Integrase Strand Transfer Inhibitor Use Research Articles

Integrase strand transfer inhibitor (INSTI) related changes in BMI and risk of diabetes: a prospective study from the RESPOND cohort consortium.

With integrase strand transfer inhibitor (INSTI) use associated with increased body mass index (BMI) and BMI increases associated with higher diabetes mellitus (DM) risk, this study explored the relationship between INSTI/non-INSTI regimens, BMI changes, and DM risk. RESPOND participants were included if they had CD4, HIV RNA, and ≥ 2 BMI measurements during follow up. Those with prior DM were excluded. DM was defined as a random blood glucose ≥ 11·1 mmol/L, HbA1c ≥ 6·5%/48 mmol/mol, use of antidiabetic medication, or site reported clinical diagnosis. Poisson regression assessed the association between natural log (ln) of time-updated BMI, current INSTI/non-INSTI, and their interactions, on DM risk. Among 20,865 people with HIV included, most were male (74%) and White (73%). Baseline median age was 45 years (IQR 37-52), with a median BMI of 24 kg/m2 (IQR 22-26). There were 785 DM diagnoses with a crude rate of 0·73 (95%CI 0·68-0·78)/100 PYFU. Ln(BMI) was strongly associated with DM (adjusted incidence rate ratio (aIRR) 16·54 per log increase, 95%CI 11·33-24·13; p<0·001). Current INSTI use associated with increased DM risk (IRR 1·58, 95%CI 1·37-1·82; p<0·001) in univariate analyses, only partially attenuated when adjusted for variables including ln(BMI) (aIRR 1·48, 95%CI 1·29-1·71; p<0·001). There was no interaction between ln(BMI), INSTI and non-INSTI use, and DM (p=0·130). In RESPOND, compared with non-INSTIs, current use of INSTIs was associated with an increased DM risk, which partially attenuated when adjusted for BMI changes and other variables.

HIV-1 diversity and pre-treatment drug resistance in the era of integrase inhibitor among newly diagnosed ART-naïve adult patients in Luanda, Angola

The surveillance of drug resistance in the HIV-1 naïve population remains critical to optimizing the effectiveness of antiretroviral therapy (ART), mainly in the era of integrase strand transfer inhibitor (INSTI) regimens. Currently, there is no data regarding resistance to INSTI in Angola since Dolutegravir-DTG was included in the first-line ART regimen. Herein, we investigated the HIV-1 genetic diversity and pretreatment drug resistance (PDR) profile against nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and INSTIs, using a next-generation sequencing (NGS) approach with MinION, established to track and survey DRMs in Angola. This was a cross-sectional study comprising 48 newly HIV-diagnosed patients from Luanda, Angola, screened between March 2022 and May 2023. PR, RT, and IN fragments were sequenced for drug resistance and molecular transmission cluster analysis. A total of 45 out of the 48 plasma samples were successfully sequenced. Of these, 10/45 (22.2%) presented PDR to PIs/NRTIs/NNRTIs. Major mutations for NRTIs (2.2%), NNRTIs (20%), PIs (2.2%), and accessory mutations against INSTIs (13.3%) were detected. No major mutations against INSTIs were detected. M41L (2%) and I85V (2%) mutations were detected for NRTI and PI, respectively. K103N (7%), Y181C (7%), and K101E (7%) mutations were frequently observed in NNRTI. The L74M (9%) accessory mutation was frequently observed in the INSTI class. HIV-1 pure subtypes C (33%), F1 (17%), G (15%), A1 (10%), H (6%), and D (4%), CRF01_AG (4%) were observed, while about 10% were recombinant strains. About 31% of detected HIV-1C sequences were in clusters, suggesting small-scale local transmission chains. No major mutations against integrase inhibitors were detected, supporting the continued use of INSTI in the country. Further studies assessing the HIV-1 epidemiology in the era of INSTI-based ART regimens are needed in Angola.

Comparison of Four Predictive Scores for Cardiovascular Risk in Mexican People with HIV.

Persons with HIV (PWH) face an increased risk of cardiovascular events due to immune activation, comorbidities, and certain antiretrovirals (ARVs). However, the current cardiovascular risk (CVR) scores are not specifically directed toward PWH. This study aimed to assess the agreement between different predictive CVR scores and explore their relationship with clinical and demographic data in Mexican PWH. A descriptive cross-sectional analysis was conducted in 200 PWH with a mean age of 42 years who were treated at a Mexican urban center from 2017 to 2018. The majority (83%) was on ARV treatment and 79.5% had undetectable viral loads (VLs). Moderate- to high-risk scores were infrequent, with Framingham Risk Score for Hard Coronary Heart Disease scores showing higher values, with very low concordance among all scores. Logistic regression analysis revealed significant associations between the CVR scores and the initial recorded VL, CD4 cell count, and elevated triglyceride levels. However, no associations were found with measures such as body mass index or abdominal circumference. Treatment with integrase strand transfer inhibitors (INSTIs), particularly first-generation inhibitors, showed strong associations with all predictive scores, notably ASCVD (odds ratio = 7.03, 95% confidence interval 1.67-29.64). The poor concordance among the CVR scores in PWH highlights the need for a specific score that considers comorbidities and ARV drugs. Despite the relatively young age of the participants, significant correlations were observed between INSTI use, initial VL, CD4 cell count, and triglyceride levels, which are factors not considered in the existing risk scores. Regardless of the actual value of the scores, screening for CVR in PWH is recommended.

