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British Journal of Clinical Pharmacology Jan 2020AIDS Clinical Trials Group study A5334s evaluated the pharmacokinetics of raltegravir before and during combined administration of ombitasvir, paritaprevir/ritonavir,... (Clinical Trial)
Clinical Trial
Raltegravir pharmacokinetics before and during treatment with ombitasvir, paritaprevir/ritonavir plus dasabuvir in adults with human immunodeficiency virus-1 and hepatitis C virus coinfection: AIDS Clinical Trials Group sub-study A5334s.
AIMS
AIDS Clinical Trials Group study A5334s evaluated the pharmacokinetics of raltegravir before and during combined administration of ombitasvir, paritaprevir/ritonavir, plus dasabuvir (OBV/PTV/r + DSV) and weight-based ribavirin in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected adults. The pharmacokinetics of OBV/PTV/r + DSV during raltegravir coadministration were also characterized.
METHODS
Adults living with HIV/HCV coinfection receiving steady-state raltegravir (400 mg twice daily) with 2 nucleos(t)ide analogues were enrolled. Pharmacokinetics of raltegravir were assessed prior to HCV therapy, and 4 weeks later following initiation of OBV/PTV/r (25/150/100 mg) once daily + DSV (250 mg) twice daily. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare the following: raltegravir pharmacokinetics with HCV therapy (week 4) vs before HCV therapy (week 0); OBV/PTV/r and DSV pharmacokinetics vs historical healthy controls; raltegravir pharmacokinetics at week 0 vs historical control adults living with HIV.
RESULTS
Eight of 11 participants had decreased raltegravir exposures after initiation of HCV therapy. The GMRs (90% CI) for maximum concentration and area under the concentration-time curve of raltegravir with vs without HCV therapy were 0.68 (0.38-1.19) and 0.82 (0.58-1.17), respectively. Comparing OBV/PTV/r pharmacokinetics in healthy controls, A5334s study participants demonstrated generally lower maximum concentration and area under the concentration-time curve values by 41-82% and 4-73%, respectively. Raltegravir exposures tended to be higher in A5334s study participants compared to adults living with HIV.
CONCLUSIONS
The majority of participants' plasma raltegravir exposures were lower after initiation of HCV therapy in coinfected adults; however, confidence intervals were wide.
Topics: 2-Naphthylamine; Acquired Immunodeficiency Syndrome; Adult; Anilides; Antiviral Agents; Coinfection; Cyclopropanes; Drug Therapy, Combination; HIV-1; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Raltegravir Potassium; Ritonavir; Sulfonamides; Uracil; Valine
PubMed: 31656054
DOI: 10.1111/bcp.14148 -
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 -
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 -
HIV Medicine Feb 2021
Topics: Anti-HIV Agents; Emtricitabine; HIV Infections; Humans; Post-Exposure Prophylaxis; Pre-Exposure Prophylaxis; Raltegravir Potassium; Tenofovir
PubMed: 33063431
DOI: 10.1111/hiv.12938 -
The New Microbiologica Oct 2017Integrase strand transfer inhibitors (INSTIs) are the preferred third agent in first-line antiretroviral therapies. Raltegravir (RAL) was the first INSTI to be approved... (Review)
Review
Integrase strand transfer inhibitors (INSTIs) are the preferred third agent in first-line antiretroviral therapies. Raltegravir (RAL) was the first INSTI to be approved and used in naïve and experienced patients. Due to its good tolerability and low side effects, RAL has been largely used also in hepatitis coinfected patients. Many years of experience in RAL use now allow literature evidence to be gathered on its safety in HIV/HCV-co-infected patients pre, during and post direct acting agents (DAA) treatment, at all possible stages. In both clinical trials and published case series, RAL has been well tolerated in patients harboring HCV co-infection and also in cirrhotic patients with mild hepatic impairment. Literature data show no major interactions or the need for dose adjustments with any of the DAA currently in use for HCV treatment, or with ribavirine. Hence, RAL can be safely administered during HCV treatment with DAA and may be used as a "temporary" regimen in patients who do not present major integrase-inhibitor mutations. Moreover, its characteristics are also favorable in case of orthotropic liver transplantation, both for the evidence of hepatic safety and for possible co-administration with immunosuppressant agents.
