ABSTRACT
Background & Aims: Bulevirtide is a first-in-class entry inhibitor antiviral treatment for chronic hepatitis D. The viral kinetics during bulevirtide therapy and the effect of combining bulevirtide with pegylated-interferon (Peg-IFN) are unknown. Methods: We used mathematical modelling to analyze the viral kinetics in two French observational cohorts of 183 patients receiving bulevirtide with or without Peg-IFN for 48 weeks. Results: The efficacy of bulevirtide in blocking cell infection was estimated to 90.3%, whereas Peg-IFN blocked viral production with an efficacy of 92.4%, albeit with large inter-individual variabilities. The addition of Peg-IFN to bulevirtide was associated with a more rapid virological decline, with a rate of virological response (>2 log of decline or undetectability) at week 48 of 86.9% (95% prediction interval [PI] = [79.7-95.0]), compared with 56.1% (95% PI = [46.4-66.7]) with bulevirtide only. The model was also used to predict the probability to achieve a cure of viral infection, with a rate of 8.8% (95% PI = [3.5-13.2]) with bulevirtide compared with 18.8% (95% PI = [11.6-29.0]) with bulevirtide + Peg-IFN. Mathematical modelling suggests that after 144 weeks of treatment, the rates of viral cure could be 42.1% (95% PI = [33.3-52.6]) with bulevirtide and 66.7% (95% PI = [56.5-76.8]) with bulevirtide + Peg-IFN. Conclusions: In this analysis of real-world data, Peg-IFN strongly enhanced the kinetics of viral decline in patients treated with bulevirtide. Randomized clinical trials are warranted to assess the virological and clinical benefit of this combination, and to identify predictors of poor response to treatment. Impact and implications: Bulevirtide has been approved for chronic HDV infection by regulatory agencies in Europe based on its good safety profile and rapid virological response after treatment initiation, but the optimal duration of treatment and the chance to achieve a sustained virological response remain unknown. The results presented in this study have a high impact for clinicians and investigators as they provide important knowledge on the long-term virological benefits of a combination of Peg-IFN and bulevirtide in patients with CHD. Clinical trials are now warranted to confirm those predictions.
ABSTRACT
Remarkable advances are being made in developing interventions for eliciting long-term remission of HIV-1 infection. The success of these interventions will obviate the need for lifelong antiretroviral therapy, the current standard-of-care, and benefit the millions living today with HIV-1. Mathematical modelling has made significant contributions to these efforts. It has helped elucidate the possible mechanistic origins of natural and post-treatment control, deduced potential pathways of the loss of such control, quantified the effects of interventions, and developed frameworks for their rational optimization. Yet, several important questions remain, posing challenges to the translation of these promising interventions. Here, we survey the recent advances in the mathematical modelling of HIV-1 control and remission, highlight their contributions, and discuss potential avenues for future developments.
Subject(s)
HIV Infections , HIV-1 , Humans , HIV Infections/drug therapy , HIV-1/physiology , Models, Theoretical , Models, Biological , Anti-HIV Agents/therapeutic useABSTRACT
Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90â¯% effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300â¯mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21â¯% and 92â¯% after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans.
Subject(s)
Antibodies, Monoclonal , COVID-19 , Mesocricetus , SARS-CoV-2 , Animals , SARS-CoV-2/immunology , SARS-CoV-2/drug effects , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/immunology , COVID-19/immunology , COVID-19/virology , Humans , Cricetinae , COVID-19 Drug Treatment , Female , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Male , Disease Models, Animal , Betacoronavirus/immunology , Betacoronavirus/drug effects , Drug Evaluation, Preclinical/methods , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic useABSTRACT
BACKGROUND: In case of high sacral slope, anterior lumbosacral fusions can be performed by retroperitoneal or transperitoneal approach using a reversed Bohlman technique with an autologous corticocancellous fibular graft. The use of a trans-lumbosacral implant can avoid the iatrogenic effects but currently, there is no implant specifically designed for this fusion technique. Could the IFUSE implant from SI BONE replace a fibular graft to avoiding the iatrogenic effect induced by sampling during a Reverse Bohlman technique? PATIENTS AND METHODS: We present the case of a 38-year-old woman with L5S1 interbody pseudarthrosis after posterior fixation for grade 2 L5-S1 spondylolisthesis with isthmic lysis of L5, and that of a 69-year-old woman who underwent a posterior T4 fusion to the pelvis for degenerative scoliosis. Both required a trans-lumbosacral instrumented fusion via an anterior approach using the reverse Bohlman technique. Surgical technique was described. RESULTS: There were no perioperative or postoperative complications. At 6 months, the patients reported a decrease in lumbar and radicular symptomatology. There were no infectious, neurological or vascular complications. CT-scans confirmed the good position and stability of the IFUSE implant. DISCUSSION: We present an innovative interbody grafting technique adapted to spines with high pelvic incidence. The surgical technique is safe, minimally invasive, and reduces surgical iatrogeny. The short and medium-term results are positive but require longer-term follow-up and a larger cohort.
