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Medicine Oct 2023Raltegravir and other third-line drugs have shown promise in improving outcomes in treatment-experienced patients. However, the efficacy and tolerability of these agents...
Raltegravir and other third-line drugs have shown promise in improving outcomes in treatment-experienced patients. However, the efficacy and tolerability of these agents vary. This study assessed real-life virologic success, long-term survival, and adverse events in patients receiving raltegravir or other third-line drugs as salvage regimens. This retrospective cohort study included adults who experienced treatment failure (human immunodeficiency syndrome-1 RNA plasma viral load >1000 copies/mL) and subsequently initiated raltegravir or other third-line drugs (darunavir/ritonavir, maraviroc, or etravirine). Propensity score matching methods were employed to account for differences at the time of switching from failing antiretroviral therapy regimens. The matched subset was analyzed using the Kaplan-Meier method and Generalized Wilcoxon tests to evaluate the probability of achieving virologic suppression (plasma viral load <50 copies/mL). Mortality rates, toxicity, treatment interruption, virologic failure, and loss to follow-up were determined using Poisson regression. One hundred and sixty-eight patients initiating salvage regimens were included, with 123 receiving raltegravir and 45 other third-line drugs. Propensity score matching resulted in a subset of 90 patients, 45 in each group. During the follow-up period, there were no significant differences observed between the groups in terms of virologic suppression (77.8% vs 82.2%, P = .73), mortality rates (4.04 vs 6.18 persons per 100 person-years [p-y]; P = .67), drug toxicity (0.00 vs 2.06 persons per 100 p-y; P = .49), treatment interruption (8.07 vs 0.00 persons per 100 p-y; P = .06), virologic failure (2.02 vs 4.12 persons per 100 p-y; P = .61), and loss of follow-up (6.05 vs 4.12 persons per 100 p-y; P = .70). Our findings indicate comparable survival and virological success rates between raltegravir and other drugs used in salvage regimens. Similar rates of drug toxicity, treatment interruption, virologic failure, and loss of follow-up were also observed. These results suggest that raltegravir may be a viable option for salvage therapy, demonstrating outcomes comparable to other third-line drugs in real life.
Topics: Adult; Humans; Raltegravir Potassium; Anti-HIV Agents; Retrospective Studies; Salvage Therapy; Darunavir; HIV Infections; Drug-Related Side Effects and Adverse Reactions; Viral Load; Treatment Outcome
PubMed: 37800823
DOI: 10.1097/MD.0000000000035407 -
CPT: Pharmacometrics & Systems... Sep 2019Raltegravir readily crosses the placenta to the fetus with maternal use during pregnancy. After birth, neonatal raltegravir elimination is highly variable and often...
Raltegravir readily crosses the placenta to the fetus with maternal use during pregnancy. After birth, neonatal raltegravir elimination is highly variable and often extremely prolonged, with some neonates demonstrating rising profiles after birth despite removal from the source of extrinsic raltegravir. To establish an appropriate dosing regimen, an integrated maternal-neonatal pharmacokinetics model was built to predict raltegravir plasma concentrations in neonates with in utero raltegravir exposure. Postnatal age and body weight were used as structural covariates. The model predicted rising or decreasing neonatal elimination profiles based on the time of maternal drug administration relative to time of birth and degree of in utero drug disposition into the central and peripheral compartments. Based on this model, it is recommended to delay the first oral dose of raltegravir until 1-2 days of age in those neonates born to mothers who received raltegravir during pregnancy, labor, and delivery.
