Gilead Sciences Research Articles

Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women.

There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women. We conducted a phase 3, double-blind, randomized, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF. Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P = 0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions. No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 1 ClinicalTrials.gov number, NCT04994509.).

Past, current, and future trends in the prevalence of primary sclerosing cholangitis and inflammatory bowel disease across England (2015–2027): a nationwide, population-based study

Primary sclerosing cholangitis (PSC) is one of the leading indications for liver transplantation in Europe, and a major risk factor for cancer in inflammatory bowel disease (IBD). However, it is not known how the epidemiology of PSC will change as that of IBD evolves. The aim of this study is to provide nationwide statistics on the past and current prevalence of PSC and IBD across England, and forecast how this is likely to change over time. We accessed and analysed a nationwide population-based administrative healthcare registry, which houses prospectively accrued data since April 1st 2001. In so doing, the past and current prevalence of PSC-IBD and IBD alone was determined among 18-60-year-olds in England, alongside average annual percentage change rates (AAPC), between the 1st of January 2015 and 2020. Past and current prevalence data, alongside trends in incidence and event-free survival rates, were then used to forecast future prevalence between 2021 and2027. In 2015, the prevalence of PSC with prior IBD diagnosis was 5.0 per 100,000 population, rising to 5.7 when including those with IBD diagnosed after PSC. In 2020, prevalence increased to 7.6 (8.6 accounting for IBD developing after PSC), yielding an AAPC of 8.8. In 2027, PSC-IBD prevalence is forecast to be 11.7 (95% prediction interval [PI]: 10.8-12.7), and 13.3 when accounting for IBD developing after PSC (AAPC: 6.4; 95% PI: 5.3-7.5). Comparatively, the prevalence of IBD alone rose among 18-60-year-olds from 384.3 in 2015 to 538.7 in 2020 (AAPC 7.0), and forecast to increase to 742.5 by 2027 (95% PI: 736.4-748.0; AAPC: 4.7, 95% PI: 4.6-4.8). The rate of growth in PSC-IBD is predicted to exceed IBD-alone. Further research is needed to understand changes in disease epidemiology, including aetiological drivers of developing (invariably progressive) liver disease in IBD, and the implications of rising case burden on health care resources. This study was supported by an unrestricted grant provided by Gilead Sciences.

HIV-1 infection kinetics, drug resistance, and long-term safety of pre-exposure prophylaxis with emtricitabine plus tenofovir alafenamide (DISCOVER): week 144 open-label extension of a randomised, controlled, phase 3 trial

Data characterising the long-term use and safety of emtricitabine plus tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis (PrEP) are scarce and there are uncertainties regarding the value of routine HIV-1 RNA testing during oral PrEP follow-up. The DISCOVER trial was a randomised, controlled, phase 3 trial in which cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV were recruited from 94 clinics in Europe and North America and randomly assigned to receive either emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily, with matched placebo tablets, or emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily, with matched placebo tablets, for at least 96 weeks. After completion of the trial, participants were offered enrolment in this 48-week open-label extension study of emtricitabine plus tenofovir alafenamide. In participants diagnosed with HIV during the randomised and open-label phases of the study, we characterised HIV-1 test results and measured HIV-1 RNA viral load retrospectively when available. Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV. Safety assessments included adverse events, laboratory parameters, and, in a subset of participants, bone mineral density. HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated using a Poisson distribution. Changes from baseline in safety endpoints were described in participants assigned to received emtricitabine plus tenofovir alafenamide and in those who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase. This trial is registered with ClinicalTrials.gov, NCT02842086, and is ongoing. Between Sept 13, 2016, and June 30, 2017, 5399 participants were enrolled and randomly assigned in DISCOVER. 2699 were assigned to receive emtricitabine plus tenofovir disoproxil fumarate and 2700 were assigned to receive emtricitabine plus tenofovir alafenamide, of whom 2693 and 2694, respectively, received at least one dose of study drug. 2115 (79%) assigned to emtricitabine plus tenofovir disoproxil fumarate switched to emtricitabine plus tenofovir alafenamide in the open-label phase, and 2070 (77%) continued with emtricitabine plus tenofovir alafenamide in the open-label phase. As of data cutoff (Dec 10, 2020), after 15 817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period, with three occurring during the open-label phase. In participants who were initially assigned to emtricitabine plus tenofovir alafenamide, the incidence was 0·13 per 100 person-years (95% CI 0·061-0·23; ten of 2670). Stored plasma samples were available for 23 of 27 participants, including 22 with incident infection. In four (17%) of 23 participants, retrospective testing detected HIV-1 RNA before serological HIV-1 test positivity; one was a suspected baseline infection. Of the three incident cases, all three were non-adherent to PrEP and none developed drug resistance. Among participants taking emtricitabine plus tenofovir alafenamide for up to 144 weeks, markers of glomerular filtration and proximal renal tubule dysfunction (β2-microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio) improved or remained stable at 144 weeks compared with baseline, bone mineral density in hip and lumbar spine increased or remained stable from baseline to week 144 (n=191), cholesterol and glucose concentrations remained stable, and median bodyweight increased by less than 1 kg per year. In participants who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase (2115 [79%] of 2693), markers of glomerular filtration and proximal renal tubule dysfunction improved or remained stable, bone mineral density increased, cholesterol concentrations increased, glucose concentrations were similar, and median bodyweight increased more compared with those who remained on emtricitabine and tenofovir alafenamide. Routine HIV-1 RNA testing for follow-up of individuals on daily oral PrEP provides modest additional clinical benefit. Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities. Gilead Sciences.

