raltegravir-potassium and abacavir

There is still no consensus on the optimal management of COVID-19 within the general population due to the emerging evidence base. High-risk groups, including kidney transplant recipients living with HIV present unique additional challenges. Here we discuss two kidney transplant recipients living with HIV with SARS-CoV-2 infection and their clinical course, and review the existing literature for this subset of challenging patients.

Topics: Adult; Anti-Bacterial Agents; Anti-HIV Agents; Atovaquone; CD4 Lymphocyte Count; CD4-CD8 Ratio; COVID-19; Dideoxynucleosides; Female; Glucocorticoids; Graft Rejection; HIV Infections; HIV-1; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Lamivudine; Male; Middle Aged; Mycophenolic Acid; Pneumonia, Pneumocystis; Prednisolone; Raltegravir Potassium; RNA, Viral; SARS-CoV-2; Tacrolimus; Trimethoprim, Sulfamethoxazole Drug Combination

With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Coinfection; Deoxycytidine; Dideoxynucleosides; Disease Progression; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Emtricitabine; Hepatitis C, Chronic; HIV Infections; Homosexuality, Male; Humans; Interferon-alpha; Lamivudine; Liver Cirrhosis; Liver Diseases; Male; Oligopeptides; Organophosphonates; Polyethylene Glycols; Proline; Pyrrolidinones; Raltegravir Potassium; Recombinant Proteins; Ribavirin; Serine Proteinase Inhibitors; Substance Abuse, Intravenous; Tenofovir; Treatment Outcome

Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge.. Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive with CD4+ counts < 200/mm3 and a viral load (VL)<500,000 copies/mL. The primary Endpoint was the proportion of patients with undetectable viremia (VL<50 copies/mL) after 48 weeks. The planned sample size for this trial was 350 patients.. In 3 years, 53 patients were screened and 46 enrolled: 22 randomized to raltegravir and 24 to darunavir/r; 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity. The snapshot analysis at 48 weeks showed a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r. Time to starting treatment was 34.5 days in raltegravir and 53 days in darunavir/r. At the as treated analysis, the median CD4 counts at 48 weeks was 297 cells/μL in raltegravir and 239 cells/μL in darunavir/r. No difference in total cholesterol, while triglycerides were higher in the darunavir/r arm. No statistical analyses were performed due to the low number of patients enrolled.. Late presenter patients are frequent but very difficult to enroll in clinical trials, especially in western countries. These regimens and the conditions of many patients could not allow the test and treat strategy. The rate of virologic success was higher than 65% in both arms with a median CD4 cell count >200/μL at week 48.. EUDRACT number: 2011-005973-21.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Delayed Diagnosis; Dideoxynucleosides; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Raltegravir Potassium; Ritonavir

Antiretroviral drugs with a lower potential to induce hepatic steatosis in human immunodeficiency virus (HIV) infection need to be identified. We compared the effect of switching efavirenz (EFV) to raltegravir (RAL) on hepatic steatosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD) receiving EFV plus 2 nucleoside analogues.. HIV-infected patients on EFV plus tenofovir/emtricitabine or abacavir/lamivudine with NAFLD were randomized 1:1 to switch from EFV to RAL (400 mg twice daily), maintaining nucleoside analogues unchanged, or to continue with EFV plus 2 nucleoside analogues. At baseline, eligible patients should show controlled attenuation parameter (CAP) values ≥238 dB/m. Changes in hepatic steatosis at 48 weeks of follow-up over baseline levels were measured by CAP.. Overall, 39 patients were included, and 19 of them were randomized to switch to RAL. At week 48, median CAP for the RAL group was 250 (Q1-Q3, 221-277) dB/m and 286 (Q1-Q3, 269-314) dB/m for the EFV group (P = .035). The median decrease in CAP values was -20 (Q1-Q3, -67 to 15) dB/m for the RAL arm and 30 (Q1-Q3, -17 to 49) dB/m for the EFV group (P = .011). CAP values <238 dB/m at week 48 were observed in 9 (47%) patients on RAL and 3 (15%) individuals on EFV (P = .029).. After 48 weeks, HIV-infected individuals switching EFV to RAL showed decreases in the degree of hepatic steatosis, as measured by CAP, compared with those continuing with EFV. In addition, the proportion of patients without significant hepatic steatosis after 48 weeks was greater for those who switched to RAL.. NCT01900015.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Body Mass Index; Body Weight; Cyclopropanes; Dideoxynucleosides; Drug Substitution; Drug Therapy, Combination; Elasticity Imaging Techniques; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Raltegravir Potassium; Tenofovir; Triglycerides; Waist-Hip Ratio

