INSTI-containing Regimen Research Articles

No accelerated progression of subclinical atherosclerosis with integrase strand transfer inhibitors compared to non-nucleoside reverse transcriptase inhibitors.

The role of integrase strand transfer inhibitors (INSTI) in the cardiovascular risk of people with HIV is controversial. To assess the association of INSTI to subclinical atherosclerosis progression measured with the carotid intima-media thickness (cIMT). Prospective study in virologically suppressed people with HIV receiving INSTI- or NNRTI-based regimens. cIMT was measured at baseline, 48 and 96 weeks. cIMT progression was analysed both as a continuous and categorical variable, defined as cIMT increase ≥ 10% and/or new carotid plaque. Adjustments through Cox proportional hazard regression and linear mixed models, and propensity score matching were conducted. 190 participants were recruited and 173 completed the 96 week follow-up. 107 (56.3%) were receiving an INSTI-containing, 128 (67.4%) a NNRTI-containing and 45 (23.7%) a NNRTI plus an INSTI-containing regimen. The overall median (IQR) 2-year change of cIMT was 0.029 (-0.041 to 0.124) mm; 87 (45.8%) participants experienced a cIMT increase ≥ 10%, of whom 54 (28.4%) developed a new carotid plaque. Adjusted Cox regression showed no differences between INSTI and NNRTI groups in the categorical 2-year progression of cIMT, both including or excluding participants receiving INSTI + NNRTI. Similar results were observed for the continuous cIMT increase through adjusted linear mixed models. Propensity score matching showed no significant differences in the 2 year cIMT change between treatment groups [0.049 mm (-0.031-0.103) in the INSTI group versus 0.047 mm (-0.023-0.115) in the NNRTI group; P = 0.647]. cIMT progression was associated with traditional cardiovascular risk factors. INSTI-based regimens are not associated with increased progression of subclinical atherosclerosis when compared to NNRTI.

Prevalence of integrase strand transfer inhibitor resistance in people living with HIV and virological failure.

This study aims to delineate the resistance profiles of integrase strand transfer inhibitors (INSTIs) among patients in southern Taiwan who had experienced antiretroviral therapy (ART) failure. We focused on individuals previously treated with highly active ART (HAART) regimens, providing insights into the implications of INSTI resistance in a broader treatment-experienced population. Data were collected from patients failing an INSTI-containing regimen in a medical center in southern Taiwan between 2009 and 2022. Virological failure was defined as a plasma viral load >1000 copies/mL. Reverse transcriptase, protease, and integrase coding regions were sequenced at failure. Resistance-associated mutations included in the 2022 International Antiviral Society (IAS)-USA list were used. Drug resistance was analyzed using the HIV Stanford HIVDB 9.4 edition algorithm. Logistic regression analysis was used to analyze the risk factors associated with INSTI failure. A total of 184 patients were enrolled for genotypic drug resistance testing due to virological failure, of whom 104 failed on nonnucleoside reverse transcriptase inhibitors, 58 on protease inhibitors (PIs), and 21 on INSTIs. Among 21 patients who failed INSTI therapy, 6 failed raltegravir-based treatment, 3 elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF), 2 bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), and 10 abacavir/dolutegravir/lamivudine (ABC/DTG/3TC). Only 10 patients had INSTI drug resistance testing results available, and 40% (4/10) showed INSTI resistance at failure. Among the seven patients who failed on second-generation INSTIs with drug resistance reports available, one harbored E157Q and another with R263K mutations, respectively. Multivariable logistic regression analysis showed that patients with INSTI failure were less likely to have pol resistance (p = 0.007, adjusted odds ratio [OR], 0.176, 95% CI, 0.050-0.618), less previous exposure to NNRTI (p = 0.003, aOR, 0.063, 95% CI, 0.010-0.401), PIs (p = 0.002, aOR, 0.030, 95% CI, 0.003-0.272), and with long duration of HAART (p = 0.018, aOR, 1.02, 95% CI, 1.003-1.037). INSTI resistance was uncommon when used as the first-line single tablet regimen in Taiwan. The results confirmed the robustness of ABC/DTG/3TC and BIC/FTC/TAF regarding integrase resistance in cases of virological failure in routine clinical care.

Effectiveness of integrase strand transfer inhibitors among treatment-naive people living with HIV/AIDS in Guangdong, China: A real-world, retrospective cohort study.

