Pooled analysis of the MANTICO2 and MONET randomized controlled trials comparing drug efficacy for early treatment of COVID-19 during Omicron waves.

BACKGROUND: The clinical effectiveness of early therapies for mild-to-moderate COVID-19, comparing antivirals and monoclonal antibodies (mAbs) during the Omicron era, has not been conclusively assessed through a post-approval comparative trial. We present a pooled analysis of two randomized clinical trials conducted during Omicron waves. Methods The MANTICO2/MONET trial is a pooled analysis of two multicentric, independent, phase-4, three-arm, superiority, randomized, open-label trials. Nonhospitalized patients with early mild-to-moderate COVID-19 (≤5 days after symptoms' onset) and at least one risk factor for disease progression were randomized 1:1:1 to receive 500mg of intravenous sotrovimab (SOT) or 600mg of intramuscular tixagevimab/cilgavimab (TGM/CGM) or oral 5-days course of nirmatrelvir/ritonavir (NMV/r) 300/100mg BID. Primary outcome was COVID-19-related hospitalization or death within 29 days after randomization. Fisher's exact test for pooled data and incidence of failure was reported as overall and by arm with respective 95% CI. Pairwise comparisons across the arms were conducted using unadjusted exact logistic regression. An analysis by means of a doubly robust marginal model using augmented inverse probability weighting (AIPW) was also conducted to estimate the potential outcomes (Pom) in each treatment group and their difference by the average treatment effect (ATE). Analysis of symptom persistence within 30 days after randomization was performed using a 2-level hierarchical mixed-effects logistic model with a random intercept at the patient's level. Point estimates and 95% confidence intervals were adjusted for age and sex and calculated using ANOVA-like methods for the mixedeffects logistic model. These trials are registred with the European Clinical Trials Database, EudraCT2021-002612-31 (MANTICO2) and EudraCT2021-004188-28 (MONET) and ClinicalTrials.gov, NCT05321394 (MANTICO2) Findings Between March 2022 and February 2023, 991 patients (SOT=332, TGM/CGM =327, NMV/r=332) were enrolled in 15 Italian centersThe overall mean age was 66 years; 482 participants (48.80%) were male and 856 vaccinated with at least a primary course ( 86%). Among the 8/991 hospitalizations observed, one resulted in death. The overall estimate of failure was 0.81% (95%CI; 0.35-1.58%). The odds ratio (OR) for the primary outcome in the NMV/r arm compared to the TGM/CGM and SOT arms was 8.41 (95% CI 1.21 to infinity; p=0.015) and 2.42 (95% CI 0.19 to infinity; p=0.499), respectively. No significant difference was observed between SOT and TGM/CGM (OR 0.32; 95% CI 0.032-1.83; p=0.174). Results were similar when we applied the marginal weighted model accounting for potential residual confounding bias. There was no evidence for a difference in the prevalence of symptoms between treatment groups, except for cough, which was higher in the SOT group compared to the other two groups at the 21-day follow-up (P=0.039) and a higher prevalence of nausea at the 7-day follow-up in the NMV/r group compared to the mAbs group (p=0.036). Interpretation NMV/r was superior to TGM/CGM in reducing hospital admission or death in clinical vulnerable patients with SARS-CoV-2 infection treated within 5 days of symptoms' onset. No significant difference in symptom prevalence over time across the arms was found. FUNDING: The trials were funded by the Italian Agency of Drugs (AIFA) in 2021.

The Omicron Variant Is Associated with a Reduced Risk of the Post COVID-19 Condition and Its Main Phenotypes Compared to the Wild-Type Virus: Results from the EuCARE-POSTCOVID-19 Study.

Post COVID-19 condition (PCC) is defined as ongoing symptoms at ≥1 month after acute COVID-19. We investigated the risk of PCC in an international cohort according to viral variants. We included 7699 hospitalized patients in six centers (January 2020-June 2023); a subset of participants with ≥1 visit over the year after clinical recovery were analyzed. Variants were observed or estimated using Global Data Science Initiative (GISAID) data. Because patients returning for a post COVID-19 visit may have a higher PCC risk, and because the variant could be associated with the probability of returning, we used weighted logistic regressions. We estimated the proportion of the effect of wild-type (WT) virus vs. Omicron on PCC, which was mediated by Intensive Care Unit (ICU) admission, through a mediation analysis. In total, 1317 patients returned for a post COVID visit at a median of 2.6 (IQR 1.84-3.97) months after clinical recovery. WT was present in 69.6% of participants, followed by the Alpha (14.4%), Delta (8.9%), Gamma (3.9%) and Omicron strains (3.3%). Among patients with PCC, the most common manifestations were fatigue (51.7%), brain fog (32.7%) and respiratory symptoms (37.2%). Omicron vs. WT was associated with a reduced risk of PCC and PCC clusters; conversely, we observed a higher risk with the Delta and Alpha variants vs. WT. In total, 42% of the WT effect vs. Omicron on PCC risk appeared to be mediated by ICU admission. A reduced PCC risk was observed after Omicron infection, suggesting a possible reduction in the PCC burden over time. A non-negligible proportion of the variant effect on PCC risk seems mediated by increased disease severity during the acute disease.

