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IntroductionDespite repeated vaccinations against SARS-CoV-2 virus, patients who are immunocompromised remain at very high risk of catching SARS-CoV-2 virus and becoming unwell. AZD7442 (Evusheld) is a long-acting monoclonal antibody treatment that has been shown in clinical trials to prevent SARS-CoV-2 infection for up to a year after a single dose. Vaccines require a healthy immune system to generate protective immunity. AZD7442 may prevent SARS-CoV-2 infection in immunocompromised individuals that may not have responded to repeated vaccinations against SARS-CoV-2 virus. Unlike vaccinations, AZD7442 reaches effective levels within the body a few hours after a single dose. The RAPID-PROTECTION trial will determine the levels of immune protection that AZD7442 offers patients at the very highest risk of SARS-CoV-2 infection and whether this protection can be further enhanced by repeated vaccination against SARS-CoV-2 virus.MethodsRAPID-PROTECTION is a multicentre, interventional and open-label adaptive platform trial that aims to recruit 350 immunocompromised participants across five UK centres. Participants will be administered AZD7442 on day 0 followed by a SARS-CoV-2 vaccination 28 days later. Participants will be randomised (1:1) to the Moderna vaccine or Pfizer/BioNTech vaccine. Participant samples will be taken at baseline and at multiple timepoints after the administration of AZD7442.AnalysisThe participant samples will be analysed to measure the function and magnitude of SARS-CoV-2 specific antibody and T-cell responses at baseline and at multiple timepoints after the administration of AZD7442. The immunological effect of the study interventions will be determined by comparison of the results of immunological assessments at baseline and subsequent timepoints.Ethics and disseminationThe trial protocol was approved by the research ethics committee of the National Health Service (reference 22/HRA/0359), Health Research Authority and Health and Care Research Wales on 25 July 2022. Findings will be disseminated through peer-reviewed journals and presented at scientific conferences.Trial registration numberISRCTN53507177.

Nearly 3 million people worldwide are coinfected with HIV and HCV. Affordable strategies for prevention are needed. We developed a novel vaccination regimen involving replication-defective and serologically distinct chimpanzee adenovirus (ChAd3, ChAd63) vector priming followed by modified vaccinia Ankara (MVA) boosts, for simultaneous delivery of HCV non-structural (NSmut) and HIV-1 conserved (HIVconsv) region immunogens. We conducted a phase I trial in which 33 healthy volunteers were sequentially enrolled and vaccinated via the intramuscular route as follows: 9 received ChAd3-NSmut [2.5 × 10 vp] and MVA-NSmut [2 × 10 pfu] at weeks 0 and 8, respectively; 8 received ChAdV63.HIVconsv [5 × 10 vp] and MVA.HIVconsv [2 × 10 pfu] at the same interval; 16 were co-primed with ChAd3-NSmut [2.5 × 10 vp] and ChAdV63.HIVconsv [5 × 10 vp] followed at week 8 by MVA-NSmut and MVA.HIVconsv [both 1 × 10 pfu]. Immunogenicity was assessed using peptide pools in ELISpot and intracellular cytokine assays. Vaccine-induced whole blood transcriptome changes were assessed by microarray analysis. All vaccines were well tolerated and no vaccine-related serious adverse events occurred. Co-administration of the prime-boost vaccine regimens induced high magnitude and broad T cell responses that were similar to those observed following immunization with either regimen alone. Median (interquartile range, IQR) peak responses to NSmut were 3,480 (2,728-4,464) and 3,405 (2,307-7,804) spot-forming cells (SFC)/10 PBMC for single and combined HCV vaccinations, respectively ( = 0.8). Median (IQR) peak responses to HIVconsv were 1,305 (1,095-4,967) and 1,005 (169-2,482) SFC/10 PBMC for single and combined HIV-1 vaccinations, respectively ( = 0.5). Responses were maintained above baseline to 34 weeks post-vaccination. Intracellular cytokine analysis indicated that the responding populations comprised polyfunctional CD4 and CD8 T cells. Canonical pathway analysis showed that in the single and combined vaccination groups, pathways associated with antiviral and innate immune responses were enriched for upregulated interferon-stimulated genes 24 h after priming and boosting vaccinations. Serologically distinct adenoviral vectors encoding HCV and HIV-1 immunogens can be safely co-administered without reducing the immunogenicity of either vaccine. This provides a novel strategy for targeting these viruses simultaneously and for other pathogens that affect the same populations. https://clinicaltrials.gov, identifier: NCT02362217.