Integrase strand transfer inhibitors (INSTIs) in anti-retroviral therapy (ART) have been recommended by the World Health Organization for their higher efficacy, favorable safety and tolerability. However, the clinical evidence supporting switching to INSTI-containing regimens in low-and-middle-income countries (LMICs) is limited, as few patients have access to these regimens. We aimed to assess the effectiveness of INSTI-containing regimens in real-world settings in China compared to government-provided free ART. We compared the short-term (first 4 mo following ART initiation) and long-term (1 year after ART initiation) effectiveness between INSTI-containing regimens and free ART drugs provided by the Chinese government in 4 dimensions: viral suppression status, immune response, liver and kidney function, and AIDS-related diseases. We obtained data from electronic medical records in the National Infectious Disease Surveillance System. To control baseline confounders, we used propensity score matching (PSM), calculated using logistic regression including socio-demographic and baseline factors. Among 12,836 patients from 2012 to 2019, 673 (5.2%) used INSTI-containing regimens. Patients with INSTI-containing regimens were matched to those with free drugs (644 vs 644). For short-term effectiveness, patients initiating INSTI-containing regimens were more likely to achieve viral suppression (81.4% vs 52.0%; P < .001). The differences in immune response, liver and kidney function and AIDS-related diseases were not significant between the 2 groups. For long-term effectiveness, viral suppression rates were similar (87.96% vs 84.59%; P = .135), with no significant differences in immune response, liver and kidney function, or AIDS-related diseases. Our study suggests that patients initiating ART with INSTI-containing regimens have worse physical status at baseline than patients starting with free ART drugs. Furthermore, we found better virological performances of INSTI-containing regimens in the short-term but not in the long-term due to a high rate of drug changes. Our findings have clinical implications and provide new evidence regarding the effectiveness of INSTI-containing regimens in LMICs.

Real-world prevalence of integrase inhibitor resistance and virological failure since adoption as guideline-preferred therapy.

Limited data reporting real-world prevalence of integrase strand transfer inhibitor resistance (INSTI-R) in the USA are available because their recommendation as first-line treatment in 2017. Reported national surveillance data in the USA estimated INSTI-R to be 6.3% as of 2018. This article aims to describe estimated prevalence of INSTI-R within a single clinic network in Chicago, IL, USA, and identify risk factors for resistance and virological failure (VF). This was a retrospective, single-centre study of adults with HIV starting an INSTI-containing regimen between September 2017 and 2020. The primary endpoint was the difference in INSTI-R of the sample population compared with the national prevalence. Other outcomes included VF and documented INSTI-R mutations. Of 948 participants screened, 321 were included. Eight people had baseline INSTI-R testing results available, of which five had INSTI-R at baseline for an estimated prevalence of 1.6%. This estimation was significantly less than the national estimated prevalence of 6.3% (p<0.001). VF occurred in 26 (7.8%) individuals. Because no participants acquired INSTI-R during the study period, investigators were unable to identify risk factors associated with the development of INSTI-R. People with high pre-treatment viral loads had 1.21 (95% CI 1.05-1.39) higher odds of VF. Amongst participants on INSTI-containing regimens, INSTI-R rates were estimated to be lower than the estimated national prevalence. Detectable pre-switch viral loads were more associated with VF than undetectable viral loads.

Cohort profile: PRESTIGIO, an Italian prospective registry-based cohort of people with HIV-1 resistant to reverse transcriptase, protease and integrase inhibitors

PurposeThe PRESTIGIO Registry was established in 2017 to collect clinical, virological and immunological monitoring data from people living with HIV (PLWH) with documented four-class drug resistance (4DR). Key research purposes...

