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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 -
International Journal of Antimicrobial... May 2021Antiretroviral therapy has been imperative in controlling the human immunodeficiency virus (HIV) epidemic. Most low- and middle-income countries have used nucleoside... (Review)
Review
Antiretroviral therapy has been imperative in controlling the human immunodeficiency virus (HIV) epidemic. Most low- and middle-income countries have used nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors extensively in the treatment of HIV. However, integrase strand transfer inhibitors (INSTIs) are becoming more common. Since their identification as a promising therapeutic drug, significant progress has been made that has led to the approval of five INSTIs by the US Food and Drug Administration (FDA), i.e. dolutegravir (DTG), raltegravir (RAL), elvitegravir (EVG), bictegravir (BIC) and cabotegravir (CAB). INSTIs have been shown to effectively halt HIV-1 replication and are commended for having a higher genetic barrier to resistance compared with NRTIs and NNRTIs. More interestingly, DTG has shown a higher genetic barrier to resistance compared with RAL and EVG, and CAB is being used as the first long-acting agent in HIV-1 treatment. Considering the increasing interest in INSTIs for HIV-1 treatment, we focus our review on the retroviral integrase, development of INSTIs and their mode of action. We also discuss each of the INSTI drugs, including potential drug resistance and known side effects.
Topics: Amides; Anti-Retroviral Agents; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Virus Replication
PubMed: 33852932
DOI: 10.1016/j.ijantimicag.2021.106343 -
The Lancet. HIV Sep 2019Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance...
BACKGROUND
Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance patterns, partly due to reduced access to viral load monitoring. We aimed to evaluate use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to improve adherence in individuals presenting with second-line viral failure.
METHODS
A5288 was a phase 4, third-line ART strategy study done at 19 urban sites in ten countries that enrolled adult participants with confirmed plasma HIV-1 RNA (viral load) of 1000 copies per mL or more after more than 24 weeks of protease inhibitor-based second-line ART. The primary objective was to use antiretrovirals (raltegravir, etravirine, and ritonavir-boosted darunavir) and diagnostic monitoring technologies, including viral load, genotyping, and adherence support to achieve viral load suppression (defined as ≤200 copies per mL) in 65% or more of participants. ART history and real-time drug resistance genotypes were used to assign participants to one of four cohorts: cohort A (no lopinavir resistance) stayed on second-line ART and cohorts B (B1, best available nucleoside reverse transcriptase inhibitors [NRTIs] plus ritonavir-boosted darunavir plus raltegravir; B2, ritonavir-boosted darunavir plus raltegravir plus etravirine; B3, ritonavir-boosted darunavir, raltegravir, and either tenofovir plus emtricitabine or tenofovir plus lamivudine), C (ritonavir-boosted darunavir plus raltegravir plus tenofovir-emtricitabine or tenofovir plus lamivudine), and D (best available NRTIs plus ritonavir-boosted darunavir plus raltegravir) were defined by increasing levels of resistance and received appropriate regimens, including new antiretrovirals. Participants in Cohort B without detectable hepatitis B surface antigen were assigned by blocked randomisation to cohorts B1 and B2, and those with detectable hepatitis B surface antigen were assigned to cohort B3. The trial is registered with ClinicalTrials.gov, number NCT01641367.
FINDINGS
From Jan 10, 2013, to Sept 10, 2015, 545 participants were enrolled. 287 (53%) were assigned to cohort A, 74 (14%) to B1, 72 (13%) to B2, eight (1%) to B3, 70 (13%) to C, and 34 (6%) to D. Overall, 349 (64%, 95% CI 60-68) participants achieved viral suppression at week 48, with proportions varying from 125 (44%) of 287 in cohort A to 65 (88%) of 74 in cohort B1, 63 (88%) of 72 in B2, eight (100%) of eight in B3, 63 (90%) of 70 in C, and 25 (74%) of 34 in D. Participants in cohort A remained on their second-line protease inhibitor, and had the most participants with grade 3 or higher adverse events (147 [51%]).
