Detectable Viremia Research Articles

A vaccine candidate based on baculovirus displaying chikungunya virus E1-E2 envelope confers protection against challenge in mice.

Chikungunya fever is a re-emerging mosquito-borne disease caused by the chikungunya virus (CHIKV) and produces acute arthritis that can progress to chronic disease with arthralgia. The first approved live-attenuated chikungunya vaccine has only recently become available for use in humans in the USA, but the access in endemic regions remains unmet. Here, we exploited the baculovirus display technology to develop a vectored vaccine candidate that exposes the CHIKV membrane proteins E1 and E2 on the baculovirus surface. Using recombinant baculovirus as vector vaccines has both productive and regulatory advantages: they are safe for handling and easy to produce in high titers and are non-pathogenic and non-replicative in mammals but have strong adjuvant properties by inducing humoral and cellular immune responses. CHIKV E1 and E2 envelope proteins with their own signal and transmembrane sequences were expressed on the surface of budded baculovirus virions. Immunization of C57BL/6 mice with non-adjuvanted recombinant baculovirus induced IgG antibodies against E2 with a predominant IgG2c subtype, neutralizing antibodies and a specific IFN-γ CD8+ T-cell response. Immunization with a second dose significantly boosted the antibody response, and mice immunized with two doses of the vaccine candidate were completely protected against challenge with CHIKV showing no detectable viremia or signs of disease. Altogether, baculovirus display of CHIKV envelope proteins served as an efficient vaccine platform against CHIKV.IMPORTANCEThe global spread of chikungunya virus (CHIKV) has disproportionately impacted the Americas that experienced a fourfold increase in 2023 in cases and deaths compared with the same period in 2022. The disease is characterized by acute fever and debilitating joint pain that can become chronic. Despite the socioeconomic burden related to the high morbidity rates of CHIKV infection, a vaccine for CHIKV is currently approved only in the USA. Vaccines are the most effective preventive measure against viral diseases, and advances in the development of different vaccine platforms such as nucleic acids and viral vectors have prompted the rapid deployment of vaccines to contain the COVID-19 pandemic. Here, we report the use of baculovirus display as a strategy for the design of a novel vaccine that provides sterilizing immunity in a mouse model of chikungunya disease. Our results encourage further research regarding the potential of baculovirus as platforms for human vaccine design.

Case series of two persons living with HIV with detectable viral loads initiated then suppressed on cabotegravir/rilpivirine with lenacapavir.

Long-acting (LA) cabotegravir/rilpivirine (CAB/RPV) is primarily prescribed for virologically suppressed persons living with HIV (PLWH). Patients experiencing pill dysphagia or profound adherence challenges were excluded from the phase 3 studies, but recent reports demonstrate successful treatment in PWLH with baseline viremia. We describe two PLWH with detectable viral loads (VL) with multidrug resistance mutations. They were unable to sustain virologic suppression on oral therapy with historical poor adherence and dysphagia. Initiation of intramuscular CAB/RPV with subcutaneous lenacapavir (LEN) injections was necessary with baseline resistance. Due to anorexia and a low muscle mass, one patient received CAB/RPV injections in the vastus lateralis rather than the gluteal muscle with a 67-day delay between injections three and four due to health challenges. Both achieved viral suppression on monthly CAB/RPV with LEN. A return to health with a BMI increase from <14kg/m2 to almost 17kg/m2 resulted in the second patient. Injectable LA ART (CAB/RPV + LEN) in PLWH with detectable viremia results in sustained virologic suppression and a return to health and should now be considered a novel option for MDR patients with an inability to adhere to oral regimens.

Virological History Predicts Non-sustained Viral Suppression With Long-Acting Cabotegravir and Rilpivirine Therapy, Independent of Pharmacokinetic Parameters

