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The Journal of Infectious Diseases Aug 2022Integrase inhibitors (INIs) are a key component of antiretroviral therapy for human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. Although INI resistance...
Spectrum of Activity of Raltegravir and Dolutegravir Against Novel Treatment-Associated Mutations in HIV-2 Integrase: A Phenotypic Analysis Using an Expanded Panel of Site-Directed Mutants.
BACKGROUND
Integrase inhibitors (INIs) are a key component of antiretroviral therapy for human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. Although INI resistance pathways are well-defined for HIV-1, mutations that emerge in HIV-2 in response to INIs are incompletely characterized.
METHODS
We performed systematic searches of GenBank and HIV-2 drug resistance literature to identify treatment-associated mutations for phenotypic evaluation. We then constructed a library of 95 mutants of HIV-2ROD9 that contained single or multiple amino acid changes in the integrase protein. Each variant was tested for susceptibility to raltegravir and dolutegravir using a single-cycle indicator cell assay.
RESULTS
We observed extensive cross-resistance between raltegravir and dolutegravir in HIV-2ROD9. HIV-2-specific integrase mutations Q91R, E92A, A153G, and H157Q/S, which have not been previously characterized, significantly increased the half maximum effective concentration (EC50) for raltegravir when introduced into 1 or more mutational backgrounds; mutations E92A/Q, T97A, and G140A/S conferred similar enhancements of dolutegravir resistance. HIV-2ROD9 variants encoding G118R alone, or insertions of residues SREGK or SREGR at position 231, were resistant to both INIs.
CONCLUSIONS
Our analysis demonstrates the contributions of novel INI-associated mutations to raltegravir and dolutegravir resistance in HIV-2. These findings should help to improve algorithms for genotypic drug resistance testing in HIV-2-infected individuals.
Topics: Anti-HIV Agents; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; HIV-2; Heterocyclic Compounds, 3-Ring; Humans; Mutation; Oxazines; Piperazines; Pyridones; Raltegravir Potassium
PubMed: 35134180
DOI: 10.1093/infdis/jiac037 -
BMC Infectious Diseases Feb 2022Global antiretroviral therapy has entered a new era. Integrase strand transfer inhibitor (INSTI) has become the first choice in acquired immunodeficiency syndrome (AIDS)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Global antiretroviral therapy has entered a new era. Integrase strand transfer inhibitor (INSTI) has become the first choice in acquired immunodeficiency syndrome (AIDS) treatment. Because INSTI has high antiviral efficacy, rapid virus inhibition, and good tolerance. However, INSTIs may increase the risk of obesity. Each INSTI has its unique impact on weight gain in patients with human immunodeficiency virus (HIV)/AIDS. This study systematically assessed different INSTIs in causing significant weight gain in HIV/AIDS patients by integrating data from relevant literature.
METHODS
PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP), and Wanfang databases were searched to find studies on the influence of different INSTIs in weight gain. Data on weight change were extracted, and a network meta-analysis was performed.
RESULTS
Eight studies reported weight changes in HIV/AIDS patients were included. Results of the network meta-analysis showed that the weight gain of HIV/AIDS patients treated with Dolutegravir (DTG) was significantly higher than that of Elvitegravir (EVG) [MD = 1.13, (0.18-2.07)]. The consistency test results showed no overall and local inconsistency, and no significant difference in the results of the direct and indirect comparison was detected (p > 0.05). The rank order of probability was DTG (79.2%) > Bictegravir (BIC) (77.9%) > Raltegravir (RAL) (33.2%) > EVG (9.7%), suggesting that DTG may be the INSTI drug that causes the most significant weight gain in HIV/AIDS patients.
CONCLUSION
According to the data analysis, among the existing INSTIs, DTG may be the drug that causes the most significant weight gain in HIV/AIDS patients, followed by BIC.
Topics: Acquired Immunodeficiency Syndrome; Body Weight; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Network Meta-Analysis; Raltegravir Potassium
PubMed: 35114968
DOI: 10.1186/s12879-022-07091-1 -
Cells Jan 2022Raltegravir (RLT) prevents the integration of HIV DNA in the nucleus, but published studies remain controversial, suggesting that it does not decrease proviral DNA....
