Hepatitis C virus RNA quantification in right and left lobes of the liver in patients with chronic hepatitis C

Summary. Quantification of hepatitis C virus RNA in liver tissue is likely to be useful in the study of the natural history, pathogenesis, progression and treatment of hepatitis C virus-associated liver disease. Quantitative measurements of hepatitis C virus RNA in liver biopsy samples using the branched DNA (bDNA) signal amplification assay were carried out. The aims of this study were threefold: first, to assess the level of hepatitis C virus RNA in biopsy samples from the right and left lobes of the liver; second, to evaluate the correlation between hepatitis C virus RNA levels in serum and liver; and third, to investigate the relationship between serum and liver hepatitis C virus RNA levels and the severity of hepatic histology in non-cirrhotic patients with chronic hepatitis C. There was a strong correlation ( r = 0.92, P < 0.01) between hepatitis C virus RNA levels in the right and left lobes of the liver as well as a strong correlation between hepatitis C virus RNA levels in liver and serum ( r = 0.82, P < 0.01). However, there was no significant correlation between the severity of hepatic histology and levels of hepatitis C virus RNA in serum and liver among patients with chronic active hepatitis classified according to Knodell's hepatic activity index (KI). Our results indicate that hepatitis C virus RNA quantification from a single liver biopsy is representative of both lobes in patients with chronic hepatitis, and suggest that serum hepatitis C virus RNA levels are a meaningful reflection of hepatitis C virus RNA levels in the liver.     

Hepatitis B virus and hepatitis C virus infections in children

PURPOSE OF REVIEW: To analyse the most relevant recent information on efficacy, duration and coverage of anti-hepatitis B virus vaccination; correlates of mother-to-child hepatitis C virus transmission; the natural history and outcomes of hepatitis B and C virus infections in children; the efficacy and safety of specific therapies. RECENT FINDINGS: Insufficient hepatitis B virus vaccine coverage and incomplete or delayed vaccine cycles need improvement in many countries. Hepatitis B virus mutants may explain some fulminant hepatitis in perinatally infected infants and vaccine failures. No interventions to prevent vertical hepatitis C virus transmission have been identified. Spontaneous clearance of hepatitis B is lower in children than in adults, while the rates appear to be similar for hepatitis C. The disease progression is slower for both infections in childhood. Several studies support the efficacy and safety of interferons and lamivudine in chronic hepatitis B or of interferons and ribavirin in chronic hepatitis C in children, but the optimal therapy remains unclear. SUMMARY: There are doubts as to the long-term persistence of anti-hepatitis B immunization in low-endemicity areas. Routine hepatitis C virus testing in pregnancy is not recommended as there are no available prophylactic measures. Although hepatitis B and C virus infections are usually asymptomatic or with mild manifestations in childhood, concerns around their long-term clinical impact suggest the need for early treatment. Children should preferably be treated in the context of targeted trials for a better understanding of the efficacy and tolerance of drugs currently used in adults.     

Hepatitis B and C virus infections in the immune compromised

PURPOSE OF REVIEW: This review compares and contrasts the natural history and treatment of hepatitis B and C virus infections in three principal populations of immune compromised individuals: (1) patients co-infected with HIV; (2) patients with liver failure secondary to hepatitis B or C virus infection who undergo liver transplantation, and (3) patients with hepatitis B or C virus infection who undergo anticancer chemotherapy. RECENT FINDINGS: Chronic liver disease resulting from hepatitis B or C virus infection progresses more rapidly in patients co-infected with HIV than in HIV negative patients. Treatment protocols for antiviral therapy are, however, similar to those used in immunocompetent individuals and although few long-term results are available, the efficacy of interferon and ribavirin therapy in hepatitis C virus/HIV infection and lamivudine in HIV/hepatitis B virus infection has been proven in the short-term. Perhaps the most important consideration is the timing of administering treatments to co-infected patients. For patients with well preserved CD4 counts and hepatitis C virus/HIV co-infection, the hepatitis infection should be treated as early as possible to avoid drug interactions of hepatitis C virus antivirals with antiretroviral therapy. Also, response to hepatitis C virus treatment appears better when treatment is administered in the context of preserved immune function. Conversely, in hepatitis B virus/HIV co-infection, hepatitis B virus antivirals are best administered with anti-retroviral therapy, thus preventing the selection of HIV viral species which may be resistant to the drugs used for hepatitis B virus. Improved graft and patient survival after liver transplant and with anticancer chemotherapy in hepatitis B virus infected patients has been proven using lamivudine prophylaxis. However, although therapy for hepatitis C virus recurrence after liver transplantation would seem rational, limited success with current treatment protocols has been achieved. SUMMARY: Although the prognosis of hepatitis B and C virus infections in the immune compromised may be inferior to that of immunocompetent individuals, such patients should have full evaluation of their viral hepatitis, and antiviral therapy should be considered.     

