Integrase Strand Transfer Inhibitor Use Research Articles

Second-Generation Human Immunodeficiency Virus Integrase Inhibitors Induce Differentiation Dysregulation and Exert Toxic Effects in Human Embryonic Stem Cell and Mouse Models.

Each year, approximately 1.1 million children are exposed in utero to human immunodeficiency virus antiretrovirals, yet their safety is often not well characterized during pregnancy. The Tsepamo study reported a neural tube defect signal in infants exposed to the integrase strand transfer inhibitor (InSTI) dolutegravir from conception, suggesting that exposure during early fetal development may be detrimental. The effects of InSTIs on 2 human embryonic stem cell (hESC) lines were characterized with respect to markers of pluripotency, early differentiation, and cellular health. In addition, fetal resorptions after exposure to InSTIs from conception were analyzed in pregnant mice. At subtherapeutic concentrations, second-generation InSTIs bictegravir, cabotegravir, and dolutegravir decreased hESC counts and pluripotency and induced dysregulation of genes involved in early differentiation. At therapeutic concentrations, bictegravir induced substantial hESC death and fetal resorptions. It is notable that first-generation InSTI raltegravir did not induce any hESC toxicity or differentiation, at any concentration tested. Exposure to some InSTIs, even at subtherapeutic concentrations, can induce adverse effects in hESCs and pregnant mice. Given the increasingly prevalent use of second-generation InSTIs, including in women of reproductive age, it is imperative to further elucidate the effect of InSTIs on embryonic development, as well as their long-term safety after in utero exposure.

Weight change with integrase strand transfer inhibitors among virally suppressed Thai people living with HIV.

We compared weight changes in virally suppressed people living with HIV (PLWH) switching to integrase strand transfer inhibitors (INSTIs) with those remaining on an INSTI or non-INSTI regimen. PLWH aged ≥18 years with weight measurements available at baseline between 2001 and 2020 were included. Viral suppression was defined as having had a viral load <400 copies/mL for 6 months. Baseline was defined as the time of switching from a non-INSTI to an INSTI regimen whilst virally suppressed (switch group) or the time that viral suppression was achieved (remain groups). Generalized estimating equations adjusted for age, sex and baseline weight were used to model weight changes 6, 12, 18 and 24 months after baseline. A total of 1673 PLWH contributed 1952 episodes of viral suppression-143 (7.3%) episodes were among PLWH who had switched from a non-INSTI to an INSTI, 102 (5.2%) episodes were among PLWH who remained on an INSTI and 1707 (87.4%) episodes were among PLWH who remained on a non-INSTI. PLWH in the switch group had significantly greater weight gain than those in the remain groups at 6, 12 and 18 months after achieving viral suppression. By 24 months, weight change on all regimens started to converge. Tenofovir alafenamide use was not significantly associated with weight gain in adjusted models. Our findings suggest that the mechanisms of weight gain due to INSTI use go beyond their superior efficacy over other antiretrovirals in controlling HIV or the effect of the 'return-to-health' phenomenon. Further research is needed to understand the mechanisms of such weight gain.

Dolutegravir in Mexico for special populations: A cost analysis perspective.

Integrase strand-transfer inhibitors (INSTI) are the latest class of antiretrovirals registered in Mexico. They include raltegravir (RAL), elvitegravir/cobicistat (EVG/c), dolutegravir (DTG) and bictegravir (BIC). Along with international guidelines, Mexico adopted the use of INSTI about two years ago as initial antiretroviral therapy (ART). This is partially due to the increase in the pre-treatment resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI), mainly efavirenz (EFV). Furthermore, INSTI depict greater efficacy, safety and less drug-drug interactions than NNRTI and protease inhibitors (PI). DTG is a second generation INSTI with a high barrier to resistance. It is recommended in international and national guidelines in a wide variety of clinical scenarios for persons living with human immunodeficiency virus (HIV) (PLWHIV), including treatment-naïve, first-line NNRTI treatment failure, simplification switch in suppressed patients, pregnancy, women with childbearing potential, adolescents and children over 6 years of age. DTG is mostly metabolized by the liver UDP-glucuronosyltransferase, and exhibits low drug-drug interactions overall; on the other hand, it has an extremely low renal elimination, therefore may be used in PLWHIV with advanced kidney disease without dose modification. Tuberculosis is a common coinfection in Mexico that requires rifampin-based anti-tuberculosis therapy, which requires increasing DTG to double dosing (50 mg BID). In Mexico, DTG-based regimens are likely to be cost-effective in many scenarios, given its acquisition costs and the particularities of the HIV population and associated clinical conditions, including a relatively high proportion of the following: i) new HIV diagnoses presenting at acquired immunodeficiency syndrome (AIDS) stage; ii) high rate of tuberculosis coinfection; iii) frequent first-line NNRTI treatment failures; and iv) relatively high proportion of infected children and adolescents.