Topics: Coinfection; HIV Infections; HIV Integrase Inhibitors; HIV-1; Hepacivirus; Hepatitis C; Humans; Raltegravir Potassium; Time; Treatment Outcome
PubMed: 28994443
DOI: No ID Found -
The Lancet. HIV Dec 2018
Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; HIV Infections; HIV-1; Humans; Raltegravir Potassium
PubMed: 30527322
DOI: 10.1016/S2352-3018(18)30332-1 -
The Annals of Pharmacotherapy Jan 2010To review the pharmacology, efficacy, safety, and resistance profiles of the integrase inhibitors raltegravir and elvitegravir. (Review)
Review
OBJECTIVE
To review the pharmacology, efficacy, safety, and resistance profiles of the integrase inhibitors raltegravir and elvitegravir.
DATA SOURCES
A search of PubMed was conducted (2000-August 2009) using the following key words: raltegravir, MK-0518, elvitegravir, and GS-9137. Articles were evaluated for content and bibliographies were reviewed. Data available exclusively in abstracts from major infectious diseases and HIV conferences were also evaluated for inclusion.
STUDY SELECTION AND DATA EXTRACTION
Studies included were in vitro investigations; Phase 1, 2, and 3 clinical trials; retrospective analyses including case reports; and pharmacokinetic and pharmacodynamic evaluations.
DATA SYNTHESIS
Raltegravir is currently approved by the Food and Drug Administration for the management of HIV-1 infection in treatment-naïve or-experienced adults as part of an optimized combination regimen. When combined with other active agents, it has demonstrated similar virologic efficacy after 96 weeks to the combination of efavirenz, tenofovir, and emtricitabine in treatment-naïve patients. Unlike many antiretrovirals, raltegravir does not enter cytochrome P450 metabolism and instead undergoes glucuronidation. Elvitegravir is in the late stages of clinical development. A Phase 2 study has demonstrated virologic efficacy in treatment-experienced patients comparable to protease inhibitor-based regimens after 24 weeks. Boosting of elvitegravir through inhibition of CYP3A4 metabolism has been investigated and suggests a pharmacokinetic profile conducive to once-daily-dosing. Phase 2 and 3 clinical trials evaluating boosted elvitegravir are in process. The Phase 2 trial combines elvitegravir with a non-ritonavir boosting agent plus tenofovir/emtricitabine given once daily as a "quad-pill" formulation. The Phase 3 trial compares once-daily ritonavir-boosted elvitegravir with twice-daily raltegravir, each given with an optimized background regimen. Both integrase inhibitors are well tolerated and raltegravir has few drug-drug interactions. Resistance mutations have been identified in patients experiencing virologic failure and cross resistance between raltegravir and elvitegravir has been confirmed.
CONCLUSIONS
The integrase inhibitors provide a novel target for antiretroviral therapy and provide an option for patients harboring resistance to other antiretrovirals.
Topics: Anti-HIV Agents; HIV Infections; Humans; Integrase Inhibitors; Pyrrolidinones; Quinolones; Raltegravir Potassium
PubMed: 20040702
DOI: 10.1345/aph.1M309 -
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 -
Investigational New Drugs Apr 2017Background The risk of pharmacokinetic interaction is important in HIV-infected cancer patients receiving concomitantly highly active antiretroviral therapy (HAART) and...
