Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C

AIM: To elucidate risk factors contributing to the development of hepatocellular carcinoma (HCC) among patients with sustained viral response (SVR) after interferon (IFN) treatment and to examine whether HCV-RNA still remained in the liver of SVR patients who developed HCC. METHODS: Two-hundred and sixty-six patients, who achieved SVR, were enrolled in this study. We retrospectively reviewed clinical, viral and histological features of the patients, and examined whether the development of HCC depends on several clinical variables using Kaplan-Meier Method. RT-PCR was used to seek HCV-RNA in 3 out of 7 patients in whom liver tissue was available for molecular analysis. RESULTS: Among the enrolled 266 patients with SVR, HCC developed in 7 patients (7/266; 2.6%). We failed to detect HCV-RNA both in cancer and non-cancerous liver tissue in all three patients. The cumulative incidence for HCC was significantly different depending on hepatic fibrosis (F3-4) (P = 0.0028), hepatic steatosis (Grade 2-3) (P = 0.0002) and age (≥ 55) (P = 0.021) at the pre-interferon treatment. CONCLUSION: The current study demonstrated that age, hepatic fibrosis, and hepatic steatosis at pre- interferon treatment might be risk factors for developing HCC after SVR.

RNA interference and antiviral therapy

RNA interference (RNAi) is an evolutionally conserved gene silencing mechanism present in a variety of eukaryotic species. RNAi uses short double-stranded RNA (dsRNA) to trigger degradation or translation repression of homologous RNA targets in a sequence-specific manner. This system can be induced effectively in vitro and in vivo by direct application of small interfering RNAs (siRNAs), or by expression of short hairpin RNA (shRNA) with non-viral and viral vectors. To date, RNAi has been extensively used as a novel and effective tool for functional genomic studies, and has displayed great potential in treating human diseases, including human genetic and acquired disorders such as cancer and viral infections. In the present review, we focus on the recent development in the use of RNAi in the prevention and treatment of viral infections. The mechanisms, strategies, hurdles and prospects of employing RNAi in the pharmaceutical industry are also discussed.

Hepatitis C virus resistance to new specifically-targeted antiviral therapy: A public health perspective

Until very recently, treatment for chronic hepatitis C virus(HCV) infection has been based on the combination of two non-viral specific drugs: pegylated interferon-α and ribavirin, which is effective in, overall, about 40%-50% of cases. To improve the response to treatment, novel drugs have been designed to specifically block viral proteins. Multiple compounds are under development, and the approval for clinical use of the first of such direct-acting antivirals in 2011(Telaprevir and Boceprevir), represents a milestone in HCV treatment. HCV therapeutics is entering a new expanding era, and a highly-effective cure is envisioned for the first timesince the discovery of the virus in 1989. However, any antiviral treatment may be limited by the capacity of the virus to overcome the selective pressure of new drugs, generating antiviral resistance. Here, we try to provide a basic overview of new treatments, HCV resistance to new antivirals and some considerations derived from a Public Health perspective, using HCV resistance to protease and polymerase inhibitors as examples.

MicroRNA-regulated viral vectors for gene therapy

Safe and effective gene therapy approaches require targeted tissue-specific transfer of a therapeutic transgene.Besides traditional approaches, such as transcriptional and transductional targeting, micro RNA-dependent posttranscriptional suppression of transgene expression has been emerging as powerful new technology to increase the specificity of vector-mediated transgene expression. Micro RNAs are small non-coding RNAs and often expressed in a tissue-, lineage-, activation- or differentiation-specific pattern. They typically regulate gene expression by binding to imperfectly complementary sequences in the 3' untranslated region(UTR) of the m RNA. To control exogenous transgene expression, tandem repeats of artificial micro RNA target sites are usually incorporated into the 3' UTR of the transgene expression cassette, leading to subsequent degradation of transgene m RNA in cel s expressing the corresponding micro RNA. This targeting strategy, first shown for lentiviral vectors in antigen presenting cells, has now been used for tissue-specific expression of vector-encoded therapeutic transgenes, to reduce immune response against the transgene, to control virus tropism for oncolytic virotherapy, to increase safety of live attenuated virus vaccines and to identify and select cell subsets for pluripotent stem cell therapies, respectively. This review provides an introduction into the technical mechanism underlying micro RNA-regulation, highlights new developments in this field and gives an overview of applications of micro RNA-regulated viral vectors for cardiac, suicide gene cancer and hematopoietic stem cell therapy, as well as for treatment of neurological and eye diseases.

