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1.
New treatments for cytomegalovirus in transplant patients.
Coppock, GM, Blumberg, E
Current opinion in nephrology and hypertension. 2019;(6):587-592
Abstract
PURPOSE OF REVIEW The purpose of this review is to highlight novel advances in prophylaxis against and treatment of CMV in kidney transplant recipients. Current options include intravenous ganciclovir and oral valganciclovir, but use of these agents is limited by side effects, such as myelosuppression as well as evolving resistance in CMV strains. RECENT FINDINGS Advances in the field include novel drugs that have shown promise in preliminary studies and are now being tested in large-scale clinical trials. Moreover, there is a developing focus in enhancing host immune responses to better protect against viral infection using anti-CMV vaccines. Studying host immune responses to CMV has also led to improved monitoring strategies, such as the QuantiFERON assay, which will allow for improved risk stratification and targeted therapies in transplant recipients. SUMMARY In summary, although options for prophylaxis and treatment against CMV have been somewhat limited to date, a number of new strategies are currently under development with several drugs in phase 3 trials. Therefore, the landscape of CMV management in kidney transplant recipients will be changing significantly in the coming years with the ultimate goal of safer and more effective therapies to combat CMV.
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Current Strategies for Elimination of HIV-1 Latent Reservoirs Using Chemical Compounds Targeting Host and Viral Factors.
Jean, MJ, Fiches, G, Hayashi, T, Zhu, J
AIDS research and human retroviruses. 2019;(1):1-24
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Abstract
Since the implementation of combination antiretroviral therapy (cART), rates of HIV type 1 (HIV-1) mortality, morbidity, and newly acquired infections have decreased dramatically. In fact, HIV-1-infected individuals under effective suppressive cART approach normal life span and quality of life. However, long-term therapy is required because the virus establish a reversible state of latency in memory CD4+ T cells. Two principle strategies, namely "shock and kill" approach and "block and lock" approach, are currently being investigated for the eradication of these HIV-1 latent reservoirs. Actually, both of these contrasting approaches are based on the use of small-molecule compounds to achieve the cure for HIV-1. In this review, we discuss the recent progress that has been made in designing and developing small-molecule compounds for both strategies.
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Switching Lamivudine with Adefovir Dipivoxil Combination Therapy to Entecavir Monotherapy Provides Better Viral Suppression and Kidney Safety.
Lian, JS, Zhang, XL, Lu, YF, Chen, JY, Zhang, YM, Jia, HY, Zhang, Z, Yang, YD
International journal of medical sciences. 2019;(1):17-22
Abstract
Introduction: Most chronic hepatitis B (CHB) patients in China are primitively treated with a combination of lamivudine (LAM) and adefovir dipivoxil (ADV). Although antiviral resistance can be avoided with this combination therapy, using it can have harmful side effects related to ADV, specifically kidney and bone injury. This study was designed to compare viral suppression and kidney safety when switching LAM and ADV combination therapy de novo to entecavir (ETV) monotherapy in patients with CHB and compensated hepatic cirrhosis. Materials and methods: In total, 360 CHB and compensated liver cirrhosis patients who received treatment of LAM and ADV combination therapy for more than 1 year were included in this study. One hundred and eighty patients continued combination therapy to serve as a control group and the other 180 patients were switched to ETV monotherapy to serve as the experimental group. The total course of therapy was 3 years. Laboratory studies were done every 3 months to measure liver and kidney function. Studies included glomerular filtration rate (eGFR), HBV-DNA, urine β2-microglobulin (β2-M) and retinol binding protein (RBP). Results: In the experimental group, an HBV-DNA level below 20 IU/ml was found in 77.65%, 85.88%, and 94.77% in years 1, 2, and 3, respectively. In the control group, HBV-DNA levels were below 20 IU/ml in 69.66%, 75.42%, and 85.80% in years 1, 2, and 3, respectively. Low HBV-DNA levels in the experimental group were significantly less common than in the control group on the second and third year; P values were 0.009 and 0.006 for years 2 and 3, respectively. The cumulative genetic mutation rate was 3.49% in the experimental group and 8.88% in the control group (P=0.044). Decreases in eGFR more than 30% from baseline were found in 0%, 0.56%, and 1.74% of patients in the experimental group and 4.49%, 9.14% and 14.79% in patients in the control group in the first, second, and third year, respectively. Serum creatinine more than 50 μmol/L above baseline was found in 0%, 0% and 1.74% of patients in the experimental group and 1.12%, 4.00% and 5.32% of patients in the control group in years 1, 2, and 3, respectively. The urine β2-M and RBP levels were abnormal more often in the experimental group than in the control group. Conclusion: Switching to ETV monotherapy can decrease HBV-DNA levels, reduce the genetic mutation rate, and prevent renal damage caused by LAM and ADV combination therapy in patients with CHB and compensated liver cirrhosis. Patients receiving LAM and ADV combination therapy de novo should be switched to ETV monotherapy immediately.
