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The Journal of Antimicrobial... Jul 2018Monotherapy with ritonavir-boosted PIs (PI/r) has been used to simplify treatment of HIV-1-infected patients. In previous studies raltegravir intensification evidenced... (Clinical Trial)
Clinical Trial
BACKGROUND
Monotherapy with ritonavir-boosted PIs (PI/r) has been used to simplify treatment of HIV-1-infected patients. In previous studies raltegravir intensification evidenced ongoing viral replication and reduced T cell activation, preferentially in subjects receiving PI-based triple ART. However, data about low-level viral replication and its consequences in patients receiving PI/r monotherapy are scarce.
METHODS
We evaluated the impact of 24 weeks of intensification with raltegravir on markers of viral persistence, cellular immune activation and inflammation biomarkers in 33 patients receiving maintenance PI/r monotherapy with darunavir or lopinavir boosted with ritonavir. ClinicalTrials.gov identifier: NCT01480713.
RESULTS
The addition of raltegravir to PI/r monotherapy resulted in a transient increase in 2-LTR (long-terminal repeat) circles in a significant proportion of participants, along with decreases in CD8+ T cell activation levels and a temporary increase in the expression of the exhaustion marker CTLA-4 in peripheral T lymphocytes. Intensification with raltegravir also reduced the number of samples with intermediate levels of residual viraemia (10-60 HIV-1 RNA copies/mL) compared with samples taken during PI/r monotherapy. However, there were no changes in cell-associated HIV-1 DNA in peripheral CD4+ T cells or soluble inflammatory biomarkers (CD14, IP-10, IL-6, C-reactive protein and D-dimer).
CONCLUSIONS
Intensification of PI/r monotherapy with raltegravir revealed persistent low-level viral replication and reduced residual viraemia in some patients during long-term PI/r monotherapy. The concomitant change in T cell phenotype suggests an association between active viral production and T cell activation. These results contribute to understanding the lower efficacy rates of PI/r monotherapies compared with triple therapies in clinical trials.
Topics: Adult; Antiretroviral Therapy, Highly Active; Darunavir; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunity, Cellular; Inflammation; Lopinavir; Lymphocyte Activation; Male; Middle Aged; Pilot Projects; Proof of Concept Study; RNA, Viral; Raltegravir Potassium; Viremia; Virus Replication
PubMed: 29635527
DOI: 10.1093/jac/dky106 -
The Pharmacogenomics Journal Jan 2023Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed...
Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir's characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.
Topics: Humans; Adult; Raltegravir Potassium; Anti-HIV Agents; HIV Infections; Polymorphism, Genetic; Viral Load
PubMed: 36266537
DOI: 10.1038/s41397-022-00293-5 -
International Journal of STD & AIDS Nov 2016Raltegravir is one of the standard antiretroviral therapy (ART) options in treatment-experienced and -naïve patients. However, efficacy data from clinical practice are...
Raltegravir is one of the standard antiretroviral therapy (ART) options in treatment-experienced and -naïve patients. However, efficacy data from clinical practice are scarce. Therefore, the efficacy of raltegravir-containing ART in clinical practice was investigated retrospectively. In all, 295 treatment-naïve and -experienced patients were analysed using two different cut-offs for virological failure (200 or 50 copies/ml). The response at week 24 and onwards was evaluated as a 'time to loss of virological response' analysis and estimated as a survival function. Additionally, dual therapy regimens (raltegravir plus boosted protease inhibitor) were compared to standard combinations in experienced patients performing a snapshot analysis at weeks 24 and 48, as well as a time to loss of virological response analysis. A total of 86.2% of the 64 treatment-naïve patients maintained virological suppression using a cut-off of 200 copies/ml (c/ml), while 67.7% maintained virological suppression with a 50 copies/ml cut-off from week 24 until the end of observation. Among the 231 treatment-experienced patients, 84.8% maintained virological suppression from week 24 onwards using a cut-off of 200 copies/ml; and 71.0% using 50 copies/ml, respectively. In the subgroup snapshot analysis at week 24, 98.3% (86.7% using a cut-off of 50 copies/ml) and at week 48, 93.3% (80.0%) of patients responded to dual therapy. Patients who were receiving a standard background therapy responded in 88.3% (81.3%) at week 24 and in 86.0% (80.7%) at week 48. Differences were not significant. This study shows again the overall long-term efficacy of raltegravir-based ART and furthermore gives reference for a comparable efficacy of dual and standard nucleos(t)ide reverse transcriptase inhibitor-backbone regimens in experienced patients on raltegravir over a period of 48 weeks in a real-life cohort where patients with severe comorbidities were included.