INTERPRETATION
Targeted real-time genotyping to select third-line ART can appropriately allocate more costly antiretrovirals to those with greater levels of HIV drug resistance.
FUNDING
National Institutes of Health.
Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Darunavir; Developing Countries; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Nitriles; Prospective Studies; Pyridazines; Pyrimidines; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Viral Load
PubMed: 31371262
DOI: 10.1016/S2352-3018(19)30146-8 -
Retrovirology Oct 2022Integrase strand transfer inhibitors (INSTIs) have improved the treatment of human immunodeficiency virus (HIV). There are currently four approved for use in... (Review)
Review
Integrase strand transfer inhibitors (INSTIs) have improved the treatment of human immunodeficiency virus (HIV). There are currently four approved for use in treatment-naïve individuals living with HIV; these include first generation raltegravir, elvitegravir, and second generation dolutegravir and bictegravir. The most recent INSTI, cabotegravir, is approved for (1) treatment of HIV infection in adults to replace current antiretroviral therapy in individuals who maintain virologic suppression on a stable antiretroviral regimen without history of treatment failure and no known resistance to its components and (2) pre-exposure prophylaxis in individuals at risk of acquiring HIV-1 infection. Cabotegravir can be administered intramuscularly as a monthly or bi-monthly injection depending on the indication. This long-acting combination has been associated with treatment satisfaction in clinical studies and may be helpful for individuals who have difficulty taking daily oral medications. Worldwide, second generation INSTIs are preferred for treatment-naïve individuals. Advantages of these INSTIs include their high genetic barrier to resistance, limited drug-drug interactions, excellent rates of virologic suppression, and favorable tolerability. Few INSTI resistance-associated mutations have been reported in clinical trials involving dolutegravir, bictegravir and cabotegravir. Other advantages of specific INSTIs include their use in various populations such as infants and children, acute HIV infection, and individuals of childbearing potential. The most common adverse events observed in clinical studies involving INSTIs included diarrhea, nausea, insomnia, fatigue, and headache, with very low rates of treatment discontinuation versus comparator groups. The long-term clinical implications of weight gain associated with second generation INSTIs dolutegravir and bictegravir warrants further study. This review summarizes key clinical considerations of INSTIs in terms of clinical pharmacology, drug-drug interactions, resistance, and provides perspective on clinical decision-making. Additionally, we summarize major clinical trials evaluating the efficacy and safety of INSTIs in treatment-naïve patients living with HIV as well as individuals at risk of acquiring HIV infection.
Topics: Adult; Child; Humans; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Raltegravir Potassium
PubMed: 36273165
DOI: 10.1186/s12977-022-00608-1 -
Journal of Acquired Immune Deficiency... Dec 2019Population modeling and simulations can be used to facilitate the conduct of phase I studies to develop safe and effective dosing regimens in neonates.
Use of Modeling and Simulations to Determine Raltegravir Dosing in Neonates: A Model for Safely and Efficiently Determining Appropriate Neonatal Dosing Regimens: IMPAACT P1110.
BACKGROUND
Population modeling and simulations can be used to facilitate the conduct of phase I studies to develop safe and effective dosing regimens in neonates.
SETTING
P1110 is an international, multicenter trial to determine safe and effective raltegravir doses in neonates at risk for HIV infection.
METHODS
P1110 used a 2-cohort adaptive design incorporating population pharmacokinetic modeling and simulations. An initial cohort of neonates received 2 single oral doses of raltegravir with standard-of-care therapy for prevention of perinatal transmission-one within 48 hours of birth and a second at 7-10 days of life. Raltegravir concentration data after administration of these doses were combined with data from a previous study of infants aged 4 weeks to 2 years. The combined database was used for population pharmacokinetic modeling and simulations to select a daily dosing regimen for investigation in a second cohort of neonates.
