Despite advances in antiretroviral therapy (ART), real-world data remain limited regarding clinical characteristics and healthcare utilization according to ART use among people living with human immunodeficiency virus (PLWH), as well as patterns of ART use in this population. This retrospective cohort study used a US healthcare claims database to identify adult PLWH from 2021 to 2024. Primary cohort included those with ≥3 human immunodeficiency virus (HIV)-1 diagnosis codes within 3 years (third code defined the index date). A nested cohort included PLWH with ≥1 ART prescription claim(s) within 180 days of follow-up. All-cause and HIV-related inpatient hospitalizations and emergency room (ER) visits were assessed before and after index date. Pharmacotherapy change within 180 days after index was assessed for the nested cohort. In the primary cohort of 51,837 PLWH, mean age was 46.5 years; 17.5

Background: Leronlimab is a humanized κ-IgG4 monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). We investigated leronlimab as a treatment option for people living with multidrug-resistant HIV-1. Setting and Methods: In a phase 2b/3, multicenter, randomized, double-blind, placebo-controlled study conducted in 21 hospital centers in the United States, treatment-experienced people living with HIV (PLWH) with documented drug resistance were randomly assigned once weekly leronlimab (350 mg subcutaneously) or matching placebo for one week overlapping existing failing antiretroviral treatment (ART), followed by a 24-week single-arm extension with weekly leronlimab combined with a new optimized background treatment (OBT). The primary endpoint was achieving ≥0.5 log 10 reduction in plasma HIV-1 RNA from baseline at the end of the one-week double-blinded treatment period. Results: 52 participants were enrolled (25 leronlimab and 27 placebo). After the one-week randomized phase, by the intent-to-treat analysis 64.0% (16/25) receiving leronlimab achieved ≥0.5 log 10 reduction in plasma HIV-1 RNA versus 23.1% (6/26) receiving placebo (p=0.0032), while by per protocol analysis 72.7% (16/22) receiving leronlimab achieved ≥0.5 log 10 reduction in plasma HIV-1 RNA versus 24.0% (6/25) receiving placebo (p=0.0008). Leronlimab was generally well tolerated with no drug-related SAEs reported. Overall, 175 adverse events were reported by 34/52 participants, with 120 (68.6%) adverse events categorized as mild. Conclusions: Leronlimab resulted in significantly reduced plasma HIV-1 within one week after addition to failing ART. After 24 weeks combined with an OBT, most participants had plasma HIV-1 RNA levels <50 copies per mL plasma, suggesting utility of leronlimab as a component of salvage therapy.

Purpose Early in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19. Methods The TEMPEST trial was a randomized, double-blind, placebo-controlled study in participants with mild-to-moderate COVID-19. Participants were randomly assigned in a 2:1 ratio to receive subcutaneous leronlimab (700 mg) or placebo on days 0 and 7. The primary efficacy endpoint was assessed by change in total symptom score based on fever, myalgia, dyspnea, and cough, at end of treatment (day 14). Findings Overall, 84 participants were randomized and treated with leronlimab (n = 56) or placebo (n = 28). No difference was observed in change in total symptom score (P = 0.8184) or other pre-specified secondary endpoints between treatments. However, in a post hoc analysis, 50.0% of participants treated with leronlimab demonstrated improvements from baseline in National Early Warning Score 2 (NEWS2) at day 14, compared with 20·8% of participants in the placebo group (post hoc; p = 0.0223). Among participants in this trial with mild-to-moderate COVID-19 adverse events rates were numerically but not statistically significantly lower in leronlimab participants (33.9%) compared with placebo participants (50.0%). Implications At the time the TEMPEST trial was designed although CCR5 was known to be implicated in COVID-19 disease severity the exact pathophysiology of SARS-CoV-2 infection was poorly understood. Today it is well accepted that SARS-CoV-2 infection in asymptomatic-to-mild cases is primarily characterized by viral replication, with a heightened immune response, accompanied by diminished viral replication in moderate-to-severe disease and a peak in inflammatory responses with excessive production of pro-inflammatory cytokines in critical disease. It is therefore perhaps not surprising that no differences between treatments were observed in the primary endpoint or in pre-specified secondary endpoints among participants with mild-to-moderate COVID-19. However, the results of the exploratory post hoc analysis showing that participants in the leronlimab group had greater improvement in NEWS2 assessment compared to placebo provided a suggestion that leronlimab may be associated with a lower likelihood of people with mild-to-moderate COVID-19 progressing to more severe disease and needs to be confirmed in other appropriately designed clinical trials.ClinicalTrials.gov number, NCT04343651 https://classic.clinicaltrials.gov/ct2/show/NCT04343651

