raltegravir-potassium and Chemical-and-Drug-Induced-Liver-Injury

There has been a major paradigm shift in the management of HIV infected patients, with earlier initiation of antiretroviral treatment and lifelong exposure to drugs for which long-term safety issues must be faced by clinicians. Within the past 5 years, new drugs from both previously established and novel therapeutic classes have been released that tend to be safer and more efficient than their former combinations. Although hepatotoxicity was one of the most common side effects from initial antiretrovirals, phase II/III safety data regarding liver tolerance from more recent drugs are reassuring. However, data on the long-term exposure to these therapeutic options are needed, and a handful of case reports are emerging, reporting rare but potentially life-threatening adverse hepatic events in patients with hepatitis co-infection or taking other hepatotoxic drugs.

Topics: Anti-Retroviral Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Cyclohexanes; Darunavir; Heterocyclic Compounds, 3-Ring; Humans; Maraviroc; Nitriles; Oxazines; Piperazines; Pyridazines; Pyridones; Pyrimidines; Pyrrolidinones; Quinolones; Raltegravir Potassium; Rilpivirine; Sulfonamides; Triazoles

In the last decade, some evidence has arisen supporting the usefulness of Asian ginseng (Panax ginseng, fam. Araliaceae) as a complementary remedy in patients receiving antiretroviral therapy. However, its role in current therapeutics remains unclear.. The patient was admitted for an acute elevation of liver enzymes, marked jaundice, and significant weight loss after taking ginseng-based tablets starting approximately 39 days prior. His past medical history (PMH) was also significant for HIV+, long-term hepatitis C, an episode of mitochondrial toxicity, and several comorbidities. His outpatient medications included raltegravir 400 mg plus lopinavir/ritonavir 400/100 mg twice daily, aspirin 100 mg daily, and esomeprazole 40 mg daily as needed.. The cessation of the ginseng lozenges led to a progressive improvement in the performance status and laboratory values. Both the Hansten and Horn nomogram and the Roussel Uclaf Causality Assessment Method indicated that the association between the ginseng medicine and the liver injury was probable (six points).. We suggest that ginseng is involved in the episode through an interaction resulting in elevated plasma concentrations of raltegravir. As a consequence, clinicians should be alert when managing patients on other CYP3A4-metabolized drugs or previous liver-damaging conditions. However, larger studies are required to explicitly clarify these statements.

Topics: Chemical and Drug Induced Liver Injury; Complementary Therapies; Cytochrome P-450 CYP3A; Herb-Drug Interactions; HIV Infections; HIV Integrase Inhibitors; Humans; Liver; Male; Middle Aged; Panax; Pyrrolidinones; Raltegravir Potassium

Integrase inhibitors are a new therapeutic modality against HIV. Raltegravir is the first integrase inhibitor to have been approved by the health authorities for human use. This drug acts by inhibiting the HIV enzyme that catalyzes integration of the virus inside the genome of the host cell. In the host cell, there is no homologue to viral integrase and consequently the potential toxicity of this drug is probably low. The results of safety studies in animal models have shown that the recommended dose in humans is lower than the dose below which no secondary effects are observed. Studies of genotoxicity and carcinogenicity, as well as of fertility and embryo development, have been negative to date. During clinical trials, raltegravir has been shown to have a very good safety profile, with few adverse effects, which were mild-to-moderate and similar to those of the comparator. The most notable were diarrhea, nausea and headache. The lipid profile of raltegravir was better than that of efavirenz. In view of the above, the risk-benefit ratio for raltegravir is positive.

Topics: Abnormalities, Drug-Induced; Animals; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Dogs; Drug Evaluation, Preclinical; Embryonic Development; Female; Gastrointestinal Diseases; Headache; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Male; Mice; Mutagenicity Tests; Pain; Pregnancy; Pyrrolidinones; Rabbits; Raltegravir Potassium; Rats

In the ANRS EASIER trial where treatment-experienced patients switched from enfuvirtide (ENF) to raltegravir (RAL), a high incidence of transaminase elevation was reported in the RAL arm.. We compared the incidence of emergent liver enzyme elevations (LEE) of grade 2 or more among patients randomized to the maintenance ENF arm or the switch RAL arm up to W24. We also assessed the overall incidence of LEE over the 48-week duration of the trial and baseline risk factors for grade 2 or more alanine aminotransferase (ALT) elevation using univariate and multivariate analyses.. During the first 24 weeks, 6/84 (7.1 %) and 2/85 patients (2.4 %) presented with ALT elevation of grade 2 or more in the RAL and ENF arms, respectively (p = 0.21). Grade 2 or more γGT and ALP elevations were seen in 18 and 11 % (p = 0.35), and 5 and 1 % (p = 0.14) of patients in the RAL and ENF arms, respectively. The 48-week incidence of grade 2 or more LEE was 11.6 per 100-pts-years for ALT, 24.5 per 100-pts-years for γ-GT and 4.5 per 100-pts-years for ALP, respectively. In the multivariate analysis, tipranavir/ritonavir use (OR 3.66; 95 % CI [1.20-11.1], p = 0.022) and elevated ALT at baseline (OR 10.3; 95 % CI [2.67-39.6], p < 10(-3)) were significantly associated with a grade 2 or more ALT elevation during follow-up.. The incidence of LEE was relatively high in these highly treatment-experienced patients switching to a RAL-based regimen. Both tipranavir/ritonavir use and high baseline ALT levels were associated with an increased risk of ALT.. ClinicalTrials.gov identifier: NCT00454337.