Comparative effectiveness of combination therapy with nirmatrelvir–ritonavir and remdesivir versus monotherapy with remdesivir or nirmatrelvir–ritonavir in patients hospitalised with COVID-19: a target trial emulation study

Remdesivir (Veklury, Gilead Sciences, Foster City, CA, USA) and nirmatrelvir-ritonavir (Paxlovid, Pfizer, New York, NY, USA) were reported to improve the outcome of patients with mild-to-moderate COVID-19 symptoms. Preclinical data suggest that nirmatrelvir-ritonavir might be more effective than remdesivir alone or in combination with nirmatrelvir-ritonavir for people at high risk of severe COVID-19. We aimed to assess the safety and effectiveness of combining remdesivir and nirmatrelvir-ritonavir compared with using each drug alone for adults hospitalised with COVID-19. In this target trial emulation study, we used electronic health records of patients aged 18 years or older who received either combination treatment of nirmatrelvir-ritonavir and remdesivir or monotherapy of either drug between March 16 and Dec 31, 2022, within 5 days of hospitalisation for COVID-19 in Hong Kong. Inverse probability of treatment weighting was applied to balance baseline patient characteristics across the treatment groups. The primary outcome was all-cause mortality. Cox proportional hazards regression adjusting weighting was used to compare the risk of all-cause mortality, intensive care unit (ICU) admission, or ventilatory support for 90 days of follow-up between groups. Between March 16 and Dec 31, 2022, 18 196 participants were identified from electronic health records and assigned to receive remdesivir (n=4232), nirmatrelvir-ritonavir (n=13 656), or nirmatrelvir-ritonavir and remdesivir (n=308). By applying an inverse probability of treatment weighting, a weighted sample composed of 18 410 recipients of nirmatrelvir-ritonavir and remdesivir combination treatment, 18 178 recipients of remdesivir monotherapy, and 18 287 recipients of nirmatrelvir-ritonavir monotherapy was obtained. After a median follow-up of 84 days (IQR 45-90), risk of mortality was lower in patients who received nirmatrelvir-ritonavir monotherapy (hazard ratio [HR] 0·18 [95% CI 0·15 to 0·20]; absolute risk reduction [ARR] -16·33% [95% CI -16·98 to -15·68]) or remdesivir and nirmatrelvir-ritonavir combination therapy (HR 0·66 [95% CI 0·49 to 0·89]; ARR -6·52% [95% CI -7·29 to -5·74]) than in patients who received remdesivir monotherapy. Similar results were observed for ICU admission or ventilatory support (nirmatrelvir-ritonavir monotherapy: HR 0·09 [95% CI 0·07 to 0·11]; ARR -10·04% [95% CI -10·53 to -9·56]; combination therapy: HR 0·68 [95% CI 0·42 to 1·12]; ARR -3·24% [95% CI -3·84 to -2·64]). Compared with combination therapy, nirmatrelvir-ritonavir monotherapy was associated with lower risk of mortality (HR 0·27 [95% CI 0·20 to 0·37]; ARR -9·81% [95% CI -10·39 to -9·24]) and ICU admission or ventilatory support (HR 0·13 [95% CI 0·08 to 0·22]; ARR -6·80% [95% CI -7·22 to -6·39]). Our study highlighted the potential for reduced risk of mortality, ICU admission, or the need for ventilatory support in patients hospitalised with COVID-19 treated with nirmatrelvir-ritonavir as a monotherapy compared with treatment regimens based on nirmatrelvir-ritonavir and remdesivir combination therapy or remdesivir monotherapy. Further randomised controlled trials are needed to support the validity of the current results. The Health and Medical Research Fund Commissioned Research on COVID-19. For the Chinese translation of the abstract see Supplementary Materials section.

Owner experience and veterinary involvement with unlicensed GS-441524 treatment of feline infectious peritonitis: a prospective cohort study.

Feline Infectious Peritonitis (FIP) has historically been a fatal coronavirus disease in cats. In recent years, the therapeutic agent GS-441524, developed by Gilead Sciences, was found to be a successful treatment for FIP in most patients in clinical trials. However, this particular drug has remained stalled in the therapeutic pipeline, leaving patients and cat owners without a licensed medication. In the meantime, online social media platforms began to emerge, connecting cat owners with a community of citizen non-veterinary professionals sourcing unlicensed GS-441524. This study prospectively followed participants (N = 141) that successfully completed 12 weeks of treatment, capturing their treatment experiences with self-administered GS-441524-like medication. A one-time survey was administered to enrolled participants with mixed format of questions (open-ended and multiple-choice) asking about treatment administration techniques, observed side effects of GS-441524, accrued cost, veterinarian involvement, impact on the cat-human bond, and social media usage. Our results show cat owners experienced a shift in treatment modality from injectable GS-441524 to pill formulation across the treatment period. The average total cost of medication has decreased since 2021 to approximately USD 3100, and participants reported the human-animal bond being affected negatively. Additionally, there was an increased trend in veterinarian awareness of GS-441524-like therapeutics and monitoring of clients undergoing treatment. Social media usage was reported as being important at the beginning of treatment to establish treatment administration but lessened by the end of treatment. This study is the first detailed, prospective account of owner experiences with unlicensed GS-441524, raising an important discussion surrounding citizen veterinary medicine.

Switching to tenofovir alafenamide in patients with virologically suppressed chronic hepatitis B and renal or hepatic impairment: final week 96 results from an open-label, multicentre, phase 2 study

Phase 3 studies in patients with chronic hepatitis B have shown tenofovir alafenamide to have non-inferior efficacy to tenofovir disoproxil fumarate, with improved renal and bone safety. We conducted this study to evaluate the safety and efficacy of switching to tenofovir alafenamide in participants with chronic hepatitis B and renal or hepatic impairment. This open-label, multicentre, phase 2 study was done in eight countries or territories at 30 sites. We recruited adults (≥18 years) with chronic hepatitis B who were virally suppressed on nucleoside or nucleotide analogues and had renal impairment (part A: moderate or severe in cohort 1 [estimated glomerular filtration rate by the Cockcroft-Gault formula (eGFRCG) 15-59 mL/min] or end-stage renal disease [eGFRCG <15 mL/min] on haemodialysis in cohort 2) or hepatic impairment including decompensation (part B: Child-Turcotte-Pugh score 7-12). Participants switched to 25 mg of tenofovir alafenamide given orally once daily for 96 weeks. The primary endpoint was the proportion of participants with viral suppression (HBV DNA <20 IU/mL) at week 24 by missing-equals-failure analysis. Efficacy (full analysis set) and safety (safety analysis set) analyses included all enrolled participants who received at least one dose of the study drug. Week 96 safety was assessed, including renal and bone parameters. This trial is registered at ClinicalTrials.gov, NCT03180619, and is completed. 124 participants (93 in part A [78 in cohort 1 and 15 in cohort 2] and 31 in part B) were enrolled between Aug 11, 2017, and Oct 17, 2018, and included in the full and safety analysis sets. 106 (85%) participants completed the study. There were 69 (74%) men and 24 (26%) women in part A and 21 (68%) men and ten (32%) women in part B. At week 24, 91 (97·8%, 95% CI 92·4 to 99·7) of 93 individuals in part A (76 [97·4%, 91·0 to 99·7] of 78 in cohort 1 and 15 [100·0%, 78·2 to 100·0] of 15 in cohort 2) and 31 (100·0%, 88·8 to 100·0) in part B had HBV DNA of less than 20 IU/mL. By week 96, the most common adverse event was upper respiratory tract infection, which occurred in 14 (15%) participants in part A and in six (19%) participants in part B. Serious adverse events occurred in 20 (22%) part A participants and in ten (32%) part B participants; none were related to treatment. No treatment-related deaths occurred. At week 96, median change in estimated glomerular filtration rate (Cockcroft-Gault method) was 1·0 mL/min (IQR -2·8 to 4·5) in cohort 1 and -2·4 mL/min (-11·4 to 10·7) in part B. Mean changes in spine and hip bone mineral density were 1·02% (SD 4·44) and 0·20% (3·25) in part A and -0·25% (3·91) and 0·28% (3·25) in part B. Tenofovir alafenamide might offer continued antiviral efficacy and a favourable safety profile for patients with renal or hepatic impairment and chronic hepatitis B switching from tenofovir disoproxil fumarate or other antivirals. Gilead Sciences.