Background & Aims: The investigational first -generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open -label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for > -52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary ef ficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. Results: Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred > -4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off -treatment or NrtI-restart phases. No drug -drug interactions between VBR + NrtI and no cases of treatment -emergent resistance among patients who adhered to treatment were observed. Conclusions: Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24 -week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This firstgeneration core inhibitor administered with NrtI for at least 52 weeks was not suf ficient for HBV cure. Clinical trial number: NCT03780543. Impact and implications: Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract Background Fostemsavir (FTR), the prodrug of the first-in-class attachment inhibitor temsavir, is indicated in combination with other antiretrovirals (ARVs) for heavily-treatment experienced (HTE) people with multidrug-resistant HIV-1 unable to construct suppressive regimens. After ∼5 years in the phase 3 BRIGHTE study, overall virologic response rate (HIV-1 RNA < 40 c/mL, Snapshot) with FTR + optimized background therapy (OBT) was 45% (120/267) in the Randomized Cohort (RC) and 22% (20/92) in the Non-Randomized Cohort (NRC). We present long-term efficacy of FTR + OBT among subgroups in BRIGHTE. Methods BRIGHTE included HTE adults with HIV-1 (N=371) failing their current ARV regimen (HIV-1 RNA > 400 c/mL) with ≤ 2 fully active and approved ARVs remaining. Participants with 1 or 2 ARVs entered the RC and received open-label FTR + OBT after an 8-day blinded placebo-controlled period; those with 0 ARVs entered the NRC and received open-label FTR + OBT from Day 0. Virologic and immunologic responses were analyzed by baseline (BL) demographics and disease characteristics. Results Of 371 participants (RC, n=272; NRC, n=99), 290 (78%) were male, 166 (45%) were aged ≥ 50 years, and 259 (70%) were White. Virologic response rates were generally comparable among subgroups and consistent with overall response rate (Table 1). Similar efficacy was observed in RC participants with 1 or 2 fully active ARVs in OBT, while both RC and NRC participants with high BL viral loads or low BL CD4+ T-cell counts had lower response rates. Nearly all subgroups demonstrated robust and continuous increases in CD4+ T-cell count from Weeks 96 to 240, with mean change from BL exceeding 200 cells/mm3 in all RC subgroups, including those with BL viral loads ≥ 100,000 c/mL or CD4+ T-cell counts < 20 cells/mm3 (Table 2). Conclusion Virologic response with FTR + OBT in HTE adults with advanced HIV-1 and limited treatment options was durable over ∼5 years, with no major differences among subgroups based on age, sex, race, or geographic region. Robust and continuous CD4+ T-cell increases were also observed, with numerically greater improvements in subgroups with lowest BL CD4+ T-cell counts. These data highlight the role of FTR as a treatment option for HTE people with multidrug-resistant HIV-1 regardless of demographic or disease characteristics. Disclosures Alftan Dyson, PharmD, GSK: Stocks/Bonds|ViiV Healthcare: Employment Judith A. Aberg, MD, Emergent BioSolutions: Institutional research grants|Frontier Technologies: Institutional research grants|Gilead: Institutional research grants|GSK: Advisor/Consultant|GSK: Institutional research grants|Janssen: Institutional research grants|Merck: Advisor/Consultant|Merck: Institutional research grants|Pfizer: Institutional research grants|Regeneron: Institutional research grants|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Institutional research grants Jean-Michel Molina, MD; PhD, Aelix: Advisor/Consultant|Gilead: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant Isabel Cassetti, MD, Gilead: Advisor/Consultant|Gilead: Institutional research grants|GSK: Advisor/Consultant|Janssen: Institutional research grants|Merck: Advisor/Consultant|Merck: Institutional research grants|ViiV Healthcare: Institutional research grants Michael Kozal, MD, ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Royalties/Licenses for chapters authored for UpToDate Bo Li, PhD, GSK: Employment|GSK: Stocks/Bonds Manyu Prakash, PhD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Andrew Clark, MD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Allan R. Tenorio, MD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Amy Pierce, BS, GSK: Stocks/Bonds|ViiV Healthcare: Employee Max Lataillade, DO, GSK: Stocks/Bonds|ViiV Healthcare: Employee