Abstract Background This study aimed to investigate factors contributing to non-sustained viral suppression, including intermittent viremia and persistent low-level viremia, during cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) injectable therapy, with a focus on pharmacokinetics (PK). Methods A prospective cohort study was conducted on people with human immunodeficiency virus (HIV, PWH) transitioning from stable oral antiretroviral therapy (ART) to bimonthly CAB + RPV LA. Standardized follow-up included close monitoring through blood sampling for plasma human immunodeficiency virus type 1 (HIV-1) viral load (VL) and multiple plasma drug concentrations measurements to analyze the connection between PK parameters and virologic outcomes. Results Among 173 patients with a median (interquartile range [IQR]) follow-up of 11.1(7.1–13.2) months and 789 pre-dose measurements, 38.7% experienced VL ≥ 20 copies/mL, and 16.2% had levels ≥50 copies/mL. Intermittent viremia occurred in 34.7% of patients, and persistent low-level viremia in 4%. Virological failure developed in 2 cases. Predictors of non-sustained viral suppression included VL at HIV diagnosis (adjusted hazard ratio [AHR]: 1.49 per log10 VL, 95% confidence interval [CI]: 1.04–2.12, P = .027), detectable viremia on oral ART (AHR: 2.45, 95% CI: 1.29–4.65, P = .006), and the level of viral suppression at transition (AHR: 0.38, 95% CI: .19–.75, P = .004). We found a significant association between low trough concentrations of CAB and RPV and episodes of detectable viremia exceeding 50 copies/mL. However, none of the assessed PK covariates predicted non-sustained viral suppression in multivariable models. Conclusions Non-sustained viral suppression in PWH transitioning from stable oral ART to CAB + RPV LA was linked to preexisting factors before transition. Higher VL pre-ART and incomplete suppression on oral therapy increased the risk, independent of PK parameters.

Hepatitis C virus detection in hospital emergency departments.

The prevalence of active hepatitis C virus (HCV) infection is higher in hospital emergency departments (EDs) than in the general population. Numerous patients who seek emergency care are unaware that they have detectable viremia, yet they fall outside established ED protocols for HCV screening. Often they belong to groups with difficult access to health care who use the ED as their point of entry to the system. The aim of this consensus paper was to develop an approach to guide ED detection of HCV infection in all Spanish hospitals. Experts from the Spanish Society of Emergency Medicine (SEMES), the Spanish Association for Study of the Liver (AEEH), and the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) met to establish criteria to guide health care professionals' decisions. The experts' review of the literature and discussion in consensus-building meetings resulted in evidence-based recommendations that consider the following aspects: 1) the population to target for HCV screening in the ED, 2) how to inform patients of the process, 3) how to carry out HCV screening, 4) how to order an HCV test, and 5) additional issues such as bundling HCV with other viral tests for comprehensive diagnosis, recording results in medical records, and implementing ways to retain and follow all patients with positive results. This consensus report provides guidelines and tools to facilitate emergency physicians' work and ensure effective detection of HCV infections and subsequent incorporation of patients into the health care system.

The EEHV1A gH/gL complex elicits humoral and cell-mediated immune responses in mice

Elephant endotheliotropic herpesvirus (EEHV) causes lethal hemorrhagic disease (HD) in Asian and African elephants. Although rapid detection of viremia and supportive treatments may improve survival rates, an effective vaccine would mitigate the devastating effects of this virus. In elephants, chronic infection with EEHV leads to adaptive immunity against glycoproteins gB and gH/gL, the core entry machinery for most herpesviruses. We previously evaluated two EEHV gB vaccines in mice but not a gH/gL vaccine. Here, we found that inoculation of mice with an adjuvanted EEHV gH/gL subunit vaccine induced a significant antibody response that was similar to the response observed in elephants chronically infected with EEHV. Moreover, the gH/gL heterodimer elicited polyfunctional T cells with a Th1 phenotype but no detectable Th2 response. These results suggest that gH/gL, possibly in combination with gB, may be suitable immunogens for a vaccine comprising herpesvirus glycoproteins that are known to mediate cell entry and infection.

Preclinical Safety Assessment of the EBS-LASV Vaccine Candidate against Lassa Fever Virus.

There are currently no prophylactic vaccines licensed to protect against Lassa fever caused by Lassa virus (LASV) infection. The Emergent BioSolutions (EBS) vaccine candidate, EBS-LASV, is being developed for the prevention of Lassa fever. EBS-LASV is a live-attenuated recombinant Vesicular Stomatitis Virus (rVSV)-vectored vaccine encoding the surface glycoprotein complex (GPC) from LASV and has two attenuating vector modifications: a gene shuffle of the VSV N gene and a deletion of the VSV G gene. Preclinical studies were performed to evaluate EBS-LASV's neurovirulence potential following intracranial (IC) injection and to determine the biodistribution and vector replication following intramuscular (IM) inoculation in mice. In addition, the potential EBS-LASV toxicity was assessed using repeated-dose IM EBS-LASV administration to rabbits. All mice receiving the IC injection of EBS-LASV survived, while mice administered the unattenuated control vector did not. The vaccine was only detected in the muscle at the injection site, draining lymph nodes, and the spleen over the first week following IM EBS-LASV injection in mice, with no detectable plasma viremia. No toxicity was observed in rabbits receiving a three-dose regimen of EBS-LASV. These studies demonstrate that EBS-LASV is safe when administered to animals and supported a first-in-human dose-escalation, safety, and immunogenicity clinical study.

Longitudinal viral load outcomes of adults with HIV after detectable viremia on tenofovir, lamivudine, and dolutegravir.