There are varying data concerning the effect of prior anti-vector immunity on the T-cell response induced by immunisation with an identical vectored vaccine containing a heterologous antigen insert. To determine whether prior exposure to ChAdOx1-SARS-CoV2 immunisation (Vaxzevria®) impacts magnitudes of antigen-specific T-cell responses elicited by subsequent administration of the same viral vector (encoding HBV antigens, ChAdOx1-HBV), healthy volunteers that had received Vaxzevria® (n = 15) or the Pfizer or Moderna mRNA COVID-19 vaccine (n = 11) between 10 and 18 weeks prior were recruited to receive a single intramuscular injection of ChAdOx1-HBV. Anti-ChAdOx1-neutralising antibody titers were determined, and vector or insert-specific T-cell responses were measured by a gamma-interferon ELISpot and intracellular cytokine staining (ICS) assay using multiparameter flow cytometry. Participants were followed for three months after the ChAdOx1-HBV injection, which was well-tolerated, and no dropouts occurred. The baseline ChAdOx1 neutralisation titers were higher in the Vaxzevria® cohort (median of 848) than in the mRNA cohort (median of 25). T-cell responses to HBV antigens, measured by ELISpot, were higher on day 28 in the mRNA group (p = 0.013) but were similar between groups on day 84 (p = 0.441). By ICS, these differences persisted at the last time point. There was no clear correlation between the baseline responses to the adenoviral hexon and the subsequent ELISpot responses. As vaccination within 3 months using the same viral vector backbone affected the insert-specific T-cell responses, a greater interval after prior adenoviral immunisation using heterologous antigens may be warranted in settings in which these cells play critical roles.

Metabolic dysfunction associated steatotic liver disease (MASLD) represents a significant and increasing burden of liver disease worldwide. The increasing prevalence of MASLD makes it a common secondary liver disease in people with chronic hepatitis B virus (HBV) infection. This study aimed to assess the prevalence of MASLD in a cohort of HBV patients attending a specialist viral hepatitis clinic and to audit the management of MASLD in this group.We reviewed electronic patient records of individuals with HBV who attended the Oxford viral liver clinic between October and December 2024. Data collected included demographics, medical history, lifestyle factors, clinical notes, imaging, and blood test results. Liver steatosis was identified via ultrasound, MRI, biopsy, or FibroScan CAP scores >280 dB/m. MASLD was defined as hepatic steatosis with at least one cardiometabolic risk factor and no harmful alcohol intake. Management practices were audited against BASL/BSG NAFLD special interest group quality standards. Descriptive statistics were used to analyse the data.Of 211 HBV patients seen during the study period, 61 (29%) had hepatic steatosis. Of these, 52 (85%) met MASLD criteria. Most had 2–3 metabolic risk factors (54%). All patients underwent annual fibrosis assessment with FibroScan. Alcohol intake was recorded in 69%, smoking status in 56%, and BMI in 62%. However, only 10% were screened for hypertension at every visit, and 13% had a QRISK3 score calculated. While 54% received weight loss advice, only 13% were given specific goals or strategies, and 13% were directed to relevant health resources. No patients received written MASLD information.The steatosis prevalence observed (29%) aligns with larger studies (29.6%–34.9%). Our audit suggests that management of patients with MASLD and HBV may be outside recommended national standards. It is possible that some quality standards were previously addressed but not captured during the study period. Nonetheless, we have identified some areas where practice could improve. There is no standardised screening method for metabolic syndrome in those with steatosis even though these represent nearly 1/3 of all people with chronic HBV seen in clinic. Furthermore, we do not routinely provide written information or signpost to sources relevant to MASLD, or to how to achieve the recommended targets. To address these gaps, we have introduced a standardised clinic letter template to improve documentation and support adherence to quality standards. A follow-up audit is planned in one year to evaluate the impact of this intervention.Abstract P8 Figure 1[Image Omitted. See PDF.]ReferencesRinella Mary E, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Journal of Hepatology 2023;79;(6):1542–1556.McPherson S, Armstrong MJ, Cobbold JF, Corless L, Anstee QM, Aspinall RJ, Barclay ST, Brennan PN, Cacciottolo TM, Goldin RD, Hallsworth K, Hebditch V, Jack K, Jarvis H, Johnson J, Li W, Mansour D, McCallum M, Mukhopadhya A, Parker R, Ross V, Rowe IA, Srivastava A, Thiagarajan P, Thompson AI, Tomlinson J, Tsochatzis EA, Yeoman A, Alazawi W. Quality standards for the management of non-alcoholic fatty liver disease (NAFLD): consensus recommendations from the british association for the study of the liver and british society of gastroenterology NAFLD special interest group. Lancet Gastroenterol Hepatol. 2022 Aug;7(8):755–769. doi: 10.1016/S2468–1253(22)00061–9. Epub 2022 Apr 28. PMID: 35490698; PMCID: PMC7614852.Machado MV, Oliveira AG, Cortez-Pinto H. Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients. J Gastroenterol Hepatol. 2011;26:1361–7.Jiang D, Chen C, Liu X, Huang C, Yan D, Zhang X, et al. Concurrence and impact of hepatic steatosis on chronic hepatitis B patients: a systematic review and meta-analysis. Ann Transl Med. 2021;9:1718. doi: 10.21037/atm-21–3052.

