Elvitegravir 150mg tablets

BackgroundWe compared the efficacy and safety profiles of ainuovirine (ANV), a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), with boosted elvitegravir (EVG), both coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), in people living with HIV-1 (PLWH) who had achieved virological suppression on previous NNRTI-based antiretroviral (ARV) regimen.MethodsThis study was a multi-centre, randomised, double-blind, active-controlled, non-inferiority trial recruiting PLWH from 10 clinical centres across China. Main inclusion criteria included age of 18-65 years (inclusive), and stably staying on an ARV regimen combining an NNRTI with a two-drug NRTI backbone for at least 12 months. Eligible participants must have maintained plasma HIV-1 ribonucleic acid (RNA) titre below 50 copies per mL confirmed on two successive tests at an interval of at least one month prior to randomisation. Participants were randomly assigned to receive ANV 150 mg plus lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate (TDF) 300 mg (ANV/3TC/TDF), or cobicistat (Cobi) 150 mg boosted EVG plus emtricitabine (FTC) 200 mg, and tenofovir alafenamide (TAF) 10 mg. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA titre at 50 copies per mL or above at week 48 using the US Food and Drug Administration snapshot algorithm, with a non-inferiority margin of 4 percentage points at a two-side 95% confidence level. This trial is active, but not recruiting, and is registered with Chinese Clinical Trial Registry (ChiCTR), number ChiCTR2100051605.FindingsBetween October 2021 and February 2022, 923 patients were screened for eligibility, among whom 762 participants were randomized and had received at least one dose of ANV/3TC/TDF (n = 381) or EVG/Cobi/FTC/TAF (n = 381). At week 48, 7 (1.8%) participants on ANV/3TC/TDF and 6 (1.6%) participants on EVG/Cobi/FTC/TAF had plasma HIV-1 RNA titre at 50 copies per mL or above, including missing virological data within the time window (the Cochran-Mantel-Haenszel method, estimated treatment difference [ETD], 0.3%, 95% CI -1.6 to 2.1), establishing the non-inferiority of ANV/3TC/TDF to EVG/Cobi/FTC/TAF. The proportions of participants experiencing at least one treatment-emergent adverse events (AEs) were comparable between the two arms (97.6% versus 97.6%). A small proportion of participants discontinued study drug due to AEs (0.3% versus 0.3%). Serious AEs occurred in 11 (2.9%) participants on ANV/3TC/TDF and 9 (2.4%) participants on EVG/Cobi/FTC/TAF, respectively, none of which was considered related to study drug at the jurisdiction of the investigator. At week 48, participants on ANV/3TC/TDF showed a significantly less weight gain from baseline compared to those on EVG/Cobi/FTC/TAF (least square mean, 1.16 versus 2.05 kg, ETD -0.90 kg, 95% CI, -1.43 to -0.37). The changes in serum lipids from baseline also favoured ANV/3TC/TDF over EVG/Cobi/FTC/TAF.InterpretationIn virologically suppressed PLWH on previous NNRTI-based ARV regimen, switch to ANV/3TC/TDF resulted in less weight gain, and improved lipid metabolism while maintaining virological suppression non-inferior to that to EVG/Cobi/FTC/TAF.FundingJiangsu Aidea Pharmaceutical & the National "Thirteenth Five-year Period" Major Innovative Drugs Research and Development Key Project of the People's Republic of China Ministry of Science and Technology.

Abstract licence: CC BY-NC-ND

A growing body of literature suggests that integrase strand transfer inhibitors (INSTIs), a cornerstone of antiretroviral therapy for the treatment of HIV infection, seem to possess antiproliferative properties against some types of cancer and/or anti-invasion effects. Preclinical studies describe as INSTIs, including dolutegravir, raltegravir, cabotegravir, and elvitegravir and some 1,2,3-triazole derivatives, can inhibit the growth of various cancer cell lines and some of them seem to also have direct inhibitory effects on human endogenous retrovirus reactivation. This review comprehensively synthesizes and analyzes this evidence, detailing the proposed multimechanistic actions behind these effects, such as induction of DNA damage, inhibition of key oncogenic pathways, triggering of oxidative stress and diverse cell death modalities. All described compounds seem to have potential effects on cancerous cells, and these effects may be also independent from their antiretroviral activity, that is, may be separated from the mere effect on suppression of human endogenous retrovirus reactivation in cancerous cells. Although the type of target cancer, the mechanisms of action (ie, enzyme or protein inhibition, oxidative stress, DNA methylation, and DNA damage) or the ultimate effects (ie, cell proliferation, migration, or invasion) were different in most of the studies and sometimes inconsistent, all these studies suggest several potential targets of INSTIs that deserve further investigations. Although the incidence of many cancers is higher in people with HIV infection compared with the general population, the relative risk has been decreasing over time for many cancers. Further studies are then needed to assess the effects of INSTI therapies on malignancies in people living with HIV. SIGNIFICANCE STATEMENT: Currently, the effects of using integrase strand transfer inhibitors (INSTIs) on cancer development in people living with HIV are difficult to determine because of the multifactorial cause of cancer in these patients and the long period in which cancer manifests. This review examines the antiproliferative properties of INSTIs, describing the proposed mechanisms through which they may exert this effect in preclinical studies.

Abstract licence: CC BY