83-OR: Metabolic Dysfunction–Associated Steatotic Liver Disease and Nonalcoholic Fatty Liver Disease Have Similar Clinical Profiles and Mortality

Introduction &amp; Objective: Metabolic dysfunction associated steatotic liver disease (MASLD) has recently replaced the term nonalcoholic fatty liver disease (NAFLD). Concern remains whether evidence generated under NAFLD definition is fully applicable to MASLD. We compared the clinical profile and outcomes of NAFLD to MASLD using population-based data. Methods: National Health and Nutrition Examination Survey (NHANES-III) with the linked Mortality file (through 2019) were used to compare groups defined as NAFLD and MASLD. Hazard ratios (HRs) of MASLD/NAFLD on all-cause mortality were calculated by cox-regression models. Results: Among 2,736 NHANES participants with NAFLD (age 47.80 years, 52.48% male, 47.66% obese, 18.26% T2D, 94.71% ≥ 1 cardiometabolic criteria), only 5.29% patients did not meet MASLD criteria. The clinical profile of MASLD was similar except for age (48.56 years) and presence of cardiometabolic risks (50.32% obese, 19.28% T2D, 100% ≥ 1 cardiometabolic criteria). There was excellent concordance between NAFLD and MASLD definitions (Cohen’s kappa coefficient=0.968 [95% CI: 0.962-0.973]). After a median follow-up of 22.83 years, there were no mortality rate differences between MASLD and NAFLD (p-values ≥ 0.05). Adjusting for socio-demographic factors, lack of healthy eating and physical activity, MASLD had a higher all-cause mortality risk (Hazard Ratio (HR)=1.15 [1.05-1.25]). However, after further adjustment for cardiometabolic risks, MASLD was not associated with increased all-cause mortality (p-value&amp;gt;0.80). Conclusions: NAFLD and MASLD are similar except MASLD subjects are older with slightly higher mortality risk, potentially due to the inclusion of cardiometabolic risk factors. These data provide evidence that NAFLD and MASLD can be used interchangeably. Disclosure Z. Younossi: Consultant; Gilead Sciences, Inc., Bainan Biotech, AbbVie Inc., Bristol-Myers Squibb Company, Abbott, Novo Nordisk, Madrigal Pharmaceuticals, Inc., Merck &amp; Co., Inc., Siemens Healthcare Diagnostics, Intercept Pharmaceuticals, Inc. J.M. Paik: None. P. Golabi: None. J. Ong: None. L. Henry: None. S. Alqahtani: Consultant; AbbVie Inc., Bristol-Myers Squibb Company, Merck &amp; Co., Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. F. Nader: None.

Impact of HCV cure on subsequent hospitalizations in people with mental disorders: Results from the French claims database

Background and Aims: Although HCV cure after direct-acting antiviral (DAA) treatment is associated with hepatic and extrahepatic benefits, few studies have assessed the impact of HCV treatment in people with mental disorders (PWMDs). Using quasi-exhaustive national data from the French administrative health care databases (SNDS), we explored whether DAA treatment in PWMDs affected hospitalizations in both psychiatric and non-psychiatric settings.Methods: All adult PWMDs identified in the SNDS with DAA treatment initiation between 2015 and 2018 and 12 months of data pre- and post-treatment were included. Individuals were algorithmically classified into one or several subgroups: “addictive disorders”, “neurotic and mood disorders”, “psychotic disorders” and “other psychiatric disorders”. A longitudinal approach was used to compare the frequency and duration of hospitalizations one year before and one year after DAA treatment.Results: In total, 17,203 individuals met the inclusion criteria. The number of patients with at least one hospitalization (any type) decreased by 28% after HCV cure. The mean numbers of hospitalizations in non-psychiatric units per patient per year were 1·2 during the pre-DAA period and 0·8 during the post-DAA period (p < 0·0001). Similarly, the number of hospitalizations in psychiatric wards decreased from 1·4 to 1·2 (p = 0.006). The duration of hospital stays decreased from 20·2 days to 16·7 days in non-psychiatric settings (p < 0·0001). These results were also homogeneous and significant across all subgroups.Conclusions: HCV cure significantly lowered the frequency and duration of hospitalizations during the year following treatment in all PWMDs subgroups, including the psychotic disorders subgroup.Funding: This study was funded by Gilead Sciences.

Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D

BackgroundIn a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear.MethodsIn this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 μg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 μg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.ResultsA total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity.ConclusionsThe combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.)

Time to re-define ‘normal’ in the context of Post-Acute COVID-19 biomarkers in the assessment of patient outcomes?