Topics: Adult; Anti-HIV Agents; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Raltegravir Potassium; Treatment Outcome; Viral Load
PubMed: 26429890
DOI: 10.1177/0956462415610678 -
AIDS Patient Care and STDs Nov 2007
Topics: Adult; Drug Approval; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; United States
PubMed: 18240897
DOI: 10.1089/apc.2007.9967 -
PloS One 2016Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods. (Clinical Trial)
Clinical Trial
BACKGROUND
Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods.
METHODS
Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5.
RESULTS
SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), but not UGT1A1 genotype.
CONCLUSION
Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy.
TRIAL REGISTRATION
Clinicaltrials.gov NCT00808184.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Camptothecin; Colorectal Neoplasms; Female; Genotype; Glucuronosyltransferase; Humans; Irinotecan; Male; Middle Aged; Phenotype; Raltegravir Potassium
PubMed: 26808671
DOI: 10.1371/journal.pone.0147681 -
HIV Medicine Feb 2020
Topics: Anti-HIV Agents; Drug Administration Schedule; Drug Compounding; Female; HIV; HIV Infections; Humans; Male; Medication Adherence; Middle Aged; RNA, Viral; Raltegravir Potassium; Treatment Outcome
PubMed: 31338932
DOI: 10.1111/hiv.12783 -
Antiviral Therapy Aug 2022We report a case of an infant with HIV receiving raltegravir granules for oral suspension and rifampicin-based TB prophylaxis. Raltegravir trough levels remained...
We report a case of an infant with HIV receiving raltegravir granules for oral suspension and rifampicin-based TB prophylaxis. Raltegravir trough levels remained subtherapeutic and viral load increased during concurrent rifampicin therapy despite using double-dosed raltegravir. Even after rifampicin therapy, a higher dose was needed. This highlights the importance of therapeutic drug monitoring and dose adjustments of raltegravir in infants with rifampicin as comedication.
Topics: Anti-HIV Agents; HIV Infections; Humans; Infant; Raltegravir Potassium; Rifampin; Viral Load
PubMed: 36062614
DOI: 10.1177/13596535221119932 -
Le Infezioni in Medicina Dec 2014Raltegravir, as the first HIV integrase inhibitor, has been used and prospectively monitored since 2010 in our HIV outpatient centre, where over 1,200 patients are...
Raltegravir, as the first HIV integrase inhibitor, has been used and prospectively monitored since 2010 in our HIV outpatient centre, where over 1,200 patients are monitored. The aim of our report is to perform an interim assessment of the background, the safety profile and the clinical-laboratory monitoring of all patients treated with a combination antiretroviral therapy (cART) including raltegravir, for at least 12 months. In all, 109 pretreated patients started a raltegravir-containing cART when aged 44.8 plus or minus 19.2 years, with a history of HIV infection lasting 13.4 plus or minus 9.7 years. All subjects were monitored for at least 12 months (mean 17.2 plus or minus 10.3 months). In the vast majority of cases (93 of 109: 85.3%), multiple (3-16) prior cART changes prompted raltegravir introduction in advanced-salvage lines: 72 of 109 (66.1%) patients had even developed a concurrent triple-class resistance to anti-HIV compounds. The most frequent companion antiretroviral agents were: darunavir/ritonavir (75 cases), maraviroc (47 subjects), and etravirine (38 cases). The most common underlying conditions were: AIDS (46 patients), liver cirrhosis (31 cases), AIDS-related or other malignancies (23 cases), and major cardio-cerebro-vascular events (18 cases). A chronic HCV and HBV hepatitis were of concern in 48 and 23 patients, respectively. The adjunct of raltegravir favourably affected all clinical-laboratory markers of HIV disease progression, and those of the broad spectrum of comorbidities, except for two patients who failed the raltegravir-containing cART due to insufficient adherence. Despite the already compromised clinical situation, a minority of subjects experienced mild-transient clinical-laboratory untoward events possibly attributable to raltegravir, such that no patients discontinued raltegravir during the observation period. Only three AIDS-defining conditions became apparent during raltegravir-based cART; chemotherapy and/or radiotherapy cycles were performed as scheduled in patients suffering from cancer; chronic hepatitis B and C progressed to liver cirrhosis and/or hepatocarcinoma in only 2 and 6 patients. Otherwise, treatment with pegylated interferon-ribavirin became feasible in 25 patients of 48 with chronic HCV. During raltegravir-containing cART, neither autoimmune disorders nor novel malignancies were diagnosed. Only mild-transient gastrointestinal disorders, fatigue, dizziness, insomnia and cutaneous rash were reported, although their relationship with the study drug was difficult to assess due to multiple comorbidities and polypharmacy. Abnormal liver function testings were observed in 57 patients (52.3%), all suffering from concurrent hepato-biliary disorders. Significant increases in serum lipids and/or lipase levels versus baseline values were never registered: serum lipid levels significantly improved after raltegravir introduction. Our experience with raltegravir underlines its excellent efficacy and safety profile, which exploits a novel mechanism of action, and displays no cross-resistance with any other antiretroviral. A progressively extended prescription in naive patients and early cART lines will allow the therapeutic potential of raltegravir to be exploited.