Raltegravir (RLT) prevents the integration of HIV DNA in the nucleus, but published studies remain controversial, suggesting that it does not decrease proviral DNA. However, there are only a few studies focused on virus-targeted cells. We aimed our study on the impact of RLT inclusion on total intra-cellular viral DNA (TID) in cellular subsets and immune effects in patients with newly acquired undetectable plasmatic viral load (UVL). Six patients having UVL using an antiretroviral combination for 6 months and CD4 T-cells > 350/mL and <500/mL were selected to receive RLT for 3 months from M0 to M3. Patients had 7 sequential viro-immunological determinations from M-1 to M5. Immune phenotypes were determined by flow cytometry and TID quantification was performed using PCR assay on purified cells. TID (median values) at the initiation of RLT in CD4 T-cells was 117 copies/millions of cells, decreased to 27.5 on M3, and remained thereafter permanently under the cut-off (<10 copies/millions of cells) in 4 out of 6 patients. This was associated with an increase of CD4 and CD4 + CD28+ T-cells and a decrease of HLA-DR expression and apoptosis of CD4 T-cells. RLT inclusion led to decreases in the viral load along with positive immune reconstitution, mainly for CD4 T-cells in HIV patients.
Topics: Adult; Aged; Apoptosis; CD28 Antigens; CD4-Positive T-Lymphocytes; Cell Proliferation; DNA, Viral; Female; HIV Infections; Humans; Kinetics; Lymphocyte Count; Male; Middle Aged; Monocytes; Phenotype; Raltegravir Potassium; Viral Load
PubMed: 35053324
DOI: 10.3390/cells11020208 -
Nucleic Acids Research Feb 2022The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed...
The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14-nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14-nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14-nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3'-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14-nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12-nsp7-nsp8 (nsp12-7-8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14-nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14-nsp10, including the known SARS-CoV-2 major protease (Mpro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment.
Topics: Antiviral Agents; Coronavirus RNA-Dependent RNA Polymerase; Drug Evaluation, Preclinical; Exoribonucleases; Genome, Viral; Genomic Instability; HIV Integrase Inhibitors; Isoindoles; Multienzyme Complexes; Organoselenium Compounds; RNA, Viral; Raltegravir Potassium; SARS-CoV-2; Viral Nonstructural Proteins; Viral Regulatory and Accessory Proteins; Virus Replication
PubMed: 35037045
DOI: 10.1093/nar/gkab1303 -
AIDS Research and Therapy Jan 2022Raltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200 mg once daily (qd) for first-line...
BACKGROUND
Raltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200 mg once daily (qd) for first-line therapy is well established. We assessed efficacy and safety of RAL 1200 mg qd, as part of triple combined antiretroviral therapy (cART), for maintenance strategy.
METHODS
The QDISS trial (NCT03195452) was a 48-week multicenter, single-arm, open-label study designed to evaluate the ability of 2 NRTIs + RAL 1200 mg qd to maintain virological suppression in HIV-1 infected subjects on a stable cART with 2 NRTIs and a third agent for at least 6 months. The primary endpoint was the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24, by the FDA snapshot algorithm.
RESULTS
Of 100 participants 91% maintained viral suppression (95% CI: 83.6-95.8) at week 24 and 89% (81.2-94.4) at week 48. At week 24, there was one virological failure, without emergence of resistance-associated mutation and 10 participants had discontinued, 4 because of adverse events (AEs). Over 48 weeks, 7 AEs of grade 3-4 were reported, one possibly study-drug related (spontaneous abortion). BMI remained stable regardless of previous therapy or baseline BMI category. Over 48 weeks, total cholesterol (p = 0.023) and LDL-cholesterol (p = 0.009) decreased, lifestyle and ease subscale significantly improved (p = 0.04). The quality of life and Patients Reported Outcomes (PROs) also improved at W12 (p = 0.007).
CONCLUSION
RAL 1200 mg qd as part of a maintenance triple therapy showed a high efficacy in virologically suppressed HIV-1 infected subjects, with good safety profile and improved lipid profile and patient reported outcomes.
TRIAL REGISTRATION
Clinical trials.gov NCT03195452 and EudraCT 2016-003702-13.
Topics: Adult; HIV Infections; HIV Seropositivity; HIV-1; Humans; Quality of Life; Raltegravir Potassium; Treatment Outcome; Viral Load
PubMed: 35033092
DOI: 10.1186/s12981-022-00428-5 -
The Pediatric Infectious Disease Journal Feb 2022We present a case report of a neonate receiving raltegravir-based postnatal HIV prophylaxis after in utero dolutegravir exposure. High levels of raltegravir and...
