Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection

BACKGROUND & AIMS: Superinfection in patients with chronic hepatitis B virus (HBV) infection is not uncommon. Acute hepatitis delta virus (HDV) superinfection is associated with severe and/or progressive liver disease. The natural course following acute hepatitis C virus (HCV) superinfection has not been well studied. The aim of this study was to investigate the impact of acute HCV superinfection. METHODS: The clinical features during acute phase and long-term outcomes of acute HCV superinfection were studied and compared with a cohort of acute HDV superinfection and a matched control group of active chronic hepatitis B. RESULTS: Acute HCV superinfection typically occurs as acute icteric hepatitis. The severity is similar to acute HDV superinfection in that hepatic decompensation developed in 34% of patients, hepatitis failure occurred in 11%, and 10% died. During a follow-up period of 1-21 years, patients with acute HCV superinfection had a significantly higher cumulated incidence of cirrhosis (48% at 10 years) and hepatocellular carcinoma (14% at 10 years, 21% at 15 years, and 32% at 20 years) than acute HDV superinfection or active chronic hepatitis B. Hepatitis B surface antigen (HBsAg) seroclearance occurred earlier in HCV superinfected patients. Continuing hepatitis after HBsAg seroclearance was observed only in HCV superinfected patients. CONCLUSIONS: Acute HCV superinfection in patients with chronic HBV infection is clinically severe during its acute phase. The long-term prognosis following acute HCV superinfection is much worse than that following HDV superinfection or active hepatitis B in terms of continuing hepatitis activity after HBsAg loss and the development of cirrhosis or hepatocellular carcinoma.     

Single (B or C), dual (BC or BD) and triple (BCD) viral hepatitis in HIV-infected patients in Madrid, Spain

INTRODUCTION: There are very limited data about the prevalence of multiple hepatitis virus infections in HIV infected individuals. In HIV uninfected individuals with triple BCD hepatitis, hepatitis D virus (HDV) appears to be the dominant virus. However, in HIV infected patients with triple hepatitis it is not known if HDV replication inhibits hepatitis B virus (HBV) and/or hepatitis C virus (HCV) replication. METHODS: We calculated the prevalence of single (B or C), dual (BC) and triple (BCD) hepatitis in 423 HIV-infected patients with positive HCV serum antibodies and/or positive serum HBsAg. In patients with multiple infections we performed an evaluation of serum markers of HBV, HCV and HDV replication. RESULTS: The prevalence of multiple hepatitis was 4.7% (95% confidence interval, 2.7-6.7%). Multiple hepatitis occurred only among patients who acquired HIV through injection drug use. The most common multiple hepatitis was triple BCD. Patients with hepatitis BC and past or chronic hepatitis D were significantly more likely to have cirrhosis and a negative serum HBeAg and HCV PCR than patients with single hepatitis B or hepatitis C. Patients with chronic hepatitis D showed uniform suppression of HBV and HCV replication markers. CONCLUSIONS: In our geographic area approximately 5% of HIV infected patients with hepatitis suffer multiple hepatitis virus infection. In patients with triple hepatitis BCD virus infection, HDV appears to be the dominant virus causing inhibition of both HBV and HCV replication.     

Hepatitis delta virus propagation enabled by hepatitis C virus—Scientifically intriguing,but is it relevant to clinical practice?

In vitro cell culture experiments and animal models have demonstrated that hepatitis delta virus (HDV) can theoretically propagate being enveloped by human pathogenic viruses other than hepatitis B virus (HBV), namely hepatitis C virus (HCV) and dengue virus. However, the clinical relevance of these findings and whether HDV replication occurs in real‐world hepatitis B surface antigen (HBsAg)–negative HCV patient cohorts remain unknown. To this aim, we analysed 323 HCV‐RNA–positive and HBsAg‐negative sera for the presence of HDV‐RNA and anti‐HDV antibodies (anti‐HDV). All 323 (100%) samples were negative for HDV‐RNA. Interestingly, 8/316 samples tested positive for anti‐HDV. The HBV serology of these eight patients showed a positive result for HBV core antibodies (anti‐HBc) indicating a seroconversion of an acute HBV infection in the past. None of the anti‐HBc–negative patients were positive for anti‐HDV. Our results indicate a distinctly low probability of replicative HDV infection in HCV mono‐infected patients in Germany. Current German clinical guidelines rightly recommend performing HDV screening only in HBsAg‐positive patients. However, larger studies on this subject should be performed in regions that are endemic for chronic HBV/HDV as well as HCV infections.     

