• Keywords
• inhibitory HIV kapsidy,
• MeSH
• Drug Combinations MeSH
• Antibodies, Monoclonal, Humanized MeSH
• HIV Fusion Inhibitors administration & dosage   pharmacology   therapeutic use   MeSH
• HIV Integrase Inhibitors administration & dosage   pharmacology   therapeutic use   MeSH
• Reverse Transcriptase Inhibitors administration & dosage   pharmacology   therapeutic use   MeSH
• Anti-HIV Agents * administration & dosage   pharmacology   therapeutic use   MeSH
• Humans MeSH
• Rilpivirine administration & dosage   pharmacology   therapeutic use   MeSH
• Antiretroviral Therapy, Highly Active methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2, 4, and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC50 = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC50 = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7×). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 μM) compared to ETV and RPV (≪1 μM). Additionally, the binding modes of compounds 2, 4, and 6 to the reverse transcriptase were studied by X-ray crystallography.

• MeSH
• HIV Infections * drug therapy   MeSH
• HIV Reverse Transcriptase metabolism   MeSH
• HIV-1 * metabolism   MeSH
• Reverse Transcriptase Inhibitors MeSH
• Anti-HIV Agents * chemistry   MeSH
• Humans MeSH
• Drug Design MeSH
• Rilpivirine therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

OBJECTIVES: The aim of this international multicentre study was to review potential drug-drug interactions (DDIs) for real-life coadministration of combination antiretroviral therapy (cART) and coronavirus disease 2019 (COVID-19)-specific medications. METHODS: The Euroguidelines in Central and Eastern Europe Network Group initiated a retrospective, observational cohort study of HIV-positive patients diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Data were collected through a standardized questionnaire and DDIs were identified using the University of Liverpool's interaction checker. RESULTS: In total, 524 (94.1% of 557) patients received cART at COVID-19 onset: 117 (22.3%) were female, and the median age was 42 (interquartile range 36-50) years. Only 115 (21.9%) patients were hospitalized, of whom 34 required oxygen therapy. The most frequent nucleoside reverse transcriptase inhibitor (NRTI) backbone was tenofovir disoproxil fumarate (TDF)/tenofovir alafenamide (TAF) with lamivudine or emtricitabine (XTC) (79.3%) along with an integrase strand transfer inhibitor (INSTI) (68.5%), nonnucleoside reverse transcriptase inhibitor (NNRTI) (17.7%), protease inhibitor (PI) (13.7%) or other (2.5%). In total, 148 (28.2%) patients received COVID-19-specific treatments: corticosteroids (15.7%), favipiravir (7.1%), remdesivir (3.1%), hydroxychloroquine (2.7%), tocilizumab (0.6%) and anakinra (0.2%). In total, 62 DDI episodes were identified in 58 patients (11.8% of the total cohort and 41.9% of the COVID-19-specific treatment group). The use of boosted PIs and elvitegravir accounted for 43 DDIs (29%), whereas NNRTIs were responsible for 14 DDIs (9.5%). CONCLUSIONS: In this analysis from the Central and Eastern European region on HIV-positive persons receiving COVID-19-specific treatment, it was found that potential DDIs were common. Although low-dose steroids are mainly used for COVID-19 treatment, comedication with boosted antiretrovirals seems to have the most frequent potential for DDIs. In addition, attention should be paid to NNRTI coadministration.

• MeSH
• Adenine therapeutic use   MeSH
• COVID-19 * MeSH
• Adult MeSH
• Emtricitabine therapeutic use   MeSH
• COVID-19 Drug Treatment MeSH
• HIV Infections * drug therapy   MeSH
• HIV Seropositivity * drug therapy   MeSH
• Reverse Transcriptase Inhibitors MeSH
• Anti-HIV Agents * therapeutic use   MeSH
• Drug Interactions MeSH
• Middle Aged MeSH
• Humans MeSH
• Retrospective Studies MeSH
• SARS-CoV-2 MeSH
• Tenofovir adverse effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH

Nucleos(t)ide analogues entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line monotherapies for chronic hepatitis B (CHB). Multiple HBV genotypes/subgenotypes have been described, but their impact on treatment response remains largely elusive. We investigated the effectiveness of ETV/TDF on HBV/D-subgenotypes, D1/D2/D3/D5, studied the structural/functional differences in subgenotype-specific reverse transcriptase (RT) domains of viral polymerase, and identified novel molecules with robust inhibitory activity on various D-subgenotypes. Transfection of Huh7 cells with full-length D1/D2/D3/D5 and in vitro TDF/ETV susceptibility assays demonstrated that D1/D2 had greater susceptibility to TDF/ETV while D3/D5 exhibited poorer response. Additionally, HBV load was substantially reduced in TDF-treated CHB patients carrying D1/D2 but minimally reduced in D3/D5-infected patients. Comparison of RT sequences of D-subgenotypes led to identification of unique subgenotype-specific residues, and molecular modeling/docking/simulation studies depicted differential bindings of TDF/ETV to the active site of their respective RTs. Replacement of signature residues in D3/D5 HBV clones with corresponding amino acids seen in D1/D2 improved their susceptibility to TDF/ETV. Using high throughput virtual screening, we identified N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases, including N6-substituted (S)-FPMP derivative of 2,6-diaminopurine (DAP) (OB-123-VK), as potential binders of RT of different D-subgenotypes. We synthesized (S)-FPMPG prodrugs (FK-381-FEE/FK-381-SEE/FK-382) and tested their effectiveness along with OB-123-VK. Both OB-123-VK and FK-381-FEE exerted similar antiviral activities against all D-subgenotypes, although FK-381-FEE was more potent. Our study highlighted the natural variation in therapeutic response of D1/D2/D3/D5 and emphasized the need for HBV subgenotype determination before treatment. Novel molecules described here could benefit future design/discovery of pan-D-subgenotypic inhibitors. IMPORTANCE Current treatment of chronic hepatitis B relies heavily on nucleotide/nucleoside analogs in particular, tenofovir disoproxil fumarate (TDF) and entecavir (ETV) to keep HBV replication under control and prevent end-stage liver diseases. However, it was unclear whether the therapeutic effects of TDF/ETV differ among patients infected with different HBV genotypes and subgenotypes. HBV genotype D is the most widespread of all HBV genotypes and multiple D-subgenotypes have been described. We here report that different subgenotypes of HBV genotype-D exhibit variable response toward TDF and ETV and this could be attributed to naturally occurring amino acid changes in the reverse transcriptase domain of the subgenotype-specific polymerase. Further, we identified novel molecules and also synthesized prodrugs that are equally effective on different D-subgenotypes and could facilitate management of HBV/D-infected patients irrespective of D-subgenotype.

• MeSH
• Antiviral Agents chemistry   pharmacology   therapeutic use   MeSH
• Hepatitis B, Chronic drug therapy   virology   MeSH
• Genotype MeSH
• Guanine analogs & derivatives   chemistry   pharmacology   therapeutic use   MeSH
• Reverse Transcriptase Inhibitors chemistry   pharmacology   therapeutic use   MeSH
• Humans MeSH
• Mutation MeSH
• Organophosphonates chemistry   pharmacology   MeSH
• Prodrugs MeSH
• Protein Domains MeSH
• Drug Design * MeSH
• RNA-Directed DNA Polymerase chemistry   genetics   MeSH
• Tenofovir chemistry   pharmacology   therapeutic use   MeSH
• Drug Resistance, Viral drug effects   genetics   MeSH
• Viral Load drug effects   MeSH
• Hepatitis B virus drug effects   enzymology   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Antiretrovirová terapie je základem léčby osob infikovaných HIV (lidským virem imunodeficience). Antiretrovirotika se rozdělují do šesti skupin podle mechanismu účinku a chemické struktury. Jedna blokují funkci tří virových enzymů a jiná brání vstupu viru do buňky. U většiny pacientů se dosáhne suprese virové replikace, která je předpokladem pro návrat, resp. udržení dostatečné funkce imunitního systému. Léčba má také význam pro omezení přenosu infekce HIV na druhé osoby. Ačkoliv léčba brání klasickým zdravotním komplikacím infekce HIV vázaným na imunodeficit, nezabrání úplně aktivaci imunitního systému a tím nebezpečí non‑AIDS komplikací. Obvyklá počáteční kombinace antiretrovirotik zahrnuje dva nukleosidové, resp. jeden nukleosidový a jeden nukleotidový inhibitor reverzní transkriptázy spolu s inhibitorem integrázy. Za určitých okolností přichází v úvahu i použití např. nových nenukleosidových inhibitorů reverzní transkriptázy nebo inhibitorů proteinázy. Vedle této konvenční terapie se zvolna prosazuje používání dvojkombinačních režimů založených na spolehlivosti dolutegraviru. Tyto režimy slibují snížení toxicity, lékových interakcí a nákladů při zachování účinku. Určité teoretické překážky nejsou vyloučeny a přínos lze očekávat u vybraných skupin pacientů.