Tuberculin as Intralesional Therapy for Viral Warts—Single-Blind, Split, Placebo, Controlled Study

Background: BCG vaccine as an antigen has proved its effectiveness as an immunotherapy for viral warts. Tuberculin is an antigenic extract of M. tuberculosis capable of eliciting an immunological skin reaction. Objective: To assess the efficacy of tuberculin intralesional injection in the treatment of viral warts. Patients and Methods: This single ,blind, placebo controlled study was conducted at the Department of Dermatology, Baghdad Teaching Hospital, Baghdad, Iraq from March 2010 to July 2011.Forty-one patients with different types of viral warts were enrolled in this study;tuberculin test was done to patients prior to instillation of intralesional treatment. Then the patients treated by intralesional tuberculin in each lesion located on the right side of the body, and intralesional distilled water in each lesion located on the left side of to a maximum of 3 injections, at 2 weeks interval or until full resolution of these lesions. Patients were evaluated every 2 weeks to assess the regression of their lesions and to record any local and systemic adverse effects. The response to treatment was evaluated by decrease in size and reduction in number of warts. Scoring of response to treatment was as follow: 1) Responders: including patients who showed complete cure or those with good response (>50% reduction). 2) Non responders: including patients who showed minimal response (<50% reduction), or those with no improvement (stable disease and disease progression). The follow up period lasted up to 2 months after the last dose. Results: Thirty out of 41 patients had completed the study, of them 14 (46.66%) patients showed response of their lesions on the right side of the body that were treated with tuberculin;15 patients showed no response, 1 patient showed minimal response, 7 patients showed good response and 7 patients showed complete cure (23.33%). Regarding the lesions treated with intralesional distilled water, 25 patients showed no response, 3 patients showed minimal response, 2(6.66) patients showed good response and no patient showed complete cure of their warts. Of the 14 responder patients to intralesional tuberculin, 10 patients were tuberculin tested positive, and 4 patients were tested negative, and of the 16 non responder patients to intralesional tuberculin, 3 patients were tuberculin tested positive, and 13 patients were tuberculin tested negative which was statistically significant difference. No side effects reported from tuberculin therapy apart from mild pain at site of injection. Conclusion: Intralesional injection of tuberculin is an effective therapy for viral warts when compared with control, possibly through its local immunological action and had no systemic immunological response. Patients with previous BCG vaccine showed better response to tuberculin injection.

Study of HIV-1 Drug Resistance in Patients Receiving Free Antiretroviral Therapy in China

To investigate the prevalence of drug-resistance mutations,resistance to antiretroviral drugs,and the subsequent virological response to therapy in treatment-naive and antiretroviral-treated patients infected with HIV/AIDS in Henan,China,a total of 431 plasma samples were collected in Queshan county between 2003 and 2004,from patients undergoing the antiretroviral regimen Zidovudine + Didanosine + Nevirapine(Azt+Ddi+Nvp).Personal information was collected by face to face interview.Viral load and genotypic drug resistance were tested.Drug resistance mutation data were obtained by analyzing patient-derived sequences through the HIVdb Program(http://hivdb.stanford.edu).Overall,38.5% of treatment-naive patients had undetectable plasma viral load(VL),the rate significantly increased to 61.9% in 0 to 6 months treatment patients(mean 3 months)(P<0.005)but again significantly decrease to 38.6% in 6 to 12 months treatment patients(mean 9 months)(P<0.001)and 40.0% in patients receiving more than 12 months treatment(mean 16 months)(P<0.005).The prevalence of drug resistance in patients who had a detectable VL and available sequences were 7.0%,48.6%,70.8%,72.3% in treatment-na?ve,0 to 6 months treatment,6 to 12 months treatment,and treatment for greater than 12 months patients,respectively.No mutation associated with resistance to Protease inhibitor(PI)was detected in this study.Nucleoside RT inhibitor(NRTI)mutations always emerged after non-nucleoside RT inhibitor(NNRTI)mutations,and were only found in patients treated for more than 6 months,with a frequency less than 5%,with the exception of mutation T215Y(12.8%,6/47)which occurred in patients treated for more than 12 months.NNRTI mutations emerged quickly after therapy begun,and increased significantly in patients treated for more than 6 months(P<0.005),and the most frequent mutations were K103N,V106A,Y181C,G190A.There had been optimal viral suppression in patients undergoing treatment for less than 6 months in Queshan,Henan.The drug resistance strains were highly prevalent in antiretroviral-treated patients,and increased with the continuation of therapy,with many patients encountering virological failure after 6 months therapy.

