Laboratory specimen rejection rate and associated factors among referred specimens at Debre Markos Referral Hospital, Ethiopia: prospective cross-sectional study.

Introduction: laboratory errors mostly emerge from the pre-analytical phase, mainly those related to collection, handling, transportation, and storage of diagnostic specimens. Specimen rejection due to improper sample collection, may lead to poor patient outcomes, such as incorrect diagnosis, inappropriate treatment, and death. This study aimed to assess the specimen rejection rate and associated factors among referred specimens at Debre Markos Referral Hospital. Methods: a prospective cross-sectional study design was applied from January 2020 to April 2020 to investigate specimen rejection rate and associated factors among referred specimens. The study population was all laboratory specimens referred for viral load, CD4 count, gene expert, and early infant diagnosis to the Debre Markos Referral Hospital laboratory. The statistical analysis was done with Statistical Package for Social Sciences version 20.0 software. Results: of the total of 2750 specimens submitted to the laboratory from January 2020 to April 2020, 37 (1.34%) specimens were rejected due to different reasons like insufficient volume, hemolysis, and an inappropriate specimen container. Specimen collector training status and experience had a significant association with the specimen rejection rate. Conclusion: the results of our study show that the specimen rejection rate among referred specimens was high, indicating that more interventions are required to decrease the specimen rejection rate.

Weight change with antiretroviral switch from integrase inhibitor or tenofovir alafenamide-based to Doravirine-Based regimens in people with HIV.

BACKGROUND: Weight gain has been well-described with integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF). Doravirine (DOR) has been identified as a relatively "weight-neutral" drug; however, there is little data describing its effect on weight change in routine clinical practice. METHODS: We conducted a retrospective chart review of weight change among people with HIV changing from an INSTI- to a non-INSTI regimen with DOR. RESULTS: At the time of ART switch, among 49 people with HIV, the mean age was 47 years, 24% were female, and 75% had HIV-1 viral load <200 copies/mL. Most (55%) people with HIV were taking bictegravir/TAF/emtricitabine prior to the switch. Although 84% switched due to concerns about weight gain, only 16% had a weight gain of ≥10% in the year preceding, and 49% had no substantial change in weight. 86% switched to DOR/lamivudine/tenofovir disoproxil fumarate. A weight decrease (-2.6% [95% CI: -5.1, -0.1%, p = .041] was seen over the year following the ART switch. Weight change prior to switch was greatest in the year 2021 compared to 2019, 2020, and 2022. CONCLUSIONS: Overall, modest changes in weight were seen following ART switch from INSTI-based regimen to a DOR-based, non-INSTI regimen. Further investigations with larger people with HIV cohorts will be helpful to guide clinical practice, while the impact of the COVID-19 pandemic on weight change should also be considered.

Circulating metabolites are associated with persistent elevations of ALT in patients with chronic hepatitis B with complete viral suppression.

Hepatitis B virus (HBV) can be completely suppressed after antiviral treatment; however, some patients with chronic hepatitis B (CHB) exhibit elevated alanine aminotransferase (ALT) levels and sustained disease progression. This study provides novel insights into the mechanism and potential predictive biomarkers of persistently elevated ALT (PeALT) in patients with CHB after complete viral inhibition. Patients having CHB with undetectable HBV DNA at least 12 months after antiviral treatment were enrolled from a prospective, observational cohort. Patients with PeALT and persistently normal ALT (PnALT) were matched 1:1 using propensity score matching. Correlations between plasma metabolites and the risk of elevated ALT were examined using multivariate logistic regression. A mouse model of carbon tetrachloride-induced liver injury was established to validate the effect of key differential metabolites on liver injury. Of the 1238 patients with CHB who achieved complete viral suppression, 40 (3.23%) had PeALT levels during follow-up (median follow-up: 2.42 years). Additionally, 40 patients with PnALT levels were matched as controls. Ser-Phe-Ala, Lys-Ala-Leu-Glu, 3-methylhippuric acid, 3-methylxanthine, and 7-methylxanthine were identified as critical differential metabolites between the two groups and independently associated with PeALT risk. Ser-Phe-Ala and Lys-Ala-Leu-Glu levels could be used to discriminate patients with PeALT from those with PnALT. Furthermore, N-acetyl- l-methionine (NALM) demonstrated the strongest negative correlation with ALT levels. NALM supplementation alleviated liver injury and hepatic necrosis induced by carbon tetrachloride in mice. Changes in circulating metabolites may contribute to PeALT levels in patients with CHB who have achieved complete viral suppression after antiviral treatment.