Introduction: Post-acute COVID-19 or Long COVID (LC) is a threat to health and well-being, and 1 in 10 infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will develop persistent symptoms. LC is associated with &gt;200 symptoms that impact quality of life and functional status. Many LC patients are being dismissed from care due to returning ‘normal’ results on ‘routine’ clinical investigations. Accordingly, the objective of the study was to explore the relationship between potential diagnostic biomarkers, symptom profile severity and functional status. Method: Participants with a confirmed history of COVID-19 were recruited from Long COVID clinics in the United Kingdom, as part of a 16-week cohort observation study. Venous blood samples were taken from 35 individuals [24 female] and assessed for standard clinical chemistry markers of inflammatory and metabolic status, including full blood count (white blood cells [WBC], red blood cells [RBC], platelets, haemoglobin, hematocrit, ferritin, mean corpuscular volume [MCV] mean corpuscular haemoglobin [MCH], mean corpuscular haemoglobin concentration [MCHC], red cell distribution width [RDW], basophils, neutrophils, lymphocytes, eosinophils, monocytes), CRP, d dimers, interleukin 6 (IL-6), and lactate dehydrogenase [LDH]. Patient-reported outcomes and symptoms were assessed by validated self-report methods including fatigue, dyspnoea, cognitive deficit, quality of life and symptom frequency and severity. Functional status was assessed via 6-Minute-Walk (6MWT). Results: Sixty-three percent of participants [17 female] had one or more values outside of expected reference ranges (WBC n=3, RBC n=6, haemoglobin n=3, haematocrit n=2, MCV n=3, MCH n=3, MCHC n= 1, RDW n=4, neutrophils n=3, lymphocytes n=5, monocytes n=1, basophils n=2, CRP n=3, ferritin n=3, d-dimer n=9). These changes were not linked to changes in function status or patient-reported outcomes ( p=&gt;0.05), but there was a significant between-group difference with those outside of expected reference ranges completing less on the 6MWT on their final visit ( p=&lt;0.05). Discussion: The pathophysiology of LC is complex and patients report broad symptoms across multiple organ systems, such as respiratory, gastrointestinal, cardiovascular, and the autonomic nervous system. Routine clinical investigations of biomarkers are vital, but assessments often return results within a pre-determined ‘normal’ range. Whilst routine testing is important, condition-specific investigations should also be explored. Further inspection of the data in reference to the symptom profile and reduced functional status demonstrates a need for more holistic approaches. Conclusion: The complex pathophysiology of LC requires further understanding and development of investigative approaches to LC diagnoses and treatment. Routine investigations of people with LC demonstrate abnormal responses, and even those that return ‘normal’ results experience debilitating symptom profiles and reduced quality of life. Due to the complex underlying mechanistic issues of LC, more specific biochemical profiling is required during clinical investigations. This study was supported by an unrestricted investigator-sponsored research grant from Gilead Sciences (#IN-UK-983-6080). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

P176 Ixekizumab significantly improves nail disease and adjacent joint tenderness and swelling in psoriatic arthritis

Abstract Background/Aims Nail psoriasis (PsO) is a strong predictor for the development of psoriatic arthritis (PsA) and has been reported in 63-83% of patients with PsA. Psoriatic nails are linked to arthritis in the adjacent distal interphalangeal joint (DIP) of fingers or interphalangeal joint of thumbs, and both can lead to severe functional impairment. In the SPIRIT-H2H study of adults with PsA, 354 of 566 participants had nail PsO and adjacent joint disease in at least one digit at baseline. At the group level, SPIRIT-H2H patients treated with ixekizumab (IXE) achieved significantly greater improvements in nail PsO compared to those treated with adalimumab (ADA). This analysis aimed to assess the treatment effects of IXE and ADA at the individual digit level among patients with PsA, nail PsO, and adjacent joint disease. Methods This post hoc analysis included 354 patients from SPIRIT-H2H (NCT03151551) treated with either IXE (N = 186) or ADA (N = 168) who had nail PsO (Nail Psoriasis Severity Index (NAPSI) total score &amp;gt;0) and adjacent joint disease (tenderness and/or swelling) in at least one digit at baseline. Treatment effects were assessed for each individual finger unit displaying nail PsO and adjacent joint disease; here, finger unit defines the nail and adjacent joint of an individual digit; adjacent joint refers to the DIP of fingers or the interphalangeal joint of thumbs. Nail PsO was measured using NAPSI in the fingers only. Joint involvement was measured by tender/swollen joint count scores (TJC68/SJC66). Patients were evaluated for both nail and joint involvement at baseline and Weeks 12, 16, 24, 32, 40, and 52. Proportions of finger units with resolution of nail PsO, and proportions of finger units with resolution of adjacent joint disease were analyzed using Chi-square tests. Non-responder imputation was used to handle missing data. Results There were 1309 (IXE=639, ADA=670) finger units affected by nail and adjacent joint disease at baseline. Resolution of psoriatic nail disease and resolution of adjacent tenderness and/or swelling of the finger unit was significantly higher with IXE vs ADA at all post-baseline assessments over 52 weeks. Joint tenderness was resolved in a significantly larger proportion of IXE-treated finger units vs ADA at all post-baseline assessments over 52 weeks. Joint swelling was resolved in a larger proportion of IXE-treated finger units vs ADA, and these differences reached statistical significance at all visits except Week 16 and Week 40. The tenderness and/or swelling of the finger unit resolved more rapidly than the adjacent nail disease. Conclusion IXE treatment showed a significant advantage over ADA in resolving nail PsO, joint tenderness, and joint swelling among the finger units with nail and adjacent joint disease of patients with PsA. Disclosure D. McGonagle: Consultancies; D. McGonagle has received consulting fees and/or honoraria and/or research grants from: AbbVie and Eli Lilly and Company. A. Kavanaugh: Consultancies; A. Kavanaugh has received consulting fees and/or honoraria from: AbbVie, Eli Lilly and Company, Janssen, Novartis, Pfizer, UCB Pharma. I. McInnes: Corporate appointments; Vice Principle &amp; Head of College for University of Glasgow, non-executive board member of NHS Greater Glasgow &amp; Clyde, non-executive director of Evelo, and trustee of Versus Arthritis. Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Cabaletta Bio, Causeway Therapeutics, Eli Lilly and Company, Gilead Sciences, Janssen, Novartis, Pfizer, Sanofi Regeneron, and UCB Pharma. L. Kristensen: Grants/research support; AbbVie, Amgen, Biogen, Bristol Myers Squibb, Eli Lilly and Company, Gilead Sciences, Janssen, Merck Sharpe &amp; Dohme, Novartis, Pfizer, and UCB Pharma. J. Merola: Consultancies; AbbVie, Amgen, Biogen, Bristol Myers Squibb, Dermavant, Eli Lilly and Company, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi Regeneron, Sun Pharma, and UCB Pharma. B. Strober: Corporate appointments; Editor-in-Chief for the Journal of Psoriasis and Psoriatic Arthritis and scientific co-director and investigator for CorEvitas Psoriasis Registry. Consultancies; AbbVie, Alamar Biosciences, Almirall, Alumis, Amgen, Arcutis, Arena Pharmaceuticals, Aristea Therapeutics, Asana Biosciences, Boehringer Ingelheim, Bristol Myers Squibb, Connect Biopharma, Dermavant. Shareholder/stock ownership; Connect Biopharma and Mindera. Honoraria; Eli Lilly and Company, Evelo Biosciences, Immunic Therapeutics, Incyte Corporation, Janssen, Kangpu Pharmaceuticals, LEO Pharma, Maruho, Meiji Seika Pharma, Mindera, Nimbus Therapeutics, Novartis. Grants/research support; Pfizer, Protagonist Therapeutics, Regeneron, Sanofi Genzyme, Sun Pharma, UCB Pharma, Union Therapeutics, Ventyx Biosciences, and vTv Therapeutics. R. Bolce: Shareholder/stock ownership; R. Bolce is an employee and shareholder of Eli Lilly and Company. J.R. Lisse: Shareholder/stock ownership; J. Lisse is an employee and shareholder of Eli Lilly and Company. J. Pustizzi: Shareholder/stock ownership; J. Pustizzi is an employee and shareholder of: Eli Lilly and Company. C. Sapin: Shareholder/stock ownership; C. Sapin is an employee and shareholder of: Eli Lilly and Company. C. Ritchlin: Honoraria; AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Janssen, Novartis, Pfizer, and UCB Pharma.

