Viral Load Data Research Articles

Age- and vaccination status-dependent isolation guidelines based on simulation of SARS-CoV-2 Delta cases in Singapore

BackgroundIn the absence of effective pharmaceutical interventions early in an infectious disease outbreak, non-pharmaceutical measures, especially isolating infected individuals, critically limit its impact. The ongoing COVID-19 pandemic has sparked debates on optimal isolation guidelines. This study proposes a variable isolation period approach (variable-period approach), tailoring isolation durations for distinct population groups with varied viral load dynamics.MethodsTo compare our variable-period approach with a fixed-period strategy, we developed a simulation model generating synthetic longitudinal SARS-CoV-2 viral load data. The data was generated from the viral dynamics model parameterized using SARS-CoV-2 Delta patient data in Singapore, accounting for age and vaccination status.ResultsFindings show that age and vaccination status significantly influence viral dynamics, with younger age and vaccination linked to shorter viral shedding durations. The variable-period framework suggests longer isolation lengths for older and unvaccinated individuals. By setting the leaking risk (risk of remaining infectious at the end of isolation) below 10%, the optimal fixed-period isolation is 14 days, with an average excess isolation burden of 7.4 unnecessary days. In contrast, the variable-period guideline reduces the excess isolation burden to 6.0 days, with the optimal isolation periods ranging from 9 to 16 days, depending on the population group. We confirmed similar results when we used the effective reproduction number as an alternative to the leaking risk.ConclusionsIn this case, study using the SARS-CoV-2 Delta variant, our analysis demonstrates that unnecessary time spent in isolation can be reduced by adopting variable-period guidelines based on patient characteristics.

Do Adolescents Living With HIV in Kenya Know Their Viral Load Results? Record Audit and Adolescent Exit Surveys in Kiambu and Nakuru Counties: A Cross-Sectional Study.

Do Adolescents Living With HIV in Kenya Know Their Viral Load Results? Record Audit and Adolescent Exit Surveys in Kiambu and Nakuru Counties: A Cross-Sectional Study.

Impact of differences between interim and post-interim analysis populations on outcomes of a group sequential trial: Example of the MOVe-OUT study.

Pre-specified interim analyses allow for more timely evaluation of efficacy or futility, potentially accelerating decision-making on an investigational intervention. In such an analysis, the randomized, double-blind MOVe-OUT trial demonstrated superiority of molnupiravir over placebo for outpatient treatment of COVID-19 in high-risk patients. In the full analysis population, the point estimate of the treatment difference in the primary endpoint was notably lower than at the interim analysis. We conducted a comprehensive assessment to investigate this unexpected difference in treatment effect size, with the goal of informing future clinical research evaluating treatments for rapidly evolving infectious diseases. The modified intention-to-treat population of the MOVe-OUT trial was divided into an interim analysis cohort (i.e. all participants included in the interim analysis; prospectively defined) and a post-interim analysis cohort (i.e. all remaining participants; retrospectively defined). Baseline characteristics (including many well-established prognostic factors for disease progression), clinical outcomes, and virologic outcomes were retrospectively evaluated. The impact of changes in baseline characteristics over time was explored using logistic regression modeling and simulations. Baseline characteristics were well-balanced between arms overall. However, between- and within-arm differences in known prognostic baseline factors (e.g. comorbidities, SARS-CoV-2 viral load, and anti-SARS-CoV-2 antibody status) were observed for the interim and post-interim analysis cohorts. For the individual factors, these differences were generally minor and otherwise not notable; as the trial progressed, however, these shifts in combination increasingly favored the placebo arm across most of the evaluated factors in the post-interim cohort. Model-based simulations confirmed that the reduction in effect size could be accounted for by these longitudinal trends toward a lower-risk study population among placebo participants. Infectivity and viral load data confirmed that molnupiravir's antiviral activity was consistent across both cohorts, which were heavily dominated by different viral clades (reflecting the rapid SARS-CoV-2 evolution). The cumulative effect of randomly occurring minor differences in prognostic baseline characteristics within and between arms over time, rather than virologic factors such as reduced activity of molnupiravir against evolving variants, likely impacted the observed outcomes. Our results have broader implications for group sequential trials seeking to evaluate treatments for rapidly emerging pathogens. During dynamic epidemic or pandemic conditions, adaptive trials should be designed and interpreted especially carefully, considering that they will likely rapidly enroll a large post-interim overrun population and that even small longitudinal shifts across multiple baseline variables can disproportionately impact prespecified efficacy outcomes at different timepoints. Shifts in prognostic factors may introduce additional variability that can be difficult to disentangle from temporal trends in epidemiology (e.g. evolutionary changes in the causative pathogen) or disease management.(ClinicalTrials.gov: NCT04575597.).