Here, we aimed to investigate the pharmacokinetics of abacavir and carbovir triphosphate (CBV-TP) with darunavir/ritonavir 900/100 mg once daily or raltegravir 400 mg twice daily.. HIV-infected subjects on abacavir (600 mg once daily) underwent steady-state pharmacokinetic assessments without and with darunavir/ritonavir or raltegravir. Within-subject changes in plasma and intracellular pharmacokinetic parameters were evaluated by geometric mean ratios (GMRs) and 90% CIs.. A total of 19 patients completed the study. With darunavir/ritonavir (versus abacavir alone), abacavir GMRs (90% CI) were 0.73 (0.66, 0.80), 0.62 (0.50, 0.77) and 0.78 (0.69, 0.87) for area under the curve (AUC), trough concentration (C(trough)) and maximum concentration (C(max)), respectively. With raltegravir, they were 1.03 (0.97, 1.10), 0.83 (0.62, 1.11) and 1.06 (0.95, 1.18), respectively. Intracellular CBV-TP GMRs (90% CI) were 0.88 (0.72, 1.07), 0.68 (0.48, 0.95) and 0.98 (0.79, 1.23) for AUC, C(trough) and C(max), respectively, with darunavir/ritonavir, and 0.96 (0.76, 1.20), 0.57 (0.33, 1.00) and 1.07 (0.85, 1.35), respectively, with raltegravir.. There was a 27% decrease in abacavir plasma exposure with darunavir/ritonavir and no changes with raltegravir. CBV-TP C(trough) was significantly decreased with darunavir/ritonavir (32%) and showed a high inter-individual variability with raltegravir.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Cross-Over Studies; Darunavir; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

Topics: Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Insulin; Lamivudine; Menopause; Nitriles; Oxazines; Piperazines; Pyridones; Pyrimidines; Raltegravir Potassium; Waist Circumference; Weight Gain

Accelerated neurological disorders are increasingly prominent among the HIV-infected population and are likely driven by the toxicity from long-term use of antiretroviral drugs. We explored potential side effects of antiretroviral drugs in HIV-infected primary human astrocytes and whether opioid co-exposure exacerbates the response. HIV-infected human astrocytes were exposed to the reverse transcriptase inhibitor, emtricitabine, alone or in combination with two protease inhibitors ritonavir and atazanavir (ERA) with and without morphine co-exposure. The effect of the protease inhibitor, lopinavir, alone or in combination with the protease inhibitor, abacavir, and the integrase inhibitor, raltegravir (LAR), with and without morphine co-exposure was also explored. Exposure with emtricitabine alone or ERA in HIV-infected astrocytes caused a significant decrease in viral replication and attenuated HIV-induced inflammatory molecules, while co-exposure with morphine negated the inhibitory effects of ERA, leading to increased viral replication and inflammatory molecules. Exposure with emtricitabine alone or in combination with morphine caused a significant disruption of mitochondrial membrane integrity. Genetic analysis revealed a significant increase in the expression of p62/SQSTM1 which correlated with an increase in the histone-modifying enzyme, ESCO2, after exposure with ERA alone or in combination with morphine. Furthermore, several histone-modifying enzymes such as CIITA, PRMT8, and HDAC10 were also increased with LAR exposure alone or in combination with morphine. Accumulation of p62/SQSTM1 is indicative of dysfunctional lysosomal fusion. Together with the loss of mitochondrial integrity and epigenetic changes, these effects may lead to enhanced viral titer and inflammatory molecules contributing to the neuropathology associated with HIV.