Integrase Strand Transfer Inhibitors Are Associated With Incident Diabetes Mellitus in People With Human Immunodeficiency Virus.

Integrase strand transfer inhibitors (INSTIs) are associated with weight gain in people with HIV (PWH). Less is known about the risk of other metabolic outcomes such as diabetes mellitus and hyperglycemia. IBM® MarketScan® databases for commercially and Medicaid-insured adults were used to identify PWH newly initiating antiretroviral therapy (ART). The primary outcome was a composite of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation and was identified using International Classification of Disease, Ninth revision, Clinical Modification (ICD-9-CM) and ICD-10-CM diagnosis and procedure codes and Current Procedural Terminology, 4th Edition (CPT-4) codes. To examine the relationship between INSTI use and the composite outcome, we estimated the risk using Cox proportional hazards models with calendar time-specific standardized mortality ratio weights. Of 42 382 PWH who initiated ART between 1 July 2007 and 30 June 2018, 22 762 (54%) were treated with INSTI-based regimens. Mean age was 38 years, 74% were male, and 19% were Medicaid insured. PWH on INSTIs were 31% more likely to develop new-onset diabetes mellitus/hyperglycemia (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.15-1.48]) compared with those who initiated non-INSTI-based regimens. When examined individually, the highest risk was associated with elvitegravir (HR, 1.54; 95% CI, 1.32-1.97; P < .001) and the lowest risk with raltegravir (HR, 1.19; 95% CI, 1.03-1.37; P = .02). INSTI use was associated with increased risk of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation.

Impact of Integrase Strand Transfer Inhibitor Use During Pregnancy on Viral Suppression at Delivery and Infant Outcomes: A Statewide Retrospective Cohort Study.

We sought to determine whether pregnant women with HIV prescribed integrase strand transfer inhibitor (INSTI) were more likely to have viral suppression at delivery and any increased risk of adverse infant outcomes. This was a retrospective, statewide cohort study of women with HIV and their HIV-exposed infants who delivered in South Carolina from 2008 to 2019. Women's antenatal AVRs were classified as INSTI or non-INSTI. We compared the percentage of women with undetectable HIV RNA viral load (<40 copies/mL) at delivery between groups. We compared the percentage of HIV-exposed singleton infants who were born preterm delivery, low birth weight, and small for gestational age and had confirmed perinatal HIV infection. Categorical outcomes were compared using the χ2 test or Fischer exact test. A total of 832 infants, including 11 sets of twins, were exposed to maternal HIV. Detailed antiretroviral regimens were available for analysis in a third of mother-infant pairs (n = 315). Half of the infants were exposed to INSTI (159) and half to non-INSTI antiretrovirals (156). Most women had an undetectable viral load at delivery (80% INSTI and 73% non-INSTI, P= 0.11). The percentage of singleton infants with adverse outcomes was similar between INSTI and non-INSTI groups: preterm delivery (21% and 16%, P = 0.3), low birth weight (19% and 21%, P = 0.7), small for gestational age (11% vs 9%, P = 0.5), and perinatal HIV infection (2.5% and 1.3%, P = 0.7). We observed that viral suppression before delivery was similar between pregnant women prescribed INSTI and non-INSTI antiretroviral therapy. The percentage of infants with adverse outcomes was similar when exposed to INSTI and non-INSTI antiretroviral therapy.

Association between integrase strand transfer inhibitor (INSTIs) use with insulin resistance and incident diabetes mellitus in persons living with HIV: A systematic review and meta-analysis protocol.

