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Frontiers in Neurology 2021We report two patients with toxic retinopathy from either ritonavir or didanosine and reviewed the literature on the topics. We provide an overview of the retinal...
Case Report: Multimodal Imaging of Toxic Retinopathies Related to Human Immunodeficiency Virus Antiretroviral Therapies: Maculopathy vs. Peripheral Retinopathy. Report of Two Cases and Review of the Literature.
We report two patients with toxic retinopathy from either ritonavir or didanosine and reviewed the literature on the topics. We provide an overview of the retinal toxicity of these two antiretroviral drugs in human immunodeficiency virus-positive patients. First, we performed a retrospective study of the medical charts of two patients examined by us, one with ritonavir maculopathy and one with didanosine peripheral retinopathy. Secondly, we searched the world literature for similar cases through PubMed and Google Scholar, using the terms "HIV," "AIDS," "ritonavir," "didanosine," "maculopathy," "retinopathy," "visual loss," and "toxicity" to retrieve the appropriate literature on the subject. Patient 1: A 49-year-old woman complained of progressive central visual loss over the past 12 months. History disclosed ongoing ritonavir therapy for the past 11 years. Ritonavir maculopathy was diagnosed, and visual loss increased relentlessly despite cessation of treatment. Patient 2: A 55-year-old man complained of slowly progressive peripheral visual field constriction for the past 5 years. History disclosed didanosine therapy for 13 years, however, stopped 4 years before the onset of visual symptoms. No alteration of therapy was offered to patient 2 as didanosine therapy was interrupted 9 years previously. Since 2011, 11 cases of ritonavir maculopathy have been reported in the literature. Relentless worsening of vision was reported in 3/7 patients despite cessation of ritonavir therapy. Didonasine peripheral retinopathy was first described in 1992, and a total of 24 patients have been reported since. Relentlessly progressive peripheral retinopathy was diagnosed despite the previous cessation of therapy in 14 patients. Ritonavir causes a slowly progressive atrophic maculopathy, and didanosine toxicity results in a relentlessly progressing peripheral atrophic retinopathy. The relentless progression of both toxic retinopathies reflects permanent alterations of the retinal metabolism by these medications. Both ritonavir and didanosine toxic retinopathies are rare events, but their clinical presentation is highly specific.
PubMed: 34220672
DOI: 10.3389/fneur.2021.663297 -
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 -
Current Drug Discovery Technologies 2022CCR5 and/or CXCR4 receptors on CD4+ T cell membranes are the active sites for HIV to bind. The different classes of drugs have a unique mechanism of action to cease the...
Effect of Anti-Retroviral Drug Impurity/Related Substances on the CCR5 and/or CXCR4 Receptors Binding Sites to Revise Resistance Mechanisms in the Clinical Implications Using Molecular Docking Studies.
BACKGROUND
CCR5 and/or CXCR4 receptors on CD4+ T cell membranes are the active sites for HIV to bind. The different classes of drugs have a unique mechanism of action to cease the virus, but we are concentrating in the first-class i.e. NNRTI that destroys the virus while it binds to the cell surface gp120 protein. The drugs are having several impurities that can be genotoxic and few are reported in the monographs.
OBJECTIVE
This study proposes the affinity of the impurities to the active site through molecular docking to a receptor (PDB ID 4MBS) from the library of analogs available for antiretroviral drugs. As these drugs are taken for the long term, this study will give a prominent idea for testing the impurities and their genotoxicity.
METHODS
We have done molecular docking of 37 impurities and drugs with the GLIDE module of schrodinger software for their binding affinities. In this study, receptor CCR5 and/or CXCR4 is selected containing glycoprotein that mediates virus binding to CD4+ T cell.
RESULTS
Didanosine E and Zidovudine D shows maximum and minimum score respectively. The selected impurities were interfering with the active binding site that may lead to any ADR or reduce the effect of API.
CONCLUSION
Conclusively, a significant role is played by Protein-Ligand interaction in structuralbased designing. Summarizing that there might be a genotoxicity effect due to competition between API and the impurities. The molecular docking was used to study the binding mechanism and to establish the docking score along with the activity. The outcome of the study can be used to design and development of novel compounds having genotoxicity.