Topics: Anti-HIV Agents; Case-Control Studies; Drug Dosage Calculations; Female; HIV Infections; Humans; Infant, Newborn; Maternal-Fetal Exchange; Models, Theoretical; Pregnancy; Raltegravir Potassium
PubMed: 31215170
DOI: 10.1002/psp4.12443 -
AIDS Reviews Apr 2021Many innovations, such as long-acting agents, new delivery modalities (injectable and nanoparticles), and novel paradigms (immunotherapy or dual therapy), have been... (Review)
Review
Many innovations, such as long-acting agents, new delivery modalities (injectable and nanoparticles), and novel paradigms (immunotherapy or dual therapy), have been introduced to facilitate the administration of antiretroviral treatment (ART) to patients infected with HIV and improve their adherence and quality of life without altering the drugs' effectiveness. Studies have investigated the use of intermittent treatment, especially weekends-off ART in HIV-suppressed patients. In this review, we analyzed data concerning intermittent ART to help determine if this strategy is reasonable for the management of patients living with HIV. The results of early studies, in 2007-2015, were encouraging, but the studies were flawed because of the small number of patients included, the absence of a control arm, and random designs with variable patterns of ART administration. From 2016, studies have included more patients, and some are prospective, randomized controlled studies. While non-nucleoside reverse transcriptase inhibitors have been most studied, treatment with integrase inhibitors also has been reported, with the findings that viral resistance did not appear when treatment failed with dolutegravir but not with raltegravir. The most recent study, QUATUOR, found that a 4-day on, 3-day off pattern was non-inferior to the continuous pattern (7 days on). Better-quality studies with long-term follow-up (96 weeks or more) are needed to determine the validity of intermittent treatment and the optimal regimens and monitoring to be used in the management of viro-logically suppressed patients living with HIV.
Topics: Anti-HIV Agents; Anti-Retroviral Agents; HIV Infections; Humans; Prospective Studies; Quality of Life; Raltegravir Potassium; Viral Load
PubMed: 33844679
DOI: 10.24875/AIDSRev.20000108 -
Antimicrobial Agents and Chemotherapy Sep 2020A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. The RalFe ANRS160 study was a...
A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. The RalFe ANRS160 study was a nonrandomized, open-label, multicenter trial enrolling HIV-infected pregnant women receiving a combined antiretroviral regimen containing 400 mg raltegravir twice daily. Biological samples were collected during the third trimester of pregnancy (between 30 and 37 weeks of gestational age) and at postpartum (4 to 6 weeks after delivery). A population pharmacokinetic model was developed with Monolix software. A total of 360 plasma samples were collected from 43 women during pregnancy and postpartum. The unbound raltegravir was described by a one-compartment model with a transit compartment with first-order absorption, evolving to bound raltegravir (by a linear binding to albumin) or metabolism to RAL-glucuronide or to a first-order elimination, with a circadian rhythm. During pregnancy, the absorption was decreased and delayed and the raltegravir elimination clearance and glucuronidation increased by 37%. Median total and unbound area under the curve from 0 to 12 h significantly decreased by 36% and 27% during pregnancy. Median total trough concentration () decreased significantly in the evening (28%); however, the median total in the morning, unbound in the morning, and unbound in the evening showed a nonsignificant decrease of 16%, 1%, and 15%, respectively, during pregnancy compared to the postpartum period. This is the first study reporting the pharmacokinetics of unbound raltegravir during pregnancy. As unbound did not significantly decrease during the third trimester, the pregnancy effect on raltegravir unbound concentrations was not considered clinically relevant. (This study has been registered at ClinicalTrials.gov under identifier NCT02099474.).
Topics: Anti-HIV Agents; Female; HIV Infections; Humans; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Raltegravir Potassium
PubMed: 32661003
DOI: 10.1128/AAC.00759-20 -
Journal of Acquired Immune Deficiency... Aug 2019Dolutegravir, an integrase strand transfer inhibitor (InSTI), is a major antiretroviral agent for HIV infection. Its use is promising, especially in low- and...
BACKGROUND
Dolutegravir, an integrase strand transfer inhibitor (InSTI), is a major antiretroviral agent for HIV infection. Its use is promising, especially in low- and middle-income countries, because of a high resistance barrier and a good safety profile. Very recently, a World Health Organization safety signal has been raised regarding neural tube defects after the first-trimester exposure. Furthermore, to date, the experience is limited regarding the use of the other InSTI drugs (raltegravir and elvitegravir) during pregnancy. Our objective is to analyze the safety of InSTI drugs in pregnant women.
SETTING
Nation-wide database cohort analysis.
METHODS
We evaluated the risk of major birth defects according to EUROCAT classification in pregnant women, which had had a first-trimester exposure to dolutegravir, raltegravir, or elvitegravir.