Subject(s)
Bone Transplantation , Lumbar Vertebrae , Sacrum , Spinal Fusion , Spondylolisthesis , Humans , Female , Spinal Fusion/methods , Aged , Lumbar Vertebrae/surgery , Spondylolisthesis/surgery , Adult , Sacrum/surgery , Bone Transplantation/methods , Scoliosis/surgery , Pseudarthrosis/surgery , Pseudarthrosis/etiology , Prostheses and ImplantsABSTRACT
Model-based tumor growth inhibition (TGI) metrics are increasingly used to predict overall survival (OS) data in Phase III immunotherapy clinical trials. However, there is still a lack of understanding regarding the differences between two-stage or joint modeling methods to leverage Phase I/II trial data and help early decision-making. A recent study showed that TGI metrics such as the tumor growth rate constant KG may have good operating characteristics as early endpoints. This previous study used a two-stage approach that is easy to implement and intuitive but prone to bias as it does not account for the relationship between the longitudinal and time-to-event processes. A relevant alternative is to use a joint modeling approach. In the present article, we evaluated the operating characteristics of TGI metrics using joint modeling, assuming an OS model previously developed using historical data. To that end, we used TGI and OS data from IMpower150-a study investigating atezolizumab in over 750 patients suffering from non-small cell lung cancer-to mimic randomized Phase Ib/II trials varying in terms of number of patients included (40 to 15 patients per arm) and follow-up duration (24 to 6 weeks after the last patient included). In this context, joint modeling did not outperform the two-stage approach and provided similar operating characteristics in all the investigated scenarios. Our results suggest that KG geometric mean ratio could be used to support early decision-making provided that 30 or more patients per arm are included and followed for at least 12 weeks.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Non-Small-Cell Lung , Clinical Trials, Phase I as Topic , Lung Neoplasms , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Clinical Trials, Phase II as Topic , Survival Analysis , Decision MakingABSTRACT
HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested to favor post-treatment control, but the circumstances and mechanisms leading to this outcome remain unclear. Here we evaluate the impact of early (week 4) vs. late (week 24 post-infection) treatment initiation in SIVmac251-infected male cynomolgus macaques receiving 2 years of therapy before analytical treatment interruption. We show that early treatment strongly promotes post-treatment control, which is not related to a lower frequency of infected cells at treatment interruption. Rather, early treatment favors the development of long-term memory CD8+ T cells with enhanced proliferative and SIV suppressive capacity that are able to mediate a robust secondary-like response upon viral rebound. Our model allows us to formally demonstrate a link between treatment initiation during primary infection and the promotion of post-treatment control and provides results that may guide the development of new immunotherapies for HIV remission.
Subject(s)
HIV Infections , Simian Acquired Immunodeficiency Syndrome , Simian Immunodeficiency Virus , Animals , Humans , Male , Simian Acquired Immunodeficiency Syndrome/drug therapy , CD8-Positive T-Lymphocytes , Anti-Retroviral Agents/therapeutic use , HIV Infections/drug therapy , Viral LoadABSTRACT
Although anti-severe acute respiratory syndrome-coronavirus 2 antibody kinetics have been described in large populations of vaccinated individuals, we still poorly understand how they evolve during a natural infection and how this impacts viral clearance. For that purpose, we analyzed the kinetics of both viral load and neutralizing antibody levels in a prospective cohort of individuals during acute infection with alpha variant. Using a mathematical model, we show that the progressive increase in neutralizing antibodies leads to a shortening of the half-life of both infected cells and infectious viral particles. We estimated that the neutralizing activity reached 90% of its maximal level within 11 days after symptom onset and could reduce the half-life of both infected cells and circulating virus by a 6-fold factor, thus playing a key role to achieve rapid viral clearance. Using this model, we conducted a simulation study to predict in a more general context the protection conferred by pre-existing neutralization titers, due to either vaccination or prior infection. We predicted that a neutralizing activity, as measured by 50% effective dose > 103 , could reduce by 46% the risk of having viral load detectable by standard polymerase chain reaction assays and by 98% the risk of having viral load above the threshold of infectiousness. Our model shows that neutralizing activity could be used to define correlates of protection against infection and transmission.