Topics: Binding Sites; Drug Contamination; Ligands; Molecular Docking Simulation; Receptors, CXCR4
PubMed: 33781190
DOI: 10.2174/1570163818666210329102901 -
The Journal of Infectious Diseases Aug 2021Liver fibrosis is associated with poor liver-related outcomes and mortality. People with human immunodeficiency virus (PWH) may be at increased risk. We aimed to... (Comparative Study)
Comparative Study
BACKGROUND
Liver fibrosis is associated with poor liver-related outcomes and mortality. People with human immunodeficiency virus (PWH) may be at increased risk. We aimed to estimate the prevalence and factors associated with liver fibrosis in PWH compared to population controls.
METHODS
This was a cross-sectional cohort study comparing 342 PWH with 2190 population controls aged 50-70 years.Transient elastography was performed and elevated liver stiffness measurement (LSM) defined as 7.6 kPa as a proxy for significant liver fibrosis. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were computed by logistic regression.
RESULTS
The prevalence of elevated LSM was higher in PWH than in uninfected controls (12% vs 7%; P < .01). Human immunodeficiency virus (HIV) infection was independently associated with elevated LSM. In multivariate analysis, elevated LSM was associated with HIV (aOR, 1.84 [95% CI, 1.17-2.88]; P < .01); higher age (per decade: aOR, 3.34 [95% CI, 1.81-6.18]; P < .01); alanine aminotransferase (ALT) (per 10 IU/L: aOR, 1.25 [95% CI, 1.05-1.49]; P < .01); body mass index (BMI) (per 1 kg/m2: aOR, 1.17 [95% CI, 1.05-1.29]; P < .01), and previous exposure to didanosine (per year: aOR, 2.26 [95% CI, 1.01-5.06]; P = .04).
CONCLUSIONS
The prevalence of elevated LSM was higher in PWH compared to population controls. Higher age, BMI, ALT, previous exposure to didanosine, and positive HIV status were independently associated with higher odds of elevated LSM.
Topics: Aged; Cross-Sectional Studies; Didanosine; Elasticity Imaging Techniques; HIV; HIV Infections; Hepatitis, Viral, Human; Humans; Liver; Liver Cirrhosis; Middle Aged; Population Control; Prevalence
PubMed: 33320268
DOI: 10.1093/infdis/jiaa763 -
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 -
European Journal of Neurology Apr 2021Human immunodeficiency virus (HIV)-associated neurological syndromes occur in affected individuals as a consequence of primary HIV infection, opportunistic infections,... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND PURPOSE
Human immunodeficiency virus (HIV)-associated neurological syndromes occur in affected individuals as a consequence of primary HIV infection, opportunistic infections, inflammation and as an adverse effect of some forms of antiretroviral treatment (ART). The aim of this systematic review was to establish the epidemiological characteristics, clinical features, pathogenetic mechanisms and risk factors of HIV-related peripheral neuropathy (PN).
METHODS
A systematic, computer-based search was conducted using the PubMed database. Data regarding the above parameters were extracted. Ninety-four articles were included in this review.
RESULTS
The most commonly described clinical presentation of HIV neuropathy is the distal predominantly sensory polyneuropathy. The primary pathology in HIVPN appears to be axonal rather than demyelinating. Age and treatment with medications belonging in the nucleoside analogue reverse transcriptase class are risk factors for developing HIV-related neuropathy. The pooled prevalence of PN in patients naïve to ARTs was established to be 29% (95% CI: 9%-62%) and increased to 38% (95% confidence interval [CI]: 29%-48%) when looking into patients at various stages of their disease. More than half of patients with HIV-related neuropathy are symptomatic (53%, 95% CI: 41%-63%). Management of HIV-related neuropathy is mainly symptomatic, although there is evidence that discontinuation of some types of ART, such as didanosine, can improve or resolve symptoms.
CONCLUSIONS
Human immunodeficiency virus-related neuropathy is common and represents a significant burden in patients' lives. Our understanding of the disease has grown over the last years, but there are unexplored areas requiring further study.
Topics: HIV; HIV Infections; Humans; Peripheral Nervous System Diseases; Risk Factors
PubMed: 33226721
DOI: 10.1111/ene.14656 -
Der Ophthalmologe : Zeitschrift Der... Dec 2020Toxic retinopathies are most frequently induced by external stimulants (e.g. nicotine, poppers, methanol) and are less frequently undesired side effects of systemic...