Topics: Adult; Aged; Ambulatory Care Facilities; Anti-Retroviral Agents; Female; HIV Infections; Humans; Italy; Male; Middle Aged; Prospective Studies; Raltegravir Potassium; Risk Factors; Treatment Outcome
PubMed: 25551844
DOI: No ID Found -
Science Advances Mar 2024People living with human immunodeficiency virus (HIV) receiving integrase strand transfer inhibitors (INSTIs) have been reported to experience virological failure in the...
People living with human immunodeficiency virus (HIV) receiving integrase strand transfer inhibitors (INSTIs) have been reported to experience virological failure in the absence of resistance mutations in integrase. To elucidate INSTI resistance mechanisms, we propagated HIV-1 in the presence of escalating concentrations of the INSTI dolutegravir. HIV-1 became resistant to dolutegravir by sequentially acquiring mutations in the envelope glycoprotein (Env) and the nucleocapsid protein. The selected Env mutations enhance the ability of the virus to spread via cell-cell transfer, thereby increasing the multiplicity of infection (MOI). While the selected Env mutations confer broad resistance to multiple classes of antiretrovirals, the fold resistance is ~2 logs higher for INSTIs than for other classes of drugs. We demonstrate that INSTIs are more readily overwhelmed by high MOI than other classes of antiretrovirals. Our findings advance the understanding of how HIV-1 can evolve resistance to antiretrovirals, including the potent INSTIs, in the absence of drug-target gene mutations.
Topics: Humans; Raltegravir Potassium; HIV Integrase Inhibitors; HIV-1; HIV Integrase; Mutation
PubMed: 38427738
DOI: 10.1126/sciadv.adn0042 -
AIDS (London, England) Oct 2019There is an increasing interest in two-drug regimens. We hypothesized that maintenance therapy with raltegravir and lamivudine would keep HIV-1 suppressed and be well... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
There is an increasing interest in two-drug regimens. We hypothesized that maintenance therapy with raltegravir and lamivudine would keep HIV-1 suppressed and be well tolerated.
METHODS
Virally suppressed HIV-1-infected adults without previous viral failures or known resistance mutations to integrase inhibitors or 3TC/FTC or chronic hepatitis B were randomized 2 : 1 to switch to fixed-dose combination 150 mg lamivudine/300 mg raltegravir twice daily or to continue therapy. Primary outcome was the proportion of patients free of therapeutic failure (defined as viral failure, change in treatment for any reason, consent withdrawal, loss to follow-up or death) at week 24. Secondary outcomes were changes in laboratory, body composition, sleep quality, adherence, and adverse effects.
RESULTS
There were 75 patients included: men 78%; median age 50 years; median CD4 622/μl. At week 24, 7 (9%) patients had therapeutic failure: raltegravir and lamivudine 2 (4%) vs. control 5 (20%). The difference in proportions of therapeutic failures raltegravir and lamivudine minus control was -0.159 (95% confidence interval: -0.353 to -0.012). There was a trend to more weight gain with raltegravir and lamivudine, but no significant changes in other secondary outcomes. Sixty-four percent of patients in each arm had at least one adverse effect. Two (6%) patients in control arm and 4 (7%) patients in raltegravir and lamivudine arm had severe adverse effects.
CONCLUSION
This pilot study suggests that switching to raltegravir along with lamivudine in patients with viral suppression maintains efficacy and is well tolerated. A larger study of longer duration is required to confirm these findings.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; Humans; Lamivudine; Maintenance Chemotherapy; Male; Middle Aged; Pilot Projects; Raltegravir Potassium; Treatment Outcome; Young Adult
PubMed: 31335805
DOI: 10.1097/QAD.0000000000002311