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The article focuses on treatment of Hepatitis C disease. Topics discussed include usage of values of incremental cost-effectiveness ratio (ICER), calculation of budget impact (BI) of a health care intervention, reduction of cost by application of price-volume agreement, lack of transparency in these strategies.

Background: Polymorphisms in IFNL3 and IFNL4, the genes encoding interferon λ3 and interferon λ4, respectively, have been associated with reduced hepatitis C virus clearance. We explored the role of such polymorphisms on the incidence of cytomegalovirus (CMV) infection in solid-organ transplant recipients.Methods: White patients participating in the Swiss Transplant Cohort Study in 2008-2011 were included. A novel functional TT/-G polymorphism (rs368234815) in the CpG region upstream of IFNL3 was investigated.Results: A total of 840 solid-organ transplant recipients at risk for CMV infection were included, among whom 373 (44%) received antiviral prophylaxis. The 12-month cumulative incidence of CMV replication and disease were 0.44 and 0.08 cases, respectively. Patient homozygous for the minor rs368234815 allele (-G/-G) tended to have a higher cumulative incidence of CMV replication (subdistribution hazard ratio [SHR], 1.30 [95% confidence interval {CI}, .97-1.74]; P = .07), compared with other patients (TT/TT or TT/-G). The association was significant among patients followed by a preemptive approach (SHR, 1.46 [95% CI, 1.01-2.12]; P = .047), especially in patients receiving an organ from a seropositive donor (SHR, 1.92 [95% CI, 1.30-2.85]; P = .001), but not among those who received antiviral prophylaxis (SHR, 1.13 [95% CI, .70-1.83]; P = .6). These associations remained significant in multivariate competing risk regression models.Conclusions: Polymorphisms in the IFNL3/4 region influence susceptibility to CMV replication in solid-organ transplant recipients, particularly in patients not receiving antiviral prophylaxis. [ABSTRACT FROM AUTHOR]

We present a patient with skin ulcers that did not respond to a 3-week course of treatment with amoxicillin–clavulanic acid. As the patient maintained a fish aquarium, mycobacterial infection was suspected. Indeed, reassessment of histopathology revealed acid-fast bacilli, and mycobacterial cultures at 30 °C grew Mycobacterium marinum. Eventually, surgical reconstruction of the tendons was needed. [ABSTRACT FROM AUTHOR]

Background: Since the implementation of universal antiretroviral therapy, kidney transplantation (K-Tx) has become a valuable option for treatment of end-stage kidney disease for people with HIV (PWH) with similar patient and graft survival as compared to HIV-uninfected patients. Little is known about the hazards and manifestations of infectious disease (ID) events occurring in kidney transplant recipients with HIV. Methods: Using linked information collected in the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS), we described in-depth demographical and clinical characteristics of PWH who received a K-Tx since 2008. Further, we performed recurrent time to event analyses to understand whether HIV was an independent risk factor for ID events. Results: Overall, 24 PWH with 57 ID events were included in this study (100% match of SHCS to STCS). Of these, 17 (70.8%) patients had at least one ID event: 22 (38.6%) viral (HIV not counted), 18 (31.6%) bacterial, one (1.8%) fungal and 16 (28.1%) probable infections. Most ID events affected the respiratory tract (25, 37.3%) or the urinary tract (13, 19.4%). Pathogen types and infection sites were similar in PWH and a matched control group of HIV-uninfected patients. HIV was not an independent risk factor for ID events (adjusted hazard ratio 0.94, p = 0.9). Conclusion: By linking data from two large national Swiss cohorts, we provided in-depth information on ID events in PWH receiving a K-Tx in Switzerland. HIV infection was not associated with an increased hazard for ID events after K-Tx. Summary: In a matched analysis based on longitudinal data from the Swiss HIV and Transplant Cohort Studies including all people with HIV who received a kidney transplantation, HIV was not an independent risk factor for infectious disease events post-transplant. [ABSTRACT FROM AUTHOR]

Objectives: In this study, we compared IFA and real-time PCR in bronchoalveolar lavage specimens of HIV infected patients. A total of 66 BALs from 62 HIV patients were included in the study. 30 IFA positive and 36 IFA negative specimens were tested with real-time PCR, targeting the major surface glycoprotein. We performed a retrospective analysis of the patient's medical records, compared the results of the IFA and PCR tests and analyzed costs, expenditure of time and personal expenses. Results: All of the 30 IFA positive samples were PCR positive. 35 of 36 IFA negative probes were also negative in the PCR assay. Considering the PCR results as a binary outcome (positive/negative) sensitivity was 100%, specificity 97.2%. The patient with negative IFA and positive PCR had a clear clinical picture of PCP and responded to PCP treatment. PCR was more than twice as expensive and time-consuming as IFA. Diagnostic accuracy for PCP of PCR and IFA was comparable in HIV-infected patients, but IFA was significantly less expensive and less time-consuming. Therefore, IFA testing can continue to be used as gold standard in the diagnosis of PCP in HIV patients. However, in special cases, IFA may lack sensitivity and PCR should be added to the diagnostic armamentarium. [ABSTRACT FROM AUTHOR]

