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HIV viral kinetics and T cell dynamics in antiretroviral naive persons starting an integrase strand transfer inhibitor and protease inhibitor regimen.

ABSTRACT: Nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens may potentially minimize antiretroviral (ART) toxicities, but demonstrate mixed efficacy and toxicity results. The impact of an integrase strand transfer inhibitor (INSTI) and protease inhibitor (PI) regimen on HIV viral dynamics and T cell kinetics remains underdescribed.To compare the effect of raltegravir + ritonavir boosted lopinavir (RAL + LPV/r) to efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) on HIV kinetics and T cell dynamics.Fifty participants naïve to ART underwent HIV viral kinetic sampling evaluated using biexponential mixed effects modeling. A subset of 28 subjects (with complete viral suppression) underwent flow cytometry and evaluation of soluble markers of inflammation at weeks 0, 4, and 48 of ART.RAL + LPV/r compared to EFV/TDF/FTC resulted in a prolonged first phase viral decay rate (18 vs. 13 days p < 0.01). From weeks 0 to 4, RAL + LPV/r was associated with a trend toward greater decreases in activated CD4+ T cells (-3.81 vs. -1.18 p = 0.09) and less decreases in activated effector memory CD4+ T cells (-0.63 vs. -2.69 p-0.07). These trends did not persist to week 48. No differences were noted at any time point for soluble markers of immune activation.The prolonged first phase viral decay observed with RAL + LPV/r in persons starting ART did not result in differences in viral suppression at week 48. We also observed trends in declines in certain cellular markers of immune activation but it remains unclear if this could translate to long-term immunologic benefits in persons on an INSTI + PI.

SUBMITTER: Karris MY

PROVIDER: S-EPMC5613656 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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HIV viral kinetics and T cell dynamics in antiretroviral naïve persons starting an integrase strand transfer inhibitor and protease inhibitor regimen.

Karris Maile Y MY Jain Sonia S Day Tyler R C TR Pérez-Santiago Josué J Goicoechea Miguel M Dubé Michael P MP Sun Xiaoying X Spina Celsa C Daar Eric S ES Haubrich Richard H RH Morris Sheldon S

HIV clinical trials 20170130 2

<h4>Background</h4>Nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens may potentially minimize antiretroviral (ART) toxicities, but demonstrate mixed efficacy and toxicity results. The impact of an integrase strand transfer inhibitor (INSTI) and protease inhibitor (PI) regimen on HIV viral dynamics and T cell kinetics remains underdescribed.<h4>Objective</h4>To compare the effect of raltegravir + ritonavir boosted lopinavir (RAL + LPV/r) to efavirenz/tenofovir disoproxil fumar ...[more]

PMID: 28134057

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Project description:There has been no systematic review of the prevalence of transmitted integrase strand transfer inhibitor (INSTI) resistance. We systematically searched the English-language PubMed database and GenBank to identify studies published since 2010 reporting 50 or more INSTI-naive HIV-1-infected adults undergoing integrase genotyping. We extracted data related to country, sample year, specimen type, sequencing method, and subtype. For studies with sequences in GenBank, we determined the prevalence of three categories of INSTI-associated resistance mutations: (1) nonpolymorphic INSTI-selected drug resistance mutations (DRMs) that we refer to as surveillance DRMs; (2) rarely selected nonpolymorphic INSTI-associated DRMs; and (3) common polymorphic accessory INSTI-selected DRMs. A total of 103 studies met inclusion criteria including 75 studies in GenBank containing integrase sequences from 16,481 INSTI-naive persons. The median sample year was 2013 (interquartile range: 2008-2014). The prevalence of INSTI surveillance DRMs, rarely selected DRMs, and common polymorphic accessory INSTI-selected DRMs were 0.5%, 0.8%, and 6.2%, respectively. There was no association between the presence of nonpolymorphic surveillance DRM and region, sample year, or subtype. Two surveillance DRMs, E138K and R263K occurred in 0.15% and 0.10% of naive sequences, respectively. Several lines of evidence suggested that the 0.5% prevalence of surveillance DRMs partly reflects the cumulative natural occurrence of these mutations in the absence of selective drug pressure. There was an unexplained temporal increase in the proportion of sequences with polymorphic accessory mutations. The prevalence of INSTI-associated surveillance DRMs is low even in regions where INSTIs have been a major component of antiretroviral therapy for several years. The presence of INSTI-associated surveillance DRMs in INSTI-naive persons likely results from actual cases of transmitted INSTI resistance and from a low background level reflecting the cumulative rare natural occurrence of several nonpolymorphic mutations.