Topics: Acetyltransferases; Anti-HIV Agents; Astrocytes; Atazanavir Sulfate; Chromosomal Proteins, Non-Histone; Dideoxynucleosides; Drug Combinations; Emtricitabine; Gene Expression Regulation; Histone Deacetylases; HIV-1; Host-Pathogen Interactions; Humans; Lopinavir; Lysosomes; Membrane Proteins; Mitochondria; Morphine; Narcotics; Nuclear Proteins; Primary Cell Culture; Protein-Arginine N-Methyltransferases; Raltegravir Potassium; Ritonavir; Sequestosome-1 Protein; Signal Transduction; Trans-Activators; Virus Replication

Raltegravir (RAL) is an HIV-1 integrase strand transfer inhibitor that is well established as a component of highly active antiretroviral therapy regimens for the treatment of adults living with human immunodeficiency virus (HIV), due to its high virological efficacy and good tolerability profile. To date, limited data are available on the use of RAL with abacavir/lamivudine (ABC/3TC). We investigated retrospectively 62 HIV-1 infected patients managed by three Italian Infectious Diseases Outpatient Departments, including 57 treatment-experienced patients and 5 treatment-naïve patients, treated with ABC/3TC plus RAL. In all five naïve patients (100%), virological suppression was achieved and maintained , while 55 experienced patients (96.5%) maintained viral suppression at the most recent review. In the treatment-experienced patients, we observed a significant decrease in triglyceride levels (p < 0.01), while liver transaminases, renal function and cholesterol levels remained substantially stable. In the 34 treatment-experienced patients who switched from a protease inhibitor (PI)-based regimen, we observed a significant improvement of total cholesterol (p=0.03) and triglyceride (p < 0.01) levels. No significant alterations were found on renal and liver function and serum lipid profile of treatment-naïve patients. Despite the small number of participants, results support the efficacy and safety of ABC/3TC plus RAL, either in treatment-naïve or treatment-experienced patients.

Topics: Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cholesterol; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Kidney Function Tests; Lamivudine; Liver Function Tests; Male; Middle Aged; Raltegravir Potassium; Treatment Outcome; Triglycerides

We studied the relationships between plasma and saliva concentrations of antiretroviral drugs to explore whether saliva can be used for therapeutic drug monitoring (TDM).. Abacavir (ABC), tenofovir (TFV), darunavir (DRV), and raltegravir (RAL) in plasma and saliva from 30 HIV-1-infected patients were quantified using liquid chromatography-tandem mass spectrometry.. Mean saliva-to-plasma concentration ratios were 0.623 (ABC), 0.024 (TFV), 0.065 (DRV), and 0.0135 (RAL), which agree with the plasma protein binding rates except TFV. Significant correlations were evident between saliva and plasma concentrations of ABC, DRV, and RAL.. This study suggests that plasma concentrations of ABC, DRV, and RAL can be estimated from their saliva concentrations and that the saliva concentration of some antiretroviral drugs reflects the unbound drug concentration in plasma.
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Topics: Adult; Aged; Anti-HIV Agents; Chromatography, Liquid; Darunavir; Dideoxynucleosides; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Protein Binding; Raltegravir Potassium; Saliva; Tandem Mass Spectrometry; Tenofovir

