Alternative Hepatitis C Treatments

Alternative Hepatitis C Treatments

The therapeutic goals of Natural treatment for Hepatitis C are as follows: Decrease iral load Normalize liver enzyme levels. Enhance/regulate immune system function. Strengthen and promote healthy liver function. Protect the liver, prevent further damage. Virological response; i.e. viral clearance, viral reduction or elimination of the virus. Starve the virus by limiting levels of iron. Optimizing cellular levels of glutathione in the body, making detoxification of the liver possible and enhancing the immune system. Stimulate regeneration of the damaged liver cells. Use of antioxidants to combat the effects of free-radicals generated by the virus. Reduce inflammation. Slow viral replication. Replace all of the inflammation-damaged liver cells. Regulate immune function/prevent auto-immune problems. Cancer preventative measures. Reverse fibrosis to prevent and improve cirrhosis

Alternative Hepatitis C Treatments Overview

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Hepatitis A Virus

Clinical disease due to HAV resembles other types of acute hepatitis, and diagnosis is generally dependent on laboratory confirmation of infection by the virus. The incubation period is approximately 28 days but can vary from 15 to 50 days. Initial symptoms include pyrexia, malaise, anorexia, which is often quite prominent, nausea, vomiting, and abdominal discomfort or pain. These initial symptoms are followed a few days later by the development of jaundice with a typical yellow discoloration of the skin, especially the sclera of eye, and darkening of the urine. The acute phase usually lasts between 1 and 3 weeks and is followed by a varying period of convalescence characterized by fatigue, malaise, anorexia, and persisting nausea. Complications are rare. Approximately 5 of patients develop cholestatic hepatitis with pruritis and steatorrhea. Fulminant hepatitis, characterized by precipitous loss of liver function rapidly leading to liver failure and death, occurs in approximately...

Ivepidemiology A Hepatitis A Virus

Considerably less virus, up to 105 particles per mL, is found in the blood, and the viremic stage coincides largely with the period that the virus is excreted into the feces. This may now explain the increasing finding of bloodborne hepatitis A infections (17). Virus is also excreted into the saliva, although it has not been established whether saliva plays any role in hepatitis A virus transmission (18). There is, for example, no evidence that sharing eating utensils, cigarettes, or kissing can transmit hepatitis A infection. By far the most common route of transmission of hepatitis A virus is the fecal-oral route, with person-to-person being the most important mode of transfer of the virus. This has been clearly demonstrated by observations of the rates of infection among household contacts of patients and among children in the setting of daycare centers (19). The virus is robust and is able to survive in water and food for 12 weeks to 10 months. As a result, foodborne outbreaks...

Pathogenesis A Hepatitis A Virus

The typical HAV pathology of the liver includes necro-inflammatory lesions in the hepatic parenchyma. The pathogenesis of hepatitis A infection does not involve direct viral cytopathology but is rather due to the host immune response. It is also not due to antibody responses to the virus. FIGURE 1 Pathogenesis of Hepatitis A virus.

Control Measures A Hepatitis A Virus

The measures generally recommended for the prevention of fecal-oral transmission of enteric pathogens are equally applicable to hepatitis A virus infection (20). These are particularly pertinent to travelers journeying to developing countries where standards of hygiene and sanitation may be poor. Water used for drinking, washing of vegetables or fruit, or brushing of teeth is a major hazard to travelers. If in doubt, water should be boiled for at least 1 minute or, at high altitudes, for a few minutes. Alternatively, proprietary chlorine tablets can be used to disinfect water (provided that the water is clear and free of contaminating organic material). Ideally, bottled water should be used for drinking. (Portable filters have not been shown to be reliable and are currently not recommended.) Ice is a common source of contamination and should not be used for drinks unless the safety of the source of the water is assured. Similar precautions would hold for iced lollipops and frozen...

Immunotherapy using hepatitis B vaccine

Hepatitis B vaccine may serve as an immunomodulator for suppressing viral replication. In a study of the therapeutic efficacy of hepatitis B vaccine, 118 treatment-naive patients with histologically and virologically proven chronic hepatitis B were randomized to receive either placebo or intramuscular hepatitis B vaccine in the form of S vaccine alone or combined pre-S2 and S vaccine 106 . After five vaccine injections were given, there was a significant but transient 6-month decrease in viral load that did not occur in controls, despite persistence of HBsAg in all patients. For the first time, hepatitis B vaccine was shown to decrease viral replication, which may pave the road for new therapies based on the concept of specific immunomodulation.

Hivhcv Knowledge Among People With Severe Mental Illness and Their Providers

AIDS is the ultimate result of HIV infection, and knowledge about AIDS-related issues among United States and Canadian psychiatric patients appears to be relatively good compared with that of nonpsychiatric groups. Correct responses to AIDS knowledge questionnaires in a variety of psychiatric patient groups ranged from 63 to 80 (Chuang and Atkinson 1996 McKinnon et al. 1996 Otto-Salaj et al. 1998), a comparable accuracy rate to that found in the general United States population (Hardy 1990). Still, many psychiatric patients held critical misinterpretations. For example, in one study 42 were unaware they could be infected by injection drug use (Katz et al. 1994), and in another, 48 believed that careful cleansing after sex would provide protection from the virus (Otto-Salaj et al. 1998). Comparable studies about HCV knowledge among patients have not been completed. Although knowledge is necessary, it is not sufficient to reduce unsafe behaviors. Preliminary findings from qualitative...

Basic Overview of Course of Illness and Treatment of HCV

Approximately 4 million persons in the United States and probably more than 100 million persons worldwide are infected with HCV. The virus has the unique ability to cause persistent infection in a majority of infected people. The immunological correlates of protection and viral clearance and the pathogenesis of liver injury are yet to be defined, but recent studies suggest the importance of cell-mediated immune responses. Although a large proportion of infected persons become chronic carriers, most have relatively mild disease with slow progression. However, chronic and progressive HCV carries significant morbidity and mortality and is a major cause of cirrhosis, end-stage liver disease, and liver cancer. Development of an effective HCV vaccine is not imminent, but recent advances in technology and basic knowledge of molecular virology and immunology may engender novel approaches to the fundamental problems encountered in vaccine development. Vaccines continue to be pursued, since...

HCV Transmission and Testing

Given preliminary estimates that one in five patients with severe mental illness is infected with HCV, a strong argument can be made that all such persons should be screened for the virus. Certainly, all patients known to be infected with HIV should be screened for anti-HCV antibodies as part of their initial evaluation, as should those with high-risk behavior. HCV is primarily spread through infected blood and is therefore a common complication of injection drug use. HCV may be spread by maternal fetal transmission and by noninjected drug use activities as well. Risk for sexual transmission is low but not absent. In a significant minority of cases the mode of transmission is unknown. Like HIV, rates of HCV in the United States are higher in African Americans and Latinos than among Caucasians. HCV infection should be confirmed with qualitative PCR assay if the patient is at low risk and the diagnosis seems in doubt. Moreover, there is a small but measurable false negative rate for...

Natural History of HCV Disease

Acute HCV disease is usually asymptomatic, but 25 -35 of patients develop some constitutional symptoms or jaundice. Serum alanine aminotransferase (ALT) levels frequently rise, fluctuate, and fall again, suggesting recovery from the acute phase. Following acute infection, however, HCV is not easily cleared by the immune system, and 75 -80 of acute HCV infections become chronic, as evidenced by persistent or intermittent HCV viremia. Patients infected with HCV should be advised to minimize or preferably discontinue intake of alcohol. Chronic HCV infection can cause inflammatory infiltration, particularly of the portal tracts, as well as focal liver cell necrosis and fibrosis that bridges between portal tracts. Hepatitis C is the leading cause of liver transplantation in the United States. About 10 -20 of patients progress to cirrhosis within 20-30 years of infection, and among those with cirrhosis, 1 -4 per year will develop hepatocel-lular carcinoma. Immunosuppression associated with...

Risk Reduction Interventions and Strategies for HIVHCV

Because HCV shares modes of transmission with HIV, groups focused on HIV risk reduction may also wish to impart information about HCV and the possibility of acquiring HCV infection through high-risk behaviors. Prevention efforts aimed at HCV are essential for patients who are currently (or at risk for) injecting drugs, because injection drug use is the risk factor responsible for the majority of HCV cases.

Accessing the Range of Hivhcvrelated Services That Psychiatric Patients Need

Mental health service settings vary in their ability to offer HIV-related interventions, and the range of services available may not yet be meeting the needs of people with severe mental illness (McKinnon et al. 1999). With respect to HCV, Mendel and Ryan's preliminary findings suggest that patients with these psychiatric disorders often are thought not good candidates for HCV treatment, with several HIV clinics implementing policies excluding patients with serious psychiatric histories from HCV treatment despite the lack of evidence to support their concerns about maintaining adherence or triggering a major psychiatric event. One medical director at a clinic in a large hospital was willing to engage severely mentally ill patients in HCV treatment, but only if they were under heavily supervised mental health care. Implementing such arrangements could be helpful in initiating treatment and conducting mental health evaluations of candidates already on HCV treatment. Screening for...

Rational Psychopharmacology for People With Hiv Hcv and Schizophrenia

Most psychiatric medications are metabolized by the liver and therefore may require more careful monitoring in those chronically infected with hepatitis C. In particular, for those who manifest clinical or laboratory signs of liver failure, medication metabolism can be dangerously reduced to the point where patients may accumulate toxic levels of drugs they normally can take. In general, it is relatively safe to use most of the psychiatric medications both with HIV and HCV treatments. In the presence of HCV illness, periodic liver function tests are the standard of care. Because some psychotropics may elevate liver enzymes (e.g., valproic acid, carbamazepine, nefazodone), it is important to check these at baseline, early after initiation of therapy (2-4 weeks), and every 2-3 months thereafter. Nevertheless, data from a large retrospective study in Seattle, Washington, found that among 94 HCV seropositive patients treated with valproic acid, 81.9 showed minimal or no evidence of serum...

