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Medicina (Kaunas, Lithuania) May 2022This article aims to describe a unique case of didanosine-induced retinal degeneration that was discovered 11 years after the drug withdrawal. The patient is a...
This article aims to describe a unique case of didanosine-induced retinal degeneration that was discovered 11 years after the drug withdrawal. The patient is a 42-year-old woman with a medical history of HIV and hepatitis C virus since 2004. She has been prescribed antiretroviral therapy since then. For the first seven years (2004-2011), the patient was prescribed a combination therapy consisting of didanosine, efavirenz, and lamivudine. The protocol was changed to atripla (efavirenz, emtricitabine, and tenofovir) from 2011 to 2021. Recently (October 2021-January 2021), the patient was prescribed eviplera (rilpivirin, emtricitabine, and tenofovir). In addition, her past medical history revealed Gougerot-Sjogren syndrome and rheumatoid arthritis. She was prescribed hydroxychloroquine (HCQ) (2009-2021) at a dose of 400 mg daily. She had no vision complaint. During her routine HCQ screening at the eye clinic, University Hospital Bretonneau, Tours, France, the widefield colour fundus photograph showed well-defined symmetric mid-peripheral areas of chorioretinal atrophy sparing the posterior pole of both eyes. Furthermore, the widefield fundus autofluorescence illustrated mid-peripheral round well-demarcation hypoautofluorescent areas of chorioretinal atrophy of both eyes. Conversely, the macular optical coherence tomography (OCT) was normal. Many of her drugs are known to be associated with retinopathy such as HCQ, tenofovir, efavirenz, and didanosine. Because our data corroborate peripheral retinal damage rather than posterior pole damage, this case report is compatible with didanosine-induced retinopathy rather than HCQ, efavirenz, or tenofovir retinal toxicity. All HIV patients who are presently or were previously on didanosine therapy should have their fundus examined utilising widefield fundus autofluorescence and photography.
Topics: Adult; Atrophy; Choroid Diseases; Didanosine; Emtricitabine; Female; HIV Infections; Humans; Hydroxychloroquine; Retinal Degeneration; Tenofovir; Tomography, Optical Coherence
PubMed: 35743998
DOI: 10.3390/medicina58060735 -
BMC Infectious Diseases May 2022As people living with HIV (PLWH) are growing older, there is increased incidence of metabolic diseases, including type 2 diabetes mellitus, for which insulin resistance...
BACKGROUND
As people living with HIV (PLWH) are growing older, there is increased incidence of metabolic diseases, including type 2 diabetes mellitus, for which insulin resistance is a key determinant. In this study, we aimed to investigate risk factors associated with insulin resistance in PLWH.
METHODS
We included well-treated PLWH without hepatitis co-infection, and with available fasting serum insulin and plasma glucose (n = 643) from the Copenhagen Comorbidity in HIV Infection Study. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). We investigated the association between risk factors and high HOMA-IR in a logistic regression model adjusted for age, sex, abdominal obesity, smoking status, and origin. When including use of thymidine analogues and/or didanosine in the model, we also adjusted for time with HIV.
RESULTS
Median (IQR) age of PLWH was 52 years (46-61), and 87% (n = 557) were male. Median (IQR) HOMA-IR was 1.86 (1.23-3.14) mmol/L × mU/L. Risk factors significantly associated with high HOMA-IR included older age, BMI ≥ 25, abdominal obesity, waist circumference, use of thymidine analogues and/or didanosine, time with HIV, and CD4 nadir < 200 cells/µL.
CONCLUSIONS
Insulin resistance in PLWH is associated with both use of thymidine analogues and/or didanosine and prior immunodeficiency suggesting that increased attention on blood glucose in these patients could be beneficial.
Topics: Diabetes Mellitus, Type 2; Didanosine; Female; HIV Infections; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Abdominal; Thymidine
PubMed: 35643429
DOI: 10.1186/s12879-022-07485-1 -
AIDS Research and Therapy Mar 2022The authors recently performed plastic surgeries for a small number of patients with hemophilia, HIV infection, and morphologic evidence of lipodystrophy. Because the...
BACKGROUND
The authors recently performed plastic surgeries for a small number of patients with hemophilia, HIV infection, and morphologic evidence of lipodystrophy. Because the pathophysiological mechanism of HIV-associated lipodystrophy remains to be elucidated, we analyzed subcutaneous adipose tissues from the patients.
