Leptin Promotes Greater Ki67 Expression in CD4+ T Cells From Obese Compared to Lean Persons Living With HIV

While antiretroviral therapy (ART) has proven effective in suppressing viremia and disease progression among people living with human immunodeficiency virus (HIV; PLWH), suboptimal CD4+ T cell reconstitution remains a major obstacle in nearly 30% of ART-treated individuals. Epidemiological studies demonstrate that obesity, or a body mass index (BMI) ≥ 30 kg/m2, is positively correlated with greater CD4+ T cell recovery in PLWH on ART. Leptin is a known immunomodulator that is produced in proportion to fat mass and is increased in obese individuals, including PLWH. We hypothesized that CD4+ T cells from obese PLWH have increased cell proliferation and cytokine production compared to cells from lean PLWH, potentially modulated by differential effects of leptin signaling. To test this hypothesis, peripheral blood mononuclear cells from obese and lean PLWH with long-term virologic suppression on the same ART regimen were pretreated with recombinant leptin and then stimulated with anti-CD3/CD28 or PMA/ionomycin to measure Ki67 expression, leptin receptor (LepR) surface expression and cytokine production. In the absence of leptin, Ki67 expression and IL-17A production were significantly higher in CD4+ T cells from obese compared to lean PLWH. However, LepR expression was significantly lower on CD4+ T cells from obese compared to lean PLWH. After leptin treatment, Ki67 expression was significantly increased in CD4+ T cells from obese PLWH compared to the lean participants. Leptin also increased IL-17A production in CD4+ T cells from obese healthy controls. In contrast, leptin decreased IL-17A production in CD4+ T cells from both obese and lean PLWH. Combined, these results demonstrate that obesity is associated with greater CD4+ T cell proliferation among PLWH, and that higher circulating leptin levels in obesity may contribute to improved CD4+ T reconstitution in PLWH initiating ART.

Dolutegravir plus lamivudine versus efavirenz plus tenofovir disoproxil fumarate and lamivudine in antiretroviral-naive adults with HIV-1 infection

Background Concerns regarding potential toxicity and drug-drug interactions during long-term treatment with three-drug active antiretroviral therapy (ART) regimens have been attracting increasing attention. We aimed to evaluate the efficacy and safety of dolutegravir (DTG) plus lamivudine (3TC) in ART-naive adults in China. Methods This prospective observational cohort study enrolled HIV-naive inpatients treated with DTG + 3TC (2DR arm) or efavirenz (EFV) plus tenofovir disoproxil fumarate (TDF) and 3TC (3DR arm). There were no limits on baseline viral load. Inflammatory biomarkers were also investigated in the 2DR arm. Results Between September 2019 and January 2020, 27 patients treated with DTG + 3TC and 28 patients treated with EFV + TDF + 3TC were enrolled in the study. At week 12, the proportion of patients with viral loads < 50 copies/mL in the 2DR arm was 81.5% (22/27) compared with 53.6% (15/28) in the 3DR arm (p < 0.01). At week 24, the proportion of patients with viral loads < 50 copies/mL in the 2DR arm was 100% (26/26) compared with 83.3% (20/24) in the 3DR arm (p < 0.05). Mean changes in CD4 cell counts from baseline at week 12 were 125.46 cells/µL in the 2DR arm and 41.20 cells/µL in the 3DR arm (p < 0.05). Mean changes in CD4 cell counts from baseline at week 24 were 209.68 cells/µL in the 2DR arm and 73.28 cells/µL in the 3DR arm (p < 0.05). Conclusions DTG + 3TC achieved virologic suppression more rapidly than EFV + TDF + 3TC after 12 and 24 weeks. DTG + 3TC could represent an optimal regimen for advanced patients. Clinical Trial Registration ChiCTR1900027640 (22/November/2019).