Dems Sars Hbv Hcv and HIV1

Current methods for the diagnosis of HCC rely on serological markers such as a-fetoprotein (AFP) 97 and certain liver enzymes as well as Des gamma car-boxyprothrombin (DCP) 98 . This type of diagnosis lacks the sensitivity to detect HCC at an early stage when therapy can be more effective. To find markers of disease progression, 2DE was employed to resolve and compare proteins present in serum obtained from individuals infected with HBV or HCV and with varying risks for the development of HCC 99,100 . In several studies, proteins expressed at different levels among diseased individuals as compared to those of healthy ones were identified as markers for disease progression as well as proteins with different N-glycosylation patterns 99-101 . In another study, 2D-MS was also employed to analyze altered plasma proteins due to SARS-CoV infection. Thirty-eight different plasma proteins from SARS patients were identified, most of which were associated with acute phase proteins 23 .

Deltavirus Hepatitis D

In 1977 a young Italian physician, Rizzetto, detected a novel antigen, which he called 5 (delta), in the nuclei of hepatocytes from particularly severe cases of hepatitis B Delta antigen was also found inside 36 nm viruslike particles, the delta agent, the outer coat of which was serologically indistinguishable from HBsAg. It transpired that the 8 agent, now known as hepatitis D virus (HDV), is a defective satellite virus, found only in association with its helper virus, HBV. The tiny RNA genome of HDV, smaller than that of any known animal virus, encodes its own nucleoprotein (the delta antigen), but the outer capsid of the HDV virion is composed of HBsAg, encoded by the genome of HBV coinfecting the same cell. Properties of Hepatitis D Virus Pioperties of Hepatitis D Virus Satellite virus requiring hepatitis 1 virus as helper, by HDV HIJV reinfection or by superinfection of f IBV carrier

Antiviral Therapy for Treatment Naive Patients with Hepatitis C Virus

Chronic hepatitis C virus (HCV) infection is recognized as a global health problem, with 170 to 200 million people estimated to be infected worldwide. In the United States, chronic HCV is the most common cause of end-stage liver disease, hepatocellular cancer, and the most frequent indication for liver transplantation 1 . Data from the third National Health and Nutrition Examination Survey (NHANES III) estimated that 2.7 million Americans have active HCV infection 2 . This figure probably underestimates the true prevalence of chronic HCV infection, however, as the study excluded high-risk groups such as prisoners and homeless people. HCV infection generally is regarded as ''a disease of decades,'' as the most significant clinical consequences occur 20 to 30 years after the initial exposure. Approximately 10,000 HCV related deaths occur each year, mostly resulting from end-stage liver disease and development of hepatocellular carcinoma (HCC) 3 . The NHANES study also revealed that HCV...

Hepaciviruses Hepatitis C and G

A series of hepatitis infections following blood transfusions was observed that could not be identified as either hepatitis A (p. 437) or hepatitis B (p. 429), and were therefore designated as non-A-non-B (NANB) hepatitis. The discovery of the hepatitis C virus (HCV) by molecular biological means in 1988 was an elegant piece of work RNA was extracted from the plasma of an infected chimpanzee, from which cDNA was produced using reverse transcriptase. The cDNA was then cloned and the corresponding proteins expressed. About one million clones were tested for reactivity with sera from patients suffering from chronic NANB hepatitis. A protein was found by this method that reacted with antibodies to NANB, whereupon the corresponding cloned DNA was used as a probe to identify further overlapping gene segments. They belong to a flavivirus with approximately 10 kb sense RNA and several genotypes. A similar strategy led to identification of a further flavivirus that also causes...

Hcv As A Hepatocarcinogen

Evidence for a causal role for HCV, a single-stranded RNA virus belonging to the Flaviviridae, in HCC is more recent but almost equally compelling. In common with HBV infection, the importance of chronic HCV infection as a risk factor for the tumor differs between developed and developing countries (74,75). In the former, whatever the incidence of HCC, HCV is a more important causal association of the tumor than is HBV, and in Japan, Italy, and Spain the virus accounts for as much as 80 of HCCs (74,75). For patients in these countries who have been referred to a hepatology clinic with chronic HCV infection, the annual risk of developing HCC ranges from 1.0 to 8.9 , with the risk being greater both in countries with higher incidences of the tumor and in patients with cirrhosis than in those with chronic hepatitis. Persistent HCV infection and alcohol abuse often (and chronic HBV infection and alcohol abuse less often) coexist as causal associations of HCC in developed countries...

Pathologic Features Of Hcvassociated Lymphoma

On diagnostic grounds, clonal lymphoid proliferation in HCV-positive patients can be divided into two main groups, monotypic lymphoproliferative disorders of undetermined significance (MLDUS) and overt lymphomas (27,28,32,65). The former cannot be recognized without clinical data, as their histopathologic picture is basically indistinguishable from that of some lymphoid tumors, which are indolent but nevertheless invariably fatal. In this section, we use the concepts and terminology of the Revised European-American-Lymphoma (REAL) Classification (66), which recently has been validated in a study sponsored by the National Cancer institute (NCI) of the United States (67) and has been adopted as operational guidelines by the World Health Organization (68). MLDUS occur in HCV-positive patients, who often show the clinical and laboratory pattern of type II MC (21,22,27,65,69). Histologically (Fig. 1), they have lymphoid infiltrates in the bone marrow and liver that resemble peripheral...

Epidemiology Of Hcvassociated Lymphoma

The etiology of NHL is poorly understood but of considerable interest because of the increasing incidence of these malignancies worldwide (30). A possible causative link between hepatotropic viruses and malignant lymphomas had been hypothesized since 1971, when an autopsy study of 814 Belgian patients with neoplastic diseases reported a significant association between cirrhosis and lymphoproliferative disorders (31). With the identification of HCV as a triggering factor of MC (20-24), its potential role in NHL was suspected (12). In 1994, HCV infection was first demonstrated in a significant percentage of Italian patients with unselected B-cell NHL, regardless of the Hepatitis C Virus (HCV) Infection and Lymphoproliferative Disorders (LPDs) Prevalence of HCV infection in LPDa Prevalence of HCV infection in LPDa HCV+

Immunebased Approaches To Hepatitis B

Although pharmacologic agents with activity against hepatitis B are in development, there has been interest in immunologic therapy of chronic hepatitis secondary to hepatitis B, potentially as an adjunct to antiviral therapy. Administration of cytokines (such as IL-12) and antibody to surface antigen are two approaches that have been studied. Longitudinal studies of chronic carriers of hepatitis B virus (HBV) suggest a role for IL-12 in viral clearance. Not only do HBV carriers have higher levels of IL-12 than controls, but further increases above baseline are noted in HBV carriers who go on to develop anti-HBe and clear HBV compared with those who have persistent HBV replication (23). Based on this observation, as well as evidence from transgenic mouse models of hepatitis B infection, it is postulated that the antiviral effect of IL-12 is mediated by interferon-7, IL-2, and tumor necrosis factor-a (TNF-a) released by HBV-specific cytotoxic T-lymphocytes (CTLs) and that the result is...

Hcv And Lymphomagenesis

A causative role of viral agents in malignant lymphomas has been established for at least two viruses, namely, Epstein-Barr virus (EBV) and human T-cell leukemia lym-phoma virus I (HTLV-l). EBV is involved in lymphomas complicating immunocompromised patients and in 30 of non-African Burkitt's lymphoma, while HTLV-l is responsible for the adult T-cell leukemia lymphoma syndrome in some geographic areas (13) (see Chapters and , respectively). Since EBV has been ubiquitous for years and the role of HTLV-1 is limited to particular patient populations, they cannot explain the increasing incidence of NHL in all parts of the world (30). HCV-associated lymphomas may represent a new model for virus-induced cancer in humans. In asymptomatic or symptomatic HCV chronically infected individuals, the intimate mechanism(s) responsible for the appearance of malignancy remains still largely obscure. A variable combination of co-factors in the development of hepatic and or lymphatic disorders in...

Hepatitis C Virus Infection And Oncogenesis

Possible role of HCV infection in oncogenesis HCV may be involved in the patho-geneis of hepatocellular carcinoma and or B-cell lymphomas directly (13,32-39,82) or through liver and or immune system disorders namely, chronic hepatitis ( cirrhosis) and mixed cryoglobulinemia (3,13,28,29,53,55-57). Both hepatocellular carcinoma and B-cell lymphoma may develop during the natural course of HCV chronic infection (64). (Modified from ref. 13.) Fig. 2. Possible role of HCV infection in oncogenesis HCV may be involved in the patho-geneis of hepatocellular carcinoma and or B-cell lymphomas directly (13,32-39,82) or through liver and or immune system disorders namely, chronic hepatitis ( cirrhosis) and mixed cryoglobulinemia (3,13,28,29,53,55-57). Both hepatocellular carcinoma and B-cell lymphoma may develop during the natural course of HCV chronic infection (64). (Modified from ref. 13.) specific HCV mutants, possibly with higher oncogenetic potential, other infectious or environmental...

Treatment Of Hcvassociated Lymphoma

The treatment of HCV-associated lymphomas does not differ substantially from that of idiopathic B-cell NHL (97). However, the occurrence in the same subject of chronic viral infection and cancer and, in some cases, of other HCV-related disorders may be a conditioning factor for an optimal therapeutic strategy (Fig. 3). In all patients with B-cell NHL the detection of HCV-related markers (anti-HCV and HCV RNA) is obviously mandatory, together with histologic classification and staging of the disease. Before the treatment and during the patient's clinical follow-up, in HCV-positive NHL patients should be carefully evaluated for chronic hepatitis, cirrhosis, hepatocellular carcinoma, mixed cryoglobulinemia syndrome, and other HCV-related disorders, such as thyroiditis and glomerulonephritis. To date, there is not sufficient information on specific complications of cancer chemotherapy in HCV-positive NHL. In a series of patients with lymphoplasmocytoid lymphoma immunocytoma, the presence...

Natural history of recurrent hepatitis C virus after transplantation

Recurrent infection, defined by the presence of detectable HCV RNA in serum and liver, occurs in essentially all patients who are viremic pretrans-plant. Kinetic studies of the early virologic events after transplantation have shown that HCV RNA levels drop abruptly during the anhepatie phase and again 8 to 24 hours after reperfusion 10 . In general, viral levels increase beginning 24 to 72 hours post-transplant, but there is considerable interpatient variability in the rate of increase in viral levels during the first postoperative week 10 . Thereafter, a progressive increase in viral load occurs in the majority of patients, with the peak viral level occurring between months 1 and 4 11 . At 1 year post-transplant, HCV RNA levels are on average 1-logio higher than pretransplant levels 12,13 . Pretransplant viral liters have been inconsistently correlated with post-transplant HCV RNA levels 13 . High pretransplant viral levels have been associated with reduced overall Fig. 1. This...