P117 Efficacy of filgotinib in patients with rheumatoid arthritis: Week 156 results from a long-term extension study

Abstract Background/Aims In the treatment of RA, JAK inhibitors are a valuable option to meet remission or low disease activity (LDA) treatment targets following an inadequate response (IR) or intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (DMARD). FIL is a JAK1 preferential inhibitor available in two doses for the treatment of moderate to severe RA. Objectives: To evaluate long-term efficacy of two doses of FIL in clinically relevant pt populations. Methods In this interim analysis, efficacy (non-responder imputation) of FIL 200 mg (FIL200) and 100 mg (FIL100) was assessed from LTE baseline (BL) to W156 in pts with an IR to methotrexate (MTX-IR) and biologics (bDMARD-IR), enrolled from FINCH 1 (NCT02889796) and 2 (NCT02873936) parent studies (PS), respectively, receiving ≥1 FIL dose in FINCH 4 (NCT03025308). Results Study design, BL characteristics and W48 outcomes for MTX-IR1 and bDMARD-IR2 pts were reported previously. For MTX-IR and bDMARD-IR pts who received FIL200 or FIL100 in the PS, W156 remission rates using Boolean 1.0 criteria were 20.5% and 15.8%, and 18.2% and 8.9%, respectively. Adopting the Boolean 2.0 criteria slightly increased remission rates for FIL200 and FIL100 at W156: +4.2% and +4.9% for MTX-IR pts, and +1.5% and +2.4% for bDMARD-IR pts, respectively. For pts rerandomized to FIL on entering the LTE, Boolean 2.0 criteria also increased remission rates vs Boolean 1.0. Both MTX-IR and bDMARD-IR pts maintained long-term Boolean remission through W156 with FIL200 and FIL100, irrespective of prior FIL. Results for Disease Activity Score 28 with C-reactive protein (DAS28-CRP) &amp;lt;2.6, Clinical Disease Activity Index (CDAI) ≤2.8, and Simplified Disease Activity Index (SDAI) ≤3.3, and mean change from PS BL in Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain are shown (Table). Similar trends in efficacy were seen for LDA and ACR response criteria. Conclusion In FINCH 4, both FIL200 and FIL100 showed sustained efficacy up to W156 in clinically relevant pt populations. Boolean 2.0 criteria classified more pts in remission, in line with the range reported in the validation study. Disclosure M.H. Buch: Consultancies; AbbVie, CESAS Medical, Galapagos, Gilead, and Pfizer (all paid to host institution). Member of speakers’ bureau; AbbVie (paid to host institution). Grants/research support; Gilead (paid to host institution). D. Aletaha: Consultancies; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. Member of speakers’ bureau; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. Grants/research support; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. R. Caporali: Consultancies; AbbVie, Fresenius, Galapagos, Lilly, Novartis, Pfizer, and UCB. Member of speakers’ bureau; AbbVie, Amgen, BMS, Celltrion, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer, and UCB. B. Combe: Consultancies; AbbVie, Galapagos, Gilead, Janssen, Lilly, Novartis, and Roche-Chugai. Member of speakers’ bureau; AbbVie, Celltrion, Galapagos, Janssen, Lilly, Pfizer, and Roche-Chugai. H. Schulze-Koops: Consultancies; AbbVie, Galapagos, Lilly, and Pfizer. Member of speakers’ bureau; AbbVie, Galapagos, Lilly, and Pfizer. J. Gottenberg: Consultancies; AbbVie, BMS, Galapagos, Gilead, Lilly, MSD, Novartis, and Pfizer. Grants/research support; BMS and Pfizer. Y. Tanaka: Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GSK, Mitsubishi-Tanabe, and Pfizer. Grants/research support; AbbVie, Asahi-Kasei Pharma, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Takeda. R. Blanco: Consultancies; AstraZeneca, Galapagos, Janssen, Novartis, and Pfizer. Member of speakers’ bureau; AbbVie, Amgen, BMS, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and Sanofi. Grants/research support; AbbVie and Roche. T. Takeuchi: Consultancies; AbbVie GK, Astellas, Chugai, Eli Lilly Japan, Gilead Sciences, Inc., Janssen Pharm K.K., Mitsubishi-Tanabe, and Pfizer Japan Inc. Member of speakers’ bureau; AbbVie GK, AYUMI, BMS, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead Sciences, Inc., Janssen Pharm K.K., Mitsubishi-Tanabe, Pfizer Japan Inc., and Sanofi K.K. Grants/research support; AbbVie GK, Asahi-Kasei Pharma, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Mitsubishi-Tanabe, Nippon Kayaku, and UCB Japan. E. V. Ekoka Omoruyi: Consultancies; Galapagos and Janssen. Shareholder/stock ownership; UCB. K. Van Beneden: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. V. Rajendran: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. C. Watson: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. F. De Leonardis: Other; Employee of Galapagos. P. Emery: Consultancies; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, Roche, and Samsung. Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, and Samsung. Grants/research support; AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, and Samsung.

