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Clinical Therapeutics Jun 2022Heavily treatment-experienced (HTE) people with multidrug-resistant HIV-1 have limited treatment options. Treatment with the first-in-class attachment inhibitor...
PURPOSE
Heavily treatment-experienced (HTE) people with multidrug-resistant HIV-1 have limited treatment options. Treatment with the first-in-class attachment inhibitor fostemsavir in addition to optimized background therapy (OBT) resulted in sustained virologic and immunologic responses in HTE participants throughout 96 weeks in the BRIGHTE trial. In the absence of long-term direct comparative evidence between fostemsavir-based and other antiretroviral regimens, this analysis indirectly compares efficacy and safety across relevant available trials, adjusting for demographic and baseline characteristics.
METHODS
A systematic literature review was conducted to identify trials with designs and populations comparable to BRIGHTE. Using matching-adjusted indirect comparison analyses, individual participant data from BRIGHTE were reweighted to create balanced populations across trials, and efficacy and safety outcomes were compared.
FINDINGS
Three comparator trials were identified, 2 of which reflected an optimized therapy without fostemsavir (OBT alone): TMB-301 (ibalizumab and OBT), BENCHMRK-1/-2 (OBT alone), and VIKING-3 (OBT alone). Compared with ibalizumab and OBT (N = 40), fostemsavir and OBT (unadjusted, N = 347; adjusted, N = 236) were associated with numerically higher nonsignificant odds of virologic suppression (odds ratio [OR] = 1.44; 95% CI, 0.74-2.80; P = 0.284) and a similar increase in CD4 cell count of approximately 65 cells/mm from baseline through week 24 (mean difference = 7.05 cells/mm; 95% CI, -60.88 to 74.98 cells/mm; P = 0.834). Compared with OBT from BENCHMRK-1/-2 (N = 237), fostemsavir and OBT (adjusted, N = 126) were associated with significantly higher odds of virologic suppression (OR = 3.26; 95% CI, 2.08-5.11; P < 0.001) and increased CD4 cell count (135.78 cells/mm; 95% CI, 91.93-179.63 cells/mm; P < 0.001) at week 96. Compared with OBT from VIKING-3 (N = 183), fostemsavir and OBT (adjusted, N = 78) were associated with numerically higher odds of virologic suppression (OR = 1.34; 95% CI, 0.78-2.30; P = 0.297) and a modest CD4 cell count increase (26.86 cells/mm; 95% CI, -10.79 to 64.52; P = 0.162) through week 48; however, differences were not significant. All-cause discontinuations and safety comparisons varied across studies.
IMPLICATIONS
Although matching-adjusted indirect comparison analyses have limitations, these results support the use of fostemsavir and OBT as an important treatment option in HTE people with multidrug-resistant HIV-1.
Topics: Anti-HIV Agents; HIV Infections; HIV-1; Humans; Organophosphates; Piperazines; Viral Load
PubMed: 35610081
DOI: 10.1016/j.clinthera.2022.04.007 -
Viruses Dec 2022Defective interfering particles (DIPs) are particles containing defective viral genomes (DVGs) generated during viral replication. DIPs have been found in various RNA... (Review)
Review
Defective interfering particles (DIPs) are particles containing defective viral genomes (DVGs) generated during viral replication. DIPs have been found in various RNA viruses, especially in influenza viruses. Evidence indicates that DIPs interfere with the replication and encapsulation of wild-type viruses, namely standard viruses (STVs) that contain full-length viral genomes. DIPs may also activate the innate immune response by stimulating interferon synthesis. In this review, the underlying generation mechanisms and characteristics of influenza virus DIPs are summarized. We also discuss the potential impact of DIPs on the immunogenicity of live attenuated influenza vaccines (LAIVs) and development of influenza vaccines based on NS1 gene-defective DIPs. Finally, we review the antiviral strategies based on influenza virus DIPs that have been used against both influenza virus and SARS-CoV-2. This review provides systematic insights into the theory and application of influenza virus DIPs.
Topics: Humans; Antiviral Agents; Influenza Vaccines; Defective Interfering Viruses; Defective Viruses; COVID-19; SARS-CoV-2; Orthomyxoviridae; Virus Replication
PubMed: 36560777
DOI: 10.3390/v14122773 -
Annals of Translational Medicine Dec 2021The association between hepatic steatosis (HS) and chronic hepatitis B (CHB) remains controversial. We performed a systematic review and meta-analysis to investigate the...
