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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 -
AIDS Research and Human Retroviruses Jan 2021HIV-1 integrase (IN) is a primary target for combination antiretroviral therapy. Only a limited number of studies report on the emergence of resistance-associated...
HIV-1 integrase (IN) is a primary target for combination antiretroviral therapy. Only a limited number of studies report on the emergence of resistance-associated mutations (RAMs) in Cameroon. We observed that 1.4% of sequence from treatment-naive patients had IN strand transfer inhibitor (INSTI) RAMs. These mutations confer resistance to raltegravir and elvitegravir. We also observed that 10.1% of the sequences have INSTI accessory RAMs. HIV-1 CRF02_AG was the predominant subtype (44.7%) in this study analyses. The occurrence of INSTI RAMs among the sequences at baseline needs to be monitored carefully.
Topics: Cameroon; Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Raltegravir Potassium
PubMed: 32640829
DOI: 10.1089/AID.2020.0022 -
Science Advances Mar 2024People living with human immunodeficiency virus (HIV) receiving integrase strand transfer inhibitors (INSTIs) have been reported to experience virological failure in the...
People living with human immunodeficiency virus (HIV) receiving integrase strand transfer inhibitors (INSTIs) have been reported to experience virological failure in the absence of resistance mutations in integrase. To elucidate INSTI resistance mechanisms, we propagated HIV-1 in the presence of escalating concentrations of the INSTI dolutegravir. HIV-1 became resistant to dolutegravir by sequentially acquiring mutations in the envelope glycoprotein (Env) and the nucleocapsid protein. The selected Env mutations enhance the ability of the virus to spread via cell-cell transfer, thereby increasing the multiplicity of infection (MOI). While the selected Env mutations confer broad resistance to multiple classes of antiretrovirals, the fold resistance is ~2 logs higher for INSTIs than for other classes of drugs. We demonstrate that INSTIs are more readily overwhelmed by high MOI than other classes of antiretrovirals. Our findings advance the understanding of how HIV-1 can evolve resistance to antiretrovirals, including the potent INSTIs, in the absence of drug-target gene mutations.
Topics: Humans; Raltegravir Potassium; HIV Integrase Inhibitors; HIV-1; HIV Integrase; Mutation
PubMed: 38427738
DOI: 10.1126/sciadv.adn0042 -
BMJ Paediatrics Open Jul 2022In 2020, Zimbabwe adopted the WHO's recommendation to use raltegravir (RAL) granule-based regimens for treatment of neonates identified with HIV at the time of birth...
BACKGROUND
In 2020, Zimbabwe adopted the WHO's recommendation to use raltegravir (RAL) granule-based regimens for treatment of neonates identified with HIV at the time of birth testing. This study explores the acceptability of RAL granules by caregivers and healthcare workers (HCWs).
METHODS
Interviews were conducted with 15 caregivers and 12 HCWs from 8 health facilities in Zimbabwe participating in the introductory pilot of RAL granules treatment for newborns. Eligible caregivers included those who had administered RAL to their infant and attended either 8th or 28th day of life appointments. Caregivers of neonates recently initiated on RAL were selected through convenience sampling. Eligible HCWs who provided RAL preparation, administration instructions and support to caregivers of neonates on RAL for at least 3 months were recruited from the same facilities as the caregivers. Interview transcripts were coded and thematically analysed.
RESULTS
Caregivers reported that their babies looked healthier after RAL initiation, with improved skin appearance and weight gain. Some caregivers wanted their child to remain on RAL beyond 28 days instead of switching regimens, as recommended by national guidelines. HCWs observed that RAL granules improved health outcomes compared with other regimens. HCWs reported challenges with caregivers understanding dosing instructions, measuring with a syringe, swirling and not shaking the medicine, discarding unused medication and following the changes in the dosing schedule and amount when RAL was initiated a few days after birth. HCWs stated that adequate counselling and repeat demonstrations were crucial to ensure that caregivers clearly understood RAL dosing and administration instructions. HCWs requested more standardised training targeting nurses with guidance on handling missed doses and clarification on mixing RAL granules with water and not breastmilk.
CONCLUSION
While feedback from caregivers and HCWs on RAL implementation was positive, barriers were also noted. Adequate training and sufficient instruction and support for caregivers would help to ensure that RAL granules are prepared, dosed and administered correctly.
Topics: Caregivers; Counseling; HIV Infections; Health Personnel; Humans; Infant; Infant, Newborn; Raltegravir Potassium
PubMed: 36053612
DOI: 10.1136/bmjpo-2022-001474 -
Clinical Pharmacokinetics Jun 2021Little is understood about neonatal pharmacokinetics immediately after delivery and during the first days of life following intrauterine exposure to maternal...