Project description:BackgroundIntegrase inhibitors (INI) induce a rapid decline of HIV-RNA in plasma and CD4+ T-cell recovery in blood. Both characteristics are also associated with immune reconstitution inflammatory syndrome (IRIS). Whether the use of INI-containing combination antiretroviral therapy (cART) increases the risk of IRIS is being questioned.MethodsStudy within the Dutch ATHENA HIV observational cohort. HIV-1 infected late presenters initiating cART after March 2009 were included if they had <200 CD4+ T-cells per μL and were diagnosed with an opportunistic infection. IRIS was defined either according to the criteria by French et al. (IRISFRENCH) or by a clinical IRIS diagnosis of the physician (IRISCLINICAL). The primary outcomes were the association between INI and the occurrence of IRISFRENCH and IRISFRENCH+CLINICAL in multivariable logistic regression.Findings672 patients with a median CD4+ T-cell count of 35 cells per μL were included. Treatment with INI was independently associated with IRISFRENCH as well as IRISFRENCH+CLINICAL (OR 2·43, 95%CI:1·45-4·07, and OR 2·17, 95%CI:1·45-3·25). When investigating INI separately, raltegravir (RAL) remained significantly associated with IRISFRENCH (OR 4·04 (95%CI:1·99-8·19) as well as IRISFRENCH+CLINICAL (OR 3·07, 95%CI:1·66-5·69), while dolutegravir (DTG) became associated with IRISFRENCH+CLINICAL after it replaced RAL as preferred INI in the cohort after 2015 (OR 4·08, 95%CI:0·99-16·82, p=0·052). Too few patients used elvitegravir to draw meaningful conclusions. Steroid initiation for IRIS was more likely in those who initiated INI versus in those who did not, but no increased hospital (re)admission or mortality rates were observed.InterpretationIn HIV late presenters from a resource rich setting, INI based treatment initiation increased the risk of IRIS. This was observed for RAL and DTG when being initiated as preferential INI in the presence of specific AIDS-conditions, indicative of channeling bias. Although we controlled for all relevant measured confounders, we cannot exclude that the observed association is partially explained by residual confounding. INI use was not associated with mortality nor hospitalization. Therefore, our observation is no reason to avoid INI in late presenters.FundingThe ATHENA database is maintained by Stichting HIV Monitoring and supported by a grant from the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment.

Project description:BackgroundNon-alcoholic Fatty Liver Disease (NAFLD) has a high prevalence among persons with HIV infection. Since Integrase Strand Transfer Inhibitors (INSTIs) are used worldwide and have been associated with weight gain, we must determine their effect in the development of NAFLD and Non-alcoholic Steatohepatitis (NASH) in these patients. The aim of this study was to explore the impact of INSTIs on variation of liver steatosis and fibrosis in the ART-naïve person with HIV, using Hepatic Steatosis Index (HSI), Fibrosis-4 Index (FIB-4), BARD score and NAFLD Fibrosis Score (NFS).MethodsWe performed a monocentric, retrospective cohort study in ART-naïve persons with HIV that initiated INSTI based regimens between December 2019 and January 2022. Data was collected at baseline, 6 and 12 months after initiation. Demographic, clinical and laboratory characteristics, hepatic steatosis, and fibrosis scores were compared between baseline and last visit at 12 months. Linear regression models were performed to analyse the associations between analytical data at baseline and hepatic scores variation during the 12 months of treatment. Models were performed unadjusted and adjusted for age and sex.Results99 patients were included in our study. 82% were male and median age was 36 years. We observed a significant increase in body mass index (BMI), HDL, platelet count, albumin, and creatinine and a significant decrease in AST levels. HSI showed no statistically significant differences during follow-up (p = 0.114). We observed a significant decrease in FIB-4 (p = 0.007) and NFS (p = 0.002). BARD score showed a significant increase (p = 0.006). The linear regression model demonstrated a significant negative association between baseline HIV RNA and FIB-4 change (β= -0.08, 95% CI [-0.16 to -0.00], p = 0.045), suggesting that higher HIV RNA loads at baseline were associated with a greater decrease in FIB-4.ConclusionINSTIs seem to have no impact on hepatic steatosis, even though they were associated with a significant increase in BMI. This might be explained by the direct effect of a dolutegravir-containing regimen and/or by the "return-to-health effect" observed with ART initiation. Furthermore, INSTIs were associated with a reduction in risk of liver fibrosis in ART-naïve persons with HIV, possibly due to their effect on viral suppression.

Project description:In the SAILING study, dolutegravir demonstrated superior virologic efficacy compared with raltegravir in treatment-experienced, integrase strand transfer inhibitor (INSTI)-naive patients with HIV-1 who harbored resistance to ≥2 antiretroviral drug classes. Significantly fewer dolutegravir-treated patients demonstrated virologic failure with treatment-emergent resistance than raltegravir-treated patients through 48 weeks. Investigator-selected background therapy (ISBT) included at least one fully active agent, selected on the basis of resistance analysis. Genotypic and phenotypic resistance testing were performed on baseline and time-of-failure samples from patients with protocol-defined virologic failure (PDVF). A post hoc analysis of SAILING (N = 715; 354 dolutegravir, 361 raltegravir) assessed efficacy in subpopulations defined by ISBT activity, resistance profiles, and treatment history. When ISBT contained only nucleoside reverse transcriptase inhibitors (NRTIs), PDVF occurred in 0% (0/32) of dolutegravir-treated patients and 21.9% (7/32) of raltegravir-treated patients (p = .005). In patients harboring M184 V whose ISBT contained lamivudine or emtricitabine plus a second NRTI, 0% (0/13) of dolutegravir- and 33.3% (4/12) of raltegravir-treated patients (p = .026) experienced PDVF. Among patients receiving protease inhibitor (PI)-containing ISBT, 6.0% (18/300) of dolutegravir-treated patients versus 11.8% (36/305) of raltegravir-treated patients (p = .012) experienced PDVF. Darunavir/ritonavir was part of ISBT in 130 dolutegravir-treated patients and 145 raltegravir-treated patients; 6 (4.6%) and 12 (8.3%), respectively, experienced PDVF (difference -3.7%; 95% confidence interval: -10.1% to 2.5%; p = .256). There was no or less virologic failure in treatment-experienced, INSTI-naive subjects receiving dolutegravir versus raltegravir, even when the ISBT was suboptimal or NRTI resistance was present at baseline. These findings are not explained by the use of PI/ritonavir-containing ISBT.

Dataset Information

HIV viral kinetics and T cell dynamics in antiretroviral naive persons starting an integrase strand transfer inhibitor and protease inhibitor regimen.

Publications

HIV viral kinetics and T cell dynamics in antiretroviral naïve persons starting an integrase strand transfer inhibitor and protease inhibitor regimen.

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