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American Journal of Ophthalmology Case... Sep 2020To report the case 47-year-old patient presenting with severe maculopathy associated with long-term ritonavir treatment.
PURPOSE
To report the case 47-year-old patient presenting with severe maculopathy associated with long-term ritonavir treatment.
METHODS
Observational case report of one patient and literature review.
RESULTS
A 47 year-old Caucasian man presented with progressive bilateral vision loss for the past 5 years. His medical history included Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) coinfection since 1992. He was treated by highly active antiretroviral therapy for 24 years including 4 years of didanosine treatment and 18 years of ritonavir treatment. Bilateral extensive macular atrophy with foveal sparing on the left eye and absence of midperipheral/peripheral retina involvement was confirmed on multimodal imaging and functional testing including swept-source OCT angiography and electroretinography.
CONCLUSION
Ritonavir associated maculopathy is a scarcely described medication-associated retinopathy. In this case, an extensive macular atrophy (with complete loss of photoreceptor, RPE and choriocapillaris layers) and subsequent cone-rod dysfunction appeared after 18 years of ritonavir exposure.
PubMed: 32803017
DOI: 10.1016/j.ajoc.2020.100783 -
Open Forum Infectious Diseases Jul 2020The development of efficacious combination antiretroviral therapy (cART) has led to a dramatic decrease in mortality in HIV-positive patients. Specific data on the...
Decreased All-Cause and Liver-Related Mortality Risk in HIV/Hepatitis B Virus Coinfection Coinciding With the Introduction of Tenofovir-Containing Combination Antiretroviral Therapy.
BACKGROUND
The development of efficacious combination antiretroviral therapy (cART) has led to a dramatic decrease in mortality in HIV-positive patients. Specific data on the impact in HIV/hepatitis B virus (HBV)-coinfected patients are lacking. In this study, all-cause and cause-specific mortality risks stratified per era of diagnosis are investigated.
METHODS
Data were analyzed from HIV/HBV-coinfected patients enrolled in the ATHENA cohort between January 1, 1998, and December 31, 2017. Risk for (cause-specific) mortality was calculated using Cox proportional hazard regression analysis, comparing patients diagnosed before 2003 with those diagnosed ≥2003. Risk factors for all-cause and liver-related mortality were also assessed using Cox proportional hazard regression analysis.
RESULTS
A total of 1301 HIV/HBV-coinfected patients were included (14 882 person-years of follow-up). One-hundred ninety-eight patients (15%) died during follow-up. The adjusted hazard ratio (aHR) for all-cause mortality in patients diagnosed in or after 2003 was 0.50 (95% CI, 0.35-0.72) relative to patients diagnosed before 2003. Similar risk reduction was observed for liver-related (aHR, 0.29; 95% CI, 0.11-0.75) and AIDS-related mortality (aHR, 0.44; 95% CI, 0.22-0.87). Use of a tenofovir-containing regimen was independently associated with a reduced risk of all-cause and liver-related mortality. Prior exposure to didanosine/stavudine was strongly associated with liver-related mortality. Ten percent of the population used only lamivudine as treatment for HBV.
CONCLUSIONS
All-cause, liver-related, and AIDS-related mortality risk in HIV/HBV-coinfected patients has markedly decreased over the years, coinciding with the introduction of tenofovir. Tenofovir-containing regimens, in absence of major contraindications, should be strongly encouraged in this population.
PubMed: 32665961
DOI: 10.1093/ofid/ofaa226 -
Nucleosides, Nucleotides & Nucleic Acids 2020Many antivirals interact with DNA and alter their expression profile. Thus, it is necessary to understand the binding mode. Didanosine, a nucleoside reverse...