Associations between change in BMI and the risk of hypertension and dyslipidaemia in people receiving integrase strand-transfer inhibitors, tenofovir alafenamide, or both compared with other contemporary antiretroviral regimens: a multicentre, prospective observational study from the RESPOND consortium cohorts

Integrase strand-transfer inhibitors (INSTIs) and tenofovir alafenamide have been associated with weight gain in several clinical trials and observational cohorts. However, whether weight gain associated with INSTIs and tenofovir alafenamide confers a higher risk of weight-related clinical events is unclear. We aimed to assess whether changes in BMI differentially increase hypertension or dyslipidaemia risk in people with HIV receiving INSTIs, tenofovir alafenamide, or both versus other contemporary regimens. This multicentre, prospective observational study analysed prospective data from RESPOND, an international consortium of HIV cohorts for which recruitment began in 2017 and is still ongoing from HIV clinics and hospitals in 37 European countries and Australia. Participants were eligible if they were aged 18 years or older, receiving INSTI-containing antiretroviral therapy (ART) regimens or a contemporary non-INSTI, did not have hypertension or dyslipidaemia at baseline, and had baseline and at least two follow-up BMI, lipid, and blood pressure measurements. We excluded participants without baseline CD4 or HIV RNA results and those receiving non-ART medications associated with weight changes, including antipsychotics and mood stabilisers, corticosteroids, insulin, and insulin secretagogues. They were followed up from baseline until the earliest hypertension or dyslipidaemia event, their last visit, or Dec 31, 2021, whichever was earlier. The primary outcomes were incidence of hypertension and dyslipidaemia, for which we used multivariable Poisson regression adjusted for time-updated BMI to determine unadjusted and adjusted incidence rate ratios (IRRs) of hypertension and dyslipidaemia in people receiving INSTIs, tenofovir alafenamide, or both, and tested for interaction between time-updated ART regimen and BMI. Of the 35 941 RESPOND participants, 9704 (7327 [75·5 %] male and 2377 [24·5%] female) were included in the hypertension analysis and 5231 (3796 [72·6%] male and 1435 [27·4%] female) were included in the dyslipidaemia analysis. In the univariable model, hypertension was more common in individuals receiving an INSTI with tenofovir alafenamide (IRR 1·70, 95% CI 1·54-1·88) or an INSTI without tenofovir alafenamide (1·41, 1·30-1·53) compared with those receiving neither INSTIs nor tenofovir alafenamide. Adjustment for time-updated BMI and confounders attenuated risk in participants receiving an INSTI with (IRR 1·48, 1·31-1·68) or without (1·25, 1·13-1·39) tenofovir alafenamide. Similarly, dyslipidaemia was more common in participants using tenofovir alafenamide with an INSTI (IRR 1·24, 1·10-1·40) and tenofovir alafenamide alone (1·22, 1·03-1·44) than in participants using neither INSTI nor tenofovir alafenamide. Adjustment for BMI and confounders attenuated the risk in participants receiving tenofovir alafenamide with an INSTI (adjusted IRR 1·21, 1·07-1·37), whereas the risk in those receiving tenofovir alafenamide alone became non-significant (1·15, 0·96-1·38). The associations between increasing BMI and risk of hypertension and dyslipidaemia did not differ between participants receiving different ART regimens (pinteraction=0·46 for hypertension; pinteraction=0·31 for dyslipidaemia). Although residual confounding cannot be entirely excluded, the use of INSTIs was associated with incident hypertension, and the use of tenofovir alafenamide was associated with dyslipidaemia, with the latter association partly mediated by weight gain. These results reiterate the need for hypertension and dyslipidaemia screening in people with HIV. The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, ViiV Healthcare, and Gilead Sciences.

Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies.

In people living with HIV (PLHIV), integrase strand transfer inhibitors (INSTIs) are part of the first-line combination antiretroviral therapy (cART), while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are alternatives. Distinct cART regimens may variably influence the risk for non-AIDS comorbidities. We aimed to compare the metabolome and lipidome of INSTI and NNRTI-based regimens. The 2000HIV study includes asymptomatic PLHIV (n = 1646) on long-term cART, separated into a discovery cohort with 730 INSTI and 617 NNRTI users, and a validation cohort encompassing 209 INSTI and 90 NNRTI users. Baseline plasma samples from INSTI and NNRTI users were compared using mass spectrometry-based untargeted metabolomic (n = 500) analysis. Perturbed metabolic pathways were identified using MetaboAnalyst software. Subsequently, nuclear magnetic resonance spectroscopy was used for targeted lipoprotein and lipid (n = 141) analysis. Metabolome homogeneity was observed between the different types of INSTI and NNRTI. In contrast, higher and lower levels of 59 and 45 metabolites, respectively, were found in the INSTI group compared to NNRTI users, of which 77.9% (81/104) had consistent directionality in the validation cohort. Annotated metabolites belonged mainly to 'lipid and lipid-like molecules', 'organic acids and derivatives' and 'organoheterocyclic compounds'. In pathway analysis, perturbed 'vitamin B1 (thiamin) metabolism', 'de novo fatty acid biosynthesis', 'bile acid biosynthesis' and 'pentose phosphate pathway' were detected, among others. Lipoprotein and lipid levels in NNRTIs were heterogeneous and could not be compared as a group. INSTIs compared to individual NNRTI types showed that HDL cholesterol was lower in INSTIs compared to nevirapine but higher in INSTIs compared to doravirine. In addition, LDL size was lower in INSTIs and nevirapine compared to doravirine. NNRTIs show more heterogeneous cardiometabolic effects than INSTIs, which hampers the comparison between these two classes of drugs. Targeted lipoproteomic and lipid NMR spectroscopy showed that INSTI use was associated with a more unfavorable lipid profile compared to nevirapine, which was shifted to a more favorable profile for INSTI when substituting nevirapine for doravirine, with evidently higher fold changes. The cardiovascular disease risk profile seems more favorable in INSTIs compared to NNRTIs in untargeted metabolomic analysis using mass-spectrometry.