Measles Infection Dose Responses: Insights from Mathematical Modeling.

How viral infections develop can change based on the number of viruses initially entering the body. The understanding of the impacts of infection doses remains incomplete, in part due to challenging constraints, and a lack of research. Gaining more insights is crucial regarding the measles virus (MV). The higher the MV infection dose, the earlier the peak of acute viremia, but the magnitude of the peak viremia remains almost constant. Measles is highly contagious, causes immunosuppression such as lymphopenia, and contributes substantially to childhood morbidity and mortality. This work investigated mechanisms underlying the observed wild-type measles infection dose responses in cynomolgus monkeys. We fitted longitudinal data on viremia using maximum likelihood estimation, and used the Akaike Information Criterion (AIC) to evaluate relevant biological hypotheses and their respective model parameterizations. The lowest AIC indicates a linear relationship between the infection dose, the initial viral load, and the initial number of activated MV-specific T cells. Early peak viremia is associated with high initial number of activated MV-specific T cells. Thus, when MV infection dose increases, the initial viremia and associated immune cell stimulation increase, and reduce the time it takes for T cell killing to be sufficient, thereby allowing dose-independent peaks for viremia, MV-specific T cells, and lymphocyte depletion. Together, these results suggest that the development of measles depends on virus-host interactions at the start and the efficiency of viral control by cellular immunity. These relationships are additional motivations for prevention, vaccination, and early treatment for measles.

Serum cytokine dysregulation signatures associated with COVID-19 outcomes in high mortality intensive care unit cohorts across pandemic waves and variants.

The aim of this study was to characterize the systemic cytokine signature of critically ill COVID-19 patients in a high mortality setting aiming to identify biomarkers of severity, and to explore their associations with viral loads and clinical characteristics. We studied two COVID-19 critically ill patient cohorts from a referral centre located in Central Europe. The cohorts were recruited during the pre-alpha/alpha (November 2020 to April 2021) and delta (end of 2021) period respectively. We determined both the serum and bronchoalveolar SARS-CoV-2 viral load and identified the variant of concern (VoC) involved. Using a cytokine multiplex assay, we quantified systemic cytokine concentrations and analyzed their relationship with clinical findings, routine laboratory workup and pulmonary function data obtained during the ICU stay. Patients who did not survive had a significantly higher systemic and pulmonary viral load. Patients infected with the pre-alpha VoC showed a significantly lower viral load in comparison to those infected with the alpha- and delta-variants. Levels of systemic CTACK, M-CSF and IL-18 were significantly higher in non-survivors in comparison to survivors. CTACK correlated directly with APACHE II scores. We observed differences in lung compliance and the association between cytokine levels and pulmonary function, dependent on the VoC identified. An intra-cytokine analysis revealed a loss of correlation in the non-survival group in comparison to survivors in both cohorts. Critically ill COVID-19 patients exhibited a distinct systemic cytokine profile based on their survival outcomes. CTACK, M-CSF and IL-18 were identified as mortality-associated analytes independently of the VoC involved. The Intra-cytokine correlation analysis suggested the potential role of a dysregulated systemic network of inflammatory mediators in severe COVID-19 mortality.

Lower HBV DNA level is associated with more severe liver fibrosis in HBeAg-positive chronic hepatitis B with normal alanine transaminase.

BACKGROUND: The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored the association between liver fibrosis and HBV DNA levels in HBeAg-positive CHB patients with normal alanine transaminase (ALT) with relatively high HBV DNA. METHODS: Six hundred and twenty-two HBeAg-positive CHB patients with normal ALT were included. Patients were divided into three categories: low (6 log10 IU/mL ≤ HBV DNA < 7 log10 IU/mL), moderate (7 log10 IU/mL ≤ HBV DNA < 8 log10 IU/mL), and high (HBV DNA ≥ 8 log10 IU/mL). APRI, FIB-4, transient elastography, or liver biopsy were used to assess liver fibrosis. RESULTS: The median age of patients was 33.0 years and 57.9% patients were male. 18.8%, 52.1%, and 29.1% of patients had low, moderate, and high HBV DNA levels, respectively. The APRI (0.33 vs. 0.26 vs. 0.26, P < 0.001), FIB-4 (1.03 vs. 0.71 vs. 0.68, P < 0.001), and LSM values (7.6 kPa vs. 5.6 kPa vs. 5.5 kPa, P = 0.086) were higher in low HBV DNA group than other two groups. Low HBV DNA group had higher proportions of significant fibrosis (24.8% vs. 9.9% vs. 3.3%, P < 0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P = 0.004) than moderate and high HBV DNA groups. Moderate (OR 3.095, P = 0.023) and low (OR 4.968, P = 0.003) HBV DNA were independent risk factors of significant fibrosis. CONCLUSION: Lower HBV DNA level was associated with more severe liver fibrosis in HBeAg-positive CHB patients with ALT.