BACKGROUND
The association between hepatic steatosis (HS) and chronic hepatitis B (CHB) remains controversial. We performed a systematic review and meta-analysis to investigate the latest concurrence rate and impact of HS on CHB patients.
METHODS
Relevant studies were identified by searching PubMed, EMBASE, and the Cochrane Library from January 1, 2000 to December 2, 2020. We calculated the pooled prevalence of HS in CHB patients using a random effects model. A subgroup analysis was performed to explore the impact of HS on CHB patients. This study is registered with PROSPERO (No. CRD42021242584).
RESULTS
A total of 98 studies with a population of 48,472 patients were included. The global prevalence of HS in CHB patients was 34.93% [95% confidence interval (CI): 32.01-37.90%]. Overweight status, hypertension, diabetes, hyperlipidemia, and metabolic syndrome showed a higher risk for developing HS in CHB patients, while positive hepatitis B e antigen (HBeAg) status was negatively associated with the presence of HS [odds ratio (OR) =0.81, 95% CI: 0.70-0.93]. The pooled analysis showed no significant association between HS and fibrosis progression (OR =0.68, 95% CI: 0.44-1.05). However, the coexistence of HS was negatively associated with the antiviral therapy response in CHB patients, including virological response (OR =0.69, 95% CI: 0.48-0.99) and alanine aminotransferase (ALT) normalization (OR =0.44, 95% CI: 0.28-0.69).
DISCUSSION
The global prevalence of HS in CHB patients is higher than previously estimated. The concurrence of HS could impact the replication of HBV and the effectiveness of antiviral therapy in CHB patients. However, coexistence with HS did not show a higher risk of developing advanced fibrosis in CHB patients.
PubMed: 35071412
DOI: 10.21037/atm-21-3052 -
Virology Journal Jun 2023ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy. This T-cell non-Hodgkin lymphoma, caused by the human T-cell leukemia virus type 1... (Meta-Analysis)
Meta-Analysis
BACKGROUND
ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy. This T-cell non-Hodgkin lymphoma, caused by the human T-cell leukemia virus type 1 (HTLV-1), is challenging to treat. There is no known treatment for ATLL as of yet. However, it is recommended to use Zidovudine and Interferon Alfa-based regimens (AZT/IFN), chemotherapy, and stem cell transplant. This study aims to review the outcome of patients with different subtypes of ATLL treated with Zidovudine and Interferon Alfa-based regimens.
METHODS
A systematic search was carried out for articles evaluating outcomes of ATLL treatment by AZT/IFN agents on human subjects from January 1, 2004, until July 1, 2022. Researchers assessed all studies regarding the topic, followed by extracting the data. A random-effects model was used in the meta-analyses.
RESULTS
We obtained fifteen articles on the AZT/IFN treatment of 1101 ATLL patients. The response rate of the AZT/IFN regimen yielded an OR of 67% [95% CI: 0.50; 0.80], a CR of 33% [95% CI: 0.24; 0.44], and a PR of 31% [95% CI: 0.24; 0.39] among individuals who received this regimen at any point during their treatment. Our subgroup analyses' findings demonstrated that patients who received front-line and combined AZT/IFN therapy responded better than those who received AZT/IFN alone. It is significant to note that patients with indolent subtypes of disease had considerably higher response rates than individuals with aggressive disease.
CONCLUSION
IFN/AZT combined with chemotherapy regimens is an effective treatment for ATLL patients, and its use in the early stages of the disease may result in a greater response rate.
Topics: Adult; Humans; Zidovudine; Interferon-alpha; Leukemia-Lymphoma, Adult T-Cell; Human T-lymphotropic virus 1; Lymphoma
PubMed: 37287047
DOI: 10.1186/s12985-023-02077-0 -
The Journal of Infectious Diseases Aug 2023This study aims to comparatively analyze clinical features, treatment, and patient outcomes between the previous and the 2022 mpox (monkeypox) outbreaks. (Meta-Analysis)
Meta-Analysis
BACKGROUND
This study aims to comparatively analyze clinical features, treatment, and patient outcomes between the previous and the 2022 mpox (monkeypox) outbreaks.
METHODS
Five bibliographic databases were searched for studies reporting clinical features, management, and patient outcomes of mpox. Systematic review and meta-analysis were performed.