Micro and Nanoparticle Based Vaccines for Hepatitis B

The incredible success of vaccinations in contributing to public health is undeniable. In fact, vaccines are the most cost-effective public health tool for disease prevention because their cost is less than the combined costs of treatment, hospitalization, and time loss from work. However, despite the availability of vaccines, cost per dose is a factor limiting the success of global vaccination campaigns, as are the limitations imposed by the need of delivering multiple vaccine doses. A number of approaches are being tested particularly for the delivery of subunit vaccines, and in recent years, a number of groups have devoted their efforts to develop nano microparticles prepared from biodegradable and biocompatible polymers as vaccine delivery systems with the goal of inducing both humoral and cellular immune responses. Some important properties of biodegradable polymers are their documented safety history, biocompatibility, and an ability to provide controlled time rate of...

HIV and Hepatitis C HCV protease cleavage prediction

As previously described in Chapter 2, viral protease is one of the enzymes typically accompanying HIV RNA and HCV into the cell (see Figure 2.10, Chapter 2). It cleaves the precursor viral polyproteins (the substrate) at specific cleavage-recognition sites when they emerge from the ribo-somes of the host cell as one long sequence (Figure 6.3(a)). When certain substrate configurations occur (a certain sequence of amino acids), the protease cleaves the viral polyprotein at a specific point in the substrate (Figure 6.3(b)). Conventionally, the polyprotein substrate is labelled with unique P identifiers (one for each amino acid) and the protease region around the active site with unique S identifiers (Figure 6.3(c)). This cleavage step is essential in the final maturation step of HIV and HCV. That is, protease is responsible for the post-translation processing

Molecular diagnosis of hepatitis B virus

Molecular Diagnosis Viral Hepatitis

Clinical applications of hepatitis B virus DNA assays In most instances, the diagnosis of acute hepatitis B can be made with se-rologic testing for HBsAg. Coincident with the appearance of HBsAg in serum, markers of active HBV replication and infectivity, specifically HBeAg and HBV DNA, appear. If the results of tests for HBsAg are equivocal, assays for HBV DNA in serum may be a useful adjunct in the diagnosis of acute HBV infection. Moreover, HBV DNA can be detected approximately 21 days before HBsAg appears in the serum 17 . Thus, HBV DNA assays may be used to diagnose acute HBV infection in those patients with high-risk exposures, such as needlestick accidents in health care workers. Molecular techniques for the detection and quantification of hepatitis B virus DNA Fig. 3. Principle of hybrid capture signal amplification assay. The target sequence is double-stranded HBV DNA. Hybridization to specific RNA probes creates RNA-DNA hybrids, which are captured on a solid phase (a tube in...

Hepatitis C Virus Infection

Since its identification in 1989 (1,2), hepatitis C virus (HCV) has been recognized as the major causative agent of posttransfusion and sporadic parenterally transmitted non-A-non-B hepatitis (3). HCV is a single-stranded, positive-sense RNA virus showing significant similarities of genomic organization with pestiviruses. The introduction of second- and third-generation enzyme-linked immunosorbent assay (ELISA) and RIBA tests significantly improved the diagnostic procedures for the detection of HCV-related antibodies (anti-HCV). Unlike many other viral infections, the detection of serum IgG class antibodies often suggests active HCV infection. However, anti-HCV may persist long after viral clearance. Thus, detection of viral RNA sequences using polymerase chain reaction (PCR) or other amplification methods is required to demonstrate infec-tous HCV (4). In patients with non-A-non-B hepatitis there is generally a good concordance between anti-HCV and PCR results. The detection of HCV...

Viral Hepatitis 21 Hepatitis A

Hepatitis A (HAV) is an RNA virus in the picornavirus family (see Table 2). The virus is easily transmitted by the fecal-oral route. In countries where the virus is endemic and sanitation is poor, most people become infected in early childhood when the disease is mild and life-long immunity results (59). Recently, a shift in the prevalence of cases from childhood to adulthood has occurred, presumably due to improved living conditions. In the United States and other industrialized nations, the prevalence of anti-HAV antibodies increases with advancing age (60). Seroprevalence in an ambulatory geriatric population (mean age 75) in New York was 94 . In a 1994 serologic study from Colorado, the prevalence of anti-HAV antibodies at ages 60, 70, and 80 was 40 , 60 , and 80 , respectively (59). The steady increase in seroprevalence with age is seen in men and women and in all races and ethnic groups. The clinical manifestations of acute hepatitis A become more severe and are associated with...

Hepatoviruses Hepatitis A Virus

The hepatitis A virus differs in some characteristics from entero-viruses, to which group it was long considered to belong. Growth in cell cultures requires long adaptation. Only one serotype is known to date. Pathogenesis and clinical picture. The clinical picture of hepatitis A, so-called epidemic or infectious hepatitis, differs in no major particulars from that of hepatitis B (p. 429). The disease nearly always takes a benign course. Only a small number of fulminant (and sometimes lethal) or chronic courses have been described. The pathogenic process at first corresponds to that of the enteroviruses, whereby hepatitis A replicates in the intestine and then, after a brief viremic episode, attacks its target organ, the liver. Disease manifestation with this pathogen, unlike most of the enteroviruses but similar to hepatitis B, involves immunological processes. Diagnosis is based on IgM detection due to the early presence of these antibodies in patient serum, in fact so...

Prevaccination screening and isolated antibody to hepatitis B core antigen

Prevaccination screening may be cost effective when the expected prevalence of prior HBV infection exceeds 30 10 , such as in the high-risk adult populations for whom hepatitis B vaccine is indicated. Occasionally potential recipients of hepatitis B vaccine test positive for antibody to hepatitis B core antigen (anti-HBc) but negative for both HBsAg and anti-HBs. Isolated anti-HBc may be found due to suppression of HBV replication by hepatitis C virus in co-infected patients 21,22 , or in the setting of low level infection with undetectable HBsAg but a positive HBV DNA by polymerase Anyone found to have isolated an anti-HBc should be retested. A diagnostic algorithm can be used for those who are persistently positive for anti-HBc only 25,26 . To distinguish among the three possibilities mentioned previously (low-level HBV infection, prior immunity without detectable anti-HBs, or false-positive result), the patient may be given a single dose of hepatitis B vaccine with follow-up...

Clinical Features of Hepatitis B

Most HBV infections are subclinical, particularly during childhood, but about one-third of adult infections are icteric. The course of acute viral hepatitis is conventionally divided into three phases (1) preicteric, (2) icteric, and (3) convalescent. Following a long incubation period of 6-26 weeks in the case of hepatitis B, the preicteric (prodromal) phase commences with malaise, lethargy, anorexia, and commonly nausea, vomiting, and pain in the right upper abdominal quandrant. A minority of patients develop at this time a type of serum sickness characterized by mild fever, urticarial rash, and polyarthritis, resembling a benign, fleeting form of acute rheumatoid arthritis. Any time from 2 days to 2 weeks after the prodromal phase begins, the icteric phase commences, heralded by dark urine (bilirubinuria) closely followed by pale stools and jaundice. The convalescent phase may be long and drawn out, with malaise and fatigue lasting for weeks. There are a number of possible outcomes...

Approach to the Management of Patients with Chronic Hepatitis C Who Failed to Achieve Sustained Virologie Response

Therapy for chronic hepatitis C virus (HCV) infection has improved dramatically since interferon (IFN) was first introduced for treatment of non-A, non-B hepatitis over 15 years ago 1-3 . Historically, standard IFN monotherapy yielded a sustained virologic response (SVR) in less than 15 of patients. The addition of ribavirin (RBV) 4,5 , and later the substitution of peginterferon (PEGIFN) for standard IFN 6-9 , led to dramatic improvements in SVR rates, which can now be achieved in 45 to 50 of patients who have HCV genotype 1 and approximately 80 of patients who have genotypes 2 or 3 10-12 . As each new improvement in HCV therapy has emerged, many patients who had failed to achieve SVR with previous, less effective therapy have been retreated. Recently, several large multicenter clinical trials have demonstrated the impact of retreating such patients with PEGIFN RBV 13-16 . In the largest of these trials, 18 of patients who had a nonresponse (NR) after treatment with IFN or IFN RBV...

Box 2 Risk factors associated with poor antiHBs response to hepatitis B vaccine

Nonresponders mounted an appreciable anti-HBs titer. When nine of the 12 refractory nonresponders were sampled, six of them carried at least one of two extended major histocompatibility complex (MHC) HLA haplotypes B44-DR7-FC31 or B8-DR3-SC01. In contrast, only two of the 11 revaccinees sampled who responded to the second vaccine series carried these haplotypes, suggesting a genetic contribution to immuno-genicity 52 . In a large series of nearly 600 subjects who received a full course of hepatitis B vaccine, an analysis of HLA haplotypes among the 20 vaccinees with the lowest anti-HBs titer responses indicated a disproportionately higher number of HLA-B8-DR3-SC01 53 . When nine of the haplotype carriers were given three additional doses of vaccine, four of the five homozygotes but none of the nine heterozygotes remained hyporesponders. These findings implicate a recessive MHC-linked trait as a cause of hyporesponse to hepatitis B vaccination 53 . Efficacy of hepatitis B vaccines...

Hepatitis

Several viruses are capable of causing hepatic inflammation. These include the Epstein-Barr virus, cytomegalovirus, herpes simplex virus, mumps, rubella, rubeola and varicella-zoster viruses, yellow fever virus, Coxsackie viruses, and adenoviruses. In most cases, infection or inflammation of the liver is part of a systemic infection with the above agents. In addition, there are a number of viruses that are primarily hepatotropic and are given alphabetical designations hepatitis A-E. Several other viruses that were initially thought to cause posttransfusion hepatitis, including hepatitis G virus or GBV-C and SEN viruses, are not currently believed to be human pathogens. Of the truly hepatotropic viruses, hepatitis A and hepatitis E generally produce self-limited disease, although fulminant hepatic failure has been reported in up to 1 -2 of infected individuals. Hepatitis D virus (or the delta agent) can produce coinfections in patients who are infected with hepatitis B, but it appears...