Antiretroviral therapy is a basis for HIV (human immunodeficiency virus) treatment of positive people. Antiretroviral drugs are divided into six groups according to the mechanism of action and chemical structure. Some block the function of three viral enzymes and other block the viral entry into the cell. In most patients, a suppression of viral replication is reached that is a pre‑requisite for the return and maintenance of sufficient immune system function. The treatment is also important for reducing the risk of HIV infection transfer to other people. Although the treatment prevents classic medical complications of HIV infection associated with immunodeficiency, it does not prevent completely the activation of immune system and the risk of non‑AIDS complications. The usual initial combination of antiretroviral drugs includes two nucleoside or rather one nucleoside and one nucleotide inhibitor of reverse transcriptase together with integrase inhibitor. In certain circumstances, the use of for example the new non‑nucleoside inhibitors of reverse transcriptase or protease inhibitors is warranted. Alongside this conventional therapy, the use of dual combination regimens based on the reliability of dolutegravir is slowly asserted. The promise of the decrease of toxicity, drug interactions and cost while maintaining efficacy comes with these regimens. Certain theoretical obstacles are not out of the question and the benefit can be expected in selected groups of patients.

• MeSH
• Anti-Retroviral Agents * adverse effects   therapeutic use   MeSH
• Antiviral Agents * adverse effects   therapeutic use   MeSH
• Drug Combinations MeSH
• Heterocyclic Compounds, 3-Ring therapeutic use   MeSH
• HIV Infections drug therapy   MeSH
• HIV Fusion Inhibitors therapeutic use   MeSH
• HIV Integrase Inhibitors therapeutic use   MeSH
• Reverse Transcriptase Inhibitors therapeutic use   MeSH
• Viral Protease Inhibitors therapeutic use   MeSH
• Anti-HIV Agents * adverse effects   therapeutic use   MeSH
• Drug Resistance MeSH
• Humans MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH

• MeSH
• Acquired Immunodeficiency Syndrome MeSH
• Anti-Retroviral Agents MeSH
• HIV MeSH
• HIV Fusion Inhibitors MeSH
• HIV Integrase Inhibitors MeSH
• Reverse Transcriptase Inhibitors MeSH
• Viral Protease Inhibitors MeSH
• Drug Therapy, Combination MeSH
• Humans MeSH
• Antiretroviral Therapy, Highly Active * MeSH
• Check Tag
• Humans MeSH

Infekce virem hepatitidy B (HBV) představuje stále celosvětově zdravotní problém s epidemiologií měnící se v závislosti na řadě faktorů, především na vakcinační politice a migraci. Chronická infekce HBV je označení pro infekci trvající déle než 6 měsíců. Jedná se o dynamický proces, který odráží interakce mezi virovou replikací a hostitelskou imunitní odpovědí. Ne všichni pacienti chronicky infikovaní HBV mají chronickou hepatitidu B. Všechny osoby chronicky infikované HBV jsou ve zvýšeném riziku progrese do jaterní cirhózy a hepatocelulárního karcinomu. Dlouhodobé podávání účinných nukleosidových nebo nukleotidových inhibitorů reverzní transkriptázy s vysokou genetickou bariérou proti vzniku rezistence (tenofovir, entekavir) představuje v současnosti nejúčinnější léčbu chronické hepatitidy B. U pacientů s mírně až středně pokročilou lze použít k léčbě i pegylovaný interferon α.

Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors predominantly vaccination policy and migration. Chronic hepatitis B means the duration of HBV infection for more than 6 months. It is a dynamic process reflecting the interaction between HBV replication and the host immune response and not all patients with chronic HBV infection have chronic hepatitis B. All patients with chronic HBV infection are in increased risk of progression to liver cirrhosis and hepatocellular carcinoma. The long-term administration of potent nucleos(t)ide analogue with high barrier of resistance (tenofovir, entecavir) represents the treatment of choice. Pegylated interferon-α can also be considered in mid to moderate chronic hepatitis B patients.

• Keywords
• entecavir,
• MeSH
• Hepatitis B, Chronic * diagnosis   drug therapy   pathology   MeSH
• Guanine analogs & derivatives   therapeutic use   MeSH
• Reverse Transcriptase Inhibitors MeSH
• Interferon-alpha administration & dosage   therapeutic use   MeSH
• Liver Cirrhosis drug therapy   pathology   MeSH
• Humans MeSH
• Tenofovir therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

BACKGROUND: The HIV drugs lopinavir and ritonavir have recently been reported to cause transient adrenal insufficiency in preterm newborns. We, therefore, considered HIV drugs as a cause of transiently elevated 17-hydroxyprogesterone (17OHP) levels in a neonatal screening test for congenital adrenal hyperplasia in a preterm girl exposed to zidovudine, efavirenz, tenofovir, and emtricitabine. OBJECTIVE: So far, HIV drugs have not been tested for their effect on steroidogenesis and the steroidogenic enzyme activity of CYP21A2 specifically in an in vitro system. METHODS: We tested the effect of efavirenz, tenofovir, emtricitabine, and zidovudine on steroidogenesis of human adrenal H295R cells. Cells were treated with the drugs at different concentrations including concentrations in therapeutic use. The effect on CYP21A2 activity was assessed by testing the conversion of radiolabeled 17OHP to 11-deoxycortisol. Cell viability was tested by an MTT assay. In addition, recombinant human CYP21A2 protein was used to assess direct drug effects on CYP21A2 activity. RESULTS: We observed significantly decreased CYP21A2 activity in both in vitro testing systems after treatment with efavirenz at therapeutic concentrations. Moreover, efavirenz affected cell viability. By contrast, the other test drugs did not affect steroidogenesis. Follow-up of our patient revealed elevated 17OHP and androgen levels during the first weeks of life, but values normalized spontaneously. Genetic testing for CYP21A2 mutations was negative. Thus, it remains unsettled whether the transient 17OHP elevation in this baby was due to a drug effect. CONCLUSION: The HIV drug efavirenz inhibits CYP21A2 activity in vitro through direct interaction with enzyme catalysis at therapeutic concentrations. This may have clinical implications for HIV treatment in children and adults. However, so far, clinical data are scarce, and further studies are needed to be able to draw clinical conclusions.

