Pregnancy outcome following infections by coxsackie, echo, measles, mumps, hepatitis, polio and encephalitis viruses

Women may be infected during pregnancy with infectious agents that are often passed unnoticed; however, the causative agent may still traverse the placenta and infect the developing embryo and fetus. Several of these agents (i.e. rubella, cytomegalovirus or Toxoplasma Gondii) may cause severe fetal damage, but most other infections in pregnancy seem to be much less dangerous to the fetus. In this review we discuss the effects of several viral infections during pregnancy where the effects on the developing embryo and fetus are infrequent, but they may sometimes cause severe neonatal disease. The following viruses are discussed: coxsackie and echoviruses, measles and mumps, polioviruses, Japanese and Venezuelan equine encephalitis viruses, West Nile virus and hepatitis viruses A, B, C, D and E. Coxsackie B virus may cause an increase in early spontaneous abortions and rarely, fetal myocarditis; echoviruses do not seem to damage the fetus; measles and mumps may cause increased early and late fetal death and neonatal measles or mumps. The viruses affecting the nervous system may increase early and late spontaneous abortions and, rarely, cause severe damage to the fetal brain. Hepatitis B virus has a high rate of vertical transmission causing fetal and neonatal hepatitis. Hepatitis A, C and E are rarely transmitted trans-placentally; if transmitted, they may cause hepatitis. There is no evidence that immunization in pregnancy against these diseases (with attenuated viruses) may adversely affect pregnancy outcome.     

Molecular strategies to inhibit the replication of RNA viruses

There are virtually no antiviral drugs available for the treatment of infections with RNA viruses. This is particularly worrisome since most of the highly pathogenic and emerging viruses are, and will likely continue to be, RNA viruses. These viruses can cause acute, severe illness, including severe respiratory disease, hemorrhagic fever and encephalitis, with a high case fatality rate. It is important to have potent and safe drugs at hand that can be used for the treatment or prophylaxis of such infections. Drugs approved for the treatment of RNA virus infections (other than HIV) are the influenza M2 channel inhibitors, amantadine and rimantadine; the influenza neuraminidase inhibitors, oseltamivir and zanamivir, and ribavirin for the treatment of infections with respiratory syncytial virus and hepatitis C virus. The molecular mechanism(s) by which ribavirin inhibits viral replication, such as depletion of intracellular GTP pools and induction of error catastrophe, may not readily allow the design of analogues that are more potent/selective than the parent drug. Highly pathogenic RNA viruses belong to a variety of virus families, each having a particular replication strategy, thus offering a wealth of potential targets to selectively inhibit viral replication. We here provide a non-exhaustive review of potential experimental strategies, using small molecules, to inhibit the replication of several RNA viruses. Other approaches, such as the use of interferon or other host-response modifiers, immune serum or neutralizing antibodies, are not addressed in this review.     

Antiviral therapy: old and current issues

Many antiviral drugs are currently approved and formally licensed for clinical use in the treatment of viral infections caused by human immunodeficiency virus, herpes simplex viruses, varicella-zoster virus, respiratory syncytial virus, cytomegalovirus, hepatitis B virus, hepatitis C virus or influenza virus. Recent decades have seen major advances in our knowledge of the natural history and pathogenesis of viral diseases as well as ongoing developments and improvements in antiviral therapy. However, research is far from complete and indeed previously unknown and unexpected issues are currently arising. This review aims to discuss some of these issues in the belief that they should be carefully addressed to enhance the management of patients with viral infections.     

Targets of emerging therapies for viral hepatitis B and C

Viral hepatitis B and C, structurally two completely different viruses, commonly infect human hepatocytes and cause similar clinical manifestations. Since their discovery, IFN has been a pillar in the treatment. However, because of the different natures of the viruses, therapeutic approaches diverge and new treatment targets are tailored specifically for each virus. Herein, the authors analyse therapeutic approaches for hepatitis B virus (HBV) and hepatitis C virus (HCV) and focus on emerging concepts that are under clinical evaluation. In particular, promising viral inhibitors for HBV and HCV are reviewed and the current status of research for gene therapy for HCV is described. Immune therapy is a fast-moving field with fascinating results which include therapeutic vaccines and toll-like receptor agonists that could improve tomorrow's treatment approaches.     

