889. Early Discontinuations and Adverse Events Among Treatment-Naïve Patients Initiating Integrase Inhibitors in a Real-world Setting

Abstract Background Cohort studies suggest higher rates of discontinuations (DCs) and adverse events (AEs) with integrase inhibitors (INSTIs) than is reported in clinical trials. Here, we assess DC of different INSTIs in combination with one of two tenofovir prodrugs in the first year following initiation defined as “early DC” in a real-world cohort of treatment-naïve patients. Methods This analysis evaluated treatment-naïve patients at a single center initiating raltegravir (RAL), elvitegravir/cobicistat (EVG/c), dolutegravir (DTG) or bictegravir (BIC) in combination with emtricitabine/tenofovir alafenamide (F/TAF) or emtricitabine/tenofovir disoproxil fumarate (F/TDF) between 10/2007-1/2020. Eligible patients had a minimum follow-up of 1 year. The primary endpoint was incidence of early INSTI DC. Secondary endpoints included AEs and risk factors for early INSTI DC and treatment-related AEs. Results 331 patients were included. Median age was 32 years, 89% were male, 43% were non-White, 8% started RAL-based therapy, 46% started EVG/c-based therapy, 22% started DTG-based therapy and 24% started BIC/F/TAF. 36 discontinued INSTI-based therapy early yielding an incidence rate of 0.17 DCs per person-years (PPY) among RAL patients, 0.14 DCs PPY among EVG/c patients, 0.22 DCs PPY among DTG patients, and 0 DCs PPY among BIC patients, p=0.006. Treatment-related AEs occurred in 27% of RAL patients, 42% of EVG/c patients, 50% of DTG patients, and 43% of BIC patients p=0.607; and were responsible for early DC rates of 0.022 in 3 EVG/c patients and 0.075 in 5 DTG patients. No treatment-related early DCs occurred among RAL or BIC patients. No evaluated factor was significantly associated with early INSTI DC, however DTG use was significantly associated with treatment-related AEs (aOR 3.46, 95% confidence interval: [1.20; 10.82]). Table 1. Risk factors for early integrase inhibitor discontinuation and treatment-related adverse events Conclusion In this cohort, early DCs occurred in 11% initiating INSTI-based therapy, however of these only 2% were treatment-related. These data support use of INSTI-based regimens as preferred options for treatment-naïve patients living with HIV due to their favorable safety and tolerability profiles. Disclosures Charlotte-Paige M. Rolle, MD MPH, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)Janssen Infectious Disease (Scientific Research Study Investigator, Advisor or Review Panel member)ViiV Healthcare (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau) Kiran Patel, PharmD, Gilead Sciences (Employee) Federico Hinestrosa, MD, AbbVie (Speaker’s Bureau)Gilead Sciences (Advisor or Review Panel member, Speaker’s Bureau)Theratechonologies (Advisor or Review Panel member)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Edwin DeJesus, MD, Gilead Sciences (Scientific Research Study Investigator, Advisor or Review Panel member)

Background. The integrase strand transfer inhibitor (INSTI)-based regimens bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), dolutegravir (DTG)+FTC/TAF, DTG/lamivudine (3TC), and DTG/rilpivirine (RPV) are all used for treatment of HIV-infected patients. Here, relative time to in vitro viral breakthrough (VB) and resistance barrier using simulated human drug exposures at either full or suboptimal treatment adherence to each regimen were compared.
Methods. Wild-type HIV-1 (IIIb)-infected MT-2 cells were exposed to the combinations of BIC+FTC+TAF, DTG+FTC+TAF, DTG+3TC, or DTG+RPV for up to 35 days or until VB. Fixed drug concentrations were the human plasma-free adjusted clinical trough concentrations (C min ) or fixed at simulated C min after missing 1 to 4 consecutive doses (C min -1 to -4), with many replicates. Drug resistance was studied by next-generation sequencing at ≥2% frequency.
Results. At drug concentrations corresponding to full adherence and 1 missed dose (C min and C min -1), no VB occurred with any regimen (Table). At C min -2, only DTG+3TC had VB, with some emergent resistance to both drugs. At C min -3, all regimens had VB: by day 12, 100% of DTG+3TC wells had VB; for BIC+FTC+TAF, DTG+FTC+TAF, and DTG+RPV, < 15% of wells had VB which began after day 14. Emergent RT or IN resistance was seen for DTG+RPV and DTG+3TC but not for BIC+FTC+TAF or DTG+FTC+TAF. At C min -4, all DTG+3TC and DTG+FTC+TAF wells had VB by day 12, while DTG+RPV had 94% VB by day 25 and BIC+FTC+TAF had 50% VB by day 35. Emergent C min -4 drug resistance was seen for all regimens but at differing frequencies; DTG+RPV had the most wells with resistance. Cumulatively, emergent RT and/or IN resistance was found in 1.3% BIC+FTC+TAF, 2.5% DTG+FTC+TAF, 7.9% DTG+3TC, and 8.8% DTG+RPV cultures.