Effect of human immunodeficiency virus infection on hepatitis C virus infection in hemophiliacs

Chronic liver disease due to hepatitis C virus (HCV) infection is a major problem in hemophiliacs. Recent reports suggested that hemophiliacs coinfected with hepatitis C virus and human immunodeficiency virus (HIV) have an increased incidence of liver failure but the mechanism of accelerated liver injury is not clear. We tested plasma from 100 hemophiliacs for anti-HCV by second generation ELISA, anti-HIV by EIA, and HCV RNA and HIV RNA by branched DNA and polymerase chain reaction assays to determine if hemophiliacs coinfected with HCV and HIV have higher HCV RNA levels and more active liver disease. Seventy-nine (79%) patients were anti-HCV positive, of whom 85% were HCV RNA positive. None of the anti-HCV-negative patients had detectable HCV RNA in plasma. Forty-two (42%) patients were anti-HIV positive, of whom 47% had detectable HIV RNA. All the anti-HIV-positive patients were also anti-HCV positive. The prevalence of both anti-HCV and anti-HIV increased significantly with age. There was no difference in HCV RNA levels between anti-HIV-positive and anti-HIV-negative patients (mean: 21±4 vs 18±5 Meq/ml), although HCV RNA levels were significantly higher in anti-HIV-positive patients with CD4 counts<200/mm³ (P=0.008). There was an inverse correlation between HCV RNA levels and CD4 counts but no correlation was found between HCV RNA and serum aminotransferase levels. We found a high prevalence of HCV and HIV coinfection in our hemophiliacs. Hepatitis C virus replication appears to be increased in patients with severe immunodeficiency secondary to progressive HIV infection. However, there was no correlation between HCV RNA and serum ALT level, suggesting that HCV is not directly cytopathic.     

Hepatitis delta virus RNA in serum of patients with chronic delta hepatitis

We studied 28 patients with chronic delta hepatitis for the presence of hepatitis delta virus (HDV) RNA in serum. The hot start polymerase chain reaction (PCR) method, in which the reaction begins at 60–80° C, showed a higher sensitivity than conventional PCR reaction. Additionally, the presence of hepatitis B (HBV) and C virus (HCV) infections were determined by PCR. HDV RNA was detected in 26 patients (93%), HBV DNA in 22 (79%), and HCV RNA in only one. Detection of HDV RNA correlated very well with detection of hepatitis delta antigen by immunostaining in the liver. In six patients HDV RNA was detectable despite the absence of HBV DNA in serum, suggesting that high levels of HBV are not required for HDV replication. Of 29 control patients with chronic hepatitis B without antibody to HDV, none had detectable HDV RNA, while all had HBV DNA in serum. Detection of HDV RNA with PCR proved highly sensitive and specific, demonstrating that virtually all patients with chronic HDV infection had ongoing viral replication.     

Influence of human immunodeficiency virus infection on hepatitis δ virus superinfection in chronic HBsAg carriers