Epidemiology, prevention and treatment of viral hepatitis with emphasis on new developments

There are a large number of viruses, such as cytomegalovirus, Epstein-Barr, Herpes simplex, mumps, varicella, yellow fever, etc., known to cause inflammatory disease of the liver, but the term viral hepatitis generally refers to the five well described hepatotropic viruses which are divided into enteral and parenteral groups based on their mode of transmission. Hepatitis A and E viruses are enterically transmitted by the faecal-oral route and do not exist in a chronic carrier state. Hepatitis B, C and D viruses are parenterally transmitted, occur both in the acute and chronic forms, and, when they persist in a chronic carrier state, they serve as a reservoir for infection and give rise to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Hepatitis G virus has recently been described but its significance in the causation of human liver disease is yet to be established. Also, the most recently described TT virus in patients with post-transfusion hepatitis awaits further studies. Acute sporadic and epidemic viral hepatitis are common world-wide, mostly in the developing countries, including Ethiopia, and account for high morbidity and mortality, especially among pregnant women. Chronic infection with hepatitis B virus is a significant problem on a global scale, affecting over 300 million people. Hepatitis C virus infection is probably the most common cause of chronic viral hepatitis, end-stage liver disease and hepatocellular carcinoma in the world, especially in sub-Saharan Africa, including Ethiopia. Therefore, this article will review and highlight the relevant epidemiological, preventive and therapeutic aspects of viral hepatitis with emphasis on new developments and recent data obtained from Ethiopian studies.     

Targets of emerging therapies for viral hepatitis B and C

Viral hepatitis B and C, structurally two completely different viruses, commonly infect human hepatocytes and cause similar clinical manifestations. Since their discovery, IFN has been a pillar in the treatment. However, because of the different natures of the viruses, therapeutic approaches diverge and new treatment targets are tailored specifically for each virus. Herein, the authors analyse therapeutic approaches for hepatitis B virus (HBV) and hepatitis C virus (HCV) and focus on emerging concepts that are under clinical evaluation. In particular, promising viral inhibitors for HBV and HCV are reviewed and the current status of research for gene therapy for HCV is described. Immune therapy is a fast-moving field with fascinating results which include therapeutic vaccines and toll-like receptor agonists that could improve tomorrow’s treatment approaches.     

Tick-borne encephalitis

Tick-borne encephalitis (TBE) is one of the most dangerous human infections occurring in Europe and many parts of Asia. The etiological agent Tick-borne encephalitis virus (TBEV), is a member of the virus genus Flavivirus, of the family Flaviviridae. TBEV is believed to cause at least 11,000 human cases of encephalitis in Russia and about 3000 cases in the rest of Europe annually. Related viruses within the same group, Louping ill virus (LIV), Langat virus (LGTV) and Powassan virus (POWV), also cause human encephalitis but rarely on an epidemic scale. Three other viruses within the same group, Omsk hemorrhagic fever virus (OHFV), Kyasanur Forest disease virus (KFDV) and Alkhurma virus (ALKV), are closely related to the TBEV complex viruses and tend to cause fatal hemorrhagic fevers rather than encephalitis. This review describes the clinical manifestations associated with TBEV infections, the main molecular-biological properties of these viruses, and the different factors that define the incidence and severity of disease. The role of ticks and their local hosts in the emergence of new virus variants with different pathogenic characteristics is also discussed. This review also contains a brief history of vaccination against TBE including trials with live attenuated vaccine and modern tendencies in developing of vaccine virus strains.     

Antiviral activity of carbohydrate-binding agents against Nidovirales in cell culture

Coronaviruses are important human and animal pathogens, the relevance of which increased due to the emergence of new human coronaviruses like SARS-CoV, HKU1 and NL63. Together with toroviruses, arteriviruses, and roniviruses the coronaviruses belong to the order Nidovirales. So far antivirals are hardly available to combat infections with viruses of this order. Therefore, various antiviral strategies to counter nidoviral infections are under evaluation. Lectins, which bind to N-linked oligosaccharide elements of enveloped viruses, can be considered as a conceptionally new class of virus inhibitors. These agents were recently evaluated for their antiviral activity towards a variety of enveloped viruses and were shown in most cases to inhibit virus infection at low concentrations. However, limited knowledge is available for their efficacy towards nidoviruses. In this article the application of the plant lectins Hippeastrum hybrid agglutinin (HHA), Galanthus nivalis agglutinin (GNA), Cymbidium sp. agglutinin (CA) and Urtica dioica agglutinin (UDA) as well as non-plant derived pradimicin-A (PRM-A) and cyanovirin-N (CV-N) as potential antiviral agents was evaluated. Three antiviral tests were compared based on different evaluation principles: cell viability (MTT-based colorimetric assay), number of infected cells (immunoperoxidase assay) and amount of viral protein expression (luciferase-based assay). The presence of carbohydrate-binding agents strongly inhibited coronaviruses (transmissible gastroenteritis virus, infectious bronchitis virus, feline coronaviruses serotypes I and II, mouse hepatitis virus), arteriviruses (equine arteritis virus and porcine respiratory and reproductive syndrome virus) and torovirus (equine Berne virus). Remarkably, serotype II feline coronaviruses and arteriviruses were not inhibited by PRM-A, in contrast to the other viruses tested.     