The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF 50 ) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines. Defined levels of SARS-CoV-2-specific binding and neutralizing antibodies elicited by the COVID-19 vaccine ChAdOx1 nCoV-19 are identified as correlates of protection against symptomatic infection.

Respiratory syncytial virus (RSV) disease is a major cause of infant morbidity and mortality. This Phase I, randomized, observer-blind, placebo- and active-controlled study evaluated an investigational vaccine against RSV (ChAd155-RSV) using the viral vector chimpanzee-adenovirus-155, encoding RSV fusion (F), nucleocapsid, and transcription antitermination proteins. Healthy 18-45-year-old adults received ChAd155-RSV, a placebo, or an active control (Bexsero) at Days (D) 0 and 30. An escalation from a low dose (5 × 109 viral particles) to a high dose (5 × 1010 viral particles) occurred after the first 16 participants. Endpoints were solicited/unsolicited and serious adverse events (SAEs), biochemical/hematological parameters, cell-mediated immunogenicity by enzyme-linked immunospot, functional neutralizing antibodies, anti RSV-F immunoglobin (Ig) G, and ChAd155 neutralizing antibodies. There were 7 participants who received the ChAd155-RSV low dose, 31 who received the ChAd155-RSV high dose, 19 who received the placebo, and 15 who received the active control. No dose-related toxicity or attributable SAEs at the 1-year follow-up were observed. The RSV-A neutralizing antibodies geometric mean titer ratios (post/pre-immunization) following a high dose were 2.6 (D30) and 2.3 (D60). The ratio of the fold-rise (D0 to D30) in anti-F IgG over the fold-rise in RSV-A-neutralizing antibodies was 1.01. At D7 after the high dose of the study vaccine, the median frequencies of circulating B-cells secreting anti-F antibodies were 133.3/106 (IgG) and 16.7/106 (IgA) in peripheral blood mononuclear cells (PBMCs). The median frequency of RSV-F-specific interferon γ-secreting T-cells after a ChAd155-RSV high dose was 108.3/106 PBMCs at D30, with no increase after the second dose. In adults previously naturally exposed to RSV, ChAd155-RSV generated increases in specific humoral and cellular immune responses without raising significant safety concerns. NCT02491463.

Background Data regarding CD4+ recovery after switching from protease inhibitor (PI)-based regimens to regimens not containing PI are scarce. Methods Subjects with virological success on first-PI-regimens who switched to NNRTI therapy (NNRTI group) or to nucleoside reverse transcriptase (NRTI)-only (NRTI group) were studied. The effect of the switch on the ongoing CD4+ trend was assessed by two-phase linear regression (TPLR), allowing us to evaluate whether a change in the CD4+ trend (hinge) occurred and the time of its occurrence. Furthermore, we described the evolution of the frequencies in CD4-count classes across four relevant time-points (baseline, before and immediately after the switch, and last visit). Finally, we explored whether the CD4+ counts evolved differently in patients who switched to NNRTI or NRTI-only regimens by considering: the overall CD4+ trends, the time to CD4+≥ 500/mm 3 after the switch, and the area-under-the-curve (AUC) of the CD4+ after the switch. Results Eight hundred and ninety-six patients, followed for a median of 2,121 days, were included. At TPLR, hinges occurred in 581/844 (68.9%), but in only 40/581 (6.9%) within a time interval (180 days) compatible with a possible relationship to the switch; furthermore, in 19/40 cases, CD4+ counts appeared to decrease after the hinges. In comparison with the NNRTI group, the NRTI group showed CD4+ count greater at baseline (P = 0.0234) and before the switch (P ≤ 0.0001), superior CD4+ T-cell increases after HAART was started, lower probability of not achieving CD4+ ≥ 500/mm 3 (P = 0.0024), and, finally, no significant differences in the CD4+ T-cell AUC after the switch after adjusting for possible confounders (propensity score and pre-switch AUC). Persistence at CD4+ < 200/mm 3 was observed in 34/435 (7.5%) patients, and a decrease below this level was found in only 10/259 (3.9%) with baseline CD4+ ≥ 350/mm 3 . Conclusions Switching from first-line PI to NNRTI- or NRTI-based regimens did not seem to impair CD4+ trend over long-term follow-up. Although the greater CD4+ increases in patients who switched to the NRTI-only regimen was due to higher CD4+ counts before the switch, several statistical analyses consistently showed that switching to this regimen did not damage the ongoing immune-reconstitution. Lastly, the observation that CD4+ T-cell counts remained low or decreased in the long term despite virological success merits further investigation.