RESULTS
Raltegravir concentration data from 6 neonates were combined with data from infants aged 4 weeks to 2 years receiving raltegravir twice daily. The combined data set allowed for successful development of a population pharmacokinetic model with reasonable precision of parameter estimates. Monte Carlo simulations were run to evaluate potential daily dosing regimens from birth to 6 weeks of age, allowing for selection of a regimen to be evaluated in a subsequent cohort of neonates receiving chronic raltegravir dosing.
CONCLUSIONS
An adaptive design incorporating population pharmacokinetic modeling and simulations was used to select a developmentally appropriate neonatal raltegravir dosing regimen in the first 6 weeks of life.
Topics: Adolescent; Adult; Anti-HIV Agents; Child; Drug Administration Schedule; Female; HIV Infections; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Models, Biological; Monte Carlo Method; Raltegravir Potassium; Young Adult
PubMed: 31658182
DOI: 10.1097/QAI.0000000000002149 -
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 -
HIV Medicine Oct 2021The aim of the present study was to compare the efficacy and durability of treatment switch to two-drug (2DR) vs. three-drug (3DR) integrase inhibitor (InSTI)-based...
OBJECTIVES
The aim of the present study was to compare the efficacy and durability of treatment switch to two-drug (2DR) vs. three-drug (3DR) integrase inhibitor (InSTI)-based regimens in a real-life setting.
METHODS
Within the ODOACRE cohort, we selected adult patients with HIV RNA < 50 copies/mL switching to an InSTI-based 2DR or 3DR. Survival analyses were performed to estimate the probability of virological failure (VF, defined as one HIV RNA > 1000 copies/mL or two consecutive HIV RNA > 50 copies/mL) and treatment discontinuation (TD, defined as any modification, intensification or interruption of the regimen), and to evaluate their predictors.
RESULTS
Overall, 1666 patients were included, of whom 1334 (80%) were treated with a 3DR (19.9%, 25.0% and 55.1% elvitegravir-, raltegravir- and dolutegravir-based, respectively) and 332 (20%) with a 2DR (79.2% dolutegravir + lamivudine and 20.8% dolutegravir + rilpivirine). Over a median (interquartile range) follow-up of 100 (52-150) weeks, 52 (3.1%) patients experienced VF with an incidence of 1.5/100 person-year of follow-up (PYFU). The estimated 96-week probability of VF was similar for the 2DR and 3DR groups (2.3% vs. 2.8%, P = 0.53), but it was higher for elvitegravir (4.9%) and raltegravir (5.0%) than for dolutegravir (1.5%) (P = 0.04). Four hundred (24%) patients discontinued their InSTI-based regimen, with an incidence of 11.3/100 PYFU. At 96 weeks, 3DRs showed a higher probability of TD for any reason (20.6% vs. 11.2%, P < 0.001) and TD for toxicity (9.0% vs. 6.6%, P = 0.02) when compared with 2DRs. A higher risk of TD for central nervous system toxicity was observed for dolutegravir than for elvitegravir and raltegravir (4.0% vs. 2.5% vs. 0.6%, P = 0.005).
CONCLUSIONS
In virologically suppressed HIV-infected patients, 2DRs showed an efficacy similar to 3DRs but with better tolerability.
