Constructing suppressive regimens for individuals with multidrug-resistant HIV-1 can be challenging. Separate analyses of 96-week outcomes from the phase 3 VIKING-3 and BRIGHTE studies demonstrate that twice-daily dolutegravir-based and fostemsavir-based regimens each provide robust viral suppression, favorable safety profiles, and CD4+ T-cell count improvement in this population. Clinical trial registration VIKING-3: ClinicalTrials.gov identification number, NCT01328041; URL, https://clinicaltrials.gov/study/NCT01328041; BRIGHTE: ClinicalTrials.gov identification number, NCT02362503; URL, https://clinicaltrials.gov/study/NCT02362503.

BACKGROUND:Heavily treatment-experienced (HTE) people with HIV (PWH) have limited antiretroviral therapy (ART) treatment options, putting them at greater risk of unfavorable human immunodeficiency virus 1 (HIV-1) disease progression. Fostemsavir (BMS-663068) efficiently suppressed viremia and increased CD4 count when combined with other antiretrovirals in HTE PWH. Its active metabolite, temsavir (BMS-626529, GSK2616713), binds a conserved pocket within the envelope glycoprotein (Env) CD4 binding site and prevents CD4-induced conformational changes. Temsavir effect on Env conformation profoundly alters its glycosylation and cleavage, thereby modifying its antigenicity and reducing gp120 shedding. Here we evaluated if fostemsavir treatment in PWH modulated the levels of nonneutralizing gp120 CD4-induced (CD4i) antibodies (Abs) associated with CD4 depletion in vitro and in PWH. METHODS:We measured the levels of anti-gp120 CD4i Abs in plasma samples taken before and after fostemsavir treatment in HTE participants from the BRIGHTE trial and the PRESTIGIO registry and compared them to those of a control ART-treated group from the SAILING trial. RESULTS:We observed a significant decline of anti-gp120 CD4i Abs in the 2 fostemsavir-treated HTE groups, but not in the control group. Moreover, this effect was unique to anti-gp120 CD4i Abs, as no significant changes were observed in the levels of antibodies targeting Gag. Functionally, this decline in CD4i Abs was associated with a reduced capacity of plasma to recognize and eliminate uninfected primary CD4+ T cells coated with soluble gp120. CONCLUSIONS:Altogether, fostemsavir may provide additional immune benefits to PWH, beyond blocking viral entry, by reducing anti-gp120 CD4i Abs levels. CLINICAL TRIALS REGISTRATION:NCT04098315, NCT01231516, and NCT02362503.

Fostemsavir (FTR) is an approved first-in-class small molecule Env antagonist for treating multi-drug resistant (MDR) HIV-1 infection. In the BRIGHTE study, viral suppression rates in heavily treatment-experienced people with HIV (PWH) increased from week 48 through week 96. Factors that contribute to this late response are not well understood. Given FTR’s ability to stabilize a native HIV-1 envelope trimer conformational state, we examined anti-HIV humoral immune responses in the BRIGHTE study to explore how evolving antibody responses in the presence of drug correlate with delayed viral suppression. 16 BRIGHTE study participants (ppt) were selected based on their time to first viremic suppression: eight early (EVS) and eight late viral suppressors (LVS). Immune responses were also analyzed in eight ppt from the SAILING study that evaluated dolutegravir. Anti-HIV Env IgG titer, cell-free and cell-to-cell neutralization activity, FcγRIIa- and FcγRIIIa-signaling, and plasma cytokines at weeks 0, 4 and 108 were examined and correlated with clinical variables associated with treatment response. FTR treatment did not significantly enhance antibody responses against reference strain of HIV in LVS compared to EVS. However, at baseline, LVS had significantly lower anti-HIV IgG titers, higher VL, lower CD4+ T-cell counts and experienced greater increases in CD4+ T-cell counts than EVS. Additionally, IL-8 levels were increased in LVS vs. EVS at treatment initiation. In comparison, SAILING ppt showed increased FcγRIIa signaling during drug treatment compared to the FTR groups. Further studies will determine if pre-treatment characteristics influence timing to viral suppression in FTR-treated individuals with MDR-HIV.