Guidelines for the screening and follow-up of infants born to anti-HCV positive mothers.

Hepatitis C virus infection in infancy largely depends on vertical transmission. The transfer of hepatitis C virus from mother to child is almost invariably restricted to children whose mother is viremic, and the rate of transmission seems to be influenced by maternal virus load, although, in the single patient, the levels of viremia cannot be used as predictors of pediatric infection. In fact, the flow-chart for screening children at risk for vertically transmitted hepatitis C virus infection takes into account maternal viremia. In children born to anti-hepatitis C virus antibody positive, hepatitis C virus-RNA negative mothers, alanine aminotransferase and anti-hepatitis C virus should be investigated at 18-24 months of life. If alanine aminotransferase values are normal and anti-hepatitis C virus is undetectable, follow-up should be interrupted. In children born to hepatitis C virus-RNA positive mothers, alanine aminotransferase and hepatitis C virus RNA should be investigated at 3 months of age: (1) hepatitis C virus-RNA positive children should be considered infected if viremia is confirmed by a second assay performed within the 12th month; (2) hepatitis C virus-RNA negative children with abnormal alanine aminotransferase should be tested again for viremia at 6-12 months, and for anti-hepatitis C virus at 18 months; (3) hepatitis C virus-RNA negative children with normal alanine aminotransferase should be tested for anti-hepatitis C virus and alanine aminotransferase at 18-24 months, and should be considered non-infected if alanine aminotransferase is normal and anti-hepatitis C virus undetectable; (4) anti-hepatitis C virus seropositivity beyond the 18th month in a never-viremic child with normal alanine aminotransferase is likely consistent with past hepatitis C virus infection.     

Management of hepatitis C virus in special populations: patient and treatment considerations.

The most common chronic blood-borne infection in the United States is caused by hepatitis C virus. An estimated 3.9 million people (1.8%) in the United States have been infected with the hepatitis C virus, excluding certain subpopulations who are at high risk for hepatitis C virus infection. Among these subpopulations are an estimated 255,000 (15%) of prison inmates and 175,000 (22%) of homeless people. Prevalence of hepatitis C virus infection is also high among veterans (6.6% overall and even higher among homeless veterans). The single most important risk factor for hepatitis C virus infection is injection drug use; up to 90% of illicit injection drug users are infected with hepatitis C virus. This review describes the prevalence of hepatitis C virus in special populations and discusses the treatment options for patients with severe disease, transplant recipients, and patients at high risk for infection. Close monitoring and management of therapeutic side effects are required to assist these patients in adhering to therapy.     