P123 Safety and efficacy of filgotinib, an update from the DARWIN 3 phase 2 long-term extension with a maximum of 8.2 years of exposure

Abstract Background/Aims DARWIN 3 (NCT02065700) is a long-term extension (LTE) study assessing the safety and efficacy of filgotinib (FIL) in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). In the DARWIN 1 (NCT01888874) and DARWIN 2 (NCT01894516) parent studies, patients received FIL in combination with MTX or FIL monotherapy, respectively. To provide an update on the safety and efficacy of FIL 200 mg (FIL200) in patients with RA, with or without MTX, with a maximum of 8.2 years of exposure. Methods Patients completing the DARWIN 1 and DARWIN 2 phase 2 studies could enter DARWIN 3, receiving FIL200[PE1] +/-MTX. The proportion of patients experiencing treatment-emergent adverse events (TEAEs) were reported, comprising data from both the parent and LTE studies. Efficacy was assessed from LTE baseline using the American College of Rheumatology (ACR) 20/50/70 criteria and DAS28-CRP, up to 264 weeks. Low disease activity and remission were defined as DAS28-CRP ≤3.2 and &amp;lt;2.6, respectively. Results In total, 739 patients were enrolled in DARWIN 3. In the FIL + MTX vs FIL monotherapy groups, TEAEs were reported for 90.9% and 92.1% of patients, respectively (Table). The most common TEAE was infection. In both treatment groups, eight patients had a TEAE leading to death (1.6% and 3.3%, respectively). Exposure-adjusted incidence rates, censored at time of first event for major adverse cardiovascular event, venous thromboembolism, herpes zoster, infections, serious infections, non-melanoma skin cancer (NMSC), malignancies excluding NMSC, gastrointestinal perforations and TEAEs leading to death, will be reported. Through five years, ACR20/50/70 responses were maintained in 86.3%/66.7%/50.7% of the FIL + MTX group and 90.8%/74.8%/51.4% of the FIL monotherapy group, respectively (observed data). DAS28-CRP low disease activity and remission rates (non-responder imputation) at DARWIN 3 baseline were 46.1%/40.1% (FIL + MTX) and 29.6%/24.8% (FIL monotherapy). At Week 264, the proportion of patients achieving low disease activity and remission were 34.0%/34.3% (FIL + MTX) and 27.0%/24.8% (FIL monotherapy). Conclusion With a maximum of 8.2 years of exposure in patients with RA, the FIL safety profile is similar between the background MTX and monotherapy treatment arms. Both arms show sustained efficacy over time. Disclosure P. Emery: Consultancies; Consultant of: AbbVie, AstraZeneca, BMS, Boehringer-Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, Roche, and Samsung. Member of speakers’ bureau; y Speakers bureau: AbbVie, AstraZeneca, BMS, Boehringer-Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, and Samsung. Grants/research support; Grant/research support from: AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, and Samsung. R. Westhovens: Consultancies; Celltrion, Galapagos, and Gilead,. Member of speakers’ bureau; Celltrion, Galapagos, and Gilead. R.H.E. Alten: Consultancies; AbbVie, Amgen, Biogen, BMS, Celltrion, Gilead, Janssen, Lilly, Medac, MSD, Mylan, Novartis, Pfizer, Roche, Sandoz, SanofiGenzyme, UCB, and VIATRIS. L. Dagna: Consultancies; AbbVie, Amgen, AstraZeneca, Biogen, Boehringer-Ingelheim, BMS, Celltrion, Eli Lilly &amp; Company, Galapagos, GlaxoSmithKline, Janssen, Kiniksa Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme,. Grants/research support; AbbVie, BMS, Celgene, GlaxoSmithKline, Janssen, Kiniksa, Merck Sharp &amp; Dohme, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI,. A. Kavanaugh: Consultancies; Amgen, AbbVie, BMS, Pfizer, UCB, Janssen, Novartis, and Pfizer. K.L. Winthrop: Consultancies; AbbVie, AstraZeneca, BMS, Eli Lilly &amp; Company, Galapagos, Gilead, GlaxoSmithKline, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB. Grants/research support; BMS and Pfizer. J. Barry: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. R. Besuyen: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. C. Corallo: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. C. Watson: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. N. Martin: Consultancies; Galapagos. M. Genovese: Corporate appointments; Gilead Sciences. Shareholder/stock ownership; Gilead Sciences. A.J. Spindler: None. M. Stanislavchuk: Grants/research support; Amgen, AstraZeneca, Celgene, Eli Lilly, Galapagos, Gilead, Human Genome, Janssen, MSD, Nichi-Iko, Pfizer, and Roche. M. Greenwald: Grants/research support; AbbVie, Aclaris, Galapagos, Janssen, Lilly, and Nimbus.

OA04 Efficacy and safety of nipocalimab in patients with moderate to severe active rheumatoid arthritis: the multicenter, randomised, double-blinded, placebo-controlled phase 2a IRIS-RA study