Abstract Background Persistent LLV (40-1000 c/mL) is associated with virologic failure, drug resistance and increased risk of inflammation and may impact morbidity and mortality. FTR (prodrug of the first-in-class attachment inhibitor temsavir) is indicated with other antiretrovirals (ARVs) for heavily treatment-experienced individuals with MDR HIV-1 unable to construct suppressive regimens. BRIGHTE participants (pts) did not have to stop FTR due to LLV. We describe outcomes and inflammatory biomarkers through Week 192 in pts with LLV (< 40, 40-400, 400-1000 and > 1000 c/mL) on FTR-based regimens from the Randomized Cohort (RC) in the BRIGHTE study. Methods BRIGHTE was a phase 3 study (N=371; RC, n=272; Non-randomized Cohort, n=99) in adults failing their current ARV regimen (HIV-1 RNA > 400 c/mL) with ≤ 2 fully active approved ARVs. Pts with 1 or 2 active ARVs entered the RC and received open-label FTR + optimized background therapy after an 8-day blinded placebo-controlled period. Virologic and immunologic responses were analyzed by baseline (BL) demographics and disease characteristics. Results At BL in the RC, 89% of pts had CD4 T-cell count < 350 cells/mm3, with 5% between 350 and < 500 cells/mm3 and 6% ≥ 500 cells/mm3. Mean CD4 T-cell increase observed in the < 40 c/mL (n=142) group was 331 cells/mm3, 40-400 c/mL (n=25) was 263 cells/mm3, 400-1000 c/mL (n=2) was 218 cells/mm3, and in pts with > 1000 c/mL (n=10) was 107 cells/mm3. Similar mean increase in CD4/CD8 ratio was observed in pts with LLV; ratio in the < 40 c/mL (n= 142) group was 0.38, 40-400 c/mL (n=25) was 0.31, 400-1000 c/mL (n=2) was 0.32, and in pts with > 1000 c/mL (n=10) was 0.09. Biomarkers showed a mean general reduction; < 40 c/mL (sCD14: −371 µg/L, n=133; sCD163: −134 µg/L, n=40; D-dimer: 0.16 mg/L, n=139), 40-400 c/mL (sCD14: −428 µg/L, n=21; sCD163: −80 µg/L, n=5; D-dimer: −0.14 mg/L, n=22), 400-1000 c/mL (sCD14: 1174 µg/L, n=2; sCD163: no data; D-dimer: 0.04 mg/L, n=2), > 1000 c/mL (sCD14: 271 µg/L, n=10; sCD163: 107 µg/L, n=3; D-dimer: 0.08 mg/L, n=10). Conclusion In pts with LLV, there is a persistent increase in CD4 T-cell count and improvement in CD4/CD8 ratio, with a general reduction in inflammatory markers up to Week 192. Results highlight the value of FTR-based regimens for sustained improvement where there is incomplete virologic suppression. Disclosures Vincenzo Spagnuolo, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Honoraria|MSD: Honoraria|ViiV Healthcare: Honoraria Natalia Gregori, MD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: employee Iacopo Marcon, PhD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: employee Fangfang Du, MS in Statistics, GSK: Employee|GSK: Stocks/Bonds (Public Company) Bo Li, PhD, GSK: Employee Marcia Wang, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Alftan Dyson, PharmD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee Manyu Prakash, PhD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: employee Andrew Clark, MD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: employee

Fostemsavir, a prodrug of the first-in-class gp120-directed attachment inhibitor temsavir, is indicated in combination with other antiretrovirals for the treatment of multidrug-resistant HIV-1 in adults who are heavily treatment-experienced (HTE). Temsavir binds to HIV-1 gp120, close to the CD4 binding site, preventing the initial interaction of HIV-1 with CD4 on the host cell. Amino acid substitutions at four positions in gp120 have been identified as important determinants of viral susceptibility to temsavir (S375H/I/M/N/T/Y, M426L/P, M434I/K, M475I), with a fifth position (T202E) recently described. For most currently circulating group M HIV-1 subtypes, the prevalence of these resistance-associated polymorphisms (RAPs) is low. As with many other antiretrovirals, the impact of RAPs is modified by other changes in the target molecule. Different regions of gp120 interact to modify the temsavir binding pocket, with multiple amino acids playing a role in determining susceptibility. Extensive variability of HIV-1 gp120 means the susceptibility of clinical isolates to temsavir is also highly variable. Importantly, in vitro measurement of the susceptibility of clinical isolates to temsavir does not necessarily capture the range of susceptibilities of the heterogeneous mix of viruses generally present in each isolate. Due to these factors and limited phenotypic clinical data, thus far, no relevant phenotypic cutoff or genotypic algorithms have been derived that reliably predict response to fostemsavir-based therapy in individuals who are HTE; therefore, pre-treatment temsavir resistance testing may be of limited benefit. In the phase III BRIGHTE study, re-suppression after virologic failure was observed in some participants despite treatment-emergent genotypic and/or phenotypic evidence of reduced temsavir susceptibility, and substantial CD4+ T-cell count increases occurred even among participants with HIV-1 RNA ⩾40 copies/mL at Week 240. Clinical management of people who are HTE and experience virologic failure during treatment with fostemsavir-based regimens requires an individualized approach with consideration of potential benefits beyond virologic suppression.