Poeple living with HIV have higher prevalence of diabetes mellitus and metabolic perturbations compared to non-HIV populations. Diabetes and metabolic syndrome co-morbidities add significant burden to HIV care. Currently, WHO recommends integrase strand transfer inhibitors (INSTIs) as the first or second line therapy in people with HIV due to overall good tolerability and safety profile. However, whether INSTI use increases the risk of incident diabetes (with or without metabolic syndrome) compared to other anti-retroviral therapies (ART) is controversial. In this systematic review and meta-analysis, we aim to examine this risk in HIV-positive populations receiving INSTIs compared to other ART regimens (not containing INSTIs). The study will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. This protocol adheres to the Standard Protocol Items for reporting systematic reviews and meta-analyses checklist. Eligibility criteria will be original peer-reviewed published articles and conference abstracts with no language or geographical restriction; that report the ocurrence of diabetes mellitus as a discrete outcome or part of metabolic syndrome, in adult PLWHIV receiving INSTIs compared to other ART regimens. PubMed/ Medline, Web of Science, Embase and Cochrane Database of Systematic Reviews will be searched from 1st- January-2000 to 31st-January-2022. Per our a priori, screening, inclusion and data extraction will be conducted separately by two investigators, and a senior researcher will be consulted in case of disagreement. The quality of included studies will be assessed by the Newcastle-Ottawa Scale (NOS) for cohort and case-control studies and the revised Cochrane risk-of-bias tool (ROB2) for randomized controlled trials. The quantitative synthesis of the study outcomes will be explored in different subgroups and sensitivity analyses. Meta regression will also be performed to further test the predictors of the outcome. Ethical approval is waived as the study is a review of published litterature. The analyses will be presented in conferences and published as a scientific article. PROSPERO registration number is; CRD42021273040.

Use of integrase inhibitors in HIV-associated tuberculosis in high-burden settings: implementation challenges and research gaps.

People living with HIV have a higher risk of developing tuberculosis, and tuberculosis is one of the leading causes of death among people living with HIV globally. Treating HIV and tuberculosis concurrently has morbidity and mortality benefits. However, HIV and tuberculosis co-treatment is challenging due to drug-drug interactions, overlapping toxicities, tuberculosis-associated immune reconstitution syndrome, and concerns for treatment failure or drug resistance. Drug-drug interactions between antiretrovirals and tuberculosis drugs are driven mainly by the rifamycins (for example, the first-line tuberculosis drug rifampicin), and dose adjustments or drug switches during co-treatment are commonly required. Several implementation challenges and research gaps exist when combining the integrase strand transfer inhibitors (INSTIs), highly potent antiretroviral drugs recommended as first-line treatment of HIV, and drugs used for the treatment and prevention of tuberculosis. Ongoing and planned studies will address some critical questions on the use of INSTIs in settings with a high tuberculosis burden, including dosing of dolutegravir, bictegravir, and cabotegravir when used with the rifamycins for both tuberculosis treatment and prevention. Failure, in the past, to include people with tuberculosis in HIV clinical treatment trials has been responsible for some of the research gaps still evident for informing optimisation of HIV and tuberculosis co-treatment.

Effect of Integrase Strand Transfer Inhibitor use on Time to HIV Viral Suppression and Viral Suppression before Delivery

Integrase strand transfer inhibitors (INSTIs) are a preferred antiretroviral (ARV) class for the prevention of perinatal HIV during pregnancy due to their ability to rapidly suppress HIV viral load and high barrier to resistance. We sought to determine if pregnant women with HIV on ARV regimens containing INSTIs achieve viral suppression faster than women taking non-INSTI ARV regimens. We sought to determine if there were differences in viral suppression at delivery between INSTI and non-INSTI regimens as well as individual INSTI drugs.

Integrase Strand Transfer Inhibitor Use and Cancer Incidence in a Large Cohort Setting.