Abstract Background/Aims Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with autoantibodies. Despite the use of targeted therapies, up to half of patients fail to achieve remission or low disease activity (LDA). Anti-citrullinated protein antibodies (ACPAs), key autoantibodies that predict progression of joint destruction in RA, are largely an immunoglobulin G (IgG) isotype. Nipocalimab is a high affinity, fully human, IgG1 monoclonal antibody that is designed to selectively block the neonatal Fc receptor (FcRn), preventing recirculation and thereby lowering IgG levels, potentially including ACPAs and other pathogenic antibodies. In this phase 2a proof-of-concept study (IRIS-RA; NCT04991753), we report the efficacy and safety of nipocalimab in patients with moderate to severe, active RA. Methods Eligible adult patients with moderate to severe RA (≥6 swollen/tender joints), positive for ACPA or rheumatoid factor, and ≥1 advanced therapies, were randomized 3:2 to receive intravenous 15 mg/kg nipocalimab or placebo every 2 weeks for 10 weeks. The primary endpoint was the change from baseline in the Disease Activity Score 28 using C-reactive protein (DAS28-CRP) at Week 12. Secondary endpoints included the proportion of patients who achieved ACR20, ACR50, ACR70, and ACR90 responses, DAS28-CRP remission, and change from baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 12. Results In total, 53 patients were enrolled (nipocalimab, n = 33; placebo, n = 20). Most patients were female (67.9%) and white (90.6%) with a median age of 59 (range, 26-74) years. Demographic and baseline disease characteristics were comparable between groups except higher CRP in placebo. At Week 12, patients treated with nipocalimab showed a numerically greater mean (standard deviation [SD]) change in DAS28-CRP score compared to the placebo group (-1.17 [1.34] vs -0.62 [0.96]; mean difference [95% confidence interval], -0.45 [-1.17-0.28]; p=0.224). A numerically higher proportion of patients achieved ACR20, ACR50, ACR70, and ACR90 responses compared to placebo. In the nipocalimab group, 7 (21.2%) patients achieved DAS28-CRP remission compared to 2 (10.0%) patients in the placebo group (treatment difference, 9.9% [-9.5-29.3%]; p=0.456). Similarly, patients in the nipocalimab group had a numerically greater mean (SD) improvement in HAQ-DI score (-0.27 [0.55] vs -0.11 [0.36], respectively). The proportion of patients with treatment-emergent adverse events (TEAEs) were 81.8% vs 60.0% in the nipocalimab vs placebo groups. In the nipocalimab group, 3 serious TEAEs were reported, including burn infection, infusion-related reaction, and deep-vein thrombosis. There were no TEAEs that led to death. Conclusion Treatment with nipocalimab resulted in consistent and numerically higher improvements across ACR20, ACR50, ACR70, and ACR90 responses, as well as DAS28-CRP, DAS28-CRP remission, and HAQ-DI, with acceptable safety profile. Nipocalimab showed activity in patients with moderate to severe RA and warrants further investigation to understand the predictors of nipocalimab response. Disclosure P.C. Taylor: Consultancies; AbbVie, Biogen, Eli Lilly, Fresenius, Galapagos, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Inc, Sanofi, Aqtual, and UCB. Grants/research support; Galapagos. G. Schett: None. F. Ibrahim: Corporate appointments; Employee of Janssen Research &amp; Development. B. Zhou: Corporate appointments; Employee of Janssen Research &amp; Development. J. Leu: Corporate appointments; Employee of Janssen Research &amp; Development. S. Liva: Corporate appointments; Employee of Janssen Research &amp; Development. Q. Wang: Corporate appointments; Employee of Janssen Research &amp; Development. R. Rojo Cella: Corporate appointments; Employee of Janssen Research &amp; Development. C.S. Karyekar: Corporate appointments; Employee of Janssen Research &amp; Development. K. Fei: Corporate appointments; Employee of Janssen Research &amp; Development.

Autologous neutralizing antibody responses after antiretroviral therapy in acute and early HIV-1.

BACKGROUNDEarly antiretroviral therapy initiation (ARTi) in HIV-1 restricts reservoir size and diversity while preserving immune function, potentially improving opportunities for immunotherapeutic cure strategies. For antibody-based cure approaches, the development of autologous neutralizing antibodies (anAbs) after acute/early ARTi is relevant but is poorly understood.METHODSWe characterized antibody responses in a cohort of 23 participants following ARTi in acute HIV (<60 days after acquisition) and early HIV (60-128 days after acquisition).RESULTSPlasma virus sequences at the time of ARTi revealed evidence of escape from anAbs after early, but not acute, ARTi. HIV-1 envelopes representing the transmitted/founder virus(es) (acute ARTi) or escape variants (early ARTi) were tested for sensitivity to longitudinal plasma IgG. After acute ARTi, no anAb responses developed over months to years of suppressive ART. In 2 of the 3 acute ARTi participants who experienced viremia after ARTi, however, anAbs arose shortly thereafter. After early ARTi, anAbs targeting those early variants developed between 12 and 42 weeks of ART and continued to increase in breadth and potency thereafter.CONCLUSIONResults indicate a threshold of virus replication (~60 days) required to induce anAbs, after which they continue to expand on suppressive ART to better target the range of reservoir variants.TRIAL REGISTRATIONClinicalTrials.gov NCT02656511.FUNDINGNIH grants U01AI169767, R01AI162646, UM1AI164570, UM1AI164560, U19AI096109, K23GM112526, T32AI118684, P30AI045008, P30AI027763, R24AI067039; Gilead Sciences grant INUS2361354; Viiv Healthcare grant A126326.

Remdesivir: A Quick Review of Pharmacotherapy

Background:: In the year 2009, Remdesivir or Veklury was discovered by Gilead Sciences for the management of hepatitis C, Ebola and Marburg virus disease through injection into a vein and then a few years later, 22nd Oct 2020 (United States), the drug was recommended for the management of COVID-19 under a provisional guideline. Objective:: The aim of this systematic review was to address pharmacotherapy approaches associated with the efficacy and side effects of remdesivir for the treatment of viral infections. Methods:: This is a focused, in-depth consequent guide approach and literature search, with a methodical assessment associated with the terms “Remdesivir,” “ Remdesivir Bioavailability,” “Remdesivir and Disease,” “ Remdesivir and COVID-19” that was done through Pubmed, Scopus, and Web of Science from their inception to 2023. Results:: 105 studies included in silico, in-vivo, and in-vitro experiments to test remdesivir therapeutic efficacy were selected based on the current, knowledgeable, and high-quality topics of manuscripts. Regarding efficacy, in addition to COVID-19, remdesivir shows therapeutic efficacy in other virus infections, such as hepatitis C, Ebola, and Marburg. In patients with COVID-19, remdesivir shortens the time to recovery, lowering progression to mechanical ventilation and decreasing hospital resources. Combination with dexamethasone in selected patients who need minimal conventional oxygen but are at high risk of severe COVID-19 was reported beneficial. Combination with chloroquine or hydroxychloroquine may cause a decrease in the antiviral activity of remdesivir, but dexamatason reported minimal or no reduction in drug exposure. However, synergistic effects were reported in combination with favipiravir, but methotrexate toxicity needs to be evaluated. Significant improvement in 'patients' conditions was reported in combination with methylprednisolone pulse therapy. Infusion-related reactions such as nausea, elevated liver enzymes, sweating, and hypotension are the most common side effects. Conclusion:: Different studies showed that with remdesivir pharmacotherapy, in addition to significant improvement in the recovery rate in those with COVID-19, the risk of adverse effects was significantly lower than in the control groups. To verify efficacy and side effects, besides attentive consideration of kidney and liver function, further evidence-based pharmacotherapy studies of remdesivir seem advantageous.