Vertical transmission of hepatitis C virus in a hospital in southern Brazil

BACKGROUND: There still are controversies concerning the vertical transmission of hepatitis C virus. AIM: To evaluate the prevalence of antibodies against hepatitis C virus in pregnant women, as well as the rate of vertical transmission of this virus. PATIENTS AND METHODS: Between August 1998 and November 1999, 1,090 consecutive pregnant women were screened for anti-hepatitis C virus; positive results were confirmed by the polymerase chain reaction assay. Patient's viral load was evaluated by the branched deoxyribonucleic acid assay. Hepatitis C virus genotype was identified by direct sequencing of the polymerase chain reaction amplification products. The same tests were performed in the children born from infected mothers at the 1st and 6th month of life. RESULTS: Of the 1,090 mothers surveyed, 29 were positive for anti-hepatitis C virus (prevalence of 2.66%). Twenty-five patients presented with hepatitis C virus RNA, with a median hepatitis C virus viral load of 3.132 +/- 5.891 MEq/mL. Twenty-two patients (six human immunodeficiency virus-coinfected) were followed and gave birth to 23 children; 18 of them had blood samples tested at the 1st month of life, and 22, at the 6th month. Vertical transmission rate was 5.56%; it affected a girl who had hepatitis C virus RNA detectable only in the 1st month sample (41.570 MEq/mL). The mother who transmitted hepatitis C virus was coinfected with human immunodeficiency virus and presented with an hepatitis C virus viral load of 3.765 MEq/mL, with 100% homology with her daughter's hepatitis C virus genotype. CONCLUSION: These results suggest that the prevalence of hepatitis C virus infection in pregnant women should not be neglected, and early diagnosis of vertical transmission and the follow up of infected children should be emphasized.     

Diagnosis of chronic hepatitis C after liver transplantation by the detection of viral sequences with polymerase chain reaction.

Chronic hepatitis frequently occurs after liver transplantation. The role of hepatitis C virus infection in patients after liver transplantation is unknown, although antibodies to HCV are detected in some of these cases. The use of polymerase chain reaction techniques for the detection of hepatitis C virus RNA should improve sensitivity and specificity, particularly in these immunosuppressed patients. Our goal was to further clarify the role of hepatitis C virus infection in chronic hepatitis occurring after liver transplantation. Patients with chronic hepatitis of uncertain origin after transplantation were identified. Serum samples taken at the time of the most recent liver biopsy that showed chronic hepatitis were tested for anti-hepatitis C virus using enzyme-linked immunoassay and supplemented by recombinant immunoblot assay (recombinant immunoblot assay I and recombinant immunoblot assay II). The samples were also tested for the presence of hepatitis C virus RNA using polymerase chain reaction. Of the 25 patients with chronic hepatitis, 15 (60%) had hepatitis C virus RNA present. Only seven (47%) of these 15 patients had anti-hepatitis C virus detected. Hepatitis C virus is a major cause of chronic hepatitis occurring after liver transplantation. The magnitude of hepatitis C virus infection will be underestimated if only currently available assays for anti-hepatitis C virus are used.     

High prevalence, low pathogenicity in hepatitis G virus in kidney transplant recipients

BACKGROUND: Prevalence and pathogenicity of hepatitis G virus infection in long-term renal transplant recipients, are not fully known. AIM: To evaluate long-term impact of HGV infection on liver disease of renal transplanted patients. PATIENTS AND METHODS: A total of 155 hepatitis B surface antigen negative kidney transplant recipients, followed for a mean of 11 years after renal transplantation, were studied. Of these 48 (31%) patients had persistently elevated serum aminotransferase values. Frozen serum samples were tested for HGV-RNA and HCV-RNA by nested reverse transcribed polymerase chain reaction, and for anti-hepatitis G virus and anti-hepatitis C virus by enzyme-linked immunosorbent assay Hepatitis C virus-RNA was typed by a line probe assay and quantified by a branched DNA signal amplification assay RESULTS: Hepatitis G virus-RNA was detected in 37 (24%) patients and anti-hepatitis G virus in another 26 (17%). Seventy (45%) patients had serum anti-hepatitis C virus and 63 of these (90%) had serum hepatitis C virus-RNA. Hepatitis G virus-RNA positive and negative patients were similar in terms of age, sex, duration of dialysis, rate of transfusion, chronic liver disease, rate of hepatitis C virus infection and immunosuppressive therapy. Fifteen (41%) hepatitis G virus-RNA seropositive patients were hepatitis C virus co-infected. Hepatitis C virus-RNA levels were significantly lower in the 15 hepatitis C virus/hepatitis G virus co-infected patients than in the 48 patients with hepatitis C virus infection only (2.2 vs 10.8 MEq/ml, p = 0.02). Only 3 hepatitis G virus carriers had persistently elevated alanine aminotransferase compared to 29 hepatitis C virus carriers (14% vs 60%, p < 0.001), 10 patients co-infected with both hepatitis G virus and hepatitis C virus, and in 6 patients with neither infection (67% vs 8%, p < 0.001). CONCLUSIONS: Hepatitis G virus infection is common among kidney transplant patients, it carries a low risk of chronic liver disease even in long-term follow-up. Low levels of hepatitis C virus-RNA found in hepatitis G virus carriers suggest an interaction between these two viruses in immunosuppressed patients.     