To inform optimal management of HIV viremia on tenofovir, lamivudine, and dolutegravir (TLD), we examined viral load (VL) outcomes of a large cohort of adult PWH on TLD in Nigeria. We conducted a retrospective study of adult PWH who had ≥1 VL after initiating TLD during January 2017-February 2023. VLs were categorized as undetectable (≤50 copies/ml), low low-level viremia (LLV, 51-199 copies/ml), high LLV (200-999 copies/ml), virologic nonsuppression (VLNS, ≥1000 copies/ml), and virologic failure (VF, ≥2 consecutive VLNS results). Among patients with ≥2 VLs on TLD, we described how viremia changed over time and examined virologic outcomes after VF. We identified predictors of subsequent VLNS using mixed-effects logistic regression and conducted planned contrasts between levels of VL result and regimen types. Analysis of 82,984 VL pairs from 47,531 patients demonstrated viral resuppression to ≤50 copies/ml at follow-up VL in 66.7% of those with initial low LLV, 59.1% of those with initial high LLV, and 48.9% of those with initial VLNS. Of 662 patients with a follow-up VL after VF, 94.6% stayed on TLD; of which 57.8% (359/621) were undetectable at next VL without regimen change. Previous low LLV [adjusted odds ratio (aOR) 1.74, 1.56-1.93], high LLV (aOR 2.35, 2.08-2.65), and VLNS (aOR 6.45, 5.81-7.16) were associated with increasingly higher odds of subsequent VLNS, whereas a previously undetectable VL (aOR 1.08, 0.99-1.71) on TLD was not. Despite increased odds of subsequent VLNS, most PWH with detectable viremia on TLD, including those with VF, will resuppress to an undetectable VL without a regimen change.

18F]FDG PET and CT findings at therapy completion of pulmonary tuberculosis: comparison between HIV-positive and HIV-negative patients and impact on treatment response assessment

Abstract Background [18F]FDG-PET/CT is a sensitive non-invasive tool for assessing treatment response in patients with pulmonary tuberculosis. The data on the performance of [18F]FDG-PET/CT for response assessment among patients infected with the human immunodeficiency virus (HIV) is limited. Here, we investigated the differences between PET and CT lung findings on end-of-treatment [18F]FDG-PET/CT among HIV-positive versus HIV-negative patients who completed anti-tuberculous therapy for pulmonary tuberculosis. Methods Patients who completed anti-tuberculous therapy for pulmonary tuberculosis and declared cured based on negative clinical and laboratory assessments for active pulmonary tuberculosis were prospectively recruited to undergo [18F]FDG-PET/CT. Patients were classified as having residual metabolic activity if PET metabolic activity was demonstrated in the lung parenchyma or complete metabolic response if there was no abnormally increased [18F]FDG avidity in the lungs and compared the CT features. We identified 10 CT lung changes, five were associated with active pulmonary tuberculosis (nodules, micronodules in tree-in-bud pattern, consolidation, pleural effusion, and [18F]FDG-avid mediastinal/hilar lymphadenopathy) and the rest were associated with inactive sequelae of prior pulmonary tuberculosis (cysts, cavities, fibrosis, bronchiectasis, and calcifications and compared their incidence between HIV-positive and HIV-negative patients. Results Seventy-five patients were included with a mean age of 36.09 ± 10.49 years. There were fifty HIV-positive patients, all of whom were on antiretroviral therapy and with a median CD4 + T-cell of 255 cells/µL (IQR: 147–488). Fifteen HIV-positive patients had detectable HIV viremia with a median viral load of 12,497 copies/mL (IQR: 158–38,841). There was a significant difference in the incidence of residual metabolic activity and complete metabolic response between HIV-positive and HIV-negative patients. (P = 0.003) HIV-positive patients were more likely to have [18F]FDG-avid lymphadenopathy and HIV-negative patients had a higher incidence of cystic lung changes. The pattern of CT lung changes was otherwise not different between HIV-positive and HIV-negative patients. (P &gt; 0.05) Conclusions The incidence of residual metabolic activity and complete metabolic response on end-of-treatment [18F]F-FDG-PET/CT are similar between HIV-positive and HIV-negative patients. The incidence of [18F]FDG-avid mediastinal/hilar lymphadenopathy is more prevalent among HIV-positive patients. The pattern of lung changes was largely similar between HIV-positive and HIV-negative patients, indicating that the presence of HIV coinfection may not influence the interpretation of end-of-treatment [18F]F-FDG-PET/CT obtained for pulmonary tuberculosis treatment response assessment.