Viral Characteristic of HIV Infected Patients Naïf of Anti-Retroviral Therapy with CD4+ T Lymphocytes Rate Greater than 350 per Microliter of Blood in LoméTogo

Objective: To evaluate the virological status of ineligible HIV patients for anti-retroviral therapy based on the criterion of CD4+ T lymphocytes rate over than 350/μl of blood. Method: This is a prospective study which was conducted from November 2011 to July 2012 in the tropical and infectious disease department of CHU Sylvanus Olympio of Lomé. All HIV-1 infected patients whose CD4+ T lymphocytes rate was ≥350/μl of blood were retained. The count of CD4+ T lymphocytes was made by cytometer FACSCalibur? flow of BD biosciences and the determination of viral load was achieved by NASBA laboratory method of Biomérieux. Results: We have recruited 102 PLWHA aged between 19 and 58 years with a median of 35 years. Biologically, 102 patients had a T-CD4 rate between 355 and 432/μl of blood. The determination of viral load showed a very high viral replication more than 10,000 copies/ml among all patients and 28 (27.5%) patients had a viral load > 100,000 copies/ml of blood. Conclusion: Our results argue for a reconsideration of the criteria for starting antiretroviral therapy in Togo by including virological data if necessary in patients with T-CD4 rate below 500/μl of blood.

Immunovirologic Evaluation of Triomune (Lamivudine, Stavudine and Nevirapine) Antiretroviral Therapy in First Line HIV-1 Adult Patients in N’Djamena, Chad

Contexte:?The fight against HIV/AIDS epidemics is one of the greatest challenges of this century. The epidemic affects generally under-developed countries, and Sub-Saharan Africa are the most concerned. The combined marketed form known as Triomune was used as first-line treatment in several sub-Saharan African Countries (60% of VIH infected people), including Chad. However, no evaluation has been done for that treatment in the country. Objective: To evaluate the efficacy and safety immuno-virological of Triomune at the General Hospital in N’Djamena/Chad. Methods: 48 HIV-1 positive patients eligible for ARV treatment were enrolled in our study, and they have been then followed for 8 months. We have measured in these patients the CD4 cell count before treatment and at the 8th month of treatment. After 8 months of treatment, we have also evaluated the Lymphocyte T CD4 and the plasma viral load (VL). Comparisons of means of CD4 lymphocytes and plasma CV (≥1000 copies/ml) were used to define treatment failure.?Results:?48 patients were under Triomune regime. The average CD4 count was decreased from 462 ± 179.22 [56 - 981] cells/mm3?before treatment to 327.23 ± 153.77 [10 - 1008] cells/mm3?at the 8th month of treatment. The mean plasma viral load for patients was 66008.62 copies/ml. The failure rate to Triomune was 43.75% (21/48).?Conclusion:?Aside from the side effects already described for Triomune, our study reveals a high treatment failure rate. Hence, there is the need of regular revisions of therapeutic regime administer in the first intention.

Treatment of Recalcitrant Viral Warts with Photodynamic Therapy with Mal and Red Light

Background: Photodynamic therapy (PDT) is a treatment for non-melanoma skin cancer. In recent years, its use has expanded to new indications. Viral warts (VW) are some of the most promising. Methods: A retrospective, descriptive, observational study was carried out. Patients who did not respond to cryotherapy were selected and were occluded with methyl aminolevulinate (MAL) for three hours and they were illuminated with red light. Tolerance to treatment was evaluated using a visual analog scale for pain (from 0 to 10). Results: A total of 15 patients with 134 VW were treated. A complete response was obtained in 13 of 15 patients (87%) and in 127 of 134 lesions (95%). The mean number of sessions was 3.1 (range 1 to 6) and the average pain score was 3.1 (range 0 to 8). Conclusions: PDT is a treatment that offers good results in the treatment of VW that are resistant to routine treatment. The treatment was well tolerated in our patient group.