Discrimination of the Veterans Aging Cohort Study Index 2.0 for Predicting Cause-specific Mortality Among Persons With HIV in Europe and North America.

Background: Predicting cause-specific mortality among people with HIV (PWH) could facilitate targeted care to improve survival. We assessed discrimination of the Veterans Aging Cohort Study (VACS) Index 2.0 in predicting cause-specific mortality among PWH on antiretroviral therapy (ART). Methods: Using Antiretroviral Therapy Cohort Collaboration data for PWH who initiated ART between 2000 and 2018, VACS Index 2.0 scores (higher scores indicate worse prognosis) were calculated around a randomly selected visit date at least 1 year after ART initiation. Missingness in VACS Index 2.0 variables was addressed through multiple imputation. Cox models estimated associations between VACS Index 2.0 and causes of death, with discrimination evaluated using Harrell's C-statistic. Absolute mortality risk was modelled using flexible parametric survival models. Results: Of 59 741 PWH (mean age: 43 years; 80% male), the mean VACS Index 2.0 at baseline was 41 (range: 0-129). For 2425 deaths over 168 162 person-years follow-up (median: 2.6 years/person), AIDS (n = 455) and non-AIDS-defining cancers (n = 452) were the most common causes. Predicted 5-year mortality for PWH with a mean VACS Index 2.0 score of 38 at baseline was 1% and approximately doubled for every 10-unit increase. The 5-year all-cause mortality C-statistic was .83. Discrimination with the VACS Index 2.0 was highest for deaths resulting from AIDS (0.91), liver-related (0.91), respiratory-related (0.89), non-AIDS infections (0.87), and non-AIDS-defining cancers (0.83), and lowest for suicides/accidental deaths (0.65). Conclusions: For deaths among PWH, discrimination with the VACS Index 2.0 was highest for deaths with measurable physiological causes and was lowest for suicide/accidental deaths.

Association between markers of hepatitis B virus infection and risk of virological rebound in people with HIV receiving antiretroviral therapy.

OBJECTIVES: The aim of this analysis was to investigate the impact of hepatitis B virus (HBV) coinfection on the risk of HIV viral rebound (VR) after achieving suppression for the first time following initiation of antiretroviral therapy (ART) in the real-world setting. DESIGN: Patients living with HIV (PLWH) who were enrolled in the ICONA Foundation Study cohort and achieved viral suppression ≤50 copies/mL for the first time after starting ART were prospectively evaluated and divided in three exposure groups according to serology test results: (a) HIV-monoinfected; (b) HIV-positive/HBcAb-positive/HBsAg-negative; (c) HIV-positive/HBsAg-positive. The occurrence of VR, defined as two consecutive HIV-RNA values >50 copies/mL after achieving viral suppression for the first time (baseline), was investigated. METHODS: Standard survival analysis by means of Kaplan-Meier curves and Cox regression analysis with the serology exposure fitted as a time-fixed covariate measured at baseline was employed after controlling for key confounding factors. RESULTS: Of a total of 5657 patients included, 4090 (72%) were HIV-monoinfected, 1342 (23.7%)were HBcAb-positive, and 225 (3.9%) were HbsAg-positive coinfected. Overall, 654 (11.5%) PLWH experienced VR > 50 copies/mL during follow-up. After controlling for all sources of measured confounding, coinfected PLWH showed an increased risk of experiencing VR compared with those who were HIV-monoinfected. In particular, the strongest associations were seen for the HIV/HBsAg-positive participants [adjusted hazard ratio (aHR) = 1.56, 95% confidence interval (CI): 1.03-2.38, p = 0.037] but an excess of risk was also seen in those who were HIV-positive/HBcAb-positive/HBsAg-negative (aHR = 1.25, 95% CI: 1.00-1.55, p = 0.047). CONCLUSIONS: Coinfection with HBV seems to have an impact on the probability of maintaining HIV viral suppression achieved for the first time after ART initiation. Of note, even PLWH positive for HBcAb, a marker of inactive HBV infection, appeared to be at higher risk of VR compared with those who were HIV-monoinfected and their HIV-RNA should be carefully monitored.

SARS-CoV-2 mRNA vaccination and short-term changes in viral load and CD4/CD8 T-cell counts in people living with HIV.