BackgroundLimited data exist examining the association between incident cancer and cumulative integrase inhibitor (INSTI) exposure.MethodsParticipants were followed from baseline (latest of local cohort enrollment or January 1, 2012) until the earliest of first cancer, final follow-up, or December 31, 2019. Negative binomial regression was used to assess associations between cancer incidence and time-updated cumulative INSTI exposure, lagged by 6 months.ResultsOf 29 340 individuals, 74% were male, 24% were antiretroviral treatment (ART)-naive, and median baseline age was 44 years (interquartile range [IQR], 36–51). Overall, 13 950 (48%) individuals started an INSTI during follow-up. During 160 657 person-years of follow-up ([PYFU] median 6.2; IQR, 3.9–7.5), there were 1078 cancers (incidence rate [IR] 6.7/1000 PYFU; 95% confidence interval [CI], 6.3–7.1). The commonest cancers were non-Hodgkin lymphoma (n = 113), lung cancer (112), Kaposi’s sarcoma (106), and anal cancer (103). After adjusting for potential confounders, there was no association between cancer risk and INSTI exposure (≤6 months vs no exposure IR ratio: 1.15 [95% CI, 0.89–1.49], >6–12 months; 0.97 [95% CI, 0.71–1.32], >12–24 months; 0.84 [95% CI, 0.64–1.11], >24–36 months; 1.10 [95% CI, 0.82–1.47], >36 months; 0.90 [95% CI, 0.65–1.26] [P = .60]). In ART-naive participants, cancer incidence decreased with increasing INSTI exposure, mainly driven by a decreasing incidence of acquired immune deficiency syndrome cancers; however, there was no association between INSTI exposure and cancer for those ART-experienced (interaction P < .0001).ConclusionsCancer incidence in each INSTI exposure group was similar, despite relatively wide CIs, providing reassuring early findings that increasing INSTI exposure is unlikely to be associated with an increased cancer risk, although longer follow-up is needed to confirm this finding.

Integrase Inhibitor Use Associated with Weight Gain in Women and Incident Diabetes Mellitus.

Excessive weight gain associated with integrase strand transfer inhibitor (InSTI) antiretrovirals is an emerging issue; however, the metabolic consequences of this effect have not been established. Our objective was to evaluate for InSTI-emergent weight gain and potential associated type 2 diabetes mellitus (T2DM) among a diverse HIV patient cohort. For this retrospective cohort study, we obtained clinical warehouse data for HIV+ patients between fiscal years 2007-17. We compared patients initiated on an InSTI with those started on an alternate regimen. Our primary outcome was percentage weight change from baseline to 24 months postinitiation using the linear mixed-effects model fit by restricted maximum likelihood. Our secondary outcome was incident T2DM as defined by a new prescription for antihyperglycemic medication within 18 months after antiretroviral therapy (ART) start. Diabetes-free survival was estimated using the Kaplan-Meier method, log-rank test, and Cox proportional-hazards model. The cohort included 1,235 individuals initiating ART, 136 (11.0%) with an InSTI. InSTI use in women was significantly associated with greater weight gain compared with non-InSTIs (11.0%, 95% confidence interval, CI: 5.22 to 16.8, p < .01), after adjusting for potential confounding variables. In a univariate analysis, InSTI use was associated with more incident T2DM diagnoses compared with non-InSTI regimens (unadjusted hazard ratio = 3.27, p = .01), although incident T2DM was not associated with weight gain. InSTIs were significantly associated with weight gain among females. We also observed an increased risk of incident diabetes mellitus among both sexes, however, unrelated to weight changes. Further prospective studies will be necessary to confirm this finding and investigate its mechanism.

Transmitted Drug Resistance Among Human Immunodeficiency Virus (HIV)-1 Diagnoses in the United States, 2014-2018.