METHODS
All six patients had previously been treated with older nucleoside analogue reverse-transcriptase inhibitors (NRTIs; stavudine, didanosine or zidovudine). Abdominal and inguinal subcutaneous fat samples were obtained from the HIV+ patients with hemophilia and HIV- healthy volunteers (n = 6 per group), and analyzed via DNA microarray, real-time PCR, flow cytometry and immunohistochemistry.
RESULTS
The time from initial NRTI treatment to collecting samples were 21.7 years in average. Cytometric analysis revealed infiltration of inflammatory M1 macrophages into HIV-infected adipose tissue and depletion of adipose-derived stem cells, possibly due to exhaustion following sustained adipocyte death. Genetic analysis revealed that adipose tissue from HIV+ group had increased immune activation, mitochondrial toxicity, chronic inflammation, progressive fibrosis and adipocyte dysfunction (e.g. insulin resistance, inhibited adipocyte differentiation and accelerated apoptosis). Of note, both triglyceride synthesis and lipolysis were inhibited in adipose tissue from patients with HIV.
CONCLUSIONS
Our findings provide important insights into the pathogenesis of HIV-associated lipodystrophy, suggesting that fat redistribution may critically depend on adipocytes' sensitivity to drug-induced mitochondrial toxicity, which may lead either to atrophy or metabolic complications.
Topics: Anti-HIV Agents; DNA, Mitochondrial; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Hemophilia A; Humans; Lipodystrophy; Subcutaneous Fat
PubMed: 35246167
DOI: 10.1186/s12981-022-00432-9 -
HIV Medicine Sep 2022Non-alcoholic fatty liver disease (NAFLD) is strongly associated with cardiovascular disease in the general population. We aimed to assess the impact of NAFLD and liver...
OBJECTIVES
Non-alcoholic fatty liver disease (NAFLD) is strongly associated with cardiovascular disease in the general population. We aimed to assess the impact of NAFLD and liver fibrosis on intermediate-high cardiovascular risk in people living with HIV.
METHODS
We included people living with HIV from three cohorts. NAFLD and significant liver fibrosis were defined using transient elastography: controlled attenuation parameter ≥288 dB/m and liver stiffness measurement ≥7.1 kPa, respectively. Cardiovascular risk was assessed with the atherosclerotic cardiovascular disease (ASCVD) risk estimator in patients aged between 40 and 75 years and categorised as low if <5%, borderline if 5%-7.4%, intermediate if 7.5%-19.9% and high if ≥20% or with the presence of a previous cardiovascular event. Patients with hepatitis B and/or hepatitis C virus co-infection, alcohol abuse and unreliable transient elastography measurements were excluded. Predictors of intermediate-high cardiovascular risk were investigated in multivariable analysis by logistic regression and also by stratifying according to body mass index (BMI; cut-offs of 25 and 30 kg/m ) and age (cut-off of 60 years).
RESULTS
Of 941 patients with HIV alone included, 423 (45%), 128 (13.6%), 260 (27.6%) and 130 (13.8%) were categorised as at low, borderline, intermediate and high ASCVD risk, respectively. Predictors of intermediate-high ASCVD risk were NAFLD (adjusted odds ratio [aOR] 2.11; 95% confidence interval [CI] 1.40-3.18; p < 0.001), liver fibrosis (aOR 1.64; 95% CI 1.03-2.59; p = 0.034), duration of HIV (aOR 1.04; 95% CI 1.02-1.06; p < 0.001), and previous exposure to thymidine analogues and/or didanosine (aOR 1.54; 95% CI 1.09-2.18; p = 0.014). NAFLD was also associated with higher cardiovascular risk in normoweight patients (aOR 2.97; 95% CI 1.43-6.16; p = 0.003), in those with BMI <30 kg/m (aOR 2.30; 95% CI 1.46-3.61; p < 0.001) and in those aged <60 years (aOR 2.19; 95% CI 1.36-3.54; p = 0.001).
CONCLUSION
Assessment of cardiovascular disease should be targeted in people living with HIV with NAFLD and/or significant liver fibrosis, even if they are normoweight and young.