OBJECTIVES: To investigate whether SARS-CoV-2 messenger RNA (mRNA) vaccination has an impact on HIV-related viro-immunological parameters. METHODS: People with HIV (PWH) in the VAXICONA-ORCHESTRA cohort who received one or more doses of SARS-CoV-2 mRNA vaccine and for whom paired measures of immuno-virological markers (viral load, clusters of differentiation [CD]4, and CD8 count 1 month before and after a vaccine dose [VD]) were available were included. Paired t-test and generalized estimating equation linear regression analyses were used to study changes over ± 1 month around the VD. Subgroup analyses were performed. RESULTS: A total of 510 PWH were enrolled: the median age was 55 years (interquartile range 46-60 years), the CD4 and CD8 count were 489 (287-719) and 790 (59-1104) cells/mm3, respectively, and 81% received three VDs. After a median of 28 (3-53) days from VD, CD4 count increased by +15 cells/mm3 (SD ± 129.7, P = 0.001) and CD8 by +12 (±250.5, P = 0.199) and the viral load decreased by -0.11 log10 (±0.88, P = 0.001). Similar results were observed after restricting the analysis to viro-suppressed PWH, with CD4 ≤200/mm3, more than 6 months of antiretroviral therapy before VD and after excluding previous COVID-19. CONCLUSIONS: A small significant increase in CD4 count and a negligible drop in HIV RNA were observed. Our findings are consistent with the hypothesis that SARS-CoV-2 mRNA vaccine can prime CD4 T spike-specific cells, even in the more immuno-compromised PWH.

Poor durability of the neutralizing response against XBB sublineages after a bivalent mRNA COVID-19 booster dose in persons with HIV.

We estimated the dynamics of the neutralizing response against XBB sublineages and T cell response in persons with HIV (PWH) with previous AIDS and/or CD4 < 200/mm3 receiving the bivalent original strain/BA.4-5 booster dose in fall 2022. Samples were collected before the shot (Day 0), 15 days, 3, and 6 months after. PWH were stratified by immunization status: hybrid immunity (HI; vaccination plus COVID-19) versus nonhybrid immunity (nHI; vaccination only). Fifteen days after the booster, 16% and 30% of PWH were nonresponders in terms of anti-XBB.1.16 or anti-EG.5.1 nAbs, respectively. Three months after, a significant waning of anti-XBB.1.16, EG.5.1 and -XBB.1 nAbs was observed both in HI and nHI but nAbs in HI were higher than in nHI. Six months after both HI and nHI individuals displayed low mean levels of anti-XBB.1.16 and EG.5.1 nAbs. Regarding T cell response, IFN-γ values were stable over time and similar in HI and nHI. Our data showed that in PWH, during the prevalent circulation of the XBB.1.16, EG.5.1, and other XBB sublineages, a mRNA bivalent vaccine might not confer broad protection against them. With a view to the 2023/2024 vaccination campaign, the use of the monovalent XBB.1.5 mRNA vaccine should be urgently warranted in PWH to provide adequate protection.

Risk of SARS-CoV-2 infection in patients with hematologic diseases receiving tixagevimab/cilgavimab as pre-exposure prophylaxis in most recent Omicron sublineages era.

OBJECTIVES: Whether pre-exposure prophylaxis (PrEP) with tixagevimab/cilgavimab 150 mg/150 mg (T/C) in individuals with hematologic disease (HD) may lead to a reduced risk of SARS-CoV-2 breakthrough infection (BTI)/hospitalization, or death in the Omicron era remains to be established. METHODS: An observational study included participants with HD who received PrEP. BTIs were defined as SARS-CoV-2 positivity by reverse transcription-polymerase chain reaction. The incidence of BTIs (95% CI) and of BTIs/hospitalization/death was calculated using the Kaplan-Meier method and as the number of BTIs per 100 person-years of follow-up according to the circulating variant of concern (VoC). A Poisson regression model was used to evaluate the association between the rate of incidence and circulating VoCs after controlling for demographics and clinical factors. RESULTS: We included 550 HD patients: 71% initiated T/C PrEP when BA.5 was the most prevalent, followed by XBB/EG, BA.2, and BA.1 (19%, 7%, and 3%, respectively). Overall, the 1-year incidence estimate of BTIs/hospitalization/death was 24% (18.7-29.4%). A greater risk of incident infections was observed when BA.5 and XBB/EG sub-lineages circulated (aRR 5.05 [2.17, 11.77]; P < .001 and 3.82 [1.50, 9.7]; P = 0.005, compared to BA.1, respectively). CONCLUSIONS: The 1-year incidence of SARS-CoV-2 BTIs/hospitalization/death was 24% which is in line with what was observed in other similar studies. The risk appeared to be higher when more recent Omicron sub-lineages were circulating suggesting a reduction of in vitro neutralization.

Persistent poor clinical outcomes of people living with HIV presenting with AIDS and late HIV diagnosis - results from the ICONA cohort in Italy, 2009-2022.