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Palivizumab and Long-term Outcomes in Cystic Fibrosis.
Fink, AK, Graff, G, Byington, CL, Loeffler, DR, Rosenfeld, M, Saiman, L
Pediatrics. 2019;(1)
Abstract
BACKGROUND The American Academy of Pediatrics does not recommend routine use of palivizumab prophylaxis for infants with cystic fibrosis (CF) but recommends consideration in infants with clinical evidence of chronic lung disease or nutritional compromise. However, the beneficial impact of palivizumab on longer-term outcomes is uncertain. METHODS We used Cystic Fibrosis Foundation Patient Registry data to assess the association of receiving palivizumab during the first 2 years of life with longer-term outcomes, including lung function at 7 years old, time to first positive Pseudomonas respiratory culture, and pulmonary-related hospitalizations during the first 7 years of life. Eligible infants were born from 2008 to 2015 and diagnosed with CF during the first 6 months of life. Demographic and clinical confounders of association between palivizumab receipt and outcomes were explored. We created propensity scores to adjust for potential confounding by indication (ie, sicker infants were more likely to receive palivizumab). For each outcome, we performed regression analyses adjusted by propensity scores. RESULTS The sample included 4267 infants; 1588 (37%) received palivizumab. Mean percent forced expiratory volume in 1 second predicted at 7 years old was similar among those who did (98.2; 95% confidence interval: 96.9-99.5) and did not (97.3; 95% confidence interval: 96.1-98.5) received palivizumab, adjusting for propensity scores. Time to first positive Pseudomonas aeruginosa culture and annual risk of hospitalization were similar among those who did and did not receive palivizumab. CONCLUSIONS At the population level, palivizumab receipt was not associated with improved longer-term outcomes in children with CF.
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Successful treatment of chronic hepatitis C virus infection with crushed glecaprevir/pibrentasvir administered via a percutaneous endoscopic gastrostomy tube: case report and review of the literature.
Tanaka, Y, Tateishi, R, Koike, K
Clinical journal of gastroenterology. 2019;(6):588-591
Abstract
Glecaprevir (GLE)/pibrentasvir (PIB) is a direct-acting antiviral regimen approved for patients infected with hepatitis C virus. No data are available on the safety and efficacy of this regimen when crushed and administered through a percutaneous endoscopic gastrostomy (PEG) tube. Here, we report a patient who successfully achieved a sustained viral response after treatment with GLE/PIB administered via a PEG tube. A 41-year-old female with chronic hepatitis C viral infection was referred to our department for treatment. She had a history of spina bifida and hydrocephalus, and she received a PEG tube for nutrition and medication due to an aftereffect of hydrocephalus. She received crushed GLE/PIB treatment through a PEG tube for 8 weeks and achieved a sustained viral response 12, without any treatment-related severe adverse events. This is the first documented case treated with GLE/PIB administered through a PEG tube. Based on this case report and a review of the literature, we discuss the safety and efficacy of direct-acting antiviral treatment via a PEG tube.