Elevated plasma apolipoprotein E levels in people living with HIV: Associations with biomarkers and HIV-specific risk factors

Background and aimsApolipoprotein E (apoE) plays a crucial role in cholesterol metabolism, and high levels of apoE in plasma are associated with cardiovascular disease and all-cause mortality. We aimed to assess if HIV is independently associated with high plasma apoE and to determine HIV-related risk factors for high plasma apoE. MethodsWe included 661 people with HIV (PWH) from the Copenhagen Comorbidity in HIV (COCOMO) study with available measurement of plasma apoE. COCOMO participants were frequency matched 1:1 on age and sex with controls from the Copenhagen General Population Study. High plasma apoE was defined as levels above the 90th percentile (66.2 mg/L). The association between HIV and high plasma apoE was assessed using logistic regression models. Among PWH, both linear and logistic regression models were used to determine HIV-specific risk factors for high plasma apoE. ResultsMean age was 52 years and 89 % were male. Median plasma apoE was 49.0 mg/L in PWH and 43.3 mg/L in controls, p < 0.001. HIV was associated with higher plasma apoE after adjusting for potential confounders, including triglycerides (odds ratio 2.14 [95 % CI: 1.39–3.29], p < 0.001). In PWH, higher plasma apoE was associated with a previous AIDS-defining condition in linear models before adjustment for triglycerides and integrase strand transfer inhibitor use in fully adjusted linear models. ConclusionsPWH had higher plasma apoE than controls even after adjusting for triglycerides. Further studies are needed to elucidate the clinical impact of high plasma apoE in PWH.

Incidence of Hyperlipidemia among Adults Initiating Antiretroviral Therapy in the HIV Outpatient Study (HOPS), USA, 2007-2021.

Current U.S. guidelines recommend integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) as initial treatment for people with HIV (PWH). We assessed long-term effects of INSTI use on lipid profiles in routine HIV care. We analyzed medical record data from the HIV Outpatient Study's participants in care from 2007 to 2021. Hyperlipidemia was defined based on clinical diagnoses, treatments, and laboratory results. We calculated hyperlipidemia incidence rates and rate ratios (RRs) during initial ART and assessed predictors of incident hyperlipidemia by using Poisson regression. Among 349 eligible ART-naïve PWH, 168 were prescribed INSTI-based ART (36 raltegravir (RAL), 51 dolutegravir (DTG), and 81 INSTI-others (elvitegravir and bictegravir)) and 181 non-INSTI-based ART, including 68 protease inhibitor (PI)-based ART. During a median follow-up of 1.4 years, hyperlipidemia rates were 12.8, 22.3, 22.7, 17.4, and 12.6 per 100 person years for RAL-, DTG-, INSTI-others-, non-INSTI-PI-, and non-INSTI-non-PI-based ART, respectively. In multivariable analysis, compared with the RAL group, hyperlipidemia rates were higher in INSTI-others (RR = 2.25; 95% confidence interval (CI): 1.29-3.93) and non-INSTI-PI groups (RR = 1.89; CI: 1.12-3.19) but not statistically higher for the DTG (RR = 1.73; CI: 0.95-3.17) and non-INSTI-non-PI groups (RR = 1.55; CI: 0.92-2.62). Other factors independently associated with hyperlipidemia included older age, non-Hispanic White race/ethnicity, and ART without tenofovir disoproxil fumarate. PWH using RAL-based regimens had lower rates of incident hyperlipidemia than PWH receiving non-INSTI-PI-based ART but had similar rates as those receiving DTG-based ART, supporting federal recommendations for using DTG-based regimens as the initial therapy for ART-naïve PWH.

