didanosine and HIV-Associated-Lipodystrophy-Syndrome

Topics: Acidosis, Lactic; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV-Associated Lipodystrophy Syndrome; Humans; Peripheral Nervous System Diseases; Practice Guidelines as Topic; Stavudine

Topics: Acidosis, Lactic; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Hemophilia A; Hemorrhage; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Nevirapine; Oxazines; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

Nucleoside reverse transcriptase inhibitors (NRTIs) differ in the type and severity of adverse effects resulting from mitochondrial abnormalities. mtDNA in peripheral blood mononuclear cells (PBMCs) was measured during the first 12 months of different NRTIs combinations and its association with clinical lipodystrophy was estimated. Extended follow-up of a randomized trial, ALBI-ANRS 070, including antiretroviral naive patients was conducted. Total DNA was extracted from available cryopreserved PBMCs at baseline and months 6 and 12. Nuclear and mitochondrial genes were amplified using a real-time PCR assay. Clinical lipodystrophy was assessed 30 months after randomization using a standardized questionnaire. A logistic regression analysis assessed the value of mtDNA to predict lipodystrophy. Mean mtDNA level (copies/cell) significantly decreased from 5847 at baseline to 3176 at month 12 (p < 0.0001). In the zidovudine + lamivudine (ZDV + 3TC) arm (n = 37), the mean mtDNA was 6098, 6807, and 3725 copies/cell for baseline, month 6, and month 12, respectively. In the stavudine + didanosine (d4T + ddI) arm (n = 40), the mean values were 5616, 5731, and 2648 copies/cell, respectively. The proportion of patients in the lowest quartile of mtDNA (<1421 copies/cell) at month 12 was higher in 18 patients with lipodystrophy (44%) than in 28 without lipodystrophy (7%) (p = 0.008). At 12 months, a larger reduction of mtDNA from baseline was observed in those started on the d4T + ddI arm. Furthermore, a low mtDNA level at month 12 was associated with the subsequent development of lipodystrophy. This marker may be of value for the early prevention of lipodystrophy in treated HIV-infected patients.

Topics: Adult; Anti-HIV Agents; Didanosine; DNA, Mitochondrial; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Leukocytes, Mononuclear; Logistic Models; Male; Reverse Transcriptase Inhibitors; Stavudine; Surveys and Questionnaires; Time Factors; Zidovudine

Long-term regional body fat outcomes have not been well described in randomized antiretroviral drug trials.. Dual x-ray absorptiometry (DXA) scans were performed every 16 weeks on a subset of 157 antiretroviral-naive participants who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine and lamivudine or stavudine and didanosine, in a multicenter trial. Participants with any available data after baseline up to week 144 contributed to this as-treated analysis.. Limb fat increased similarly in all groups during the first 32 weeks. After week 32, limb fat changed by - 1.7% per year for zidovudine-lamivudine and by -19.0% per year for didanosine-stavudine (mixed model analysis of variance [MMANOVA], P < 0.0001). Adjusting for nucleoside backbone, there was an additional decrease in limb fat of -8.7% per year for the combined nelfinavir and nelfinavir + efavirenz group compared with the efavirenz group (MMANOVA, P = 0.03). Among participants receiving zidovudine-lamivudine, after week 32, limb fat changed by +2.7% per year with efavirenz and by -7.9% per year for the combined nelfinavir and nelfinavir + efavirenz group (MMANOVA, P = 0.03).. Over 144 weeks, zidovudine-lamivudine was superior to didanosine-stavudine with regard to limb fat loss. The combination of zidovudine, lamivudine, and efavirenz showed no overall pattern suggesting limb fat loss over time and was significantly superior to the pooled zidovudine-lamivudine-nelfinavir (with and without efavirenz) arms.