Hepatitis E Virus

The development of serological tests for hepatitis A and hepatitis B viruses demonstrated that a significant proportion of cases of hepatitis were due to neither of these viruses (36). This led to the coining of the term non-A, non-B hepatitis, of which two forms were epidemiologically apparent a parenteral form with routes of transmission, which appeared similar to parenterally spread hepatitis B virus infection, and an enterically spread non-A, non-B hepatitis with routes of transmission similar to enterically spread hepatitis A virus. Enterically spread non-A, non-B hepatitis was apparently responsible for vast epidemics of waterborne hepatitis on the Indian subcontinent, Southeast Asia, Asian republics of the former USSR, Africa, and Central America. The development of serological tests confirmed that the etiolog-ical agent was a novel virus, unrelated to hepatitis A, and that infection was considerably more widespread than suggested by the geographic location of the large...

Halothane hepatitis

The precise link between the use of halothane and the subsequent development of hepatitis remains unclear. The incidence is extremely low, being in the region of 1 10000-20000 halothane administrations. The clinical picture is one of jaundice, with a massive rise in plasma aminotransferases several days after the exposure to halothane, associated with severe hepatic necrosis. The mortality rate is approximately 50 . Severe liver damage is unlikely to occur after a single exposure in adults, but repeat administration at an interval of less than 3 months should be avoided, particularly in obese, middle-aged females. With the current range of alternatives this should no longer be necessary. The risk to children appears to be much less.

HCV Treatment

Diagnostic testing to determine the presence of HCV viremia and the extent of liver pathology should be completed as early as possible in the care of a patient infected with HCV. Liver biopsy is useful in evaluating liver damage and deciding type of treatment elevation in serum transaminases in the absence of inflammation or fibrosis typically is not an indication for treatment. Patients with active HCV infection or evidence of chronic liver disease should be referred to a specialist with experience in treating hepatitis C for evaluation and guidance regarding possible treatment. Treatment recommendations should be individualized, and not all patients with HCV should receive treatment. Factors to be considered in the selection of patients for treatment include the patient's immune status the presence of moderate to severe inflammation and or fibrosis, which predicts the likelihood of progression to cirrhosis in the absence of treatment the likelihood of a favorable response to...

Lcms Hiv1 and HCV

Two studies have used LC MS MS to identify differential protein expression in HIV- or HCV-infected cells. In the first study, traditional HPLC (ion exchange and reverse-phase columns) coupled to an ultrasensitive ion trap MS was employed to identify proteins that were unique to MDM and to identify proteins present in HIV-1-infected MDM lysates by microsequencing 31 . The second study used normal hepatocytes and immortalized human hepatocytes that can be induced to express the entire HCV ORF. The two different cell types were labeled with an isotopically light (12C for stimulated) or heavy (13C, for control cells) reagent called isotope-coded affinity tag (ICAT) the two differentially labeled samples were then combined and digested with trypsin. Digested peptides were separated by strong cation-exchange chromatography, affinity purified with an avidin cartridge, and subjected to LC-ESI-MS MS. This study led to the identification of 2159 unique proteins that could be used as markers for...

HCV Infection

The establishment of chronic HCV infection and poor responsiveness to current therapeutic regimens (IFN-a and ribavirin) may be associated with impaired virus-specific T cell responses, and enhanced levels of immunosuppressive cytokines like IL-10. IL-10 production has been investigated ex vivo in HCV-infected patients and in vitro following stimulation with viral proteins. HCV core and NS3 antigens have been suggested to induce IL-10 production by PBMCs of chronically HCV-infected patients.84'135-137 IL-10 levels have also been reported to be modulated following stimulation of PBMC from chronically infected patients with PHA or LPS.138-140 Plasma IL-10 levels were also elevated in patients with chronic infection compared to those that have cleared infection.84 However, plasma IL-10 levels were not predictive of disease progression or recovery following IFN-a treatment.141 Furthermore, virus-specific CD4 and CD8 T cells from chronically infected patients have exhibited impaired...

Hepatitis A

The enterically transmitted disease known first as inlectious hepatitis, to distinguish it from serum hepatitis (hepatitis B), then as hepatitis A, was known for many years before its causal agent was identified unequivocally in 1973 by demonstration of a 27 nm icosahedral virus in patients' feces using immunoelectron microscopy (Fig. 23-6). Biophysical and biochemical studies later established hepatitis A virus as a member of the family Picornavtridae. For a time hepatitis A virus (HAV) was classified as enterovirus type 72, but it was eventually accorded the status of a separate genus, Hepatovirus, on the basis of a number of differences from the enteroviruses, including stability of Fig. 23.6 Hepatitis A virus. Negatively stained preparation of virions clumped by antibody as seen by immunoelectTon microscopy Bar, 100 ran (CoiiTtesy Drs J Marshall and I. D Gust ) It is widely assumed that hepatitis A virus, known to enter the body by ingestion, multiplies first in intestinal...

Hepatitis B Mutants

Using molecular biological methods refined in recent years, more and more HBV mutants have been found with one or more amino acid exchanges in certain proteins. HBs or PreS mutants are so-called escape mutants that can cause a new infection or recidivation despite immune protection by antibodies to HBs. Similarly, pre-HBVc or HBVc mutants can lead to a reactivation of HBV replication and thus to a chronic hepatitis, since they block formation of the HBe antigen and thus the point of attack for the cellular immune defenses. These HBc mutants are frequently observed under interferon therapy. Hepatitis D pathogen. A certain percentage of HBV-infected persons, which varies geographically, are also infected by a second hepatitis virus discovered at the end of the seventies in Italy, the delta agent or hepatitis D virus (HDV). It was originally thought to be a new HBV antigen. In fact, it is an unclassified RNA virus that codes for the delta antigen. Its capsid consists of HBs antigen,...

Chronic hepatitis B

Development of a chronic hepatitis B infection is revealed by a changed antigen-antibody profile the two antigens HBs and HBc (and raised transaminases) persist for over six months, whereby antibodies to HBe and HBs are not produced. A subsequent late seroconversion of HBe antigen to anti-HBe antibodies supports a better prognosis. Thorough clarification of chronic cases must include either immunohistological testing for HBV antigens in liver biopsies or PCR testing for the presence of viral DNA, and thus Dane particles, in patient serum. Epidemiology and prevention. Humans are the sole reservoir of HBV. Transmission is parenteral, either with blood or body fluids containing HBV (sexual intercourse) that come into contact with mucosa, lesions, or microlesions in the skin. In transmission by blood, the tiniest amounts contaminating syringe needles, ear-piercing needles, tattooing instruments, etc. suffice to produce an infection. Hepatitis B infections from blood transfusions have been...

Hepatitis C Virus

The term non-A, non-B hepatitis (NANBH) was introduced in the mid-1970s to describe inflammatory liver disease not attributable to infection with HAV or HBV (4). In 1978, the NANBH agent was shown to be transmissible to chimpanzees, as evidenced by the development of liver pathology, including detection of characteristic cytoplasmic tubular structures by electron microscopy (14). Filtration studies showed that the NANBH agent(s) was < 80 nm in size and thus likely to be a virus. Sensitivity to chloroform indicated that the NANBH virus is enveloped. In 1989, Choo et al. reported the molecular cloning of an NANBH agent from plasma collected from a well-characterized, chronically infected chimpanzee with a high infectious titer of NANBH agent (46). The plasma was subjected to extensive ultracentrifugation to pellet small viruses, and total nucleic acid was extracted from the pellet. The nucleic acid was denatured and cDNA was synthesized by reverse transcription to obtain clones of any...

Hepatitis C

With the introduction of sensitive assays for screening blood for hepatitis B virus in the late 1970s, it was anticipated that posttransfusion hepatitis would be virtually eliminated, but this was not to be. There remained a substantial residue of cases which were called non-A, non-B hepatitis (NANBH). The causative agent remained frustratingly elusive for over a decade and has still not been convincingly cultured in vitro nor visualized by electron miscro-scopy. Nevertheless, in 1989, a team of molecular biologists in the United States succeeded in an ambitious assignment which seemed to many to be unachievable. The ingenious protocol they devised serves as a prototype which could be applied in the future to the discovery not only of additional NANBH viruses but also of many other currently unknown noncultivable infectious agents. Bradley and colleagues had previously demonstrated that hepatitis could be transmitted to chimpanzees by inoculation of factor VIII known to have been...

Hepatitis E Viruses

An infectious inflammation of the liver endemic to Asia, Central America, and parts of Africa is apparently transmitted by the fecal-oral route. The RNA genome of the culprit agent has now been sequenced and the virus in question, the hepatitis E virus, has been classified with the caliciviruses. It occurs in at least 13 variants divided into three groups. In-vitro culturing of HEV has not succeeded to date. Pathogenesis and clinical picture. The clinical course of hepatitis E infections tends to be benign and resembles that of hepatitis A. It shows no chronicity. However, infections in the third trimester of pregnancy have a lethality rate of 10-40 . Epidemiology. HEV causes repeated outbreaks of considerable dimensions in the parts of the world mentioned above. The infections can be traced to contaminated drinking water. Hepatitis E is imported to central Europe as a traveler's infection, although apparently less frequently than hepatitis A. No specific prophylactic...

Viral Hepatitis

Our knowledge of viral hepatitis has developed remarkably over the last two decades Accordingly we have devoted a good deal of space elsewhere in this volume to the five major known agents, hepatitis A (Chapter 23), hepatitis B and D (Chapter 22), hepatitis C (Chapter 26), and hepatitis E (Chapter 24). Here, we simply produce a summary (Table 36-10) which brings together for easy comparison some of the main clinical and epidemiologic features of the five hepatitis viruses, that is, those whose main or only target appears to be the liver. It is remarkable that, although the acute diseases caused by these five viruses are clinically indistinguishable, the agents themselves are totally different, belonging in fact to five different families. The major generalizations that should be extracted from Table 36-10 are that (1) hepatitis A and E viruses are spread via the enteric route, whereas hepatitis B, C, and D viruses are transmitted parenterally, sexually, and (in one case at least)...