1518. Prevalence of Integrase Inhibitor Resistance within an Urban Clinic Network After Adoption as First-line Therapy

Abstract Background Limited data outside of randomized controlled trials exist reporting the prevalence of integrase inhibitor resistance (INSTI-R) since the approval and recommendation of INSTIs as first-line treatment for HIV. National surveillance data in 2018 estimated INSTI-R to be 6.3% in people with HIV (PWH) who had never achieved viral suppression, with 0.8% attributed to transmitted drug resistance (TDR). The purpose of this study was to describe the prevalence of INSTI-R in patients from a single urban clinic network on INSTI-containing regimens. Prevalence amongst University of Illinois Chicago Community Clinic Network (UCCN) patients on INSTI-containing single-tablet regimens specifically was previously reported. Methods This was a retrospective study of adult PWH followed at UCCN prescribed an INSTI-containing regimen between September 2017 and September 2020 with &amp;gt; two recorded HIV-1 RNA viral loads collected &amp;gt; 12 months apart. The primary endpoint was the difference in INSTI-R in UCCN patients compared to national data. Other outcomes included development of virologic failure (VF), defined as &amp;gt; 200 copies/mL in two consecutive HIV-1 RNA viral loads, and patient specific factors associated with VF. The primary endpoint was analyzed using a chi-square test. All other data are presented as descriptive statistics. Results Of 948 patients screened, 321 were included and followed an average of 30 months. Baseline characteristics are presented in Table 1. A total of 5 subjects had INSTI-R prior to switch resulting in a prevalence of 1.6%, which was significantly less than the national prevalence of 6.3% (p&amp;lt; 0.001). Of note, all patients with INSTI-R were previously treated with first generation INSTIs and none were deemed TDR. Study-defined VF occurred in 26 subjects (8.1%). Seven subjects (26.9%) were not taking antiretrovirals for &amp;gt; six weeks at the time of study-defined VF. Outcomes of patients with VF are outlined in Table 2. Subjects with a pre-treatment viral load &amp;gt; 100,000 were more likely to experience VF (p=0.0485). Conclusion Among UCCN patients on INSTI-containing regimens, INSTI-R rates were lower than the estimated national prevalence; however, this comparison is limited due to the large proportion of subjects with viral suppression at baseline. Disclosures All Authors: No reported disclosures

ART-related medication errors in hospitalized people with HIV in the INSTI-era: analysis from 2 health systems in South Georgia, U.S.

ABSTRACT ART-related medication errors occur at high rates in hospitalized people with HIV (PWH), but few studies included modern regimens. As such, we evaluated ART-related medication errors in hospitalized PWH in an era where use of INSTI-based regimens dominate. This multi-center, retrospective cohort included PWH at least 18 years hospitalized in South Georgia, U.S. between March 2016 and March 2018. Of those eligible for inclusion, 400 were randomly selected and included. Three hundred sixty-three inpatient ART-related medication errors occurred in 203 patients during the study period due to incorrect scheduling (44%), an incorrect or incomplete regimen (27%), and drug–drug interactions (27%). Approximately 25% of errors persisted to discharge. Medication errors were more likely to occur in patients receiving NNRTI- or PI-containing multi-tablet regimens, whereas those receiving INSTI-containing multi-tablet regimens were less likely to experience a medication error. ART-related medication errors are less likely in patients receiving INSTI-containing multi-tablet regimens. Ensuring appropriate transition of ART throughout hospitalization remains an area in need of significant improvement.

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.

1259. Bictegravir or Dolutegravir-Containing Antiretroviral Regimens in Solid Organ Transplantation: Single-Center Experience

