or from follow-up samples for both cART–naïve and cART–experienced patients. The isolates were subtype A, followed by C and D in 41.5%, 22%, and 12.2% of the patients, respectively. No transmitted HIVDR was detected, as scored using the surveillance drug resistance mutations (DRMs) list. However, in 3 of the 18 samples from cART-naïve patients, the clinical Rega interpretation algorithm scored 44D or 138A as non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated polymorphisms. The most observed nucleoside reverse transcriptase inhibitor (NRTI) mutation was 184V. The mutation was found in 16 patients, causing resistance to lamivudine and emtricitabine. Nineteen patients had NNRTI resistance mutations, the most common of which was 103N, observed in eight patients. These high levels of resistance call for regular drug resistance surveillance in Tanzania to inform the control of the emergence and transmission of HIVDR.


Author(s):  
Divyanshu Sharma ◽  
Prerna Chaturvedi

Antiretroviral therapy [ART] has been developed remarkably within last three decades, since the first NRTI (nucleoside reverse transcriptase inhibitor) developed. For the mostly patients the challenge of complete and sustain suppression of viral has been clarify, since the triple therapy arrived. Convenient pill burden and tolerability are the main limiting factor for enhancing the long term benefit of ART. ABACAVIR (ABA) and LAMIVUDINE (LAM) are synthetic nucleotide analog (SNA) that showing a synergistic and potent inhibitory effect on human immunodeficiency virus-I (HIV-I), causative agent of AIDS. ABA and LAM belongs to nucleoside reverse transcriptase inhibitor (NRTI) class. As per new therapeutic strategy these two antiretroviral (ARV) drugs are required for the treatment of AIDS. When ARV regimens changed due to lack to virologic response ABA should be avoided. ABA is getting converted in to the active metabolite (carbovir triphosphate) which is an deoxyguanosine-5’ triphosphate analog by intracellular enzymes. LAM gets converted in its active 5’-triphosphate metabolite through phosphorylation. Chemically, ABA is (1S, cis)-4-[2-amino-6-(cyclopropyl amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulphate and LAM is (2R, cis)-4-amino-1-(2-hydroxymethyl-1, 3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Fig. 1 and 2 show ABA and LAM’s structure respectively.


Author(s):  
Wendy Ankrom ◽  
Deanne Jackson Rudd ◽  
Andrea Schaeffer ◽  
Deborah Panebianco ◽  
Evan J. Friedman ◽  
...  

MK-8507 is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor in clinical development with potential for once-weekly oral administration for the treatment of HIV-1 infection. Two randomized, double-blind, placebo-controlled phase 1 studies in adults without HIV-1 evaluated the safety, tolerability, and pharmacokinetics of single and multiple doses of MK-8507; drug interaction with midazolam (a cytochrome P450 3A4 substrate) and food effect were also assessed. In Study 1, 16 participants received oral ascending single doses of MK-8507 (2–400 mg) or placebo in an alternating fashion. In Study 2, 24 participants received ascending single doses of MK-8507 (400–1200 mg) or placebo and multiple doses (once weekly for 3 weeks) of MK-8507 (100–400 mg) or placebo. MK-8507 pharmacokinetics were approximately dose proportional at 2–1200 mg. MK-8507 had a time to maximum concentration of 2–7 hours and a mean terminal half-life of ∼58–84 hours. MK-8507 doses ≥100 mg achieved a plasma concentration at 168 hours post-dose (7 days) associated with antiviral efficacy. A high-fat meal had no clinically meaningful effect on MK-8507 pharmacokinetics, and MK-8507 400 mg once weekly had no clinically meaningful effect on midazolam pharmacokinetics. Single and multiple doses of MK-8507 were generally well tolerated. No trends with dose and no clinically meaningful changes were observed in vital signs, electrocardiograms, and laboratory safety tests. The pharmacokinetics and safety data are supportive of once-weekly oral administration and support further clinical investigation of MK-8507 for the treatment of HIV-1 infection. Over the last 3 decades, substantial improvements have been made in oral HIV antiretroviral therapies (ART), which now offer people living with HIV (PLWH) the potential for a near-normal life expectancy (1, 2). To achieve this, individuals must maintain life-long viral suppression, which requires daily administration of efficacious medication (3). Issues surrounding tolerability, complicated regimens, and treatment fatigue from daily dosing can lead to poor adherence and suboptimal viral suppression (3–6). Regimens can become complex when there is the need to take multiple pills, requirement to take a medication fasted or with food, or the potential for interactions with other medications, including those required to treat HIV-related comorbidities (3, 78). New treatment options that are not only highly effective but also offer excellent tolerability, a high barrier to resistance, favorable drug interaction profiles, and the potential for less frequent dosing remain the focus of much clinical research (7, 9). While 1 pill once a day meets the needs of many PLWH, for others daily administration poses challenges, including treatment fatigue and daily reminders and/or stigma associated with ART (10, 11). While treatment regimens that can be taken less often than daily are attractive to many PLWH, the long-acting injectable combination of cabotegravir/rilpivirine is currently the only treatment option available without daily dosing; however, administration requires injection by a health care professional (12), potentially posing other challenges.


eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Alexander O Pasternak ◽  
Jelmer Vroom ◽  
Neeltje A Kootstra ◽  
Ferdinand WNM Wit ◽  
Marijn de Bruin ◽  
...  

BACKGROUND: It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress HIV replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).METHODS: CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n=100, n=124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically-measured adherence to ART.RESULTS: In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho=0.70 and rho=0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj=0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj=0.048 and padj=0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals.CONCLUSIONS: All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.


2021 ◽  
Author(s):  
Immaculate Lillian Nankya ◽  
Eva Nabulime ◽  
Fred Kyeyune ◽  
Cissy Mutuluza Kityo ◽  
Miguel Mateu Quinones

Abstract Objective To determine the prevalence of multi-drug resistant variants among patients failing on a nucleoside reverse transcriptase inhibitor (NRTI) based regimen with a detectable viral load ≥ 1000 copies/ml among patients harboring HIV subtype A, C and D. Methods Samples were obtained from patients who were failing on an NRTI based regimen. Sanger based sequencing was performed as part of the standard of care. Mutation analysis was performed using the Stanford HIV drug Resistance database. A subset of these patient samples was further analyzed using the Next Generation Sequencing (NGS) technology and analysis of the drug resistance mutations was performed at the 20% and 1% cut off Results Analysis of the Non-nucleoside reverse transcriptase inhibitor (NNRTI) coding region revealed that the K101 and the Y181 mutations were more predominant among subtype C than subtype A and D. Although Thymidine analog mutations (TAMs) were prevalent in all subtypes, our analyses showed that these mutations occurred in significantly less proportions among subtype C infections when compared with the subtype A and D counterparts. Furthermore, the Q151M mutation complex which involves mutations in multiple domains was significantly more prominent among patients harboring subtype C variants. Analysis using NGS revealed that minority drug resistant mutations that confer multi-drug resistance (MDR) were present even in patients who exhibited a susceptible genotype based on the Sanger sequencing technique. Conclusion Although HIV-1 MDR variants occur in all subtypes, their predominance is subtype specific with TAMs being significantly more predominant among subtype A and D while the Q151M complex being significantly more predominant among patients harboring subtype C viruses. Even in patients with a susceptible genotype based on Sanger technology, minority variants are present and their evolution to full blown MDR occurs over time such that by the time they are detectable, cross resistance to other drugs has occurred in some cases.


2021 ◽  
Author(s):  
Alexander O. Pasternak ◽  
Jelmer Vroom ◽  
Neeltje A. Kootstra ◽  
Ferdinand W.N.M. Wit ◽  
Marijn de Bruin ◽  
...  

AbstractBACKGROUNDIt remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress HIV replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).METHODSCA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n=100, n=124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically-measured adherence to ART.RESULTSIn both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho=0.70 and rho=0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj=0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj=0.048 and padj=0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals.CONCLUSIONSAll current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.


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