Comorbidities and HIV-related factors associated with mental health symptoms and unhealthy substance use among older adults living with HIV in low- and middle-income countries: a cross-sectional study.

People with HIV (PWH) are vulnerable to mental health and substance use disorders (MSDs), but the extent to which these are associated with other non-communicable diseases in ageing PWH populations remains poorly documented. We assessed comorbidities associated with symptoms of MSD among PWH ≥40 years in the Sentinel Research Network (SRN) of the International epidemiology Database to Evaluate AIDS (IeDEA). Baseline data collected between June 2020 and September 2022, from 10 HIV clinics in Asia, Latin America and Africa contributing to the SRN, were analysed. Symptoms of MSDs and comorbidities were assessed using standardized questionnaires, anthropometric and laboratory tests, including weight, height, blood pressure, glucose, lipids, chronic viral hepatitis and liver transient elastography. HIV viral load, CD4 count and additional routine clinical data were accessed from participant interview or medical records. HIV and non-HIV clinical associations of mental illness symptoms and unhealthy substance use were analysed using logistic regression. Mental illness symptoms were defined as moderate-to-severe depressive symptoms (PHQ-9 score >9), moderate-to-severe anxiety symptoms (GAD-7 >9) or probable post-traumatic stress disorder (PCL-5 >32). Unhealthy substance use was defined as ASSIST score >3, or AUDIT ≥7 for women (≥8 for men). Of 2614 participants assessed at baseline study visits, 57% were female, median age was 50 years, median CD4 was 548 cells/mm3 and 86% had HIV viral load <1000 copies/ml. Overall, 19% had mental illness symptoms, 15% unhealthy substance use, 49% BMI >25 kg/m2, 38% hypertension, 15% type 2 diabetes, 35% dyslipidaemia, 34% liver disease and 23% history of tuberculosis. BMI >25 and dyslipidaemia were found in 54% and 40% of those with mental illness symptoms compared to 49% and 34% of those without. Mental illness symptoms were not significantly associated with the clinical factors assessed. Unhealthy substance use was more likely among those with dyslipidaemia (OR 1.55, CI 1.16-2.09, p = 0.003), and less likely in those with BMI >25 (OR 0.48, CI 0.30-0.77, p = 0.009). Improved integration of MSD and comorbidity services in HIV clinical settings, and further research on the association between MSD and comorbidities, and care integration among older PWH in low-middle-income countries, are required.

Wastewater surveillance overcomes socio-economic limitations of laboratory-based surveillance when monitoring disease transmission: The South African experience during the COVID-19 pandemic.

Wastewater and environmental surveillance has been promoted as a communicable disease surveillance tool because it overcomes inherent biases in laboratory-based communicable disease surveillance. Yet, little empirical evidence exists to support this notion, and it remains largely an intuitive, though highly plausible hypothesis. Our interdisciplinary study uses WES data to show evidence for underreporting of SARS-CoV-2 in the context of measurable and statistically significant associations between economic conditions and SARS-CoV-2 incidence and testing rates. We obtained geolocated, anonymised, laboratory-confirmed SARS-CoV-2 cases, wastewater SARS-CoV-2 viral load data and socio-demographic data for Gauteng Province, South Africa. We spatially located all data to create a single dataset for sewershed catchments served by two large wastewater treatment plants. We conducted epidemiological, persons infected and principal component analysis to explore the relationships between variables. Overall, we demonstrate the co-contributory influences of socio-economic indicators on access to SARS-CoV-2 testing and cumulative incidence, thus reflecting that apparent incidence rates mirror access to testing and socioeconomic considerations rather than true disease epidemiology. These analyses demonstrate how WES provides valuable information to contextualise and interpret laboratory-based epidemiological data. Whilst it is useful to have these associations established for SARS-CoV-2, the implications beyond SARS-CoV-2 are legion for two reasons, namely that biases inherent in clinical surveillance are broadly applicable across pathogens and all pathogens infecting humans will find their way into wastewater albeit in varying quantities. WES should be implemented to strengthen surveillance systems, especially where economic inequalities limit interpretability of conventional surveillance data.