Summary of Forgiveness and Barrier to Resistance of INSTI-Containing Regimens
Conclusion. Regimen forgiveness and resistance barrier are important factors in long term treatment. These INSTI-based regimens had high in vitro forgiveness and resistance barriers with concentrations simulating high adherence. When multiple missed doses were simulated in vitro, BIC+FTC+TAF had the highest forgiveness and barrier to resistance. When compared to DTG+3TC and DTG+FTC+TAF, DTG+RPV had higher forgiveness but lower resistance barrier after several simulated missed doses.  Background. Cohort studies suggest higher rates of discontinuations (DCs) and adverse events (AEs) with integrase inhibitors (INSTIs) than is reported in clinical trials. Here, we assess DC of different INSTIs in combination with one of two tenofovir prodrugs in the first year following initiation defined as "early DC" in a real-world cohort of treatment-naïve patients.

Early Discontinuations and Adverse Events Among Treatment-Naïve Patients Initiating Integrase Inhibitors in a Real-world Setting
Methods. This analysis evaluated treatment-naïve patients at a single center initiating raltegravir (RAL), elvitegravir/cobicistat (EVG/c), dolutegravir (DTG) or bictegravir (BIC) in combination with emtricitabine/tenofovir alafenamide (F/TAF) or emtricitabine/tenofovir disoproxil fumarate (F/TDF) between 10/2007-1/2020. Eligible patients had a minimum follow-up of 1 year. The primary endpoint was incidence of early INSTI DC. Secondary endpoints included AEs and risk factors for early INSTI DC and treatment-related AEs.
Results. 331 patients were included. Median age was 32 years, 89% were male, 43% were non-White, 8% started RAL-based therapy, 46% started EVG/c-based therapy, 22% started DTG-based therapy and 24% started BIC/F/TAF. 36 discontinued INSTI-based therapy early yielding an incidence rate of 0.17 DCs per person-years (PPY) among RAL patients, 0.14 DCs PPY among EVG/c patients, 0.  Methods. We conducted a retrospective chart review along with a real time survey of PLWH who are receiving HIV care at UConn Health. Participants who were switched to or added an INSTI to their ART regimen between 2012 -2020 were included (n=204). Patient weight was recorded in 3-month intervals for two years prior to and two years after INSTI initiation. Lipid profile parameters and hemoglobin A1c were noted pre and post INSTI switch. A survey was administered to rate perception of weight gain, body appearance, and medication adherence on a five-point Likert scale. Statistical methods included Chi-square test and Fisher's Exact test for categorical data, and T-test or Kruskal-Wallis test for continuous data.

Evaluation of Association Among Integrase Inhibitors for HIV Treatment, Weight Gain, and Body Image
Results. Patients started on or switched to any INSTI regimen experienced a mean weight gain of 5 and 7 pounds at 12 and 24 months, respectively (p < 0.001). Weight gain was greatest with raltegravir and elvitegravir (Figure 1,2). Bictegravir regimens resulted in a 4 pound weight loss at 24 months. An INSTI switch increased cholesterol by a mean of of 7.9mg/dL (p=0.05), with no effect on other parameters. A switch to Bictegravir increased HDL by 4mg/dL (p=0.04) and decreased triglycerides by 35mg/dL (p=0.04). Survey results showed that 100% of patients denied missing ART doses despite 69% mentioning weight gain due to ART. 97% of patients were satisfied with their ART regimen, with the majority disagreeing that their body image was negatively affected.

Conclusion.
We demonstrate a link between INSTI use and weight gain up to two years following INSTI initiation, with the most weight gained within the first 12 months. Elvitegravir and raltegravir are associated with greater weight gain whereas bictegravir demonstrates weight loss and beneficial effects on lipid profile. Despite weight gain, most patients remained adherent and satisfied with their medication and denied negative perceptions of body image.
Disclosures. Background. Weight gain is being observed for a wide range of antiretroviral treatments. Weight gains are higher for people taking first-line integrase inhibitor based treatments, especially those including TAF/FTC. Weight gains are higher for women and people of colour. Clinical obesity increases the risks of cardiovascular disease, diabetes, adverse birth outcomes and could lower survival rates. Anti-obesity treatments are needed to supplement lifestyle interventions and counteract progressive weight gains, but are not routinely provided as part of HIV care.
Methods. Costs of production for FDA-recommended weight loss treatments and anti-diabetic medications (orlistat, naltrexone-bupropion, topiramate, phentermine, semaglutide, liraglutide and metformin) were estimated using an established and published methodology based on costs of active pharmaceutical ingredients (API), extracted from the global shipping records database Panjiva. This was compared with national drug list price data from a range of low, medium, and high-income countries.