OBJECTIVES: Limited data are available on the long-term outcomes in recent years for late HIV diagnosis (LD). METHODS: All subjects with HIV enrolled in the ICONA cohort in 2009-2022 who started antiretroviral treatment (ART) within 4 months from diagnosis were included and divided into: (i) pre-ART CD4 count ≥350/mm3 without AIDS (non-LD), (ii) pre-ART CD4 count <350/mm3 without AIDS (LD asymptomatic), and (iii) with AIDS events pre-ART (LD-AIDS). The estimated probability and independent risk for mortality (all-cause and cause-specific) and treatment failure were evaluated. RESULTS: Of 6813 participants (2448 non-LD, 3198 LD asymptomatic, and 1167 LD-AIDS), 161 (2.4%) died after ART initiation. At survival analysis, a higher probability of all-cause mortality has been identified for LD than non-LD (P <0.001) and within the former, for LD-AIDS over LD asymptomatic (P <0.001). After adjusting for confounders, LD showed a higher risk of all-cause mortality (vs non-LD adjusted hazard ratio (aHR) 5.51, P <0.001) and, in particular, being an AIDS presenter predicted a greater risk of all-cause (aHR = 4.42, P <0.001), AIDS-related (adjusted subhazard ratio [aSHR] = 16.86, P <0.001), and non-AIDS-related mortality (aSHR = 1.74, P = 0.022) than the rest of the late presenters. Among the short-term survivors in the LD-AIDS group, the long-term mortality was mediated by the lack of immune recovery at 2 years. Finally, LD compared with non-LD and, particularly, among the former, LD-AIDS over LD asymptomatic showed a greater risk of treatment failure. CONCLUSIONS: In recent years, LD subjects, particularly, AIDS presenters, remained at a higher risk of poorer outcomes. Public health strategies for early HIV diagnosis are urgently needed to constrain the mortality gap.

Development and validation of a prediction score for failure to casirivimab/imdevimab in hospitalized patients with COVID-19 pneumonia.

Introduction: Casirivimab and imdevimab (CAS/IMV) are two non-competing, high-affinity human IgG1 anti-SARS-CoV-2 monoclonal antibodies, that showed a survival benefit in seronegative hospitalized patients with COVID-19. This study aimed to estimate the day-28 risk of mechanical ventilation (MV) and death in individuals hospitalized for severe COVID-19 pneumonia and receiving CAS/IMV. Additionally, it aimed to identify variables measured at the time of hospital admission that could predict these outcomes and derive a prediction algorithm. Methods: This is a retrospective, observational cohort study conducted in 12 hospitals in Italy. Adult patients who were consecutively hospitalized from November 2021 to February 2022 receiving CAS/IMV were included. A multivariable logistic regression model was used to identify predictors of MV or death by day 28 from treatment initiation, and ß-coefficients from the model were used to develop a risk score that was derived by means of leave-one-out internal cross-validation (CV), external CV, and calibration. Secondary outcome was mortality. Results: A total of 480 hospitalized patients in the training set and 157 patients in the test set were included. By day 28, 36 participants (8%) underwent MV and 28 died (6%) for a total of 58 participants (12%) experiencing the composite primary endpoint. In multivariable analysis, four factors [age, PaO2/FiO2 ratio, lactate dehydrogenase (LDH), and platelets] were independently associated with the risk of MV/death and were used to generate the proposed risk score. The accuracy of the score in the area under the curve (AUC) was 0.80 and 0.77 in internal validation and test for the composite endpoint and 0.87 and 0.86 for death, respectively. The model also appeared to be well calibrated with the raw data. Conclusion: The mortality risk reported in our study was lower than that previously reported. Although CAS/IMV is no longer used, our score might help in identifying which patients are not likely to benefit from monoclonal antibodies and may require alternative interventions.

In-hospital mortality during the wild-type, alpha, delta, and omicron SARS-CoV-2 waves: a multinational cohort study in the EuCARE project.

Background: Investigating outcomes of hospitalised COVID-19 patients throughout the pandemic is crucial to understand the impact of different SARS-CoV-2 variants. We compared 28-day in-hospital mortality of Wild-type, Alpha, Delta, and Omicron variant infections. Whether the difference in risk by variant varied by age was also evaluated. Methods: We conducted a cohort study including patients ≥18 years, hospitalised between 2020 and 02-01 and 2022-10-15 with a SARS-CoV-2 positive test, from nine countries. Variant was classified based on sequenced viruses or from national public metadata. Mortality was compared using the cumulative incidence function and subdistribution hazard ratios (SHR) adjusted for age, sex, calendar time, and comorbidities. Results were shown age-stratified due to effect measure modification (P < 0.0001 for interaction between age and variant). Findings: We included 38,585 participants: 19,763 Wild-type, 6387 Alpha, 3640 Delta, and 8795 Omicron. The cumulative incidence of mortality decreased throughout the study period. Among participants ≥70 years, the adjusted SHR (95% confidence interval) for Delta vs. Omicron was 1.66 (1.29-2.13). This estimate was 1.66 (1.17-2.36) for Alpha vs. Omicron, and 1.34 (0.92-1.95) for Wild-type vs. Omicron. These were 1.21 (0.81-1.82), 1.21 (0.68-2.17), and 0.98 (0.53-1.82) among unvaccinated participants. When comparing Omicron sublineages, the aSHR for BA.1 was 1.92 (1.43-2.58) compared to BA.2 and 1.52 (1.11-2.08) compared to BA.5. Interpretation: The herein observed decrease in in-hospital mortality seems to reflect a combined effect of immunity from vaccinations and previous infections, although differences in virulence between SARS-CoV-2 variants may also have contributed. Funding: European Union's Horizon Europe Research and Innovation Programme.