Impact of Integrase Sequences From HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine

The FLAIR study demonstrated noninferiority of monthly long-acting cabotegravir + rilpivirine vs daily oral dolutegravir/abacavir/lamivudine for maintaining virologic suppression. Three participants who received long-acting therapy had confirmed virologic failure (CVF) at Week 48, and all had HIV-1 that was originally classified as subtype A1 and contained the baseline integrase polymorphism L74I; updated classification algorithms reclassified all 3 as HIV-1 subtype A6. Retrospectively, the impact of L74I on in vitro sensitivity and durability of response to cabotegravir in HIV-1 subtype B and A6 backgrounds was studied. Site-directed L74I and mutations observed in participants with CVF were generated in HIV-1 subtype B and a consensus integrase derived from 3 subtype A6 CVF baseline sequences. Rilpivirine susceptibility was assessed in HIV-1 subtype B and A1 containing reverse transcriptase mutations observed in participants with CVF. HIV-1 subtype B L74I and L74I/G140R mutants and HIV-1 subtype A6 I74L and I74/G140R mutants remained susceptible to cabotegravir; L74I/Q148R double mutants exhibited reduced susceptibility in HIV-1 subtypes B and A6 (half maximal effective capacity fold change, 4.4 and 4.1, respectively). Reduced rilpivirine susceptibility was observed across HIV-1 subtypes B and A1 with resistance-associated mutations K101E or E138K (half maximal effective capacity fold change, 2.21 to 3.09). In cabotegravir breakthrough experiments, time to breakthrough was similar between L74 and I74 viruses across HIV-1 subtypes B and A6; Q148R was selected at low cabotegravir concentrations. Therefore, the L74I integrase polymorphism did not differentially impact in vitro sensitivity to cabotegravir across HIV-1 subtype B and A6 integrase genes (ClinicalTrials.gov identifier: NCT02938520).

Long-term safety and efficacy of rilpivirine in combination with nucleoside/nucleotide reverse transcriptase inhibitors in HIV-1 infected patients: 336-week rollover study of phase 2b and 3 clinical studies

Background To evaluate the long-term safety and efficacy of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in human immunodeficiency virus (HIV)–infected patients. Methods RPV-treated HIV-infected patients from phase 2b or 3 studies rolled-over into this phase 3, open-label study and received RPV 25 mg once daily (QD) with choice of two NRTIs. Adverse events (AEs), plasma viral load, CD4+ cell count, and antiviral resistance were evaluated. Results Of the 482 patients treated, 437 (>90%) patients discontinued study treatment; 371 (77%) had switched to commercially available RPV, 14 (2.9%) discontinued due to AEs, and 6 (1.2%) had virologic failure. In this rollover study, patients were followed up to week 336, although data was limited beyond 288 weeks. Forty-five (9.3%) patients were still undergoing treatment at the time of data cut-off for the current analysis (8 February 2018). The most frequently reported AEs were pregnancy in 7 (1.5%) patients and syphilis in 5 (1.0%) patients. Grade 3–4 AEs were reported in 17 (3.5%) patients, and AEs possibly related to RPV in 23 (4.8%) patients. Over 288 weeks of treatment, 80.1% (95% CI: 74.9%; 84.3%) of patients maintained virologic suppression (HIV-1 RNA <50 copies/mL). The absolute CD4+ cell count increased over time until week 192 and remained constant thereafter. Conclusions RPV 25 mg QD in combination with an investigator-selected background regimen of two NRTIs demonstrated sustained long-term virologic suppression. The treatment was well-tolerated with no new safety findings.

Crushed bictegravir/emtricitabine/tenofovir alafenamide in a human immunodeficiency virus-positive patient with pancreatic cancer

We present the case of a 78-year-old African American man with a history of human immunodeficiency virus diagnosed in 2007 who was newly diagnosed with pancreatic cancer. A percutaneous endoscopic gastrostomy tube was placed during the initial inpatient visit of pancreatic cancer diagnosis due to persistent dysphagia. Due to PEG placement and the patient’s wish to continue his previous antiretroviral therapy, the patient crushed his fixed-dose bictegravir/emtricitabine/tenofovir alafenamide under the direction of a physician and has maintained virologic suppression.