Management of hepatitis C in HIV-infected persons.

The life expectancy of HIV-infected persons has extended significantly since the introduction of highly active antiretroviral therapies. Although classical opportunistic infections are now rarely seen, the toxicity of antiretroviral drugs as well as liver disease caused by hepatitis viruses represent an increasing cause of morbidity and mortality among HIV-positive persons. Since the rate of hepatitis C virus (HCV) infection is high among HIV carriers (up to 75% among intravenous drug users), HCV/HIV coinfection is widely prevalent. Predisposing liver damage favors a higher rate of hepatotoxicity of antiretroviral drugs, which can limit the benefit of HIV treatment in some individuals. Overall, severe hepatotoxicity appears in around 10% of subjects who began triple combinations including either protease inhibitors or non-nucleosides. The progression to cirrhosis seems to occur faster in the setting of HIV infection, and conversely recent data demonstrate that HCV infection can accelerate the progression to AIDS in HIV-positive persons. Although clinicians have been reluctant to treat hepatitis C in HIV-infected people, this therapeutic nihilism is unwarranted. The availability of new more successful regimens to treat hepatitis C, in particular using the new pegylated forms of interferon in combination with ribavirin, open new hopes for the care of HIV-HCV-coinfected persons.     

Acyclovir: an update of the clinical applications of this antiherpes agent

This paper reviews the clinical evaluation of acyclovir in the treatment of herpes-virus infections, predominantly those due to herpes simplex and varicella-zoster viruses. Intravenous, oral and topical acyclovir have been reported to be effective in the therapy of a wide variety of established herpes simplex virus infections and the systemic drug has been shown to be capable of suppressing reactivation of that virus. Although acyclovir has less activity against varicella-zoster virus, infections caused by this agent are also susceptible to intravenous and possibly oral therapy. Clinical efficacy against Epstein-Barr virus and cytomegalovirus infections has not been demonstrated but several studies are currently in progress. Limited evidence of in vivo activity against hepatitis B virus also requires further evaluation. Continued studies on tolerance of the drug in clinical use has confirmed the early promise of this selective antiviral, whilst initial concern about the development of widespread resistance has not been borne out in practice.     

Section Review Anti-infectives: Developments in viral hepatitis during 1995

The discovery of hepatitis C virus (HCV) in 1987 and the subsequent development of diagnostic tests has accounted for the majority of cases of viral hepatitis throughout the world. However, a significant number of cases cannot be assigned to any of the viral hepatitis groups (A - E). During 1995 two companies reported the identification of novel hepatitis viruses known as GBV-B and hepatitis G virus (HGV), which were found to be responsible for a large proportion of the remaining undiagnosed cases. Sequence analysis of these two viruses revealed them to be isolates of the same virus and, moreover, to be close homologues of HCV. The clinical significance of these new viruses is currently unclear, but preliminary epidemiologic evidence suggests they are often found as co-infections with HCV. The close similarity of these viruses to HCV and the fact that related viruses have also been identified which infect small primates, suggests that they may be useful as surrogate agents for the identification of novel therapeutic agents against HCV. Current therapeutic agents against HCV are still disappointing although more encouraging data have been reported on long-term combination therapy with interferon-′ and ribavirin. Studies have continued aimed towards developing assays for biochemical functions specified by viral proteins and these are stili mainly focused on the multi-functional NS3 protein.     

Viruses and cancer.

The fact that viruses can cause cancer in animals has been appreciated since the turn of the century. The widely held belief that viruses had little to do with cancer in humans has only recently been dispelled. Two classes of human retrovirus (HTLV and HIV) have been discovered in the last decade and the malignant potential of hepatitis B virus, Epstein Barr Virus and the human papilloma virus have been documented not only by confirming their association with disease by large scale epidemological studies but also at the molecular level. Indeed detailed investigation of the way viruses can cause cancer can reveal new insights into 'final common pathways' and hopefully provide new approaches for treatment over and above the real possibility that virus associated cancers can potentially be vaccinated against.     