Abstract Background Constructing suppressive regimens in individuals with MDR HIV-1 can be challenging. We assessed populations with limited ART options in the BRIGHTE study using FTR-based regimens and the VIKING-3 study using DTG-based regimens. Methods BRIGHTE was a phase 3 study (N=371; Randomized Cohort [RC], n=272; Non-randomized Cohort, n=99) in adults failing current ART (HIV-1 RNA > 400 c/mL) with ≤ 2 fully active approved ARVs. Participants (pts) with 1 or 2 active ARVs entered the RC and received open-label FTR + optimized background therapy (OBT) after an 8-day blinded placebo-controlled period. In the RC, the most common agent in initial OBT was DTG (84%), with 64% taking it twice daily (BID). VIKING-3 (n=183) was a single-arm open-label phase 3 study in adults with INI-resistant virus receiving DTG 50 mg BID + failing regimen (without raltegravir or elvitegravir) through Day 7, then the regimen was optimized with ≥ 1 fully active ARV and DTG continued. Virologic and immunologic response was analyzed by baseline (BL) demographics and characteristics. Results BRIGHTE pts were male (n=290, 78%), median age 48 years and White (n=259, 70%). Observed antiviral response in the RC was 81% (< 40 c/mL, n=128) and 88% (< 400 c/mL, n=140). Mean CD4 increase from BL was 204.7 cells/mm3, with BL mean CD4 count 152.5 cells/mm3. VIKING-3 pts were male (n=141, 77%), median age 48 years and 71% (n=130) White. Antiviral response observed in VIKING-3 was 84% (< 50 c/mL, n=101) and 93% (< 400 c/mL, n=111). Mean CD4 increase was 192 cells/mm3, with BL mean CD4 count 202 cells/mm3. Safety across study populations was as follows: BRIGHTE (RC), n=92 (34%) serious adverse events (AEs), n=57 (21%) drug-related AEs and n=7 (3%) AEs leading to withdrawal; VIKING-3, n=60 (33%) serious AEs, n=52 (28%) drug-related AEs and n=8 (4%) AEs leading to withdrawal. Conclusion Despite limited ARV options in individuals with MDR HIV-1, data demonstrate that over 96 weeks both DTG (BID) and FTR-based regimens provide robust viral suppression and CD4 T-cell improvement. Although differences in BL characteristics exist, immunosuppression was more profound in BRIGHTE pts. FTR and DTG were commonly used together in BRIGHTE, engaging different mechanisms of action. Data provide further support for effective ARVs for individuals living with MDR HIV-1. Disclosures Antonella Castagna, MD, Bristol-Myers Squibb: Advisor/Consultant|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Merck Sharp & Dohme: Advisor/Consultant|Merck Sharp & Dohme: Grant/Research Support|Merck Sharp & Dohme: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Honoraria Natalia Gregori, MD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: employee Iacopo Marcon, PhD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: employee Fangfang Du, MS in Statistics, GSK: Employee|GSK: Stocks/Bonds (Public Company) Bo Li, PhD, GSK: Employee Marcia Wang, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Alftan Dyson, PharmD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee Clifford B. Jones, BSc MSc MB ChB, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee Manyu Prakash, PhD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: employee Andrew Clark, MD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: employee