Time to SARS-CoV-2 clearance in African, Caucasian, and Asian ethnic groups.

BACKGROUND: COVID-19 may become a seasonal disease. SARS-CoV-2 active circulation coupled with vaccination efforts has undoubtedly modified the virus dynamic. It is therefore important investigate SARS-CoV-2 dynamic in different groups of population following the course of spatiotemporal variance and immunization. METHODS: To investigate SARS-CoV-2 clearance in different ethnic groups and the impact of immunization, we recruited 777 SARS-CoV-2-positive patients (570 Africans, 156 Caucasians, and 51 Asians). Participants were followed and regularly tested for 2 months until they had two negative tests. RESULTS: The vaccination rate was 64.6%. African individuals were less symptomatic (2%), Caucasians (41%) and Asians (36.6%). On average, viral clearance occurred after 10.5 days. Viral load at diagnosis was inversely correlated with viral clearance (p < 0.0001). The time of SARS-CoV-2 clearance was higher in Africans and Caucasians than in Asians (Dunn's test p < 0.0001 and p < 0.05, respectively). On average, viral clearance occurred within 9.5 days during the second semester (higher rate of vaccination and SARS-CoV-2 exposition), whereas it took 13.6 days during the first semester (lower rate of vaccination and SARS-CoV-2 exposition) (Mann-Whitney t-test p < 0.0001). CONCLUSION: In conclusion, ethnicity and spatiotemporal changes including SARS-CoV-2 exposition and immunization affect SARS-CoV-2 clearance.

Thermostable vacuum foam dried Newcastle disease vaccine: Process optimization and pilot-scale study.

Vacuum foam drying (VFD) has been shown to improve the thermostability and long-term shelf life of Newcastle Disease Virus (NDV). This study optimized the VFD process to improve the shelf life of NDV at laboratory-scale and then tested the optimized conditions at pilot-scale. The optimal NDV to T5 formulation ratio was determined to be 1:1 or 3:2. Using the 1:1 virus to formulation ratio, the optimal filling volumes were determined to be 13-17% of the vial capacity. The optimized VFD process conditions were determined to be at a shelf temperature of 25℃ with a minimum overall drying time of 44 h. The vaccine samples prepared using these optimized conditions at laboratory-scale exhibited virus titer losses of ≤ 1.0 log10 with residual moisture content (RMC) below 3%. Furthermore, these samples were transported for 97 days around China at ambient temperature without significant titer loss, thus demonstrating the thermostability of the NDV-VFD vaccine. Pilot-scale testing of the NDV-VFD vaccine at optimized conditions showed promising results for up-scaling the process as the RMC was below 3%. However, the virus titer loss was slightly above 1.0 log10 (approximately 1.1 log10). Therefore, the NDV-VFD process requires further optimization at pilot scale to obtain a titer loss of ≤ 1.0 log10. Results from this study provide important guidance for possible industrialization of NDV-VFD vaccine in the future. KEY POINTS: • The process optimization and scale-up test of thermostable NDV vaccine prepared through VFD is reported for the first time in this study. • The live attenuated NDV-VFD vaccine maintained thermostability for 97 days during long distance transportation in summer without cold chain conditions. • The optimized NDV-VFD vaccine preparations evaluated at pilot-scale maintained acceptable levels of infectivity after preservation at 37℃ for 90 days, which demonstrated the feasibility of the vaccine for industrialization.

The impact of immunosuppression on the mortality and hospitalization of Monkeypox: a systematic review and meta-analysis of the 2022 outbreak.