Human Immunodeficiency Virus (HIV) viral load suppression status and associated factors among pregnant women receiving Highly Active Antiretroviral Therapy (HAART) in Ethiopia

BackgroundMothers with an undetectable viral load pose no risk of transmitting the Human Immunodeficiency Virus (HIV) to their fetuses. However, there is limited information on the HIV viral suppression status (≤ 1000 RNA copies/mL) among pregnant mothers at the national level. This study aimed to assess the HIV viral load suppression status among pregnant women and identify factors associated with unsuppressed maternal viral levels (> 1000 RNA copies/mL).MethodsWe conducted a cross-sectional study using secondary data from the national HIV viral load data repository. The study included all pregnant women who initiated antiretroviral therapy (ART) and underwent routine HIV viral load testing. Data were collected from July 2022 to June 2023 (2015 Ethiopian Fiscal Year (EFY)). Analysis was performed using STATA v.17, with descriptive statistics (frequency, percentage, mean, and standard deviation) calculated. A mixed-effects logistic regression model was used to quantify the strength of associations between variables and HIV viral load status (suppressed vs. unsuppressed), expressed through odds ratios.Variables showing a significant association with the outcome (p < 0.02) were selected for further analysis using multiple logistic regression models.ResultsThe analysis included a total of 13,000 mothers with complete data from viral load tests conducted on pregnant women. The HIV viral suppression rate among these women before delivery was 96.8%. Among those with suppressed results, 96.5% had an undetectable HIV viral load. Multiple binary logistic regression analysis indicated that individuals aged 19–29 had 3.17 times higher odds (AOR 3.17, 95% CI 1.17–5.17, p = 0.002) of having an unsuppressed viral load compared to those under 19. Additionally, individuals with poor adherence to treatment had 12.6 times higher odds of experiencing unsuppressed viral loads (AOR 12.64, 95% CI 10.74–14.54, p = 0.001). However, no significant association was found between the timing of viral load testing and unsuppressed maternal HIV viral load.ConclusionThe findings indicate that while the overall rates of HIV viral suppression among pregnant women are high, specific demographic factors such as age and treatment adherence play crucial roles in achieving undetectable viral loads. The data suggests a need for targeted interventions focusing on mothers age from 19 to 30 years and strategies to improve adherence to treatment regimens to enhance outcomes further.The results have significant implications for policy and clinical practices aimed at improving health outcomes for mothers and newborns affected by HIV/AIDS.

Maternal Phenotype, Infant Size and Breast Milk Composition in Women Living With HIV.

The impact of maternal factors on the size of HIV-exposed-uninfected (HEU) infants and breast milk composition is poorly understood. Anthropometry, bio-electrical impedance, haemoglobin and HIV viral load data of women living with HIV (WLWH) and without HIV (WLWOH) were compared and related to their infants' anthropometric Z-scores and breast milk macronutrients 6 weeks and 6 months postnatally. At both time points, WLWH (6-week: n = 83; 6-month: n = 63) had lower reactance (measure of body cell mass) (6-week: p = 0.016; 6-month: p < 0.001), phase angle (PhA) (measure of cell health) (6-week: p = 0.001; 6-month: p = 0.002) and haemoglobin (6-week: p = 0.002; 6-month: p = 0.004) than WLWOH (6-week: n = 90; 6-month: n = 73). HEU infants had lower weight-for-age Z-scores (WAZ) (6-week: p = 0.010; 6-month: p = 0.005). Breast milk composition did not differ between groups. At 6 weeks, HEU infants had lower head circumference-for-age Z-scores (HCAZ) (p = 0.014). Bivariate regression demonstrated maternal HIV predicted lower infant WAZ (ß = -0.442; p = 0.011) and HCAZ (ß = -0.445; p = 0.014). Maternal body mass index (BMI) and mid-upper arm circumference were positively associated with breast milk protein content (ß = 0.018; p = 0.014 and ß = 0.025; p = 0.002, respectively). At 6 months (bivariate regression) maternal HIV predicted lower infant WAZ (ß = -0.609; p = 0.005) and length-for-age Z-scores (ß = -0.741; p = 0.018). Higher maternal BMI and PhA were associated with higher infant WAZ (ß = 0.622; p = 0.015 and ß = 0.055; p = 0.017, respectively). On multivariable analysis, maternal HIV remained a predictor of lower WAZ (ß = -0.568; p = 0.024). In conclusion, maternal HIV infection and phenotype predict the size of infants and breast milk composition up to 6 months postnatally.