Hepatitis B

Hepatitis B is produced by a DNA virus classified as a hepadnavirus type 1 (40-42). There are multiple serotypes. More than 300 million people suffer from chronic hepatitis B virus (HBV) infection more than 75 of affected individuals live in Asia or are of Asian origin. The usual incubation period is 2-3 mo but may be as short as 45 d and as long as 6 mo. The frequency of clinical illness with jaundice is different at different ages. Fewer than 10 of the patients acquiring infection when younger than 5 yr of age develop jaundice, while 30-50 of those older than 5 yr of age develop this clinical sign. The death rate associated with acute HBV infection is low, from 0.5 to 1.0 , and the rate of chronic infection is quite variable depending on the age at acquisition. For example, more than 90 of neonates infected with HBV will develop chronic infection and a carrier state, compared with 50 of infants, 10 of children older than 5 yr of age, and < 5 of adults. If patients develop chronic...

Hepatitis E

The story of the original discovery of hepatitis E virus (HEV) in Soviet Central Asia is worthy of Scheherazade. An intrepid Soviet virologist, Balayan, investigating an outbreak of hepatitis in Tashkent, volunteered himself to drink a pooled filtrate of stools from the patients sure enough he developed hepatitis. After recovering a novel 32 nm virus from his own feces, he inoculated a filtrate of that material into monkeys, which in turn developed biochemical evidence of hepatitis and excreted in their stools a virus which he identified, by immunoelectron microscopy (IEM) using convalescent human sera, to be the same virus as was present in the original patients Similar viruses were later recovered by others from enterically transmitted non-A, non-R hepatitis (ET-NANBH) outbreaks in India and many other countries of Asia as well as North Africa and Mexico. Bradley and colleagues then demonstrated that these several strains reacted in JEM with acute-phase sera from cases from many...

Hepatitis B Virus

Hepadnavirus Replication

HBV is the first human hepatitis virus from which the proteins and genome could be identified and characterized. Before discovery of the viruses, two types of hepatitis (hepatitis A for infectious hepatitis and hepatitis B for serum hepatitis) were differentiated on the basis of transmission routes and other epidemiologic characteristics (4). Hepatitis A virus (HAV) was transmitted by the fecal-oral route, whereas hepatitis B virus (HBV) was transmitted parenterally. In 1963, Blumberg et al. Studied genetic polymorphisms of serum proteins, and discovered a previously unknown antigen that formed a precipitin line with the serum of a multiply transfused hemophiliac in the blood of an Australian aborigine (Australia antigen) (5). The significance of Australia antigen was soon recognized by its specific association with hepatitis B. By using immune electron microscopic methods, Dane and colleagues in 1970 first described the 42-nm particles that came to be known later as Dane particles...

Groupings Based on Epidemiologic Pathogenic Criteria

Sexually transmitted viruses include some herpesviruses and papillomaviruses thai cause lesions in flic genital tract, as well as certain retroviruses and hepatitis viruses that are often transmitted during sexual activity but cause generalized disease. Hepafitis viruses are olten considered together bccause the liver constitutes the principal target. Formerly including the viruses of yellow fever and Rift Valley fever, the term is now generally restricted to hepatitis A, R, C, D, and E viruses. Epidemiological they are diverse, for hepatitis A and E are spread by the enteric route, whereas hepatitis B, C, and D are transmitted parcn-terally (by blood) or sexually Because each hepatitis virus belongs to a tax-onomically different family, each is considered in a different chapter in Part II of this book

Andy S Yu MDa Ramsey C Cheung MDbc Emmet B Keeffe MDc

More than 350 million people worldwide are infected with the hepatitis B virus (HBV), and more than 1 million of them die each year of liver failure or hepatocellular carcinoma (HCC) 1 . The HBV prevalence varies widely from 0.1 to 20 in different geographic regions in the world, depending on the predominant age of infection and major mode of transmission 2 . There are currently 1.25 million HBV carriers in the United States, contributing to 17,000 hospitalizations and 5000 deaths annually 3 . As HBV is transmitted by body fluids, infection can be minimized by proper infection control practices, risk-reduction counseling, virus deactivation of plasma-derived products, and screening donors of blood, solid organs, and semen 4 . However the most effective way to prevent transmission of HBV is by immunization 5 . The national strategy to eliminate HBV transmission in the United States focuses on four major categories of subjects, including (1) neonates, (2) infants, (3) adolescents, and...

Infection by Other Routes

The genital tract is the route of entry of several important pathogens. Herpes simplex viruses and papillomaviruses produce lesions on the genitalia and perineum. Many others, for example HIV, HTLV, and hepatitis B and C viruses, do not produce local lesions but are sexually transmitted.

Invasion of Other Organs

Almost any organ may be infected via the bloodstream with one or another kind of virus, but most viruses have well-defined organ and tissue tropisms. The clinical importance of infection of various organs and tissues depends in part on their role in the economy of the body. Thus invasion of the liver, causing severe hepatitis, as in yellow fever and infections with the hepatitis vuuses, may be a life-threatening situation, with the additional possibility in the case of hepatitis B and C of the establishment of a chronic carrier state that may eventually result in hepatocellular carcinoma. The critical importance of such organs as the brain, heart, and lung is equally self-evident. Thus the most dangerous viral infections tend to be those that cause encephalitis, pneumonia, carditis, hepatitis, or hemorrhagic fever.

Other Routes of Shedding

Many viruses can be found in semen or vaginal secretions. Viruses shed from the genital tract depend on mucosal contact for successful transmission. They include HIV, herpes simplex type 2 virus, and some papillomaviruses. Several other viruses, such as other herpesviruses, hepatitis B and C viruses, and HTLV, are now known to be readily transmissible sexually. Viremia is a most important vehicle, not only of viral spread within the host, but also for transmission between hosts. Blood is the usual source from which arthropods acquire viruses by inserting their proboscis into a capillary, and blood may also be the route of transfer of viruses to the ovum or fetus. Hepatitis B, C, and D viruses, HIV, and HTLV were once commonly spread by blood transfusion, and today are often transmitted between intravenous drug users via contaminated needles

Viral Virulence and Host Resistance

Variability in the response of individuals to infection is regularly observed during epidemics. For example, during an outbreak of influenza some people (mainly old persons or those with preexisting respiratory disease) may die, while others will suffer a brief attack but quickly recover. The great majority of arbovirus and enterovirus infections are subclinical for every individual who develops encephalitis during an arbovirus epidemic, or paralytic poliomyelitis during a poliovirus outbreak, dozens more will have no symptoms, the only evidence of infection being a sharp rise in antibody titer. The dose of infecting virus may play a part in determining these differences, but genetic and physiologic factors in the host are probably more important. A unique opportunity to observe the wide variation in innate resistance of healthy young adults of the same age and sex, receiving an identical dose of virus by the same route, arose in 1942 when more than 45,000 U.S. military personnel were...

Predictors of nonresponse

Other studies have confirmed the predictive roles of increasing age, male gender, smoking status, and obesity that may be alternatively represented by higher weight-height index 33,36,46-49 . Medical conditions that compromise the immune system may negatively affect the response to hepatitis B vaccine. In a cohort of homosexual males, low antibody response of anti-HBs < 10 mlU mL or nonresponse to hepatitis B vaccine occurred in seven of 16 patients infected with HIV compared with six of 68 HIV-negative vaccinees (P 0.002). Furthermore, the median anti-HBs titers after immunization in the HIV-negative and HIV-positive responders were 205 and 15 sample ratio units, respectively 50 . Other risk factors for nonresponse include other conditions that may compromise the immune system, such as chronic cardiopulmonary disorders, renal failure, hemodialysis, and prior organ transplantation (Box 2) 51 . Nonresponse to hepatitis B vaccine may also be modulated by genetic factors. When a...

Immune Response Genes

Susceptibility of mice to infection with some viruses, for example, cytomegaloviruses, retroviruses, and lymphocytic choriomeningitis virus, has been shown to be linked to particular MHC genotypes. Many reports of such associations in humans have appeared in the literature, for example, affecting susceptibility resistance to AIDS or seroconversion following hepatitis B vaccination, but the correlations are generally not as dramatic as in the case of, for example, the association of ankylosing spondylitis with HLA B27. Many years ago it was shown that the susceptibility of different strains of mice to mouse hepatitis virus was associated with macrophage susceptibility.

Physiologic Factors Affecting Resistance

Older infants and children tend to suffer less severely from many virus infections than do premature infants or adults. For example, varicella virus, usually the cause of an uncomplicated disease in children, may produce severe pneumonia in adults, and mumps is complicated by orchitis much more often in adults than in children poliovirus, hepatitis virus, and EB virus infections are all much more serious in adults. There are few striking differences in the susceptibility of males and females to viral infections, except in the obvious instances of viruses with a predilection for tissues such as testis, ovaries, or mammary glands Pregnancy significantly increases the likelihood of severe disease following infection with certain viruses, an effect that was very pronounced in smallpox and is also seen in infections with hepatitis viruses, especially hepatitis E virus. Latent herpesvirus infections are often reactivated during pregnancy, contaminating the birth canal and leading to...

Vaccine nonresponse and its management

Among individuals who do not respond to the initial series of hepatitis B vaccine, half may convert after an additional one to three doses 60,85 . Hypo-responders are more likely to seroconvert than nonresponders 86 . The use of investigational mix-particle vaccines containing pre-Sl, pre-S2, and S subunits does not enhance the seroconversion rate achieved by a standard S-unit vaccine of equivalent dosage 87 . Likewise, doubling administered doses for revaccination does not confer any immunologic advantage 88 . Nonresponders to a second series of vaccination are unlikely to develop adequate anti-HBs titers with further vaccine doses 5 . Another potential alternative is the use of vaccine adjuvants to enhance the immunogenicity of existing vaccines 89,90 . Clinical algorithms to reimmunize nonresponders have been described 86 . The use of granulocyte-macrophage colony stimulating factor (GM-CSF) as vaccine adjuvant operates by enhancing memory cell generation via both T and B cell...