Prevalence and analysis of acquired and transmitted integrase strand transfer inhibitor-associated HIV-1 drug resistance in Chongqing, China

ABSTRACT In this study, we examined the occurrence of acquired and transmitted drug resistance to integrase strand transfer inhibitor (INSTI) in HIV-1 strains in Chongqing (China) for guiding for the routine testing of INSTI-associated HIV-1 genotype resistance. Plasma samples were obtained from HIV-1 patients at Chongqing Public Health Medical Center from July 2019 to August 2022. Besides, amplification, sequence, and analysis of the portion of the HIV-1 pol gene that encodes the integrase protein were implemented to identify INSTI resistance. Integrase sequence data was harvested for a comprehensive cohort of 1032 patients infected with HIV-1. This cohort consisted of 564 ART-naive patients, 465 ART-treated patients, and 3 patients with an unknown treatment history. Within the study group, we identified INSTI resistance in 21 patients (2.03%, 21/1032), including 17 ART-treated patients (3.66%, 17/465). Among the ART-treated patients, 12 were INSTI-treated (11.76%, 12/102), 5 were INSTI-naive (1.38%, 5/363), and 4 were ART-ineffective patients (0.71%, 4/564). The prevalent major resistance mutation was Q148R (0.48%, 5/1032), while the most prevalent accessory resistance mutation was E157Q (1.65%, 17/1032). In light of the above, it is recommended that the incidence of accessory genotype analysis should be considered before starting any future INSTI-based therapy, especially in patients with drug resistance to NRTIs and NNRTIs and the reduction of INSTI sensitivity should be carefully monitored and investigated. Regular monitoring for resistance should be implemented after the use of INSTIs, and, importantly, ongoing monitoring of the decreasing susceptibility to INSTIs is crucial following the initiation of treatment with INSTIs.

Integrase strand-transfer inhibitor use and cardiovascular events in adults with HIV: an emulation of target trials in the HIV-CAUSAL Collaboration and the Antiretroviral Therapy Cohort Collaboration

A recent observational study suggested that the risk of cardiovascular events could be higher among antiretroviral therapy (ART)-naive individuals with HIV who receive integrase strand-transfer inhibitor (INSTI)-based ART than among those who receive other ART regimens. We aimed to emulate target trials separately in ART-naive and ART-experienced individuals with HIV to examine the effect of using INSTI-based regimens versus other ART regimens on the 4-year risk of cardiovascular events. We used routinely recorded clinical data from 12 cohorts that collected information on cardiovascular events, BMI, and blood pressure from two international consortia of cohorts of people with HIV from Europe and North America. For the target trial in individuals who had previously never used ART (ie, ART-naive), eligibility criteria were aged 18 years or older, a detectable HIV-RNA measurement while ART-naive (>50 copies per mL), and no history of a cardiovascular event or cancer. Eligibility criteria for the target trial in those with previous use of non-INSTI-based ART (ie, ART-experienced) were the same except that individuals had to have been on at least one non-INSTI-based ART regimen and be virally suppressed (≤50 copies per mL). We assessed eligibility for both trials for each person-month between January, 2013, and January, 2023, and assigned individuals to the treatment strategy that was compatible with their data. We estimated the standardised 4-year risks of cardiovascular events (myocardial infarction, stroke, or invasive cardiovascular procedure) via pooled logistic regression models adjusting for time and baseline covariates. In per-protocol analyses, we censored individuals if they deviated from their assigned treatment strategy for more than 2 months and weighted uncensored individuals by the inverse of their time-varying probability of remaining uncensored. The denominator of the weight was estimated via a pooled logistic model that included baseline and time-varying covariates. The analysis in ART-naive individuals included 10 767 INSTI initiators and 8292 non-initiators of INSTI. There were 43 cardiovascular events in INSTI initiators (median follow-up of 29 months; IQR 15-45) and 52 in non-initiators (39 months; 18-47): standardised 4-year risks were 0·76% (95% CI 0·51 to 1·04) in INSTI initiators and 0·75% (0·54 to 0·98) in non-INSTI initiators; risk ratio 1·01 (0·57 to 1·57); risk difference 0·0089% (-0·43 to 0·36). The analysis in ART-experienced individuals included 7875 INSTI initiators and 373 965 non-initiators. There were 56 events in INSTI initiators (median follow-up 18 months; IQR 9-29) and 3103 events (808 unique) in non-INSTI initiators (26 months; 15-37) in non-initiators: standardised 4-year risks 1·41% (95% CI 0·88 to 2·03) in INSTI initiators and 1·48% (1·28 to 1·71) in non-initiators; risk ratio 0·95 (0·60 to 1·36); risk difference -0·068% (-0·60 to 0·52). We estimated that INSTI use did not result in a clinically meaningful increase of cardiovascular events in ART-naive and ART-experienced individuals with HIV. National Institute of Allergy and Infectious Diseases and National Institute on Alcohol Abuse and Alcoholism.

Effect of Integrase Strand Transfer Inhibitor Use on Time to HIV Viral Suppression before Delivery.