Transmitted human immunodeficiency virus (HIV) drug resistance can threaten the efficacy of antiretroviral therapy and pre-exposure prophylaxis (PrEP). Drug-resistance testing is recommended at entry to HIV care in the United States and provides valuable insight for clinical decision making and population-level monitoring. We assessed transmitted drug-resistance-associated mutation (TDRM) prevalence and predicted susceptibility to common HIV drugs among US persons with HIV diagnosed during 2014-2018 who had a drug resistance test performed ≤3 months after HIV diagnosis and reported to the National HIV Surveillance System and who resided in 28 jurisdictions where ≥20% of HIV diagnoses had an eligible sequence during this period. Of 50 747 persons in the analysis, 9616 (18.9%) had ≥1 TDRM. TDRM prevalence was 0.8% for integrase strand transfer inhibitors (INSTIs), 4.2% for protease inhibitors, 6.9% for nucleoside reverse transcriptase inhibitors (NRTIs), and 12.0% for non-NRTIs. Most individual mutations had a prevalence <1.0% including M184V (0.9%) and K65R (0.1%); K103N was most prevalent (8.6%). TDRM prevalence did not increase or decrease significantly during 2014-2018 overall, for individual drug classes, or for key individual mutations except for M184V (12.9% increase per year; 95% confidence interval, 5.6-20.6%). TDRM prevalence overall and for individual drug classes remained stable during 2014-2018; transmitted INSTI resistance was uncommon. Continued population-level monitoring of INSTI and NRTI mutations, especially M184V and K65R, is warranted amidst expanding use of second-generation INSTIs and PrEP.

Integrase Strand Transfer Inhibitor Start or Switch Impacts Learning in Women With HIV.

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). Women's Interagency HIV Study, a multisite, prospective, cohort study. 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. 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. 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.

Antiretroviral Therapy Anchor-based Trends in Body Mass Index Following Treatment Initiation Among Military Personnel with HIV.

Weight gain and obesity in people living with HIV have been associated with increased risk for non-AIDS-related comorbidities, and integrase strand transfer inhibitor (INSTI)-based regimens may lead to comparatively more weight gain than other regimens. We evaluated body mass index (BMI) following antiretroviral therapy (ART) initiation among participants in the U.S. Military HIV Natural History Study (NHS). NHS participants with available baseline weight and height data initiating ART from 2006 to 2017 were considered for analysis. Antiretroviral therapy was categorized by anchor class to include INSTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Linear growth-curve modeling was used to predict BMI changes from ART initiation through 2 years of follow-up in participants stratified by baseline BMI (<25 vs ≥25 kg/m2) at ART start and anchor drug class. These models were adjusted for demographic- and HIV-related characteristics. Of 961 NHS participants started on initial ART between 2006 and 2017, 491 men who had available baseline BMI data and were virally suppressed (<200 c/mL) at 1 and 2 years of follow-up were included. Overall, the predicted BMI increased at each time point over 2 years regardless of baseline BMI. There was a trend toward less weight gain for non-INSTI regimens regardless of demographic- or HIV-related factors (-0.65 kg/m2/yr, P = .070). In participants with BMI <25, all regimens were associated with BMI gains except in those with high viral load (≥100,000 copies/mL) started on PI regimens (-1.91 kg/m2/yr, P = .000; n = 13). For those participants with BMI ≥25, only INSTI- and PI-based regimens were significantly associated with increased BMI (INSTI 0.54 kg/m2/y, P = .000; PI 0.39 kg/m2/yr, P = .006). Non-nucleoside reverse transcriptase inhibitors were not associated with weight gain regardless of race- or HIV-related characteristics. African Americans with BMI ≥25 were more likely to gain weight as compared to Whites (0.99 kg/m2/yr, P = .016). Specific anchor drug-based predictions revealed that only INSTI use among African Americans was significantly associated with BMI gains (1.85 kg/m2/yr, P = .007); NNRTI- and PI-related weight change was not significant as compared to Whites. In our cohort of young military members with HIV infection, those with BMI <25 experienced BMI gains across all ART classes. Among those with BMI ≥25, African Americans on INSTI regimens had the greatest BMI gains. Further studies are needed to determine whether NNRTI regimens should be considered in certain individuals at risk for INSTI-associated weight gain.