Topics: Adult; Aged; Cardiovascular Diseases; Elasticity Imaging Techniques; HIV Infections; Heart Disease Risk Factors; Humans; Liver; Liver Cirrhosis; Middle Aged; Non-alcoholic Fatty Liver Disease; Prospective Studies; Risk Factors
PubMed: 35199429
DOI: 10.1111/hiv.13274 -
Viruses Dec 2021At Bristol-Myers (BM) (1985-1990), John C. Martin started his HIV career with directing the clinical development of didanosine (ddI) and stavudine (d4T). During this... (Review)
Review
At Bristol-Myers (BM) (1985-1990), John C. Martin started his HIV career with directing the clinical development of didanosine (ddI) and stavudine (d4T). During this period, he became aware of the acyclic nucleoside phosphonates (ANPs), such as ()-HPMPA and PMEA, as potential antiviral drugs. Under his impulse, BM got involved in the evaluation of these ANPs, but the merger of BM with Squibb (to become BMS) incited John to leave BM and join Gilead Sciences, and the portfolio of the ANPs followed the transition. At Gilead, John succeeded in obtaining the approval from the US FDA for the use of cidofovir in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients, which was reminiscent of John's first experience with ganciclovir (at Syntex) as an anti-CMV agent. At Gilead, John would then engineer the development of tenofovir, first as TDF (tenofovir disoproxil fumarate) and then as TAF (tenofovir alafenamide) and various combinations thereof, for the treatment of HIV infections (), TDF and TAF for the treatment of hepatitis B (HBV) infections (), and TDF and TAF in combination with emtricitabine for the prophylaxis of HIV infections ().
Topics: Alanine; Anti-HIV Agents; Drug Therapy, Combination; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV; HIV Infections; Hepatitis B; History, 20th Century; History, 21st Century; Humans; Pre-Exposure Prophylaxis; Reverse Transcriptase Inhibitors; Tenofovir
PubMed: 34960679
DOI: 10.3390/v13122410 -
Journal of Vitreoretinal Diseases 2022This article describes a case of didanosine (DDI)-associated retinal toxicity in a patient with a heterozygous pathogenic variant in the CRB1 gene.
PURPOSE
This article describes a case of didanosine (DDI)-associated retinal toxicity in a patient with a heterozygous pathogenic variant in the CRB1 gene.
METHODS
Case report.
RESULTS
A middle-aged patient with HIV controlled on HAART therapy, and a remote 10-year year history of treatment with DDI and tenofivir, presented with external ophthalmoplegia and well-circumscribed, midperipheral patterns of bilateral pigmentary retinopathy and chorioretinal atrophy in both eyes. Genetic testing revealed a heterozygous pathogenic variant in the gene that encodes a protein (Crumbs homolog 1) involved in regulation of cell polarity and junctions and is localized adjacent to mitochondria in the ellipsoid and myoid area.
CONCLUSIONS
This case highlights a potential role for genetic susceptibility to retinal toxicity in DDI-associated retinal toxicity. Large, prospective pharmacogenomics studies may be informative to further elucidate the role of genetic risk factors in drug-induced retinal toxicity.
PubMed: 37007923
DOI: 10.1177/24741264211044599 -
Journal of Acquired Immune Deficiency... Feb 2022Little is known regarding the long-term effects of antiretroviral (ARV) exposure on body composition for people living with HIV (PLWH) since early childhood. This study...
BACKGROUND
Little is known regarding the long-term effects of antiretroviral (ARV) exposure on body composition for people living with HIV (PLWH) since early childhood. This study explores changes in body fat distribution in relation to ARV exposure.
METHODS
We conducted a prospective study of adults with perinatal HIV (n = 70) using dual-energy X-ray absorptiometry and standard anthropometrics. Trunk to limb fat ratio and waist to hip ratio were compared cross-sectionally to 47 matched controls. Furthermore, changes in body composition and ARV exposure were evaluated longitudinally in a subset of 40 PLWH with a median follow-up of 7 years.
RESULTS
Cross-sectional comparisons of PLWH with controls revealed significantly higher waist to hip ratio, trunk to limb fat ratio, HOMA-IR, and triglycerides, whereas BMI did not differ. Among PLWH with longitudinal follow-up, the prevalence of overweight increased from 27.5% to 52.5% and obesity from 12.5% to 25%; waist to hip and trunk to limb fat ratios also increased (P < 0.0001). Changes in waist to hip ratio were positively correlated with longer exposure during follow-up to darunavir (r = 0.36; P = 0.02), whereas increases in trunk to limb fat ratio were positively correlated with longer exposure to stavudine (r = 0.39; P = 0.01) and didanosine (r = 0.39; P = 0.01) but inversely associated with emtricitabine (r = -0.33; P = 0.04). Increases in waist to hip ratio were correlated with increases in triglyceride levels (r = 0.35; P = 0.03).