Abstract Background Solid organ transplantation (SOT) is the definitive treatment for end-organ failure in HIV-positive recipients. Bictegravir (BIC) or dolutegravir (DTG) based antiretroviral therapy (ART) is the preferred ART due to high efficacy, excellent tolerability and minimal drug interactions, yet there is a paucity of data on these second generation integrase inhibitors (INSTIs) in SOT. We report the Memorial Transplant Institute’s experience using second generation INSTI-containing ART with or without emtricitabine/tenofovir alafenamide (FTC/TAF) in persons with HIV. Table 1.Demographics and clinical features of 16 patients with HIV undergoing solid organ transplantation (SOT).3TC: lamivudine; AA: African American; BIC: bictegravir; DTG: dolutegravir; F: female; FTC: emtricitabine; H: Hispanic/Latino/a/x; IN: integrase; M: male; NH: Non-Hispanic/Latino/a/x; PR: protease; RPV: rilpivirine; RT: reverse transcriptase; SOT: solid organ transplantation; TAF: tenofovir alafenamide; W: whiteTable 2.Clinical course of 8 patients with HIV after solid organ transplantation (SOT).3TC: lamivudine; ABC: abacavir; ART: antiretroviral therapy; ATV: atazanavir; BIC: bictegravir; c: cobicistat; DTG: dolutegravir; DRV: darunavir; eFGR: estimated glomerular filtration rate; ETR: etravirine; FTC: emtricitabine; r: ritonavir; RAL: raltegravir; RPV: rilpivirine; RTV: ritonavir; SOT: solid organ transplantation; TAF: tenofovir alafenamide Methods This single-center observational study compiles data from medical records of all persons with HIV undergoing SOT seen by the Division of Infectious Disease from January 2017 through April 2022. We report clinical information and ART management of SOT candidates and recipients in our center. Results Sixteen patients met inclusion criteria: 8 SOT candidates (7 kidney, 1 heart) and 8 SOT recipients (all kidney). Demographics are presented in Table 1. Patients were 63% male with a mean age of 55 years, CD4 323 cells/mm3, and living with HIV for 16 years. ART regimens were BIC/FTC/TAF (50%), DTG/rilpivirine (RPV) (19%), DTG + FTC/TAF (19%) and RPV/FTC/TAF + DTG (6%), and DTG/lamivudine (6%). All pharmacokinetic enhancers were discontinued to avoid drug interactions with anti-rejection medications. Last on-treatment HIV RNA was &amp;lt; 200 copies/mL for 100% of patients. The clinical course of 8 post-renal transplant recipients is presented in Table 2. The most common post-SOT regimen was BIC/FTC/TAF. Post-SOT patients maintained HIV RNA &amp;lt; 200 copies/mL. No ART-related adverse effects were documented. Two allograft- or life-threatening infections and one episode of acute antibody rejection was reported. Expectedly, serum creatinine decreased and estimated glomerular filtration rate increased post-renal transplant. Conclusion We provide additional insight into the use of BIC- and DTG-containing ART with or without FTC/TAF in the peri-SOT period. Our growing experience suggests second generation INSTI-containing ART regimens with or without FTC/TAF are effective and well tolerated following kidney transplantation. Additional research on the use of second generation INSTIs in the SOT patient population is needed. Disclosures All Authors: No reported disclosures.

2069. Prevalence of Cabotegravir and Rilpivirine Resistance Associated Mutations Among Treatment Experienced Patients in a South Carolina Outpatient Clinic

Abstract Background Cabotegravir/rilpivirine (CAB/RPV) long-acting (LA) injectable was recently approved as a switch therapy for people living with HIV (PLWHIV) who are virologically suppressed on oral combination antiretroviral therapy (cART). Data demonstrates RPV resistance associated mutations (RAMs) correlated with CAB/RPV treatment failure. This is the first real-world retrospective, observational study evaluating epidemiology of RPV and CAB RAMs in a heavily treatment experienced population of PLWHIV. Methods A cohort of PLWHIV were screened for transition eligibility to CAB/RPV therapy in a large clinic in the Southeastern U.S. between April 1, 2021 and January 31, 2022. The following baseline characteristics were collected: gender, age, race, Charlson Comorbidity Index, current cART, and prior cART exposure. The Stanford University HIV Drug Resistance Database was utilized to evaluate the inferred resistance level for reverse transcriptase (RT), integrase strand transfer inhibitor (INSTI), and protease inhibitor (PI) sequences. Results Among 115 patients included, 64.3% were males who were predominately African American (83.4%), with a median age of 37 years old and Charlson Comorbidity Index of 1.65. Ten (8.69%) individuals had at least one RPV or CAB RAM. Among these, 7 (6%) and 3 (2.6%) displayed RPV and CAB resistance, respectively. The most prevalent types of RAMs for RPV specifically were Y181I/C (n = 4) and E138A (n = 2). Five of 7 individuals with RPV RAMs had history of cART use without documented exposure to RPV-containing regimens. Moreover, 2 of 3 individuals with CAB RAMs had history of cART with exposure to an integrase-containing regimen. Conclusion This is the first study that characterizes susceptibility patterns that may affect CAB/RPV in clinical practice. Within this rural Southeastern population, prevalence of RPV RAMs is higher than CAB RAMs, and RPV RAMs were commonly observed as transmitted resistance whereas CAB RAMs were typically associated with prior history of exposure to INSTI-containing regimen. It is pertinent to assess the genotypic resistance profile of RTs and history of cART exposure prior to transitioning to CAB/RPV to decrease the risk of virologic failure due to RAMs. Disclosures P. Brandon Bookstaver, PharmD, Spero Therapeutics: Advisor/Consultant.

Drug Resistance to Integrase Strand-Transfer Inhibitors among HIV-1-Infected Adults in Guangdong, China.