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Patient characteristics and analgesic efficacy of antiviral therapy in postherpetic neuralgia.
Lin, YT, Wang, LK, Hung, KC, Wu, ZF, Chang, CY, Chen, JY
Medical hypotheses. 2019;:109323
Abstract
Postherpetic neuralgia (PHN) is the most common complication of shingles caused by reactivation of varicella zoster virus (VZV). Management of PHN is often suboptimal while using current conventional treatments. Antiviral therapy was used to reduce PHN-associated pain in two small trials which showed conflicting results. We hypothesize the analgesic efficacy of antiviral therapy on PHN is affected by patient characteristics including pathophysiology of the participants and serum vitamin D levels. Pathophysiology of PHN includes neuronal excitability and chronic VZV ganglionitis (persistent active VZV infection in ganglions). VZV-DNA positivity or a positive IgG coupled with a positive IgM indicates recent or current VZV infection. Positive VZV-DNA or IgG/IgM tests are used to confirm whether the patients experience chronic VZV ganglionitis. Antiviral therapy decreases pain in PHN patients with chronic VZV ganglionitis; whereas, antiviral therapy shows no effects in PHN patients with negative VZV-DNA or IgM. Vitamin D is a natural antiviral mediator. Studies show a high prevalence of vitamin D deficiency in hepatitis B/C virus-infected patients. Serum vitamin D levels and vitamin D supplementation are factors which affect the antiviral efficacy on hepatitis B/C virus infection. Serum 25-OHD levels of hospitalized patients with shingles were significantly lower compared to healthy controls. Accordingly, PHN patient may have a high prevalence of vitamin D deficiency which negatively affects the antiviral efficacy. Vitamin D supplementation may improve the antiviral efficacy on PHN. Future trials regarding antiviral therapy on PHN should consider patient characteristics and should be conducted among different subgroups of PHN patients.
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Comparative efficacy of tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B: A systematic review and meta-analysis.
Chen, MB, Wang, H, Zheng, QH, Zheng, XW, Fan, JN, Ding, YL, Niu, JL
PloS one. 2019;(11):e0224773
Abstract
OBJECTIVE To compare the efficacy of tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B. METHODS The Web of Science, PubMed, Cochrane Library, EMBASE, Clinical Trials and China National Knowledge Infrastructure(CNKI) databases were electronically searched to collect randomized controlled trials (RCTs) regarding the comparison between tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B (CHB) since the date of database inception to July 2019. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. RevMan 5.3 software was used for the meta-analysis. RESULTS Early on, tenofovir had a greater ability to inhibit the hepatitis B virus, I2 = 0% [RR = 1.08, 95% CI (1.03, 1.13), P<0.01] (96 weeks). Entecavir can normalize the ALT levels earlier, I2 = 0% [RR = 0.87, 95% CI (0.77, 0.98), P = 0.02] (48 weeks). However, there was no statistically significant difference between TDF and ETV at 144 weeks. Tenofovir was as effective as entecavir in terms of HBeAg clearance and HBeAg seroconversion, I2 = 0% [RR = 1.05, 95% CI (0.68, 1.62), P = 0.82]; I2 = 69% [RR = 0.93, 95% CI (0.54, 1.61), P = 0.80]. The difference in the incidence of elevated creatine kinase levels was not statistically significant I2 = 0% [RR = 0.66, 95% CI (0.27, 1.60), P = 0.35]. CONCLUSIONS Tenofovir and entecavir were equally effective in the treatment of patients with nucleos(t)ide analogue-naive chronic hepatitis B. In addition, TDF has an advantage in the incidence of hepatocellular carcinoma. Additional RCTs and a large-sample prospective cohort study should be performed.
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Viral Infections and Interferons in the Development of Obesity.