Objective: To evaluate the safety and efficacy of switching highly treatment-experienced people with HIV (HTE PWH) from rilpivirine/emtricitabine/tenofovir alafenamide (RPV/FTC/TAF) plus dolutegravir (DTG) to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus doravirine (DOR). A pharmacokinetic (PK) analysis was conducted to assess the potential interaction between BIC and DOR. Design and methods: This open-label switch trial enrolled HTE PWH from a primary care private practice in the United States. Eligible participants were male, aged ≥45 years, with documented viral resistance to protease inhibitors, nucleoside reverse transcriptase inhibitors, and/or nonnucleoside reverse transcriptase inhibitors but no resistance to RPV or DOR, and no K65R or T69 insertion mutations. Virologic suppression (≤50 copies/ml) while on RPV/FTC/TAF plus DTG for ≥6 months was required prior to enrollment. The primary endpoint of the study was virologic suppression (<50 and <200 copies/ml) at 48 weeks. Secondary endpoints included safety, tolerability, changes in body mass index (BMI), and identification of PK parameters of BIC and DOR. Results: Twenty males [median age: 65 years (range, 46–74), median time since HIV diagnosis: 37 years (range, 12–42)] completed the study. BIC/FTC/TAF plus DOR was well tolerated with no serious or treatment-related adverse events reported and no appreciable changes in BMI from baseline to Week 48. At Week 48, 100% of participants had <50 viral copies/ml. PK parameters for BIC and DOR (n = 10) were consistent with published data. Conclusions: Switching from RPV/FTC/TAF plus DTG to BIC/FTC/TAF plus DOR was well tolerated and efficacious in HTE men aged ≥45 years with HIV.

Background Chronic hepatitis B (CHB) remains a major cause of morbidity and mortality. EDP-514 is a potent core inhibitor of hepatitis B virus (HBV) that reduces viral load reduction in HBV-infected chimeric mice. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics (PK) of EDP-514 in healthy subjects and antiviral activity in patients with CHB. Methods In Part 1, 82 subjects received placebo or EDP-514 in fed or fasted state as single ascending doses of 50–800 mg and multiple ascending doses of 200–800 mg for 14 days. In Part 2, 24 HBV DNA-suppressed, nucleos(t)ide (NUC)-treated (i.e., NUC-suppressed) CHB patients received EDP-514 200–800 mg or placebo for 28 days. Results EDP-514 was well tolerated in healthy subjects and CHB patients with most adverse events of mild intensity. In Part 1, EDP-514 exposure increased in an approximately dose proportional manner up to 600 mg after single doses and up to 400 mg after 14-day dosing. In Part 2, EDP-514 exposure increased linearly with dose on Day 1 and Day 28, with some accumulation for Day 28 and median trough concentrations (Ctrough) approximately 20-fold above the protein-adjusted 50% effective concentration (EC50) for the dose range. Mean change in HBV RNA from baseline to Day 28 was −2.03, −1.67, −1.87, and −0.58 log U/mL in the 200 mg, 400 mg, 800 mg, and placebo CHB groups, respectively. Conclusions EDP-514 was well tolerated, had a PK profile supporting once daily dosing, and reduced HBV RNA levels in NUC-suppressed CHB patients.

Background & Aims: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core in-hibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naive patients with cHBV. Methods: HBeAg-positive, treatment-naive patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. Results: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA -4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO +ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p < 0.0001 and p < 0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. Conclusions: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naive patients with cHBV, with a favourable safety and tolerability profile. Clinical trial number: NCT03577171 Lay summary: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naive patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Mean (SEM) HBV DNA levels change from baseline through the end of the treatment period by Cohort Conclusion: All dose levels of ALG-000184 were well tolerated, exhibited predictable PK, and resulted in similar, substantial antiviral activity in untreated CHB subjects, regardless of HBeAg status.