We sought to determine whether pregnant individuals with human immunodeficiency virus (HIV) prescribed integrase strand transfer inhibitor (INSTI) antiretrovirals (ARVs) achieve viral suppression faster than individuals taking non-INSTI regimens and to determine whether there were differences in viral suppression at delivery among INSTI ARVs. This is a retrospective cohort study of pregnant individuals with HIV who delivered a live infant during the study period (January 1, 2009-December 31, 2020). Patients' ARV therapy (ART) was classified as including INSTI or non-INSTI. We compared the proportion of individuals with viral suppression at delivery by group and individual INSTI ARVs using χ2 and Fisher exact tests. A log rank test was used to compare time to viral suppression on ARVs. During the study period, 168 individuals delivered a live infant. Most of the patients were diagnosed as having HIV before pregnancy and had taken ARVs before conception (76%), but fewer than half had an undetectable viral load at the first antenatal visit (45%). During pregnancy, 46% were prescribed INSTI and 54% were prescribed non-INSTI ARVs. Most had an undetectable HIV RNA viral load at delivery (75% INSTI and 72% non-INSTI, P = 0.7). The time to viral suppression was similar between groups (log rank test P = 0.43). Viral suppression at delivery was similar among INSTI ARVs: raltegravir (53%), elvitegravir (88%), dolutegravir (73%), and bictegravir (88%) (P = 0.13). Despite recommendations to prescribe INSTI in pregnancy for rapid viral suppression, we did not find a significant difference in time to viral suppression when pregnant individuals were taking non-INSTI ARVs. We did not find that one INSTI ARV was superior for viral suppression.

Effectiveness and safety of integrase strand transfer inhibitors in Spain: a prospective real-world study.

Second-generation integrase strand transfer inhibitors (INSTIs) are preferred treatment options worldwide, and dolutegravir (DTG) is the treatment of choice in resource-limited settings. Nevertheless, in some resource-limited settings, these drugs are not always available. An analysis of the experience with the use of INSTIs in unselected adults living with HIV may be of help to make therapeutic decisions when second-generation INSTIs are not available. This study aimed to evaluate the real-life effectiveness and safety of dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), and raltegravir (RAL) in a large Spanish cohort of HIV-1-infected patients. Real-world study of adults living with HIV who initiated integrase INSTIs DTG, EVG/c, and RAL-based regimens in three settings (ART-naïve patients, ART-switching, and ART-salvage patients). The primary endpoint was the median time to treatment discontinuation after INSTI-based regimen initiation. Proportion of patients experiencing virological failure (VF) (defined as two consecutive viral loads (VL) ≥200 copies/mL at 24 weeks or as a single determination of VL ≥1,000 copies/mL while receiving DTG, EVG/c or RAL, and at least 3 months after INSTI initiation) and time to VF were also evaluated. Virological effectiveness of EVG/c- and RAL-based regimens was similar to that of DTG when given as first-line and salvage therapy. Treatment switching for reasons other than virological failure was more frequent in subjects receiving EVG/c and, in particular, RAL. Naïve patients with CD4+ nadir <100 cells/μL were more likely to develop VF, particularly if they initiated RAL or EVG/c. In the ART switching population, initiation of RAL and EVG/c was associated with both VF and INSTI discontinuation. There were no differences in the time to VF and INSTI discontinuation between DTG, EVG/c and RAL. Immunological parameters improved in the three groups and for the three drugs assessed. Safety and tolerability were consistent with expected safety profiles. Whereas second-generation INSTIs are preferred treatment options worldwide, and DTG is one of the treatment of choices in resource-limited settings, first-generation INSTIs may still provide high virological and immunological effectiveness when DTG is not available.

Incidence of cardiometabolic outcomes among people living with HIV-1 initiated on integrase strand transfer inhibitor versus non-integrase strand transfer inhibitor antiretroviral therapies: a retrospective analysis of insurance claims in the United States.

Integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART) has been associated with weight gain, though there is limited information on associations between ART-related weight gain and cardiometabolic outcomes among people living with HIV-1 (PLWH). We, therefore, evaluated risks of incident cardiometabolic outcomes following INSTI versus non-INSTI-based ART initiation in the United States. We conducted a retrospective study using IBM MarketScan Research Databases (12 August 2012-31 January 2021). Treatment-naïve PLWH initiating ART (index date) on/after 12 August 2013 (approval date of the first second-generation INSTI, dolutegravir) were included and censored at regimen switch/discontinuation, end of insurance eligibility or end of data availability. We used inverse probability of treatment weights constructed with baseline (12 months pre-index) characteristics to account for differences between INSTI- and non-INSTI-initiating cohorts. Doubly robust hazard ratios (HRs) obtained from weighted multivariable Cox regression were used to compare time to incident cardiometabolic outcomes (congestive heart failure [CHF], coronary artery disease, myocardial infarction, stroke/transient ischemic attack, hypertension, type II diabetes, lipid disorders, lipodystrophy and metabolic syndrome) by INSTI-initiation status. Weighted INSTI (mean age = 39 years, 23% female, 70% commercially insured, 30% Medicaid insured) and non-INSTI (mean age = 39 years, 24% female, 71% commercially insured, 29% Medicaid insured) cohorts included 7059 and 7017 PLWH, respectively. The most common INSTI-containing regimens were elvitegravir-based (43.4%), dolutegravir-based (33.3%) and bictegravir-based (18.4%); the most common non-INSTI-containing regimens were darunavir-based (31.5%), rilpivirine-based (30.4%) and efavirenz-based (28.3%). Mean±standard deviation follow-up periods were 1.5±1.5 and 1.1±1.2 years in INSTI- and non-INSTI-initiating cohorts, respectively. INSTI initiators were at a clinically and significantly increased risk of experiencing incident CHF (HR = 2.12, 95% confidence interval [CI] = 1.08-4.05; p = 0.036), myocardial infarction (HR = 1.79, 95% CI = 1.03-5.65; p = 0.036) and lipid disorders (HR = 1.26, 95% CI = 1.04-1.58; p = 0.020); there was no evidence of an increased risk for other individual or composite outcomes. Over a short average follow-up period of <2 years, INSTI use among treatment-naïve PLWH was associated with an increased risk of several cardiometabolic outcomes, such as CHF, myocardial infarction and lipid disorders, compared to non-INSTI use. Further research accounting for additional potential confounders and with longer follow-up is warranted to more accurately and precisely quantify the impact of INSTI-containing ART on long-term cardiometabolic outcomes.