Tian, Y, Jennings, J, Gong, Y, Sang, Y
Biomolecules. 2019;(11)
Abstract
Obesity is now a prevalent disease worldwide and has a multi-factorial etiology. Several viruses or virus-like agents including members of adenoviridae, herpesviridae, slow virus (prion), and hepatitides, have been associated with obesity; meanwhile obese patients are shown to be more susceptible to viral infections such as during influenza and dengue epidemics. We examined the co-factorial role of viral infections, particularly of the persistent cases, in synergy with high-fat diet in induction of obesity. Antiviral interferons (IFNs), as key immune regulators against viral infections and in autoimmunity, emerge to be a pivotal player in the regulation of adipogenesis. In this review, we examine the recent evidence indicating that gut microbiota uphold intrinsic IFN signaling, which is extensively involved in the regulation of lipid metabolism. However, the prolonged IFN responses during persistent viral infections and obesogenesis comprise reciprocal causality between virus susceptibility and obesity. Furthermore, some IFN subtypes have shown therapeutic potency in their anti-inflammation and anti-obesity activity.
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2018 Ebola virus disease outbreak in Équateur Province, Democratic Republic of the Congo: a retrospective genomic characterisation.
Mbala-Kingebeni, P, Pratt, CB, Wiley, MR, Diagne, MM, Makiala-Mandanda, S, Aziza, A, Di Paola, N, Chitty, JA, Diop, M, Ayouba, A, et al
The Lancet. Infectious diseases. 2019;(6):641-647
Abstract
BACKGROUND The 2018 Ebola virus disease (EVD) outbreak in Équateur Province, Democratic Republic of the Congo, began on May 8, and was declared over on July 24; it resulted in 54 documented cases and 33 deaths. We did a retrospective genomic characterisation of the outbreak and assessed potential therapeutic agents and vaccine (medical countermeasures). METHODS We used target-enrichment sequencing to produce Ebola virus genomes from samples obtained in the 2018 Équateur Province outbreak. Combining these genomes with genomes associated with known outbreaks from GenBank, we constructed a maximum-likelihood phylogenetic tree. In-silico analyses were used to assess potential mismatches between the outbreak strain and the probes and primers of diagnostic assays and the antigenic sites of the experimental rVSVΔG-ZEBOV-GP vaccine and therapeutics. An in-vitro flow cytometry assay was used to assess the binding capability of the individual components of the monoclonal antibody cocktail ZMapp. FINDINGS A targeted sequencing approach produced 16 near-complete genomes. Phylogenetic analysis of these genomes and 1011 genomes from GenBank revealed a distinct cluster, confirming a new Ebola virus variant, for which we propose the name "Tumba". This new variant appears to have evolved at a slower rate than other Ebola virus variants (0·69 × 10-3 substitutions per site per year with "Tumba" vs 1·06 × 10-3 substitutions per site per year without "Tumba"). We found few sequence mismatches in the assessed assay target regions and antigenic sites. We identified nine amino acid changes in the Ebola virus surface glycoprotein, of which one resulted in reduced binding of the 13C6 antibody within the ZMapp cocktail. INTERPRETATION Retrospectively, we show the feasibility of using genomics to rapidly characterise a new Ebola virus variant within the timeframe of an outbreak. Phylogenetic analysis provides further indications that these variants are evolving at differing rates. Rapid in-silico analyses can direct in-vitro experiments to quickly assess medical countermeasures. FUNDING Defense Biological Product Assurance Office.
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Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.
Carrat, F, Fontaine, H, Dorival, C, Simony, M, Diallo, A, Hezode, C, De Ledinghen, V, Larrey, D, Haour, G, Bronowicki, JP, et al
Lancet (London, England). 2019;(10179):1453-1464
Abstract
BACKGROUND Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort. METHODS We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458. FINDINGS Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27). INTERPRETATION Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection. FUNDING INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.