Heavily treatment-experienced persons living with HIV currently in care in Italy: characteristics, risk factors, and therapeutic options-the ICONA Foundation cohort study.

OBJECTIVES: Heavily treatment-experienced (HTE) people living with HIV (PLWH) pose unique challenges due to limited antiretroviral treatment (ART) options. Our study aimed to investigate the prevalence and features of HTE individuals followed up in the Italian Cohort Naïve Antiretrovirals (ICONA) cohort as of December 31, 2021. METHODS: HTE were defined based on meeting specific conditions concerning their current ART and their ART history up to December 31, 2021. Descriptive statistics were performed by HTE status. Regression analyses explored factors associated with becoming HTE based on pre-ART patients' characteristics. Cluster dendrogram analysis provided insights into subgroups with inadequate responses based on clusters of differentiation (CD4) counts and viral load (VL) trajectories. RESULTS: Among the 8758 PLWH actively followed in our cohort, 163 individuals (1.9%), mainly female, younger, Italian, and infected through heterosexual contact, met the HTE criteria. A lower CD4 count at ART initiation (odds ratio [OR] 1.60 per 100 cells/mmc lower CD4, 95% confidence interval [CI] 1.06-2.41, P = 0.03) and hepatitis C virus antibody positivity (OR 1.90, 95% CI 1.16-3.11, P = 0.01) were associated with higher HTE risk. Thirty PLWH exhibited ongoing immune-virological failure (18% of the HTE subgroup and 0.003% of the total population). Thirty PLWH exhibited ongoing immune-virological failure (i.e., with a current CD4 count <200 cells/mmc or VL>200 copies/mL). A cluster analysis identified 13 (43%) with a current CD4 count <200 cells/mmc. Also, notably, 19/30 (63%) had major acquired resistance-associated mutations to at least one antiretroviral drug class. CONCLUSIONS: HTE is rare in our cohort and tends to co-exist with major resistance mutations. A focused investigation into treatment history and immuno-virological response is warranted, particularly given the availability of new antiretroviral drugs.

Impact of COVID-19 pandemic on retention in care of native and migrant people with HIV in the ICONA cohort.

BACKGROUND: COVID-19 pandemic challenged the UNAIDS 90-90-90 targets. How the COVID-19 pandemic affected HIV retention in care and whether it has disproportionally affected migrant people with HIV (PWH) remained to be investigated. METHODS: PWH in ICONA Cohort in follow-up in each of the study periods were included: 01/09/2019-29/02/2020 (pandemic period) and 01/03/2018-31/08/2018 (historical period, as a control). Risk of temporary loss to follow-up (LTFU, defined as no data recorded for a person for one year) was analyzed by logistic regression, with migrant status as the main exposure variable. Difference in difference (DID) analysis was applied to evaluate the effect of COVID-19 pandemic in the different risk of LTFU between natives and migrants. RESULTS: 8864 (17.1% migrants) and 8071 (16.8% migrants) PWH constituted the pandemic and the historical period population, respectively. Proportion of PWH defined as LTFU in the pandemic period was 10.5% in native and 19.6% in migrant PWH. After controlling for age, sex and geographical location of enrolling site, risk of temporary LTFU was higher for migrants than native PWH [adjusted odds ratio 1.85 (95%CI 1.54-2.22)] in pandemic period. In PWH contributing to both periods, LTFU was 9.0% (95% CI 8.3-9.8) in natives vs 17.0% (95% CI 14.7-19.4) in migrants during the pandemic. Instead, LTFU was 1.2% (95%CI 0.9, 1.5) in natives vs 2.2% (95% CI 1.3-3.1) in migrants during the historical period, with a resulting DID of 7.0% (95% CI 4.4-9.6). CONCLUSIONS: A greater proportion of LTFU in migrant PWH was observed in both periods, which remained unaltered over time. Interventions to reduce LTFU of migrants are necessary.

Immunogenicity and reactogenicity of modified vaccinia Ankara pre-exposure vaccination against mpox according to previous smallpox vaccine exposure and HIV infection: prospective cohort study.