#1654 Infectious complications after kidney transplantation: a retrospective study

Abstract Background and Aims Infection is a major cause of morbidity among kidney transplant recipients. Allograft rejection is a frequent cause of dysfunction and its treatment increases the risk for both common and opportunistic infections. Nevertheless, its exact impact on infection incidence and further worsening of allograft dysfunction is not fully known. We aimed to characterize the incidence, nature, and severity of infectious complications following kidney transplantation, their association with previous rejection and its impact on allograft function. Method This was a single center retrospective study covering all patients transplanted between July 2021 and June 2023 in a tertiary referral center. Demographic and clinical data were collected from patient records, including donor and patient features, graft function over time and occurrence of either infection or rejection. Logistic regressions were adjusted considering sex, age, blood type and presence of diabetes as independent variables. Results A total of 139 patients were considered, 49 (35.3%) were women and 90 (64.7%) were men. Mean age was 49.6 ± 13.0 years. Median follow-up time was 375 [194-596] days. The main cause of renal disease was diabetes (37 patients, 26.8%) and most patients (113; 81.9%) were on hemodialysis for a median vintage of 3 [2.3] years. Considering the 139 transplants performed, 113 (81.2%) were isolated kidney, 24 (17.4%) were simultaneous kidney-pancreas and 2 (1.4%) were simultaneous kidney-liver transplantation. Eleven (7.9%) were living donor. During follow-up time, in-hospital infection occurred in 34 (24.4%) patients, mostly urinary (13, 38%) and blood stream (11, 32%) infections. These events significantly delayed hospital discharge (15.88 ± 8.52 vs 26.05 ± 14.3 days, p-value=0.001). During the follow up, a total of 107 (77%) patients developed 220 infection episodes leading to 47 hospital admissions. Urinary infections (64, 28.8%) and cytomegalovirus (CMV) viremia (64, 28.8%) were the most common at median follow-up time of 85.5 [40.25-183.75] and 159 [43.25-258.5] days, respectively. Median timing of diagnosis was 400.8 [203-614] days after transplant. They were much more common during the first three months (0.014 vs 0.002 per follow-up day). There were no differences in infection incidence between type of donor (p=0.76), type of allograft (p=0.361), immunosuppression protocol (thymoglobulin or basiliximab, p=0.45), renal replacement therapy or presence of diabetes. Regarding urinary infections, days of urinary catheterization (p=0.905), need for catheter replacement (p=0.092) or presence of residual diuresis (p=0.375) had no impact on infection rates. A positive correlation was found, between the number of infection episodes and creatinine increase over the first year (r=0.386; p&amp;lt;0.000). Allograft rejection was diagnosed and treated through protocol biopsy in 25 (18%) cases. These patients presented 17 confirmed episodes of infection over the three following months. Nine of them (36%) were CMV detectable viremias. Patients with a history of rejection had significantly more infections (1.49 ± 1.22 vs 2.20 ± 1.26, p=0.01), even after adjustment (p=0.006). Conclusion Early infections after kidney transplantation negatively impact hospital length of stay and allograft function. Furthermore, immunosuppressive treatment of allograft rejection carries a higher risk of infection. Further research is needed to clarify the impact of specific subsets of allograft rejection and immunosuppression protocols on the incidence of various types of infectious complications which could impair short-term renal function.

Trends in preterm birth in women living with HIV in Switzerland over the last three decades: A multicentric, prospective, cohort study.

HIV infection and its management during pregnancy to reduce perinatal transmission has been associated with preterm birth (PTB). This management has drastically changed. We aimed to evaluate changes in rates of PTB over 34 years in women living with HIV (WLWH) in Switzerland, and to identify factors and interventions associated with these changes. We analysed data from 1238 singleton pregnancies, prospectively collected by the Swiss Mother and Child HIV Cohort Study (MoCHiV) and the Swiss HIV Cohort Study (SHCS) between 1986 and 2020. Rates of PTB in this cohort were compared with that of the general Swiss population for three time periods according to changing treatment strategies recommended at the time. We evaluated the association of PTB with sociodemographic, HIV infection and obstetric variables in uni- and multivariate logistic regression. Rate of PTB in WLWH was highest prior to 2010 (mean 20.4%), and progressively decreased since then (mean 11.3%), but always remained higher than in the general population (5%). Older maternal age, lower CD4 count and detectable viraemia at third trimester (T3), drug consumption and mode of delivery were all significantly associated with both PTB and period of study in univariate analysis. There was no association between PTB and type of antiretroviral regimen. No difference was found in the rate of spontaneous labor between PTB and term delivery groups. Only higher CD4 count at T3 and vaginal delivery were significantly associated with a decrease in PTB over time in multivariate analysis. Preterm birth in WLWH in Switzerland has drastically decreased over the last three decades, but remains twice the rate of that in the general population. Improved viral control and changes in mode of delivery (vaginal birth recommended if viral loads are low near birth) have led to this progress.