We present a case report of a neonate receiving raltegravir-based postnatal HIV prophylaxis after in utero dolutegravir exposure. High levels of raltegravir and dolutegravir can potentially cause bilirubin toxicity as they compete for albumin binding and follow the same metabolic pathway through UGT1A1. This case suggests delaying initiation of raltegravir-based postnatal prophylaxis by 24-48 hours after in utero dolutegravir exposure.
Topics: Anti-HIV Agents; Antibiotic Prophylaxis; Female; HIV Infections; Heterocyclic Compounds, 3-Ring; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Maternal Exposure; Oxazines; Piperazines; Pregnancy; Pregnancy Complications, Infectious; Pyridones; Raltegravir Potassium
PubMed: 35017453
DOI: 10.1097/INF.0000000000003364 -
AIDS Research and Human Retroviruses Jun 2022The impact of HIV antiretroviral therapy (ART) on immune dysregulation associated with hepatitis C virus (HCV)/HIV coinfection is incompletely understood. We serially... (Randomized Controlled Trial)
Randomized Controlled Trial
The impact of HIV antiretroviral therapy (ART) on immune dysregulation associated with hepatitis C virus (HCV)/HIV coinfection is incompletely understood. We serially assessed monocyte activation (neopterin, sCD14, and sCD163) and T cell activation (HLA-DR, CD38) and immune exhaustion [program cell death protein 1 (PD1), TIGIT] in HIV/HCV-coinfected individuals who participated in a randomized trial performed in Vietnam designed to assess the hepatotoxicity of raltegravir (RAL)- versus efavirenz (EFV)-based therapy when used as first-time ART in combination with tenofovir disoproxil fumarate and emtricitabine. Baseline pre-ART values were compared with those from ART-naive HIV-monoinfected and HIV-seronegative individuals. Before ART, HIV/HCV-coinfected individuals had higher levels of neopterin, sCD14, and sCD163, and increased frequencies of CD38HLA-DR, PD1, and TIGIT CD4 and CD8 T cells compared with ART-naive HIV-monoinfected or HIV-seronegative individuals (all < .01). Most parameters did not normalize despite 72 weeks of ART. In particular sCD163 persisted at high levels. Improvement over 72 weeks in fibrosis as assessed by FibroScan correlated with reductions in plasma sCD163 and in the frequencies of T cell activation, single PD1, TIGIT, and dual PD1TIGIT CD8 T cells. A nonsignificant tendency toward more favorable effects on monocyte and T cell immune activation and on T cell exhaustion were seen with RAL-compared with EFV-based therapy. The initiation of ART in HIV/HCV-coinfected individuals is associated with incomplete improvement in monocyte and T cell immune activation and exhaustion, which was associated with some corresponding improvement in liver fibrosis.
Topics: Alkynes; Benzoxazines; Coinfection; Cyclopropanes; HIV Infections; HLA-DR Antigens; Hepacivirus; Hepatitis C; Humans; Lipopolysaccharide Receptors; Neopterin; Raltegravir Potassium; Vietnam
PubMed: 34861767
DOI: 10.1089/AID.2021.0076 -
The Pediatric Infectious Disease Journal Jan 2022Limited data exist regarding how medications for pediatric use can be developed to minimize medication errors. The integrase inhibitor raltegravir was developed for use...
BACKGROUND
Limited data exist regarding how medications for pediatric use can be developed to minimize medication errors. The integrase inhibitor raltegravir was developed for use in neonates (≥2 kg). Anticipating that neonatal administration would be performed primarily by mothers with varying degrees of health literacy, a health literate, patient-focused, iterative process was conducted to update/redesign the raltegravir granules for oral suspension pediatric kit and instructions for use (IFU) for neonatal use to be ready for regulatory submission.
METHODS
Prototypes of an updated/redesigned raltegravir IFU were systematically assessed through multi-stage, iterative testing and evaluation involving untrained lay individuals with varying levels of health literacy, healthcare professionals and health literacy experts.
RESULTS
This iterative process resulted in numerous refinements to the IFU and kit, including wording, layout, presentation, colored syringes and additional instructional steps. The revised raltegravir pediatric kit and IFU (to include neonatal dosing) were approved by the US Food and Drug Administration in 2017 and the European Union in 2018. No reported medication errors related to IFU utilization had been reported as of March 2021, reflecting >3 years of commercial use worldwide.
CONCLUSIONS
This patient-focused process produced health literate instructions for preparing and administering an antiretroviral for neonatal use with complex dosing requirements. Testing demonstrated that lay users with a range of health literacy levels were able to accurately mix, measure and administer the product. This process demonstrates how a neonatal medication can be optimized for use through collaboration between the infectious disease expert community and a manufacturer.