946. Risk factors and Metabolic Implications of Integrase Inhibitor Associated Weight Gain

BackgroundExcessive weight gain associated with integrase strand transfer inhibitor (InSTI) antiretrovirals is an emerging issue in the current antiretroviral treatment (ART) era. Despite the known association between excess weight and impaired glucose tolerance in the general population, the metabolic implications of InSTI-associated weight gain have not been established. The objective of this study was to evaluate the presence of InSTI-associated weight gain amongst a diverse, urban population and to investigate potential risk factors and metabolic implications.MethodsWe obtained demographic, pharmacy and laboratory data from the hospital clinical data warehouse for ART-naïve adult HIV+ patients at Boston Medical Center between fiscal year (FY) 2007-2017. We compared patients who initiated on an InSTI to those with an alternate regimen (i.e. PI, NNRTI) who remained on their initial regimen for at least 18 months. Individuals with diabetes mellitus (DM) prescription or ICD 9/10 code prior to ART initiation were excluded. Our primary outcome was percent weight change in the first 24 months of ART estimated by linear mixed effects model fit by restricted maximum likelihood. Our secondary outcome was incident DM diagnosis in the 18 months after ART using progression-free survival (PFS). PFS rates were estimated by the Kaplan-Meier method and log-rank test, and Cox proportional-hazards model were determined, all using R v3.6.2.ResultsBetween FY 2007-2017, 139 patients were initiated on InSTIs and 1117 were initiated on alternative anchor regimens. Approximately, one third of the cohort was female and more than 75% were non-white. InSTI use in women was associated with increased weight gain in the first 24 months of ART compared to non-InSTIs (+9.57%, p = 0.002, Figure 1). InSTI use was associated with more incident DM diagnoses in the first 18 months of ART compared to non-InSTI regimens (HR = 3.27, p = 0.014).Figure 1: Percentage weight change from baseline at ART initiation between InSTI and non-InSTI regimens ConclusionFemales have higher InSTI-associated weight gain which suggests they may be more susceptible to adverse metabolic issues. InSTI use appears to be associated with an increased incidence of DM diagnoses following ART initiation. Further prospective and controlled studies will be necessary to describe the mechanism of this effect and refine HIV management strategies.Disclosures Archana Asundi, MD, Gilead (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)ViiV (Scientific Research Study Investigator) Nina H. Lin, MD, Gilead Sciences (Scientific Research Study Investigator)ViiV (Scientific Research Study Investigator)

1049. Weight Gain in Persons Living with HIV (PLWH) Treated with Bictegravir Compared to Other Integrase Strand Transfer Inhibitors

BackgroundRecent studies have given rise to the concern that some integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy may lead to weight gain in PLWH. The objectives of this study were to compare the incidence of weight gain following initiation of bictegravir (BIC) compared to other INSTIs, and to assess whether any differences were associated with changes in metabolic indices.MethodsPatients from the VA San Diego Healthcare System (VASDHS) were included in this retrospective cohort study if they were at least 18 years old and being treated for HIV with an INSTI that was started exclusively with FTC/TAF for at least 6 months. INSTI-containing regimens were excluded if initiated with non-FTC/TAF antiretroviral agents or if the patient was pregnant, using prescription weight loss drugs, or did not have weights recorded after the start of the studied regimen. The primary outcome was weight gain at 12 and 18 months after the start of the studied regimen. Secondary outcomes included changes in parameters used to define metabolic syndrome. Statistical analysis was performed using Mann-Whitney U, Chi-square, and Spearman’s Rho tests.Results560 patients with 809 instances of new INSTI prescriptions from VASDHS during November 2015 to October 2019 were reviewed for inclusion. Raltegravir-based regimens were excluded from analysis due to the limited number of eligible regimens. Study groups included group 1 (BIC, n=265), group 2 (elvitegravir/cobicistat, n=123), and group 3 (dolutegravir, n=35). There were no significant differences in baseline weight between groups. Median weight change at 12 months was 2.8 lbs. in group 1, 4.4 lbs. in group 2 (p=0.328 vs. group 1), and 5.3 lbs. in group 3 (p=0.133 vs. group 1). At 18 months, median weight change was 4.5 lbs. in group 1, 3.4 lbs. in group 2 (p=0.597 vs. group 1), and 7.7 lbs. in group 3 (p=0.585 vs. group 1). Within group 1, there was a significant increase in weight at 3, 6, 12, and 18 months compared to index date.ConclusionThese results support the growing body of evidence associating INSTI use with weight gain, which was persistent over 18 months in all groups and in the context of a consistent FTC/TAF backbone in this study. No significant differences in magnitude of weight gain were observed between INSTIs.Disclosures All Authors: No reported disclosures

Metabolic Changes Associated With the Use of Integrase Strand Transfer Inhibitors Among Virally Controlled Women.