SUMMARY. It is generally agreed that hepatitis B virus (HBV) replication is reduced by hepatitis δ virus infection (HDV) and augmented by human immunodeficiency virus (HIV) infection. However, the precise nature of the interactions between HBV. HDV and HIV is controversial. The aim of this study was to evaluate the impact of HIV infection on HBV and HDV replication, and on histological scores during δ virus super-infection in HDV-positive. chronic carriers of hepatitis B surface antigen (HBsAg). We studied 38 men and six women, 15 of whom were HIV-positive and all of whom had at least one marker of HDV infection. Serum hepatitis B e antigen (HBeAg), HBV DNA, HDV RNA, anti-δ antigen antibodies (anti-HD) IgM, anti-HD IgG and hepatitis δ antigen (HDAg) were tested for in the serum and liver, respectively; anti-hepatitis C virus (HCV) antibodies were detected using a second-generation recombinant immunoblot assay. Histological specimens were scored blindly according to Knodell's classification for periportal and intralobular necrosis, portal inflammation and fibrosis. HBV DNA was detected more frequently in the HIV-positive patients than in those who were HIV-negative (25 vs 0% P = 0.01), while markers of HDV replication (serum anti-HD IgM. serum HDV RNA and liver HDAg) were as frequent in the HIV-positive patients (69%, 40% and 50% respectively) as in those who were HIV-negative (75%, 52% and 30%. respectively; P>0.05). By contrast, 31% of the HIV-positive patients were serum HDAg-positive compared to only 6% of the HIV-negative patients (P = 0.001). HDV antigenaemia and anti-HD antibodies usually fluctuated in the HIV-positive patients during follow-up. The mean Knodell score was similar in the HIV-positive (11.5 ± 3.2) and HIV-negative (10.7 ± 2) subgroups, as was the mean semi-quantitative index of hepatic necrosis, inflammation and fibrosis. Our results provide evidence that in HDV-positive patients: (1) HIV infection counters the inhibitory effect of HDV superinfection on HBV replication; (2) serum anti-HD IgM, HDV RNA and liver HDAg are not more frequent in HIV-positive than in HIV-negative patients, suggesting that HIV infection has no effect on HDV replication (although the significance of the increased frequency of HD antigenaemia remains unclear): (3) the histological severity of liver disease is not influenced by HIV status.     

Quantitative HBsAg and HDV‐RNA levels in chronic delta hepatitis

Background: Hepatitis delta virus (HDV) causes severe liver disease. Aims: To investigate the quantitative HDV‐RNA, HBsAg and hepatitis B virus (HBV)DNA levels in correlation to histological, biochemical and demographical parameters in patients with chronic HDV infection as similar data in a large series of HDV patients are missing. Methods: Eighty HDV patients were recruited in Germany, Turkey and Greece; quantitative determination of HDV‐RNA, HBsAg and HBV‐DNA was performed by real‐time polymerase chain reaction, the Architect HBsAg assay and Cobas TaqMan HBV test respectively. Results: All patients were infected with HDV‐genotype 1. Thirty‐five patients (48%) had significant fibrosis (Ishak 3–4) and 15 (20.5%) had cirrhosis. HDV viraemia ranged from 1.1 × 10³ to 8.4 × 10⁷ copies/ml with 60% of patients showing HDV‐RNA levels above 10⁵ copies/ml accompanied by low HBV viraemia (<10⁵ copies/ml). However, HDV‐RNA and HBV‐DNA levels showed no direct inverse correlation. HDV‐RNA correlated positively with HBsAg and negatively with age. HBsAg correlated negatively with age and positively with histological grading. Only γ‐glutamyltranspeptidase was independently associated with cirrhosis (P=0.032), while no biochemical parameter was associated with grading. Conclusions: (i) HBsAg levels correlated with HDV viraemia in chronic HDV. (ii) Biochemical parameters did not accurately indicate the stage and grade of liver disease in chronic HDV and thus liver biopsy seems to remain the major tool for the evaluation of delta hepatitis patients.     

Quantification of serum markers of hepatitis B (HBV) and Delta virus (HDV) infections in patients with chronic HDV infection