Electron transport chain capacity expands yellow fever vaccine immunogenicity

Vaccination has successfully controlled several infectious diseases although better vaccines remain desirable. Host response to vaccination studies have identified correlates of vaccine immunogenicity that could be useful to guide development and selection of future vaccines. However, it remains unclear whether these findings represent mere statistical correlations or reflect functional associations with vaccine immunogenicity. Functional associations, rather than statistical correlates, would offer mechanistic insights into vaccine-induced adaptive immunity. Through a human experimental study to test the immunomodulatory properties of metformin, an anti-diabetic drug, we chanced upon a functional determinant of neutralizing antibodies. Although vaccine viremia is a known correlate of antibody response, we found that in healthy volunteers with no detectable or low yellow fever 17D viremia, metformin-treated volunteers elicited higher neutralizing antibody titers than placebo-treated volunteers. Transcriptional and metabolomic analyses collectively showed that a brief course of metformin, started 3 days prior to YF17D vaccination and stopped at 3 days after vaccination, expanded oxidative phosphorylation and protein translation capacities. These increased capacities directly correlated with YF17D neutralizing antibody titers, with reduced reactive oxygen species response compared to placebo-treated volunteers. Our findings thus demonstrate a functional association between cellular respiration and vaccine-induced humoral immunity and suggest potential approaches to enhancing vaccine immunogenicity.

Seroprevalence of West Nile Virus in Tampa Bay Florida Patients Admitted to Hospital during 2020-2021 for Respiratory Symptoms.

West Nile virus (WNV) is an arbovirus spread primarily by Culex mosquitoes, with humans being a dead-end host. WNV was introduced to Florida in 2001, with 467 confirmed cases since. It is estimated that 80 percent of cases are asymptomatic, with mild cases presenting as a non-specific flu-like illness. Currently, detection of WNV in humans occurs primarily in healthcare settings via RT-PCR or CSF IgM when patients present with severe manifestations of disease including fever, meningitis, encephalitis, or acute flaccid paralysis. Given the short window of detectable viremia and requirement for CSF sampling, most WNV infections never receive an official diagnosis. This study utilized enzyme-linked immunosorbent assay (ELISA) to detect WNV IgG antibodies in 250 patient serum and plasma samples collected at Tampa General Hospital during 2020 and 2021. Plaque reduction neutralization tests were used to confirm ELISA results. Out of the 250 patients included in this study, 18.8% of them were IgG positive, consistent with previous WNV exposure. There was no relationship between WNV exposure and age or sex.

Detectable Virological Load and Associated Factors among People Living with HIV on Antiretroviral Treatment: A Retrospective Study.

The complete and prolonged suppression of viral load is the primary objective of HAART in people living with HIV. Some people may experience therapeutic failure, while others may achieve virological suppression but are unable to maintain it, developing persistent or single detection of low-level viremia. This study aims to evaluate the determinants of a detectable viral load among patients on HAART to identify and address them promptly. In this retrospective study, all patients referring to the Infectious Disease Operative Unit of the Vito Fazzi Hospital in Lecce, Puglia, older than 18 years, receiving HAART for at least 12 months as of 30 June 2022, were included. For each patient, demographic characteristics such as age, sex, educational level, stable relationship, cohabitation, employment status, and information relating to habits and lifestyles such as physical activity, use of drugs, and substances or supplements for sport, abuse of alcohol, and smoking were collected. Degree of comorbidity was quantified according to the Charlson Comorbidity Index, and the presence of obesity and the COVID-19 infection was also considered. Univariable and multivariable logistic regression models were used to assess the association between patients' characteristics and the outcome. In the multivariable logistic regression model, the odds were lower for the duration of therapy (OR: 0.96; p = 0.0397), prescriber's perception of adherence to therapy (OR: 0.50; p < 0.0001), and Nadir CD4+ T-cell count (OR: 0.85; p = 0.0329), and higher for the presence of AIDS (OR: 1.89; p = 0.0423) and COVID-19 (OR: 2.31; p = 0.0182). Our findings support the early initiation of HAART to achieve virological suppression. Additionally, measures to improve adherence to therapy should be adopted to ensure better outcomes for patients.

Detectable Viremia at Presentation Is a Predictor of Disease Severity in Chikungunya.