The use of antiretroviral (ARV) drugs with central nervous system (CNS) penetration effectiveness (CPE) may be useful in the treatment of HIV-associated neurocognitive disorder (HAND) as well as targeting a CNS reservoir in strategies to achieve a functional cure for HIV. However, increased cognitive deficits are linked to at least one of these drugs (efavirenz). As mitochondrial dysfunction has been found with a number of ARVs, and as such can affect neuronal function, the objective of this study was to assess the effects of ARV with high CPE for toxicological profiles on presynaptic nerve terminal energy metabolism. This subcellular region is especially vulnerable in that a constant supply of ATP is required for the proper maintenance of neurotransmitter release and uptake supporting proper neuronal function. We evaluated the effects of acute treatment with ten different high CPE ARVs from five different drug classes on rat cortical and striatal nerve terminal bioenergetic function. While cortical nerve terminal bioenergetics were not altered, striatal nerve terminals exposed to efavirenz, nevirapine, abacavir, emtricitabine, zidovudine, darunavir, lopinavir, raltegravir, or maraviroc (but not indinavir) exhibit reduced mitochondrial spare respiratory capacity (SRC). Further examination of efavirenz and maraviroc revealed a concentration-dependent impairment of striatal nerve terminal maximal mitochondrial respiration and SRC as well as a reduction of intraterminal ATP levels. Depletion of ATP at the synapse may underlie its dysfunction and contribute to neuronal dysfunction in treated HIV infection.

Topics: Adenosine Triphosphate; Alkynes; Animals; Anti-HIV Agents; Benzoxazines; Cerebral Cortex; Corpus Striatum; Cyclohexanes; Cyclopropanes; Darunavir; Dideoxynucleosides; Dose-Response Relationship, Drug; Emtricitabine; Lopinavir; Male; Maraviroc; Mitochondria; Neurons; Nevirapine; Oxidative Phosphorylation; Permeability; Presynaptic Terminals; Raltegravir Potassium; Rats; Rats, Long-Evans; Triazoles; Zidovudine

A liquid chromatography-tandem mass spectrometry assay for the determination of abacavir (ABC), tenofovir (TFV), darunavir (DRV), and raltegravir (RAL) in human plasma and saliva was developed and validated to investigate the applicability of saliva as an appropriate specimen for therapeutic drug monitoring. As internal standards, TFV was chosen for ABC, ABC was chosen for TFV, RAL for DRV, and DRV for RAL. Sample preparation involved protein precipitation with acetonitrile, evaporation of solvent using a centrifugal evaporator, and reconstitution by dissolving the residue in mobile phase. Liquid chromatography was performed on a C18 reverse phase column (1.5 × 50 mm, 5 μm) isocratically at a flow rate of 0.2 mL/min using 5mM formic acid-3% (v/v) acetonitrile as the mobile phase for ABC and TFV and 5mM formic acid-35% (v/v) acetonitrile as the mobile phase for DRV and RAL. The run time was 6 min, and the retention time was approximately 2.0 min for TFV, 2.5 min for RAL, and 4-4.5 min for ABC and DRV. Analytes were detected using tandem mass spectrometry in positive electrospray ionization mode. The precursor/product ion transitions (m/z) were 287.3/191.2 for ABC, 288.5/176.2 for TFV, 548.3/392.3 for DRV, and 445.3/109.5 for RAL, and were monitored on a triple-quadrupole mass spectrometer operated in the multiple reaction monitoring mode. The linearity of the assay was assessed in the range 1-10,000 ng/mL for all four drugs. Within-run and between-run mean accuracy, precision, and the extraction recovery for all drugs were -14.5-18.1%, 1.2-13.1%, and 86.0-111.1%, respectively. The proposed assay is sufficiently sensitive and accurate to quantify these drugs in plasma and saliva, and is suitable for investigating the relationship between drug concentrations in plasma and saliva.