CONCLUSION
This study presents strong evidence for persistent and worsening central adiposity in young adults with lifelong HIV and extensive ARV exposure. As this cohort ages, continued evaluation of the body composition and metabolic impact of lifelong ARV therapy is warranted to optimize long-term health.
Topics: Absorptiometry, Photon; Antiviral Agents; Body Composition; Body Mass Index; Child, Preschool; Cross-Sectional Studies; HIV Infections; Humans; Obesity; Obesity, Abdominal; Prospective Studies; Young Adult
PubMed: 34693931
DOI: 10.1097/QAI.0000000000002841 -
Medicinal Research Reviews Mar 2022John Charles Martin should be remembered as a visionary medicinal chemist who was involved in the coinvention, development, or management of many FDA-approved antiviral...
John Charles Martin should be remembered as a visionary medicinal chemist who was involved in the coinvention, development, or management of many FDA-approved antiviral drugs such as ganciclovir, stavudine, didanosine, cidofovir, oseltamivir, adefovir dipivoxil, tenofovir disoproxil fumarate, tenofovir alafenamide, sofosbuvir, and remdesivir.
Topics: Antiviral Agents; Humans; Tenofovir
PubMed: 34636044
DOI: 10.1002/med.21858 -
Scientific Reports Aug 2021Drug repurposing is one of the modern techniques used in the drug discovery to find out the new targets for existing drugs. Insilico methods have a major role in this...
Drug repurposing is one of the modern techniques used in the drug discovery to find out the new targets for existing drugs. Insilico methods have a major role in this approach. We used 60 FDA approved antiviral drugs reported in the last 50 years to screen against different cancer cell receptors. The thirteen compounds selected after virtual screening are analyzed for their druggability based on ADMET parameters and found the selectivity of guanine derivatives-didanosine, entecavir, acyclovir, valganciclovir, penciclovir, ganciclovir and valacyclovir as suitable candidates. The pharmacophore model, AARR, suggested based on the common feature alignment, shows that the two fused rings as in guanine and two acceptors-one from keto-oxygen (A5) and other from the substituent attached to nitrogen of imidazole ring (A4) give the druggability to the guanine derivatives. The NBO analysis on N9 is indicative of charge distribution from the ring to substituents, which results in delocalization of negative character in most of the ligands. The molecular dynamics simulations also pointed out the importance of guanine scaffold, which stabilizes the ligands inside the binding pocket of the receptor. All these results are indicative of the selectivity of guanine scaffold in anticancer drug development, especially as PARP1 inhibitors in breast, ovarian and prostate cancer. As these seven molecules are already approved by FDA, we can safely go for further preclinical trials.
Topics: Antineoplastic Agents; Computational Biology; Drug Development; Drug Discovery; Drug Repositioning; Guanine; Humans; Molecular Structure; Neoplasms
PubMed: 34376738
DOI: 10.1038/s41598-021-95507-4 -
Ocular Immunology and Inflammation 2022Didanosine is an adenosine analog, part of the nucleoside reverse-transcriptase inhibitor family. Since the description of didanosine-induced retinopathy in the early...
INTRODUCTION
Didanosine is an adenosine analog, part of the nucleoside reverse-transcriptase inhibitor family. Since the description of didanosine-induced retinopathy in the early 1990s, little is known about the progression of this toxic retinopathy and the putative underlying mitochondrial defect.
OBJECTIVES
We report long-term follow-up for cases of didanosine-induced retinopathy and discuss a new hypothesis for pathophysiology based on the alteration of endogenous adenosine on the photoreceptor outer segment turnover and phagocytosis by the retinal pigment epithelium.
METHODS
Ophthalmic data from six cases (12 eyes) of didanosine-induced retinopathy from a single institution were retrospectively analyzed.
RESULTS
All patients displayed bilateral retinal alterations in the mid-periphery. Despite didanosine discontinuation, patients with advanced areas of patchy chorioretinal atrophy appeared to have a faster progression than those with limited lesions. Full-field electroretinogram revealed generalized rod-cone dysfunction in most cases that remained stable over time.
CONCLUSION
We propose new guidelines including early screening and long-term observations.
Topics: Humans; Didanosine; Follow-Up Studies; Retrospective Studies
PubMed: 34255599
DOI: 10.1080/09273948.2021.1927117