BACKGROUND AND OBJECTIVE
Little is understood about neonatal pharmacokinetics immediately after delivery and during the first days of life following intrauterine exposure to maternal medications. Our objective was to develop and evaluate a novel, physiologically based pharmacokinetic modeling workflow for predicting perinatal and postnatal disposition of commonly used antiretroviral drugs administered prenatally to pregnant women living with human immunodeficiency virus.
METHODS
Using previously published, maternal-fetal, physiologically based pharmacokinetic models for emtricitabine, dolutegravir, and raltegravir built with PK-Sim/MoBi, placental drug transfer was predicted in late pregnancy. The total drug amount in fetal compartments at term delivery was estimated and subsequently integrated as initial conditions in different tissues of a whole-body, neonatal, physiologically based pharmacokinetic model to predict drug concentrations in the neonatal elimination phase after birth. Neonatal elimination processes were parameterized according to published data. Model performance was assessed by clinical data.
RESULTS
Neonatal physiologically based pharmacokinetic models generally captured the initial plasma concentrations after delivery but underestimated concentrations in the terminal phase. The mean percentage error for predicted plasma concentrations was - 71.5%, - 33.8%, and 76.7% for emtricitabine, dolutegravir, and raltegravir, respectively. A sensitivity analysis suggested that the activity of organic cation transporter 2 and uridine diphosphate glucuronosyltransferase 1A1 during the first postnatal days in term newborns is ~11% and ~30% of that in adults, respectively.
CONCLUSIONS
These findings demonstrate the general feasibility of applying physiologically based pharmacokinetic models to predict washout concentrations of transplacentally acquired drugs in newborns. These models can increase the understanding of pharmacokinetics during the first postnatal days and allow the prediction of drug exposure in this vulnerable population.
Topics: Adult; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; Humans; Infant, Newborn; Models, Biological; Oxazines; Piperazines; Placenta; Pregnancy; Pyridones; Raltegravir Potassium
PubMed: 33527213
DOI: 10.1007/s40262-020-00977-w -
Microbiology Spectrum Dec 2022To ensure the long-term efficacy of dolutegravir (DTG), we evaluated the genotypic profile in viral reservoirs among patients on third-line (3L) antiretroviral therapy...
Evaluation of Circulating and Archived HIV-1 Integrase Drug-Resistance Variants among Patients on Third-Line ART in Cameroon: Implications for Dolutegravir-Containing Regimens in Resource-Limited Settings.
To ensure the long-term efficacy of dolutegravir (DTG), we evaluated the genotypic profile in viral reservoirs among patients on third-line (3L) antiretroviral therapy (ART) in Cameroon, according to prior exposure to raltegravir (RAL). A facility-based study was conducted from May through December 2021 among patients on 3L ART from HIV treatment centers in Yaoundé and Douala. Viral load was measured, and genotyping was performed on plasma RNA and proviral DNA. HIV-1 drug resistance mutations were interpreted using HIVdb.v9.1 and phylogeny analysis was performed using MEGA.v7, with < 0.05 considered significant. Of the 12,093 patients on ART, 53 fully met our inclusion criteria. The median (IQR) age was 51 years (40 to 55 years), and the male/female ratio was 4/5. The median duration on integrase strand-transfer inhibitors (INSTI)-containing regimens was 18 months (12 to 32 months), and 15.09% (8/53) were exposed to RAL. The most administered 3L ART was TDF+3TC+DTG+DRV/r (33.96%, 18/53). Only 5.66% (3/53) had unsuppressed viremia (>1000 copies/mL). Resistance testing in proviral DNA was successful for 18/22 participants and revealed 1/18 patients (5.56%, in the RAL-arm) with archived mutations at major resistance positions (G140R and G163R). Five subtypes were identified, CRF02_AG (12/18), CRF22_01AE (3/18), A1 (1/18), G (1/18), and F2 (1/18). In Cameroon, 3L-experienced patients had a good virological response with a low level of archived mutations in the integrase. This finding underscored the use of DTG-containing ART for heavily treated patients in similar programmatic settings. However, patients with prior exposure to RAL should be closely monitored following a stratified or personalized approach to mitigate risks of INSTI-resistance, alongside pharmacovigilance. We described the analysis of the genotypes of the population within third-line antiviral therapy in Cameroon, with a focus on defining the effects of prior raltegravir (RAL) treatment and resistance mutations for current dolutegravir (DTG) treatment. While supporting the current transition to DTG-containing ART in resource-limited settings toward the achievement of the UNAIDS' goal of HIV elimination by 2030, our findings suggested that RAL-exposed patients may need a specific monitoring approach either in a stratified or personalized model of third-line ART to ensure the long-term success of DTG-containing regimens.