833. Efficacy and Safety of Long-Acting Cabotegravir + Rilpivirine in Participants with HIV/HCV Co-infection: ATLAS-2M 48-Week Results

Background The phase IIIb ATLAS-2M study demonstrated non-inferiority of long-acting (LA) cabotegravir (CAB) + rilpivirine (RPV) dosed every 8 weeks (Q8W) compared with every 4 weeks (Q4W) for maintenance of virologic suppression. Hepatitis C virus (HCV) co-infection occurs in ~6% of people with HIV due to shared modes of transmission. We report efficacy and safety of CAB + RPV LA in participants with HIV/HCV co-infection in ATLAS-2M. Methods Participants with HIV-1 RNA &lt; 50 c/mL receiving CAB + RPV LA Q4W (transitioned from ATLAS [NCT02951052]) or oral comparator ART were randomized 1:1 to receive CAB + RPV LA Q4W or Q8W. Baseline HCV RNA was assessed by polymerase chain reaction. Participants with symptomatic chronic HCV infection requiring treatment within 12 months or liver enzymes not meeting entry criteria were excluded. Week 48 assessments included proportion with HIV-1 RNA ≥50 and &lt; 50 c/mL (Snapshot algorithm), general and hepatic safety, and pharmacokinetics. Results HIV/HCV co-infection was present in 10 (1%) of 1045 participants, 60% of whom were female at birth. At Week 48, 9/10 (90%) and 972/1035 (94%) participants with HIV/HCV co-infection and HIV mono-infection, respectively, had HIV-1 RNA &lt; 50 c/mL (adjusted difference, 4.1; 95% CI, −14.5 to 22.6). No participants with HIV/HCV co-infection had HIV-1 RNA ≥50 c/mL (vs 14/1035 [1%] with HIV mono-infection) or confirmed virologic failure through Week 48 (vs 10 [1%] with HIV mono-infection); 1/10 (10%) discontinued for reasons other than adverse events (AEs). Excluding injection site reactions (ISRs), AEs and serious AEs were reported in 4 (40%) and 0 participants with HIV/HCV co-infection, respectively; the only AE reported in &gt;1 participant was injection site pain (n=5; 50%). In participants with HIV/HCV co-infection, all ISRs were grade 1/2; none led to withdrawal. No hepatic laboratory abnormalities were reported in participants with HIV/HCV co-infection through Week 48; rates were low in those with HIV mono-infection (Table). Plasma CAB and RPV concentrations were similar between groups. Conclusion CAB + RPV LA was effective and well tolerated in this small cohort of participants with HIV and asymptomatic HCV co-infection. Disclosures Ronald D’Amico, DO, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Paul Benn, MB ChB FRCP, ViiV Healthcare (Employee) Shanker Thiagarajah, MB ChB, GlaxoSmithKline (Employee, Shareholder) Susan L. Ford, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Eileen Birmingham, MD, MPH, Janssen Research and Development (Employee, Shareholder) Ojesh R. Upadhyay, MPH, MBA, GlaxoSmithKline (Employee) Louise Garside, PhD, GlaxoSmithKline (Employee) Rodica Van Solingen-Ristea, MD, Janssen Research and Development (Employee)ViiV Healthcare (Employee) Kati Vandermeulen, M.SC., Janssen Research and Development (Employee) William Spreen, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

877. North American Phase 3/3b Experience with Long-Acting Cabotegravir and Rilpivirine: Efficacy, Safety, and Virologic Outcomes