5-(1-Substituted) alkyl pyrimidine nucleosides as antiviral (herpes) agents

The treatment of viral diseases remains one of the major challenges to modern medicine. During the past two decades there has been increased recognition of the consequences of serious viral illnesses that are not controlled by vaccination. These illnesses include human immunodeficiency virus, human herpes viruses, and viruses that cause hepatitis. There are now eight pathogens recognized in the herpes virus family that cause infections in humans. Infections by the herpes viruses are opportunistic and often life-threatening, leading to significant morbidity and mortality in the increasing number of chronically immune compromised individuals such as AIDS patients, cancer patients and transplant recipients on immunosuppressive therapy. Nearly all individuals with AIDS are infected with one or more of the herpes viruses. Antiviral therapy with guanosine nucleoside analogs acyclovir and ganciclovir has had a major impact on diseases caused by herpes simplex virus type-1 and type-2 (HSV-1, HSV-2), Varicella zoster virus (VZV), and human cytomegalovirus (HCMV) but development of resistant virus strains and the absence of any effective treatment for other members of the herpes family provide a stimulus for increased search of new agents effective against various herpes viruses. Pyrimidine nucleosides have taken up an important role in the therapy of virus infection. Significant progress in the study of anti-herpes nucleosides has been made by the advent of 5-substituted pyrimidine nucleosides such as 5-iodo-, 5-ethyl-, 5-(2-chloroethyl)-, and (E)-5-(2-bromovinyl)- derivatives of 2'-deoxyuridine. These are highly specific inhibitors of HSV-1, HSV-2, and/or VZV infections. However, Epstein Barr virus (EBV) and HCMV are much less sensitive to these agents. In 5-substituted pyrimidine nucleosides the nature of substituents, particularly at the C-5 position, has been found to be an important determinant of anti-herpes activity. Structural requirements at the C-2 carbon of the 5-substituent of pyrimidine nucleosides have been well established for anti-herpes activity. However, there is little qualitative or mechanistic knowledge of the derivatives with substitution at the C-1 carbon of the 5-substituent of pyrimidine nucleosides. During the last few years of our research, we have investigated a variety of C-1 functionalized substituents at the 5-position of the pyrimidine nucleosides to determine their usefulness as antiviral (herpes) agents. In the 5-(1-substituted) group of pyrimidine nucleosides, we demonstrated that novel substituents present at the C-1 carbon of the 5-side chain of the pyrimidine nucleosides are important determinants of potent and broad spectrum antiviral (herpes) activity including EBV and HCMV. In this article the work on design, synthesis and structure activity relationships of several 5-[(1-substituted) alkyl (or vinyl)] pyrimidine nucleoside derivatives as potential inhibitors of herpes viruses is reviewed.     

Fulminant viral hepatitis

In the United Kingdom and United States of America, fulminant viral hepatitis is due mainly to sporadic (non-parenteral) non-A, non-B hepatitis and hepatitis B whereas that caused by hepatitis A virus is very uncommon and by the herpes viruses remains rare. Recent advances in fulminant non-A, non-B hepatitis have come with the identification and cloning of a virus (27-34 nm) in the enteral variety (hepatitis E) which is prevalent in the Indian sub-continent, North Africa and elsewhere, especially in pregnant women. Virus-like particles (50-70 nm) with ultrastructural features similar to the togaviridae and flaviviridae have been identified in some patients with fulminant non-A, non-B hepatitis in the United Kingdom. The relation to hepatitis C virus, recently identified as a major cause of chronic post-transfusion (parenteral) non-A, non-B hepatitis, awaits serological analysis. The recent demonstration that persistence of active viral replication can occur in some cases of fulminant hepatitis types A and B using monoclonal antibody and molecular biology techniques challenges the classical views on the pathogenesis of these varieties of fulminant viral hepatitis.     

Developments in antiviral drug design, discovery and development in 2004

This article summarizes key aspects of progress made during 2004 toward the design, discovery and development of antiviral agents for clinical use. Important developments in the identification, characterization and clinical utility of inhibitors of human immunodeficiency virus; the hepatitis viruses, hepatitis B, hepatitis C; the herpes family of viruses, herpes simplex viruses 1 and 2, varicella zoster virus, Epstein-Barr virus and human cytomegalovirus; the respiratory viruses, influenza, respiratory syncytial virus, human metapneumovirus, picornaviruses, measles and the severe acute respiratory syndrome coronavirus; human papilloma virus; rotavirus; Ebola virus and West Nile virus, are reviewed.     

