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Viruses Nov 2022Integrase Strand Transfer Inhibitors (INSTIs) are currently used as the most effective therapy in the treatment of human immunodeficiency virus (HIV) infections.... (Review)
Review
Integrase Strand Transfer Inhibitors (INSTIs) are currently used as the most effective therapy in the treatment of human immunodeficiency virus (HIV) infections. Raltegravir (RAL) and Elvitegravir (EVG), the first generation of INSTIs used successfully in clinical treatment, are susceptible to the emergence of viral resistance and have a high rate of cross-resistance. To counteract these resistant mutants, second-generation INSTI drugs have been developed: Dolutegravir (DTG), Cabotegravir (CAB), and Bictegravir (BIC). However, HIV is also able to develop resistance mechanisms against the second-generation of INSTIs. This review describes the mode of action of INSTIs and then summarizes and evaluates some typical resistance mutations, such as substitution and insertion mutations. The role of unintegrated viral DNA is also discussed as a new pathway involved in conferring resistance to INSTIs. This allows us to have a more detailed understanding of HIV resistance to these inhibitors, which may contribute to the development of new INSTIs in the future.
Topics: Humans; HIV Integrase Inhibitors; Raltegravir Potassium; HIV Infections; Heterocyclic Compounds, 3-Ring; Mutation; Integrases; HIV Integrase; Drug Resistance, Viral
PubMed: 36560595
DOI: 10.3390/v14122591 -
The New England Journal of Medicine Sep 2022Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as... (Comparative Study)
Comparative Study
BACKGROUND
Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited.
METHODS
We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results.
RESULTS
Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar.
CONCLUSIONS
Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Cobicistat; Cohort Studies; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Infant, Newborn; Oxazines; Piperazines; Pregnancy; Premature Birth; Pyridones; Quinolones; Raltegravir Potassium; Rilpivirine; Ritonavir; United States
PubMed: 36053505
DOI: 10.1056/NEJMoa2200600 -
Journal of the International AIDS... Nov 2022Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in... (Review)
Review
INTRODUCTION
Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0-19 years.
METHODS
Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009-March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted.
RESULTS AND DISCUSSION
In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0-50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug.
CONCLUSIONS
These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes.
Topics: Child; Adolescent; Humans; Raltegravir Potassium; HIV Integrase Inhibitors; HIV Infections; Heterocyclic Compounds, 3-Ring
PubMed: 36377082
DOI: 10.1002/jia2.25970 -
Nephrology, Dialysis, Transplantation :... Mar 2017Chronic kidney disease (CKD) is a critical comorbidity for patients living with HIV, with an estimated prevalence between 2.4 and 17%. Such patients are increasingly... (Review)
Review
Chronic kidney disease (CKD) is a critical comorbidity for patients living with HIV, with an estimated prevalence between 2.4 and 17%. Such patients are increasingly affected by diseases associated with ageing, including cardiovascular disease and CKD, and the prevalence of risk factors such as smoking and dyslipidaemia is increased in this population. Proteinuria is also now recognized as a common finding in individuals living with HIV. While combination antiretroviral (ARV) treatments reduce CKD in the HIV-infected population overall, some ARV drugs have been shown to be nephrotoxic and associated with worsening renal function. Over the last few years, several highly efficacious new ARV agents have been introduced. This brief review will look at the novel agents dolutegravir, raltegravir, elvitegravir, cobicistat, tenofovir alafenamide fumarate and atazanavir, all of which have been licensed relatively recently, and describe issues relevant to renal function, creatinine handling and potential nephrotoxicity. Given the prevalence of CKD, the wide range of possible interactions between HIV, ARV therapy, CKD and its treatments, nephrologists need to be aware of these newer agents and their possible effect on kidneys.
Topics: Adenine; Alanine; Anti-HIV Agents; Atazanavir Sulfate; Cobicistat; Creatinine; Disease Progression; HIV Infections; Heterocyclic Compounds, 3-Ring; Humans; Oxazines; Piperazines; Proteinuria; Pyridones; Quinolones; Raltegravir Potassium; Renal Insufficiency, Chronic; Tenofovir
PubMed: 27190354
DOI: 10.1093/ndt/gfw064 -
Life Sciences Nov 2022To assess the potential direct effects of the integrase strand-transfer inhibitors (INsTIs) dolutegravir, bictegravir, and raltegravir, drugs used as treatment for...