RESULTS
In total, 73 studies were included in the systematic review, of which 33 studies were subjected to meta-analysis. Previous outbreaks substantially affected children, whereas the 2022 outbreak primarily affected male adults, of which 94.66% (95% confidence interval [CI], 88.03-98.95) were men who have sex with men. Furthermore, 72.47% (95% CI, 51.04-89.71) reported high-risk sexual activity and the overall human immunodeficiency virus (HIV) prevalence was 37.65% (95% CI, 30.09-45.50). Skin lesions remain the typical symptom; however, their anatomic distribution differed. Systemic manifestations were common, but rectal pain was unique to the 2022 outbreak. The estimated overall fatality during past outbreaks in Africa was 4.61% (95% CI, 2.39%-7.35%), whereas 6.34% (95% CI, 3.35%-10.10%) of patients from the 2022 outbreak required hospitalization. Antiviral treatment, in particular tecovirimat, has been prescribed for a subset of patients, but the efficacy remains inconclusive.
CONCLUSIONS
These findings are important for better understanding the disease and guiding adequate response to mpox outbreaks.
Topics: Adult; Child; Humans; Male; Female; Homosexuality, Male; Mpox (monkeypox); Sexual and Gender Minorities; Antiviral Agents; Disease Outbreaks; Pelvic Pain
PubMed: 36735342
DOI: 10.1093/infdis/jiad034 -
JHEP Reports : Innovation in Hepatology Jun 2023Antivirals represent the mainstay of chronic hepatitis B treatment given their efficacy and tolerability, but rates of functional cure remain low during long-term...
BACKGROUND & AIMS
Antivirals represent the mainstay of chronic hepatitis B treatment given their efficacy and tolerability, but rates of functional cure remain low during long-term therapy. Treatment discontinuation has emerged as a strategy to maintain partial cure and achieve functional cure in select patient groups. We aimed to evaluate how data from treatment discontinuation studies exploring novel viral and/or immune markers could be applied to the functional cure program.
METHODS
Treatment discontinuation studies evaluating novel viral and/or immune markers were identified by a systematic search of the PubMed database through to October 30, 2022. Data extraction focused on information regarding novel markers, including identified cut-off levels, timing of measurement, and associated effect on study outcomes of virological relapse, clinical relapse, and HBsAg seroclearance.
RESULTS
From a search of 4,492 citations, 33 studies comprising a minimum of 2,986 unique patients met the inclusion criteria. Novel viral markers, HBcrAg and HBV RNA, were demonstrated across most studies to be helpful in predicting off-therapy partial cure, with emerging evidence to support a link with functional cure. From novel immune marker studies, we observed that treatment discontinuation has the potential to trigger immune restoration, which may be associated with a transient virological relapse. To this end, these studies support the combination of virus-directing agents with immunomodulator therapies to induce two key steps underlying functional cure: viral antigen load reduction and restoration of the host immune response.
CONCLUSIONS
Patients with a favourable profile of novel viral and immune markers stand to benefit from a trial of antiviral treatment discontinuation alongside novel virus-directing agents with the aim of achieving functional cure without excessive risk of severe clinical relapse.
IMPACT AND IMPLICATIONS
Select patients with chronic hepatitis B undergoing nucleoside analogue therapy may benefit from a trial of treatment discontinuation, aiming to maintain partial cure and/or achieve functional cure. We propose a profile of novel viral and immune markers to identify patients who are likely to achieve these goals without excessive risk of hepatic decompensation. Furthermore, treatment discontinuation may also be considered as a therapeutic strategy to trigger immune restoration, which may increase the chance of functional cure when used in conjunction with novel virus-directing agents.
PubMed: 37138673
DOI: 10.1016/j.jhepr.2023.100720 -
BMC Infectious Diseases May 2021Identifying and treating individuals with high risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease is critical for eliminating the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Identifying and treating individuals with high risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease is critical for eliminating the disease. We aimed to conduct a systematic review and meta-regression analysis to quantify the dose-response relationship between interferon-gamma release assay (IGRA) levels and the risk of progression to active TB.
METHODS
We searched PubMed and Embase from 1 January 2001 to 10 May 2020 for longitudinal studies that reported the risk of progression from latent to active TB as a function of baseline IGRA values. We used a novel Bayesian meta-regression method to pool effect sizes from included studies and generate a continuous dose-response risk curve. Our modeling framework enabled us to incorporate random effects across studies, and include data with different IGRA ranges across studies. The quality of included studies were assessed using the Newcastle-Ottawa scale (NOS).