Topics: Absorptiometry, Photon; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Body Composition; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Prospective Studies; Stavudine; Time Factors; Treatment Outcome; United States; Zidovudine

Comparisons of body composition and metabolic changes among antiretroviral-naive patients randomly assigned to didanosine and stavudine- (ddI+d4T) vs. abacavir and lamivudine- (ABC+3TC) containing regimens were assessed in a nested substudy of an ongoing multicenter randomized trial. At baseline and every 4 months, body cell mass and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. The rates of change (unit/mo) estimated using the slopes of regression lines and overall mean changes from baseline were compared by study assignment. Among 96 patients enrolled, 46 received ddI+d4T- and 50 received ABC+3TC-containing regimens with a median follow-up of 32.4 months. For both study arms, an overall increase in the rates of change was seen for body cell mass. For ddI+d4T, after an initial increase, the rates of change declined for regional fat and total body fat compared with an increase for ABC+3TC, with the 2 arms being significantly different (P<0.05). For high-density lipoprotein cholesterol rates of change, ddI+d4T decreased, while ABC+3TC increased. For both arms, low-density lipoprotein cholesterol decreased, while triglycerides increased. Early and sustained increases in insulin and insulin resistance were seen only for ddI+d4T. In this prospective study, metabolic and body composition changes varied according to whether subjects received ddI+d4T or ABC+3TC.

Topics: Adult; Anti-HIV Agents; Body Composition; Didanosine; Dideoxynucleosides; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin; Insulin Resistance; Lamivudine; Lipids; Male; Middle Aged; Prospective Studies; Stavudine

To determine the incidence and risk factors for developing diabetes mellitus in a cohort of Thai HIV-infected patients on long-term combination antiretroviral therapy (cART).. Prospective study conducted between July 1996 and 30 April 2015.. A total of 1748 patients (60% men) who did not have diabetes mellitus prior to ART were assessed twice a year. Incident diabetes mellitus was defined as either having two consecutive fasting glucose levels more than 126 mg/dl, or reporting antidiabetes mellitus medication/diabetes mellitus diagnosis after starting cART. Incidence rates were calculated per 1000 person-year follow-up. Multivariate Cox regression was used to determine risk factors for the development of diabetes mellitus.. During a median follow-up of 9 years (16 274 person-year of follow-up), 123 patients developed new-onset diabetes mellitus, resulting in an incidence rate of 7.6 (95% confidence interval 6.3-9) per 1000 person-year of follow-up. From the multivariate models, age more than 35 years, male sex, BMI at least 25 kg/m, family history of diabetes, abnormal waist circumference, lipodystrophy and exposure to didanosine were significantly associated with incident diabetes mellitus. The diabetes mellitus group had higher mortality rate (8.1 vs. 4.1%, P = 0.04). A significantly higher proportion diabetes vs. nondiabetes patients developed cardiovascular and cerebrovascular complications (8.9 vs. 3.6%, P = 0.008) or chronic kidney disease stage III (estimated glomerular filtration rate <60 ml/min/1.73 m) (15.3 vs. 1.9%, P < 0.001) over total follow-up.. In addition to traditional risk factors, lipodystrophy and use of didanosine were strongly associated with development of incident diabetes. Given the higher rate of cardiovascular-cerebrovascular complications and chronic kidney disease among patients with diabetes mellitus, careful assessment and appropriate management of diabetes mellitus are essential.

Topics: Adult; Antiretroviral Therapy, Highly Active; Asian People; Body Mass Index; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Didanosine; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Incidence; Male; Obesity, Abdominal; Proportional Hazards Models; Renal Insufficiency, Chronic; Reverse Transcriptase Inhibitors; Risk Factors; Thailand; Treatment Outcome