Integrase strand transfer inhibitors (INSTIs) have been associated with weight gain among women living with HIV. We aimed to investigate the association between INSTIs and change in cardiometabolic risk indicators. Retrospective cohort. Data from 2006 to 2017 were analyzed from women living with HIV enrolled in the longitudinal Women's Interagency HIV Study who were virally controlled on antiretroviral therapy (ART) for ≥5 consecutive semiannual visits. Women who switched/added an INSTI to ART (INSTI group) were compared with women who remained on non-INSTI ART (non-INSTI group). Outcomes included changes in fasting lipids and glucose, hemoglobin A1c (HbA1c), blood pressure (BP), and incident diabetes, hypertension, and insulin resistance. Outcomes were measured 6-12 months before and 6-18 months after INSTI switch/add in the INSTI group with comparable visits in the non-INSTI group. Longitudinal linear regression models compared change over time in each outcome by the study group. One thousand one hundred eighteen participants (234 INSTI, 884 non-INSTI) were followed for a median 2.0 (Q1 1.9, Q3 2.0) years. Participants were median age 49 years, 61% Black, and 73% overweight or obese (body mass index ≥25 kg/m). Compared with non-INSTI, the INSTI group experienced greater increases in HbA1c (+0.05 vs. -0.06 mg/dL, P = 0.0318), systolic BP (+3.84 vs. +0.84 mm Hg, P = 0.0191), and diastolic BP (+1.62 vs. -0.14 mm Hg, P = 0.0121), with greatest change in HbA1c among women on INSTIs with ≥5% weight gain. INSTI use was associated with unfavorable changes in HbA1c and systolic and diastolic BP during short-term follow-up. Further research is needed to understand long-term cardiometabolic effects of INSTI use.

Prevalence of integrase strand transfer inhibitor resistance mutations in antiretroviral-naive HIV-1-infected individuals in Cameroon.

In Cameroon, the integrase (IN) strand transfer inhibitor (INSTI) dolutegravir was recently introduced for the treatment of HIV-1 infection. Since pretreatment HIV-1 drug resistance can jeopardize the success of ART, and considering the high heterogeneity of circulating HIV-1 subtypes in Cameroon, we investigated the prevalence of pretreatment HIV-1 resistance to INSTIs. Fingerprick dried blood spot samples were collected from 339 newly diagnosed HIV-1-infected individuals between 2015 and 2016 in four hospitals in Cameroon. Universal primers were designed to amplify the HIV-1 IN region from amino acid 1 to 276. Amplicons were sequenced with Illumina next-generation sequencing and analysed with the Polymorphism Analysis Sequencing (PASeq) platform, using the Stanford HIV Drug Resistance Database to interpret HIV-1 drug resistance mutations (DRMs). The amplification/sequencing success rate was 75.2% with 255/339 sequences obtained. Applying a cut-off of 1%, major DRMs to INSTIs were detected in 13 (5.1%) individuals, but only 1 individual harboured an INSTI DRM (E92G) at a nucleotide frequency ≥15%. However, 140/255 (54.9%) individuals harboured polymorphic accessory INSTI DRMs, mainly at high frequencies. In line with that observation, HIV-1 subtype diversity among individuals was high. Pretreatment HIV-1 resistance to INSTIs was low in the study sites, which supports the use of INSTIs in Cameroon. Nevertheless, further studies are necessary to assess the impact of polymorphic accessory INSTI DRMs on INSTI-based ART regimens.

HIV-1 Integrase Inhibitors: A Comparative Review of Efficacy and Safety.