RESULTS
We included 34 studies representing 581,956 person-years of follow-up with a total of 788 incident cases of TB in the meta-regression analysis. Higher levels of interferon-gamma were associated with increased risk of progression to active tuberculosis. In the dose-response curve, the risk increased sharply between interferon-gamma levels 0 and 5 IU/ml, after which the risk continued to increase moderately but at a slower pace until reaching about 15 IU/ml where the risk levels off. Compared to 0 IU/ml, the relative risk of progression to active TB among those with interferon-gamma levels of 0.35, 1, 5, 10, 15, and 20 IU/ml were: 1.64 (1.28-2.08), 2.90 (2.02-3.88), 11.38 (6.64-16.38), 19.00 (13.08-26.90), 21.82 (14.65-32.57), and 22.31 (15.43-33.00), respectively. The dose-response relationship remains consistent when limiting the analysis to studies that scored highest in the NOS.
CONCLUSION
The current practice of dichotomizing IGRA test results simplifies the TB infection disease continuum. Evaluating IGRA test results over a continuous scale could enable the identification of individuals at greatest risk of progression to active TB.
Topics: Bayes Theorem; Disease Progression; Humans; Interferon-gamma; Interferon-gamma Release Tests; Latent Tuberculosis; Longitudinal Studies; Male; Mycobacterium tuberculosis; Regression Analysis; Risk Factors; Tuberculin Test
PubMed: 34022827
DOI: 10.1186/s12879-021-06141-4 -
Clinical Gastroenterology and... Jun 2021Chronic viral hepatitis is a leading cause of worldwide liver-related morbidity and mortality, despite the availability of effective treatments that reduce or prevent... (Review)
Review
BACKGROUND & AIMS
Chronic viral hepatitis is a leading cause of worldwide liver-related morbidity and mortality, despite the availability of effective treatments that reduce or prevent complications in most patients. Electronic-health (eHealth) technologies have potential to intervene along the whole cascade of care. We aimed to summarize available literature on eHealth interventions with respect to conventional screening, diagnostic and treatment outcomes in chronic hepatitis B (HBV) and hepatitis C (HCV).
METHODS
We systematically reviewed MEDLINE, EMBASE, Cochrane Library and international conference abstracts, including studies published from 2009 - 2020. Overall 80 studies were included, covering electronic medical record (EMR) interventions (n=39), telemedicine (n=20), mHealth (n=5), devices (n=4), clinical decision support (n=3), web-based (n=5), social media (n=1) and electronic communication (n=3).
RESULTS
Compared to standard care, EMR alerts increase screening rates in eligible populations including birth cohort screening in HCV, universal HCV screening in Emergency Departments, ethnic groups with high HBV prevalence, and HBV screening prior to immunosuppression. Direct messaging alerts to providers and automated testing may have a greater effect. No significant difference was found in sustained virological response outcomes between telemedicine and face-to-face management for community, rural and prison cohorts in HCV in the direct acting antiviral era of treatment, with higher patient satisfaction in telemedicine groups.
CONCLUSIONS
EMR alerts significantly increase screening rates in eligible cohorts in both chronic HBV and HCV. Telemedicine is equally efficacious to face-to-face care in HCV treatment. Other eHealth technologies show promise; however rigorous studies are lacking.
Topics: Antiviral Agents; Electronics; Hepatitis C, Chronic; Humans; Mass Screening; Telemedicine
PubMed: 32896632
DOI: 10.1016/j.cgh.2020.09.011 -
Clinical Infectious Diseases : An... Jul 2021People who inject drugs (PWID) experience barriers to accessing testing and treatment for hepatitis C virus (HCV) infection. Opioid agonist therapy (OAT) may provide an... (Meta-Analysis)
Meta-Analysis
Association Between Opioid Agonist Therapy and Testing, Treatment Uptake, and Treatment Outcomes for Hepatitis C Infection Among People Who Inject Drugs: A Systematic Review and Meta-analysis.
BACKGROUND
People who inject drugs (PWID) experience barriers to accessing testing and treatment for hepatitis C virus (HCV) infection. Opioid agonist therapy (OAT) may provide an opportunity to improve access to HCV care. This systematic review assessed the association of OAT and HCV testing, treatment, and treatment outcomes among PWID.
METHODS
Bibliographic databases and conference presentations were searched for studies that assessed the association between OAT and HCV testing, treatment, and treatment outcomes (direct-acting antiviral [DAA] therapy only) among PWID (in the past year). Meta-analysis was used to pool estimates.