Background Cabotegravir (CAB) plus rilpivirine (RPV) is the first complete long-acting (LA) regimen recommended by treatment guidelines for the maintenance of HIV-1 virologic suppression. CAB+RPV LA dosed every 4 weeks (Q4W) or every 8 weeks (Q8W) demonstrated noninferior efficacy in multinational Phase 3/3b trials. This post hoc descriptive analysis summarizes efficacy, virologic outcomes, safety, and treatment preference for US and Canadian (CAN) participants through Week (W) 48. Methods This analysis focuses on data for US/CAN participants naive to CAB+RPV (n=376) from the larger pooled population of the ATLAS, FLAIR, and ATLAS-2M Phase 3/3b studies (N=1245). Endpoints included the proportion of participants with plasma HIV-1 RNA ≥ 50 and &lt; 50 c/mL at W48 (FDA Snapshot algorithm), incidence of confirmed virologic failure (CVF; 2 consecutive HIV-1 RNA ≥ 200 c/mL), safety, and treatment preference through W48. Results 376 US/CAN participants received CAB+RPV LA Q4W or Q8W. Median (range) age was 39y (20–74); 14.9% were female, 66.0% were White. At W48, 93.1% (350/376) maintained virologic suppression (HIV-1 RNA &lt; 50 c/mL), 1.9% (7/376) had HIV-1 RNA ≥ 50 c/mL, and 0.8% (3/376) met the CVF criterion, consistent with the overall global pooled population (Table 1). Two of the three participants with CVF had ≥ 2 of the three baseline factors (archived RPV resistance-associated mutations [RAMs], HIV subtype A6/A1, body mass index [BMI] ≥ 30 kg/m2) previously associated with CVF. Among the US/CAN participants with a single baseline factor, none met CVF. Overall, archived RPV RAMs were observed in 3.2% (12/376), HIV subtype A6/A1 in 1.1% (4/376), and BMI ≥ 30 kg/m2 in 26.3% (99/376) of participants. Safety and injection site reaction findings were similar to the overall pooled population (Table 2). Most participants (120/134, 89.6%) preferred LA over oral dosing (7/134, 5.2%). Table 1. Snapshot outcomes following CAB+RPV LA Q4W and Q8W at Week 48 in participants naive to CAB+RPV from ATLAS, FLAIR, and ATLAS-2M (ITT-E population) Table 2. Safety summary through Week 48 following CAB+RPV LA Q4W and Q8W or comparator ART in participants naive to CAB+RPV from ATLAS, FLAIR, and ATLAS-2M Conclusion In US/CAN Phase 3/3b trial participants, CAB+RPV LA was highly effective and well tolerated, with outcomes consistent with the overall pooled population. Baseline prevalence of archived RPV RAMs and subtype A6/A1 was low and aligned with regional prevalence/surveillance data. CAB+RPV LA provides a tolerable and effective injectable LA treatment option for virologically suppressed US/CAN individuals with HIV. Disclosures Babafemi O. Taiwo, MBBS, Gilead (Consultant)Merck (Consultant)ViiV Healthcare (Consultant) Darrell Tan, MD PhD, Abbvie (Grant/Research Support)Gilead (Grant/Research Support)GlaxoSmithKline (Scientific Research Study Investigator)ViiV Healthcare (Grant/Research Support) Parul Patel, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Paula Teichner, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Joseph Polli, PhD, FAAPS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Louise Garside, PhD, GlaxoSmithKline (Employee) Ronald D’Amico, DO, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Christine L. Talarico, M.S., GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Rodica Van Solingen-Ristea, MD, Janssen Research and Development (Employee)ViiV Healthcare (Employee) Bryan Baugh, MD, Janssen, Johnson & Johnson (Employee, Shareholder) William Spreen, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Michael Aboud, MBChB, MRCP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Matthew Bosse, DO, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

902. Unreturned Pill Bottles in the 1489 and 1490 Clinical Trials: An Important Measure of Poor Adherence that Is Often Ignored in Pill Count Calculations