AIMS
To assess the potential direct effects of the integrase strand-transfer inhibitors (INsTIs) dolutegravir, bictegravir, and raltegravir, drugs used as treatment for people living with human immunodeficiency virus (PLWH), on human adipose cells.
MAIN METHODS
Drugs were added to the differentiation medium of human Simpson-Golabi-Behmel syndrome (SGBS) adipose cells and morphological adipogenesis was monitored for 10 days. Also, adipocytes were exposed to drugs following differentiation (day 14). The gene expression levels of selected adipogenesis markers, adipocyte metabolism markers, adipokines, and cytokines were determined by quantitative-reverse transcription polymerase-chain reaction. The release of adiponectin and leptin into the culture medium was measured using specific enzyme-linked immunosorbent assay, and release of interleukin-6 and chemokine (CC motif) ligand-2 using Multiplex assays.
KEY FINDINGS
Overall morphological adipogenesis was unaltered by INsTIs. The expression of adipogenesis marker genes (peroxisome proliferator-activated receptor-Ɣ and lipoprotein lipase) was slightly reduced in dolutegravir-treated differentiating adipocytes. Bictegravir repressed gene expression and the release of pro-inflammatory cytokines in differentiating adipocytes. Dolutegravir and raltegravir increased interleukin-6 gene expression, but only dolutegravir increased interleukin-6 release. Dolutegravir repressed adiponectin expression and release in differentiating adipocytes and had a similar but milder effect on leptin. Drug treatment of mature adipocytes reduced adiponectin gene expression in response to dolutegravir.
SIGNIFICANCE
The INsTIs studied do not have a significant effect on human adipose cell differentiation but exert distinct effects on gene expression and secretion of adipokines and cytokines. These findings will help understand and manage the effects of INsTI-containing treatments on body weight and metabolic dysregulation in PLWH.
Topics: Adipocytes; Adipokines; Adiponectin; Amides; Cytokines; Heterocyclic Compounds, 3-Ring; Humans; Inflammation; Integrases; Interleukin-6; Leptin; Ligands; Lipoprotein Lipase; Oxazines; Peroxisome Proliferator-Activated Receptors; Piperazines; Pyridones; Raltegravir Potassium
PubMed: 36096241
DOI: 10.1016/j.lfs.2022.120948 -
AIDS (London, England) Aug 2017To compare the frequency and risk factors of toxicity-related treatment discontinuations between raltegravir and dolutegravir.
OBJECTIVE
To compare the frequency and risk factors of toxicity-related treatment discontinuations between raltegravir and dolutegravir.
DESIGN
Prospective cohort study.
METHODS
All antiretroviral therapy (ART)-naïve and ART-experienced HIV-infected individuals from the Swiss HIV Cohort Study who initiated raltegravir or dolutegravir between 2006 and 2015 were investigated concerning treatment modification within the first year.
RESULTS
Of 4041 patients initiating ART containing raltegravir (n = 2091) or dolutegravir (n = 1950), 568 patients discontinued ART during the first year, corresponding to a rate of 15.5 [95% confidence interval (CI) 14.5-16.9] discontinuations per 100 patient-years. Only 10 patients on raltegravir (0.5%) and two patients on dolutegravir (0.1%) demonstrated virologic failure. The main reason for ART discontinuation was convenience expressed as patient's wish, physician's decision, or treatment simplification (n = 302). Toxicity occurred in 4.3% of patients treated with raltegravir and 3.6% with dolutegravir, respectively. In multivariable analysis, the only independent risk factor for discontinuing ART because of toxicity was female sex (hazard ratio 1.98, 95% CI 1.45-2.71, P < 0.001).Neuropsychiatric complaints were the most commonly reported toxic adverse events and more frequent in the dolutegravir (n = 33, 1.7%) compared with the raltegravir group (n = 13, 0.6%). Risk of discontinuation for neurotoxicity was lower for raltegravir than for dolutegravir in multivariable analysis (hazard ratio 0.46, 95% CI 0.22-0.96, P = 0.037).