Background Chikungunya is a mosquito-borne re-emerging disease that has caused a significant number of outbreaks recently in diverse geographic settings across the globe. It leads to severe debilitating illness in a significant proportion of persons who are infected. Measures to limit the impact produced by recurrent outbreaks of the disease are limited and there is an urgent clinical need for early identification of those predisposed to develop severe disease. A comprehensive understandingregarding the proportion of individuals predisposed to developing severe disease is lacking as its correlation with detectable viremia is hinted at by some studies. In this context, we hypothesized that detectable viremia reflected in the diagnostic RT-PCR assay could be significantly associated with the development of severe disease in Chikungunya among those diagnosed on the basis of seroconversion. Our study aims to confirm the same in relation to disease severity among the suspected patients of Chikungunya in the setting of a tertiary care center. Methods In a prospective observational study at a tertiary care center, a total number of 1021 Chikungunya suspects presenting within seven days of illness were screened with Chikungunya Virus IgM ELISA from 2021 to 2023. Those having positive IgM results were further tested with RT-PCR in a blinded manner. According to the information entered into the predesigned form and the hospital follow-up/discharge data, the cases where symptoms like fever and joint pain persisted beyond two weeks were classified as severe versus those resolving within two weeks as mild. The patients in each group were compared for their clinical symptoms and association with the disease severity with detectable viremia (RT-PCR positivity). Results We identified a total of 178 (17.4%) lab-confirmed Chikungunya IgM-positive cases amongst the recruited patients. Here a total of 31 (18.9%) cases could be classified as severe and 133 (74.7%) as mild illness, the remaining 14 patients were excluded from analysis due to insufficientclinical data. Severe illness was significantly higher in elderly individuals belonging to more than 60 years (p = 0.01). Viremia was detected in 16 (9%), those with detectable viremia had higher odds (OR = 4.1) of manifesting as severe disease. Among the severe cases, the proportion of cases with RT-PCR positivity (8, 25.8%) at presentation was significantly higher (P = 0.01) versus those who presented with mild disease (7, 5.5%). Conclusion Our study reveals a correlation betweendetectable viremia in Chikungunya virus (CHIKV) patients and an increased risk of manifesting into a severe disease, where severe cases exhibited a significantly higher proportion of viremia, indicated by RT-PCR positivity. This study hints at the presence of viremia, joint symptoms, and elderly age as potentially useful clinical predictors of disease outcomes, these may serve as indicators for closer monitoring among individuals seeking medical attention due to Chikungunya infection.However, we need to validate these findings in future longitudinal studies incorporating multiple, time-bound follow-up data on clinical outcomes, viral titers, and itslong-term complications.

Strategies of hepatitis C virus elimination for people who inject drugs receiving opioid agonist therapy in the era of direct‐acting antivirals

AbstractIncreased uptake of hepatitis C virus (HCV) treatment among people who inject drugs (PWID) is critical to achieve HCV elimination goals. This study attempted to observe the influence of different referral strategies among HCV‐infected PWID for direct‐acting antivirals (DAA). From January 2019 to November 2020, approximately 190 PWID regularly received opioid agonist therapies (OAT) in the drug addiction rehabilitation clinic of our institute. Among these, those with positive anti‐HCV were further referred to our hepatology clinics for HCV viremia screening and treatment. According to physician involvement, referral strategies were divided into three models including patient self‐intention referral (SR); intensive referral (IR) where patients were referred by clinicians; and fast‐intensive referral (FIR) where patients were referred by clinicians with a fast‐screening and easy‐treatment program. A total of 121 HCV‐infected PWID were enrolled and 71 (58.7%) of them received the referrals: 16 (22.5%) in the SR model, 36 (50.7%) in the IR model, and 19 (26.8%) in the FIR model. Monthly average referred patient number was 2.7 people in the SR model, 2.8 people in the IR model, and 4.8 people in the FIR model, respectively. Among the 71 referred patients, 64 (90.1%) had detectable HCV viremia with genotype distributions being genotype 1a (G1a) in 23 patients (35.9%), G1b in 10 (15.6%), G2 in 5 (7.8%), G3 in 6 (9.4%), and G6 in 20 (31.3%). Except for three patients who refused treatment, 61 patients underwent and completed DAA treatment including 35 patients for Maviret, 15 for Epclusa, 9 for Harvoni, and 2 for Zepatier. Excluding three patients who were lost to follow‐up and one becoming reinfected, 57 (93.4%) eventually achieved a sustained virologic response. Although HCV treatment uptake among PWID in this hospital‐based setting remained suboptimal, the FIR model with a quick‐to‐screen and easy‐to‐treat program was proven practicable in the hospital setting. Further innovative strategies are required to reach all HCV‐infected PWID receiving OAT.