P-553. The Impact of Six-Months Antiretroviral Drug Dispensing on Viral Load Suppression in 18 Health Facilities in Mozambique From 2019 to 2023

Abstract Background In 2019, Mozambique adopted the six-months antiretroviral drug dispensing (6MMD) for all eligible People Living with HIV (PLHIV) subgroups. Patients on 6MMD, pick up their antiretroviral drugs at the clinics every six months. As of June 2023, the model was rolled out to 85 health facilities (HFs) and overall viral load suppression was 93%. We analyzed United States President’s Plan for AIDS Relief (PEPFAR) program monitoring and evaluation data to understand the impact of six-months drug dispensing on viral load suppression. Methods At the end of June 2023, we analyzed Viral Load data obtained from electronic patients tracking system (EPTS) an OpenMRS used by PEPFAR to report HIV data nationally in all PEPFAR supported sites in Mozambique. Based on the volume of clients served ( &amp;gt;1000 PLHIV) by each health facility, we selected 9 out of 85 health facilities that implemented six-months antiretroviral drug dispensing and 9 that were not implementing, and we compared the overall percentage of viral load suppression at each HF in June 2019 and June 2023.Viral load was considered suppressed if &amp;lt; 1000 copies/ml in the last consultation for patient enrolled on 6MMD and in the last 6 months for patient not enrolled on 6MMD. All the 18 HFs were PEPFAR supported sites. Results As by June 2023, the 18 HFs selected had 126,719 PLHIV on treatment, representing 6% of PLHIV on treatment in the country. Overall Viral load suppression in June 2019 &amp; June 2023 in the 9 HFs with 6MMD ranged from 69 – 72% &amp; 91 – 94% while in the 9 HFs that were not implementing 6MMD ranged from 69 – 74% &amp; 78 – 89%. Conclusion In the sites we assessed, six-months antiretroviral drug dispensing contributed to reduce HIV transmission by improving viral load suppression rates in Mozambique. Disclosures All Authors: No reported disclosures

Impact of COVID-19 Public Health Measures on Antiretroviral Therapy Use Among Ugandans Living with HIV in Sero-Different Couples.

Antiretroviral therapy (ART) use and HIV suppression among people living with HIV (PLHIV) are critical for HIV control and prevention. Extreme restrictions on movement early during the COVID-19 pandemic in Uganda may have impeded the ability to initiate and sustain access to and use of ART. From our stepped-wedge cluster-randomized trial of an integrated PrEP and ART intervention for HIV-serodifferent couples at 12 ART clinics in Uganda, we identified participants who enrolled and had a 6-month post-ART initiation viral load measured before the beginning of the first COVID-19 lockdown (Period 1), participants whose enrollment and 6-month viral load measurement straddled pre-COVID and COVID lockdown times (Period 2), and participants whose enrollment and 6-month viral load were quantified entirely during COVID-19 (Period 3). ART and viral load data were abstracted from standard-of-care HIV clinic records. We used adjusted generalized estimating equation models to compare viral suppression between the different periods. We enrolled 1,381 PLHIV, including 896 (64.9%) in Period 1, 260 (18.8%) in Period 2, and 225 (16.3%) in Period 3. Almost all (1371, 99.3%) initiated ART within 90days of enrollment and 59.2% had baseline CD4 > 350 cells/mm3. Among those enrolled, 88.8% of participants in Period 1 were virally suppressed (< 1000 copies/mL) within six months of ART initiation, 80.5% in Period 2, and 88.2% in Period 3. All pairwise comparisons demonstrated statistically similar levels of viral suppression. Despite COVID-19 lockdown measures, PLHIV in serodifferent partnerships successfully initiated ART and attained and maintained viral suppression.