Integrase strand-transfer inhibitor (INSTI)-containing regimens have gradually been administered in Guangdong Province, China beginning in 2016, and INSTI-related drug resistance (DR) may occur and should be monitored among HIV-1-infected patients. To investigate the prevalence of INSTI-related resistance among HIV-1-infected individuals in Guangdong and provide evidence for the optimal administration of INSTIs. This study recruited 1208 HIV-1-infected patients (including 404 ART-naive and 804 ART-experienced patients) between June 2021 and April 2022. The entire integrase gene was amplified from blood plasma. Demographic and epidemiological information were collected. INSTI mutations and susceptibility were interpreted using the Stanford HIV Drug Resistance Database HIVdb program. Of the 1208 enrolled individuals, 2.65% (32/1208) carried at least one INSTI major or accessory drug resistance mutation (DRM), with 1.49% (6/404) being from ART-naive individuals and 3.23% (26/804) from ART-experienced individuals. Among them, seven polymorphic major mutations were detected. Although no INSTI drug resistance was found among treatment-naive patients, seven ART-experienced patients (0.87%, 7/804) carried mutations conferring resistance to INSTIs. The overall prevalence of INSTI DRMs and DR was comparatively low among ART-naive and ART-treated populations in Guangdong; however, INSTI-related polymorphic mutations were observed. Surveillance should be reinforced before transfer to INSTI-containing regimens.

One in 10 Virally Suppressed Persons With HIV in The Netherlands Experiences ≥10% Weight Gain After Switching to Tenofovir Alafenamide and/or Integrase Strand Transfer Inhibitor.

BackgroundWe determined the frequency of and factors associated with ≥10% weight gain and its metabolic effects in virally suppressed people with human immunodeficiency virus (PWH) from the Dutch national AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort switching to tenofovir alafenamide (TAF) and/or integrase strand transfer inhibitor (INSTI).MethodsWe identified antiretroviral therapy–experienced but TAF/INSTI-naive PWH who switched to a TAF and/or INSTI-containing regimen while virally suppressed for >12 months. Individuals with comorbidities/comedication associated with weight change were excluded. Analyses were stratified by switch to only TAF, only INSTI, or TAF + INSTI. Factors associated with ≥10% weight gain were assessed using parametric survival models. Changes in glucose, lipids, and blood pressure postswitch were modeled using mixed-effects linear regression and compared between those with and without ≥10% weight gain.ResultsAmong 1544 PWH who switched to only TAF, 2629 to only INSTI, and 918 to combined TAF + INSTI, ≥10% weight gain was observed in 8.8%, 10.6%, and 14.4%, respectively. Across these groups, weight gain was more frequent in Western and sub-Saharan African females than Western males. Weight gain was also more frequent in those with weight loss ≥1 kg/year before switching, age <40 years, and those discontinuing efavirenz. In those with ≥10% weight gain, 53.7% remained in the same body mass index (BMI) category, while a BMI change from normal/overweight at baseline to obesity at 24 months postswitch was seen in 13.9%, 11.7%, and 15.2% of those switching to only TAF, only INSTI, and TAF + INSTI, respectively. PWH with ≥10% weight gain showed significantly larger, but small increases in glucose, blood pressure, and lipid levels. Lipid increases were limited to those whose switch included TAF, whereas lipids decreased after switching to only INSTI.ConclusionsWeight gain of ≥10% after switch to TAF and/or INSTI was common in virally suppressed PWH, particularly in females and those starting both drugs simultaneously. Consequent changes in metabolic parameters were, however, modest.

Socioeconomic status largely explains integrase inhibitors-related body composition differences in chronically infected men living with HIV.

Substantial body composition alterations have been reported after starting combined antiretroviral therapy (cART). We characterized a cohort of chronically infected and virologically suppressed (VL < 50 copies/ml) men (≥50years old) living with HIV (MLWH) who were switched to integrase inhibitors (INSTI), and compared their body composition parameters and proinflammatory/endocrine profiles to age-matched MLWH on integrase inhibitor free (non-INSTI) regimens, taking into account neighborhood-level measures of socioeconomic status (SES). In addition, we used previously published HIV-seronegative men of the same age as controls. We used dual energy X-ray absorptiometry to quantify body composition parameters, and measured plasma proinflammatory/endocrine markers in 56 MLWH. We compared body composition to a publicly available dataset of 450 HIV-seronegative men of similar age. Within the MLWH group, body composition and plasma proinflammatory/endocrine markers were compared between individuals on INSTI and non-INSTI regimens, accounting for SES. Men living with HIV tended to have a greater android/gynoid ratio compared to HIV-seronegative men (p < 0.001). INSTI usage in MLWH was associated with lower adiposity measures when compared to non-INSTI, although these differences largely disappeared after controlling for SES. Proinflammatory/endocrine markers were similar for INSTI and non-INSTI MLWH. Among cART-experienced MLWH, those receiving INSTI-containing regimens had modestly lower adiposity compared to non-INSTI MLWH, although these differences were explained by SES. Future studies examining the relationship between INSTI use and body composition should consider the impact of SES.