The CCR5-specific antibody Leronlimab is being investigated as a novel immunotherapy that can suppress HIV replication with minimal side effects. Here we studied the virological and immunological consequences of Leronlimab in chronically CCR5-tropic HIV-1 infected humans (n = 5) on suppressive antiretroviral therapy (ART) and in ART-naïve acutely CCR5-tropic SHIV infected rhesus macaques (n = 4). All five human participants transitioned from daily combination ART to self-administered weekly subcutaneous (SC) injections of 350 mg or 700 mg Leronlimab and to date all participants have sustained virologic suppression for over seven years. In all participants, Leronlimab fully occupied CCR5 receptors on peripheral blood CD4+ T cells and monocytes. In ART-naïve rhesus macaques acutely infected with CCR5-tropic SHIV, weekly SC injections of 50 mg/kg Leronlimab fully suppressed plasma viremia in half of the macaques. CCR5 receptor occupancy by Leronlimab occurred concomitant with rebound of CD4+ CCR5+ T-cells in peripheral blood, and full CCR5 receptor occupancy was found in multiple anatomical compartments. Our results demonstrate that weekly, self-administered Leronlimab was safe, well-tolerated, and efficacious for long-term virologic suppression and should be included in the arsenal of safe, easily administered, longer-acting antiretroviral treatments for people living with HIV-1. Trial Registration: ClinicalTrials.gov Identifiers: NCT02175680 and NCT02355184 .

BACKGROUND & AIMS:HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS:Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS:Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS:In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER:NCT03576066. LAY SUMMARY:Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

The number of confirmed cases of infection with SARS-CoV-2, the virus causing Coronavirus disease 2019 (COVID-19), continues to increase and is associated with substantial morbidity and mortality in virtually every country in the world. Although in the long-term mass vaccinations remains the most promising approach to control the pandemic, evidence suggests that new variants of the virus have emerged that may be able to evade the immune responses triggered by current vaccines. Therefore despite the recent approval of a number of SARS-CoV-2 vaccines there remains considerable urgency for effective treatments for COVID-19. Severe-to-critical COVID-19 has been shown to be associated with a dysregulated host immune response to SARS-CoV-2 with elevated levels of C–C chemokine receptor type 5 (CCR5) ligands including chemokine C–C ligands 3, 4, 5, as well as interleukins 6 and 10. Leronlimab, a CCR5-specific humanised IgG4 monoclonal antibody originally developed for the treatment of HIV has been studied for the treatment of COVID-19. In the TEMPEST trial which compared leronlimab to placebo in subjects with mild-to-moderate COVID-19, a post hoc analysis showed that leronlimab led to improvements from baseline in National Early Warning Score 2 (NEWS2) at Day 14 in the sub-set of people with more severe disease. Data has also been released on a further ongoing, randomized, placebo-controlled phase 3 registrational trial of leronlimab in 394 people with severe-to-critical COVID-19. The results show that Day 28 mortality was reduced (P ​= ​0.0319) in the subset of participants receiving leronlimab plus other pre-specified commonly used COVID-19 treatments including dexamethasone administered as part of their standard of care (SOC) compared to participants receiving placebo plus other pre-specified commonly used COVID-19 treatments including dexamethasone as part of their SOC. Several cases have recently been reported demonstrated that treatment with leronlimab restores immune function and achieves clinical improvement in people with critical COVID-19. Here we report on a further case of a critically ill person who was treated with leronlimab. This person had been on extracorporeal membrane oxygenation (ECMO) for an extended period of time before receiving 4 doses of leronlimab. The male subject received his first dose of leronlimab on Day 79 of hospitalization he was weaned off ECMO by Day 84 and discharged from the ECMO intensive care unit on Day 91.

Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0-7 and patient D (p=0.027) from day 0-14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection.

Antiretroviral therapy (ART) fails to fully restore immune function and is not curative. A single infusion of CCR5 gene-edited autologous CD4 + T cells (SB-728-T) led to sustained increases in CD4 + T cell counts, improved T cell homeostasis, and reduced the estimated size of the HIV reservoir. These outcomes were associated with the expansion and long-term persistence of a novel CCR5 gene-edited CD4 + T memory stem cell (CD45RA int RO int T SCM ) subset that can replenish the pool of more differentiated memory cells. We showed that novel CD45RA int RO int T SCM cells are transcriptionally distinct from the previously described CD45RA + T SCM and are minimally differentiated cells uncommitted to a specific Th-lineage. Subsequently, we showed in an independent trial that infusion of the SB-728-T cell product resulted in partial control of viral replication upon cessation of ART which was correlated with the frequencies of CCR5 gene-edited T SCM and their T EM progeny. Interestingly, one participant that remained off ART to this date demonstrated long-term maintenance of CCR5 gene-edited cells and increased frequency of polyfunctional HIV-specific CD4 + and CD8 + T cells, contributing to low levels of viral load 5 years post-infusion. Consequently, the generation of HIV protected memory CD4 + T cells by CCR5 disruption can contribute toward novel interventions aimed at achieving a sustained ART-free viral remission of HIV disease.