BACKGROUND: Limited data is available regarding the severity and mortality of Mpox in individuals with immunocompromised conditions. Therefore, we performed this meta-analysis to understand the impact of HIV- or non-HIV-associated immunosuppression on the severity of Mpox requiring hospitalization and mortality. METHODS: A thorough literature search was performed from 2022 up to January 2024. The results were presented as odds ratios (ORs). We only included patients who required hospitalization for severity rather than isolation. RESULTS: A total of 34 studies were included in this analysis. Our analysis did not find a significant difference in the hospitalization risk between HIV-positive individuals and those who were HIV-negative (OR = 1.03; P = 0.85; 7 studies; CD4 count of fewer than 200 cells/µL was less than 0.5% across all studies). Patients with a CD4 count lower than 200 cells/µL or an unsuppressed RNA viral load (> 200 copies/ml) had a significantly higher hospitalization risk (OR = 5.3, P < 0.001) and (OR = 3, P < 0.001), respectively. Most of the reported deaths were reported in patients with HIV with CD4 counts below 200 cells/µL, with some fatal cases occurring in non-HIV immunosuppressed patients, particularly organ transplant recipients. Based on the autopsy findings, Mpox was confirmed in multiple organs, particularly the digestive tract, lung, and testes. Furthermore, some studies documented cases of death that were suspected to be related to hemophagocytic lymphohistiocytosis (HLH) and immune reconstitution inflammatory syndrome (IRIS). Most of the death reports showed concomitant non-Mpox infections at the time of hospitalization and death CONCLUSIONS: Our finding shows that Mpox acts as an opportunistic pathogen in immunocompromised individuals. These individuals should be prioritized for early care and closely monitored for signs of deteriorating clinical conditions. Clinical manifestations and autopsy findings strongly suggest Mpox dissemination to multiple organs, particularly the digestive tract, and lungs. However, the presence of concomitant non-Mpox infections complicates the assessment of the attribution of Mpox to death. Caution should be exercised when interpreting data suggesting poorer outcomes in individuals with non-HIV immunosuppression, as current evidence is scarce and further research is needed.

Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2.

In the wake of the COVID-19 pandemic caused by SARS-CoV-2, questions emerged about the potential effects of Bacillus Calmette-Guérin (BCG) vaccine on the immune response to SARS-CoV-2 infection, including the neurodegenerative diseases it may contribute to. To explore this, an experimental study was carried out in BCG-stimulated and non-stimulated k18-hACE2 mice challenged with SARS-CoV-2. Viral loads in tissues determined by RT-qPCR, histopathology in brain and lungs, immunohistochemical study in brain (IHC) as well as mortality rates, clinical signs and plasma inflammatory and coagulation biomarkers were assessed. Our results showed BCG-SARS-CoV-2 challenged mice presented higher viral loads in the brain and an increased frequency of neuroinvasion, with the greatest differences observed between groups at 3-4 days post-infection (dpi). Histopathological examination showed a higher severity of brain lesions in BCG-SARS-CoV-2 challenged mice, mainly consisting of neuroinflammation, increased glial cell population and neuronal degeneration, from 5 dpi onwards. This group also presented higher interstitial pneumonia and vascular thrombosis in lungs (3-4 dpi), BCG-SARS-CoV-2 mice showed higher values for TNF-α and D-dimer values, while iNOS values were higher in SARS-CoV-2 mice at 3-4 dpi. Results presented in this study indicate that BCG stimulation could have intensified the inflammatory and neurodegenerative lesions promoting virus neuroinvasion and dissemination in this experimental model. Although k18-hACE2 mice show higher hACE2 expression and neurodissemination, this study suggests that, although the benefits of BCG on enhancing heterologous protection against pathogens and tumour cells have been broadly demonstrated, potential adverse outcomes due to the non-specific effects of BCG should be considered.

The question of screening organ donors for hepatitis e virus: a case report of transmission by kidney transplantation in France and a review of the literature.