Many HIV antiretroviral medications have been associated with chronic liver injury. HIV-infected patients frequently develop HIV and highly active antiretroviral treatment-associated lipodystrophy syndrome (HALS), characterized by accumulation of intra-abdominal fat, insulin resistance, and hepatic steatosis. We sought to determine whether long-term exposure to specific antiretroviral medications or the presence of HALS predispose HIV-infected patients to the development of cirrhosis.. HIV-infected patients with cirrhosis who received care in the Veterans Affairs Healthcare System nationally in 2009 were matched by hepatitis C virus (HCV) coinfection status and year of first visit for HIV to the Veterans Affairs Healthcare System with HIV-infected patients without cirrhosis in a 1 : 3 ratio.. Among HIV/HCV coinfected patients (593 with cirrhosis and 1591 matched controls), HALS was associated with a significantly increased risk for cirrhosis (adjusted odds ratio 1.6, 95% confidence interval 1.1-2.3), especially among Black patients (adjusted odds ratio 2.9, 95% confidence interval 1.6-5.2). In addition, among HIV/HCV coinfected patients, longer cumulative exposures to all antiretroviral medications, all nucleoside reverse transcriptase inhibitors, all protease inhibitors, and selected individual medications (didanosine, stavudine, and nelfinavir) were found to be significantly associated with cirrhosis. In contrast, among HIV-infected patients not coinfected with HCV (245 with cirrhosis and 658 matched controls), HALS or exposure to antiretroviral medications was found not to be significantly associated with cirrhosis, with the exception of didanosine.. HALS and cumulative exposure to nucleoside reverse transcriptase inhibitors and protease inhibitors, especially stavudine, didanosine, and nelfinavir, were found to be associated with the development of cirrhosis in HIV/HCV coinfected patients, but not in HIV-monoinfected patients.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Case-Control Studies; Coinfection; Didanosine; Female; Hepatitis C; Hispanic or Latino; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Liver Cirrhosis; Male; Middle Aged; Nelfinavir; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine; Time Factors

We previously demonstrated that HIV infection is associated with peripheral and central lipoatrophy in women. We now describe the association of specific antiretroviral drugs (ARV) with body fat changes over a four-year period from 1999 to 2003. 775 HIV-positive and 205 HIV-negative women in the Women's Interagency HIV Study with anthropometric measurements, weight, bioelectric impedance analysis and ARV collected semiannually were included in analysis. Exposure to ARV was defined as report of use for 3 consecutive semiannual study visits. The average 6-month change in weight, percent total body fat, and circumference measurements (i.e., hip, waist, chest, arm, and thigh) was compared between those exposed and those unexposed to the specific ARV for any of the same three consecutive visits. Weight, percent total body fat, and hip, waist, thigh, chest, and arm circumferences decreased in HIV-positive women, but increased in HIV-negative women on average for every six-month interval over the 4-year study period. Among the HIV-positive women, didanosine was the only ARV associated with decreases in circumference measures in the hip (-0.65 cm, 95% confidence interval [CI]: -1.18, -0.12), waist (-0.71 cm, 95% CI: -1.37, -0.04), chest (-0.71 cm, 95% CI: -1.17, -0.26), and arm (-0.23 cm, 95% CI: -0.48, 0.03; p = 0.08). These prospective data suggest that fat loss continues to predominate in HIV-positive women and exposure to didanosine for at least 12 months may further worsen fat loss.

Topics: Adiposity; Adult; Anthropometry; Anti-HIV Agents; Case-Control Studies; Didanosine; Female; HIV-Associated Lipodystrophy Syndrome; Humans; Prospective Studies

The objectives of our study were to describe the characteristics of a subset of patients who had been prescribed serum lactate in clinical practice within a large cohort of HIV-infected patients and to determine the factors associated with hyperlactataemia. Hyperlactataemia (> or =2 mmol/l) was found in 219 [29% (95% confidence interval: 25.3-31.7)] of the 768 HIV-infected participants. In multivariate analysis (logistical regression), an increased risk of hyperlactataemia was associated with increasing age, CD4 count <500/mm3, triglycerides >2.2 mmol/L, lipoatrophy and stavudine use. In a second model coding for the NRTI-based drug combinations, only those including stavudine were associated with an increased risk of hyperlactataemia. In a third model including exposure duration to NRTIs, we estimated a 20% increased risk of hyperlactataemia per year of exposure to didanosine or stavudine. The risk of hyperlactataemia could increase over time in patients treated with these drugs and is also closely associated with increased age, decreased CD4 count, lipodystrophy and increased plasma triglycerides. It could be proposed that patients having one or more of these risk factors undergo regular monitoring of plasma lactate and renal function to prevent lactic acidosis.

