didanosine and Hepatitis-C

Topics: Acidosis, Lactic; Anti-HIV Agents; Antiviral Agents; Didanosine; DNA, Mitochondrial; Drug Synergism; Hepatitis C; HIV Infections; Humans; Metabolic Clearance Rate; Pancreatitis; Ribavirin

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

The impact of antiretroviral drug exposure and associated lipodystrophy and/or insulin resistance (IR) on advanced liver fibrosis in HIV/HCV-coinfected patients is not fully documented. We determined the prevalence of advanced liver fibrosis (defined by hepatic stiffness ≥9.5 kPa) and associated factors, focusing on the impact of highly active antiretroviral therapy and its major adverse effects (lipodystrophy and IR), in 671 HIV/HCV-coinfected patients included in the ANRS CO13 HEPAVIH cohort. One hundred ninety patients (28.3%) had advanced liver fibrosis. In univariate analysis, advanced liver fibrosis was significantly associated with male sex, higher body mass index, HCV infection through intravenous drug use, a lower absolute CD4 cell count, a longer history of antiretroviral treatment, longer durations of protease inhibitors, non-nucleoside reverse transcriptase inhibitors and NRTI exposure, lipodystrophy, diabetes, and a high homeostasis model assessment method (HOMA) value. The only antiretroviral drugs associated with advanced liver fibrosis were efavirenz, stavudine and didanosine. In multivariate analysis, male sex (OR 2.0, 95% CI 1.1-3.5; P = 0.018), HCV infection through intravenous drug use (OR 2.0, 95% CI 1.1-3.6; P = 0.018), lipodystrophy (OR 2.0, 95% CI 1.2-3.3; P = 0.01), median didanosine exposure longer than 5 months (OR 1.7, 95% CI 1.0-2.8; P = 0.04) and a high HOMA value (OR 1.1, 95% CI 1.0-1.2; P = 0.005) remained significantly associated with advanced liver fibrosis. Mitochondrial toxicity and IR thus appear to play a key role in liver damage associated with HIV/HCV-coinfection, and this should be taken into account when selecting and optimizing antiretroviral therapy. Antiretroviral drugs with strong mitochondrial toxicity (e.g. didanosine) or a major effect on glucose metabolism should be avoided.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Antiviral Agents; Benzoxazines; CD4 Lymphocyte Count; Coinfection; Cyclopropanes; Didanosine; Female; Hepatitis C; HIV Infections; Humans; Insulin Resistance; Lipodystrophy; Liver Cirrhosis; Male; Middle Aged; Mitochondria; Sex Factors; Stavudine

Topics: Biopsy; Didanosine; Fatty Liver; Hepatitis C; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Stavudine

(1) In patients who are infected with both HIV and hepatitis C virus (HCV), treatment of hepatitis C slightly increases the risk of lactic acidosis associated with antiretroviral treatment, especially when the latter includes didanosine. (2) If a modification in antiretroviral treatment is needed and if treatment for hepatitis C is likely to be necessary, then it is best to avoid didanosine. However, systematic replacement of didanosine is not necessary, given the small magnitude of risk of lactic acidosis. (3) Fatigue, digestive problems, weight loss and dyspnea are signs of lactic acidosis.

Topics: Acidosis, Lactic; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Comorbidity; Contraindications; Didanosine; Drug Interactions; Drug Therapy, Combination; Hepatitis C; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Recombinant Proteins; Reverse Transcriptase Inhibitors; Ribavirin

Nucleoside analogues may induce mitochondrial toxicity, particularly didanosine. Ribavirin increases didanosine exposure, which might be clinically relevant when coadministered in HIV/HCV-coinfected patients.. To evaluate, among 89 patients receiving highly active antiretroviral therapy (HAART) and therapy for chronic hepatitis C, clinically relevant mitochondrial toxicity in those treated with concomitant ribavirin and didanosine (n=35, 39%).. From January 2000 to July 2002 longitudinal analysis of the incidence and clinical course of didanosine-related hyperamylasaemia, pancreatitis, hyperlactataemia/lactic acidosis or neuropathy. Risk factors were evaluated using univariate and multivariate Cox's proportional hazards model.. Among 35 patients who received concomitant didanosine (400 mg/day in 86%) and ribavirin (> or = 10 mg/kg/day in 91%), 20 (57%) developed one or more adverse events after a mean of 87 days. Most frequent laboratory abnormalities were hyperamylasaemia (18 patients, 51%) and hyperlactataemia (eight patients, 23%). Acute pancreatitis and symptomatic hyperlactataemia developed in 10 (28%) and six (17%) patients, respectively. Two patients (6%) with pancreatitis and severe lactic acidosis died; the other patients recovered uneventfully despite continuation of anti-HCV therapy in 83% after didanosine withdrawal in 40%. In the Cox's model higher baseline amylase levels (HR: 1.04, 95% CI: 1.02-1.06, P=0.001) and three nucleoside reverse transcriptase inhibitor-based HAART (HR: 5.3, 95% CI: 1.73-16.24, P=0.003) were significantly associated to toxicity.. The coadministration of didanosine and ribavirin should be avoided in HIV/HCV-coinfected patients, due to a high rate of clinically significant toxicity, particularly in triple nucleoside-based HAART. Amylase levels should be strictly monitored, especially if elevated at baseline.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; Didanosine; Female; Hepatitis C; HIV Infections; Humans; Incidence; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Proportional Hazards Models; Ribavirin