Subject(s)
COVID-19 , Humans , Antibodies, Neutralizing , Prospective Studies , SARS-CoV-2ABSTRACT
Two-stage and joint modeling approaches are the two main approaches to investigate the link between longitudinal tumor size data and overall survival (OS) and anticipate clinical trial outcome. We here used a large database composed of one phase II and five phase III clinical trials evaluating atezolizumab (an immunotherapy) in monotherapy or in combination with chemotherapies in 3699 patients with non-small cell lung cancer to evaluate the differences between both approaches in terms of parameter estimates, magnitude of covariate effects, and ability to predict OS. Although the two-stage approach may underestimate the magnitude of the impact of tumor growth rate (KG ) on OS compared to joint modeling approach (hazard ratios [HRs] of 0.42-2.52 vs. 0.25-2.85, respectively, for individual KG varying from the 5th and 95th percentiles), this difference did not lead into poorer performance of the two-stage approach to describe the OS distribution in the six clinical studies. Overall, two-stage and joint modeling approaches accurately predicted OS HR with a median (range) difference with the observed OS HR of 0.02 (0.01-0.18) and 0.03 (0.00-0.19), in all cases considered, respectively (e.g., for IMpower150: 0.80 [0.66-0.95] vs. 0.82 [0.70-0.95], respectively, whereas the observed OS HR was 0.80). In our setting, the two-stage approach accurately predicted the benefit of atezolizumab on OS. Further work is needed to verify if similar results are achieved using phase Ib or phase II clinical trials where the number of patients and measurements is limited as well as in other cancer indications.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Lung Neoplasms/pathology , Antibodies, Monoclonal, Humanized/therapeutic use , Proportional Hazards Models , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Despite use of tecovirimat since the beginning of the 2022 outbreak, few data have been published on its antiviral effect in humans. We here predict tecovirimat efficacy using a unique set of data in nonhuman primates (NHPs) and humans. We analyzed tecovirimat antiviral activity on viral kinetics in NHP to characterize its concentration-effect relationship in vivo. Next, we used a pharmacological model developed in healthy volunteers to project its antiviral efficacy in humans. Finally, a viral dynamic model was applied to characterize mpox kinetics in skin lesions from 54 untreated patients, and we used this modeling framework to predict the impact of tecovirimat on viral clearance in skin lesions. At human-recommended doses, tecovirimat could inhibit viral replication from infected cells by more than 90% after 3 to 5 days of drug administration and achieved over 97% efficacy at drug steady state. With an estimated mpox within-host basic reproduction number, R0, equal to 5.6, tecovirimat could therefore shorten the time to viral clearance if given before viral peak. We predicted that initiating treatment at symptom onset, which on average occurred 2 days before viral peak, could reduce the time to viral clearance by about 6 days. Immediate postexposure prophylaxis could not only reduce time to clearance but also lower peak viral load by more than 1.0 log10 copies/mL and shorten the duration of positive viral culture by about 7 to 10 days. These findings support the early administration of tecovirimat against mpox infection, ideally starting from the infection day as a postexposure prophylaxis.
