Newly approved integrase inhibitors for clinical treatment of AIDS

Gu, Wan-Gang

doi:10.1016/j.biopha.2014.09.013

Cited by 14 publications

(12 citation statements)

References 68 publications

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“…The C-terminal domain, residues 220–288, contributes to DNA binding [6]. Currently, only three IN inhibitors, i.e., raltegravir, elvitegravir, and dolutegravir, have been approved by the FDA [7]. However, these drugs have limited clinical benefit because long-term treatments may lead to the emergence of drug resistance and side effects [8].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Anti-HIV-1 Integrase and Anti-Inflammatory Activities of Compounds from Betula alnoides Buch-Ham

Chaniad

Sudsai

Septama

et al. 2019

Advances in Pharmacological Sciences

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Betula alnoides is a medicinal plant in Thai traditional longevity preparations. The crude extracts of this plant possess various biological activities. However, the isolated compounds from this plant have no reports of anti-HIV-1 integrase (IN) activity. Therefore, the present study aims to investigate the anti-HIV-1 integrase and anti-inflammatory effects of isolated compounds from this plant and predict the interaction of compounds with integrase active sites. From the bioassay-guided fractionation of the ethanol extract of B. alnoides stems using chromatographic techniques, five pentacyclic triterpenoid compounds were obtained. They are betulinic acid (1), betulin (2), lupeol (3), oleanolic acid (4), and ursolic acid (5). Compound 2 exhibited the most potent inhibitory activity against HIV-1 IN, with an IC50 value of 17.7 μM. Potential interactions of compounds with IN active sites were investigated using computational docking. The results indicated that active compounds interacted with Asp64, a residue participating in 3′-processing, and Thr66, His67, and Lys159, residues participating in strand-transfer reactions of the integration process. Regarding anti-inflammatory activity, all compounds exerted significant inhibitory effects on LPS-induced nitric oxide production (IC50 < 68.7 μM). Thus, this research provides additional scientific support for the use of B. alnoides in traditional medicine for the treatment of HIV patients.

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Section: Introductionmentioning

confidence: 99%

Evaluation of Anti-HIV-1 Integrase and Anti-Inflammatory Activities of Compounds from Betula alnoides Buch-Ham

Chaniad

Sudsai

Septama

et al. 2019

Advances in Pharmacological Sciences

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“…After the publication of the results of randomized clinical trials performed against efavirenz‐containing combination antiretroviral therapy (cART), raltegravir (RAL), the first available antiretroviral agent belonging to the class of HIV integrase strand transfer inhibitors (INSTIs), has been approved for both ART‐experienced patients and first‐line therapy in ART‐naïve patients . It was widely introduced across Europe starting from 2010 . Although a satisfactory tolerability profile in patients, including those with underlying comorbidities, and proportionally limited drug–drug interactions have generally been shown, a slight excess of cancers was observed in interim analyses of clinical trials including RAL‐based regimens which was not, however, confirmed in subsequent analyses .…”

Section: Introductionmentioning

confidence: 99%

Incidence of cancer and overall risk of mortality in individuals treated with raltegravir‐based and non‐raltegravir‐based combination antiretroviral therapy regimens

et al. 2017

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ObjectivesThere are currently few data on the long‐term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association.MethodsThe EuroSIDA cohort was divided into three groups: those starting RAL‐based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression.ResultsThe RAL cohort included 1470 individuals [with 4058 person‐years of follow‐up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non‐AIDS‐related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95–1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37–2.61). In intention‐to‐treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84–1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90–1.61) and 0.83 (95% CI 0.70–0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47–1.14 for RAL vs. HIST; RR 0.95; 95% CI 0.65–1.39 for RAL vs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53–1.43 for RAL vs. HIST; RR 1.14; 95% CI 0.76–1.72 for RAL vs. CONC).ConclusionsWe found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups.