Defining the Critical Requisites for Accurate Simulation of SARS-CoV-2 Viral Dynamics: Patient Characteristics and Data Collection Protocol.

Mathematical models of viral dynamics are crucial in understanding infection trajectories. However, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load data often includes limited sparse observations with significant heterogeneity. This study aims to: (1) understand the impact of patient characteristics in shaping the temporal viral load trajectory and (2) establish a data collection protocol (DCP) to reliably reconstruct individual viral load trajectories. We collected longitudinal viral load data for SARS-CoV-2 Delta and Omicron variants from 243 patients in Singapore (2021-2022). A viral dynamics model was calibrated using patients' age, symptom presence, and vaccination status. We accessed associations between these patient characteristics and aspects of viral dynamics using linear regression models. We evaluated the accuracy of viral load trajectory estimation under different simulated DCPs by varying patient numbers, test frequencies, and test intervals. Older unvaccinated individuals had a longer viral shedding duration due to lower infection and cell death rates. Higher peak viral loads were found in older, symptomatic, and vaccinated individuals, with earlier peaks in younger vaccinated individuals. Symptom presence and vaccination resulted in a shorter time from infection to diagnosis. To accurately estimate viral dynamics, more frequent tests, longer test intervals, and larger patient samples are required. For 500 patients, a 21-day follow-up with measurements every 3 days and an 8-day follow-up with daily measurements was optimal for the Delta and Omicron variants, respectively. Patient characteristics significantly impacted viral dynamics. Our analytic approach and recommended DCPs can enhance preparedness and response to emerging pathogens beyond SARS-CoV-2.

Assessment of Pregnancy Status in Patients with Acquired Immunodeficiency Syndrome and their Partners.

HIV is a globally prevalent infection for which there is currently no cure or vaccine. As the number of individuals with HIV infection increases, so does the number of individuals wishing to have children despite being infected. This situation has highlighted issues related to couples where one partner is infected while the other is not (serodiscordant couples) and couples where both partners are positive. Major issues include pregnancy complications, transmission to the child, and potential side effects of the ART treatment on the health of the child. Women living with HIV who become pregnant or contract the virus during pregnancy are at risk for both maternal and perinatal morbidity and mortality, especially if the virus is not adequately controlled. Additionally, there is a risk of vertical transmission through breastfeeding during pregnancy and postpartum. To mitigate the consequences of HIV during pregnancy, it is ideal to start with prepregnancy counseling and plan pregnancies during periods of minimal viral load using appropriate methods. There are limited studies and shared experiences regarding fertility status and issues of HIV/AIDS patients, especially in Turkey. Hence, this study aimed to investigate the fertility status of HIV/AIDS patients and their partners followed up in our clinic, shed light on the encountered issues, and share our experiences. This retrospective, observational, single-center cross-sectional study included HIV/AIDS patients and their partners followed at Hatay Mustafa Kemal University (MKÜ) Medical Faculty Hospital from January 2018 to December 2023. Demographic data of the patients, their sexual orientations, HIV/AIDS status of their partners and children, treatments received, CD4 cell counts, and viral load data were retrospectively obtained from the automation system of our hospital and patient files. Among the couples, there were 21 pairs where both partners were HIV positive, 10 pairs where the woman was HIV positive and the man was seronegative (serodiscordant), and 5 pairs where the man was HIV positive and the woman was seronegative. In our study, eight couples with both partners HIV positive had nine children, and six couples with women who were HIV positive (serodiscordant) had ten children. The five couples with men who were HIV positive (serodiscordant) had six children. No vertical transmission was observed in our study, but three patients did not attend regular follow-ups. During the follow-up period, no seroconversion was detected in the partners of serodiscordant patients. The average gestational age was 38 weeks, and the average birth weight was 2873 ± 349 grams. Our study found no vertical transmission and no seroconversion in partners of serodiscordant couples. Issues related to pregnancy in HIV-positive couples can be managed with pre-pregnancy counseling by specialists, protective methods, appropriate ART, and perinatal follow- up.