Subject(s)
Antiviral Agents , Mpox (monkeypox) , Animals , Humans , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzamides , Isoindoles/adverse effectsABSTRACT
The presence of free severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid-antigen in sera (N-antigenemia) has been shown in COVID-19 patients. However, the link between the quantitative levels of N-antigenemia and COVID-19 disease severity is not entirely understood. To assess the dynamics and clinical association of N-antigen sera levels with disease severity in COVID-19 patients, we analyzed data from patients included in the French COVID cohort, with at least one sera sample between January and September 2020. We assessed N-antigenemia levels and anti-N IgG titers, and patient outcomes was classified in two groups, survival or death. In samples collected within 8 days since symptom onset, we observed that deceased patients had a higher positivity rate (93% vs. 81%; p < 0.001) and higher median levels of predicted N-antigenemia (2500 vs. 1200 pg/mL; p < 0.001) than surviving patients. Predicted time to N-antigen clearance in sera was prolonged in deceased patients compared to survivors (23.3 vs 19.3 days; p < 0.0001). In a subset of patients with both sera and nasopharyngeal (NP) swabs, predicted time to N-antigen clearance in sera was prolonged in deceased patients (p < 0.001), whereas NP viral load clearance did not differ between the groups (p = 0.07). Our results demonstrate a strong relationship between N-antigenemia levels and COVID-19 severity on a prospective cohort.
Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Prospective Studies , Antibodies, Viral , Patient AcuityABSTRACT
The role of antiviral treatment in coronavirus disease 2019 hospitalized patients is controversial. To address this question, we analyzed simultaneously nasopharyngeal viral load and the National Early Warning Score 2 (NEWS-2) using an effect compartment model to relate viral dynamics and the evolution of clinical severity. The model is applied to 664 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23) randomly assigned to either standard of care (SoC) or SoC + remdesivir. Then we use the model to simulate the impact of antiviral treatments on the time to clinical improvement, defined by a NEWS-2 score lower than 3 (in patients with NEWS-2 <7 at hospitalization) or 5 (in patients with NEWS-2 ≥7 at hospitalization), distinguishing between patients with low or high viral load at hospitalization. The model can fit well the different observed patients trajectories, showing that clinical evolution is associated with viral dynamics, albeit with large interindividual variability. Remdesivir antiviral activity was 22% and 78% in patients with low or high viral loads, respectively, which is not sufficient to generate a meaningful effect on NEWS-2. However, simulations predicted that antiviral activity greater than 99% could reduce by 2 days the time to clinical improvement in patients with high viral load, irrespective of the NEWS-2 score at hospitalization, whereas no meaningful effect was predicted in patients with low viral loads. Our results demonstrate that time to clinical improvement is associated with time to viral clearance and that highly effective antiviral drugs could hasten clinical improvement in hospitalized patients with high viral loads.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Antiviral Agents/therapeutic use , Hospitalization , Viral LoadABSTRACT
The impact of variants of concern (VoC) on SARS-CoV-2 viral dynamics remains poorly understood and essentially relies on observational studies subject to various sorts of biases. In contrast, experimental models of infection constitute a powerful model to perform controlled comparisons of the viral dynamics observed with VoC and better quantify how VoC escape from the immune response. Here we used molecular and infectious viral load of 78 cynomolgus macaques to characterize in detail the effects of VoC on viral dynamics. We first developed a mathematical model that recapitulate the observed dynamics, and we found that the best model describing the data assumed a rapid antigen-dependent stimulation of the immune response leading to a rapid reduction of viral infectivity. When compared with the historical variant, all VoC except beta were associated with an escape from this immune response, and this effect was particularly sensitive for delta and omicron variant (p<10-6 for both). Interestingly, delta variant was associated with a 1.8-fold increased viral production rate (p = 0.046), while conversely omicron variant was associated with a 14-fold reduction in viral production rate (p<10-6). During a natural infection, our models predict that delta variant is associated with a higher peak viral RNA than omicron variant (7.6 log10 copies/mL 95% CI 6.8-8 for delta; 5.6 log10 copies/mL 95% CI 4.8-6.3 for omicron) while having similar peak infectious titers (3.7 log10 PFU/mL 95% CI 2.4-4.6 for delta; 2.8 log10 PFU/mL 95% CI 1.9-3.8 for omicron). These results provide a detailed picture of the effects of VoC on total and infectious viral load and may help understand some differences observed in the patterns of viral transmission of these viruses.