Background Fostemsavir, a first-in-class attachment inhibitor that binds to the viral envelope protein gp120, is approved for heavily treatment-experienced persons with HIV-1 with limited treatment options. We explored changes in immunologic and coagulopathy parameters in the BRIGHTE study: a phase 3 trial that evaluated fostemsavir plus optimized background therapy in heavily treatment-experienced adults with multidrug-resistant HIV-1.Methods CD4+ T-cell count, CD4+/CD8+ ratio, soluble CD14, soluble CD163, and D-dimer levels were measured through 96 weeks in participants with 1 or 2 fully active antiretroviral agents available at screening. No formal statistical analyses were performed.Results Among 272 participants, increases were observed from baseline to week 96 in CD4+ T-cell count (mean increase, +205 cells/mm3) and CD4+/CD8+ ratio (mean increase, +0.24). The proportion of observed participants with a CD4+/CD8+ ratio >= 0.45 increased from 9% (25/272) at baseline to 40% (85/213) at week 96. From baseline to week 96, we also observed trends toward decreases in the following (mean [SD] change): soluble CD14, -738.2 (981.8) mu g/L; soluble CD163, -138.0 (193.4) mu g/L; and D-dimer, -0.099 (0.521) mg/L fibrinogen-equivalent units. Decreases in biomarkers were generally observed among subgroups by baseline disease characteristics, virologic response, and CD4+ T-cell count.Conclusions These data suggest that heavily treatment-experienced persons with multidrug-resistant HIV-1 treated with fostemsavir + optimized background therapy may have improvements in immune parameters, including markers of monocyte activation and coagulopathy.Clinical Trials Registration NCT02362503 (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02362503). In the phase 3 BRIGHTE study, heavily treatment-experienced adults with multidrug-resistant HIV-1 had robust improvements in immune parameters and markers of monocyte activation and coagulopathy through 96 weeks of fostemsavir-based therapy, regardless of baseline disease characteristics and virologic response.

Objective: Metabolic dysfunction associated fatty liver disease (MAFLD) is over-represented in people with HIV (PWH). Maraviroc (MVC) and/or metformin (MET) may reduce MAFLD by influencing inflammatory pathways and fatty acid metabolism. Design: Open-label, 48-week randomized trial with a 2 x 2 factorial design. Setting: Multicenter HIV clinics. Participants: Nondiabetic, virologically suppressed PLWH, aged at least 35 years, with confirmed/suspected MAFLD (≥1 biochemical/anthropometric/radiological/histological features). Intervention: Adjunctive MVC; MET; MVC+MET vs. antiretroviral therapy (ART) alone. Primary outcome: Change in liver fat fraction (LFF) between baseline and week-48 using magnetic resonance proton density fat fraction (MR PDFF). Results: Six sites enrolled 90 participants (93% male; 81% white; median age 52 [interquartile range, IQR 47–57] years) between March 19, 2018, and November 11, 2019. Seventy percent had imaging/biopsy and at least one 1 MAFLD criteria. The analysis included 82/90 with week-0 and week-48 scans. Median baseline MR PDFF was 8.9 (4.6–17.1); 40, 38, 8, and 14% had grade zero, one, two, and three steatosis, respectively. Mean LFF increased slightly between baseline and follow-up scans: 2.22% MVC, 1.26% MET, 0.81% MVC+MET, and 1.39% ART alone. Prolonged intervention exposure (delayed week-48 scans) exhibited greater increases in MR PDFF (estimated difference 4.23% [95% confidence interval, 95% CI 2.97–5.48], P < 0.001). There were no differences in predicted change for any intervention compared to ART alone: MVC (-0.42% [95% CI -1.53 to 0.68, P = 0.45]), MET (-0.62 [-1.81 to 0.56, P = 0.30]), and MVC+MET (-1.04 [-2.74 to 0.65, P = 0.23]). Steatosis grade remained unchanged in 55% and increased in 24%. Conclusion: Baseline levels of liver fat were lower than predicted. Contrary to our hypothesis, neither MVC, MET, or the combination significantly reduced liver fat as measured by MRPDFF compared to ART alone.