Factors associated with the emergence of integrase resistance mutations in patients failing dual or triple integrase inhibitor-based regimens in a French national survey.

Successful 2-drug regimens (2DRs) for HIV were made possible by the availability of drugs combining potency and tolerability with a high genetic barrier to resistance. How these deal with resistance development/re-emergence, compared with 3DRs, is thus of paramount importance. A national survey including patients who were either naive or experienced with any 2DR or 3DR but failing integrase strand transfer inhibitor (INSTI)-containing regimens [two consecutive plasma viral load (VL) values >50 copies/mL] was conducted between 2014 and 2019. Genotypic resistance tests were interpreted with the v28 ANRS algorithm. Overall, 1104 patients failing any INSTI-containing regimen (2DRs, n = 207; 3DRs, n = 897) were analysed. Five hundred and seventy-seven (52.3%) patients were infected with a B subtype and 527 (47.3%) with non-B subtypes. Overall, 644 (58%) patients showed no known integrase resistance mutations at failure. In multivariate analysis, factors associated with the emergence of at least one integrase mutation were: high VL at failure (OR = 1.24 per 1 log10 copies/mL increase); non-B versus B subtype (OR = 1.75); low genotypic sensitivity score (GSS) (OR = 0.10 for GSS = 2 versus GSS = 0-0.5); and dolutegravir versus raltegravir (OR = 0.46). Although 3DRs versus 2DRs reached statistical significance in univariate analysis (OR = 0.59, P = 0.007), the variable is not retained in the final model. This study is one of the largest studies characterizing integrase resistance in patients failing any INSTI-containing 2DR or 3DR in routine clinical care and reveals factors associated with emergence of integrase resistance that should be taken into consideration in clinical management. No difference was evidenced between patients receiving a 2DR or a 3DR.

INSTI-Based Initial Antiretroviral Therapy in Adults with HIV, the HIV Outpatient Study, 2007-2018.

We evaluated treatment duration and viral suppression (VS) outcomes with integrase strand transfer inhibitor (INSTI)-based regimens versus other contemporary regimens among adults in routine HIV care. Eligible participants were seen during January 1, 2007 to June 30, 2018 at nine U.S. HIV clinics, initiated antiretroviral therapy (ART) (baseline date), and had ≥2 clinic visits thereafter. We assessed the probability of remaining on a regimen and achieving HIV RNA <200 copies/mL on initial INSTI versus non-INSTI ART by Kaplan-Meier analyses and their correlates by Cox regression. Among 1,005 patients, 335 (33.3%) were prescribed an INSTI-containing regimen and 670 (66.7%) a non-INSTI regimen, which may have included non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and other agents. In both groups, most patients were male, nonwhite, and aged <50 years. Comparing the INSTI with non-INSTI group, the median baseline log10 HIV viral load (VL; copies/mL) was 4.6 versus 4.5, and the median CD4+ cell count (cells/mm3) was 352 versus 314. In Kaplan-Meier analysis, the estimated probabilities of remaining on initial regimens at 2 and 4 years were 58% and 40% for INSTI and 51% and 33% for non-INSTI group, respectively (log-rank test p = .003). In multivariable models, treatment with an INSTI (vs. non-INSTI) ART was negatively associated with a regimen switch [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.56-0.81, p < .001] and was positively associated with achieving VS (HR 1.52; CI 1.29-1.79, p < .001), both irrespective of baseline VL levels. Initial INSTI-based regimens were associated with longer treatment durations and better VS than non-INSTI regimens. Results support INSTI regimens as the initial therapy in U.S. treatment guidelines.