Risk of HIV Viral Rebound in the Era of Universal Treatment in a Multicenter Sample of Persons With HIV in Primary Care.

Antiretroviral therapy (ART) is recommended for people with HIV (PWH), irrespective of CD4 cell count, to improve their health and reduce the risk of transmission to sexual partners through long-term viral suppression. We identified risk factors for viral rebound among patients with a period of stable viral suppression to inform counseling and monitoring. We conducted a multisite, retrospective study of PWH with a 2-year period of sustained viral suppression in the United States using the Centers for AIDS Research Network of Integrated Clinical Systems cohort. We used multivariable logistic regression to identify characteristics independently associated with any viral rebound (viral load [VL] ≥200 copies/mL) and sustained viral rebound (VL ≥200 copies/mL followed by a VL that was also ≥200 copies/mL within 6 months), within 2 years of follow-up. Among 3496 eligible patients with a 2-year period of sustained viral suppression, most (90%) continued to have viral suppression over 2 additional years; 10% experienced viral rebound, and 4% experienced sustained viral rebound. In multivariable analyses, Black race, current smoking, integrase strand transfer inhibitor use, and 5- to 9-year duration of ART were positively associated, and being age ≥50 years was negatively associated, with any viral rebound. Only current smoking and 5- to 9-year (vs 2- to 4-year) duration of ART were positively associated, and being age ≥60 years was negatively associated, with sustained viral rebound. Most people retained in clinical care and with HIV viral suppression on ART will have persistent viral suppression. However, some patients may benefit from additional treatment adherence support.

Low level of HIV-1C integrase strand transfer inhibitor resistance mutations among recently diagnosed ART-naive Ethiopians

With the widespread use of Integrase strand transfer inhibitors (INSTIs), surveillance of HIV-1 pretreatment drug resistance is critical in optimizing antiretroviral treatment efficacy. However, despite the introduction of these drugs, data concerning their resistance mutations (RMs) is still limited in Ethiopia. Thus, this study aimed to assess INSTI RMs and polymorphisms at the gene locus coding for Integrase (IN) among viral isolates from ART-naive HIV-1 infected Ethiopian population. This was a cross-sectional study involving isolation of HIV-1 from plasma of 49 newly diagnosed drug-naive HIV-1 infected individuals in Addis-Ababa during the period between June to December 2018. The IN region covering the first 263 codons of blood samples was amplified and sequenced using an in-house assay. INSTIs RMs were examined using calibrated population resistance tool version 8.0 from Stanford HIV drug resistance database while both REGA version 3 online HIV-1 subtyping tool and the jumping profile Hidden Markov Model from GOBICS were used to examine HIV-1 genetic diversity. Among the 49 study participants, 1 (1/49; 2%) harbored a major INSTIs RM (R263K). In addition, blood specimens from 14 (14/49; 28.5%) patients had accessory mutations. Among these, the M50I accessory mutation was observed in a highest frequency (13/49; 28.3%) followed by L74I (1/49; 2%), S119R (1/49; 2%), and S230N (1/49; 2%). Concerning HIV-1 subtype distribution, all the entire study subjects were detected to harbor HIV-1C strain as per the IN gene analysis. This study showed that the level of primary HIV-1 drug resistance to INSTIs is still low in Ethiopia reflecting the cumulative natural occurrence of these mutations in the absence of selective drug pressure and supports the use of INSTIs in the country. However, continues monitoring of drug resistance should be enhanced since the virus potentially develop resistance to this drug classes as time goes by.

CD4/CD8 Ratio Recovery Among People Living With HIV Starting With First-Line Integrase Strand Transfer Inhibitors: A Prospective Regional Cohort Analysis.

We evaluated trends in CD4/CD8 ratio among people living with HIV (PLWH) starting antiretroviral therapy (ART) with first-line integrase strand transfer inhibitors (INSTI) compared with non-INSTI-based ART, and the incidence of CD4/CD8 ratio normalization. All PLWH enrolled in adult HIV cohorts of IeDEA Asia-Pacific who started with triple-ART with at least 1 CD4, CD8 (3-month window), and HIV-1 RNA measurement post-ART were included. CD4/CD8 ratio normalization was defined as a ratio ≥1. Longitudinal changes in CD4/CD8 ratio were analyzed by linear mixed model, the incidence of the normalization by Cox regression, and the differences in ratio recovery by group-based trajectory modeling. A total of 5529 PLWH were included; 80% male, median age 35 years (interquartile range [IQR], 29-43). First-line regimens were comprised of 65% NNRTI, 19% PI, and 16% INSTI. The baseline CD4/CD8 ratio was 0.19 (IQR, 0.09-0.33). PLWH starting with NNRTI- (P = 0.005) or PI-based ART (P = 0.030) had lower CD4/CD8 recovery over 5 years compared with INSTI. During 24,304 person-years of follow-up, 32% had CD4/CD8 ratio normalization. After adjusting for age, sex, baseline CD4, HIV-1 RNA, HCV, and year of ART initiation, PLWH started with INSTI had higher odds of achieving CD4/CD8 ratio normalization than NNRTI- (P < 0.001) or PI-based ART (P = 0.015). In group-based trajectory modeling analysis, INSTI was associated with greater odds of being in the higher ratio trajectory. INSTI use was associated with higher rates of CD4/CD8 ratio recovery and normalization in our cohort. These results emphasize the relative benefits of INSTI-based ART for immune restoration.