Types of Epidemiologic Investigations

Epidemiologic aspects of several specifically human diseases that have not been reproduced in other animals have been studied in human volunteers for example, early work with yellow fever, hepatitis viruses, rhino-viruses, and a range of other respiratory viruses involved human volunteer studies. Many major discoveries that have led to the control of viral diseases were possible only with the use of human volunteers. An absolute requirement is that the investigators obtain informed consent from the subjects or, in the case of minors, from their parents. It is essential in such work that careful consideration be given to any short- or long-term risks that may be involved, including the possibility of transferring other agents that may be present in the inoculum as contaminants.

Hygiene and Sanitation

Hygiene and sanitation have had a profound effect on the incidence of enteric infections, both viral and bacterial. Viruses that infect the intestinal tract are shed in feces, and in many human communities recycling of feces back into the mouth following fecal contamination of food or water is common. A more voluminous and more fluid output (diarrhea) increases the environmental contamination. Hands contaminated at the time of defecation and inadequately washed may transfer viruses directly or indirectly to food, which is a particular problem if it occurs among those responsible for the preparation of meals to be eaten by others, in many densely populated parts of the world there are no reticulated sewerage systems, and sewage may seep into wells, streams, or other drinking water supplies, particularly after heavy rains. Explosive outbreaks of hepatitis E, poliomyelitis, or gastroenteritis occur from time to time even in sewered areas when sewerage mains burst or overflow to...

Jeffrey S Glenn MD PhD

Hepatitis C virus (HCV) is a significant cause of morbidity and mortality, infecting over 150 million people worldwide 1,2 . In spite of recent progress, current therapies remain inadequate for the majority of patients 3-5 . The study of HCV molecular virology is providing an increasing number of new anti-HCV targets. These are being translated into the development of new drugs that offer the prospect of more effective antiviral therapies. This article provides a concise review and update of the major highlights in these efforts.

Overview of life cycle

HCV is a positive, single-stranded, RNA virus. Its 9.6-kb genome encodes a single 3000 amino acid polyprotein that is proteolytically processed by a combination of cellular and viral proteinases into structural (components of the mature virus) and nonstructural (elements proposed to help replicate new virions) proteins (Fig. 1) 6-8 . Flanking this long protein-encoding sequence are conserved nontranslated regions at the 5' and 3' ends of the RNA genome. These contain highly structured elements that represent important cis-acting signals for initiating replication and translation of the viral genome.

Hepadnaviridae and Deltavirus

Clinical Features of Hepatitis B 362 Deltavirus (Hepatitis D) 373 In 1963 Blumberg, a geneticist investigating hereditary factors in the sera of isolated racial groups, discovered an antigen in the serum of an Australian aborigine that reacted with sera from multiply transfused American hemophiliacs. In due course the antigen was demonstrated to be present on the surface of particles with three different morphologic forms (Fig. 22-1) and to be associated with the disease serum hepatitis, now known as hepatitis B. The 22 nm particles of Australia antigen, subsequently renamed HBsAg, for hepatitis B surface antigen, were found to be noninfectious, but the 42 nm particles were shown to be infectious virions capable of transmitting hepatitis to chimpanzees. The unique characteristics of these viruses led to their classification within a new family, named Hepadmi'iridae to reflect the association with hepatitis and the DNA genome. The very small genome replicates via a unique mechanism....

Pathogenesis and Immunity

The tropism of HBV for hepatocytes appears to be determined, in part at least, by os-acting regulatory elements in the HBV genome. The state of differentiation of the liver cells may also be important, and certain viral enhancer elements are inducible by hormones. There is evidence of at least limited viral replication also in bile duct epithelium, pancreatic acinar cells, B lymphocytes, and monocytes. Liver biopsy at the height of acute hepatitis reveals necrosis of liver parenchyma and the accompanying histopathology shown in Fig. 22-5. By immunofluorescence or immunoelectron microscopy HBcAg is demonstrable in the cytoplasm and nucleus of infected hepatocytes in acute or chronic active hepatitis, whereas HBsAg is seen only in the cytoplasm. By autoradiography, HBV DNA is found in the cytoplasm of productively infected cells but integrated into the chromosomes of chronically infected carriers in the low replicative phase. HBsAg and HBeAg (but not HBcAg), as well as virions, viral...

Caliciviridae and Astroviridae

Hepatitis E Virus 411 Although it had been recognized for many years that gastroenteritis could be transmitted to human volunteers by ingestion of bacteria-free filtrates of feces from patients with diarrhea, it was not until 1972 that the first of the many types of viruses involved was identified, by immunoelectron microscopy (IEM). Nofwalk virus, named for the town in Ohio that hosted the outbreak yielding the virus, was the prototype of a succession of small round-structured viruses whose taxonomic status remained unclear until 1991 when sequencing of the genome made it apparent that they belong to the family Caliciviridae. Caliciviruses had been well known for years to veterinary virologists interested in such major animal pathogens as vesicular exanthema of swine virus and feline calicivirus. In 1991 the genome of the noncultivable agent of another important enterically transmitted disease, hepatitis E, was cloned and sequenced, and the virus was provisionally classified as a...

Box 1 Indications and contraindications to therapy

Necro-inflammation and fibrosis on liver biopsy Hepatitis C virus RNA positive The efficacy of alpha interferon for treatment of HCV first was recognized when Hoofnagle et al published their preliminary findings in 1986 when HCV was known as non-A, non-B hepatitis 11 . They treated 10 patients with chronic non-A, non-B hepatitis with varying doses (0.5 to 5 million U) up to 12 months. The aminotransferases levels improved in 8 of 10 patients and in 3 patients who had follow-up biopsies done after 1 year of therapy showing marked improvement in liver histology. Several subsequent studies, including a large, multi-center, randomized clinical trial in the United States by Davis et al confirmed the initial finding that long-term IFN therapy improved liver function tests and liver histology 12 . The US Food and Drug Administration (FDA) approved alpha interferon monotherapy for the treatment of chronic HCV infection in 1993. In 1997, The NIH released the consensus statement recommending...

Laboratory Diagnosis

Coronaviruses are difficult to grow in cultured cells and hence are rarely recovered from humans. HCV-OC43 and related strains were originally isolated in organ cultures of human embryonic trachea or nasal epithelium. Organ culture is too intricate a technique for a diagnostic laboratory, but some strains can be isolated directly in diploid fibroblast lines from human embryonic lung or intestine. Foci of granular cells become evident after a week and may progress to vacuolation before disintegrating syncytia may form in

Clinical Features

Crimean-Congo hemorrhagic fever commences abruptly with fever, headache, and severe back and abdominal pain, and progresses to extensive hemorrhages from almost any site, with melena, hematemesis, hematuria, and a hemorrhagic skin rash (Fig. 33-4). Leukopenia, thrombocytopenia, proteinuria, and hepatitis are key findings. Blood loss from internal bleeding leads to shock, pulmonary edema, and death. Case-fatality rates range from 5 to 50 , depending on the availability of modern medical care.

Box 1 Predictors of response in prior relapsers

Similar predictors of response have been recently reported in relapsers to combination standard IFN and RBV therapy who are retreated with PEG IFN and RBV. Genotype non-1 and low viral load are predictors of a favorable response 43,44 . In one study, the absence of HCV viremia at week 6, as determined by the transcription-mediated amplification assay, was highly predictive of SVR (80 in the overall study population, 92 in genotype non-1 patients) 44 . Herrine et al assessed the efficacy of mycophenolate mofetil and amantadine in addition to PEG IFN and RBV in a pilot study 43 . They treated 124 patients (106 relapsers, 18 breakthrough relapsers) who were randomized to receive PEG IFN alfa-2a 180 mg once weekly in addition to one of four following treatment arms (1) RBV at 800 to 1000 mg daily, (2) mycophenolate at 1000 mg twice daily, (3) amantadine at 100 mg twice daily, or (4) amantadine at 100 mg twice daily and RBV at 800 to 1000 mg daily. End-of-treat-ment response rates were...

Scott W Biggins MD Norah A Terrault MD MPH

Chronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation in the United States and Europe, and more than 20,000 patients worldwide have undergone transplantation for complications of chronic hepatitis C. In North America, HCV accounts for 15 to 50 of all liver transplants performed 1 . Available prevalence data predict that this proportion will likely increase as the number of persons with chronic hepatitis C developing cirrhosis and hepatocellular carcinoma in North America rises over the next 1 to 2 decades 2,3 . Recurrent HCV infection is universal in those with viremia before transplantation, and the rate of histologic disease progression after transplantation is more rapid. The risk of death and allograft failure is increased in HCV-positive transplant recipients (hazard ratio HR 1.23 and 1.30) compared with HCV-negative recipients 4 . The risk of cirrhosis is as high as 30 within 5 to 10 years after transplantation 5-7 . Retransplantation...

Vital Genitourinary Infections

Several other very important human pathogens are shed in semen and in female genital secretions and are transmitted by sexual intercourse but cause no disease in the genital tract itself. Foremost among these, ol course, are the human immunodeficiency viruses HIV-1 and H1V-2, but the list also includes the human T-cell lymphotropic viruses HTLV-1 and HTLV-2, hepatitis B and C viruses, and the herpesviruses, cytomegalovirus, and (probably) Fpstein-Barr virus. Many more viruses are regularly conveyed between male homosexuals, depending largely on their particular sexual activities and number of partners. These include enteric viruses such as hepatitis A as well as those just listed. Herpes simplex virus, adenovirus 37 Adenovirus 11 Hepatitis B virus Cytomegalovirus Many other important human pathogens causing major diseases not involving the genital or urinary tract clinically are nevertheless transmitted sexually. These include HIV-1 and -2, HTLV-1 and -2, hepatitis B and C viruses,...

Viral Infections in Immunocompromised Patients

Carry the risk of iatrogenic transmission of exogenous viruses such as cytomegalovirus or Epstein-Barr virus, which may overwhelm a patient already desperately ill the once considerable danger of transmitting HIV, hepatitis B, and hepatitis C in this way has almost disappeared as a result of the introduction of universal screening of blood, blood products, and organ donors (not yet completely for hepatitis C). Severely burnt patients are also highly vulnerable to invasion by herpes simplex viruses. The magnitude of the problem is dramatically illustrated by the observation that it is quite standard for more than one, and sometimes all six, of the herpesviruses (HSV-1 and HSV-2, VZV, CMV, EBV, and HHV-6) to be reactivated in bone-marrow transplant recipients in some series, up to 25 of all such patients have died of CMV pneumonia alone Similarly, AIDS patients characteristically suffer the consequences of successive reactivation, sometimes in a roughly predictable order as their CD4+ T...