An evaluation of the US Food and Drug Administration's Adverse Event Reporting System identified that patients coinfected with human immunodeficiency virus and chronic hepatitis C virus who were treated with a regimen of ribavirin and didanosine, with or without stavudine, were at increased risk for events associated with mitochondrial toxicity, including fatal hepatic failure, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis. In response, the US product labels for didanosine and ribavirin have been revised to caution clinicians against coadministration of these drugs.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; Humans; Male; Middle Aged; Mitochondria; Reverse Transcriptase Inhibitors; Ribavirin; Stavudine

To evaluate the antiviral triple combination didanosine (ddI), interferon-alfa (IFN-alpha), and ribavirin for potential synergy in inhibition of HIV-1 replication in vitro.. Phytohaemagglutinin-stimulated cord blood mononuclear cells were infected with HIV-1(IIIB) or the HXB2D molecular clone of HIV-1 then cultured with interleukin-2 with ddI, ribavirin or IFN-alpha, alone and in combination. Reverse transcriptase activity was measured after 7 days to determine the inhibitory concentration of 50% (IC(50)) for the various drugs in replicate assays. Analysis of combined effects was performed using both the median effect principle (CalcuSyn, Biosoft) and three-dimensional modelling (MacSynergy II).. The triple combination was highly synergistic against HIV-1 in vitro with combination indices < 1. The mean IC(50) was reduced from 6.85 to 0.90 micromol/l (P < 0.001) for ddI and from 6.58 to 1.00 micromol/l (P < 0.001) for IFN-alpha. No increased cytotoxicity was observed. Results were similar with both viral strains and using both analyses. In the triple combination, increasing concentrations of IFN-alpha resulted only a slight enhancement of synergy: synergy volumes were 134 [95% confidence limit (CL), 77-191] with 5 U IFN-alpha and 214.92 (95% CL, 116-314) with 10 U. This supporting the observation that the majority of the synergistic activity was derived from the combination of ddI and ribavirin, with IFN-alpha providing additional additive suppression.. This novel triple combination has the potential to provide simultaneous activity against both HIV and hepatitis C and deserves further study to determine if can be safely administered in the clinical setting.

Topics: Anti-HIV Agents; Cells, Cultured; Didanosine; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation, Preclinical; Drug Synergism; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Interferon-alpha; Ribavirin; Virus Replication

Topics: Adult; Alanine Transaminase; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; Hepatitis B; Hepatitis C; HIV Infections; Humans; Incidence; Liver; Male; Middle Aged; Stavudine

Pancreatitis and lactic acidosis are severe and life-threatening adverse events associated with nucleoside analogue antiretroviral therapy used to treat HIV infection. The drug from this class most commonly associated with these adverse events is stavudine, although zidovudine and didanosine have also been implicated. Ribavirin is a nucleoside analogue used in combination with interferon alfa to treat hepatitis C. Because of similar mechanisms of action, the combination of these 2 drugs could potentially increase such toxicity. A case of fatal lactic acidosis and pancreatitis is described in an HIV-infected patient coinfected wtih hepatitis C on a didanosine-containing antiretroviral regimen after treatment of hepatitis C was initiated with ribavirin and pegylated interferon alfa-2b. Extreme caution should be exercised when didanosine and ribavirin are used concomitantly because of the increased risk of mitochondrial toxicity and the syndrome of severe metabolic acidosis with elevated lactic acid levels.

Topics: Acidosis, Lactic; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Synergism; Drug Therapy, Combination; Fatal Outcome; Hepatitis C; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Pancreatitis; Recombinant Proteins; Ribavirin; Risk Factors; Viral Load

Topics: Anti-HIV Agents; Antiviral Agents; Didanosine; Drug Synergism; Drug Therapy, Combination; Hepatitis C; HIV Infections; HIV-1; Humans; Interferon-gamma; Ribavirin

Topics: Anti-HIV Agents; Antiviral Agents; Didanosine; Drug Interactions; Drug Labeling; Hepatitis C; HIV Infections; Humans; Ribavirin

Topics: Adult; Anti-HIV Agents; Antiviral Agents; Didanosine; Drug Interactions; Hepatitis C; HIV Seropositivity; HIV-1; Humans; Middle Aged; Mitochondria; Pancreatitis; Ribavirin

We present a case of liver failure in a haemophilic patient coinfected with transfusion acquired human immunodeficiency (HIV) and hepatitis C (HCV) viruses. The case illustrates the interaction of multiple viruses with accelerated progression to end stage liver disease and ultimately death. We report the impact on the patient management of two liver biopsies, which diagnosed an initial drug induced hepatitis and subsequently an atypical HCV related hepatitis.

Topics: Anti-Bacterial Agents; Anti-HIV Agents; Clarithromycin; Didanosine; Hemophilia A; Hepacivirus; Hepatitis C; HIV Infections; Humans; Liver Failure, Acute; Male; Middle Aged; Zidovudine