Acquired immunodeficiency syndrome and infection with hepatitis viruses in individuals abusing drugs by injection

The abuse by injection of heroin or other drugs has long been associated with liver disease caused by hepatitis B virus (HBV) and other viruses. Increasingly severe hepatic and virological complications of parenteral drug abuse have been reported due to infection with new viruses or concomitant alcohol abuse. The hepatitis delta virus (HDV) can replicate and cause liver infection only in the presence of HBV; such infection in HBV carriers may cause rapidly progressive and clinically significant liver disease. Liver cirrhosis is frequently detected in parenteral drug abusers who have chronic infection with both HBV and HDV or who also abuse alcohol. More than one quarter of those persons with acquired immunodeficiency syndrome (AIDS) in the United States of America are homosexual or heterosexual males who are parenteral drug abusers. Existing evidence implicates parenteral drug abusers in the spread of hepatitis viruses and the retrovirus associated with AIDS to the general population. To cope with these serious problems the authors suggest that more intensive international co-operation is needed, particularly with a view to promoting data collection, research and the exchange of knowledge and experience on measures that have been effective in dealing with parenteral drug abuse and its complications.     

婴儿肝炎综合征90例临床分析

目的：探讨婴儿肝炎综合征（IHS）的病因、临床表现、治疗及预后。方法：对确诊为婴儿肝炎综合征的90例病例资料及临床观察结果和随访进行回顾性分析。结果：痛原学检查巨细胞包涵体病毒（CMV）感染最多见,占52．22％,其次是乙型肝炎病毒、金黄色葡萄球菌、大肠杆菌等。结论：CMV、HBV、葡萄球菌感染是婴儿肝炎综合征的主要病因,对母孕期CMV、HBV感染的治疗和预防是阻断IHS的有效途径,早发现、早诊断及早治疗IHS是避免发生严重并发症、降低死亡率和减轻后遗症的关键措施之一。     

再生障碍性贫血感染的研究进展

再生障碍性贫血是一种外周全血细胞减少的骨髓衰竭综合征。感染是再生障碍性贫血患者死亡的主要原因。再生障碍性贫血患者的免疫妥协状态与化疗导致的中性粒细胞减少的免疫妥协状态不同,其导致的感染也有所不同。长期粒细胞减少是发生侵袭性真菌病和细菌感染的最大危险因素。中性粒细胞减少的恢复能明显提高生存率,粒细胞减少期间的支持治疗可起到很大的保护作用。再生障碍性贫血患者合并侵袭性真菌病最常见的致病菌为曲霉菌属、假丝酵母菌属、接合菌属和镰刀菌属。合并细菌感染的致病菌包括：革兰阳性菌如凝固酶阴性的葡萄球菌属、肠球菌、凝固酶阳性的金黄色葡萄球菌、梭状芽胞杆菌、微球菌甲型溶血性链球菌、单核细胞增生李斯特菌、蜡样芽胞杆菌;革兰阴性菌如大肠埃希杆菌、沙门菌、脆弱拟杆菌、肺炎克雷伯杆菌、亲水性气单胞菌属、铜绿假单胞菌。再生障碍性贫血患者合并病毒感染相对少见,但可出现疱疹病毒科、社区获得性呼吸道病毒感染和甲型、乙型、丙型病毒性肝炎。     

Drug Interactions Between Psychoactive Substances and Antiretroviral Therapy in Individuals Infected With Human Immunodeficiency and Hepatitis Viruses

The liver disease characteristic of alcohol dependence encompasses three main related entities: steatosis, alcoholic hepatitis, and cirrhosis. Alcoholic cirrhosis is a leading cause of global morbidity and mortality. Alcohol intake among injecting drug users is a major contributor to transmission of viral infections, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C viruses (HCV). HIV and HCV coinfected patients develop liver diseases earlier and more severely than the monoinfected individuals, including hepatocellular carcinoma. Interactions exist between the therapeutic drugs used to minimize and control the drug and alcohol dependence. Furthermore, drug–drug interactions occur between the highly active antiretroviral therapy (HAART) and alcohol, different HAART components and methadone, or each one of the therapies with the other, thus contributing to a higher toxicity level. With the evolution of effective antiretroviral therapy, survival of persons with HIV, and the syndrome it causes, acquired immunodeficiency syndrome (AIDS) has increased dramatically. Drug–drug interactions may appear between alcohol and anti-HBV or anti-HCV, therapy in the presence or absence of anti-HIV therapy. Several other medical-, social-, and drug-related factors of this population have to be considered when providing HAART. Because many coinfected patients also have problems with substance use, dealing with their drug dependence is an important first step in an attempt to improve adherence to and tolerance of antiviral therapy. It is necessary to minimize the risk of liver disease acceleration and/or reinfection with hepatitis viruses. Knowledge of potential drug interactions between methadone, antiretroviral therapy, psychoactive drugs, and antipsychotics and the role of coinfection with HBV or HCV and the drugs used in eradicating viral hepatitis permits suitable antiretroviral combinations.