Topics: Acidosis, Lactic; Acquired Immunodeficiency Syndrome; Adult; Age Factors; Anti-HIV Agents; CD4 Antigens; Cohort Studies; Didanosine; Drug Therapy, Combination; HIV-Associated Lipodystrophy Syndrome; Humans; Lactic Acid; Longitudinal Studies; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine; Triglycerides

NRTI-induced host toxicity is proposed to involve cellular mitochondrial DNA (mtDNA) depletion. Determinants of cellular mtDNA copy number from HIV-infected patients receiving HAART and HIV-seronegative controls were investigated from subcutaneous fat samples, and relation with antiretroviral regimen was studied.. HIV-infected patients receiving HAART (n = 50), HIV-infected patients not currently under HAART regimen (n = 2) and HIV-seronegative controls (n = 9) of similar age and BMI were enrolled prospectively when undergoing Coleman's lipostructure for correction of facial lipoatrophy or plastic surgery, respectively. After centrifugation, abdominal fat tissue was collected and stored at -80 degrees C. MtDNA analysis was blindly performed after a total DNA extraction from adipose tissue, followed by a real-time PCR quantification. The log of mtDNA copies/cell in adipose tissue [log(DNA)] was compared between groups by means of analysis of variance.. The log(DNA) in adipose tissue of HIV-infected patients was significantly lower than in the HIV-seronegative control group (P < 0.0001). In HIV-infected patients, log(DNA) was significantly reduced in the 50 NRTI-treated patients (P < 0.01), but not when considering mtDNA level according to the use of PI or NNRTI in current HAART regimen. In NRTI-treated patients, only stavudine (n = 20) and didanosine (n=14) were significantly and independently associated with reduced mtDNA level (P < 0.0001 and <0.05, respectively). Currently stavudine or didanosine-treated patients had a significant reduced mtDNA level compared to past users (P < 0.0001 and <0.05, respectively). Other clinical, biological, and immuno-virological variables than NRTI did not correlate significantly to adipocyte mtDNA level.. This study supports that current treatment by NRTI is a main determinant of mtDNA depletion in adipose tissue of HIV-seropositive patients with peripheral fat wasting. Stavudine or didanosine current intake is significantly associated with mtDNA depletion in vivo, that could be reversible after the discontinuation of these molecules, when considering mtDNA level according to current use versus past use of these molecules.

Topics: Adipose Tissue; Adolescent; Adult; Aged; Anti-HIV Agents; Didanosine; DNA, Mitochondrial; Female; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Nevirapine; Reverse Transcriptase Inhibitors; Stavudine; Stevens-Johnson Syndrome

Nucleoside analogues are suspected of playing a role in peripheral fat loss in patients during long-term treatment with antiretroviral drugs.. We compared the long-term effects of stavudine (10 microM), zidovudine (1 muM), didanosine (10 microM), abacavir (4 microM), lamivudine (10 microM), and tenofovir (1 microM), near their maximum concentration values, on the differentiation, lipid accumulation, survival and mitochondrial function of differentiating 3T3-F442A and differentiated 3T3-L1 adipocytes.. None of the nucleoside reverse transcriptase inhibitors (NRTI) markedly altered the differentiation of 3T3-F442A cells, as shown by the unmodified percentage of cells with lipid droplets on day 7 and the expression of the early differentiation markers CCAAT/enhancer binding protein (C/EBP) beta (on day 2) and sterol regulatory element-binding protein. However, stavudine and zidovudine altered the lipid phenotype, decreasing the lipid content and expression of markers involved in lipid metabolism, namely C/EBPalpha, peroxisome proliferator-activated receptor gamma, adipocyte lipid binding protein 2, fatty acid synthase and acetyl-coenzyme A carboxylase. Stavudine and zidovudine, contrary to the other NRTI, drove 5-10% of 3T3-F442A cells towards apoptosis, and reduced the lipid content and survival of differentiated 3T3-L1 adipocytes. Stavudine and zidovudine increased mitochondrial mass by two to fourfold, and lowered the mitochondrial membrane potential (JC-1 stain) as did zalcitabine (0.2 microM). Co-treatment with zidovudine plus lamivudine, or zidovudine plus lamivudine and abacavir, did not increase the effect of zidovudine on cell viability or apoptosis.. The thymidine analogues stavudine and zidovudine decreased lipid content, mitochondrial activity, and adipocyte survival in vitro.

Topics: 3T3-L1 Cells; Adenine; Adipocytes; Animals; Apoptosis; Cell Differentiation; Didanosine; Dideoxynucleosides; HIV-1; HIV-Associated Lipodystrophy Syndrome; Lamivudine; Lipid Metabolism; Mice; Mitochondria; Organophosphonates; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Zidovudine