Temsavir binds directly to the HIV-1 envelope glycoprotein gp120 and selectively inhibits interactions between HIV-1 and CD4 receptors. Previous studies identified gp120 amino acid positions where substitutions are associated with reduced susceptibility to temsavir. The mechanism by which temsavir susceptibility is altered in these envelope glycoproteins was evaluated. Pseudoviruses encoding gp120 substitutions alone (S375H/I/M/N, M426L, M434I, M475I) or in combination (S375H + M475I) were engineered on a wild-type JRFL background. Temsavir-gp120 and CD4-gp120 binding kinetics and ability of temsavir to block CD4-gp120 binding were evaluated using the purified polymorphic gp120 proteins and a Creoptix (R) WAVE Delta grating-coupled interferometry system. Fold-change in half-maximal inhibitory concentration (IC50) in JRFL-based pseudoviruses containing the aforementioned polymorphisms relative to that of wild-type ranged from 4-fold to 29,726-fold, while temsavir binding affinity for the polymorphic gp120 proteins varied from 0.7-fold to 73.7-fold relative to wild-type gp120. Strong correlations between temsavir IC50 and temsavir binding affinity (r = 0.7332; P = 0.0246) as well as temsavir binding on-rate (r = -0.8940; P = 0.0011) were observed. Binding affinity of gp120 proteins for CD4 varied between 0.4-fold and 3.1-fold compared with wild-type gp120; no correlations between temsavir IC50 and CD4 binding kinetic parameters were observed. For all polymorphic gp120 proteins, temsavir was able to fully block CD4 binding; 3 polymorphs required higher temsavir concentrations. Loss of susceptibility to temsavir observed for gp120 polymorphisms strongly correlated with reductions in temsavir binding on-rate. Nonetheless, temsavir retained the ability to fully block CD4-gp120 engagement given sufficiently high concentrations.

Previous data suggest a lack of cross-resistance between the gp120-directed attachment inhibitor temsavir (active moiety of fostemsavir) and the CD4-directed post-attachment inhibitor ibalizumab. Recently, analysis of HIV-1 envelopes with reduced sensitivity to both inhibitors was undertaken to determine whether they shared genotypic correlates of resistance. Sequences from 2 envelopes with reduced susceptibility to both agents were mapped onto a temsavir-bound gp120 structure. Residues within 5.0 Å of the temsavir binding site were evaluated using reverse genetics. Broader applicability and contextual determinants of key substitutions were further assessed using envelopes from participants in the phase 3 BRIGHTE study. Temsavir sensitivity was measured by half-maximal inhibitory concentration (IC50) and ibalizumab sensitivity by IC50 and maximum percent inhibition (MPI). One envelope required substitutions of E113D and T434M for full restoration of temsavir susceptibility. Neither substitution nor their combination affected ibalizumab sensitivity. However, in the second envelope, an E202 substitution (HXB2, T202) was sufficient for observed loss of susceptibility to both inhibitors. One BRIGHTE participant with no ibalizumab exposure had an emergent K202E substitution at protocol-defined virologic failure, with reduced sensitivity to both inhibitors. Introducing T202E into previously susceptible clinical isolates reduced temsavir potency by ≥ 40-fold and ibalizumab MPI from >99% to ∼80%. Interestingly, introduction of the gp120 V5 region from a highly ibalizumab-susceptible envelope mitigated the E202 effect on ibalizumab but not temsavir. A rare HIV-1 gp120 E202 mutation reduced temsavir susceptibility, and depending on sequence context, could result in reduced susceptibility to ibalizumab.

IntroductionFostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes.MethodsThe phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant’s first visit (February 23, 2015) through the last participant’s last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm3, exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm3 at any time during 48-week analysis periods through week 192.ResultsThrough a median of 258 weeks (range, 0.14–319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19–related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm3, 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm3 at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm3 at any time vs those sustaining <200 cells/mm3. No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm3.ConclusionsCumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment.Clinical trial numberNCT02362503, https://clinicaltrials.gov/study/NCT02362503.

Background Chronic inflammation persists in some people living with human immunodeficiency virus (HIV) during antiretroviral therapy and is associated with premature aging. The glycoprotein 120 (gp120) subunit of HIV-1 envelope sheds and can be detected in plasma, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasma soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, linked to CD4 depletion in vitro, contribute to chronic inflammation, immune dysfunction, and subclinical cardiovascular disease in participants of the Canadian HIV and Aging Cohort Study with undetectable viremia.Methods Cross-sectional assessment of sgp120 and anti-cluster A antibodies was performed in 386 individuals from the cohort. Their association with proinflammatory cytokines and subclinical coronary artery disease was assessed using linear regression models.Results High levels of sgp120 and anti-cluster A antibodies were inversely correlated with CD4+ T cell count and CD4/CD8 ratio. The presence of sgp120 was associated with increased levels of interleukin 6. In participants with detectable atherosclerotic plaque and detectable sgp120, anti-cluster A antibodies and their combination with sgp120 levels correlated positively with the total volume of atherosclerotic plaques.Conclusions This study showed that sgp120 may act as a pan toxin causing immune dysfunction and sustained inflammation in a subset of people living with HIV, contributing to the development of premature comorbid conditions. Soluble glycoprotein 120 (sgp120) is detected in the plasma of people living with HIV-1 with undetectable viremia. The presence of sgp120 and anti-cluster A antibodies is associated with correlates of immune dysfunction, chronic inflammation, and subclinical cardiovascular disease.