CONCLUSION
In this, large cohort raltegravir and dolutegravir-containing regimen demonstrated a high virologic efficacy. Drug toxicity was infrequent and discontinuation because of neuropsychiatric events within the first year of treatment was only marginal higher with dolutegravir compared with raltegravir. However, monitoring of neurotoxic side-effects of dolutegravir is important.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Heterocyclic Compounds, 3-Ring; Humans; Male; Mental Disorders; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Raltegravir Potassium; Switzerland; Withholding Treatment; Young Adult
PubMed: 28692533
DOI: 10.1097/QAD.0000000000001590 -
Clinical Pharmacokinetics Sep 2020Bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir are members of the latest class of antiretrovirals available to treat human immunodeficiency virus... (Review)
Review
Bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir are members of the latest class of antiretrovirals available to treat human immunodeficiency virus (HIV) infection, the integrase strand transfer inhibitors. Integrase strand transfer inhibitors are potent inhibitors of the HIV integrase enzyme with IC values in the low nanogram per milliliter range and they retain antiviral activity against strains of HIV with acquired resistance to other classes of antiretrovirals. Each of the integrase strand transfer inhibitors have unique pharmacokinetic/pharmacodynamic properties, influencing their role in clinical use in specific subsets of patients. Cabotegravir, approved for use in Canada but not yet by the US Food and Drug Administration, is formulated in both oral and intramuscular formulations; the latter of which has shown efficacy as a long-acting extended-release formulation. Cabotegravir, raltegravir, and dolutegravir have minimal drug-drug interaction profiles, as their metabolism has minimal cytochrome P450 involvement. Conversely, elvitegravir metabolism occurs primarily via cytochrome P450 3A4 and requires pharmacokinetic boosting to achieve systemic exposures amenable to once-daily dosing. Bictegravir metabolism has similar contributions from both cytochrome P450 3A4 and uridine 5'-diphospho-glucuronosyltransferase 1A1. Bictegravir, dolutegravir, and raltegravir are recommended components of initial regimens for most people with HIV in the US adult and adolescent HIV treatment guidelines. This review summarizes and compares the pharmacokinetics and pharmacodynamics of the integrase strand transfer inhibitor agents, and describes specific pharmacokinetic considerations for persons with hepatic impairment, renal dysfunction, pregnancy, and co-infections.
Topics: Adolescent; Adult; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Pregnancy; Pyridones; Raltegravir Potassium
PubMed: 32462541
DOI: 10.1007/s40262-020-00898-8 -
Journal of the International AIDS... Jul 2020As integrase inhibitors become available in low- and middle-income countries (LMICs), they offer the potential to expand extremely limited treatment options available to...
INTRODUCTION
As integrase inhibitors become available in low- and middle-income countries (LMICs), they offer the potential to expand extremely limited treatment options available to children and adolescents. In LMICs, only small numbers have used raltegravir, primarily as part of third-line regimens. Using data from the IeDEA global consortium, we aimed to describe the characteristics of children on raltegravir-containing regimens and their outcomes.
METHODS
We included data from 1994 to 2017 from children (age <18 years), from East and Southern Africa, Asia and South America, who received cART regimens containing raltegravir for ≥90 days. We describe their characteristics at raltegravir start, and their immunological and virological outcomes.
RESULTS AND DISCUSSION
In total, 62 children were included, with median age at raltegravir initiation of 14.3 years (IQR 11.2 to 15.8) and median CD4 count of 276 cells/µL (IQR 68 to 494). Among 40 (65%) with drug resistance testing prior to raltegravir, 71% were resistant to at least one protease inhibitor (PI), and 32% had high-level resistance to at least one drug class. Most (n = 50; 81%) received raltegravir as part of third-line cART following PI-based regimens, and were on regimens containing four or more drugs (n = 47, 76%). By database closure, median duration on raltegravir was 2.0 years (IQR 0.8 to 3.0), 1 (1.6%) patient had died, 6 (9.7%) were lost to follow-up and 21 (34%) had discontinued raltegravir. Among 15 patients reporting reasons for stopping raltegravir, six discontinued because it was no longer available. Within one year of starting raltegravir, among 53 patients with VL measures, 40 (75%) had VL < 1000 copies/mL, and among 54 with a reported CD4 count, 45 (83%) and 36 (67%) were ≥350 and ≥500 cells/µL, respectively, with median CD4 count increasing to 517.5 cells/µL (IQR 288 to 810).