Topics: Adult; Cohort Studies; HIV Infections; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Lamivudine; Oxazines; Raltegravir Potassium; Viral Load
PubMed: 34318591
DOI: 10.1111/hiv.13146 -
International Journal of Antimicrobial... Nov 2019Integrase strand transfer inhibitors (INSTIs) are the most recent class of antiretroviral drugs with potent and durable antiviral activity used to treat human... (Meta-Analysis)
Meta-Analysis Review
Integrase strand transfer inhibitors (INSTIs) are the most recent class of antiretroviral drugs with potent and durable antiviral activity used to treat human immunodeficiency virus type 1 (HIV-1) infection. However, development of drug resistance increases the risk of treatment failure, disease progression and mortality. A better understanding of drug efficacy and resistance against INSTIs is crucial for their efficient use and the development of new antiretrovirals. A meta-analysis of studies reporting efficacy and resistance data on INSTI use in HIV-infected patients was performed. Odds ratios (ORs) of efficacy outcome data favouring INSTI use in different clinical settings demonstrated that INSTIs have higher efficacy compared with drugs of other classes. For combination antiretroviral therapy-naïve patients and virologically-suppressed patients who switched to INSTI-based therapy, the OR was 1.484 (95% CI 1.229-1.790) and 1.341 (95% CI 0.913-1.971), respectively. ORs of resistance data indicated decreased treatment-emergent resistance development to dolutegravir (DTG) upon virological failure than to non-INSTIs (OR = 0.081, 95% CI 0.004-1.849), whereas the opposite was observed for raltegravir (RAL) (OR = 3.137, 95% CI 1.827-5.385) and elvitegravir (EVG) (OR = 1.886, 95% CI 0.569-6.252). Pooled analysis of resistance data indicated that development of resistance to DTG and bictegravir was rare, whereas EVG and RAL had low genetic barriers to resistance and the intensive cross-resistance between them limits INSTI efficiency. Efficient means of monitoring the emergence of resistance to INSTIs and the development of drugs with high genetic barriers are clear paths for future research.
Topics: Amides; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; Humans; Microbial Sensitivity Tests; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Virus Replication
PubMed: 31398480
DOI: 10.1016/j.ijantimicag.2019.08.008 -
Drugs & Aging Nov 2021There are approximately 40 million people living with HIV globally, and 21% (7.9 million) are older adults (aged > 50 years) as of 2019. The average age of... (Review)
Review
There are approximately 40 million people living with HIV globally, and 21% (7.9 million) are older adults (aged > 50 years) as of 2019. The average age of HIV-positive patients is predicted to increase to 58 by 2035. The favorable clinical efficacy of integrase strand transfer inhibitors has led to high rates of viral suppression and have now become the preferred agents by the AIDS guideline when initiating antiretroviral therapy. There are concerns of increasing adverse effects from HIV medications, such as integrase strand transfer inhibitors, as a result of changes in pharmacodynamic and pharmacokinetic parameters within the older population. The authors aim to describe the safety concerns of the current integrase strand transfer inhibitors based upon a narrative literature review, including recommendations for drug-drug interactions, and relevant comorbidities to consider for selection of the most appropriate integrase strand transfer inhibitor for older people living with HIV. Raltegravir is a well-tolerated option with minor adverse events; however, adherence to a twice-daily regimen may be difficult in older patients who are also taking many other medications for various comorbidities. Elvitegravir is also well tolerated with limited adverse effects, but has many drug-drug interactions that may pose problems for older patients with polypharmacy. Dolutegravir has been associated with more frequent adverse events, such as neuropsychiatric disorders.
Topics: Aged; Drug Interactions; HIV Infections; HIV Integrase Inhibitors; Humans; Integrases; Pyridones; Raltegravir Potassium
PubMed: 34494229
DOI: 10.1007/s40266-021-00894-y -
Journal of the Pediatric Infectious... Apr 2021We present the first published case of raltegravir-associated drug-reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a child without characteristic...
Raltegravir-associated Drug-Reaction With Eosinophilia and Systemic Symptoms Syndrome in a Pediatric Patient Without Characteristic Human Leukocyte Antigen B*57:01 or B*53:01 alleles.
We present the first published case of raltegravir-associated drug-reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a child without characteristic human leukocyte antigen haplotypes HLA-B*57:01 or HLA-B*53:01. A 4-year-old African American female with perinatally acquired human immunodeficiency virus infection was hospitalized for DRESS after starting a raltegravir-based antiretroviral regimen.
Topics: Alleles; Child; Child, Preschool; Drug Hypersensitivity Syndrome; Eosinophilia; Female; HLA Antigens; HLA-B Antigens; Humans; Pharmaceutical Preparations; Raltegravir Potassium
PubMed: 32766769
DOI: 10.1093/jpids/piaa089