OBJECTIVES:Fostemsavir is a novel attachment inhibitor used with other antiretrovirals in heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. Real-world immunological and virological responses were assessed in individuals starting fostemsavir in the OPERA cohort. METHODS:Among adults with HIV-1 starting fostemsavir between 2 July 2020 and 1 September 2022, 6-month and 12-month changes in CD4 T-cell count and CD4%, and maintenance/achievement of viral load (VL) <50 copies/mL were described and stratified by baseline VL (suppressed: <50 copies/mL; viraemic: ≥50 copies/mL) and CD4 count (high: ≥350 cells/μL; low: <350 cells/μL). RESULTS:Of 182 individuals starting fostemsavir, 64% were viraemic (34% low CD4, 30% high CD4) and 36% were suppressed (16% low CD4, 20% high CD4). The suppressed/low CD4 group had the largest median increases in CD4 count (6-month: 30 cells/μL [interquartile range {IQR} 9-66], 12-month: 66 cells/μL [IQR 17-125]), and CD4% (6-month: 1.0% [IQR -0.3-2.8], 12-month: 1.9% [IQR 1.3-3.9]). Regardless of baseline VL, those with a high baseline CD4 count experienced a greater variability in immunological response than those with low CD4 counts (12-month standard deviation range 172-231 cells/μL vs. 69-90 cells/μL). VL <50 copies/mL was maintained in most suppressed individuals; nearly half of the viraemic/high CD4 group and a third of the viraemic/low CD4 group achieved a VL <50 copies/mL at either timepoint. CONCLUSIONS:After 6 or 12 months of fostemsavir use, virological response was low in viraemic individuals, although most suppressed individuals did maintain suppression. While immunological response varied across individuals, virologically suppressed HTE individuals with low CD4 counts may benefit from immunological improvements with fostemsavir.

Background As the population of people with HIV ages, concerns over managing age-related comorbidities, polypharmacy, immune recovery, and drug-drug interactions while maintaining viral suppression have arisen. We present pooled TANGO and SALSA efficacy and safety results dichotomized by age (< 50 and ≥ 50 years). Methods Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily dolutegravir/lamivudine (DTG/3TC) fixed-dose combination vs continuing current antiretroviral regimen (CAR) were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 copies/mL (Snapshot, intention-to-treat exposed) and safety were analyzed by age category. Adjusted mean change from baseline in CD4 + cell count was assessed using mixed-models repeated-measures analysis. Results Of 1234 participants, 80% of whom were male, 29% were aged ≥ 50 years. Among those aged ≥ 50 years, 1/177 (< 1%) DTG/3TC participant and 3/187 (2%) CAR participants had HIV-1 RNA ≥ 50 copies/mL at 48 weeks; proportions with HIV-1 RNA < 50 copies/mL were high in both treatment groups (≥ 92%), consistent with overall efficacy and similar to observations in participants aged < 50 years (≥ 93%). Regardless of age category, CD4 + cell count increased or was maintained from baseline with DTG/3TC. Change from baseline in CD4 + /CD8 + ratio was similar across age groups and between treatment groups. One CAR participant aged < 50 years had confirmed virologic withdrawal, but no resistance was detected. In the DTG/3TC group, incidence of adverse events (AEs) was similar across age groups. Proportions of AEs leading to withdrawal were low and comparable between age groups. Although drug-related AEs were generally low, across age groups, drug-related AEs were more frequent in participants who switched to DTG/3TC compared with those who continued CAR. While few serious AEs were observed in both treatment groups, more were reported in participants aged ≥ 50 years vs < 50 years. Conclusions Among individuals with HIV-1, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile, including in those aged ≥ 50 years despite higher prevalence of concomitant medication use and comorbidities. Trial registration number: TANGO, NCT03446573 (February 27, 2018); SALSA, NCT04021290 (July 16, 2019).