CONCLUSIONS
Among children in LMICs, the initial use of raltegravir has been primarily for post PI-based cART. We found good virological and immunological outcomes despite frequent prior triple-class failure and high levels of drug resistance. Both access to raltegravir and long-term adherence to regimens with large pill-burdens remain challenging. Policies which promote earlier access to new drugs and simplify daily regimens for children and adolescents in LMICs are needed.
Topics: Adolescent; Africa, Southern; Asia; CD4 Lymphocyte Count; Child; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Poverty; Raltegravir Potassium; South America; Treatment Outcome; Viral Load
PubMed: 32722897
DOI: 10.1002/jia2.25580 -
Journal of Acquired Immune Deficiency... Dec 2014We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum. (Clinical Trial)
Clinical Trial
OBJECTIVE
We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum.
METHODS
International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is an ongoing prospective study of antiretroviral PK during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady-state 12-hour PK profiles performed during pregnancy and at 6- to 12-week postpartum. Targets were trough concentration above 0.035 μg/mL, the estimated 10th percentile in nonpregnant historical controls.
RESULTS
Median raltegravir area under the curve was 6.6 μg·h/mL for second trimester (n = 16), 5.4 μg·h/mL for third trimester (n = 41), and 11.6 μg·h/mL postpartum (n = 38) (P = 0.03 postpartum vs second trimester, P = 0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester, and postpartum subjects, respectively, with wide variability (<0.010-0.917 μg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were <400 copies per milliliter in 92% of women at delivery. Adverse events included elevated liver transaminases in 1 woman and vomiting in 1. All infants with known status are HIV uninfected.
CONCLUSIONS
Median raltegravir area under the curve was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.
Topics: Adult; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimesters; Pyrrolidinones; Raltegravir Potassium; Young Adult
PubMed: 25162818
DOI: 10.1097/QAI.0000000000000318 -
International Journal of Nanomedicine 2021Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV),...
INTRODUCTION
Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV), raltegravir (RAL), and dapivirine (DAP) have been developed to prevent and treat HIV-1 via different mechanisms of action. In parallel, a promising biological candidate, griffithsin (GRFT), has demonstrated outstanding preclinical safety and potency against HIV-1. While ARV co-administration has been shown to enhance virus inhibition, synergistic interactions between ARVs and the oxidation-resistant variant of GRFT (Q-GRFT) have not yet been explored. Here, we co-administered Q-GRFT with TFV, RAL, and DAP, in free and encapsulated forms, to identify unique protein-drug synergies.
METHODS
Nanoparticles (NPs) were synthesized using a single or double-emulsion technique and release from each formulation was assessed in simulated vaginal fluid. Next, each ARV, in free and encapsulated forms, was co-administered with Q-GRFT or Q-GRFT NPs to evaluate the impact of co-administration in HIV-1 pseudovirus assays, and the combination indices were calculated to identify synergistic interactions. Using the most synergistic formulations, we investigated the effect of agent incorporation in NP-fiber composites on release properties. Finally, NP safety was assessed in vitro using MTT assay.
RESULTS
All active agents were encapsulated in NPs with desirable encapsulation efficiency (15-100%), providing ~20% release over 2 weeks. The co-administration of free Q-GRFT with each free ARV resulted in strong synergistic interactions, relative to each agent alone. Similarly, Q-GRFT NP and ARV NP co-administration resulted in synergy across all formulations, with the most potent interactions between encapsulated Q-GRFT and DAP. Furthermore, the incorporation of Q-GRFT and DAP in NP-fiber composites resulted in burst release of DAP and Q-GRFT with a second phase of Q-GRFT release. Finally, all NP formulations exhibited safety in vitro.
CONCLUSIONS
This work suggests that Q-GRFT and ARV co-administration in free or encapsulated forms may improve efficacy in achieving prophylaxis.
Topics: Anti-HIV Agents; Anti-Retroviral Agents; Cell Death; Cell Line; Drug Compounding; Drug Liberation; Drug Synergism; Female; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Lectins; Nanoparticles; Particle Size; Plant Lectins; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrimidines; Raltegravir Potassium; Recombinant Proteins; Tenofovir
PubMed: 33623382
DOI: 10.2147/IJN.S287310