Introduction Translation of the evidence regarding the protective role of highly active antiretroviral therapy (HAART) on HIV sexual transmission rates into sexual behaviour patterns of HIV‐infected subjects remains largely unexplored. This study aims to describe frequency of self‐reported condom use among women living with HIV in Italy and to investigate the variables associated with inconsistent condom use (ICU). Methods DIDI (Donne con Infezione Da HIV) is an Italian multicentre study based on a questionnaire survey performed during November 2010 and February 2011. Women‐reported frequency of condom use was dichotomized in “always” versus “at times”/“never” (ICU). Results Among 343 women, prevalence of ICU was 44.3%. Women declared a stable partnership with an HIV‐negative (38%) and with an HIV‐positive person (43%), or an occasional sexual partner (19%). Among the 194 women engaged in a stable HIV‐negative or an occasional partnership, 51% reported fear of infecting the partner. Nonetheless, 43% did not disclose HIV‐positive status. Less than 5% of women used contraceptive methods other than condoms. At multivariable analysis, variables associated with ICU in the subgroup of women with a stable HIV‐negative or an occasional HIV‐unknown partner were: having an occasional partner (AOR 3.51, 95% confidence interval [CI] 1.44–8.54, p=0.005), and reporting fear of infecting the sexual partner (AOR 3.20, 95% CI 1.43–7.16, p=0.004). Current use of HAART together with virological control in plasma level did not predict ICU after adjusting for demographic, behavioural and HIV‐related factors. With regard to socio‐demographic factors, lower education was the only variable significantly associated with ICU in the multivariate analysis (AOR 2.27, 95% CI 1.07–4.82, p=0.03). No association was found between high adherence to HAART and ICU after adjusting for potential confounders (AOR 0.89, 95% CI 0.39–2.01, p=0.78). Conclusions Currently in Italy, the use of HAART with undetectable HIV RNA in plasma as well as antiretroviral adherence is not associated with a specific condom use pattern in women living with HIV and engaged with a sero‐discordant or an HIV‐unknown partner. This might suggest that the awareness of the protective role of antiretroviral treatment on HIV sexual transmission is still limited among HIV‐infected persons, at least in this country.

Background We assessed the virological response of DRV/r‐based dual therapy in drug‐experienced patients included in the Italian antiretroviral resistance database (ARCA). Materials and Methods Patients included in the study were treated with DRV/r in association with raltegravir (RAL), etravirine (ETV) or maraviroc (MAR) following treatment failure(s) and with a resistance test and at least one follow‐up visit available. Observation was censored at last visit under dual therapy and survival analysis and proportional hazard models were used, taking virological failure (confirmed >50 c/mL HIV‐RNA) as the end‐point. Results Of the total 221 patients included, 149 (67.4%) started DRV/r with RAL, 45 (20.4%) with ETV, 27 (12.2%) with MAR. Patients characteristics at the start of dual regimen were as follows: mean number of previous regimens, nine (IQR: 5–13); non‐B subtype, 17 (7.7%); median CD4 count, 347 (IQR: 246–544); undetectable viral load, 74 (33.5%). Full DRV/r resistance was detected in one (0.5%, HIV‐DB interpretation system), 13 (5.9%, ANRS) and 17 patients (7.7%, Rega). 69 virological failures (31.2%) were observed during follow‐up. At survival analysis, the overall proportion of failure was 29.2% at one year and 33.8% at two years. The proportion of failure was lower in patients starting with undetectable versus detectable viral load (13.3% and 25.2% versus 37.4% and 38.8% at one and two years, respectively, p=0.001 for both analyses) and in patients treated with DRV 600 BID versus 800 QD (HR: 0, 56; 95% CI 0.31–0.99; p<0.05). By regimen, patients treated with DRV/r‐RAL showed a non‐significant lower proportion of failure (27.7% at one year, 32.0% at two years) if compared with DRV/r‐MAR (35.9%, 47.1%) and DRV/r‐ETV (34.1%, 34.1% at one and two years). In the adjusted proportional model, no significant difference among the three regimens was detected. A significant lower risk of failure was associated with higher overall GSS (HIV‐DB HR: 0.53, 95% CI 0.32–0.88, p=0.014; Rega 0.60, 0.40‐0.88, p<0.01; ANRS 0.55, 0.34–0.90, p=0.017), while a higher risk of failure was associated with detectable HIV‐RNA (3.02, 1.70–5.72, p<0.001). Conclusions Among experienced patients, the best candidates to dual‐therapy regimens including DRV/r are those with undetectable viral load and higher GSS. The association with RAL is the most commonly used but no clear advantage with respect to ETV or MAR was observed in our dataset, possibly due to the limited sample size.