Background The risk of pharmacokinetic interaction is important in HIV-infected cancer patients receiving concomitantly highly active antiretroviral therapy (HAART) and anti-cancer systemic treatments. We aimed to evaluate the safety profile of raltegravir-based HAART in cancer patients receiving multi-kinase inhibitors (MKIs). Patients and Methods We conducted a retrospective medical record review of adult, HIV-infected cancer patients treated in our institutions from January 2010 to December 2015. Patients eligible for the present analysis were those receiving a raltegravir-based HAART at the time of the initiation of a MKI for the treatment of advanced solid tumors. Treatment-related toxicity, virological outcomes and pharmacokinetic profile of MKIs were examined. Results Twelve patients (7 males, median age 55 years) were identified. Seven had sarcoma/GIST, 3 had hepatocellular carcinoma, one had pancreatic neuroendocrine tumor, and one had NSCLC. Patients received the following MKIs: imatinib (n = 3), sorafenib (n = 3), pazopanib (n = 3), sunitinib (n = 2) and erlotinib (n = 1). The mean CD4+ count at baseline was 929 cells/mm, and 860 cells/mm after completion of MKI treatment. In all patients, HIV viral loads remained below the limit of detection (40 copies/ mm) during the whole MKI treatment. No virological failure occurred. No unexpected or serious adverse event related either to raltegravir-based HAART or to MKIs was observed. The trough plasma concentrations of MKIs were assessed in 8 patients, and were found normal in all but one case (not related to raltegravir-based HAART). Conclusions The present data represent the first documentation of the concomitant use of raltegravir-containing HAART and MKIs in HIV-infected adult patients with advanced non-AIDS defining malignancies, with a reassuring safety profile.
Topics: Adult; Aged; Anti-HIV Agents; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Drug Interactions; Female; HIV Infections; Humans; Male; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Raltegravir Potassium; Viral Load
PubMed: 27838867
DOI: 10.1007/s10637-016-0405-0 -
The Lancet. HIV May 2020Although antiretroviral regimens containing integrase inhibitors rapidly suppress HIV viral load in non-pregnant adults, few published data from randomised controlled... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Although antiretroviral regimens containing integrase inhibitors rapidly suppress HIV viral load in non-pregnant adults, few published data from randomised controlled trials have compared the safety and efficacy of any integrase inhibitor to efavirenz when initiated during pregnancy. We compared safety and efficacy of antiretroviral therapy with either raltegravir or efavirenz in late pregnancy.
METHODS
An open-label, randomised controlled trial was done at 19 hospitals and clinics in Argentina, Brazil, South Africa, Tanzania, Thailand, and the USA. Antiretroviral-naive pregnant women (20-<37 weeks gestation) living with HIV were assigned to antiretroviral regimens containing either raltegravir (400 mg twice daily) or efavirenz (600 mg each night) plus lamivudine 150 mg and zidovudine 300 mg twice daily (or approved alternative backbone regimen), using a web-based, permuted-block randomisation stratified by gestational age and backbone regimen. The primary efficacy outcome was plasma HIV viral load below 200 copies per mL at (or near) delivery. The primary efficacy analysis included all women with a viral load measurement at (or near) delivery who had viral load of at least 200 copies per mL before treatment and no genotypic resistance to any study drugs; secondary analyses eliminated these exclusion criteria. The primary safety analyses included all women who received study drug, and their infants. This trial is registered with Clinicaltrials.gov, number NCT01618305.
FINDINGS
From Sep 5, 2013, to Dec 11, 2018, 408 women were enrolled (206 raltegravir, 202 efavirenz) and 394 delivered on-study (200 raltegravir, 194 efavirenz); 307 were included in the primary efficacy analysis (153 raltegravir, 154 efavirenz). 144 (94%) women in the raltegravir group and 129 (84%) in the efavirenz group met the primary efficacy outcome (absolute difference 10%, 95% CI 3-18; p=0·0015); the difference primarily occurred among women enrolling later in pregnancy (interaction p=0·040). Frequencies of severe or life-threatening adverse events were similar among mothers (30% in each group; 61 raltegravir, 59 efavirenz) and infants (25% in each group; 50 raltegravir, 48 efavirenz), with no treatment-related deaths.
INTERPRETATION
Our findings support major guidelines. The integrase inhibitor dolutegravir is currently a preferred regimen for the prevention of perinatal HIV transmission with raltegravir recommended as a preferred or alternative integrase inhibitor for pregnant women living with HIV.
FUNDING
Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute of Allergy and Infectious Diseases.
Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Outcome Assessment, Health Care; Pregnancy; Pregnancy Complications, Infectious; Raltegravir Potassium; Viral Load; Young Adult; Zidovudine
PubMed: 32386720
DOI: 10.1016/S2352-3018(20)30038-2