Background Infectious diseases (IDs) are highly relevant after solid organ transplantation in terms of morbidity and mortality, being among the most common causes of death. Patients undergoing kidney retransplantation (re-K-Tx) have been already receiving immunosuppressive therapy over a prolonged period, potentially facilitating subsequent infections. Comparing ID events after re-K-Tx and first kidney transplantation (f-K-Tx) can delineate patterns and risks of ID events associated with prolonged immunosuppression. Methods We included adult patients with records on f-K-Tx and re-K-Tx in the Swiss Transplant Cohort Study. We analyzed ID events after f-K-Tx and re-K-Tx within the same patients and compared infection rates, causative pathogens, and infection sites. Recurrent time-to-event analyses were performed for comparison of infection rates. Results A total of 59 patients with a median age of 47 years (range, 18–73) were included. Overall, 312 ID events in 52 patients occurred. In multivariable recurrent event modeling, the rate of ID events was significantly lower after re-K-Tx (hazard ratio, 0.70; P =.02). More bacterial (68.9% vs 60.4%) and fungal (4.0% vs 1.1%) infections were observed after f-K-Tx but fewer viral infections (27.0% vs 38.5%) as compared with re-K-Tx (P =.11). After f-K-Tx, urinary and gastrointestinal tract infections were more frequent; after re-K-Tx, respiratory tract and surgical site infections were more frequent (P <.001). Conclusions ID events were less frequent after re-K-Tx. Affected sites differed significantly after f-K-Tx vs re-K-Tx. [ABSTRACT FROM AUTHOR]

Background The immunogenicity of the standard influenza vaccine is reduced in solid-organ transplant (SOT) recipients, so new vaccination strategies are needed in this population. Methods Adult SOT recipients from 9 transplant clinics in Switzerland and Spain were enrolled if they were >3 months after transplantation. Patients were randomized (1:1:1) to a MF59-adjuvanted or a high-dose vaccine (intervention), or a standard vaccine (control), with stratification by organ and time from transplant. The primary outcome was vaccine response rate, defined as a ≥4-fold increase of hemagglutination-inhibition titers to at least 1 vaccine strain at 28 days postvaccination. Secondary outcomes included polymerase chain reaction–confirmed influenza and vaccine reactogenicity. Results A total of 619 patients were randomized, 616 received the assigned vaccines, and 598 had serum available for analysis of the primary endpoint (standard, n = 198; MF59-adjuvanted, n = 205; high-dose, n = 195 patients). Vaccine response rates were 42% (84/198) in the standard vaccine group, 60% (122/205) in the MF59-adjuvanted vaccine group, and 66% (129/195) in the high-dose vaccine group (difference in intervention vaccines vs standard vaccine, 0.20; 97.5% confidence interval [CI],.12–1); P <.001; difference in high-dose vs standard vaccine, 0.24 [95% CI,.16–1]; P <.001; difference in MF59-adjuvanted vs standard vaccine, 0.17 [97.5% CI,.08–1]; P <.001). Influenza occurred in 6% of the standard, 5% in the MF59-adjuvanted, and 7% in the high-dose vaccine groups. Vaccine-related adverse events occurred more frequently in the intervention vaccine groups, but most of the events were mild. Conclusions In SOT recipients, use of an MF59-adjuvanted or a high-dose influenza vaccine was safe and resulted in a higher vaccine response rate. Clinical Trials Registration Clinicaltrials.gov NCT03699839. [ABSTRACT FROM AUTHOR]

However, comparing p50 temporal changes between alive and dead patients, we observed a significant difference between late p50s, 23.0 ± 1.6 mmHg in alive patients vs. 33.2 ± 7.9 mmHg in deceased patients ( I p i < 0.01). Despite these correction factors, we found significant p50 temporal changes in critically ill COVID-19 patients with negative outcome, which we have analyzed and reported as an interesting mechanism never previously analyzed in critically ill COVID-19 patients (late p50s 23.0 ± 1.6 mmHg in alive patients vs. 33.1 ± 7.9 mmHg in dead patients, I p i < 0.01). Because we focused on the observation of p50 temporal changes in critical ill COVID-19 patients, we cannot speculate on the causes of these changes (especially in patients with negative outcome), which are remaining actually unknown. [Extracted from the article]

Background. Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients. Methods. Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes. Results. Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1B rs16944; P = .01 for DEFB1 rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor a secretion by PBMCs. Conclusions. Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification. [ABSTRACT FROM AUTHOR]