Pharmacokinetics and safety of coformulated bictegravir, emtricitabine, and tenofovir alafenamide in children aged 2 years and older with virologically suppressed HIV: a phase 2/3, open-label, single-arm study

Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. Gilead Sciences.

Associations between change in BMI and the risk of hypertension and dyslipidaemia in people receiving integrase strand-transfer inhibitors, tenofovir alafenamide, or both compared with other contemporary antiretroviral regimens: a multicentre, prospective observational study from the RESPOND consortium cohorts

Integrase strand-transfer inhibitors (INSTIs) and tenofovir alafenamide have been associated with weight gain in several clinical trials and observational cohorts. However, whether weight gain associated with INSTIs and tenofovir alafenamide confers a higher risk of weight-related clinical events is unclear. We aimed to assess whether changes in BMI differentially increase hypertension or dyslipidaemia risk in people with HIV receiving INSTIs, tenofovir alafenamide, or both versus other contemporary regimens. This multicentre, prospective observational study analysed prospective data from RESPOND, an international consortium of HIV cohorts for which recruitment began in 2017 and is still ongoing from HIV clinics and hospitals in 37 European countries and Australia. Participants were eligible if they were aged 18 years or older, receiving INSTI-containing antiretroviral therapy (ART) regimens or a contemporary non-INSTI, did not have hypertension or dyslipidaemia at baseline, and had baseline and at least two follow-up BMI, lipid, and blood pressure measurements. We excluded participants without baseline CD4 or HIV RNA results and those receiving non-ART medications associated with weight changes, including antipsychotics and mood stabilisers, corticosteroids, insulin, and insulin secretagogues. They were followed up from baseline until the earliest hypertension or dyslipidaemia event, their last visit, or Dec 31, 2021, whichever was earlier. The primary outcomes were incidence of hypertension and dyslipidaemia, for which we used multivariable Poisson regression adjusted for time-updated BMI to determine unadjusted and adjusted incidence rate ratios (IRRs) of hypertension and dyslipidaemia in people receiving INSTIs, tenofovir alafenamide, or both, and tested for interaction between time-updated ART regimen and BMI. Of the 35 941 RESPOND participants, 9704 (7327 [75·5 %] male and 2377 [24·5%] female) were included in the hypertension analysis and 5231 (3796 [72·6%] male and 1435 [27·4%] female) were included in the dyslipidaemia analysis. In the univariable model, hypertension was more common in individuals receiving an INSTI with tenofovir alafenamide (IRR 1·70, 95% CI 1·54-1·88) or an INSTI without tenofovir alafenamide (1·41, 1·30-1·53) compared with those receiving neither INSTIs nor tenofovir alafenamide. Adjustment for time-updated BMI and confounders attenuated risk in participants receiving an INSTI with (IRR 1·48, 1·31-1·68) or without (1·25, 1·13-1·39) tenofovir alafenamide. Similarly, dyslipidaemia was more common in participants using tenofovir alafenamide with an INSTI (IRR 1·24, 1·10-1·40) and tenofovir alafenamide alone (1·22, 1·03-1·44) than in participants using neither INSTI nor tenofovir alafenamide. Adjustment for BMI and confounders attenuated the risk in participants receiving tenofovir alafenamide with an INSTI (adjusted IRR 1·21, 1·07-1·37), whereas the risk in those receiving tenofovir alafenamide alone became non-significant (1·15, 0·96-1·38). The associations between increasing BMI and risk of hypertension and dyslipidaemia did not differ between participants receiving different ART regimens (pinteraction=0·46 for hypertension; pinteraction=0·31 for dyslipidaemia). Although residual confounding cannot be entirely excluded, the use of INSTIs was associated with incident hypertension, and the use of tenofovir alafenamide was associated with dyslipidaemia, with the latter association partly mediated by weight gain. These results reiterate the need for hypertension and dyslipidaemia screening in people with HIV. The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, ViiV Healthcare, and Gilead Sciences.

Residual Moisture Determination in Lyophilized Drug Product Samples Using FT-NIR: A Comparison of Data Processing Methods

Introduction: Remdesivir for injection is a Gilead Sciences manufactured drug product approved by the FDA to treat COVID-19. One of the critical attributes of this drug product, which is lyophilized, is its water moisture content. The current method used to determine the water content of remdesivir is the Karl Fischer titration method. The Karl Fischer method is considered the gold standard for determining the residual water moisture content of lyophilized drug products in the pharmaceutical industry. However, it is timeconsuming, can at times be sensitive to difficult-to-control techniques, and most importantly is destructive. The purpose of this study was to create a non-destructive residual water moisture determination method using FT-NIR. Methods: Three FT-NIR methods were proposed as a non-destructive alternative to Karl Fischer method: partial least squares regression, Beer’s law and area under the curve, and Beer’s law and peak height. Results were statistically validated using RMSEC, RMSEP, and R2, and the percent differences of predicted and accepted residual moisture values were compared with external validation vials. Results: Results showed that the partial least squares regression method produced a 0.999 correlation coefficient and a 95% performance index score, highlighting the accuracy between the actual Karl Fischer moisture values and the predicted FT-NIR moisture values. The Beer’s law methods produced acceptable correlation coefficients of 0.996 and 0.982 for the peak area and height, respectively, but comparisons between the actual and predicted values were not as closely matched as the partial least squares method. Conclusion: Our results support the use of a non-destructive partial least squares FT-NIRbased moisture contest method, which is a useful alternative to the destructive Karl Fischer method for determining residual water moisture of lyophilized drug products. Only an FTNIR instrument and chemometric statistical software along with the appropriately trained/educated analysts, and routine Karl Fischer instrumentation to measure/determine moisture content values of either water spiked or lyo-thieved and normal lyophilized samples are required.

Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure.

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.