The newest class of antiretrovirals for all persons living with HIV are the integrase strand transfer inhibitors (INSTIs). Since 2007, five INSTIs have been introduced: raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. The INSTIs have favorable pharmacokinetic and pharmacodynamic properties, which contribute to both their effectiveness and their ease of use. With the exception of cabotegravir, each INSTI is US Food and Drug Administration approved for treatment-naïve individuals initiating antiretroviral therapy. All of the INSTIs, except raltegravir, are approved for antiretroviral treatment simplification for virologically suppressed patients without INSTI resistance. Data also support the use of dolutegravir and raltegravir in individuals with antiretroviral resistance as part of an optimized antiretroviral regimen. INSTIs are generally well tolerated by people living with HIV compared with older classes of antiretrovirals, but emerging data suggest that some INSTIs contribute to weight gain. Due to their efficacy, safety, and ease of use, HIV treatment guidelines recommend oral INSTIs as preferred components of antiretroviral therapy for individuals initiating therapy. The newest INSTI, cabotegravir, represents an alternative to oral administration of life-long antiretroviral therapy with the availability of a long-acting injectable formulation. This review summarizes the current use of INSTIs in adults living with HIV, highlighting the similarities and differences within the class related to pharmacodynamics, pharmacokinetics, safety, dosing, and administration that contribute to their role in modern antiretroviral therapy.

Brief Report: Integrase Strand Transfer Inhibitors Are Associated With Lower Risk of Incident Cardiovascular Disease in People Living With HIV.

Several antiretroviral therapy (ART) classes have been associated with increased myocardial infarction (MI) risk. Cardiovascular disease in people living with HIV (PLWH) on integrase strand transfer inhibitors (INSTI) has not been examined. Here we aim to examine this. Retrospective cohort design study. We used the IBMMarketScan databases for U.S. commercially insured and Medicaid covered adults to identify PLWH newly initiated on ART between January 1, 2008 and December 30, 2015. Major adverse cardiac event (MACE), a composite of acute MI, ischemic stroke, coronary artery bypass grafting, and percutaneous coronary intervention was the primary outcome. We used calendar time-specific probability-weighted Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for the association between INSTI use and MACE. We used propensity score weighting methods to account for potential confounding. Twenty thousand two hundred forty-two new ART initiators were identified. 5069 (25%) PLWH initiated INSTI-based regimens. 203 MACE events occurred; acute MI 16 (0.32%) vs 66 (0.43%), stroke 24 (0.47%) vs 54 (0.36), coronary artery bypass grafting 2 (0.04%) vs 9 (0.06%), percutaneous coronary intervention 7 (0.14%) vs 25 (0.16%) of INSTI users vs non-users. INSTI-based ART was associated with significantly lower risk of MACE events (hazard ratios 0.79; 95% confidence intervals: 0.64 to 0.96) compared with non-INSTI-based regimens. In this cohort, INSTI-based regimens were associated with a 21% decreased risk of incident cardiovascular disease. These finding require validation in other cohorts and with longer follow-up.

First-line HIV treatment outcomes following the introduction of integrase inhibitors in UK guidelines.

Objective:To investigate the characteristics and outcomes of people who initiated different antiretroviral therapy (ART) regimens during the era of integrase strand transfer inhibitors (INSTIs).Design:UK-based observational cohort study.Methods:UK Collaborative HIV Cohort study participants were included if they had started ART between 1 January 2012 and 30 June 2017. Virological failure was defined as the first of two consecutive plasma HIV RNA more than 50 copies/ml, at least 6 months after starting ART. Follow-up was censored at ART discontinuation, class switch or death. The risk of virological failure among those on INSTI, protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens was compared using Kaplan–Meier and Cox regression methods.Results:Of 12 585 participants, 45.6% started a NNRTI, 29.0% a protease inhibitor and 25.4% an INSTI regimen. Over a median follow-up of 20.3 months (interquartile range 7.9–38.9), 7.5% of participants experienced virological failure. Compared with those starting an NNRTI regimen, people receiving INSTIs or protease inhibitors were more likely to experience virological failure: INSTI group adjusted hazard ratio 1.52, 95% confidence interval 1.19–1.95, P = 0.0009; protease inhibitor group adjusted hazard ratio 2.70, 95% confidence interval 2.27–3.21, P less than 0.0001, likelihood ratio test P less than 0.0001.Conclusion:First-line INSTI regimens were associated with a lower risk of virological failure than protease inhibitor regimens but both groups were more likely to experience virological failure than those initiating treatment with a NNRTI. There is likely to be residual channelling bias resulting from selected use of INSTIs and protease inhibitors in specific clinical contexts, including in those with a perceived risk of poor adherence.