The development of new antiviral agents such as nucleoside analogues or acyclic nucleotide analogues (ANPs) and prodrugs thereof is an ongoing task. We report on the synthesis of three types of lipophilic triphosphate analogues of (R)-PMPA and dialkylated diphosphate analogues of (R)-PMPA. A highly selective release of the different nucleotide analogues ((R)-PMPA-DP, (R)-PMPA-MP, and (R)-PMPA) from these compounds was achieved. All dialkylated (R)-PMPA-prodrugs proved to be very stable in PBS as well as in CEM/0 cell extracts and human plasma. In primer extension assays, both the monoalkylated and the dialkylated (R)-PMPA-DP derivatives acted as (R)-PMPA-DP as a substrate for HIV-RT. In contrast, no incorporation events were observed using human polymerase γ. The dialkylated (R)-PMPA-compounds exhibited significant anti-HIV efficacy in HIV-1/2 infected cells (CEM/0 and CEM/TK-). Remarkably, the dialkylated (R)-PMPA-MP derivative 9a showed a 326-fold improved activity as compared to (R)-PMPA in HIV-2 infected CEM/TK- cells as well as a very high SI of 14,000. We are convinced that this study may significantly contribute to advancing antiviral agents developed based on nucleotide analogues in the future.
- MeSH
- adenin MeSH
- HIV-2 MeSH
- látky proti HIV * chemie MeSH
- lidé MeSH
- nukleotidy MeSH
- organofosfonáty * chemie MeSH
- prekurzory léčiv * chemie MeSH
- tenofovir farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: In the last decade, substantial differences in the epidemiology of, antiretroviral therapy (ART) for, cascade of care in and support to people with HIV in vulnerable populations have been observed between countries in Western Europe, Central Europe (CE) and Eastern Europe (EE). The aim of this study was to use a survey to explore whether ART availability and therapies have evolved in CE and EE according to European guidelines. METHODS: The Euroguidelines in Central and Eastern Europe (ECEE) Network Group conducted two identical multicentre cross-sectional online surveys in 2019 and 2021 concerning the availability and use of antiretroviral drugs (boosted protease inhibitors [bPIs], integrase inhibitors [INSTIs] and nucleoside reverse transcriptase inhibitors [NRTIs]), the introduction of a rapid ART start strategy and the use of two-drug regimens (2DRs) for starting or switching ART. We also investigated barriers to the implementation of these strategies in each region. RESULTS: In total, 18 centres participated in the study: four from CE, six from EE and eight from Southeastern Europe (SEE). Between those 2 years, older PIs were less frequently used and darunavir-based regimens were the main PIs (83%); bictegravir-based and tenofovir alafenamide-based regimens were introduced in CE and SEE but not in EE. The COVID-19 pandemic did not significantly interrupt delivery of ART in most centres. Two-thirds of centres adopted a rapid ART start strategy, mainly in pregnant women and to improve linkage of care in vulnerable populations. The main obstacle to rapid ART start was that national guidelines in several countries from all three regions did not support such as strategy or required laboratory tests first; an INSTI/NRTI combination was the most commonly prescribed regimen (75%) and was exclusively prescribed in SEE. 2DRs are increasingly used for starting or switching ART (58%), and an INSTI/NRTI was the preferred regimen (75%) in all regions and exclusively prescribed in SEE, whereas the use of bPIs declined. Metabolic disorders and adverse drug reactions were the main reasons for starting a 2DR; in the second survey, HIV RNA <500 000 c/ml and high cluster of differentiation (CD)-4 count emerged as additional important reasons. CONCLUSIONS: In just 2 years and in spite of the emergence of the COVID-19 pandemic, significant achievements concerning ART availability and strategies have occurred in CE, EE and SEE that facilitate the harmonization of those strategies with the European AIDS Clinical Society guidelines. Few exceptions exist, especially in EE. Continuous effort is needed to overcome various obstacles (administrative, financial, national guideline restrictions) in some countries.