Viral interaction and clinical implications of coinfection of hepatitis C virus with other hepatitis viruses

Coinfection with other hepatitis viruses modifies the viral profile in serum and leads to more liver damage and more rapid progression during the course of hepatitis C virus infection. The viral interference is not only carried out by virus-virus or by virus-cell interactions but also by an enhanced immune response. A superinfecting viral infection does not crossactivate protective immune responses to the pre-existing virus albeit the latter can become undetectable. The induced cytokine stimulation might enhance the hepatic inflammation. Moreover, hepatitis B virus coinfection increases the risk of development of hepatocellular carcinoma in hepatitis C virus patients through common necro-inflammatory pathways or by direct oncogenic activity of hepatitis B virus. Viral interaction also complicates the management of the coinfection because hepatitis C virus impairs the humoral response to hepatitis A virus and hepatitis B virus vaccines, and because pharmacological suppression of hepatitis C virus endangers dually infected patients with reactivation of coinfected hepatitis B virus. Optimized strategies and follow-up are thus necessary in the treatment of infection with multiple viruses. It seems thus necessary to look for markers of hepatitis B virus and/or hepatitis D virus infection in chronic hepatitis patients positive for hepatitis C virus antibodies but negative for hepatitis C virus RNA, and equally well to search for hepatitis C virus RNA in HBsAg-negative/anti-HBc-positive patients with a low level of serum hepatitis B virus DNA.     

Serum autoantibodies and the diagnosis of type-1 autoimmune hepatitis in Italy: a reappraisal at the light of hepatitis C virus infection.

Antinuclear antibodies with the homogeneous pattern (ANA-H) and smooth muscle antibodies with antiactin specificity (SMA-AA) are regarded as the serum markers of type-1 autoimmune chronic hepatitis. Their diagnostic relevance, however, has been questioned recently after the detection of signs of hepatitis C virus infection in autoimmune chronic hepatitis patients. To further evaluate this point, antihepatitis C virus antibodies were sought by two second generation assays (ELISA 2 and RIBA 2) in 100 Italian patients with chronic liver disease of unknown aetiology, including 46 with (autoimmune chronic hepatitis) and 54 without the above antibodies (cryptogenic). By ELISA 2, antihepatitis C virus, although significantly prevalent in cryptogenic (83%), were found also in a substantial proportion of autoimmune chronic hepatitis patients (46%) (p < 0.0001), their occurrence was confirmed by RIBA 2 in almost all cases (96% and 86%, respectively). Autoimmune patients with either ANA-H or SMA-AA exhibited similar antihepatitis C virus prevalences (59% and 52%, respectively); by contrast, the eight cases positive for both the autoantibodies were consistently antihepatitis C virus negative. These findings confirm that in countries with high hepatitis C virus circulation (like Italy) an overlap between autoimmune chronic hepatitis and hepatitis C virus infection, reflected by 'true' antihepatitis C virus antibodies, does occur. The detection of ANA-H or SMA-AA, in fact, identifies chronic liver disease patients with a relatively low prevalence of antihepatitis C virus, but does not exclude hepatitis C virus infection. Positive findings for both ANA-H and SMA-AA, however, is an appropriate marker for hepatitis C virus free 'primary' autoimmune chronic hepatitis.     