Topics: Adult; Alanine Transaminase; Chemical and Drug Induced Liver Injury; Drug Substitution; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Incidence; Liver Function Tests; Male; Middle Aged; Peptide Fragments; Raltegravir Potassium; Risk Factors

Potential liver toxicity is an important consideration for antiretroviral selection among patients coinfected with HIV and viral hepatitis (B and/or C). We sought to describe the hepatic safety profile of raltegravir in this population.. Using data from HIV clinical cohorts at Johns Hopkins University and the University of North Carolina at Chapel Hill, we evaluated factors associated with liver enzyme elevations (LEEs) and calculated adverse event incidence rates for patients initiated on raltegravir-containing regimens prior to 1 January 2010. LEEs were graded according to Division of AIDS definitions.. During the study period, 456 patients received raltegravir - of whom 36% were hepatitis-coinfected (138 HCV, 17 HBV, 11 HBV+HCV). Coinfected patients were more likely to have baseline abnormal LEEs and developed severe (grade 3-4) LEEs at a rate 3.4× that of HIV-monoinfected patients (95% CI 1.28, 9.61). Among all participants, the incidence rate for first occurrence of severe LEEs was 5 per 100 person-years (95% CI 3, 7). In adjusted analyses, coinfected patients had a 2.7-fold increased hazard of severe LEEs (95% CI 1.03, 7.04). 60% of severe abnormalities occurred within 6 months after starting raltegravir; the drug was discontinued in 3 (1.3%) coinfected patients and 18 (6.2%) monoinfected patients.. Compared with HIV-monoinfected patients, those with HIV-hepatitis coinfection are at increased hazard of developing LEEs on raltegravir, at a level similar to other antiretrovirals. Severe events were uncommon, rarely leading to raltegravir discontinuation. With appropriate monitoring, raltegravir-based therapy is safe in hepatitis-coinfected patients.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Coinfection; Female; Hepatitis B; Hepatitis C; HIV Infections; Humans; Liver; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load; Young Adult

Topics: Adolescent; Adult; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Pregnancy Outcome; Raltegravir Potassium; Viral Load; Viremia; Young Adult

Liver enzyme elevations (LEE) were investigated in 2717 episodes of initiation of antiretroviral therapy since January 2010 in 1982 HIV patients. Serum hepatitis C virus (HCV)-RNA was positive in 24%. Any grade of LEE was recognized in 9% of episodes, being 6% in HCV-negative and 17% in HCV-positive patients (P < 0.001). Grades 3-4 LEE only occurred in 0.4% of patients. Overall, LEE were more frequent with ritonavir-boosted darunavir and atazanavir than with raltegravir and etravirine.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Coinfection; Cyclopropanes; Darunavir; Female; Follow-Up Studies; Hepatitis C; HIV Infections; Humans; Liver; Male; Nevirapine; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.

Topics: Adult; Carbamates; Cardiomyopathies; Chemical and Drug Induced Liver Injury; Creatine Kinase; Cyclohexanes; Drug Substitution; Drug Therapy, Combination; Fatty Liver; Furans; Hepatitis C, Chronic; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Liver Cirrhosis; Male; Maraviroc; Organophosphates; Pyrrolidinones; Raltegravir Potassium; Sulfonamides; Triazoles

In HIV-infected patients with HCV-related chronic hepatitis, liver impairment and drug toxicity may substantially reduce the number of possible therapeutic options.. we here describe the case of an HCV-HIV coinfected woman who had repeated severe episodes of drug-related liver toxicity with indinavir, saquinavir, fosamprenavir, and darunavir, with minimal further therapeutic options left in this class. Previous treatment-limiting side effects with efavirenz and nevirapine also precluded use of non-nucleoside reverse transcriptase inhibitors. Introduction of an integrase-inhibitor regimen based on raltegravir, tenofovir, and emtricitabine allowed a prompt achievement of undetectable viral load and a substantial rise of CD4 count to high levels, with no subsequent episodes of hepatic toxicity, and no other side effects.. given the relatively common prevalence of HCV-related chronic hepatitis among people with HIV, raltegravir might represent an important alternative option for a substantial number of patients who cannot be treated with protease inhibitors or NNRTI because of drug-related hepatic toxicity.

Topics: Adenine; Adult; Antiviral Agents; CD4-Positive T-Lymphocytes; Chemical and Drug Induced Liver Injury; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver; Lymphocyte Count; Organophosphonates; Protease Inhibitors; Pyrrolidinones; Raltegravir Potassium; Tenofovir; Treatment Outcome; Viral Load