Background: Pre-exposure vaccination with MVA-BN has been widely used against mpox to contain the 2022 outbreak. Many countries have defined prioritized strategies, administering a single dose to those historically vaccinated for smallpox, to achieve quickly adequate coverage in front of low supplies. Using epidemiological models, real-life effectiveness was estimated at approximately 36%-86%, but no clinical trials were performed. Few data on MVA-BN immunogenicity are currently available, and there are no established correlates of protection. Immunological response in PLWH in the context of the 2022 outbreak was also poorly described. Methods: Blood samples were collected from participants eligible for pre-exposure MVA-BN vaccination before (T1) receiving a full course of vaccine (single-dose for vaccine-experienced or smallpox-primed and two-dose for smallpox vaccine-naïve or smallpox non-primed) and one month after the last dose (T2 and T3, respectively). MPXV-specific IgGs were measured by in-house immunofluorescence assay, using 1:20 as screening dilution, MPXV-specific nAbs by 50% plaque reduction neutralization test (PRNT50, starting dilution 1:10), and IFN-γ-producing specific T cells to MVA-BN vaccine, by ELISpot assay. Paired or unpaired t-test and Wilcoxon or Mann-Whitney test were used to analyse IgG and nAbs, and T-cell response, as appropriate. The probability of IgG and nAb response in vaccine-experienced vs. vaccine-naïve was estimated in participants not reactive at T1. The McNemar test was used to evaluate vaccination's effect on humoral response both overall and by smallpox vaccination history. In participants who were not reactive at T1, the proportion of becoming responders one month after full-cycle completion by exposure groups was compared by logistic regression and then analysed by HIV status strata (interaction test). The response was also examined in continuous, and the Average Treatment Effect (ATE) of the difference from baseline to schedule completion according to previous smallpox vaccination was estimated after weighting for HIV using a linear regression model. Self-reports of adverse effects following immunization (AEFIs) were prospectively collected after the first MVA-BN dose (T1). Systemic (S-AEFIs: fatigue, myalgia, headache, GI effects, chills) and local (L-AEFIs: redness, swelling, pain) AEFIs were graded as absent (grade 0), mild (1), moderate (2), or severe (3). The maximum level of severity for S-AEFIs and L-AEFIs ever experienced over the 30 days post-dose by vaccination exposure groups were analysed using a univariable multinomial logistic regression model and after adjusting for HIV status; for each of the symptoms, we also compared the mean duration by exposure group using an unpaired t-test. Findings: Among the 164 participants included, 90 (54.8%) were smallpox vaccine-experienced. Median age was 49 years (IQR 41-55). Among the 76 (46%) PLWH, 76% had a CD4 count >500 cells/µL. There was evidence that both the IgG and nAbs titers increased after administration of the MVA-BN vaccine. However, there was no evidence for a difference in the potential mean change in humoral response from baseline to the completion of a full cycle when comparing primed vs. non-primed participants. Similarly, there was no evidence for a difference in the seroconversion rate after full cycle vaccination in the subset of participants not reactive for nAbs at T1 (p = 1.00 by Fisher's exact test). In this same analysis and for the nAbs outcome, there was some evidence of negative effect modification by HIV (interaction p-value = 0.17) as primed people living with HIV (PLWH) showed a lower probability of seroconversion vs. non-primed, and the opposite was seen in PLWoH. When evaluating the response in continuous, we observed an increase in T-cell response after MVA-BN vaccination in both primed and non-primed. There was evidence for a larger increase when using the 2-dose vs. one-dose strategy with a mean difference of -2.01 log2 (p ≤ 0.0001), after controlling for HIV. No evidence for a difference in the risk of developing any AEFIs of any grade were observed by exposure group, except for the lower risk of grade 2 (moderate) fatigue, induration and local pain which was lower in primed vs. non-primed [OR 0.26 (0.08-0.92), p = 0.037; OR 0.30 (0.10-0.88), p = 0.029 and OR 0.19 (0.05-0.73), p = 0.015, respectively]. No evidence for a difference in symptom duration was also detected between the groups. Interpretation: The evaluation of the humoral and cellular response one month after the completion of the vaccination cycle suggested that MVA-BN is immunogenic and that the administration of a two-dose schedule is preferable regardless of the previous smallpox vaccination history, especially in PLWH, to maximize nAbs response. MVA-BN was safe as well tolerated, with grade 2 reactogenicity higher after the first administration in vaccine-naïve than in vaccine-experienced individuals, but with no evidence for a difference in the duration of these adverse effects. Further studies are needed to evaluate the long-term duration of immunity and to establish specific correlates of protection. Funding: The study was supported by the National Institute for Infectious Disease Lazzaro Spallanzani IRCCS "Advanced grant 5 × 1000, 2021" and by the Italian Ministry of Health "Ricerca Corrente Linea 2".

Characterization and outcomes of difficult-to-treat patients starting modern first-line ART regimens: Data from the ICONA cohort.

OBJECTIVES: Treatment failures to modern antiretroviral therapy (ART) raise concerns, as they could reduce future options. Evaluations of occurrence of multiple failures to modern ART are missing and their significance in the long run is unclear. METHODS: People with HIV (PWH) in the ICONA cohort who started a modern first-line ART were defined as 'difficult to treat' (DTT) if they experienced ≥1 among: i) ≥2 VF (2 viral loads, VL>200 copies/mL or 1 VL>1000 copies/mL) with or without ART change; ii) ≥2 treatment discontinuations (TD) due to toxicity/intolerance/failure; iii) ≥1 VF followed by ART change plus ≥1 TD due to toxicity/intolerance/failure. A subgroup of the DTT participants were matched to PWH that, after the same time, were non-DTT. Treatment response, analysing VF, TD, treatment failure, AIDS/death, and SNAE (Serious non-AIDS event)/death, were compared. Survival analysis by KM curves and Cox regression models were employed. RESULTS: Among 8061 PWH, 320 (4%) became DTT. Estimates of becoming DTT was 6.5% (95% CI: 5.8-7.4%) by 6 years. DTT PWH were significantly older, with a higher prevalence of AIDS and lower CD4+ at nadir than the non-DTT. In the prospective analysis, DTT demonstrated a higher unadjusted risk for all the outcomes. Once controlled for confounders, significant associations were confirmed for VF (aHR 2.23, 1.33-3.73), treatment failure (aHR 1.70, 1.03-2.78), and SNAE/death (aHR 2.79, 1.18-6.61). CONCLUSION: A total of 6.5% of PWH satisfied our definition of DTT by 6 years from ART starting. This appears to be a more fragile group who may have higher risk of failure.