BACKGROUND: Hepatitis E is a potentially serious infection in organ recipients, with an estimated two-thirds of cases becoming chronic, and with a subsequent risk of cirrhosis and death. In Europe, transmission occurs most often through the consumption of raw or undercooked pork, more rarely through blood transfusion, but also after solid organ transplantation. Here we describe a case of Hepatitis E virus (HEV) infection transmitted following kidney transplantation and review the literature describing cases of HEV infection transmitted by solid organ transplantation. CASE PRESENTATION: Three weeks after kidney transplantation, the patient presented with an isolated minimal increase in GGT and hepatic cytolysis 6 months later, leading to the diagnosis of genotype 3c hepatitis E, with a plasma viral load of 6.5 log10IU/mL. In retrospect, HEV RNA was detected in the patient's serum from the onset of hepatitis, and in the donor's serum on the day of donation, with 100% identity between the viral sequences, confirming donor-derived HEV infection. Hepatitis E had a chronic course, was treated by ribavirin, and relapsed 10 months after the end of treatment. DISCUSSION: Seven cases of transmission of HEV by solid organ transplantation have been described since 2012 without systematic screening for donors, all diagnosed at the chronic infection stage; two patients died. HEV organ donor transmission may be underestimated and there is insufficient focus on immunocompromised patients in whom mild liver function test impairment is potentially related to hepatitis E. However, since HEV infection is potentially severe in these patients, and as evidence accumulates, we believe that systematic screening of organ donors should be implemented for deceased and living donors regardless of liver function abnormalities, as is already the case in the UK and Spain. In January 2024, the French regulatory agency of transplantation has implemented mandatory screening of organ donors for HEV RNA.

Human papillomavirus in women infected with human immunodeficiency virus: association with viral load and lymphocyte count.

Women living with human immunodeficiency virus are at an increased risk of developing cancers related to human papillomavirus (HPV). Thus, it is important to combine clinical assessments, serological screening, and HPV data for planning prevention policies. This study aimed to identify HPV and its specific types in the cervical, anal, and oral mucosa of HIV-seropositive women, associating it with viral load and lymphocyte count. Sociodemographic characteristics, health data (CD4+ and CD8+ T cell counts and viral load), and biological samples (cervical, anal, and oral) were collected from 86 HIV-positive women undergoing antiretroviral therapy. Data were classified according to the presence or absence of HPV-DNA, HPV-DNA presence at one or more anatomic sites, and level of oncogenic risk, considering low- and high-risk oncogenic HPV-DNA groups. The presence of HPV in the cervicovaginal site was 65.9%, 63.8% in anal canal, and 4.2% in oral mucosa. A viral load ≥75 HIV copies/mL was associated with the presence of HPV-DNA. There was an association between viral load and the low-risk HPV or high-risk HPV groups. We found a high prevalence of HPV infection in HIV-seropositive women, particularly in the cervical and anal mucosa, with viral load ≥75 HIV copies/mL being associated with HPV-DNA presence.

MPXV DNA kinetics in bloodstream and other body fluids samples.

Since spring 2022, the global epidemiology of the monkeypox virus (MPXV) has changed. The unprecedented increase of human clade II MPXV cases worldwide heightened concerns about this emerging zoonotic disease. We analysed the positivity rates, viral loads, infectiousness, and persistence of MPXV DNA for up to 4 months in several biological samples from 89 MPXV-confirmed cases. Our data showed that viral loads and positivity rates were higher during the first two weeks of symptoms for all sample types. Amongst no-skin-samples, respiratory specimens showed higher MPXV DNA levels and median time until viral clearance, suggesting their usefulness in supporting MPXV diagnosis, investigating asymptomatic patients, and monitoring viral shedding. Infectious virus was cultured from respiratory samples, semen, and stools, with high viral loads and collected within the first 10 days. Notably, only one saliva and one semen were found positive for viral DNA after 71 and 31 days from symptoms, respectively. The focus on bloodstream samples showed the best testing sensitivity in plasma, reporting the overall highest MPXV DNA detection rate and viral loads during the 3-week follow-up as compared to serum and whole-blood. The data here presented can be useful for MPXV diagnostics and a better understanding of the potential alternative routes of its onward transmission.

A comparative analysis of clinical outcomes between conversion to mTOR inhibitor and calcineurin inhibitor reduction in managing BK viremia among kidney transplant patients.

BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols adds to the complexity of managing this condition. This study aimed to compare the two treatment approaches. The study population consisted of patients who underwent kidney transplantation between January 2016 and June 2020 at two tertiary hospitals in Korea. Patients diagnosed with BK viremia were evaluated based on their initial viral load and the treatment methods. The 'Reduction group' involved dose reduction of tacrolimus while the 'Conversion group' included tacrolimus discontinuation and conversion to sirolimus. A total of 175 patients with an initial viral load (iVL) ≥ 3 on the log10 scale were evaluated within two iVL intervals (3-4 and 4-5). In the iVL 4-5 interval, the Reduction group showed potential effectiveness in terms of viral clearance without statistically significant differences. However, within the iVL 3-4 interval, the Reduction group demonstrated superior viral clearance and a lower incidence of biopsy-proven acute rejection (BPAR) than the Conversion group. The renal function over 12 months after BKV diagnosis showed no statistically significant difference. Reducing tacrolimus compared to converting to mTORi would be a more appropriate treatment approach for BK viral clearance in kidney transplantation. Further research is warranted in a large cohort of patients.