- MeSH
- COVID-19 * epidemiologie MeSH
- HIV infekce * farmakoterapie epidemiologie MeSH
- inhibitory proteas terapeutické užití MeSH
- látky proti HIV * terapeutické užití MeSH
- lidé MeSH
- pandemie MeSH
- průřezové studie MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
- Klíčová slova
- inhibitory HIV kapsidy,
- MeSH
- fixní kombinace léků MeSH
- humanizované monoklonální protilátky MeSH
- inhibitory HIV fúze aplikace a dávkování farmakologie terapeutické užití MeSH
- inhibitory HIV-integrasy aplikace a dávkování farmakologie terapeutické užití MeSH
- inhibitory reverzní transkriptasy aplikace a dávkování farmakologie terapeutické užití MeSH
- látky proti HIV * aplikace a dávkování farmakologie terapeutické užití MeSH
- lidé MeSH
- rilpivirin aplikace a dávkování farmakologie terapeutické užití MeSH
- vysoce aktivní antiretrovirová terapie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Léčba infekce HIV modifikovala původně smrtelnou infekci do typicky chronického onemocnění s potřebou celoživotní léčby. U léčených pacientů však nedochází ke kompletní normalizaci imunitní aktivace, známek zánětu a protrombotického stavu. Tento stav je důsledkem mnoha faktorů, za hlavní příčinu je ale považována reziduální produkce RNA HIV-1 a virových proteinů infikovanými buňkami v buněčných rezervoárech. Perzistence imunitní aktivace/zánětu/protrombotického stavu vede k patofyziologii „sterilního zánětu“ a tzv. non -AIDS onemocněním, která se u infikovaných manifestují o jednu až dvě dekády dříve. Přes veškerá úskalí a nežádoucí sekundární projevy antiretrovirotik dokázala léčba infekce HIV zvrátit trajektorii fatální pandemie a umožnila přistoupit k terapeutickým modalitám, které byly ještě před několika lety absolutně nepředstavitelné. Transplantace solidních orgánů je pro pacienty s infekcí HIV dnes zcela legitimní terapeutická metoda a vysoce supresivní léčba umožňuje dokonce transplantaci od dárce s infekcí HIV. Níže uvedený text předkládá stručný přehled základních úskalí, ale i úspěchů současné vysoce supresivní léčby infekce HIV.
Treatment of HIV infection has modified the initially fatal infection into a typically chronic disease requiring lifelong treatment. However, there is no complete normalization of immune activation, signs of inflammation and prothrombotic state in treated patients. This condition is the result of many factors, but the main cause is thought to be the residual production of HIV-1 RNA and viral proteins by infected cells in cellular reservoirs. Persistence of immune activation/inflammation/prothrombotic state leads to the pathophysiology of "sterile inflammation" and so-called non-AIDS diseases, which manifest one to two decades earlier in those infected. Despite all the pitfalls and unwanted secondary manifestations of antiretroviral drugs, the treatment of HIV infection has managed to reverse the trajectory of a fatal pandemic and has made it possible to approach therapeutic modalities that were absolutely unimaginable just a few years ago. Solid organ transplantation is now a completely legitimate therapeutic method for patients living with HIV, and highly suppressive treatment even allows transplantation from an HIV-infected donor. The text below presents a brief overview of the basic pitfalls, but also of the successes, of the current highly suppressive treatment of HIV infection.
Progresivní multifokální leukoencefalopatie je vzácným demyelinizačním onemocněním CNS, vyskytujícím se téměř výhradně u imunokompromitovaných osob - nejčastěji jako pozdní komplikace infekce virem HIV. V této práci prezentujeme pacienta s PML, u něhož byla tato diagnóza prvotní diagnózou, která vedla ke zjištění HIV infekce, a zároveň se jedná o prvního pacienta s touto diagnózou na Neurologické klinice FN Olomouc.
Progressive multifocal leukoencephalopathy is a rare demyelinating disorder of the central nervous system, which is found almost entirely in immunocompromised persons - mostly as late complication of HIV infection. We present a case report of rare situation, in which the diagnosis of PML preceded the diagnosis of long-lasting HIV infection. This patient was also the first patient with this diagnosis in Neurology department of The University Hospital Olomouc.