The interplay between hepatitis B (HBV) and delta (HDV) viruses is complex and not always characterized during chronic HDV infection. We assessed the clinical usefulness of new quantitative assays for HBV and HDV serum markers in a retrospective cross‐sectional study. Sera obtained from 122 HDV genotype 1 and HBV genotype D coinfected, anti‐HIV‐negative patients (71 males; median age 49.8 [21.7‐66.9] years), recruited consecutively in two geographical areas (Italy 69 patients, Romania 53 patients) with different HBV and HDV epidemiology, were tested for HBsAg, HBV‐DNA, HBcrAg, total anti‐HBc, HDV‐RNA, IgM and total anti‐HDV using quantitative assays. Cirrhosis, which showed comparable prevalence in the two cohorts, was diagnosed in 97 of 122 (79.5%) patients. At multivariate analysis, cirrhosis was associated with lower total anti‐HBc/IgM anti‐HDV ratio (OR 0.990, 95% CI 0.981‐0.999, P = .038), whereas disease activity was associated with higher total anti‐HDV (OR 10.105, 95% CI 1.671‐61.107, P = .012) and HDV‐RNA levels (OR 2.366, 95% CI 1.456‐3.844, P = .001). HDV‐RNA serum levels showed a positive correlation with HBV‐DNA (ρ = 0.276, P = .005), HBsAg (ρ = 0.404, P < .001) and HBcrAg (ρ = 0.332, P < .001). The combined quantitative profiling of HBV and HDV serum markers identifies specific patterns associated with activity and stage of chronic hepatitis D (CHD). HDV pathogenicity depends on the underlying active HBV infection in spite of the inhibition of its replication. HDV‐RNA, IgM anti‐HDV, total anti‐HDV, total anti‐HBc, HBsAg and HBcrAg serum levels qualify for prospective studies to predict progressive CHD and identify candidates to antiviral therapy.     

Role of hepatitis B virus, hepatitis D virus and other determinants on suppression of hepatitis C viraemia in HIV infected patients with chronic HCV infection: a longitudinal evaluation

The role of hepatitis B virus (HBV) or hepatitis D virus (HDV) coinfections as determinants of hepatitis C virus (HCV) suppression in the setting of HIV-HCV coinfection are poorly understood. Our aim was to assess whether HCV viral replication may be affected by HBV or HDV coinfection in the setting of immunodeficiency driven by HIV.Among the 138 enrolled patients 28(20.3%) tested HCV RNA negative and 110 (79.7%) tested HCV RNA negative. The HCV RNA negative patients showed an higher rate of HBsAg positivity compared with those tested HCVRNA positive [12/28 (42.9%) and 5/110 (4.6%), respectively]. Patients with HCV-HBV-HDV coinfection had the highest chance of having an undetectable HCV RNA (adjusted odds ratio (AOR): 92.0, 95% confidence interval (CI) 5.7-1483.5, p<0.0001). Furthermore, HBV coinfection per se was also found to be independently associated with negative HCV viraemia (AOR: 18.5, 95% CI 2.4-143.5, p<0.0001). HBsAg-positive patients with negative HCV viraemia maintained undetectable levels over time. Our results support a direct role of HBV and HDV coinfections in suppressing HCV viraemia in HIV infected patients. This effect is durable over time, and is not influenced by HAART including anti-HBV drugs.     

Spontaneous hepatitis B surface antigen clearance in a long-term follow-up study of patients with chronic type B hepatitis. Lack of correlation with hepatitis C and D virus superinfection

We investigated the frequency of HBsAg clearance and the possible role of viral superinfection in a long-term follow-up of 184 patients with chronic hepatitis B (CHB). Our subjects were 184 patients with chronic hepatitis B and the follow-up was 12–216 months (mean 66.2±53.7 months). The investigative methods used were: immunoenzymatic assays for HBV, HCV, HDV, and HIV markers; polymerase chain reaction (PCR) for HBV DNA; and liver biopsy and immunoperoxidase. During the follow-up, 20 of the 184 patients cleared serum HBsAg. A comparison of patients with persistent HBsAg (group I) and of those who cleared this marker (group II) showed a significant difference in mortality (P=0.002) between the two groups and a tendency to a more severe exacerbation (flare) in group II (P=0.07). Antibodies to hepatitis C and D virus as well as antibodies to HIV were equally distributed in both groups. Thirteen patients (7.9%) from group I, but none from group II, subsequently developed hepatocellular carcinoma. These results suggest that the frequency of spontaneous clearance of HBsAg during chronic HBV infection is low. No determinant factor for the clearance was found, including the presence of liver cirrhosis. Serum HBV DNA was undetectable by PCR after clearance in 16 out of 17 patients. Some of these findings were presented at the Biennial Scientific Meeting of the International Association for the Study of the Liver, held in Brighton, UK, in June 1992.     