Subject(s)
COVID-19 , Animals , SARS-CoV-2/genetics , Cell Movement , Macaca fascicularis , PrimatesABSTRACT
Because SARS-CoV-2 constantly mutates to escape from the immune response, there is a reduction of neutralizing capacity of antibodies initially targeting the historical strain against emerging Variants of Concern (VoC)s. That is why the measure of the protection conferred by vaccination cannot solely rely on the antibody levels, but also requires to measure their neutralization capacity. Here we used a mathematical model to follow the humoral response in 26 individuals that received up to three vaccination doses of Bnt162b2 vaccine, and for whom both anti-S IgG and neutralization capacity was measured longitudinally against all main VoCs. Our model could identify two independent mechanisms that led to a marked increase in measured humoral response over the successive vaccination doses. In addition to the already known increase in IgG levels after each dose, we identified that the neutralization capacity was significantly increased after the third vaccine administration against all VoCs, despite large inter-individual variability. Consequently, the model projects that the mean duration of detectable neutralizing capacity against non-Omicron VoC is between 348 days (Beta variant, 95% Prediction Intervals PI [307; 389]) and 587 days (Alpha variant, 95% PI [537; 636]). Despite the low neutralization levels after three doses, the mean duration of detectable neutralizing capacity against Omicron variants varies between 173 days (BA.5 variant, 95% PI [142; 200]) and 256 days (BA.1 variant, 95% PI [227; 286]). Our model shows the benefit of incorporating the neutralization capacity in the follow-up of patients to better inform on their level of protection against the different SARS-CoV-2 variants. Trial registration: This clinical trial is registered with ClinicalTrials.gov, Trial IDs NCT04750720 and NCT05315583.
Subject(s)
Antibodies, Neutralizing , COVID-19 , Humans , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , Immunoglobulin G , SARS-CoV-2/genetics , VaccinationABSTRACT
In advanced cancer patients, tumor burden is calculated using the sum of the longest diameters (SLD) of the target lesions, a measure that lumps all lesions together and ignores intra-patient heterogeneity. Here, we used a rich dataset of 342 metastatic bladder cancer patients treated with a novel immunotherapy agent to develop a Bayesian multilevel joint model that can quantify heterogeneity in lesion dynamics and measure their impact on survival. Using a nonlinear model of tumor growth inhibition, we estimated that dynamics differed greatly among lesions, and inter-lesion variability accounted for 21% and 28% of the total variance in tumor shrinkage and treatment effect duration, respectively. Next, we investigated the impact of individual lesion dynamics on survival. Lesions located in the liver and in the bladder had twice as much impact on the instantaneous risk of death compared to those located in the lung or the lymph nodes. Finally, we evaluated the utility of individual lesion follow-up for dynamic predictions. Consistent with results at the population level, the individual lesion model outperformed a model relying only on SLD, especially at early landmark times and in patients with liver or bladder target lesions. Our results show that an individual lesion model can characterize the heterogeneity in tumor dynamics and its impact on survival in advanced cancer patients.
Subject(s)
Neoplasms , Nonlinear Dynamics , Humans , Bayes Theorem , Neoplasms/pathologyABSTRACT
Longitudinal models of biomarkers such as tumour size dynamics capture treatment efficacy and predict treatment outcome (overall survival) of a variety of anticancer therapies, including chemotherapies, targeted therapies, immunotherapies and their combinations. These pharmacological endpoints like tumour dynamic (tumour growth inhibition) metrics have been proposed as alternative endpoints to complement the classical RECIST endpoints (objective response rate, progression-free survival) to support early decisions both at the study level in drug development as well as at the patients level in personalised therapy with checkpoint inhibitors. This perspective paper presents recent developments and future directions to enable wider and robust use of model-based decision frameworks based on pharmacological endpoints.