RESULTS
Of 9877 articles identified, 22 studies conducted in Australia, Europe, North America, and Thailand were eligible and included. Risk of bias was serious in 21 studies and moderate in 1 study. Current/recent OAT was associated with an increased odds of recent HCV antibody testing (4 studies; odds ratio (OR), 1.80; 95% confidence interval [CI], 1.36-2.39), HCV RNA testing among those who were HCV antibody-positive (2 studies; OR, 1.83; 95% CI, 1.27-2.62), and DAA treatment uptake among those who were HCV RNA-positive (7 studies; OR, 1.53; 95% CI, 1.07-2.20). There was insufficient evidence of an association between OAT and treatment completion (9 studies) or sustained virologic response following DAA therapy (9 studies).
CONCLUSIONS
OAT can increase linkage to HCV care, including uptake of HCV testing and treatment among PWID. This supports the scale-up of OAT as part of strategies to enhance HCV treatment to further HCV elimination efforts.
Topics: Analgesics, Opioid; Antiviral Agents; Australia; Europe; Hepatitis C; Hepatitis C, Chronic; Humans; North America; Pharmaceutical Preparations; Substance Abuse, Intravenous; Thailand; Treatment Outcome
PubMed: 32447375
DOI: 10.1093/cid/ciaa612 -
Drugs Dec 2020Based on current evidence, recent guidelines of the National Institute of Health, USA indicated the use of remdesivir and dexamethasone for the treatment of COVID-19...
BACKGROUND
Based on current evidence, recent guidelines of the National Institute of Health, USA indicated the use of remdesivir and dexamethasone for the treatment of COVID-19 patients with mild-moderate disease, not requiring high-flow oxygen. No therapeutic agent directed against the immunologic pathogenic mechanisms related to the cytokine release syndrome complicating the disease was indicated.
OBJECTIVES
The purpose of this review was to assess the clinical impact of different therapies for COVID-19; thus, helping to identify the optimal management of the disease. To explain the rationale for the different therapeutic approaches, the characteristics of SARS-CoV-2, the pathogenesis of COVID-19, and the immune response triggered by SARS-CoV-2 infection were reported.
METHODS
The efficacy assessment of the different treatments was performed by a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Available English language published articles including randomised controlled trials, open-label trials of antivirals and immune therapies extracted from Medline, Google Scholar, and MedRxiv databases were analysed. For inclusion, the primary end point of the trials had to be the efficacy as measured by the improvement of clinical features, or mortality, or the Intensive Care Unit Admission rate, or the discharge number. Case reports, paediatric studies, and studies without control group were excluded. The literature search was extended up to August 15, 2020.
RESULTS
After the removal of duplicate articles, and the exclusion of studies not meeting the eligibility criteria, 2 trials of lopinavir/ritonavir, 1 of favipiravir, 3 of remdesivir, 1 of dexamethasone, 3 of hydroxychloroquine, 2 of colchicine, 6 of tocilizumab, 1 of sarilumab, 1 of siltuximab, 2 of anakinra, 3 of baricitinib, 1 of ruxolitinib, 1 of mavrilimumab, and 1 of itolizumab were suitable for the review. Among antivirals, only remdesivir significantly reduced the time to recovery, and mortality. Data for chloroquine and hydroxychloroquine were largely inconclusive. In a large trial, dexamethasone 6 mg/day reduced mortality by one-third. Trials of tocilizumab and sarilumab did not definitively demonstrate efficacy. Anakinra significantly reduced the mortality in 2 trials. Three retrospective trials on a cumulative number of 145 patients, reported the efficacy of baricitinib, with significant reduction of intensive care unit admission, and deaths. These results were recently confirmed by the ACTT-2 trial. Due to paucity of studies and to the small size clinical series, the results of other immune therapies were not conclusive.
CONCLUSIONS
Beyond the supportive therapy, up to now the best therapeutic approach for COVID-19 may be a three-step combination therapy, including remdesivir 100 mg/day (200 mg loading dose on first day) in the first stage of the disease, and combined dexamethasone 6 mg/day plus baricitinib 4 mg/day to target the immune dysregulation triggered by the SARS-CoV-2 infection. The promising results of anakinra should be confirmed by the ongoing RCTs.
Topics: Adenosine Monophosphate; Alanine; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antiviral Agents; Biological Products; COVID-19; Cytokines; Dexamethasone; Drug Therapy, Combination; Humans; Inflammation Mediators; Intensive Care Units; Pandemics; Retrospective Studies; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33068263
DOI: 10.1007/s40265-020-01421-w