Background. We investigated the incidence and outcome of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV)-infected individuals before and after the introduction of combination antiretroviral therapy (cART) in 1996. Methods. From 1988 through 2007, 226 cases of PML were reported to the Swiss HIV Cohort Study. By chart review, we confirmed 186 cases and recorded all-cause and PML-attributable mortality. For the survival analysis, 25 patients with postmortem diagnosis and 2 without CD4+ T cell counts were excluded, leaving a total of 159 patients (89 before 1996 and 70 during 1996-2007). Results. The incidence rate of PML decreased from 0.24 cases per 100 patient-years (PY; 95% confidence interval [CI], 0.20-0.29 cases per 100 PY) before 1996 to 0.06 cases per 100 PY (95% CI, 0.04-0.10 cases per 100 PY) from 1996 onward. Patients who received a diagnosis before 1996 had a higher frequency of prior acquired immunodeficiency syndrome-defining conditions (P = .007) but similar CD4+ T cell counts (60 vs. 71 cells/μL; P = .25), compared with patients who received a diagnosis during 1996 or thereafter. The median time to PML-attributable death was 71 days (interquartile range, 44-140 days), compared with 90 days (interquartile range, 54-313 days) for all-cause mortality. The PML-attributable 1-year mortality rate decreased from 82.3 cases per 100 PY (95% CI, 58.8-115.1 cases per 100 PY) during the pre-cART era to 37.6 cases per 100 PY (95% CI, 23.4.-60.5 cases per 100 PY) during the cART era. In multivariate models, cART was the only factor associated with lower PML-attributable mortality (hazard ratio, 0.18; 95% CI, 0.07-0.50; P < .001), whereas all-cause mortality was associated with baseline CD4+ T cell count (hazard ratio per increase of 100 cells/μL, 0.52; 95% CI, 0.32-0.85; P = .010) and cART use (hazard ratio, 0.37; 95% CI, 0.19-0.75; P = .006). Conclusions. cART reduced the incidence and PML-attributable 1-year mortality, regardless of baseline CD4+ T cell count, whereas overall mortality was dependant on cART use and baseline CD4+ T cell count. [ABSTRACT FROM AUTHOR]

Patient information leaflets can reduce antibiotic prescription rates by improving knowledge and encouraging shared decision making (SDM) in patients with respiratory tract infections (RTI). The effect of these interventions in antibiotic low-prescriber settings is unknown. We conducted a pragmatic pre-/post interventional study between October 2022 and March 2023 in Swiss outpatient care. The intervention was the provision of patient leaflets informing about RTIs and antibiotics use. Main outcomes were the extent of SDM, antibiotic prescription rates, and patients' awareness/knowledge about antibiotic use in RTIs. 408 patients participated in the pre-intervention period, and 315 patients in the post- intervention period. There was no difference in the extent of SDM (mean score (range 0-100): 65.86 vs. 64.65, p = 0.565), nor in antibiotic prescription rates (no prescription: 89.8% vs. 87.2%, p = 0.465) between the periods. Overall awareness/knowledge among patients with RTI was high and leaflets showed only a small effect on overall awareness/knowledge. In conclusion, in an antibiotic low-prescriber setting, patient information leaflets may improve knowledge, but may not affect treatment decisions nor antibiotic prescription rates for RTIs., (© 2024. The Author(s).)

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain 1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting., (© 2023. The Author(s).)

COVID-19, a systemic multi-organ disease resulting from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is known to result in a wide array of disease outcomes, ranging from asymptomatic to fatal. Despite persistent progress, there is a continued need for more accurate determinants of disease outcomes, including post-acute symptoms after COVID-19. In this study, we characterised the serum metabolomic changes due to hospitalisation and COVID-19 disease progression by mapping the serum metabolomic trajectories of 71 newly hospitalised moderate and severe patients in their first week after hospitalisation. These 71 patients were spread out over three hospitals in Switzerland, enabling us to meta-analyse the metabolomic trajectories and filter consistently changing metabolites. Additionally, we investigated differential metabolite-metabolite trajectories between fatal, severe, and moderate disease outcomes to find prognostic markers of disease severity. We found drastic changes in serum metabolite concentrations for 448 out of the 901 metabolites. These results included markers of hospitalisation, such as environmental exposures, dietary changes, and altered drug administration, but also possible markers of physiological functioning, including carboxyethyl-GABA and fibrinopeptides, which might be prognostic for worsening lung injury. Possible markers of disease progression included altered urea cycle metabolites and metabolites of the tricarboxylic acid (TCA) cycle, indicating a SARS-CoV-2-induced reprogramming of the host metabolism. Glycerophosphorylcholine was identified as a potential marker of disease severity. Taken together, this study describes the metabolome-wide changes due to hospitalisation and COVID-19 disease progression. Moreover, we propose a wide range of novel potential biomarkers for monitoring COVID-19 disease course, both dependent and independent of the severity.

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential., (© 2023. The Author(s).)

Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2' site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization, and, similar to fp.006 and hr2.016, protects mice expressing human angiotensin-converting enzyme 2 against infection when present as a bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae, including SARS-CoV-2 variants.

Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity, and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month time frame. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both prefusion and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sublineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants., Competing Interests: R.M., J.B., C.S.-F., I.B., F.M., K.C., N.S., G.L., C.S., E.C., E.A.D.J., J.R.D., N.C., C.H.-D., A.T., A.A., H.W.V., A.L., D.C., and L.Pi. are or were employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. C.G. is an external scientific consultant to Humabs BioMed SA. The other authors declare no competing interests., (© 2022 The Authors.)