Subject(s)
Neoplasms , Precision Medicine , Humans , Neoplasms/drug therapy , Biomarkers , Treatment Outcome , Drug DevelopmentABSTRACT
PURPOSE: Several studies have raised the hypothesis that immunotherapy may exacerbate the variability in individual lesions, increasing the risk of observing divergent kinetic profiles within the same patient. This questions the use of the sum of the longest diameter to follow the response to immunotherapy. Here, we aimed to study this hypothesis by developing a model that estimates the different sources of variability in lesion kinetics, and we used this model to evaluate the impact of this variability on survival. METHODS: We relied on a semimechanistic model to follow the nonlinear kinetics of lesions and their impact on the risk of death, adjusted on organ location. The model incorporated two levels of random effects to characterize both between- and within-patient variability in response to treatment. The model was estimated on 900 patients from a phase III randomized trial evaluating programmed death-ligand 1 checkpoint inhibitor atezolizumab versus chemotherapy in patients with second-line metastatic urothelial carcinoma (IMvigor211). RESULTS: The within-patient variability in the four parameters that characterize individual lesion kinetics represented between 12% and 78% of the total variability during chemotherapy. Similar results were obtained during atezolizumab, except for the durability of the treatment effects, for which the within-patient variability was markedly larger than during chemotherapy (40% v 12%, respectively). Accordingly, the occurrence of divergent profile consistently increased over time in patients treated with atezolizumab and was equal to about 20% after 1 year of treatment. Finally, we show that accounting for the within-patient variability provided a better prediction of most at-risk patients than a model relying solely on the sum of the longest diameter. CONCLUSION: Within-patient variability provides valuable information for the assessment of treatment efficacy and the detection of at-risk patients.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Kinetics , Immunotherapy/adverse effectsABSTRACT
Antiviral treatments against hepatitis B virus (HBV) suppress viral replication but do not eradicate the virus, and need therefore to be taken lifelong to avoid relapse. Mathematical models can be useful to support the development of curative anti-HBV agents; however, they mostly focus on short-term HBV DNA data and neglect the complex host-pathogen interaction. This work aimed to characterize the effect of treatment with lamivudine and/or pegylated interferon (Peg-IFN) in 1,300 patients (hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative) treated for 1 year. A mathematical model was developed incorporating two populations of infected cells, namely I 1 , with a high transcriptional activity, that progressively evolve into I 2 , at a rate δ tr , representing cells with integrated HBV DNA that have a lower transcriptional activity. Parameters of the model were estimated in patients treated with lamivudine or Peg-IFN alone (N = 894), and the model was then validated in patients treated with lamivudine plus Peg-IFN (N = 436) to predict the virological response after a year of combination treatment. Lamivudine had a larger effect in blocking viral production than Peg-IFN (99.4-99.9% vs. 91.8-95.1%); however, Peg-IFN had a significant immunomodulatory effect, leading to an enhancement of the loss rates of I 1 (×1.7 in HBeAg-positive patients), I 2 (> ×7 irrespective of HBeAg status), and δ tr (×4.6 and ×2.0 in HBeAg-positive and HBeAg-negative patients, respectively). Using this model, we were able to describe the synergy of the different effects occurring during treatment with combination and predicted an effect of 99.99% on blocking viral production. This framework can therefore support the optimization of combination therapy with new anti-HBV agents.
Subject(s)
Hepatitis B, Chronic , Lamivudine , Humans , Lamivudine/pharmacology , Lamivudine/therapeutic use , Hepatitis B virus/genetics , Interferon-alpha/therapeutic use , Interferon-alpha/adverse effects , Hepatitis B e Antigens/pharmacology , Hepatitis B e Antigens/therapeutic use , DNA, Viral , Hepatitis B, Chronic/drug therapy , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Therapy, Combination , Polyethylene Glycols , Recombinant Proteins/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: Monkeypox DNA has been detected in skin lesions, saliva, oropharynx, urine, semen, and stool of patients infected during the 2022 clade IIb outbreak; however, the viral dynamics within these compartments remain unknown. We aimed to characterise the viral load kinetics over time in various parts of the body. METHODS: This was an observational, prospective, multicentre study of outpatients diagnosed with monkeypox in two hospitals and two sexual health clinics in Spain between June 28, 2022, and Sept 22, 2022. Men and women aged over 18 years were eligible if they reported having symptom onset within the previous 10 days of presentation, and were ineligible if disease was severe enough to be admitted to hospital. Samples were collected from five body locations (skin lesions, oropharynx, rectum, semen or vagina, and a dried blood spot) at six time points up to 57 days after the screening visit. Samples were analysed by quantitative PCR and a subset by cell culture. The primary endpoint was time from symptom onset to viral DNA clearance. FINDINGS: Overall, 1663 samples were collected from 77 study participants. 75 (97%) participants were men, the median age was 35·0 years (IQR 29·0-46·0), and 39 (51%) participants were living with HIV. The median time from symptom onset to viral clearance was 25 days (95% CI 23-28) in the skin lesions, 16 days (13-19) in the oropharynx, 16 days (13-23) in the rectum, 13 days in semen (9-18), and 1 day in blood (0-5). The time from symptom onset to viral clearance for 90% of cases was 41 days (95% CI 34-47) in skin lesions and 39 days (27-56) in semen. The median viral load in skin lesions was 7·3 log10 copies per mL (IQR 6·5-8·2) at baseline, compared with 4·6 log10 copies per mL (2·9-5·8) in oropharyngeal samples, 5·0 log10 copies per mL (2·9-7·5) in rectal samples, 3·5 log10 copies per mL (2·9-4·7) in semen samples, and 4·0 log10 copies per mL (4·0-4·0) in blood specimens. Replication-competent viruses were isolated in samples with high DNA levels (>6·5 log10 copies per mL). INTERPRETATION: In immunocompetent patients with mild monkeypox disease, PCR data alone would suggest a contact isolation period of 3 to 6 weeks but, based on detection of replication-competent virus, this time could be reduced. Based on findings from this cohort of patients, semen testing and prolonged use of condoms after recovery from monkeypox might not be necessary. FUNDING: University Hospital Germans Trias i Pujol and the YoMeCorono. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.