Fast standard error estimation for joint models of longitudinal and time-to-event data based on stochastic EM algorithms.

Maximum likelihood inference can often become computationally intensive when performing joint modeling of longitudinal and time-to-event data, due to the intractable integrals in the joint likelihood function. The computational challenges escalate further when modeling HIV-1 viral load data, owing to the nonlinear trajectories and the presence of left-censored data resulting from the assay's lower limit of quantification. In this paper, for a joint model comprising a nonlinear mixed-effect model and a Cox Proportional Hazards model, we develop a computationally efficient Stochastic EM (StEM) algorithm for parameter estimation. Furthermore, we propose a novel technique for fast standard error estimation, which directly estimates standard errors from the results of StEM iterations and is broadly applicable to various joint modeling settings, such as those containing generalized linear mixed-effect models, parametric survival models, or joint models with more than two submodels. We evaluate the performance of the proposed methods through simulation studies and apply them to HIV-1 viral load data from six AIDS Clinical Trials Group studies to characterize viral rebound trajectories following the interruption of antiretroviral therapy (ART), accounting for the informative duration of off-ART periods.

The kinetics of SARS-CoV-2 infection based on a human challenge study

Studying the early events that occur after viral infection in humans is difficult unless one intentionally infects volunteers in a human challenge study. Here, we use data about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in such a study in combination with mathematical modeling to gain insights into the relationship between the amount of virus in the upper respiratory tract and the immune response it generates. We propose a set of dynamic models of increasing complexity to dissect the roles of target cell limitation, innate immunity, and adaptive immunity in determining the observed viral kinetics. We introduce an approach for modeling the effect of humoral immunity that describes a decline in infectious virus after immune activation. We fit our models to viral load and infectious titer data from all the untreated infected participants in the study simultaneously. We found that a power-law with a power h < 1 describes the relationship between infectious virus and viral load. Viral replication at the early stage of infection is rapid, with a doubling time of ~2 h for viral RNA and ~3 h for infectious virus. We estimate that adaptive immunity is initiated ~7 to 10 d postinfection and appears to contribute to a multiphasic viral decline experienced by some participants; the viral rebound experienced by other participants is consistent with a decline in the interferon response. Altogether, we quantified the kinetics of SARS-CoV-2 infection, shedding light on the early dynamics of the virus and the potential role of innate and adaptive immunity in promoting viral decline during infection.

Are social protection and food security accelerators for adolescents to achieve the Global AIDS targets?

Without effective, scalable interventions, we will fail to achieve the Global AIDS Targets of zero AIDS-related deaths, zero HIV transmission and zero discrimination. This study examines associations of social protection and food security among adolescents living with HIV (ALHIV), with three Global AIDS Targets aligned outcomes: antiretroviral treatment (ART) adherence and viral suppression, HIV transmission risk behaviour and enacted stigma. We conducted three study visits over 2014-2018 with 1046 ALHIV in South Africa's Eastern Cape province. Standardized surveys provided information on receipt of government-provided cash transfers and past-week food security, alongside self-reported ART adherence, sexual debut and condom use, and enacted HIV-related stigma. Viral load (VL) data was obtained through data extraction from patient files and linkage with National Health Laboratory Service test results (2014-2020). We used a multivariable random-effects regression model to estimate associations between receiving government cash transfers and food security and three outcomes: ART adherence and viral suppression, delayed sexual debut or consistent condom use and no enacted stigma. We tested moderation by sex and age and fitted disaggregated models for each outcome. Among the 933 ALHIV completing all three study visits, 55% were female, and the mean age was 13.6 years at baseline. Household receipt of a government cash transfer was associated with improvements on all outcomes: ART adherence and viral suppression (aOR 2.03, 95% CI 1.29-3.19), delayed sexual debut or consistent condom use (aOR 1.62, 95% CI 1.16-2.27) and no enacted stigma(aOR 2.33, 95% CI 1.39-3.89). Food security was associated with improvements on all outcomes: ART adherence and viral suppression (aOR 1.73, 95% CI 1.30-2.30), delayed sexual debut or consistent condom use (aOR 1.30, 95% CI 1.03-1.64) and no enacted stigma (aOR 1.91, 95% CI 1.32-2.76). Receiving both cash transfers and food security increased the probability of ART adherence and VL suppression from 36% to 60%; delayed sexual debut or consistent condom use from 67% to 81%; and no enacted stigma from 84% to 96%. Government-provided cash transfers and food security, individually and in combination, are associated with improved outcomes for ALHIV aligned with Global AIDS Targets. They may be important, and underutilized, accelerators for achieving these targets.