Viral load non-suppression status among women exposed to Dolutegravir-based versus Efavirenz-based regimens in Ethiopia: A before-and-after study.

BACKGROUND: High viral load during pregnancy and breastfeeding period is the risk factor for vertical transmission of human immunodeficiency virus (HIV). Currently, Dolutegravir (DTG)-based regimens are recommended to attain adequate viral load suppression (VLS) among women. However, its effect on VLS has not been investigated among women in PMTCT care in Ethiopia. OBJECTIVE: This study aimed to investigate the rate of viral load non-suppression among women exposed to DTG-based versus Efavirenz (EFV)-based regimens in Ethiopia. METHODS: An uncontrolled before-and-after study design was conducted among 924 women (462 on EFV-based and 462 on DTG-based regimens) enrolled in PMTCT care from September 2015 to February 2023. The outcome variable was the viral load (VL) non-suppression among women on PMTCT care. A modified Poisson regression model was employed, and the proportion was computed to compare the rate of VL non-suppression in both groups. The risk ratio (RR) with a 95% confidence interval (CI) was calculated to assess viral load non-suppression among women on DTG-based and EFV-based regimens by adjusting for other variables. RESULTS: The overall rate of non-suppressed VL was 16.2% (95% CI: 14.0-18.8%). Mothers on DTG-based regimens had approximately a 30% (adjusted risk ratio (aRR): 0.70; 95% CI: 0.52-0.94) lesser risk of developing non-suppressed VL than women on EFV-based regimens. Besides, older women were 1.38 times (aRR: 1.38; 95% CI: 1.04-1.83); mothers who did not disclose their HIV status to their partners were 2.54 times (aRR: 2.54; 95% CI: 1.91-3.38); and mothers who had poor or fair adherence to antiretroviral (ARV) drugs were 2.11 times (aRR: 2.11; 95% CI: 1.45-3.07) at higher risk of non-suppressed VL. CONCLUSION: Women on DTG-based regimens had a significantly suppressed VL compared to those on EFV-based regimens. Thus, administering DTG-based first-line ART regimens should be strengthened to achieve global and national targets on VLS.

Long-term safety and impact of immune recovery in heavily treatment-experienced adults receiving fostemsavir for up to 5 years in the phase 3 BRIGHTE study.

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

Proof of infectivity of hepatitis E virus particles from the ejaculate of chronically infected patients.

Recently, hepatitis E virus (HEV, Paslahepevirus balayani) particles were detected for the first time in the ejaculate of two chronically infected patients. Since then, we have been able to detect HEV in ejaculate in five further patients, and thus in a total of seven out of nine (78%) chronically infected men (age 36-67 years, median 56 years). In five patients, the HEV RNA concentration was more than 100-fold higher compared to the serum, while in two patients, the viral load was more than 10-fold lower. However, it has remained unclear whether viral particles shed in the ejaculate were infectious, as a previous cell culture model had failed to demonstrate the infectivity. In the current study, we employed an optimized HEV cell culture system based on overconfluent PLC/PRF/5 cells to investigate the infectivity of HEV particles from ejaculate and other body fluids. With this approach, we were able to show for the first time that HEV particles in the ejaculate from several patients were infectious. HEV replicated to high viral loads of 1e9 HEV RNA copies per ml. This indicates that HEV-positive ejaculate could bear a risk of infection for sexual partners.

A novel within-host model of HIV and nutrition.