Sexual network characteristics, condomless anal intercourse, and the HIV care cascade among MSM living with controlled versus uncontrolled HIV infection in Lima, Peru: a population-based cross-sectional analysis

Despite high rates of HIV transmission among men who have sex with men (MSM) in Lima, Peru, limited data exist on the sexual network characteristics or risk factors for secondary HIV transmission among MSM with uncontrolled HIV infection. We report the frequency of serodiscordant, condomless anal intercourse (CAI) and associated sexual network characteristics among MSM in Lima with detectable HIV viremia and compare to those with undetectable viremia. This cross-sectional analysis includes MSM who tested positive for HIV-1 during screening for a trial of partner management and STI control (June 2022-January 2023). Participants were tested for HIV, gonorrhoea, chlamydia, and syphilis, and completed questionnaires on their demographic characteristics, sexual identity and behaviour, sexual network structures and engagement in HIV care. Of 665 MSM, 153 (23%) had detectable (>200 copies/mL) viremia. 75% (499/662) of men living with HIV were previously diagnosed, with 94% (n=469/499) reporting that they were on ART, and 93% (n=436/469) virally suppressed. 96% (n=147/153) of men with detectable viremia reported serodiscordant CAI with at least one of their last three sexual partners, and 74% (n=106/144) reported the same with all three of their recent partners. In contrast, 62% (n=302/489) of men with undetectable viral load reported serodiscordant CAI with all of their last three partners (p<0.01). 23% of men living with HIV in Peru had detectable viremia, of whom almost all (96%) reported recent serodiscordant CAI. The primary gap in the HIV care cascade lies in awareness of HIV serostatus, suggesting that improved access to HIV testing could be a key prevention strategy in Peru. Funding for this study was provided by NIH/NIMH grants R01 MH118973 (PI: Clark) and R25 MH087222 (PI: Clark).

Immune response to the recombinant herpes zoster vaccine in people living with HIV over 50 years of age compared to non-HIV age-/gender-matched controls (SHINGR’HIV): a multicenter, international, non-randomized clinical trial study protocol

BackgroundThe burden of herpes zoster (shingles) virus and associated complications, such as post-herpetic neuralgia, is higher in older adults and has a significant impact on quality of life. The incidence of herpes zoster and post-herpetic neuralgia is increased in people living with HIV (PLWH) compared to an age-matched general population, including PLWH on long-term antiretroviral therapy (ART) with no detectable viremia and normal CD4 counts. PLWH – even on effective ART may- exhibit sustained immune dysfunction, as well as defects in cells involved in the response to vaccines. In the context of herpes zoster, it is therefore important to assess the immune response to varicella zoster virus vaccination in older PLWH and to determine whether it significantly differs to that of HIV-uninfected healthy adults or younger PLWH. We aim at bridging these knowledge gaps by conducting a multicentric, international, non-randomised clinical study (SHINGR’HIV) with prospective data collection after vaccination with an adjuvant recombinant zoster vaccine (RZV) in two distinct populations: in PLWH on long-term ART (> 10 years) over 50 years of and age/gender matched controls.MethodsWe will recruit participants from two large established HIV cohorts in Switzerland and in France in addition to age-/gender-matched HIV-uninfected controls. Participants will receive two doses of RZV two months apart. In depth-evaluation of the humoral, cellular, and innate immune responses and safety profile of the RZV will be performed to address the combined effect of aging and potential immune deficiencies due to chronic HIV infection. The primary study outcome will compare the geometric mean titer (GMT) of gE-specific total IgG measured 1 month after the second dose of RZV between different age groups of PLWH and between PLWH and age-/gender-matched HIV-uninfected controls.DiscussionThe SHINGR’HIV trial will provide robust data on the immunogenicity and safety profile of RZV in older PLWH to support vaccination guidelines in this population.Trial registrationClinicalTrials.gov NCT05575830. Registered on 12 October 2022. Eu Clinical Trial Register (EUCT number 2023-504482-23-00).

Feasibility of Implementing a Low-Barrier Long-Acting Injectable Antiretroviral Program for HIV Treatment and Prevention for People Experiencing Homelessness.