Viral Monitoring and Prevalence of Viral Failure in HIV-1 Infected Children under First Line Antiretroviral Therapy during the First 60 Months of Treatment in Yaoundé, Cameroon: A Serial Cross Sectional Analysis

Objective: The objective was to measure the prevalence of viral failure (VF) in HIV-1-infected children on first-line antiretroviral therapy (ART) in routine practice. Methods: Serial cross sectional analysis of viral load (VL) in HIV-1 infected children on first-line ART for ≥24 weeks was done. VL was measured by Real-Time-Polymerase chain reaction (biocentrics). Samples were collected at 6, 12, 24, 36, 48, 60 months of treatment. Main measurement: Virological failure (VF) defined by a one-off VL > 1000 copies/ml. Results: 375 children aged ≤16 years on first-line-ART were included. Median age at ART start was 4.2 years and ≥50% have started ART ≤3rd birthday. A total of 717 measurements of VL were collected. VF was rated between 18% and 26% from 6 - 60 months (mean 20.2%), 95% IC [13.1 - 27.3] at the threshold of 1000 copies/ml, not too different at the threshold of 400 copies/ml, 21% - 30% (mean 23.9%), 95% IC [16.3 - 31.5], p = 0.9. Conclusion: In Yaounde, almost 20% of children on first-line of adherent-ART can experiment VF while improving immune status urging improvement of adherence.

The Risk of Severe Acute Kidney Injury Requiring Renal Replacement Therapy in Viral Hemorrhagic Fevers. A Review of Literature

Objective: It demonstrates the correlation of the viral hemorrhagic fever with kidney failure and the treatment as well as the outcome. Method: A PubMed search of the English literature from 1999 to 2019 was performed using “viral hemorrhagic fever, Case Report, Renal Failure” as the subject. The inclusion criteria were the following: 1) case report and case series of two or more patients;2) the report detailed the clinical presentation and reported the status of the renal system;3) the report described the management of renal failure if any;and 4) the etiology of the infection is known and is one of the known agents of viral hemorrhagic fever, listed on the centers of disease control website. We excluded infections related to vaccination related to viral hemorrhagic fever. Result: We found the mean age of these patients was 41.5. The male to female ratio was about 3.5:1. Dengue and Hantaviruses constituted 70.5% of patients. The overall mortality of the study cohort was 32.2%. Half of the patients had acute kidney injury and required renal replacement therapy. The chi-square statistic is 0.41;The p-value is 0.51;The chi-square statistic is 6.4254. Overall mortality was 32.3% in one cohort of 78 patients. The illness goes through several stages [1] [2] of clinical features and some viruses in the group have a high case fatality rate. Conclusions: Early diagnosis with aggressive supportive care is critical for improving clinical outcomes. Renal involvement is common. Amongst the cohort reviewed, of patients who had acute kidney injury, half of the patients required renal replacement support. However, some viruses cause greater kidney injury than others, for instance, kidney injury is more severe in Dengue hemorrhagic fevers when compared to Hantaviruses. Simultaneous management of public health by prevention and control of outbreaks is particularly important.

Crimean-Congo hemorrhagic fever:Pathogenesis,transmission and public health challenges