Toxic retinopathies are most frequently induced by external stimulants (e.g. nicotine, poppers, methanol) and are less frequently undesired side effects of systemic drugs (e.g. hydroxychloroquine, ethambutol, MEK, ERK, FLT3 or checkpoint inhibitors, didanosine, pentosan polysulfate sodium) or intravitreally applied drugs. The clinical symptoms of undesired side effects of drugs are often similar to retinal diseases from other causes, which interferes with the recognition of the undesired side effects of drugs. Clinical findings, pathophysiological mechanisms and if advisable strategies for screening are discussed. The focus is on the presentation of confirmed undesirable side effects with established associations for medications which have long been approved. For novel medications, in addition potential but not proven associations are presented to facilitate the recognition of additional cases with side effects for these medications.
Topics: Humans; Pentosan Sulfuric Polyester; Retinal Diseases
PubMed: 33211161
DOI: 10.1007/s00347-020-01260-w -
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 -
Cytokine Dec 2020Lipodystrophy is common in HIV-infected patients receiving protease inhibitors (PIs), stavudine, and zidovudine. Adipocytokines may be altered in lipodystrophy. We... (Clinical Trial)
Clinical Trial
BACKGROUND
Lipodystrophy is common in HIV-infected patients receiving protease inhibitors (PIs), stavudine, and zidovudine. Adipocytokines may be altered in lipodystrophy. We evaluated risk factors, adipocytokine levels, insulin resistance, and lipid profiles in HIV-infected adolescents with different lipodystrophy types.
METHODS
A cross-sectional study was conducted in 80 perinatally HIV-infected adolescents receiving PI-based highly active antiretroviral therapy for ≥ 6 months. Patients underwent oral glucose tolerance tests and measurements of high-molecular-weight (HMW) adiponectin, leptin, resistin, insulin, and lipids. They were classified into 3 groups based on the clinical findings: no lipodystrophy, isolated lipoatrophy, and any lipohypertrophy (isolated lipohypertrophy or combined type).
RESULTS
Of the 80 patients (median age, 16.7 years), 18 (22.5%) had isolated lipoatrophy, while 8 (10%) had any lipohypertrophy (four with isolated lipohypertrophy, and four with the combined type). In a multivariate analysis, longer exposure to stavudine (OR: 1.03; 95% CI, 1.01-1.06; p = 0.005) and indinavir (OR: 1.03; 95% CI, 1.01-1.06; p = 0.012) were associated with lipoatrophy, while longer exposure to didanosine (OR: 1.04; 95% CI, 1.01-1.08; p = 0.017) and indinavir (OR: 1.10; 95% CI, 1.00-1.21; p = 0.045) were associated with any lipohypertrophy. Leptin levels were highest in the any-lipohypertrophy group and lowest in the isolated-lipoatrophy group (p = 0.013). HMW adiponectin levels were significantly lowest in the any-lipohypertrophy group and highest in the no-lipodystrophy group (p = 0.001). There were no significant differences in the levels of resistin among the three groups (p = 0.234). The prevalence of insulin resistance (p = 0.002) and prediabetes/diabetes (p < 0.001) were significantly highest in the any-lipohypertrophy group. Patients with lipoatrophy and those without lipodystrophy had comparable degrees of insulin resistance (p = 0.292). In multiple linear regression analysis, adjusted for age, sex, and waist-height ratio, HMW adiponectin levels were associated with Matsuda index (β = 0.5; p = 0.003) and quantitative insulin sensitivity check index (QUICKI) (β = 40.1; p = 0.010) and almost significantly associated with homeostatic model assessment of insulin resistance (HOMA-IR) (p = 0.054). Leptin and resistin levels were not associated with HOMA-IR, Matsuda index, or QUICKI (all p > 0.05).
CONCLUSIONS
Abnormal glucose metabolism and dysregulation of adipocytokines were common in the HIV-infected adolescents with lipohypertrophy and the combined type. Preventive screening for cardiovascular diseases caused by metabolic alterations should be routinely performed.
Topics: Adipokines; Adolescent; Adult; Blood Glucose; Cross-Sectional Studies; Female; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Male
PubMed: 32920318
DOI: 10.1016/j.cyto.2020.155145