109. Preexisting Resistance and Week 48 Virologic Outcomes After Switching to B/F/TAF in African American Adults with HIV

BackgroundThe BRAAVE 2020 study is evaluating the safety and efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among virologically suppressed Black adults with HIV. At Week (W) 24, 0.6% (2/328) on B/F/TAF vs 1.8% (3/165) who stayed on their baseline 3 drug regimen (SBR) had HIV-1 RNA ≥ 50 c/mL demonstrating noninferiority of B/F/TAF. Here, resistance analyses and virologic outcomes at W48 are described.MethodsEnrollment criteria permitted prior treatment failure, except on an INSTI-containing regimen, and allowed documented resistance to NNRTIs, PIs and/or NRTIs, except for K65R/E/N, ≥ 3 thymidine analog mutations (TAMs), or T69-insertions; primary INSTI resistance (-R) was excluded. Preexisting drug resistance was assessed with historical genotypes and proviral DNA genotyping. B/F/TAF outcomes were determined by last on-treatment HIV-1 RNA through W48.ResultsAltogether, 495 participants enrolled (B/F/TAF n=330, SBR n=165). Preexisting primary NRTI-R, NNRTI-R, and PI-R substitutions were observed in 14% (70/495), 21% (102/495), and 13% (62/495), respectively. M184V/I and TAMs were detected in 10% (51/495) and 7% (34/495), respectively. Primary INSTI-R was detected post-randomization in 2% (11/495); all continued on study and were included in efficacy analyses. At W24, 163 in the SBR group switched to B/F/TAF (SBR to B/F/TAF). W48 outcomes were determined for 489 participants who had ≥ 1 post-switch HIV-1 RNA measurement: 99% (324/327) in the B/F/TAF and 100% (162/162) in the SBR to B/F/TAF groups had HIV-1 RNA < 50 copies/mL at their last study visit, including 100% (68/68) with NRTI-R (50 of whom had archived M184V/I and post-switch data), and 100% (11/11) with INSTI-R (Table). No participant had treatment emergent resistance to study drugs.Table. BRAAVE 2020 Preexisting Resistance and Virologic Suppression at Week 48 (Last On-treatment Observation Carried Forward Analysis) ConclusionPreexisting resistance was common among virologically suppressed Black adults in BRAAVE 2020, notably M184V/I, TAMs, and NNRTI-R. High rates of virologic suppression were maintained through 48 weeks of B/F/TAF treatment and there were no failures with de novo resistance, indicating that B/F/TAF is an effective treatment option for virologically suppressed people with HIV with or without preexisting resistance to NNRTIs, PIs, or non-tenofovir NRTIs.DisclosuresKristen Andreatta, MSc, Gilead Sciences (Employee, Shareholder) Michelle L. D’Antoni, PhD, Gilead Sciences (Employee, Shareholder) Silvia Chang, Masters, Gilead Sciences (Employee, Shareholder) Aiyappa Parvangada, MS Computational Biology, Gilead Sciences (Employee) Christiana Blair, MS, Gilead Sciences (Employee, Shareholder) Sean E. Collins, MD, MS, Gilead Sciences (Employee) Kirsten L. White, PhD, Gilead Sciences, Inc. (Employee, Shareholder)

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

Comparative effectiveness of antiretroviral drug classes for the treatment of HIV infection in patients with high viral loads: a multicentre retrospective cohort study.

We aimed to compare the effectiveness of antiretroviral therapy (ART) classes for achieving HIV RNA suppression to <50 HIV-1 RNA copies/mL within 6months of initiation with high viral loads (VLs). Secondary objectives were to compare viral suppression (VS) at 12weeks and 12months, partial HIV RNA suppression to <200 copies/mL, time to VS, time to rebound, and change in CD4 cell count. This was a multicentre, retrospective, observational study. Adult patients were included if they initiated ART between January 2005 and December 2016 with a VL ≥100000 copies/mL. There were 220 patients included in the study. The median VL was 252919 [interquartile range (IQR) 149472-500000] copies/mL. Nonnucleoside reverse transcriptase inhibitor (NNRTI) recipients were more likely to achieve VS by 6months compared to those initiating ART containing protease inhibitors (PIs) [75.4% vs. 44.1%, respectively; odds ratio (OR) 3.34; 95% confidence interval (CI) 1.62-6.90] or integrase strand transfer inhibitors (INSTIs) (75.4% vs. 55.8%, respectively; OR 2.40; 95% CI 1.03-5.58). VS at 12weeks was more frequent with INSTI-containing regimens than with PIs (28.9% vs. 9.0%, respectively; OR 4.10; 95% CI 1.69-9.92). VS at 12months did not significantly differ between treatment regimens. Median time to complete VS for INSTI, PI and NNRTI recipients was 22.3 (95% CI 13.4-33), 30.1 (95% CI 25-36) and 19.9 (95% CI 16-22.3) weeks, respectively. There were no significant differences in time to viral rebound or change in CD4 cell counts. Patients with high VLs initiated on NNRTIs were more likely to achieve VS by 6months on ART compared to INSTI and PI recipients.