The dangerous Crimean-Congo hemorrhagic fever virus(CCHFV),an encapsulated negative-sense RNA virus of the family Nairoviridae,is transmitted from person to person via ticks.With a case fatality rate between 10%to 40%,the most common ways that the disease may spread to humans are via tick bites or coming into touch with infected animals'blood or tissues.Furthermore,the transfer of bodily fluids between individuals is another potential route of infection.There is a wide range of symptoms experienced by patients throughout each stage,from myalgia and fever to extreme bruising and excess bleeding.Tick management measures include minimising the spread of ticks from one species to another and from people to animals via the use of protective clothing,repellents,and proper animal handling.In order to prevent the spread of illness,healthcare workers must adhere to stringent protocols.Despite the lack of an authorised vaccine,the main components of treatment now consist of preventative measures and supportive care,which may include the antiviral medicine ribavirin.We still don't know very much about the virus's mechanisms,even though advances in molecular virology and animal models have improved our understanding of the pathogenesis of CCHFV.A critical need for vaccination that is both safe and effective,as well as for quick diagnosis and efficient treatments to lessen the disease's impact in areas where it is most prevalent.Important steps towards lowering Crimean-Congo hemorrhagic fever mortality and morbidity rates were to anticipatethe future availability of immunoglobulin products.

New gene therapy strategies for hepatic fibrosis

The liver is the largest internal organ of the body, which may suffer acute or chronic injury induced by many factors, leading to cirrhosis and hepatocarcinoma. Cirrhosis is the irreversible end result of fibrous scarring and hepatocellular regeneration, characterized by diffuse disorganization of the normal hepatic structure, regenerative nodules and fibrotic tissue. Cirrhosis is associated with a high co-morbidity and mortality without effective treatment, and much research has been aimed at developing new therapeutic strategies to guarantee recovery. Liver-based gene therapy has been used to downregulate specific genes, to block the expression of deleterious genes, to delivery therapeutic genes, to prevent allograft rejection and to augment liver regeneration. Viral and non-viral vectors have been used, with viral vectors proving to be more efficient. This review provides an overview of the main strategies used in liver-gene therapy represented by non-viral vectors, viral vectors, novel administration methods like hydrodynamic injection, hybrids of two viral vectors and blocking molecules, with the hope of translating findings from the laboratory to the patient′s bed-side.

RNAi,a new therapeutic strategy against viral infection

RNA interference (RNAi) is an adaptive defense mechanism triggered by double-stranded RNA (dsRNA). It is a powerful reverse genetic tool that has been widely employed to silence gene expression in mammalian and human cells.RNAi-based gene therapies, especially in viral diseases have become more and more interesting and promising. Recently,small interfering RNA (siRNA) can be used to protect host from viral infection, inhibit the expression of viral antigen and accessory genes, control the transcription and replication of viral genome, hinder the assembly of viral particles, and display influences in virus-host interactions. In this review, we attempt to present recent progresses of this breakthrough technology in the above fields and summarize the possibilities of siRNA-based drugs.

Fundus manifestations and HIV viral loads of AIDS patients before and after HAART

AIM: To investigate the fundus manifestations and human immunodeficiency virus(HIV) viral loads of acquired immune deficiency syndrome(AIDS) patients before and after highly active antiretroviral therapy(HAART).METHODS: This retrospective study included 21 AIDS patients(42 eyes) who presented to the Department of Ophthalmology, Peking Union Medical College Hospital, from 2007 to 2011. Among the patients, 16 showed a good response to HAART, 3 presented drug resistance and 2 were pre-HAART. All patients underwent comprehensive ophthalmic examinations. The HIV viral loads and the CD4+ T-cell counts were also determined.RESULTS: The best-corrected visual acuity(BCVA) of 38 eyes(19 patients) was improved, and cytomegalovirus retinitis(CMVR) in 5 eyes(3 patients) regressed after HAART. Furthermore, 16 patients treated with effective HAART had decreased plasma HIV viral loads(<78 copies/mL)and increased CD4+ T-cell counts(343±161 cells/μL, P<0.005), but the HIV viral load in tears was still detected at 2404 copies/mL. The CD4+ T-cell count was lower in the CMVR group than in the non-CMVR group(P=0.022), but the HIV viral load in the tears was not significantly different between the two groups(P=0.439).CONCLUSION: Most patients with AIDS show a good viral response with a decreased HIV viral load and an increased CD4+ T-cell count in plasma after HAART. However, the HIV viral load remain quite high in the tear samples. Based on our results, we suggest that AIDS patients undergo long-term HAART that should not be interrupted.

Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases

Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to delay or possibly stop further progression of the neurodegenerative disease in affected patients. Adeno-associated virus has been the vector of choice in recent clinical trials of therapies for neurodegenerative diseases due to its safety and efficiency in mediating gene transfer to the central nervous system. This review aims to discuss and summarize the progress and clinical applications of adeno-associated virus in neurodegenerative disease in central nervous system. Results from some clinical trials and successful cases of central neurodegenerative diseases deserve further study and exploration.

Gene and cell therapy based treatment strategies for inflammatory bowel diseases

Inflammatory bowel diseases(IBD)are a group of chronic inflammatory disorders most commonly affecting young adults.Currently available therapies can result in induction and maintenance of remission,but are not curative and have sometimes important side effects.Advances in basic research in IBD have provided new therapeutic opportunities to target the inflammatory process involved.Gene and cell therapy approaches are suitable to prevent inflammation in the gastrointestinal tract and show therefore potential in the treatment of IBD.In this review,we present the current progress in the field of both gene and cell therapy and future prospects in the context of IBD.Regarding gene therapy,we focus on viral vectors and their applications in preclinical models.The focus for cell therapy is on regulatory T lymphocytes and mesenchymal stromal cells,their potential for the treatment of IBD and the progress made in both preclinical models and clinical trials.

Applications and developments of gene therapy drug delivery systems for genetic diseases

Genetic diseases seriously threaten human health and have always been one of the refractory conditions facing humanity.Currently,gene therapy drugs such as siRNA,shRNA,antisense oligonucleotide,CRISPR/Cas9 system,plasmid DNA and miRNA have shown great potential in biomedical applications.To avoid the degradation of gene therapy drugs in the body and effectively deliver them to target tissues,cells and organelles,the development of excellent drug delivery vehicles is of utmost importance.Viral vectors are the most widely used delivery vehicles for gene therapy in vivo and in vitro due to their high transfection efficiency and stable transgene expression.With the development of nanotechnology,novel nanocarriers are gradually replacing viral vectors,emerging superior performance.This review mainly illuminates the current widely used gene therapy drugs,summarizes the viral vectors and non-viral vectors that deliver gene therapy drugs,and sums up the application of gene therapy to treat genetic diseases.Additionally,the challenges and opportunities of the field are discussed from the perspective of developing an effective nano-delivery system.

Room for improvement in the treatment of pancreatic cancer: Novel opportunities from gene targeted therapy

Pancreatic cancer is one of the highest and in fact,unchanged mortality-associated tumor,with an exceptionally low survival rate due to its challenging diagnostic approach.So far,its treatment is based on a combination of approaches(such as surgical resection with or rarely without chemotherapeutic agents),but with finite limits.Thus,looking for additional space to improve pancreatic tumorigenesis therapeutic approach,research has focused on gene therapy with unexpectedly growing horizons not only for the treatment of inoperable pancreatic disease,but also for its early stages.In vivo gene delivery viral vectors,despite few disadvantages(possible immunogenicity,toxicity,mutagenicity,or high cost),could be one of the most efficient cancer gene therapeutic strategies for clinical application due to their superiority compared with other systems(ex vivo delivery strategies).Their dominance consists of simple preparation,easy operation and a wide range of functions.Adenoviruses are one of the most common used vectors,inducing strong immune as well as inflammatory reactions.Oncolytic virotherapy,using the above mentioned in vivo viral vectors,is one of the most promising nonpathogenic,highly-selective cytotoxic anti-cancer therapy using anti-cancer agents with high anti-tumor potency and strong oncolytic effect.There have been a variety of targeted therapeutic and pre-clinical strategies tested for gene therapy in pancreatic cancer such as gene-editing systems(e.g.,clustered regularly interspaced palindromic repeats-Cas9),RNA interference technology(e.g.,microRNAs,short hairpin RNA or small interfering RNA),adoptive immunotherapy and vaccination(e.g.,chimeric antigen receptor T-cell therapy)with encouraging results.

Current status of gene therapy in melanoma treatment

Melanoma is the deadliest type of skin cancer and which has a high ability of metastasis.Surgery is an effective method to treat I or II stage melanoma patients.However,there are few treatment options for metastatic melanoma.Gene therapy is one of the attractive options and is considered as the future direction for treating melanoma.This review mainly discusses the properties and challenges of the various gene therapies in melanoma,especially the delivery systems and gene targeting.