• MeSH
• Benzoxazines * administration & dosage   adverse effects   MeSH
• Cell Line MeSH
• Adult MeSH
• HIV Infections drug therapy   MeSH
• Pregnancy Complications, Infectious drug therapy   MeSH
• Reverse Transcriptase Inhibitors * administration & dosage   adverse effects   MeSH
• Adrenal Hyperplasia, Congenital * chemically induced   enzymology   MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Premature Birth * chemically induced   enzymology   MeSH
• Steroid 21-Hydroxylase antagonists & inhibitors   metabolism   MeSH
• Pregnancy MeSH
• Prenatal Exposure Delayed Effects * chemically induced   enzymology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

Infekce virem hepatitidy B (HBV) je stále celosvětově zdravotním problém s měnicí se epidemiologií v závislosti na řadě faktorů, především na vakcinační politice a migraci. Chronická infekce HBV je označení pro infekci trvající déle než 6 měsíců. Jde o dynamický proces, který odráží interakce mezi virovou replikací a hostitelskou imunitní odpovědí. Ne všichni pacienti chronicky infikovaní HBV mají chronickou hepatitidu B. Všechny osoby chronicky infikované HBV jsou ve zvýšeném riziku progrese do jaterní cirhózy a hepatocelulárního karcinomu. Dlouhodobé podávání účinných nukleosidových nebo nukleotidových inhibitorů virové DNA polymerázy – reverzní transkriptázy s vysokou genetickou bariérou proti vzniku rezistence (tenofovir, entekavir) představuje v současnosti nejúčinnější léčbu chronické hepatitidy B. U pacientů s mírně až středně pokročilou HBV lze použít k léčbě i pegylovaný interferon alfa.

Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors predominantlyvaccination policy and migration. Chronic hepatitis B means the duration of HBV infection for more than 6 months.It is a dynamic process reflecting the interaction between HBV replication and the host immune response and not all patientswith chronic HBV infection have chronic hepatitis B. All patients with chronic HBV infection are in increased risk of progression toliver cirrhosis and hepatocellular carcinoma. The long-term administration of potent nucleos(t)ide analogue with high barrier ofresistance (tenofovir, entecavir) represents the treatment of choice. Pegylated interferon-alpha can also be considered in mid tomoderate chronic hepatitis B patients.

• Keywords
• pegylovaný interferon alfa, entekavir,
• MeSH
• Alanine Transaminase MeSH
• Anti-Retroviral Agents classification   therapeutic use   MeSH
• Hepatitis B, Chronic * diagnosis   pathology   therapy   MeSH
• Guanine analogs & derivatives   MeSH
• Hepatitis B e Antigens MeSH
• Hepatitis B epidemiology   classification   pathology   MeSH
• Reverse Transcriptase Inhibitors classification   therapeutic use   MeSH
• Interferon-alpha therapeutic use   MeSH
• Humans MeSH
• Practice Guidelines as Topic MeSH
• Tenofovir MeSH
• Drug Resistance, Viral MeSH
• Hepatitis B virus * pathogenicity   drug effects   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH
• Geographicals
• Czech Republic MeSH
• Europe MeSH

• MeSH
• Acquired Immunodeficiency Syndrome * epidemiology   drug therapy   transmission   MeSH
• Anti-Retroviral Agents administration & dosage   therapeutic use   MeSH
• HIV Infections epidemiology   drug therapy   transmission   MeSH
• HIV Integrase Inhibitors administration & dosage   therapeutic use   MeSH
• HIV Protease Inhibitors administration & dosage   therapeutic use   MeSH
• Reverse Transcriptase Inhibitors administration & dosage   therapeutic use   MeSH
• Drug Therapy, Combination methods   standards   MeSH
• Anti-HIV Agents * administration & dosage   therapeutic use   MeSH
• Humans MeSH
• Pre-Exposure Prophylaxis methods   MeSH
• Practice Guidelines as Topic MeSH
• Check Tag
• Humans MeSH