In-host modeling of dengue virus and non-structural protein 1 and the effects of ivermectin in patients with acute dengue fever.

The increased incidence of dengue poses a substantially global public health challenge. There are no approved antiviral drugs to treat dengue infections. Ivermectin, an old anti-parasitic drug, had no effect on dengue viremia, but reduced the dengue non-structural protein 1 (NS1) in a clinical trial. This is potentially important, as NS1 may play a causal role in the pathogenesis of severe dengue. This study established an in-host model to characterize the plasma kinetics of dengue virus and NS1 with host immunity and evaluated the effects of ivermectin, using a population pharmacokinetic-pharmacodynamic (PK-PD) modeling approach, based on two studies in acute dengue fever: a placebo-controlled ivermectin study in 250 adult patients and an ivermectin PK-PD study in 24 pediatric patients. The proposed model described adequately the observed ivermectin pharmacokinetics, viral load, and NS1 data. Bodyweight was a significant covariate on ivermectin pharmacokinetics. We found that ivermectin reduced NS1 with an EC50 of 67.5 μg/mL. In silico simulations suggested that ivermectin should be dosed within 48 h after fever onset, and that a daily dosage of 800 μg/kg could achieve substantial NS1 reduction. The in-host dengue model is useful to assess the drug effect in antiviral drug development for dengue fever.

Unsuppressed HIV Viral Load and Related Factors in Patients Receiving Antiretroviral Treatment in Tanganyika Province, Democratic Republic of Congo (DRC)

Antiretroviral treatment (ART) has revolutionized the management of the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), enabling long-term viral load (VL) suppression in patients. Despite the proven effectiveness of ART, a significant proportion of patients with HIV receiving ART fail to achieve viral load suppression (VLS). This study aimed to identify factors associated with low VLS in the Tanganyika province. An unmatched case–control study was conducted from January 2022 to June 2023, including 22 care facilities with viral load data. Data were collected from patient records. For each reviewed record, the patient was invited for an interview upon providing informed consent. Data were analyzed using SPSS version 27. In a multivariable binary logistic regression model, variables with a p-value &lt; 0.05 and a 95% confidence interval for the adjusted odds ratio were considered significantly associated with unsuppressed VL. A total of 462 individuals, including 156 cases and 306 controls, were included in the study. The mean age (standard deviation) of participants was 42.12 (±11.6) years. The following covariates were significantly associated with unsuppressed VL: poor HIV status disclosure to a confidant [adjusted OR = 2.10, 95% CI (1.33–3.31), p = 0.001], poor ART adherence [adjusted OR = 2.01, 95% CI (1.25–3.23), p = 0.004], ART interruption [adjusted OR = 3.43, 95% CI (2.00–5.88), p &lt; 0.001], no participation in support groups [adjusted OR = 2.16, 95% CI (1.25–3.71), p = 0.005], baseline WHO clinical stage 3 and 4 [adjusted OR = 2.24, 95% CI (1.32–3.79), p = 0.003], opportunistic infections (OIs) [adjusted OR = 2.30, 95% CI (1.27–4.16), p = 0.006], and non-communicable chronic diseases (NCDs) [adjusted OR = 2.30, 95% CI (1.10–4.79), p = 0.026]. Given the clear association between several factors and unsuppressed VL, prevention should involve the implementation of innovative strategies targeting at-risk patient groups. Strengthening the monitoring of these factors among active patients at each appointment is recommended to achieve this goal.

Antiviral capacity of the early CD8 T-cell response is predictive of natural control of SIV infection: Learning in vivo dynamics using ex vivo data.