Rate of response to initial antiretroviral therapy according to level of pre-existing HIV-1 drug resistance detected by next-generation sequencing in the strategic timing of antiretroviral treatment (START) study.

OBJECTIVES: The main objective of this analysis was to evaluate the impact of pre-existing drug resistance by next-generation sequencing (NGS) on the risk of treatment failure (TF) of first-line regimens in participants enrolled in the START study. METHODS: Stored plasma from participants with entry HIV RNA >1000 copies/mL were analysed using NGS (llumina MiSeq). Pre-existing drug resistance was defined using the mutations considered by the Stanford HIV Drug Resistance Database (HIVDB v8.6) to calculate the genotypic susceptibility score (GSS, estimating the number of active drugs) for the first-line regimen at the detection threshold windows of >20%, >5%, and >2% of the viral population. Survival analysis was conducted to evaluate the association between the GSS and risk of TF (viral load >200 copies/mL plus treatment change). RESULTS: Baseline NGS data were available for 1380 antiretroviral therapy (ART)-naïve participants enrolled over 2009-2013. First-line ART included a non-nucleoside reverse transcriptase inhibitor (NNRTI) in 976 (71%), a boosted protease inhibitor in 297 (22%), or an integrase strand transfer inhibitor in 107 (8%). The proportions of participants with GSS <3 were 7% for >20%, 10% for >5%, and 17% for the >2% thresholds, respectively. The adjusted hazard ratio of TF associated with a GSS of 0-2.75 versus 3 in the subset of participants with mutations detected at the >2% threshold was 1.66 (95% confidence interval 1.01-2.74; p = 0.05) and 2.32 (95% confidence interval 1.32-4.09; p = 0.003) after restricting the analysis to participants who started an NNRTI-based regimen. CONCLUSIONS: Up to 17% of participants initiated ART with a GSS <3 on the basis of NGS data. Minority variants were predictive of TF, especially for participants starting NNRTI-based regimens.

Long Term Assessment of Anti-SARS-CoV-2 Immunogenicity after mRNA Vaccine in Persons Living with HIV.

(1) Background: Waning of neutralizing and cell-mediated immune response after the primary vaccine cycle (PVC) and the first booster dose (BD) is of concern, especially for PLWH with a CD4 count ≤200 cells/mm3. (2) Methods: Neutralizing antibodies (nAbs) titers by microneutralization assay against WD614G/Omicron BA.1 and IFNγ production by ELISA assay were measured in samples of PLWH at four time points [2 and 4 months post-PVC (T1 and T2), 2 weeks and 5 months after the BD (T3 and T4)]. Participants were stratified by CD4 count after PVC (LCD4, ≤200/mm3; ICD4, 201-500/mm3, and HCD4, >500/mm3). Mixed models were used to compare mean responses over T1-T4 across CD4 groups. (3) Results: 314 PLWH on ART (LCD4 = 56; ICD4 = 120; HCD4 = 138) were enrolled. At T2, levels of nAbs were significantly lower in LCD4 vs. ICD4/HCD4 (p = 0.04). The BD was crucial for increasing nAbs titers above 1:40 at T3 and up to T4 for WD614G. A positive T cell response after PVC was observed in all groups, regardless of CD4 (p = 0.31). (4) Conclusions: Waning of nAbs after PVC was more important in LCD4 group. The BD managed to re-establish higher levels of nAbs against WD614G, which were retained for 5 months, but for shorter time for Omicron BA.1. The T cellular response in the LCD4 group was lower than that seen in participants with higher CD4 count, but, importantly, it remained above detectable levels over the entire study period.

Predictive Factors for Pregnancy-Related Persistent Pelvic Girdle Pain (PPGP): A Systematic Review.