Long-acting (LA) antiretrovirals may provide meaningful benefit to people who use drugs and people experiencing homelessness (PEH) who face disproportionate structural and psychosocial barriers in adhering to daily oral HIV antiretroviral therapy or pre-exposure prophylaxis (PrEP), but their use in these populations has not been studied. The Maria X. Martinez Health Resource Center is a low-barrier (eg, no appointment) community-based clinic serving San Francisco PEH. A multidisciplinary care model with robust monitoring and outreach support was developed to provide LA antiretroviral therapy (ART) and LA-PrEP to eligible patients experiencing difficulties adhering to oral antiretrovirals. Feasibility was assessed by evaluating the rates of HIV viremia and on-time injections among patients receiving LA antiretrovirals over the first 24 months of program implementation. Between November 2021 and November 2023, 33 patients initiated LA-ART or LA-PrEP (median age, 37 years; 27% transgender/nonbinary; 73% non-White; 27% street homeless; 52% sheltered homeless; 30% with opioid use disorder; 82% with methamphetamine use disorder). Among 18 patients with HIV, 14 initiated LA-ART injections with detectable viremia (median CD4 count, 340 cells/mm 3 ; mean log 10 viral load, 3.53; SD, 1.62), 8 had never previously been virally suppressed, and all but 1 achieved or maintained virologic suppression (mean, 9.67 months; SD, 8.30). Among 15 LA-PrEP patients, all remained HIV negative (mean, 4.73 months; SD, 2.89). Of 224 total injections administered, 8% were delayed >7 days. The implementation of LA antiretrovirals is feasible in low-barrier, highly supportive clinical settings serving vulnerable PEH. Expansion of such programs will be critical in ending the HIV epidemic.

Glycylglycine promotes the solubility and antigenic utility of recombinant HCV structural proteins in a point-of-care immunoassay for detection of active viremia

BackgroundAlthough E. coli is generally a well-opted platform for the overproduction of recombinant antigens as heterologous proteins, the optimization of expression conditions to maximize the yield of functional proteins remains empirical. Herein, we developed an optimized E. coli (BL21)-based system for the overproduction of soluble immunoreactive HCV core/envelope proteins that were utilized to establish a novel immunoassay for discrimination of active HCV infection.MethodsThe core/E1-E2 genes were amplified and expressed in E. coli BL21 (DE3) in the absence/presence of glycylglycine. The antigenic performance of soluble proteins was assessed against 63 HCV-seronegative (Ab−) sera that included normal and interferent sera (HBV and/or chronic renal failure), and 383 HCV-seropositive (Ab+) samples that included viremic (chronic/relapsers) and recovered patients’ sera. The color intensity (OD450) and S/Co values were estimated.ResultsThe integration of 0.1–0.4M glycylglycine in the growth media significantly enhanced the solubility/yield of recombinant core and envelope proteins by ~ 225 and 242 fold, respectively. This was reflected in their immunoreactivity and antigenic performance in the developed immunoassay, where the soluble core/E1/E2 antigen mixture showed 100% accuracy in identifying HCV viremic sera with a viral RNA load as low as 3800 IU/mL, without cross-reactivity against normal/interferent HCV-Ab−sera. The ideal S/Co threshold predicting active viremia (> 2.75) showed an AUC value of 0.9362 (95% CI: 0.9132 to 0.9593), with 87.64, 91.23% sensitivity and specificity, and 94.14, 82.11% positive and negative predictive values, respectively. The different panels of samples assayed with our EIA showed a good concordance with the viral loads and also significant correlations with the golden standards of HCV diagnosis in viremic patients. The performance of the EIA was not affected by the immunocompromised conditions or HBV co-infection.ConclusionThe applicability of the proposed platform would extend beyond the reported approach, where glycylglycine, low inducer concentration and post-induction temperature, combined with the moderately-strong constitutive promoter enables the stable production of soluble/active proteins, even those with reported toxicity. Also, the newly developed immunoassay provides a cost-effective point-of-care diagnostic tool for active HCV viremia that could be useful in resource-limited settings.

A practical guide to real-world implementation of pre-emptive therapy for Cytomegalovirus disease prevention in high-risk seronegative liver transplant recipients with seropositive donors.

The Comparison of Antiviral Preventative Strategies In Liver Transplant (CAPSIL) study showed pre-emptive therapy (PET) to be superior to antiviral prophylaxis for Cytomegalovirus (CMV) disease prevention in high-risk CMV seronegative liver transplant recipients (LTRs)with seropositive donors (D+R-). Despite the statistical superiority of PET over prophylaxis in research settings, PET is perceived as a logistically more complex strategy that requires careful coordination of weekly CMV PCR testing, prompt initiation of CMV antivirals upon viremia detection, and timely cessation of antivirals following viremia resolution. Transplant centers may be hesitant to use PET for CMV disease prevention in D+R- LTRs out of concern that PET coordination is not feasible in clinical practice. We recently described our experience using PET in CMV D+R- LTRs in a real-world setting, and found it to be as effective for CMV disease prevention as PET performed as part of a clinical trial. Here, we describe a systematic approach for PET implementation in real-world settings and provide practical tools to address anticipated challenges. This framework can support transplant programs in overcoming logistical barriers to PET and incorporating an evidence-based and cost-effective CMV prevention strategy into routine care for high-risk CMV D+R- LTRs.