- MeSH
- antiretrovirové látky terapeutické užití MeSH
- diferenciální diagnóza MeSH
- HIV séropozitivita MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- oportunní infekce doprovázející AIDS * diagnóza farmakoterapie komplikace MeSH
- počítačová rentgenová tomografie MeSH
- progrese nemoci MeSH
- progresivní multifokální leukoencefalopatie * diagnóza imunologie patofyziologie MeSH
- virus JC izolace a purifikace MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
PURPOSE: We aimed to compare the effects of P-glycoprotein (ABCB1) on the intestinal uptake of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), and metabolites, tenofovir isoproxil monoester (TEM) and tenofovir (TFV), and to study the molecular mechanism of drug-drug interaction (DDI) between sofosbuvir (SOF) and TDF/TAF. METHODS: Bidirectional transport experiments in Caco-2 cells and accumulation studies in precision-cut intestinal slices prepared from the ileal segment of rodent (rPCIS) and human (hPCIS) intestines were performed. RESULTS: TDF and TAF were extensively metabolised but TAF exhibited greater stability. ABCB1 significantly reduced the intestinal transepithelial transfer and uptake of the TFV(TDF) and TFV(TAF)-equivalents. However, TDF and TAF were absorbed more efficiently than TFV and TEM. SOF did not inhibit intestinal efflux of TDF and TAF or affect intestinal accumulation of TFV(TDF) and TFV(TAF)-equivalents but did significantly increase the proportion of absorbed TDF. CONCLUSIONS: TDF and TAF likely produce comparable concentrations of TFV-equivalents in the portal vein and the extent of permeation is reduced by the activity of ABCB1. DDI on ABCB1 can thus potentially affect TDF and TAF absorption. SOF does not inhibit ABCB1-mediated transport of TDF and TAF but does stabilise TDF, albeit without affecting the quantity of TFV(TDF)-equivalents crossing the intestinal barrier. Our data thus suggest that reported increases in the TFV plasma concentrations in patients treated with SOF and TDF result either from a DDI between SOF and TDF that does not involve ABCB1 or from a DDI involving another drug used in combination therapy.
- MeSH
- adenin metabolismus MeSH
- alanin MeSH
- Caco-2 buňky MeSH
- fumaráty MeSH
- HIV infekce * farmakoterapie MeSH
- látky proti HIV * MeSH
- lidé MeSH
- P-glykoprotein MeSH
- P-glykoproteiny MeSH
- sofosbuvir terapeutické užití MeSH
- tenofovir MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- ViiV Healthcare, Vocabria(cabotegravir), Recambys(rilpivirin),
- MeSH
- AIDS * farmakoterapie MeSH
- antiretrovirové látky * farmakologie terapeutické užití MeSH
- fixní kombinace léků MeSH
- lidé MeSH
- rozvrh dávkování léků MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Česká republika MeSH
- MeSH
- antiretrovirové látky aplikace a dávkování terapeutické užití MeSH
- fixní kombinace léků MeSH
- HIV infekce * epidemiologie farmakoterapie přenos MeSH
- látky proti HIV aplikace a dávkování farmakologie terapeutické užití MeSH
- lidé MeSH
- rilpivirin aplikace a dávkování terapeutické užití MeSH
- uprchlíci MeSH
- vysoce aktivní antiretrovirová terapie MeSH
- Check Tag
- lidé MeSH
BACKGROUND: Men experience twice the mortality of women while on ART in sub-Saharan Africa (SSA) largely due to late HIV diagnosis and poor retention. Here we propose to conduct an individually randomized control trial (RCT) to investigate the impact of three-month home-based ART (hbART) on viral suppression among men who were not engaged in care. METHODS AND DESIGN: A programmatic, individually randomized non-blinded, non-inferiority-controlled trial design (ClinicalTrials.org NCT04858243). Through medical chart reviews we will identify "non-engaged" men living with HIV, ≥15years of age who are not currently engaged in ART care, including (1) men who have tested HIV-positive and have not initiated ART within 7 days; (2) men who have initiated ART but are at risk of immediate default; and (3) men who have defaulted from ART. With 1:1 computer block randomization to either hbART or facility-based ART (fbART) arms, we will recruit men from 10-15 high-burden health facilities in central and southern Malawi. The hbART intervention will consist of 3 home-visits in a 3-month period by a certified male study nurse ART provider. In the fbART arm, male participants will be offered counselling at male participant's home, or a nearby location that is preferred by participants, followed with an escort to the local health facility and facility navigation. The primary outcome is the proportion of men who are virally suppressed at 6-months after ART initiation. Assuming primary outcome achievement of 24.0% and 33.6% in the two arms, 350 men per arm will provide 80% power to detect the stated difference. DISCUSSION: Identifying effective ART strategies that are convenient and accessible for men in SSA is a priority in the HIV world. Men may not (re-)engage in facility-based care due to a myriad of barriers. Two previous trials investigated the impact of hbART on viral suppression in the general population whereas this trial focuses on men. Additionally, this trial involves a longer duration of hbART i.e., three months compared to two weeks allowing men more time to overcome the initial psychological denial of taking ART.
- MeSH
- HIV infekce * farmakoterapie MeSH
- látky proti HIV * terapeutické užití MeSH
- lidé MeSH
- novorozenec MeSH
- poradenství MeSH
- randomizované kontrolované studie jako téma MeSH
- samotestování MeSH
- zdravotnická zařízení MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- protokol klinické studie MeSH
- Research Support, N.I.H., Extramural MeSH
- Geografické názvy
- Malawi MeSH