Topics: Female; Humans; Male; Middle Aged; Cameroon; HIV Infections; HIV Integrase; Raltegravir Potassium; Resource-Limited Settings; Adult
PubMed: 36259973
DOI: 10.1128/spectrum.03420-22 -
Antimicrobial Resistance and Infection... Aug 2020Sub-Saharan African countries are transitioning to dolutegravir-based regimens, even for patients with extensive previous drug exposure, including first-generation...
First case of Dolutegravir and Darunavir/r multi drug-resistant HIV-1 in Cameroon following exposure to Raltegravir: lessons and implications in the era of transition to Dolutegravir-based regimens.
BACKGROUND
Sub-Saharan African countries are transitioning to dolutegravir-based regimens, even for patients with extensive previous drug exposure, including first-generation integrase strand-transfer inhibitors (INSTI) such as raltegravir. Such exposure might have implications on cross-resistance to dolutegravir-based antiretroviral therapies (ART).
CASE PRESENTATION
We report a 65 years old Cameroonian, previously exposed to raltegravir, and failing on third-line treatment with multi-drug resistance to darunavir/r and dolutegravir. Genotypic resistance testing (GRT) and viral tropism were performed during monitoring time points. The patient initiated ART in August 2007. At the time point of the first (29.04.2010), second (01.12.2017) and third (08.08.2019) GRT, prior ART exposure included 3TC, d4T, NVP and EFV; additionally TDF, DRV/r and RAL; and additionally ABC and DTG respectively. First GRT revealed mutations associated with resistance only to first-generation Non-nucleoside reverse transcriptase inhibitors (NNRTI). Second GRT revealed mutations associated with high-level resistance to all NRTIs, first generation NNRTIs, all ritonavir boosted protease inhibitors (PI/r), and all INSTI, while viral tropism (using geno2pheno) revealed a CCR5-tropic virus with a false positive rate (FPR) of 60.9% suggesting effectiveness of maraviroc (MRV). The third GRT showed high-level resistance to NRTI, NNRTI, all PI and all INSTI, with additional mutations (H221HY for NNRTI and S147G for INSTI), and a CCR5-tropic virus with a slightly reduced FPR (57.0%). Without any locally available active therapeutic option, the patient has been on a maintenance therapy with "DRV/r (600mg x 2/day)+TDF+3TC" and patient/family-centered adherence has been reinforced. Since the first viral load (VL) measurement in 2010, the patient has had 12 VL tests with the VL ranging from 4.97 Log to 6.44 Log copies/mL and the CD4 count never exceeded 200 cells/μL.
CONCLUSIONS
As African countries transition to dolutegravir-based regimens, prior raltegravir-exposure may prompt selection (and potential transmission) of dolutegravir-resistance, supporting case surveillance.
Topics: Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Cameroon; Darunavir; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Male; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Viral Load
PubMed: 32843050
DOI: 10.1186/s13756-020-00799-2 -
The Journal of Antimicrobial... Nov 2020Antiretroviral dual regimens including lamivudine and one boosted PI or dolutegravir are warranted in order to optimize combination ART (cART), prevent long-term...
BACKGROUND
Antiretroviral dual regimens including lamivudine and one boosted PI or dolutegravir are warranted in order to optimize combination ART (cART), prevent long-term toxicity and reduce the cost of treatments.
OBJECTIVES
We hypothesized that a maintenance dual regimen of lamivudine plus raltegravir would be effective and as well tolerated as the dual maintenance combination of lamivudine plus dolutegravir.
METHODS
We performed an observational, retrospective study of HIV-infected patients on suppressive ART who switched to a dual regimen containing lamivudine 300 mg once daily plus raltegravir 1200 mg once daily or dolutegravir 50 mg once daily.
RESULTS
In total, 109 patients (79 men; mean age 46.4 years; mean CD4+ T lymphocyte count 605 cells/mm3) were enrolled. Overall, 50 subjects switched to lamivudine plus raltegravir (Group A) and 59 to lamivudine plus dolutegravir (Group B). After 12 months, 45 patients (90%) in Group A and 52 (88.1%) in Group B had HIV RNA <20 copies/mL. No patients had severe adverse effects in either group, and the percentages of patients with mild adverse effects were comparable, except for a higher incidence of headache and sleeping disturbances in Group B than in Group A (30.5% versus 14%, P < 0.001). A comparable and non-significant weight increase was reported in both groups (+1.91 kg in Group A and +2.28 kg in Group B).
CONCLUSIONS
In our study, dual therapies containing lamivudine plus raltegravir or dolutegravir in virologically suppressed patients showed high and comparable efficacy, as well as good tolerability.
Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Retrospective Studies; Viral Load
PubMed: 32728708
DOI: 10.1093/jac/dkaa319 -
Journal of Acquired Immune Deficiency... Apr 2021Integrase strand transfer inhibitors (INSTIs) are first-line regimens for HIV treatment. We aimed to examine their impact on cognitive performance and depressive...
BACKGROUND
Integrase strand transfer inhibitors (INSTIs) are first-line regimens for HIV treatment. We aimed to examine their impact on cognitive performance and depressive symptoms in women with HIV (WWH).
SETTING
Women's Interagency HIV Study, a multisite, prospective, cohort study.
METHODS
WWH who started or switched to INSTI-based antiretroviral therapy (ART) and completed neuropsychological testing and the Center for Epidemiological Studies-Depression (CES-D) scale before and after INSTI start/switch were included in the analyses. Primary outcomes were demographically corrected cognitive domain T-scores. Linear mixed-effects models adjusted for relevant covariates were used to examine effects of start/switch of any INSTI and individual INSTI drugs on cognition and CES-D scores.
RESULTS
Six hundred thirty-nine WWH, median age 49 (interquartile range 12) years, 66% Black non-Hispanic, had neuropsychological and CES-D scale data before and after INSTI start/switch. Although 14% started INSTI-based ART, the remainder switched to INSTI-based ART from another regimen. Overall, any INSTI use was associated with poorer learning post-INSTI. Specifically, use of dolutegravir and elvitegravir, but not raltegravir, was associated with poorer learning. In analyses restricted to INSTI switch, any INSTI use, and dolutegravir use, was associated with poorer learning. Among those switching from a PI-based regimen, INSTIs overall and dolutegravir remained associated with poorer learning; switching from a nonnucleoside reverse transcriptase inhibitor to dolutegravir was also associated with poorer learning. INSTI start/switch was not related to depressive symptom changes.
CONCLUSIONS
INSTI use was associated with poorer learning among WWH. These changes were mainly observed in elvitegravir and dolutegravir users, indicating that the impact of INSTI on cognition in WWH may not be a class effect.
Topics: Adult; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Integrases; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Quinolones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; United States
PubMed: 33394812
DOI: 10.1097/QAI.0000000000002608 -
AIDS Research and Human Retroviruses Jan 2021International guidelines recommend the use of integrase strand transfer inhibitor (INI)-based regimens as first-line antiretroviral (ARV) in both naive and experienced...
International guidelines recommend the use of integrase strand transfer inhibitor (INI)-based regimens as first-line antiretroviral (ARV) in both naive and experienced HIV-infected patients. We analyzed a multicenter cohort of HIV-infected patients, both naive and experienced, starting an ARV, including an INI. Chi-square test and nonparametric tests were used to assess differences in categorical and continuous variables, respectively. Kaplan-Meier survival analysis was performed to estimate the probability of maintaining the study drug and Cox-regression analysis to evaluate predictors of discontinuation. We enrolled 4,343 patients: 3,143 (72.4%) were males, with a median age of 49 years (interquartile range 41-55). Naive patients were 733 (16.9%), of whom 168 (22.9%) were AIDS presenters. Overall, 2,282 patients (52.5%) started dolutegravir (DTG), 1,426 (32.8%) raltegravir (RAL), and 635 (14.7%) elvitegravir (EVG). During 10,032 patient years of follow-up (PYFU), we observed 1,278 discontinuations (13 per 100 PYFU); 448 of them (35%) due to simplification and 355 (28%) to toxicities (98 for central nervous system toxicity). Reasons of discontinuation were different between INIs. Estimated probability of maintaining DTG at 3 and 4 years were 81.5% [95% confidence interval (CI): 80.5-82.5] and 76.3% (95% CI: 73.9-78.7), respectively; RAL 61.6% (95% CI: 60.2-63.0) and 54.1% (95% CI: 52.7-55.5); EVG 71.6% (95% CI: 69.2-74.0) and 68.3% (95% CI: 65.3-71.3) ( < .001). At a multivariable analysis, being on a RAL-based ARV [vs. DTG, adjusted hazard ratio (aHR) 2.9, 95% CI: 2.3-3.6, < .001], a EVG-based ARV (vs. DTG, aHR 1.3 95% CI: 1.1-1.7, = .049), and a peak HIV-RNA >500k cp/mL (aHR 1.3, 95% CI: 1.1-1.6, = .006) predicted INI discontinuation. Our data confirm the good tolerability of INIs in clinical practice. Differences emerge between the three drugs in reasons for discontinuation.
Topics: HIV Infections; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Italy; Male; Middle Aged; Oxazines; Piperazines; Raltegravir Potassium
PubMed: 32998526
DOI: 10.1089/AID.2020.0078