- Critical assessment of approaches for molecular docking to elucidate associations of HLA alleles with adverse drug reactions. [Journal Article]
- MIMol Immunol 2018 Aug 17; 101:488-499
- Adverse drug reactions have been linked with genetic polymorphisms in HLA genes in numerous different studies. HLA proteins have an essential role in the presentation of self and non-self peptides, a...
Adverse drug reactions have been linked with genetic polymorphisms in HLA genes in numerous different studies. HLA proteins have an essential role in the presentation of self and non-self peptides, as part of the adaptive immune response. Amongst the associated drugs-allele combinations, anti-HIV drug Abacavir has been shown to be associated with the HLA-B*57:01 allele, and anti-epilepsy drug Carbamazepine with B*15:02, in both cases likely following the altered peptide repertoire model of interaction. Under this model, the drug binds directly to the antigen presentation region, causing different self peptides to be presented, which trigger an unwanted immune response. There is growing interest in searching for evidence supporting this model for other ADRs using bioinformatics techniques. In this study, in silico docking was used to assess the utility and reliability of well-known docking programs when addressing these challenging HLA-drug situations. The overall aim was to address the uncertainty of docking programs giving different results by completing a detailed comparative study of docking software, grounded in the MHC-ligand experimental structural data - for Abacavir and to a lesser extent Carbamazepine - in order to assess their performance. Four docking programs: SwissDock, ROSIE, AutoDock Vina and AutoDockFR, were used to investigate if each software could accurately dock the Abacavir back into the crystal structure for the protein arising from the known risk allele, and if they were able to distinguish between the HLA-associated and non-HLA-associated (control) alleles. The impact of using homology models on the docking performance and how using different parameters, such as including receptor flexibility, affected the docking performance were also investigated to simulate the approach where a crystal structure for a given HLA allele may be unavailable. The programs that were best able to predict the binding position of Abacavir were then used to recreate the docking seen for Carbamazepine with B*15:02 and controls alleles. It was found that the programs investigated were sometimes able to correctly predict the binding mode of Abacavir with B*57:01 but not always. Each of the software packages that were assessed could predict the binding of Abacavir and Carbamazepine within the correct sub-pocket and, with the exception of ROSIE, was able to correctly distinguish between risk and control alleles. We found that docking to homology models could produce poorer quality predictions, especially when sequence differences impact the architecture of predicted binding pockets. Caution must therefore be used as inaccurate structures may lead to erroneous docking predictions. Incorporating receptor flexibility was found to negatively affect the docking performance for the examples investigated. Taken together, our findings help characterise the potential but also the limitations of computational prediction of drug-HLA interactions. These docking techniques should therefore always be used with care and alongside other methods of investigation, in order to be able to draw strong conclusions from the given results.
- Equilibrative nucleoside transporter 1 (ENT1, SLC29A1) facilitates transfer of the antiretroviral drug abacavir across the placenta. [Journal Article]
- DMDrug Metab Dispos 2018 Aug 10
- Abacavir is a preferred antiretroviral drug for preventing mother-to-child HIV transmission; however, mechanisms of its placental transfer have not been satisfactorily described to date. Because abac...
Abacavir is a preferred antiretroviral drug for preventing mother-to-child HIV transmission; however, mechanisms of its placental transfer have not been satisfactorily described to date. Because abacavir is a nucleoside-derived drug, we hypothesized that the nucleoside transporters, ENTs (SLC29A) and/or Na+ dependent CNTs (SLC28A), may play a role in its passage across the placenta. To test this hypothesis, we performed uptake experiments using BeWo cell line, human fresh villous fragments and microvillous plasma membrane (MVM) vesicles. Employing endogenous substrates of nucleoside transporters, [3H] adenosine (ENTs, CNT2, and CNT3) and [3H] thymidine (ENTs, CNT1, and CNT3), we showed significant activity of ENT1 and CNT2 in BeWo cells while experiments in the villous fragments and MVM vesicles, representing model of apical membrane of syncytiotrophoblast, revealed only ENT1 activity. When testing [3H] abacavir uptakes, we showed that of nucleoside transporters, ENT1 plays the dominant role in abacavir uptake into placental tissues, whereas contribution of Na+ dependent transport, most likely mediated by CNTs, was observed only in BeWo cells. Subsequent experiments with dually perfused rat term placentas showed that Ent1 contributes significantly to overall [3H] abacavir placental transport. Finally, we quantified the expression of SLC29A in first- and third-trimester placentas, revealing that SLC29A1 is the dominant isoform. Neither SLC29A1 nor SLC29A2 expression changed over the course of placental development, but there was considerable inter-individual variability in their expression. Therefore, drug-drug interactions and the effect of inter-individual variability in placental ENT1 expression on abacavir disposition into fetal circulation should be further investigated to guarantee safe and effective abacavir-based combination therapies in pregnancy.
- Adverse Drug Reactions Among Patients Initiating Second-Line Antiretroviral Therapy in South Africa. [Journal Article]
- DSDrug Saf 2018 Jul 24
- CONCLUSIONS: The rates of AEs were lowest among patients receiving a TDF-based second-line regimen. Patients with poorer health at the time of switch were at higher risk of AEs when receiving second-line ART and may require closer monitoring to improve the durability of second-line therapy.
