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Cells May 2021After the introduction of antiretroviral treatment (ART) back in 1996, the lifespan of people living with HIV (PLWH) has been substantially increased, while the major... (Review)
Review
After the introduction of antiretroviral treatment (ART) back in 1996, the lifespan of people living with HIV (PLWH) has been substantially increased, while the major causes of morbidity and mortality have switched from opportunistic infections and AIDS-related neoplasms to cardiovascular and liver diseases. HIV itself may lead to liver damage and subsequent liver fibrosis (LF) through multiple pathways. Apart from HIV, viral hepatitis, alcoholic and especially non-alcoholic liver diseases have been implicated in liver involvement among PLWH. Another well known cause of hepatotoxicity is ART, raising clinically significant concerns about LF in long-term treatment. In this review we present the existing data and analyze the association of LF with all ART drug classes. Published data derived from many studies are to some extent controversial and therefore remain inconclusive. Among all the antiretroviral drugs, nucleoside reverse transcriptase inhibitors, especially didanosine and zidovudine, seem to carry the greatest risk for LF, with integrase strand transfer inhibitors and entry inhibitors having minimal risk. Surprisingly, even though protease inhibitors often lead to insulin resistance, they do not seem to be associated with a significant risk of LF. In conclusion, most ART drugs are safe in long-term treatment and seldom lead to severe LF when no liver-related co-morbidities exist.
Topics: Anti-HIV Agents; Enzyme Inhibitors; HIV Infections; Humans; Liver Cirrhosis
PubMed: 34063534
DOI: 10.3390/cells10051212 -
Pharmaceutics Apr 2021Fluoroquinolones (FQs) are a widespread class of broad-spectrum antibiotics prescribed as a first line of defense, and, in some cases, as the only treatment against...
Fluoroquinolones (FQs) are a widespread class of broad-spectrum antibiotics prescribed as a first line of defense, and, in some cases, as the only treatment against bacterial infection. However, when administered orally, reduced absorption and bioavailability can occur due to chelation in the gastrointestinal tract (GIT) with multivalent metal cations acquired from diet, coadministered compounds (sucralfate, didanosine), or drug formulation. Predicting the extent to which this interaction reduces in vivo antibiotic absorption and systemic exposure remains desirable yet challenging. In this study, we focus on quinolone interactions with magnesium, calcium and aluminum as found in dietary supplements, antacids (Maalox) orally administered therapies (sucralfate, didanosine). The effect of FQ-metal complexation on absorption rate was investigated through a combined molecular and pharmacokinetic (PK) modeling study. Quantum mechanical calculations elucidated FQ-metal binding energies, which were leveraged to predict the magnitude of reduced bioavailability via a quantitative structure-property relationship (QSPR). This work will help inform clinical FQ formulation design, alert to possible dietary effects, and shed light on drug-drug interactions resulting from coadministration at an earlier stage in the drug development pipeline.
PubMed: 33919271
DOI: 10.3390/pharmaceutics13050594 -
SLAS Discovery : Advancing Life... Mar 2021A novel bioinformatic approach for drug repurposing against emerging viral epidemics like Covid-19 is described. It exploits the COMPARE algorithm, a public program from...
A novel bioinformatic approach for drug repurposing against emerging viral epidemics like Covid-19 is described. It exploits the COMPARE algorithm, a public program from the National Cancer Institute (NCI) to sort drugs according to their patterns of growth inhibitory profiles from a diverse panel of human cancer cell lines. The data repository of the NCI includes the growth inhibitory patterns of more than 55,000 molecules. When candidate drug molecules with ostensible anti-SARS-CoV-2 activities were used as seeds (e.g., hydroxychloroquine, ritonavir, and dexamethasone) in COMPARE, the analysis uncovered several molecules with fingerprints similar to the seeded drugs. Interestingly, despite the fact that the uncovered drugs were from various pharmacological classes (antiarrhythmic, nucleosides, antipsychotic, alkaloids, antibiotics, and vitamins), they were all reportedly known from published literature to exert antiviral activities via different modes, confirming that COMPARE analysis is efficient for predicting antiviral activities of drugs from various pharmacological classes. Noticeably, several of the uncovered drugs can be readily tested, like didanosine, methotrexate, vitamin A, nicotinamide, valproic acid, uridine, and flucloxacillin. Unlike pure in silico methods, this approach is biologically more relevant and able to pharmacologically correlate compounds regardless of their chemical structures. This is an untapped resource, reliable and readily exploitable for drug repurposing against current and future viral outbreaks.
Topics: Algorithms; Antiviral Agents; COVID-19; Cell Line; Computational Biology; Data Mining; Databases, Pharmaceutical; Dexamethasone; Drug Discovery; Drug Repositioning; Humans; Lucanthone; SARS-CoV-2
PubMed: 33267713
DOI: 10.1177/2472555220975672 -
PloS One 2020Although physical function decline is common with aging, the burden of this impairment remains underestimated in patients living with HIV (PLHIV), particularly in the...
Although physical function decline is common with aging, the burden of this impairment remains underestimated in patients living with HIV (PLHIV), particularly in the older people receiving antiretroviral treatment (ART) and living in sub-Saharan Africa (SSA). PLHIV aged ≥50 years old and on ART since ≥6 months were included (N = 333) from three clinics (two in Côte d'Ivoire, one in Senegal) participating in the International epidemiological Databases to Evaluate AIDS (IeDEA) West Africa collaboration. Physical function was measured using the Short Physical Performance Battery (SPPB), the unipodal balance test and self-reported questionnaires. Grip strength was also assessed. Logistic regression was used to identify the factors associated with SPPB performance specifically. Median age was 57 (54-61) years, 57.7% were female and 82.7% had an undetectable viral load. The mean SPPB score was 10.2 ±1.8. Almost 30% had low SPPB performance with the 5-sit-to-stand test being the most altered subtest (64%). PLHIV with low SPPB performance also had significantly low performance on the unipodal balance test (54.2%, p = 0.001) and low mean grip strength (but only in men (p = 0.005)). They also showed some difficulties in daily life activities (climbing stairs, walking one block, both p<0.0001). Age ≥60 years (adjusted OR (aOR) = 3.4; CI95% = 1.9-5.9,), being a female (aOR = 2.1; CI95% = 1.1-4.1), having an abdominal obesity (aOR = 2.1; CI95% = 1.2-4.0), a longer duration of HIV infection (aOR = 2.9; CI95% = 1.5-5.7), old Nucleoside reverse transcriptase inhibitors (NRTIs) (i.e., AZT: zidovudine, ddI: didanosine, DDC: zalcitabine, D4T: stavudine) in current ART (aOR = 2.0 CI95% = 1.1-3.7) were associated with low SPPB performance. As in western countries, physical function limitation is now part of the burden of HIV disease complications of older PLHIV living in West Africa, putting this population at risk for disability. How to screen those impairments and integrate their management in the standards of care should be investigated, and specific research on developing adapted daily physical activity program might be conducted.
Topics: Aged; Aged, 80 and over; Anti-HIV Agents; Cote d'Ivoire; Cross-Sectional Studies; Female; HIV Infections; Humans; Male; Middle Aged; Physical Functional Performance; Postural Balance; Prevalence; Risk Factors; Self Report; Senegal; Standard of Care
PubMed: 33091061
DOI: 10.1371/journal.pone.0240906 -
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 -
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