While most individuals suffer progressive disease following HIV infection, a small fraction spontaneously controls the infection. Although CD8 T-cells have been implicated in this natural control, their mechanistic roles are yet to be established. Here, we combined mathematical modeling and analysis of previously published data from 16 SIV-infected macaques, of which 12 were natural controllers, to elucidate the role of CD8 T-cells in natural control. For each macaque, we considered, in addition to the canonical in vivo plasma viral load and SIV DNA data, longitudinal ex vivo measurements of the virus suppressive capacity of CD8 T-cells. Available mathematical models do not allow analysis of such combined in vivo-ex vivo datasets. We explicitly modeled the ex vivo assay, derived analytical approximations that link the ex vivo measurements with the in vivo effector function of CD8-T cells, and integrated them with an in vivo model of virus dynamics, thus developing a new learning framework that enabled the analysis. Our model fit the data well and estimated the recruitment rate and/or maximal killing rate of CD8 T-cells to be up to 2-fold higher in controllers than non-controllers (p = 0.013). Importantly, the cumulative suppressive capacity of CD8 T-cells over the first 4-6 weeks of infection was associated with virus control (Spearman's ρ = -0.51; p = 0.05). Thus, our analysis identified the early cumulative suppressive capacity of CD8 T-cells as a predictor of natural control. Furthermore, simulating a large virtual population, our model quantified the minimum capacity of this early CD8 T-cell response necessary for long-term control. Our study presents new, quantitative insights into the role of CD8 T-cells in the natural control of HIV infection and has implications for remission strategies.

Modelling the effectiveness of an isolation strategy for managing mpox outbreaks with variable infectiousness profiles

The global outbreak of mpox in 2022 and subsequent sporadic outbreaks in 2023 highlighted the importance of nonpharmaceutical interventions such as case isolation. Individual variations in viral shedding dynamics may lead to either premature ending of isolation for infectious individuals, or unnecessarily prolonged isolation for those who are no longer infectious. Here, we developed a modeling framework to characterize heterogeneous mpox infectiousness profiles – specifically, when infected individuals cease to be infectious – based on viral load data. We examined the potential effectiveness of three different isolation rules: a symptom-based rule (the current guideline in many countries) and rules permitting individuals to stop isolating after either a fixed duration or following tests that indicate that they are no longer likely to be infectious. Our analysis suggests that the duration of viral shedding ranges from 23 to 50 days between individuals. The risk of infected individuals ending isolation too early was estimated to be 8.8% (95% CI: 6.7–10.5) after symptom clearance and 5.4% (95% CI: 4.1–6.7) after 3 weeks of isolation. While these results suggest that the current standard practice for ending isolation is effective, we found that unnecessary isolation following the infectious period could be reduced by adopting a testing-based rule.

Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion.

Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption.

Estimating the COVID-19 prevalence from wastewater

Wastewater based epidemiology has become a widely used tool for monitoring trends of concentrations of different pathogens, most notably and widespread of SARS-CoV-2. Therefore, in 2022, also in Rhineland–Palatinate, the Ministry of Science and Health has included 16 wastewater treatment sites in a surveillance program providing biweekly samples. However, the mere viral load data is subject to strong fluctuations and has limited value for political deciders on its own. Therefore, the state of Rhineland–Palatinate has commissioned the University Medical Center at Johannes Gutenberg University Mainz to conduct a representative cohort study called SentiSurv, in which an increasing number of up to 12,000 participants have been using sensitive antigen self-tests once or twice a week to test themselves for SARS-CoV-2 and report their status. This puts the state of Rhineland–Palatinate in the fortunate position of having time series of both, the viral load in wastewater and the prevalence of SARS-CoV-2 in the population. Our main contribution is a calibration study based on the data from 2023-01-08 until 2023-10-01 where we identified a scaling factor (0.208±0.031\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$0.208 \\pm 0.031$$\\end{document}) and a delay (5.07±2.30\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$5.07 \\pm 2.30$$\\end{document} days) between the virus load in wastewater, normalized by the pepper mild mottle virus (PMMoV), and the prevalence recorded in the SentiSurv study. The relation is established by fitting an epidemiological model to both time series. We show how that can be used to estimate the prevalence when the cohort data is no longer available and how to use it as a forecasting instrument several weeks ahead of time. We show that the calibration and forecasting quality and the resulting factors depend strongly on how wastewater samples are normalized.