- Risk of Cardiovascular Disease Associated With Exposure To Abacavir Among Individuals With HIV: A Systematic Review And Meta-analyses Of Results From Seventeen Epidemiologic Studies. [Review]
- IJInt J Antimicrob Agents 2018 Jul 21
- CONCLUSIONS: Our findings suggest an increased risk of CVD from recent abacavir exposure. The risk remained elevated after adjusting for potential confounders. Further investigations are needed to understand CVD risk from cumulative exposure.
- HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies. [Review]
- OHOpen Heart 2018; 5(2):e000823
- HIV infection is a risk factor for cardiovascular disease (CVD). This risk is accentuated by certain combination antiretroviral therapies (cARTs), independent of their effects on lipid metabolism and...
HIV infection is a risk factor for cardiovascular disease (CVD). This risk is accentuated by certain combination antiretroviral therapies (cARTs), independent of their effects on lipid metabolism and insulin sensitivity. We sought to define potential mechanisms for this association through systematic review of clinical and preclinical studies of CVD in the setting of HIV/cART from the English language literature from 1989 to March 2018. We used PubMed, Web of Knowledge and Google Scholar, and conference abstracts for the years 2015-March 2018. We uncovered three themes: (1) a critical role for the HIV protease inhibitor (PI) ritonavir and certain other PI-based regimens. (2) The importance of platelet activation. Virtually all PIs, and one nucleoside reverse transcriptase inhibitor, abacavir, activate platelets, but a role for this phenomenon in clinical CVD risk may require additional postactivation processes, including: release of platelet transforming growth factor-β1; induction of oxidative stress with production of reactive oxygen species from vascular cells; suppression of extracellular matrix autophagy; and/or sustained proinflammatory signalling, leading to cardiac fibrosis and dysfunction. Cardiac fibrosis may underlie an apparent shift in the character of HIV-linked CVD over the past decade from primarily left ventricular systolic to diastolic dysfunction, possibly driven by cART. (3) Recognition of the need for novel interventions. Switching from cART regimens based on PIs to contemporary antiretroviral agents such as the integrase strand transfer inhibitors, which have not been linked to clinical CVD, may not mitigate CVD risk assumed under prior cART. In conclusion, attention to the effects of specific antiretroviral drugs on platelet activation and related profibrotic signalling pathways should help: guide selection of appropriate anti-HIV therapy; assist in evaluation of CVD risk related to novel antiretrovirals; and direct appropriate interventions.
- Pediatric Neurodevelopmental Functioning Following in utero Exposure to Triple-NRTI vs. Dual-NRTI + PI ART in a Randomized Trial, Botswana. [Journal Article]
- JAJ Acquir Immune Defic Syndr 2018 Jul 10
- CONCLUSIONS: Neurodevelopmental outcomes in 24-month-old HEU children of HIV-infected mothers with baseline CD4≥200 were similar in those randomized to a dual-NRTI+PI-based versus a triple-NRTI-based ART regimen, suggestive of lack of short term toxicity. Monitoring of long term toxicity and newer regimens is warranted.
- Epidemiological, clinical, and laboratory factors associated with chronic kidney disease in Mexican HIV-infected patients. [Journal Article]
- JBJ Bras Nefrol 2018 Jul 10
- CONCLUSIONS: CKD was a frequent complication in HIV-infected patients. These findings confirm the importance of screening and the early detection of CKD, as well as the importance of identifying and treating traditional and non-traditional risk factors associated with CKD.
- Drugs and Lactation Database (LactMed) [BOOK]
- BOOKNational Library of Medicine (US): Bethesda (MD)
- In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. Published experience with abacavir during breastfeeding is limited. In countrie...
In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. Published experience with abacavir during breastfeeding is limited. In countries in which no acceptable, feasible, sustainable and safe replacement feeding is available, World Health Organization guidelines recommend that all women with an HIV infection who are pregnant or breastfeeding should be maintained on antiretroviral therapy for at least the duration of risk for mother-to-child transmission. Mothers should exclusively breastfeed their infants for the first 6 months of life; breastfeeding with complementary feeding should continue through at least 12 months of life up to 24 months of life. The first choice regimen for nursing mothers is tenofovir, efavirenz and either lamivudine or emtricitabine. If these drugs are unavailable, alternative regimens include: 1) zidovudine, lamivudine and efavirenz; 2) zidovudine, lamivudine and nevirapine; or 3) tenofovir, nevirapine and either lamivudine or emtricitabine. Exclusively breastfed infants should also receive 6 weeks of prophylaxis with nevirapine.
- Severe cholestatic hepatitis related to abacavir/lamivudine/dolutegravir antiretroviral treatment in a HIV-1 infected subject. [Journal Article]
- AIDSAIDS 2018 Jul 31; 32(12):1727-1729
New Search Next
- ProTide generated long-acting abacavir nanoformulations. [Journal Article]
- CCChem Commun (Camb) 2018 Jul 24; 54(60):8371-8374
- Abacavir pronucleotide nanoformulations (NM3ABC) were prepared as a novel long acting slow effective release antiretroviral therapy. Single NM3ABC treatment of human monocyte-derived macrophages prod...
Abacavir pronucleotide nanoformulations (NM3ABC) were prepared as a novel long acting slow effective release antiretroviral therapy. Single NM3ABC treatment of human monocyte-derived macrophages produced sustained intracellular carbovir-triphosphate and antiretroviral activities for up to 30 days.