Association between integrase strand transfer inhibitor use with insulin resistance and incident diabetes mellitus in persons living with HIV: a systematic review and meta-analysis

Whether integrase strand transfer inhibitors (INSTIs) are associated with a higher risk of incident type 2 diabetes mellitus (DM) than other antiretroviral therapies (ART) needs to be established.MEDLINE, Embase, Web...

Integrase Strand Transfer Inhibitor Use in Children with Perinatal HIV-1 Infection: A Narrative Review.

Integrase strand transfer inhibitors (INSTIs), including raltegravir (RAL), dolutegravir (DTG), elvitegravir (EVG), bictegravir (BIC), and cabotegravir (CAB), are increasingly used, given excellent data on their efficacy, effectiveness, and tolerability profile in adults, while data in children are accumulating. To review the most recent evidence on the efficacy, effectiveness, safety, and resistance of INSTIs in children, a quick narrative review of the available literature data was performed using the MEDLINE/PubMed and Scopus databases, including only English-language studies, published between 2009 and 2022. Six studies (259 children) on RAL use, 17 studies (3,448 children) on DTG, 2 studies (73 children) on EVG, and 1 study (102 children) on BIC were retrieved. Results on efficacy and effectiveness were close to those reported in adult studies, suggesting similarities between children and adult population. Resistance to RAL was detected in four studies, ranging between 5.0% to 35.3% of participants. In four studies resistance to DTG occurred in 12.4% to 22% of children. Adverse events to RAL have been uncommon reported. In studies on EVG, 8% to 74% of children developed uveitis, nausea, or abdominal pain. In DTG studies, the proportion of weight gain ranged from 10% to 87%, and neuropsychiatric effects ranged 1% to 16% of participants. One BIC study reported adverse events >10% of participants. The evidence supports high efficacy and low toxicity of INSTIs in pediatric and adolescent populations.

1276. Noninvasive Assessment of Change in Hepatic Fibrosis Following Initiation of Integrase Inhibitors in Women Living with HIV

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in persons with HIV and can lead to hepatic fibrosis. Integrase strand-transfer inhibitors (INSTIs), first-line agents in antiretroviral therapy (ART), are associated with increased body mass index (BMI), particularly in women living with HIV (WLWH). We evaluated change in hepatic fibrosis risk following INSTI initiation in WLWH. Table 1.Change over time in hepatic fibrosis scores among group switching to INSTI-regimens versus group staying on non-INSTI regimens INSTI=integrase strand-transfer inhibitor; SD=standard deviation; FIB-4=Fibrosis-4 Score (calculated by Age*AST/[platelet count*ALT1/2]; APRI=AST to Platelet Ratio Index (calculated by [AST/AST upper limit of normal]/platelet count); NFS = Non Alcoholic Fatty Liver Disease Fibrosis Score (calculated by -1.675+(0.037*age) + (0.094*body mass index)+(1.13*hyperglycemia or diabetes [yes=1, no=0])+ (0.99*AST/ALT)-(0.013*platelet count)-(0.66*albumin)); CI=Confidence Interval. Linear regression model with unstructured covariance matrix for repeated observations with a person. Adjusted models for all outcomes included the following covariates: age, race/ethnicity, education, baseline CD4 lymphocyte count, baseline antiretroviral anchor drug, and abacavir, tenofovir disoproxil fumarate, and tenofovir alafenamide use. Body mass index was included in models for FIB-4 and APRI only. Age was included for APRI only. Methods Data from 2007-2020 were analyzed from virologically-suppressed WLWH enrolled in the Women’s Interagency HIV Study (WIHS). We excluded WLWH with untreated viral hepatitis, heavy alcohol use and autoimmune or metabolic chronic liver disease. WLWH who switched to or added an INSTI to ART were compared to women who remained on non-INSTI ART. Outcomes included change in noninvasive markers of hepatic fibrosis: Fibrosis-4 (FIB4), AST to Platelet Ratio Index (APRI), and NAFLD fibrosis score (NFS), measured 4-12 months before and 4-19 months post INSTI switch/add. Longitudinal linear regression models compared change over time in each outcome by group, adjusted for covariates. Results 872 WIHS participants (323 INSTI, 549 non-INSTI) were followed for a median 3.0 years (Q1 2.0, Q3 4.5). Mean age was 47.2 years (SD 9.0), 61% were Non-Hispanic Black, and mean BMI was 31.4 (8.8) kg/m2. Absolute mean changes in FIB4, APRI, and NFS scores were +0.021, -0.005, +0.194, respectively, in the INSTI group compared to +0.003, -0.011, +0.016, respectively, in the non-INSTI group (Table 1). No significant differences in mean AST and ALT change between the INSTI and non-INSTI groups were noted. There was a significant increase in NFS score in the INSTI group (p&amp;lt; 0.0001) and this difference remained in adjusted models (p=0.0135). Compared to the non-INSTI group, a larger proportion of participants in the INSTI group changed to a higher NFS risk category: 15.7% vs 9.0%, p=0.014. Conclusion Starting INSTIs was associated with minimal change in FIB4 and APRI scores but increased NFS score in WLWH. The increase in NFS score likely reflects BMI gain with INSTI use, as BMI is not factored into FIB4 or APRI calculators and AST and ALT did not change significantly. Nonetheless, patients starting INSTIs need close monitoring of metabolic changes and low thresholds for additional noninvasive liver fibrosis testing. Disclosures Michael A. Yu, MD, Ligera: Advisor/Consultant Maria L L. Alcaide, MD, Gilead: Advisor/Consultant Adaora A. Adimora, MD, MPH, Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support Jennifer C. Price, MD, PhD, Abbvie: Grant/Research Support|Gilead: Grant/Research Support|Merck: Grant/Research Support Phyllis C. Tien, MD, MSc, Gilead: Grant/Research Support|Merck: Grant/Research Support Cecile D. Lahiri, MD, MS, Theratechnologies: Advisor/Consultant.

HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment.

Children born to mothers, with or at risk, of human immunodeficiency virus type-1 (HIV-1) infection are on the rise due to affordable access of antiretroviral therapy (ART) to pregnant women or those of childbearing age. Each year, up to 1.3 million HIV-1-infected women on ART have given birth with recorded mother-to-child HIV-1 transmission rates of less than 1%. Despite this benefit, the outcomes of children exposed to antiretroviral drugs during pregnancy, especially pre- and post- natal neurodevelopment remain incompletely understood. This is due, in part, to the fact that pregnant women are underrepresented in clinical trials. This is underscored by any potential risks of neural tube defects (NTDs) linked, in measure, to periconceptional usage of dolutegravir (DTG). A potential association between DTG and NTDs was first described in Botswana in 2018. Incidence studies of neurodevelopmental outcomes associated with DTG, and other integrase strand transfer inhibitors (INSTIs) are limited as widespread use of INSTIs has begun only recently in pregnant women. Therefore, any associations between INSTI use during pregnancy, and neurodevelopmental abnormalities remain to be explored. Herein, United States Food and Drug Administration approved ARVs and their use during pregnancy are discussed. We provide updates on INSTI pharmacokinetics and adverse events during pregnancy together with underlying mechanisms which could affect fetal neurodevelopment. Overall, this review seeks to educate both clinical and basic scientists on potential consequences of INSTIs on fetal outcomes as a foundation for future scientific investigations.

HIV-1 integrase resistance associated mutations and the use of dolutegravir in Sub-Saharan Africa: A systematic review and meta-analysis.

As sub-Saharan Africa (SSA) countries are transitioning to dolutegravir (DTG)-based ART, baseline data are required for optimal monitoring of therapeutic response. In this frame, we sought to generate up-to-date evidence on the use of integrase-strand transfer inhibitors (INSTI) and associated drug resistance mutations (DRMs) within SSA. In this systematic review and meta-analysis, we included randomized and non-randomized trials, cohort-studies, cross-sectional studies, and case-reports published on INSTI or integrase DRMs in SSA. We included studies of patients exposed to DTG, raltegravir (RAL) or elvitegravir (EVG). Primary outcomes were "the rate of virological control (VC:<50copies/ml)" and "the presence of DRMs" on INSTI-based regimens among patients in SSA. We synthesised extracted data using subgroup analysis, and random effect models were used where appropriate. Additional analyses were conducted to assess study heterogeneity. We identified 1,916 articles/citations through database searches, of which 26 were included in the analysis pertaining to 5,444 patients (mean age: 37±13 years), with 67.62% (3681/5444) female. Specifically, 46.15% (12/26) studies focused on DTG, 26.92% (7/26) on RAL, 23.08% (6/26) on both DTG and RAL, and 3.85% (1/26) on EVG. We found an increasing use of DTG overtime (0% before 2018 to 100% in 2021). Median treatment duration under INSTI-based regimens was 12 [9-36] months. Overall, the rate of VC was 88.51% [95%CI: 73.83-97.80] with DTG vs. 82.49% [95%CI: 55.76-99.45] and 96.55% [95%CI: 85.7-100.00] with RAL and EVG, respectively. In univariate analysis, VC with DTG-containing vs. other INSTI-regimens was significantly higher (OR = 1.44 [95%CI: 1.15-1.79], p = 0.0014). Among reported DRMs at failure, the only DTG resistance-mutations were G118R and R263K. In SSA, DTG presents a superiority effect in VC compared to other INSTIs. Nonetheless, the early detection of INSTI-DRMs calls for sentinel surveillance for a successful transition and a sustained efficacy of DTG in SSA. PROSPERO Registration Number: CRD42019122424.