Furqaan Ahmed MD Ira M Jacobson MD

The treatment for chronic hepatitis C (CHC) has evolved over the last decade from standard interferon (IFN) monotherapy to combination therapy with standard IFN and ribavirin (RBV) and more recently, pegylated (PEG) IFN and RBV combination therapy. As each successive regimen has led to improved sustained virologic response (SVR) rates, the issue of retreating those patients who did not achieve a sustained response with previous therapy arises. A relapse after therapy is defined as viral clearance with a negative hepatitis C virus (HCV) RNA by polymerase chain reaction (PCR) during therapy and reappearance of the virus after treatment is discontinued. This article focuses on the treatment of patients who have relapsed after being treated with IFN or a combination of IFN and RBV. Relapse to PEG IFN and RBV will also be discussed.

Properties of Coronaviridae

Receptor Destroying Enzyme

Two genera, Coronavirus and Torovirus, contain viruses infecting humans. The genus Coronavirus includes two human serotypes causing respiratory disease, the prototype strains being HCV-229E and HCV-OC43, which are clearly distinguishable from one another by neutralization or hemagglutination inhibition. The status of the human enteric coronaviruses and human toroviruses has yet to be determined.

Families of RNA Viruses

Genus Hepatovirus (hepatitis A-Iike viruses) The Picornavirtdae (pica, micro-micro rrn, sigla for ribonucleic acid) comprise small nonenveloped icosahedral viruses 25-30 nm in diameter, which contain a single molecule of plus sense ssRNA (7.5-8.5 kb), and replicate in the cytoplasm (see Table 2-2). The genus Enterovirus includes 3 polio-viruses, 32 human echoviruses, 29 coxsackieviruses, and a few other human enteroviruses. Most of these viruses usually produce inapparent enteric infections, but the polioviruses may also cause paralysis other enteroviruses are sometimes associated with meningoencephalitis, rashes, carditis, myositis, conjunctivitis, and mild upper respiratory tract disease. The only human pathogen in the genus Hepatovirus is human hepatitis A virus. The genus Rhhiovirus includes well over 100 serotypes that affect humans they are the most frequent viruses causing the common cold. The caliciviruses (caSix, cup) are icosahedral viruses whose virions are 35-40 nm in...

Marc G Ghany MDa Edward C Doo MDb

Infection with the hepatitis B virus (HBV) is a significant global public health problem. Over one third of the world population has been exposed to the virus, and an estimated 400 million people are chronically infected 1,2 . Up to 40 of chronically infected individuals will be at risk for cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC), and each year, an estimated 500,000 deaths occur from these complications. Advances in molecular biology techniques have led to a better understanding of the natural history and pathogenesis of HBV-related liver disease, resulting in the development of potent antiviral agents. Some of these agents can be used safely as maintenance therapy for patients who fail to clear the virus following standard durations of treatment. Overall, the advent of newer therapies has provided a wider range of therapeutic options for chronic hepatitis B (CHB) infection. This article focuses on the natural history of CHB-related liver disease,...

Spread by the Bloodstream Viremia

Hepatitis Virus Spreading Organism

Fig. 6-5 Types of interactions between viruses and macrophages, exemplified by the Kupffer cells lining a sinusoid in the liver (1) Macrophages may fail to phagocy lose virions, for example, in Venezuelan equine encephalitis virus infection this is an important factor favoring piolonged viremia (2) Virions may be phagocytosed and destroyed. Because the macrophage system is so efficient, viremia with such viruses can be maintained only if virions entei the blood as fast as they are removed. (3) Virions may be phagocytosed and (hen passively transferred to adjacent cells (hepatocytes in (he liver) If, like Rift Valley fever or hepatitis B viruses, the virus replicates in these cells it can cause clinical hepatitis, and the virus produced m the liver can produce a high level of viremia (4) Virions may be phagocylosed by macrophages and (hen replicate in them With some viruses, such as lactate dehydrogenase virus in mice, only macrophages are infected (4A), and progeny virions enhance the...

Paul H Hayashi MD Adrian M Di Bisceglie MD

Patients with, or at risk for, hepatocellular carcinoma (HCC) present special challenges to the clinician. Despite improved understanding of HCC, current guidelines and treatment algorithms are still inadequate. The gastroenterologist or primary care physician may provide screening and prevention, but clinical care after HCC has occurred is a specialized task. A multidisciplinary team including a hepatologist, oncologist, transplant surgeon, interventional radiologist, and liver histopathologist may be needed. Team coordination and expertise is highly important, and most available at tertiary care referral centers. In this article, some of the challenging and controversial issues regarding HCC detection, diagnosis, prevention, and care are reviewed, with particular emphasis on hepatitis B- and C-associated HCC. Although not always evidenced-based, practice guidelines or standard of care practices are summarized.

Viral Enhancers Promoters and Transcription Factors

Enhancer regions have been defined in the genomes of retroviruses, several herpesviruses, and hepatitis B virus, and in all cases they appear to influence the tropism of the relevant viruses by regulating the expression of viral genes in specific types of cells. The DNA of a dermatotropic type of papillomavirus contains an enhancer that is specifically active only in ker-atinocytes, indeed only in a subset of these cells. Further evidence for the tissue specificity of papovavirus enhancers comes from studies of transgenic mice containing the early gene region of JC polyomavirus, a common human virus which very occasionally causes a neurologic disease, progressive multifocal leukoencephalopathy the offspring of transgenic mice bearing early genes from the JC virus develop a neurologic disease characterized pathologically by dysfunction of myelin-producing oligodendroglia, which mimics the naturally occurring disease.

Mechanisms of Survival of Viruses in Nature

Several factors contribute to optimal transmission of viruses. Some relate to properties of the virion itself, others to the extent and nature of shedding from the body, and others to social interactions. Enveloped viruses infecting mucosal surfaces bud from the apical surface of epithelial cells to maximize shedding into the outside world. Obviously, human-to-human transmission will be enhanced by shedding of high liters of virus containing a high proportion of infectious virions. Respiratory viruses tend to be shed over a relatively brief period (a few days) but are expelled in high concentration as an aerosol generated by explosive sneezing or coughing, thus ensuring transmission to dose contacts. Enteric viruses are also shed in large numbers but usually for a longer period (a week or more) in feces, which may contaminate hands, fomites, food, and water. Enveloped respiratory viruses are relatively labile, especially during summer or in the tropics year-round. In contrast, most...

Viral Damage to Tissues and Organs

Diarrhea Rotavirus

In some situations infected cells may show no obvious damage, but, as discussed in Chapter 5, specialized cells may carry out their functions less effectively after infection. For example, lymphocytic choriomeningitis virus infection of hybridoma cells appears harmless, but less antibody is produced by infected than by uninfected cells. In mice, the same virus has no cytopathic effect on cells of the anterior pituitary, but the output of growth hormone is reduced and as a result the mice are runted likewise, persistent infection of insulin-producing islet cells in the pancreas may result in a lifelong elevation of blood glucose levels (diabetes). Other viruses may indirectly alter the expression of cell surface MHC molecules, leading to destruction of the infected cells by immunologic mechanisms thus, enhanced class II MHC expression after infection of glial cells by mouse hepatitis virus, perhaps due to the production of interferon -y, may render these cells susceptible to immune...

Viruses of Humans

Properties of Hepadmviridae 359 Clinical Features of Hepatitis B 362 Pathogenesis and Immunity 364 Laboratory Diagnosis 366 Epidemiology 369 Control 369 Deltavirus (Hepatitis D) 373 Further Reading 379 Properties of Picornaviridae 382 Polioviruses 385 Other Enteroviruses 391 Rhinoviruses 398 Hepatitis A 400 Further Reading 405 Caliciviruses Associated with Gastroenteritis Hepatitis E 411 Astroviruses 415 Further Reading 417 Flavivirus Encephalitides 443 Tick-Borne Flavivirus Hemorrhagic Fevers Hepatitis C 445 Further Reading 449

Julie C Servoss MDab Lawrence S Friedman MDacd

Hbs Hbeag Mrna

Hepatitis B virus (HBV) is a hepadnavirus with a 3200-base-pair genome that consists of partially double-stranded DNA (dsDNA) and a lipoprotein outer envelope (Fig. 1). The HBV genome has four overlapping open reading frames with four major genes designated pre-S S, C, P, and X. The pre-S genes (S1 and S2) code for the hepatocyte receptor-binding site, whereas the S (surface) gene codes for hepatitis B surface antigen (HBsAg). The C (core) gene codes for hepatitis B core antigen (HBcAg) and hepatitis B e antigen (HBeAg), whereas the P (polymerase) gene encodes the HBV DNA polymerase. The X gene encodes a protein that transactivates transcriptional promoters. Eight genotypes (A-H) of HBV have been identified based on nucleotide sequence divergences of at least 8 . HBV genotypes differ in their predominant geographic occurrence and response to therapy with interferon. Genotype A is the predominant genotype in the United States and is more responsive to interferon than genotype D which...

Routes of vaccine administration

Hepatitis B vaccine is traditionally administered intramuscularly, using a needle of 1.0 to 1.5 inches in length and 20- to 25-gauge in caliber. The preferred injection site is the deltoid muscle in adults and anterolateral thigh muscle in infants. Among 194 health care workers who received intramuscular buttock injections of hepatitis B vaccination, only 58 subsequently developed detectable anti-HBs titers 36 . This finding was verified by a prospective randomized trial where health care workers who received immunization in the arm achieved higher seroconversion rate of 93 and GMT of 1454 mlU mL, as compared with those who were injected in the buttock. Among those who received buttock injection, the seroconversion rate (83 versus 72 ) and the GMT (387 mlU mL versus 85 mlU mL) were higher with the use of 2-inch needles versus 1-inch needles 37 . Buttock injection makes intramuscular delivery of the vaccine difficult and should be avoided. Intradermal injection of vaccine leads to very...