Many antivirals interact with DNA and alter their expression profile. Thus, it is necessary to understand the binding mode. Didanosine, a nucleoside reverse transcriptase inhibitor, is used to treat HIV infection in patients with or without acquired immunodeficiency syndrome. Understanding the mechanism of interaction of this nucleoside reverse transcriptase inhibitor with DNA can prove useful in the development of a rational drug designing system. In vitro studies (UV-vis, fluorescence, and viscometry techniques) under physiological conditions (Tris-HCl buffer solutions, pH 7.4) show that didanosine drug interacts with calf-thymus DNA (ct-DNA) via partial intercalative binding mode. UV-visible spectroscopy confirmed the formation didanosine-DNA complex with a binding strength of about 1.5 × 10 M thus indicating their biological worth. Dye displace experiments and viscometry confirmed that didanosine partially intercalates toward DNA molecules. Negative value of Gibb's-free energy change revealed that the process is spontaneous. The thermodynamic parameters such as enthalpy change (Δ) and entropy change (Δ) showed that the acting forces between didanosine and ct-DNA mainly included hydrophobic interactions.
Topics: Animals; Cattle; DNA; Didanosine; Humans; Hydrophobic and Hydrophilic Interactions; Reverse Transcriptase Inhibitors; Spectrophotometry, Ultraviolet; Thermodynamics
PubMed: 32643522
DOI: 10.1080/15257770.2020.1780435 -
Drug Metabolism and Disposition: the... Jul 2020Equilibrative nucleoside transporters (ENTs) transport nucleosides across the blood-testis barrier (BTB). ENTs are of interest to study the disposition of nucleoside...
Equilibrative nucleoside transporters (ENTs) transport nucleosides across the blood-testis barrier (BTB). ENTs are of interest to study the disposition of nucleoside reverse-transcriptase inhibitors (NRTIs) in the human male genital tract because of their similarity in structure to nucleosides. HeLa S3 cells express ENT1 and ENT2 and were used to compare relative interactions of these transporters with selected NRTIs. Inhibition of [H]uridine uptake by NBMPR was biphasic, with IC values of 11.3 nM for ENT1 and 9.6 μM for ENT2. Uptake measured with 100 nM NBMPR represented ENT2-mediated transport; subtracting that from total uptake represented ENT1-mediated transport. The kinetics of ENT1- and ENT2-mediated [H]uridine uptake revealed no difference in J (16.53 and 30.40 pmol cm min) and an eightfold difference in K (13.6 and 108.9 μM). The resulting fivefold difference in intrinsic clearance (J/K) for ENT1- and ENT2 transport accounted for observed inhibition of [H]uridine uptake by 100 nM NBMPR. Millimolar concentrations of the NRTIs emtricitabine, didanosine, lamivudine, stavudine, tenofovir disoproxil, and zalcitabine had no effect on ENT transport activity, whereas abacavir, entecavir, and zidovudine inhibited both transporters with IC values of ∼200 µM, 2.5 mM, and 2 mM, respectively. Using liquid chromatography-tandem mass spectrometry and [H] compounds, the data suggest that entecavir is an ENT substrate, abacavir is an ENT inhibitor, and zidovudine uptake is carrier-mediated, although not an ENT substrate. These data show that HeLa S3 cells can be used to explore complex transporter selectivity and are an adequate model for studying ENTs present at the BTB. SIGNIFICANCE STATEMENT: This study characterizes an in vitro model using S-[(4-nitrophenyl)methyl]-6-thioinosine to differentiate between equilibrative nucleoside transporter (ENT) 1- and ENT2-mediated uridine transport in HeLa cells. This provides a method to assess the influence of nucleoside reverse-transcriptase inhibitors on natively expressed transporter function. Determining substrate selectivity of the ENTs in HeLa cells can be effectively translated into the activity of these transporters in Sertoli cells that comprise the blood-testis barrier, thereby assisting targeted drug development of compounds capable of circumventing the blood-testis barrier.