Update on the management and treatment of viral hepatitis

This review aims to summarize the current evidence on the treatment of viral hepatitis, focusing on its clinical management. Also, future treatment options and areas of potential research interest are detailed. PubMed and Scopus databases were searched for primary studies published within the last ten years. Keywords included hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus, hepatitis D virus (HDV), hepatitis E virus, and treatment. Outcomes reported in the studies were summarized, tabulated, and synthesized. Significant advances in viral hepatitis treatment were accomplished, such as the advent of curative therapies for hepatitis C and the development and improvement of hepatitis A, hepatitis B, and hepatitis E vaccination. Drugs that cure hepatitis B, going beyond viral suppression, are so far unavailable; however, targeted antiviral drugs against HBV (immunomodulatory therapies and gene silencing technologies) are promising approaches to eradicating the virus. Ultimately, high vaccination coverage and large-scale test-and-treat programmes with high screening rates may eliminate viral hepatitis and mitigate their burden on health systems. The development of curative hepatitis C treatment renewed the enthusiasm for curing hepatitis B, albeit further investigation is required. Novel therapeutic options targeting HDV life cycle are currently under clinical investigation.     

Hepatitis C virus infection in medical personnel after needlestick accident.

Hepatitis C virus infections in medical personnel after needlestick accidents have been documented generally by detection of seroconversion to a hepatitis C virus nonstructural region antigen, c100-3 (a marker of infection). We tested for hepatitis C virus core-derived antibodies and genomic RNA in addition to c100-3 antibody in 159 cases of needlestick exposure that did not involve patients positive for HBsAg. Of these we found 68 cases with index patients positive for both hepatitis C virus RNA and antibodies and members negative for antibodies to HCV core or c100-3 before the needlestick accidents. Seven of these medical personnel became infected with hepatitis C virus after the accidents. Their hepatitis was generally subclinical or self-limited and transient, except for one patient in whom liver enzyme elevation persisted along with the antibodies. In our study, the risk of hepatitis C virus transmission from a single needlestick accident with hepatitis C virus RNA-positive blood was 10%, considerably higher than the 4% estimated in a previous study. We found that donor blood with antibody to an hepatitis C virus core-derived peptide with enzyme-linked immunosorbent assay optical densities greater than 2.0 carried a significant risk of transmitting hepatitis C virus to needlestick victims. No hepatitis C virus seroconversions occurred in medical personnel exposed to hepatitis C virus antibody-negative or hepatitis C virus RNA-negative blood; however, one such exposure resulted in a very mild non-A, non-B, non-C hepatitis.     

Hepatitis C tested prevalence and comorbidities among veterans in the US Northwest

GOALS: (1) Investigate the epidemiology of hepatitis C virus infection among patients seen in the Veterans Administration Northwest Network; (2) examine time trends in testing practices and results; and (3) estimate the prevalence of hepatitis C virus infection among active patients. BACKGROUND: Hepatitis C virus infection causes chronic hepatitis and cirrhosis and is a leading cause of end-stage liver disease. Hepatitis C virus antibodies are estimated to be present in 1.8% of the US population, but reports of its prevalence among US veterans range from 1.7 to 35%. STUDY: Retrospective review of computerized medical records of veterans tested for hepatitis C from October 1994 through December 2000 (n = 37,938) at 8 Northwest Veterans Administration Medical Centers. RESULTS: Among tested veterans, 8230 (21.7%) had evidence of hepatitis C virus infection. The number of patients tested increased annually from 2335 to 18,191, while the proportion with first-time positive hepatitis C test results decreased from 35 to 10%. This drop in tested prevalence was associated with a shift away from testing individuals at highest risk--those with positive hepatitis B serostatus, repeatedly elevated alanine transaminase levels, and drug use disorder diagnoses. We estimate that 11.4% of the Northwest Network veteran users are hepatitis C virus seropositive, with a lower bound of 4.0% and upper bound of 19.5%. CONCLUSIONS: Although estimates of hepatitis C virus infection rates among veteran users of the Veterans Administration system remain higher than those for the general population, changes in testing practice make generalizations from earlier studies hazardous.     