Topics: Anti-Retroviral Agents; Calibration; Chromatography, Liquid; Darunavir; Dideoxynucleosides; Drug Monitoring; Humans; Ions; Limit of Detection; Mass Spectrometry; Raltegravir Potassium; Reproducibility of Results; Saliva; Solvents; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Temperature; Tenofovir

An analytical methodology based on micellar liquid chromatography has been developed to quantify abacavir, lamivudine and raltegravir in plasma. These three antiretroviral drugs are prescribed as a set in highly active antiretroviral therapy to acquired immunodeficiency syndrome patients. The experimental procedure consists in the dilution of the sample in micellar media, followed by filtration and, without cleanup step. The analytes were resolved in less than 30min using a mobile phase of 0.05M sodium dodecyl sulphate at pH 7, running at 1mLmin(-1) under isocratic mode at room temperature through a C18 column (125×4.6mm, 5μm particle size). The UV detection wavelength was set at 260nm. The method was successfully validated following the requirements of ICH guidelines in terms of: linear range (0.25-2.5μgmL(-1)), linearity (r(2)>0.990), intra- and interday precision (<6.8%) and accuracy (92.3-104.2%) and robustness (<7.1%). To the extent of our knowledge, this is the first published method to quantify these three drugs in plasma. Several blood samples from AIDS patients taking this HAART set provided by a local hospital were analyzed with satisfactory results.

Topics: Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Chromatography, Liquid; Dideoxynucleosides; Lamivudine; Micelles; Plasma; Pyrrolidinones; Raltegravir Potassium; Sodium Dodecyl Sulfate

Topics: Adult; Anti-HIV Agents; Brain Edema; Darunavir; Diagnosis, Differential; Dideoxynucleosides; Emergencies; Female; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Hypertension, Malignant; Hypertensive Encephalopathy; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Nitriles; Posterior Leukoencephalopathy Syndrome; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral

We describe five patients with HIV-2 infection (four antiretroviral-experienced and one antiretroviral-naive) treated with a regimen containing raltegravir. All responded to treatment as demonstrated by viral load and CD4(+) T-cell count monitoring. Our series confirms the clinical effectiveness of raltegravir in HIV-2-infected patients when given with other antiretrovirals to which the virus is susceptible.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Evidence-Based Medicine; Female; HIV Infections; HIV-2; Humans; Male; Middle Aged; Mutation; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

A 38-year-old HIV positive man suffered from right upper abdominal pain and oesophageal reflux syndromes. He was in a good general state of health and nutrition with no concomitant symptoms.. A small bowel tumor and slight soor esophagitis had been diagnosed by esophago-gastroduodenoscopy. The tumor was histologically classified as Burkitt?s lymphoma.. The patient received 6 cycles of chemotherapy according to the B-ALL protocol, and antiretroviral therapy with lamivudine (300 mg), abacavir (600 mg) und raltegravir (2 × 400 mg) was initiated immediately. After the first cycle of chemotherapy a complete remission of Burkitt?s lymphoma was achieved. Laboratory parameters recovered after completion of 6 cycles to a value of 400 CD4-positive lymphocytes/mm (3) with a viral load of HIV-1-RNA 20 - 300 copies/ml in plasma.. Immediate initiation of antiretroviral therapy is essential after the diagnosis of AIDS-defining symptoms. The choice of an appropriate treatment regimen is a critical factor in order to avoid toxic drug interactions and adverse events while maintaining a highly effective treatment.

Topics: Adult; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; CD4 Lymphocyte Count; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Duodenal Neoplasms; HIV Seropositivity; Humans; Intestine, Small; Lamivudine; Lymphoma, AIDS-Related; Male; Pyrrolidinones; Raltegravir Potassium; Remission Induction; Viral Load

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; Dideoxynucleosides; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Cardiovascular Diseases; Dideoxynucleosides; Drug Interactions; HIV Infections; Humans; Interleukin-2; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium

Topics: Acyclovir; Anti-HIV Agents; Circumcision, Male; Cyclohexanes; Dideoxynucleosides; Drug Interactions; Female; Hepatitis C; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Maraviroc; Multicenter Studies as Topic; Nitriles; Organic Chemicals; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Triazoles