Frequent delayed spontaneous seroclearance of hepatitis B virus after incident HBV infection among adult high‐risk groups

High rates (~25%) of developing chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen (HBsAg)‐positive for > 6 months following infection) have been observed in people who use drugs (PWUD) and men who have sex with men (MSM). We aimed to estimate the frequency of delayed HBsAg seroclearance, along with its determinants, and time to delayed HBsAg seroclearance. Data were used from MSM and PWUD enrolled in the Amsterdam Cohort Studies (1985‐2002) who had anti‐hepatitis B core antibody seroconversion. Potential determinants for standard HBsAg seroclearance, delayed HBsAg seroclearance and chronic HBV were examined using multinominal logistic regression. Time to HBsAg seroclearance was estimated using Kaplan‐Meier curves. A total of 147 incident HBV infections occurred during follow‐up. On initial HBsAg testing after infection (6‐12 months), 42 (29%) were HBsAg‐positive and 105 (71%) were HBsAg‐negative (‘standard HBsAg seroclearance’). Of the 42 initially HBsAg‐positive individuals, 22 subsequently tested HBsAg‐negative (of whom 7 (31.8%) were HBV DNA positive at last visit, suggesting occult HBV). Overall, 15 became HBsAg‐negative and HBV DNA‐negative (‘delayed HBsAg seroclearance’), while 27 remained HBsAg and/or HBV DNA‐positive (‘chronic HBV’). The 5‐year cumulative probability of delayed HBsAg seroclearance was 41.6% for initially HBsAg‐positive individuals. Delayed HBsAg seroclearance and remaining chronically infected were associated with younger age and HIV/hepatitis C virus (HCV)‐co‐infection. In conclusion, delayed HBsAg seroclearance is common in these key adult populations at‐risk for HBV, while proportion developing HBV chronicity (18%) is still higher compared to the general population (~5%). Given the proportion of individuals with occult HBV infection and that HCV direct‐acting antivirals can lead to HBV reactivation, HBV DNA testing in HCV co‐infected MSM/PWUD are warranted prior to treatment initiation.     

Hepatitis B virus infection: co-infection with hepatitis C virus, hepatitis D virus, and human immunodeficiency virus

Hepatitis B virus (HBV) shares routes of transmission, namely exchange of infected body fluids, sharing of contaminated needles, and blood transfusion, with other hepatotropic viruses, such as hepatitis C virus (HCV) and hepatitis D virus (HDV) and with systemic retroviral infections, such as the human immunodeficiency virus (HIV). Thus, many HBV infected patients are co-infected with other viral pathogens. Co-infection appears to increase the risk of progression of liver disease and may have important ramifications on choice of antiviral medication and treatment regimen. This article reviews the current knowledge of co-infection of HBV with HCV, HDV, and HIV.     

Current therapy for hepatitis C or D or immunodeficiency virus concurrent infection with chronic hepatitis B

Concurrent hepatitis C virus (HCV), hepatitis delta virus (HDV), or human immunodeficiency virus (HIV) infection with chronic hepatitis B virus (HBV) appears to increase the risk of progressive liver disease including liver cirrhosis and hepatocellular carcinoma. There is a 10% prevalence of HCV infection in chronic HBV or HDV infection. Serological evidence of previous exposure to HBV is found in more than 80% of HIV-positive patients in the high risk group. Notably, the most recently acquired virus tends to suppress the pre-existing virus. In chronic HBV infection acquired perinatally or in early childhood, usually HCV is dominant and may suppress or even displace HBV and HDV. Less frequently, HBV or HDV suppresses HCV. It is generally agreed that the dominant virus should be identified in order to make appropriate treatment decisions. Studies with standard interferon (IFN) to treat patients with HCV dominantly dual HBV/HCV infection have showed only limited virological response. But high dose of IFN has been demonstrated with better response rate. Combined ribavirin with standard or pegylated IFN therapy could achieve a sustained HCV clearance rate comparable with those infected with HCV alone. On the contrary, patients with HBV dominantly dual viral infection might indicate more appropriate addition of lamivudine to IFN than ribavirin. Additionally, patients with concurrent infection of HBV and HDV, IFN seems to be the only effective agent. However, the efficacy of IFN is related to the dose. High dose of IFN [9 MU tiw (thrice per week)] and longer treatment duration (at least 2 years) have been shown to achieve adequate virological response. In patients with concurrently infected HBV and HIV, anti-HBV therapy should be considered for all patients with evidence of liver disease, irrespective of the CD4 cell count. In patients not requiring antiretroviral therapy, HBV therapy should be preferentially based on IFN, adefovir, or telbivudine. In contrast, in patients with CD4 cell counts <350 cells/μl or those already on antiretroviral therapy, agents with double anti-HBV and anti-HIV activity are preferred. At present, the evidence of therapeutic efficacy is not sufficient to make a recommendation in treating patients with dual HBV/HCV or HBV/HDV or HBV/HIV infection. Further studies of the well-designed, larger scale are needed to elucidate the role of different regimens or combination in the treatment of dual viral infection.     