Anti-hepatitis C virus treatment may prevent the progression of liver fibrosis in non-responder human immunodeficiency virus/hepatitis C virus coinfected patients

AimTo evaluate changes in liver histology in patients with human immunodeficiency virus/hepatitis C virus coinfection non-responders to a suboptimal Interferon + Ribavirine regimen.Materials and methodsWe investigated 49 patients with two sequential liver biopsies: 18 were non-responders to Interferon + Ribavirine treatment (Group hepatitis C virus Rx) administered after the 1st liver biopsy who underwent a 2nd liver biopsy after a median period of 3.92 year and 31 were patients who remained untreated for hepatitis C virus disease (Group hepatitis C virus untreated) after the 1st liver biopsy because of refusal and underwent a 2nd liver biopsy after a median period of 5.05-years. Most patients in both groups were under highly active antiretroviral therapy. At the time of 1st liver biopsy similar degrees of necro-inflammation, fibrosis and steatosis were observed in both groups. Changes in liver lesions between 1st and 2nd liver biopsys were adjusted for different intervals between liver biopsys by a mathematic formula.ResultsLiver fibrosis did not change in 88.9% of patients in Group hepatitis C virus Rx and in 77.4% in Group hepatitis C virus untreated. A marked deterioration in liver fibrosis was observed in 5 (16%) patients in Group hepatitis C virus untreated and in none in Group hepatitis C virus treated. Necro-inflammation and steatosis remained substantially unchanged in both groups.ConclusionLiver histology remained substantially unchanged in human immunodeficiency virus/hepatitis C virus patients non-responder to anti-hepatitis C virus therapy over 4 years observation, suggesting an effective anti-hepatitis C virus early treatment for all hepatitis C virus/human immunodeficiency virus coinfected patients who can reasonably tolerate therapy.     

Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance

BACKGROUND & AIMS: Acute hepatitis C virus infection accounts for approximately 20% of cases of acute hepatitis today. The aim of this study was to define the natural course of the disease and to contribute to the development of treatment strategies for acute hepatitis C virus. METHODS: The diagnosis of acute hepatitis C virus in 60 patients was based on seroconversion to anti-hepatitis C virus antibodies or clinical and biochemical criteria and on the presence of hepatitis C virus RNA in the first serum sample. RESULTS: Fifty-one of 60 (85%) patients presented with symptomatic acute hepatitis C virus. In the natural (untreated) course of acute symptomatic hepatitis C (n = 46), spontaneous clearance was observed in 24 patients (52%), usually within 12 weeks after the onset of symptoms, whereas all asymptomatic patients (n = 9) developed chronic hepatitis C. The start of antiviral therapy (interferon-alpha with or without ribavirin) beyond 3 months after the onset of acute hepatitis induced sustained viral clearance in 80% of treated patients. CONCLUSIONS: The management of acute hepatitis C has to take into account the high rate of spontaneous viral clearance within 12 weeks after the onset of symptomatic disease. Treatment of only those patients who remain hepatitis C virus RNA positive for more than 3 months after the onset of disease led to an overall viral clearance (self-limited and treatment induced) in 91% of patients, and unnecessary treatment was avoided in those with spontaneous viral clearance. Patients with asymptomatic acute hepatitis C virus infection are unlikely to clear the infection spontaneously and should be treated as early as possible.     

Molecular epidemiology of hepatitis C virus infection among intravenous drug users

Background/Aims: The clinico-pathologic features of hepatitis C virus infection intravenous drug users are different from those found in other hepatitis C virus-infected patients. Our airm was to test whether specific viral variants circulate within this particular patient population.Methods: We studied the distribution of hepatitis C virus genotypes in 90 drug addicts and 484 controls, according to the method described by Okamoto.Results: Hepatitis C virus type 1a and 3a infections were more frequent among intravenous drug users than in 125 age-matched controls (48.8% and 21.1% vs 17.6% and 11.2%), accounting for the majority of infections in intravenous drug users. Analysis of hepatitis C virus genotypes according to age showed that, in the general population, hepatitis C virus types 1a and 3a were more prevalent among patients younger than 40 years of age than in older individual (17.6% and 11.2% vs. 1.4% and 0.6%).Conclusions: These findings suggest that hepatitis C virus types 1a and 3a were recently introduced in Italy, presumably via needle-sharing among intravenous drug users, and from this reservoir they are extending to the general population, particularly among younger subjects.