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“…In 2007, the US Food and Drug Administration (FDA) approved the first INSTI (raltegravir; RAL); subsequently, elvitegravir (EVG) and dolutegravir (DTG) passed clinical trials and were licensed in 2012 and August 2013, respectively [ 6 , 7 ]. INSTIs suppress viral integration by blocking integrase (IN), which is the active site in the HIV-1 strand transfer step [ 8 ]. In the presence of an INSTI, the host’s repair enzymes recircularize the pro-viral DNA, and the viral replication cycle is aborted [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…In the presence of an INSTI, the host’s repair enzymes recircularize the pro-viral DNA, and the viral replication cycle is aborted [ 9 , 10 ]. Compared with traditional anti-HIV agents, INSTIs significantly reduce the rate of fall in viral load of drug-naive and -experienced patients infected with HIV-1 [ 8 ]. RAL is well tolerated and displays satisfactory activity against HIV-1 strains.…”

Section: Introductionmentioning

confidence: 99%

Therapy-Emergent Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 Patients: A Subgroup Meta-Analysis of Clinical Trials

et al. 2016

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BackgroundIntegrase strand transfer inhibitors (INSTIs) are a novel class of anti-HIV agents that show high activity in inhibiting HIV-1 replication. Currently, licensed INSTIs include raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG); these drugs have played a critical role in AIDS therapy, serving as additional weapons in the arsenal for treating patients infected with HIV-1. To date, long-term data regarding clinical experience with INSTI use and the emergence of resistance remain scarce. However, the literature is likely now sufficiently comprehensive to warrant a meta-analysis of resistance to INSTIs.MethodsOur team implemented a manuscript retrieval protocol using Medical Subject Headings (MeSH) via the Web of Science, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases. We screened the literature based on inclusion and exclusion criteria and then performed a quality analysis and evaluation using RevMan software, Stata software, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). We also performed a subgroup analysis. Finally, we calculated resistance rates and risk ratios (RRs) for the three types of drugs.ResultsWe identified 26 references via the database search. A meta-analysis of the RAL data revealed that the resistance rate was 3.9% (95% CI = 2.9%-4.9%) for the selected randomized controlled trials (RCTs). However, the RAL resistance rate reached 40.9% (95% CI = 8.8%-72.9%) for the selected observational studies (OBSs). The rates of resistance to RAL that were associated with HIV subtypes A, B, and C as well as with more complex subtypes were 0.1% (95% CI = -0.7%-0.9%), 2.5% (95% CI = 0.5%-4.5%), 4.6% (95% CI = 2.7%-6.6%) and 2.2% (95% CI = 0.7%-3.7%), respectively. The rates of resistance to EVG and DTG were 1.2% (95% CI = 0.2%-2.2%) and 0.1% (95% CI = -0.2%-0.5%), respectively. Furthermore, we found that the RRs for antiviral resistance were 0.414 (95% CI = 0.210–0.816) between DTG and RAL and 0.499 (95% CI = 0.255–0.977) between EVG and RAL. When RAL was separately co-administered with nuclear nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors (PIs), the rates of resistance to RAL were 0.2% (95% CI = -0.1%-0.5%) and 0.2% (95% CI = -0.2%-0.6%), respectively. The ten major integrase mutations (including N155H, Y143C/R, Q148H/R, Y143Y/H, L74L/M, E92Q, E138E/A, Y143C, Q148Q and Y143S) can reduce the sensitivity of RAL and EVG. The resistance of DTG is mainly shown in 13 integrase mutations (including T97T/A, E138E/D, V151V/I, N155H, Q148, Y143C/H/R, T66A and E92Q).ConclusionsOur results reveal that the DTG resistance rate was lower than the RAL resistance rate in a head-to-head comparison. Moreover, we confirmed that the EVG resistance rate was lower than the RAL resistance rate. In addition, our results revealed that the resistance rate of RAL was lower than that of efavirenz. The rates of resistance to RAL, EVG and DTG were specifically 3.9%, 1.2% and 0.1%, respectively. Compared with other types of antiv...

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Newly approved integrase inhibitors for clinical treatment of AIDS

Cited by 14 publications

References 68 publications

Evaluation of Anti-HIV-1 Integrase and Anti-Inflammatory Activities of Compounds from Betula alnoides Buch-Ham

Evaluation of Anti-HIV-1 Integrase and Anti-Inflammatory Activities of Compounds from Betula alnoides Buch-Ham

Incidence of cancer and overall risk of mortality in individuals treated with raltegravir‐based and non‐raltegravir‐based combination antiretroviral therapy regimens

Therapy-Emergent Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 Patients: A Subgroup Meta-Analysis of Clinical Trials

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