Background: Non-alcoholic fatty liver disease (NAFLD), a manifestation of metabolic syndrome, is over-represented in people living with HIV (PLWH). Maraviroc, a C-C chemokine receptor type-5 (CCR5) inhibitor, and metformin, a biguanide anti-glycaemic, may reduce hepatic steatosis/steatohepatitis through their influence on inflammatory pathways (metformin & maraviroc), and free fatty acid metabolism (metabolism).Methods: MAVMET (NCT#:03129113), is a multi-centre, open-label, 48-week randomised trial with a 2x2 factorial design of adjunctive maraviroc (MVC); metformin (MET); maraviroc+metformin (MVC+MET) vs. antiretroviral therapy (ART) alone in non-diabetic, virologically-suppressed PLWH, aged ≥35 years, with confirmed/suspected NAFLD (≥1 biochemical/anthropometric/radiological/ histological feature suggestive of/confirming hepatic steatosis). The primary outcome was change in liver fat percentage between baseline and week 48, using the Magnetic Resonance Proton Density Fat Fraction (MR PDFF), analysed using linear regression, and adjusted for COVID-19-related delays in week-48 scans.Findings: 90 participants [93% male; 81% white ethnicity; median age 52 (IQR 47-57) years], were enrolled between 19-Mar-2018 and 11-November-2019 from six UK sites; 70% with imaging/biopsy plus ≥1 criteria for NAFLD. The primary analysis included 82/90 with both week 0 and 48 scans. Mean (Standard deviation, SD) baseline PDFF was 11.8% (8.7); 40%, 38%, 8% and 14% had grade 0,1, 2 and 3 hepatic steatosis respectively. Mean PDFF (SD) at week 48 was 12.9% (9.0). Hepatic steatosis grade remained unchanged in 55% and increased in 24% (n=20). Remaining on study drugs for longer (delayed week-48 scans) was associated with greater increases in liver fat percentage. The small decreases (absolute and relative to ART alone) in liver fat percentage with MVC or MET [MVC -0.42% (95% CI -1.53-0.68, p=0.45), MET -0.62 (-1.81-0.56, p=0.30), MVC+MET -1.04 (-2.74-0.65, p=0.23)] were non-significant.Interpretation: Baseline levels of liver fat were lower than predicted. Contrary to our hypothesis, neither MVC, MET or the combination, significantly reduced the LFF compared to ART alone.Trial Registration: MAVMET was registered at ClinicalTrials.gov (NCT#: 03129113) and with EudraCt (2016- 163 003575-21). Funding: ViiV Healthcare, UK funded the study as an independent academic grant (ViiV Reference Etrack Number 204817).Declaration of Interest: We declare no competing interests.Ethical Approval: Ethical approval was authorised by the London-Hampstead Research Ethics Committee 161 (17/LO/0998). MAVMET was granted Clinical Trial Authorisation (CTA# 00316/0247/001- 162 0001). All participants provided written informed consent prior to study procedures.

Efficacy and safety of the attachment inhibitor fostemsavir + optimized background therapy (OBT) were evaluated through 48 and 96 weeks in the phase 3 BRIGHTE trial in heavily treatment-experienced (HTE) adults failing their current antiretroviral regimen. Here, we report 240-week efficacy and safety of fostemsavir + OBT in adults with multidrug-resistant human immunodeficiency virus (HIV)-1 in BRIGHTE. Heavily treatment-experienced adults failing their current regimen entered the randomized cohort (RC; 1–2 fully active antiretrovirals available) or non-randomized cohort (NRC; no fully active antiretrovirals available) and received open-label fostemsavir + OBT (starting Day 8 in RC and Day 1 in NRC). Endpoints included proportion with virologic response (HIV-1 RNA < 40 copies/mL, Snapshot), immunologic efficacy, and safety. At Week 240, 45

While HIV-1-mediated CD4 downregulation protects infected cells from antibody-dependent cellular cyto-toxicity (ADCC), shed gp120 binds to CD4 on uninfected bystander CD4+ T cells, sensitizing them to ADCC mediated by HIV+ plasma. Soluble gp120-CD4 interaction on multiple immune cells also triggers a cytokine burst. The small molecule temsavir acts as an HIV-1 attachment inhibitor by preventing envelope glycoprotein (Env)-CD4 interaction and alters the overall antigenicity of Env by affecting its processing and glycosylation. Here we show that temsavir also blocks the immunomodulatory activities of shed gp120. Tem-savir prevents shed gp120 from interacting with uninfected bystander CD4+ cells, protecting them from ADCC responses and preventing a cytokine burst. Mechanistically, this depends on temsavir's capacity to prevent soluble gp120-CD4 interaction, to reduce gp120 shedding, and to alter gp120 antigenicity. This sug-gests that the clinical benefits provided by temsavir could extend beyond blocking viral entry.