PIN4 IMPACT OF ADHERENCE ON VIRAL SUPPRESSION IN PATIENTS WITH HIV RECEIVING BICTEGRAVIR OR DOLUTEGRAVIR REGIMENS

Previous real-world studies have shown (1) reduced adherence with more complex, multi-tablet regimens (MTR) relative to simple, single-tablet regimens (STR) and (2) reduced virologic control with decreased regimen adherence. This study evaluated adherence and virologic suppression with second-generation integrase inhibitors (INSTIs) bictegravir (BIC) and dolutegravir (DTG) in patients with HIV. EMR, prescription and dispensing data for 2,217 patients initiating STR BIC/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) or DTG/abacavir/lamivudine (DTG/ABC/3TC) or MTR DTG + tenofovir disoproxil fumarate/emtricitabine (DTG+TDF/FTC) or DTG+TAF/FTC between August 2013 - August 2019 were collected from 5 US practices. Adherence was defined as proportion of days covered (PDC) at 6 months. To determine treatment effects on adherence, we used (1) multiple imputation with predictive posterior matching for missing baseline measures, (2) mixed effects logistic regression to adjust for source heterogeneity, and (3) propensity score matching (PSM) using imputed baseline labs and demographics, allowing for squares and first order interactions between all included predictors. In addition to adherence, we assessed viral suppression (<200 copies/mL) in a subset of 655 patients at 6 months (-1 week to + 2 months). In observed data, 80% PDC was significantly higher (p<0.01) with STR BIC/FTC/TAF compared to any dolutegravir-regimen and with STR DTG/ABC/3TC in comparison to MTR DTG+TDF/FTC or DTG+TAF/FTC (p<0.01). After PSM, adherence was only significantly different with STR BIC/FTC/TAF compared to MTR DTG+TDF/FTC or DTG+TAF/FTC (p<0.01). Viral suppression at 6 months for patients with measures (n=655) was favorably impacted by PDC ≥80% (OR 2.27 [1.26-4.07] p<0.01). Consistent with studies of legacy regimens, these data suggest that simplifying 2nd generation INSTI-containing regimens to a single tablet aids in adherence and greater adherence improves virologic outcomes.

Integrase Inhibitor-Based Antiretroviral Therapy Among Women Living with HIV: Data from the OPERA Cohort

Women face unique complexities in HIV treatment yet are underrepresented in antiretroviral therapy (ART) studies. This analysis assessed the one-year durability of the first integrase strand transfer inhibitor (INSTI)-based regimens prescribed to women in a large cohort of patients living with HIV in care. Women with HIV who initiated their first INSTI-containing regimen between 08/12/2013 and 11/30/2015 were identified in the OPERA cohort, a collaboration of 79 US outpatient clinics. Discontinuation within the first year of treatment with an INSTI was compared between dolutegravir (DTG), raltegravir (RAL) and elvitegravir (EVG), using multivariable Cox regression and Kaplan- Meier estimates. Virologic response and regimen modifications were described and compared across INSTIs. A total of 537 treatment-naïve (DTG: 39%, EVG: 48%, RAL: 13%) and 878 treatmentexperienced (DTG: 57%, EVG: 29%, RAL: 13%) women were analyzed. In the first twelve months after initiation, women taking EVG or RAL were more likely to discontinue their initial INSTI than those taking DTG among both treatment-naïve (adjusted hazard ratio EVG vs. DTG: 1.59 (95% CI: 1.09, 2.39); RAL vs. DTG: 2.46 (1.49, 4.05)) and treatment-experienced women (EVG vs. DTG: 1.39 (1.02, 1.88); RAL vs. DTG: 2.17 (1.51, 3.12)). Following discontinuation of the initial INSTI, women commonly switched to a regimen containing a different drug from the INSTI class (treatment-naïve DTG: 34%, RAL: 33% EVG: 41%; treatment-experienced DTG: 23%, RAL: 19% EVG: 41%). In treatment-naïve and treatment-experienced women living with HIV, women taking DTG had the lowest risk for early (≤1 year) discontinuation.