Topics: Blood-Testis Barrier; Drug Evaluation, Preclinical; Equilibrative Nucleoside Transporter 1; Equilibrative-Nucleoside Transporter 2; HeLa Cells; Humans; Inhibitory Concentration 50; Nucleosides; Reverse Transcriptase Inhibitors; Zidovudine
PubMed: 32393653
DOI: 10.1124/dmd.120.090720 -
PloS One 2020Cellular immunometabolism among people living with HIV (PLWH) on antiretroviral therapy (ART) remains under investigated. We assessed the relationships between...
BACKGROUND
Cellular immunometabolism among people living with HIV (PLWH) on antiretroviral therapy (ART) remains under investigated. We assessed the relationships between mitochondrial oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) and blood parameters associated with HIV immune dysregulation.
METHODS
PLWH ≥40 years old and on stable ART ≥3 months were enrolled (N = 149). OXPHOS complex I (CI, NADH dehydrogenase) and complex IV (CIV, cytochrome c oxidase) protein levels in PBMCs were quantified using immunoassays. Monocyte subsets and markers of T-cell activation, senescence, and exhaustion were measured on PBMC by flow cytometry. Plasma inflammatory mediators were quantified using a multiplex assay. HIV-uninfected group (N = 44) of similar age, gender, and ethnicity had available OXPHOS levels.
RESULTS
PLWH had a median age of 51 years. Majority were male (88.6%), Caucasian (57.7%), and with undetectable plasma HIV RNA <50 copies/mL (84.6%). Median CI level was lower in PLWH compared with the HIV-seronegative group (65.5 vs 155.0 optical density/μg protein x 103, p <0.0001). There was no significant difference in median CIV levels. Lower OXPHOS levels correlated with lower CD4% and CD4/CD8 ratio. On multivariable linear regression adjusted for age, current use of zidovudine/didanosine, and HIV RNA (detectable versus undetectable), lower OXPHOS levels were significantly associated with higher MPO, SAA, SAP, and sVCAM, and higher frequencies of intermediate (CD14++CD16+) monocytes and TIGIT+TIM3+ CD4 T-cell (p<0.01).
CONCLUSION
CI PBMC protein levels were decreased in PLWH on ART. Decreased OXPHOS correlated with disease severity and inflammation. Further studies on the relationship between immunometabolism and immune dysregulation in HIV are warranted.
Topics: Anti-HIV Agents; CD4-CD8 Ratio; Cross-Sectional Studies; Female; HIV Infections; HIV-1; Hawaii; Host-Pathogen Interactions; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Mitochondria; Oxidative Phosphorylation; RNA, Viral; Severity of Illness Index
PubMed: 32353005
DOI: 10.1371/journal.pone.0231761 -
AIDS (London, England) Jul 2020To evaluate whether there is an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU) exposed in utero to specific antiretroviral...
OBJECTIVE
To evaluate whether there is an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU) exposed in utero to specific antiretroviral medications.
DESIGN
Prospective cohort study of CHEU enrolled from 2007 to 2017.
METHODS
We evaluated children for neurologic case status, including microcephaly, febrile seizures, seizure disorders, ophthalmologic disorders, and other neurologic disorders. Adjusted relative risks (aRRs) were estimated for the association between in-utero antiretroviral exposure and neurologic case using log-binomial regression, accounting for potential confounders. Sensitivity analyses were conducted to evaluate robustness of findings.
RESULTS
Among 3747 eligible CHEU, 231 (6.2%) met neurologic case criteria (95% CI 5.4--7%). Most eligible children (86%) were exposed in utero to combination antiretroviral regimens. In adjusted models, children exposed to efavirenz at any time during pregnancy had higher risk of neurologic case status (aRR = 1.53, 95% CI 0.94--2.51). This association was stronger when comparing efavirenz exposure at conception to no exposure during pregnancy (aRR = 1.92, 95% CI 1.09--3.36) and considering follow-up and case diagnosis only through age 2 (aRR = 2.14, 95% CI 1.11--4.12). Children exposed to didanosine at conception and during the first trimester had increased risk of neurologic case status (aRR = 2.28, 95% CI 1.07--4.87 and aRR = 2.02, 95% CI 1.01--4.04, respectively), compared with didanosine-unexposed children. Children with dolutegravir exposure had some suggestion of increased risk of neurologic case (aRR = 2.43, 95% CI 0.75--7.84), which was observed consistently across several sensitivity analyses.