Rna Viruses

Family Hepadnavtridae (Hepatitis B-Iike Viruses) Genus- Orthohepadnavirua (mammalian hepatitis B-like viruses) Human hepatitis B virus and related viruses of other animals, all highly host-specific, comprise the family Hepadnavtridae (hepar, liver dna, sigla for deoxyribonucleic acid). The virions are spherical particles 42 nm in diameter, The hepadnaviruses replicate in hcpatocytes and cause hepatitis, which may progress to a chronic carrier state, cinhosis, and primary hepatocellular carcinoma. The most important species is human hepatitis B virus, but hepadnaviruses also occur in woodchucks, ground squirrels, Pekin ducks, and herons.

Other Viruses

There are a number of known human viruses that are as yel not allocated to families, including hepatitis D virus and the unusual agents that cause the subacute spongiform encephalopathies. Hepatitis D Virus Hepatitis D virus, recently assigned to the genus Dcltavirus, is a satellite virus, the replication of which is dependent on simultaneous infection of cells with a hepadnavirus. The virion is about 32 nm in diameter and consists of the 24 kDa delta (8) antigen encapsidaled by the surface antigen of the helper hepatitis 13 virus. I he genome of onlv I 7 kb of covalenlly closed circular minus sense ssRNA contains regions of extensive base pairing and probably exisls as a partially double-stranded rodlike structure with self-cleaving ribonucleic (ribozyme) activity, similar to the plant virus satellites. Known only as a virus of humans who aie simultaneously infected vith hepatitis B virus, hepatitis D virus causes severe disease which often progresses to chronic hepatitis and or...

Diagnosis

HCC in cirrhotic patients is diagnosed by (1) alpha fetoprotein (AFP) level, (2) imaging studies, and (3) histologic diagnosis. The AFP level is normally less than 15 to 20 ng mL in adults. The higher the AFP level, the more specific it is for HCC. An AFP greater than 400 ng mL in a cirrhotic with a vascular hepatic mass on imaging is diagnostic. Unfortunately, many HCC cases have only modestly elevated AFP values. Sensitivities are as low as 45 even for a low cutoff of 20 ng mL 4 . Moreover, hepatocyte regeneration during and after flares in chronic hepatitis may increase AFP levels in the absence of HCC. Other serologic markers, such as des g-carboxyprothrombin and glypican-3, have shown promise but are not widely used clinically in the United States 5,6 .

Mutation Rates

The error rate in the replication of viral RNA is much higher than that of viral or cellular DNA, because there is no cellular proofreading mechanism for RNA. For example, the base substitution rate in the 11-kb genome of vesicular stomatitis virus is ICM to 10 4 per base per replication cycle, so that nearly every progeny genome will be different from its parent and from one another in at least one base. This rate of base substitution is about one million times higher than the average rate in eukaryotic DNA Of course, most of the base substitutions are deleterious and the genomes containing them are lost. However, nonlethal mutations in the genome of RNA viruses accumulate very rapidly. For example, sequence analysis of the genome of two isolates of hepatitis C virus obtained from a chronically infected patient at an interval of 13 years showed that the mutation rate was about 2 x 10 1 base substitutions per genome site per year. The nucleotide changes were unevenly distributed...

Prevention

Primary prevention of hepatitis C and B virus infection through control of high-risk behavior (eg, intravenous drug use), adequate screening of blood products, and vaccination are likely to be highly effective if such programs and policies were to be widely implemented. The annual incidence of hepatitis C infection has fallen in the United States since the 1970s, when intravenous drug use was more widespread and screening tests for hepatitis C were unavailable. The AIDS epidemic seems to have considerably decreased intravenous drug use. Posttransfusion hepatitis C has become exceedingly rare since the implementation of improved anti-hepatitis C virus antibody testing by American blood banks in 1992. A vaccine for hepatitis C remains elusive because of lack of host protective antibody and viral immune escape mechanisms. The incidence of hepatitis B fell with the decline in intravenous drug use, and safer sexual practices caused by AIDS awareness. Available vaccine will significantly...

Alimentary Tract

There are other protective mechanisms in the intestinal tract from the stomach downward, acid, bile, and proteolytic enzymes may inactivate viruses. In general, viruses that cause intestinal infection, such as enteroviruses, rotaviruses, and caliciviruses (Table 6-2), are acid- and bile-resistant. Rotaviruses and caliciviruses are now recognized as the major causes of viral diarrhea, whereas the great majority of intestinal infections by enteroviruses and adenoviruses are asymptomatic. Some of the enteroviruses (e.g., polio-viruses), and hepatitis A and E viruses, are important causes of generalized infection but do not produce signs referable to the intestinal tract.

Info

Introduced in this way replicate in the vector. Viruses that are transmitted by and replicate in arthropod vectors are called arboviruses Infection can be acquired through the bite of an animal, as in rabies. Finally, introduction of a virus by skin penetration may be iatrogenic, that is, as a result of human intervention, such as transmission of hepatitis B and C viruses and HIV by contaminated needles or blood transfusion. Generalized infection of the skin, producing an exanthem such as is found in measles, chickenpox, rubella, and several arbovirus diseases, is due to viral dissemination via the bloodstream.

Immunogenicity

The HBsAg particle is the immunogen in both plasma-derived and recombinant hepatitis B vaccines. This envelope protein composed of several allelic subtype determinants but only one common group-specific determinant a, which allows cross-protectivity among different subtypes 28,29 . Vaccinated subjects may have transiently detectable HBsAg in the serum within the first 24 hours. HBV vaccines stimulate active synthesis of anti-HBs conferring immunity. The first commercially available hepatitis B vaccine in the United States, licensed in 1981, was derived from chemically treated or heat-inactivated sub-viral particles that were obtained from plasma of chronic HBV carriers. Physician acceptance of these vaccines was initially impeded by the unfounded concern of the product carrying other blood-borne infectious agents 5 . Plasma-derived products still account for more than 80 of all hepatitis B vaccines used worldwide however, in the United States the plasma-derived product has been...

Virus Shedding

Fig. 6-1) in generalized infections a greater variety of modes of shedding is recognized (see Fig. 6-4), and some viruses are shed from multiple sites, for example, hepatitis B virus, HIV, or cytomegalovirus in semen, cervical secretions, milk, and saliva. The amount of virus shed in an excretion or secretion is important in relation to transmission. Very low concentrations may be irrelevant unless very large volumes of infected material are transferred on the other hand, some viruses occur m such high concentrations that a minute quantity of material, for example, less than 5 xl, can transmit infection.

Passive Immunity

There is abundant evidence for the efficacy of antibody in preventing infection. For example, artificial passive immunization (injection of antibodies) temporarily protects against hepatitis A or B, rabies, measles, varicella, and several other viral infections (see Chapter 13). Furthermore, natural passive immunization protects the newborn for the first few months of life against most of the infections that the mother has experienced. In humans this occurs in two ways (1) maternal antibodies of the IgG class cross the placenta and protect the fetus and the newborn infant during pregnancy and for several months after birth (2) antibodies of the fgA class are secreted in the mother's milk at a concentration of 1.5 grams per liter (and considerably higher in the early colostrum), conferring protection against enteric infections as long as breast-feeding continues. If the infant encounters viruses when maternal immunity is waning, the virus replicates to only a limited extent, causing no...

Summary

Immunization is the most effective way to prevent transmission of HBV and, hence, the development of acute or chronic hepatitis B. The national strategy to eliminate transmission of the virus in the United States includes vaccination of all newborn infants, children, adolescents, and high-risk adults. Postexposure prophylaxis is also advocated, depending on the vaccination and anti-HBs status of the exposed person. Seroprotection after vaccination, defined as anti-HBs > 10 mlU mL, is achieved in over 95 of all vaccinees. The hepatitis B vaccines are very well tolerated with usually minimal adverse effects. Predictors of non-response include increasing age, male gender, obesity, tobacco smoking, and immunocompromising chronic disease. For those who remain nonresponders after the second series of vaccination, adjuvants such as GM-CSF may be considered, but their results are variable.

Chronic Infections

Hepatitis B Hepatitis B is the most important chronic viral infection of humans, especially in Asia and Africa, where there are some 250 million carriers. During acute infections the virus replicates in the liver and circulates in the plasma, usually in association with a great excess of smaller particles composed of viral surface antigen (HBsAg). In most infected individuals HBsAg and virions are cleared from the circulation, but in 5-10 , including over 90 of those infected during infancy, a persistent infection is established which can extend for many years, often for life. The carrier state is characterized by continuous production of HBsAg and usually infectious particles, which are plentiful in the bloodstream and less so in semen and saliva, hence the danger of such persons as blood donors and sexual partners. Some carriers develop chronic hepatitis and cirrhosis, and hepatitis B virus (HBV) is an important cause of primary hepatocellular carcinoma. In acute hepatitis B and in...

Change of Lifestyle

Certain lifestyles that have become common in Western countries during the last few decades, such as the sharing of needles during the intravenous administration of addictive drugs and promiscuous male homosexuality, are associated with increased risks of infection with a variety of agents, notably hepatitis B and C viruses and HIV. Observations on the incidence of gonorrhea in developed countries suggest that fear of AIDS has increased the use of condoms and somewhat reduced the incidence of promiscuous male homosexual practices, but in general changes in lifestyle designed to reduce the incidence of disease are difficult to achieve, as is evident with cigarette smoking and alcoholism.

Clinical Application

Diseases against which no satisfactory vaccine is available, including those with a large number of different etiologic agents, are prime targets for antiviral chemotherapy. The common cold is an admirable example on both counts, but there are so many serotypes that chemotherapeutic agents, to be sufficiently broad spectrum, will need to be directed at molecules (or ligands) that are conserved across the genus Rhinovirus. Other respiratory infections, gastroenteritis, hepatitis, and infectious mononucleosis must also be high on the list of priorities. Effective chemotherapy is also needed to treat reactivation of latent infections such as herpes simplex and zoster, even though the latent infection itself will not be eliminated. Reactivation of herpesvirus infections is a particular problem in immunocompromised individuals, such as AIDS patients or transplant recipients. Chronic infections, for example, hepatitis B and C, AIDS, congenital rubella, or cytomegalovirus infections, may be...