Subject(s)
Mpox (monkeypox) , Male , Humans , Female , Adult , Middle Aged , Prospective Studies , Spain/epidemiology , Semen , Saliva , Viral LoadABSTRACT
The COVID-19 pandemic has exemplified that rigorous evaluation in large animal models is key for translation from promising in vitro results to successful clinical implementation. Among the drugs that have been largely tested in clinical trials but failed so far to bring clear evidence of clinical efficacy is favipiravir, a nucleoside analogue with large spectrum activity against several RNA viruses in vitro and in small animal models. Here, we evaluate the antiviral activity of favipiravir against Zika or SARS-CoV-2 virus in cynomolgus macaques. In both models, high doses of favipiravir are initiated before infection and viral kinetics are evaluated during 7 to 15 days after infection. Favipiravir leads to a statistically significant reduction in plasma Zika viral load compared to untreated animals. However, favipiravir has no effects on SARS-CoV-2 viral kinetics, and 4 treated animals have to be euthanized due to rapid clinical deterioration, suggesting a potential role of favipiravir in disease worsening in SARS-CoV-2 infected animals. To summarize, favipiravir has an antiviral activity against Zika virus but not against SARS-CoV-2 infection in the cynomolgus macaque model. Our results support the clinical evaluation of favipiravir against Zika virus but they advocate against its use against SARS-CoV-2 infection.
Subject(s)
COVID-19 Drug Treatment , Zika Virus Infection , Zika Virus , Amides , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Macaca fascicularis , Pandemics , Primates , Pyrazines , SARS-CoV-2 , Zika Virus Infection/drug therapyABSTRACT
Recent studies have highlighted the importance of ecological interactions in dysbiosis of gut microbiota, but few focused on their role in antibiotic-induced perturbations. We used the data from the CEREMI trial in which 22 healthy volunteers received a 3-day course of ceftriaxone or cefotaxime antibiotics. Fecal samples were analyzed by 16S rRNA gene profiling, and the total bacterial counts were determined in each sample by flux cytometry. As the gut exposure to antibiotics could not be experimentally measured despite a marked impact on the gut microbiota, it was reconstructed using the counts of susceptible Escherichia coli. The dynamics of absolute counts of bacterial families were analyzed using a generalized Lotka-Volterra equations and nonlinear mixed effect modeling. Bacterial interactions were studied using a stepwise approach. Two negative and three positive interactions were identified. Introducing bacterial interactions in the modeling approach better fitted the data, and provided different estimates of antibiotic effects on each bacterial family than a simple model without interaction. The time to return to 95% of the baseline counts was significantly longer in ceftriaxone-treated individuals than in cefotaxime-treated subjects for two bacterial families: Akkermansiaceae (median [range]: 11.3 days [0; 180.0] vs. 4.2 days [0; 25.6], p = 0.027) and Tannerellaceae (13.7 days [6.1; 180.0] vs. 6.2 days [5.4; 17.3], p = 0.003). Taking bacterial interaction as well as individual antibiotic exposure profile into account improves the analysis of antibiotic-induced dysbiosis.