In this paper we develop a four compartment within-host model of nutrition and HIV. We show that the model has two equilibria: an infection-free equilibrium and infection equilibrium. The infection free equilibrium is locally asymptotically stable when the basic reproduction number $ \mathcal{R}_0 < 1 $, and unstable when $ \mathcal{R}_0 > 1 $. The infection equilibrium is locally asymptotically stable if $ \mathcal{R}_0 > 1 $ and an additional condition holds. We show that the within-host model of HIV and nutrition is structured to reveal its parameters from the observations of viral load, CD4 cell count and total protein data. We then estimate the model parameters for these 3 data sets. We have also studied the practical identifiability of the model parameters by performing Monte Carlo simulations, and found that the rate of clearance of the virus by immunoglobulins is practically unidentifiable, and that the rest of the model parameters are only weakly identifiable given the experimental data. Furthermore, we have studied how the data frequency impacts the practical identifiability of model parameters.

[Detection rates and high concentration of herpesvirus (Orthoherpesviridae) DNA in autopsy materials from patients with COVID-19 fatal outcome].

INTRODUCTION: SARS-CoV-2 infection causes immune disorders that create conditions for the reactivation of human herpesviruses (HHVs). However, the estimates of the HHVs effect on the course and outcome of COVID-19 are ambiguous. Аim - to study the possible relationship between the HHV reactivation and the adverse outcome of COVID-19. MATERIALS AND METHODS: Postmortem samples from the brain, liver, spleen, lymph nodes and lungs were obtained from 59 patients treated at the Moscow Infectious Diseases Hospital No.1 in 2021-2023. The group 1 comprised 39 patients with fatal COVID-19; group 2 (comparison group) included 20 patients not infected with SARS-CoV-2 who died from various somatic diseases. HHV DNA and SARS-CoV-2 RNA were determined by PCR. RESULTS: HHV DNA was found in autopsy samples from all patients. In group 1, EBV was most often detected in lymph nodes (94%), HHV-6 in liver (68%), CMV in lymph nodes (18%), HSV in brain (16%), VZV in lung and spleen (3% each). The detection rates of HHVs in both groups was similar. Important differences were found in viral load. In patients with COVID-19, the number of samples containing more than 1,000 copies of HHV DNA per 100,000 cells was 52.4%, in the comparison group - 16.6% (p < 0.002). An association has been established between the reactivation of HSV and HHV-6 and the severity of lung damage. Reactivation of EBV correlated with increased levels of liver enzymes. CONCLUSION: Reactivation of HHVs in patients with fatal COVID-19 was associated with severe lung and liver damages, which indicates a link between HHV reactivation and COVID-19 deaths.

Potential for high dynamic range Sedia Limiting Antigen antibody assay to support viral load monitoring during antiretroviral therapy.

INTRODUCTION: Viral Load (VL) monitoring is a crucial component of patient care during antiretroviral therapy (ART) but is not routinely available in many resource-constrained settings, where millions of patients will require care for decades to come. We hypothesise a serologic 'recent infection' test (Sedia LAg assay) which has a high dynamic range for detecting antigen-driven antibody response can provide informative proxies for VL trajectories. METHODS: A retrospective study where we analysed data linked via specimens in a well-described repository for recent infection test benchmarking (CEPHIA collaboration). Patient panels were comprised of 1) observations straddling ART start; 2) observations from a period of stable viral suppression; 3) observations straddling rebound after a period of viral suppression. We analysed an individual's Sedia LAg ELISA normalised optical density (ODn) trends within these categories. Using groups 2) and 3) we evaluated the specificity and sensitivity of a proposed proxy for "the latest observation is at a time of VL rebound"; proxy was defined as follows: we estimated patient-specific mean-previous-ODn for all observations with at least two preceding virally suppressed observations. We considered various thresholds to define both "VL suppression" and "ODn uptick". RESULTS: In regression analysis by category: 1) ODn gradients are statistically significantly negative just after ART-start (p = 0.010); 2) During periods of stable viral suppression, ODn tended to decline, but not statistically significantly, for a range of clinically meaningful "VL suppression" thresholds; 3) comparing ODn values just before, versus at, "VL rebound", ODn changes were statistically significantly increasing at rebound (p = 0.001). In the analysis comparing groups 2) and 3), at a Z score threshold of 0.8, the proposed proxy for a first viral rebound had an observed specificity and sensitivity both close to 90%. CONCLUSION: The high dynamic range of serological tests previously investigated for defining 'recent infection' has potential, as demonstrated using the Sedia LAg ELISA, to provide meaningful information about the success of ART, during treatment initiation, at times of stable suppression, and to flag possible viral rebound. It should be investigated how this can be combined with patient management workflows and (clinical and) other data, to provide efficiencies in long-term monitoring viral control in resource-limited settings.