Background Adherence to antiretroviral therapy is important for HIV suppression. In clinical trials, adherence is commonly measured by pill count; limitations are that unreturned pills may not have been taken and unreturned pill bottle data are omitted. This analysis focuses on the relationship between unreturned pill bottles as a measure of poor adherence and the overall effect on virologic success rates across all treatment groups. Methods Pill bottle return category (all bottles returned or ≥1 bottle unreturned) and return rates for participants across all treatment groups from two treatment-naïve INSTI clinical trials (Studies 1489 and 1490) were calculated. Association of bottle return category or rates with virologic events through week 144, including last on-treatment observation carried forward (LOCF) outcome, was determined; comparisons used Fisher’s exact or Wilcoxon rank sum test. Results Virologic suppression with ≥95% adherence by pill count can differ for those with unreturned pill bottles (Figure). In these studies, 60% of participants returned all their pill bottles through week 144; if one visit with ≥1 unreturned bottle was allowed, this percentage increased to 81%. The mean bottle return rate was 94% and did not differ by study, treatment arm, or sex. Failure to return pill bottles was significantly associated with lower suppression rates. Additionally, significant differences in pill bottle return rate (p &lt; 0.01) were observed by week 144 LOCF outcome (95% vs 77% mean return rate for those with HIV RNA &lt; 50 c/mL vs ≥50 c/mL), need for resistance testing (95% vs 77% return rate for those not tested vs tested), confirmed virologic failure (VF) (94% vs 90% return rate for those without VF vs with VF) and blip status (95% vs 92% return rate for those without blips vs with blips). HIV-1 Viral Loads of Two Participants with ≥95% Adherence by Pill Count through Week 144 Conclusion In these treatment-naïve INSTI clinical trials, failure to return pill bottles was associated with lower suppression rates. Although the calculated adherence rates in these studies was relatively high (median ≥95%), these calculations did not account for unreturned pill bottles. We believe that assessing adherence by both pill count and pill bottle return rate may provide a more complete picture of adherence in clinical trials. Disclosures Rima K. Acosta, BS, Gilead Sciences, Inc. (Employee, Shareholder) Grace Q. Chen, BS, Gilead Sciences, Inc. (Employee) Hailin Huang, PhD, Gilead Sciences, Inc. (Employee, Shareholder) Hui Liu, PhD, Gilead Sciences, Inc. (Employee, Shareholder) Kirsten L. White, PhD, Gilead Sciences, Inc (Employee, Shareholder)

11. People Living with HIV During the COVID-19 Pandemic: Who Did (or Did Not) Receive Annual Influenza Vaccination?

Background Nationally, younger adults and racial minorities have lower levels of influenza vaccination (influenza vaccination = vaccine) than non-Hispanic White adults. During the 2015-16 season, most vaccine decliners in our program were male, black, and 45-66 years of age. As part of a quality improvement (QI) initiative to increase 2020-21 vaccine coverage amongst PLWH, we sought to compare patient characteristics between vaccine recipients and non-recipients. Methods Our program cares for 60% of Delawareans with HIV. The largest site in Wilmington was the QI site. IRB exemption was received, and pre-defined sociodemographic and HIV-specific variables were extracted from the EMR and CareWare from 1 Oct 2020 through 31 March 2021. Patient reports of external vaccine required confirmation. All PLWH ≥ 18 years of age, including those newly establishing care, met eligibility criteria. Comparisons between vaccinated and unvaccinated PLWH were performed using Wilcoxon rank sum tests for continuous variables and chi-squared tests for categorical variables. A multivariable logistic regression model, including age, sex, race, insurance, poverty level, HIV status, and virologic suppression, was used to predict vaccine. Results 780 patients met study inclusion criteria and 86% (667/780) received vaccine. Characteristics of PLWH with and without vaccine are presented in Table 1. Older age, lower HIV viral load, and virologic suppression had a statistically significant (p&lt; 0.05) association with vaccine receipt in unadjusted analysis. Only older age (p&lt; 0.01) was significantly associated with vaccine in logistic regression modeling (Table 2), however this relationship was non-linear. Table 1. Characteristics of patients living with HIV during the 2020-2021 Influenza vaccination season Table 2. Multivariable Analysis of Baseline Characteristics Conclusion A very high rate of PLWH received vaccine, far exceeding local and national benchmarks, with EMR data unlikely to have fully captured all vaccines. The role of the COVID-19 pandemic in vaccine amongst PLWH is not yet known. While older age was associated with vaccine in adjusted analysis, the number of unvaccinated patients was small, confidence intervals wide, and associations consequently weak. Larger studies are needed to further investigate factors associated with vaccine receipt amongst PLWH. Disclosures Deborah A. Kahal, MD,MPH, FACP, Gilead (Speaker’s Bureau)Viiv (Speaker’s Bureau)