Topics: HIV Infections; HIV Integrase Inhibitors; Health Literacy; Health Personnel; Humans; Infant, Newborn; Medication Errors; Patient-Centered Care; Raltegravir Potassium
PubMed: 34694252
DOI: 10.1097/INF.0000000000003334 -
PloS One 2021To investigate the durability of the first integrase inhibitor-based regimen in a HIV geriatric multicentric prospective cohort and to explore the reasons of regimen...
OBJECTIVE
To investigate the durability of the first integrase inhibitor-based regimen in a HIV geriatric multicentric prospective cohort and to explore the reasons of regimen discontinuation.
DESIGN
This is an analysis conducted on the Geriatric Patients Living with HIV/AIDS (GEPPO) cohort, an Italian prospective observational multicentre cohort of people living with HIV with 65 years of age or more.
METHODS
The analysis was performed using R (version 4.0.2). The tests performed were two sided assuming a 5% significance level (Kruskal-Wallis test, Chi-squared test, log-rank test and a Cox Proportional Hazard model). The proportion of participants discontinuing the three regimens was displayed using cumulative curves.
RESULTS
Among 1531 patients enrolled between 2017 and 2019 in the GEPPO cohort, we included 822 participants in this analysis. At baseline, median age was 69.8, the immunovirological profile good, multimorbidity was present in 42.3% of participants, while 27.4% were on polypharmacy. Overall, 483, 243 and 96 participants received DTG, RAL and EVG/c respectively as first InSTI. At the end of the follow up 6.4%, 21.1% and 22.9% participants discontinued DTG, RAL and EVG/c respectively. Using a log-rank test, EVG showed a significantly lower durability than DTG (p<0.001) or RAL (p 0.05) or both, DTG and RAL (p<0.001). Among participants who discontinued their regimen we found 0 virological failure and 56.7% simplification/deprescription.
CONCLUSIONS
The three integrase inhibitors considered showed a good durability and no virological failures in geriatric patients such as those enrolled in the GEPPO cohort when used in a two or three drug regimen.
Topics: Aged; Amides; Anti-Retroviral Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Longitudinal Studies; Male; Medication Adherence; Oxazines; Piperazines; Polypharmacy; Proportional Hazards Models; Prospective Studies; Pyridones; Quinolones; Raltegravir Potassium; Treatment Outcome
PubMed: 34644336
DOI: 10.1371/journal.pone.0258533 -
Annals of Clinical and Translational... Oct 2021Human T-cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive myelopathy. A high proviral load (PVL)... (Clinical Trial)
Clinical Trial
OBJECTIVE
Human T-cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive myelopathy. A high proviral load (PVL) is one of the main risk factors for HAM/TSP. Recently, it was shown that raltegravir could inhibit cell-free and cell-to-cell transmission of HTLV-1 in vitro. Given the substantial clinical experience in human immunodeficiency virus infection and its excellent safety profile, this agent may be an attractive therapeutic option for HAM/TSP patients.
METHODS
Sixteen subjects with HAM/TSP received raltegravir 400 mg orally twice daily in an initial 6-month treatment phase, followed by a 9-month post-treatment phase. HTLV-1 PVLs were assessed using droplet digital PCR from the PBMCs every 3 months, and from the CSF at baseline, month 6, and month 15. We also evaluated the ability of raltegravir to regulate abnormal immune responses in HAM/TSP patients.
RESULTS
While a downward trend was observed in PBMC and/or CSF PVLs of some patients, raltegravir overall did not have any impact on the PVL in this HAM/TSP patient cohort. Clinically, all patients' neurological scores and objective measurements remained relatively stable, with some expected variability. Immunologic studies showed alterations in the immune profiles of a subset of patients including decreased CD4 CD25 T cells and spontaneous lymphoproliferation.
INTERPRETATION
Raltegravir was generally well tolerated in this HAM/TSP patient cohort. A subset of patients exhibited a mild decrease in PVL as well as variations in their immune profiles after taking raltegravir. These findings suggest that raltegravir may be a therapeutic option in select HAM/TSP patients.
CLINICAL TRIAL REGISTRATION NUMBER
NCT01867320.
Topics: Adult; Aged; Female; Humans; Integrase Inhibitors; Male; Middle Aged; Paraparesis, Tropical Spastic; Pilot Projects; Raltegravir Potassium; Treatment Outcome
PubMed: 34562313
DOI: 10.1002/acn3.51437