Background and Objectives: To identify the most frequently reported predictive factors for the persistency of pregnancy-related pelvic girdle pain (PPGP) at 3-6 months after childbirth in women with PPGP alone or PPGP in association with pregnancy-related lower back pain (PLBP). Methods: Eligibility criteria: Two authors independently selected studies excluding PPGP determined by a specific, traumatic, gynecological/urological cause or isolated PLBP and studies that did not include the presence/absence of PPGP as the the primary outcome. We, instead, included studies with an initial assessment in pregnancy (within 1 month of delivery) and with a follow-up of at least 3 months after delivery. Data sources: The research was performed using the databases of Medline, Cochrane, Pedro, Scopus, Web of Science and Cinahl from December 2018 to January 2022, following the indications of the PRISMA statement 2021 and the MOOSE checklist. It includes observational cohort studies in which data were often collected through prospective questionnaires (all in English). Study appraisal and risk of bias: Two independent authors performed evaluations of the risk of bias (ROB) using the quality in prognostic studies (QUIPS) tool. Synthesis of results: An in-depth qualitative analysis was conducted because, due to a high degree of heterogeneity in the data collection of the included studies and a lack of raw data suitable for quantitative analysis, it was not possible to carry out the originally planned meta-analyses for the subgroups. Results: The research process led to the inclusion of 10 articles which were evaluated using the QUIPS tool: 5 studies were evaluated as low ROB and 5 were evaluated as moderate ROB. High levels of pain in pregnancy, a large number of positive provocation tests, a history of lower back pain and lumbo-pelvic pain, high levels of disability in pregnancy, neurotic behavior and high levels of fear-avoidance belief were identified as strong predictors of long-term PPGP, while there was weak or contradictory evidence regarding predictions of emotional distress, catastrophizing and sleep disturbances. Discussion: The impossibility of carrying out the meta-analysis by subgroups suggests the need for further research with greater methodological rigor in the acquisition of measures based on an already existing PPGP core predictors/outcome sets.

Evaluating immunological and inflammatory changes of treatment-experienced people living with HIV switching from first-line triple cART regimens to DTG/3TC vs. B/F/TAF: the DEBATE trial.

Background: The aim of this randomized clinical trial (RCT) was to compare immunological changes in virally suppressed people living with HIV (PLWH) switching from a three-drug regimen (3DR) to a two-drug regimen (2DR). Methods: An open-label, prospective RCT enrolling PLWH receiving a 3DR who switched to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or dolutegravir/lamivudine (DTG/3TC) was performed. Blood was taken at baseline and months 6 and 12. The primary outcome was the change in CD4+ or CD8+ T-cell counts and CD4/CD8 ratio over time points. The secondary outcomes were the changes in immunological and inflammatory parameters. Parametric mixed-linear models with random intercepts and slopes were fitted separately for each marker after controlling for potential confounders. Results: Between the two arms (33 PLWH each), there was no difference in CD4+ or CD8+ T cells, CD4/CD8 ratio, and IL-6 trajectories. PLWH switching to DTG/3TC had increased levels of both transitional memory and terminally differentiated CD4+ T cells (arm-time interaction p-value = 0.02) and to a lesser extent for the corresponding CD8+ T-cell subsets (p = 0.09). Significantly lower levels of non-classical monocytes were detected in the B/F/TAF arm at T6 (diff = -6.7 cells/mm3; 95% CI; -16, +2.6; p-value for interaction between arm and time = 0.03). All differences were attenuated at T12. Conclusion: No evidence for a difference in absolute CD4+ and CD8+ T-cell counts, CD4/CD8 ratio, and IL-6 trajectories by study arm over 12 months was found. PLWH on DTG/3TC showed higher levels of terminally differentiated and exhausted CD4+ and CD8+ T lymphocytes and non-classical monocytes at T6. Further studies are warranted to better understand the clinical impact of our results. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04054089.

'Being disabled' as an exclusion criterion for clinical trials: a scoping review.

BACKGROUND: People with disabilities (PWDs) are often excluded from biomedical research, but comprehensive data regarding their participation in clinical trials are not available. The objective of this study was to assess the rates of exclusion of PWDs from recent medical scientific research. METHODS: The protocol of the study was designed according to PRISMA-ScR (PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) extension for Scoping Reviews) guidelines. All completed interventional clinical trials registered on ClinicalTrials.gov between 2010 and 2020 regarding the 10 leading causes of global disability-adjusted life-years according to the Global Burden of Disease Study were analysed. An exclusion criterion from the study was considered explicit if it could be associated with one of the following seven categories: disability, physical impairment, cognitive impairment, behavioural or psychiatric disorders, language and communication impairment, sensory impairment. Comorbidities not more clearly defined and researcher discretion regarding exclusion of study participants were considered to be 'implicit exclusion criteria'. We assessed the appropriateness of explicit exclusion criteria in relation to the primary objectives of the trials and labelled them as 'absolute', 'relative' or 'questionable'. RESULTS: The total number of trials analysed was 2710; 170 were paediatric trials (6.3%), 2374 were adult trials (87.6%) and 166 were trials including subjects of all ages (6.1%). Explicit exclusion criteria were found in 958 trials (35.3%). The disability category most frequently excluded was behavioural or psychiatric disorders, present in 588 trials (61.4%). In only 3% and 1% of the trials, the exclusion criteria were considered either 'absolute' or 'questionable', while in 96% the exclusion criteria were judged as 'relative'. Implicit exclusion criteria were present in 1205 trials (44.5%). CONCLUSIONS: This study highlights the high rate of exclusion of PWDs from biomedical research and the widespread use of ill-defined exclusion criteria in clinical trials. It underscores the importance of more inclusive study designs so that PWDs can become active participants in research.