CONCLUSION
Efavirenz and didanosine exposure during pregnancy were associated with higher risk of neurologic abnormalities in CHEU, and dolutegravir exposure showed some suggestive associations, which warrant further monitoring.
Topics: Abnormalities, Drug-Induced; Adult; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Male; Microcephaly; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Prospective Studies; Treatment Outcome
PubMed: 32310900
DOI: 10.1097/QAD.0000000000002550 -
Journal of Biomolecular Structure &... Apr 2021Hepatitis B virus (HBV), a small enveloped DNA virus, attacks the human liver causing both acute and chronic diseases. Current therapeutic drugs use the nucleos(t)ide...
Hepatitis B virus (HBV), a small enveloped DNA virus, attacks the human liver causing both acute and chronic diseases. Current therapeutic drugs use the nucleos(t)ide analogues (NAs) as a competitive inhibitor against HBV reverse transcriptase (HBV-RT), an essential enzyme pivotally involved in viral replication. Unfortunately, this treatment still causes the development of resistant variants of HBV against NAs. As HBV-RT is homologous to the human immunodeficiency virus reverse transcriptase (HIV-RT), it is reasonable to treat HBV-RT with anti-HIV drugs. In the present study, we aimed to investigate the structural dynamics and susceptibility of the known anti-HIV drugs (stavudine [d4T], didanosine [DDI], and zidovudine [ZDV]) against HBV-RT enzyme in comparison to the anti-HBV drug lamivudine (3TC) and deoxythymidine triphosphate (dTTP) substrate using several computational approaches. The calculations revealed that seven polar residues (K32, R41, D83, S85, D205, N236, and K239) and three hydrophobic residues (A86, A87, and F88) of HBV-RT as well as the adjacent DNA strands play an important role in the ligand binding. In addition, the H-bond pattern of d4T is similar to that of 3TC, especially at the residues A86 and A87. Such interactions promote the favorable conformation of ligand in the HBV-RT binding pocket, while the several different conformations of ligand are found in the unbound state. The predicted binding free energy results based on QM/MM-GBSA and MM/GB(PB)SA methods suggested that the susceptibility towards HBV-RT of d4T and ZDV is higher than that of 3TC and dTTP. Altogether, this work sheds light on the potentiality of d4T and ZDV as a promising drug for HBV-infected patients harboring 3TC resistance.Communicated by Ramaswamy H. Sarma.
Topics: Anti-HIV Agents; HIV Infections; Hepatitis B virus; Humans; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine
PubMed: 32308149
DOI: 10.1080/07391102.2020.1751715 -
MSystems Apr 2020As of today (7 April 2020), more than 81,000 people around the world have died from the coronavirus disease 19 (COVID-19) pandemic. There is no approved drug or vaccine...
As of today (7 April 2020), more than 81,000 people around the world have died from the coronavirus disease 19 (COVID-19) pandemic. There is no approved drug or vaccine for COVID-19, although more than 10 clinical trials have been launched to test potential drugs. In an urgent response to this pandemic, I developed a bioinformatics pipeline to identify compounds and drug candidates to potentially treat COVID-19. This pipeline is based on publicly available single-cell RNA sequencing (scRNA-seq) data and the drug perturbation database "Library of Integrated Network-Based Cellular Signatures" (LINCS). I developed a ranking score system that prioritizes these drugs or small molecules. The four drugs with the highest total score are didanosine, benzyl-quinazolin-4-yl-amine, camptothecin, and RO-90-7501. In conclusion, I have demonstrated the utility of bioinformatics for identifying drugs than can be repurposed for potentially treating COVID-19 patients.
PubMed: 32291351
DOI: 10.1128/mSystems.00297-20