RESULTS
We found a major birth defect rate of 1.9% in the general population between 2012 and 2016. As InSTI drugs are not used as first-line therapy in pregnant women, we found a very low exposure in this population. Among 49, 240, and 70 pregnancy outcomes exposed to dolutegravir, raltegravir, and elvitegravir, respectively, during the first trimester, there were 2, 3, and 1 major birth defects, respectively. There was no case of neural tube defect.
CONCLUSIONS
Drug exposure to InSTI is limited in our nation-wide database. Nevertheless, our data do not support a pharmacovigilance signal on neural tube defects in women exposed to dolutegravir, raltegravir or elvitegravir during pregnancy. Owing to a small number of pregnancy outcomes, these results need to be confirmed with further studies.
Topics: Adult; Anti-Retroviral Agents; Cohort Studies; Congenital Abnormalities; Drug Resistance, Viral; Female; France; HIV Infections; HIV Integrase Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Neural Tube Defects; Oxazines; Pharmacovigilance; Piperazines; Pregnancy; Pyridones; Quinolones; Raltegravir Potassium; Treatment Outcome; Young Adult
PubMed: 31021990
DOI: 10.1097/QAI.0000000000002065 -
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 -
The Lancet. HIV Jun 2024Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of three antiretroviral therapy regimens for treatment-naive African adults living with HIV-2 (FIT-2): a pilot, phase 2, non-comparative, open-label, randomised controlled trial.
BACKGROUND
Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches.
METHODS
This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per μL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants.
FINDINGS
Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47-66) in the ritonavir-boosted lopinavir group and 59% (49-68) in the raltegravir group.
INTERPRETATION
The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen.
FUNDING
ANRS MIE.
Topics: Humans; HIV Infections; Adult; Male; Female; HIV-2; Tenofovir; Pilot Projects; CD4 Lymphocyte Count; Emtricitabine; Anti-HIV Agents; Treatment Outcome; Ritonavir; Lopinavir; Raltegravir Potassium; Lamivudine; Viral Load; Antiretroviral Therapy, Highly Active; Middle Aged; Zidovudine; Drug Therapy, Combination; HIV-1
PubMed: 38740027
DOI: 10.1016/S2352-3018(24)00085-7 -
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 -
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 -
Journal of Acquired Immune Deficiency... Dec 2022Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081 compared antepartum changes in weight and body mass index (BMI) in pregnant women initiating raltegravir- or efavirenz-based combined antiretroviral therapy (cART) and examined associations between rates of weight gain and APOs.
SETTING
NICHD P1081 enrolled antiretroviral-naive pregnant women living with HIV in the second and third trimester in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States.
METHODS
Two hundred eighty-one women enrolled between 20 and 31 gestational weeks were randomized to raltegravir- or efavirenz-based cART and followed for ≥4 weeks. A low rate of weight gain was defined as <0.18 kg/wk and high as >0.59 kg/wk. We compared weight gain and BMI increase between treatment arms using Kruskal-Wallis tests. Logistic regression was used to investigate the association between weight gain and APOs.
RESULTS
Raltegravir-based cART was associated with significantly higher antepartum weight gain (median 0.36 kg/wk versus 0.29 kg/wk, P = 0.01) and BMI increase (median 0.14 kg/m 2 /wk versus 0.11 kg/m 2 /wk, P = 0.01) compared with efavirenz-based treatment. Women on raltegravir had less low weight gain (18% versus 36%) and more high weight gain (21% versus 12%) ( P = 0.001). Women with low weight gain were more likely than those with normal weight gain to have small for gestational age infants or a composite of APOs.
CONCLUSIONS
A raltegravir-based antiretroviral regimen was associated with significantly higher antepartum rate of weight gain and BMI increase compared with efavirenz-based treatment in antiretroviral-naive pregnant women.
Topics: Female; Pregnancy; Humans; United States; Raltegravir Potassium; National Institute of Child Health and Human Development (U.S.); HIV Infections; Integrase Inhibitors; Weight Gain
PubMed: 36049477
DOI: 10.1097/QAI.0000000000003081