De novo hepatitis B virus infection in hepatocellular carcinoma following eradication of hepatitis C virus by interferon therapy

Epidemiological studies have revealed that hepatocellular carcinoma (HCC) is still observed in hepatitis C virus (HCV)‐positive patients with a sustained response to interferon (IFN) treatment, although a substantial decrease in the incidence of hepatocellular carcinoma (HCC) has been achieved in those patients. Why HCC develops in patients who have a complete clearance of HCV remains unclear. Here, we provided evidence of latent hepatitis B virus (HBV) infection in an initially HCV‐positive chronic hepatitis patient who developed HCC after the complete eradication of HCV by IFN therapy. Although he was initially negative for anti‐hepatitis B surface antigen (HBsAg) or circulating HBV DNA but positive for anti‐hepatitis B core antigen (anti‐HBc) in his sera, he developed HBsAg and HBV DNA during the course of the management of a series of cancers. HBV DNA was detectable in the liver tissues before HBV reactivation and the viral sequences derived from his anti‐HBc‐positive liver showed 100% homology to that from the serum after HBsAg appearance. These findings indicates that HCV‐positive individuals who are positive for anti‐HBc in the absence of HBsAg could have latent HBV infection in their liver tissues and intrahepatic HBV infection may play a pivotal role in the development of HCC after the IFN‐mediated eradication of HCV.     

Reactivation of hepatitis B virus during interferon‐free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co‐infection

Direct‐acting antiviral agents (DAA) for hepatitis C virus (HCV) are not effective for hepatitis B virus (HBV), which may be suggestive of reactivation of anti‐HBe hepatitis during interferon (IFN)‐free DAA therapy in HBV/HCV co‐infected patients with inactive HBV. A 69‐year‐old male patient was diagnosed with chronic hepatitis due to HBV/HCV co‐infection with serum levels of alanine aminotransferase (ALT) of 94 U/L, HCV RNA of 4.2 log IU/mL and HBV DNA of 2.5 log copies/mL. HCV was thought to be responsible for the hepatitis activity because of low level of HBV core‐related antigen (3.1 log U/mL). He was treated with combination therapy of daclatasvir and asunaprevir. Serum ALT gradually increased, and reached 237 U/L on day 43 in spite of undetectable HCV RNA. Serum HBV DNA was increasing to 7.0 log copies/mL at that time. The treatment was stopped due to suspicion of drug‐induced liver injury and/or HBV reactivation. Administration of entecavir reduced HBV DNA levels, followed by improvement in ALT levels. This report proposes that close monitoring of HBV DNA during the anti‐HCV DAA therapy and the commencement of anti‐HBV therapy with nucleoside analogs after the increase of HBV DNA should be considered in patients with HBV/HCV co‐infection.     

Profound suppression of chronic hepatitis C following superinfection with hepatitis B virus.

BACKGROUND: Hepatitis B virus (HBV) and hepatitis C virus (HCV) share similar transmission routes; thus, coinfection is frequent. The consequences of acute HBV infection in patients with chronic hepatitis C are unknown. METHODS: We describe a 47-year-old male with chronic hepatitis C who acquired HBV and then spontaneously and apparently completely cleared HCV but developed chronic hepatitis B. Five serum samples collected over 14 months and lymphoid cells obtained after acquiring HBV were tested for HCV and HBV by both standard assays and ultra-sensitive polymerase chain reaction/nucleic acid hybridization (PCR/NAH) (sensitivity approximately 2 IU/ml). RESULTS: After superinfection with HBV, HBV surface antigen-positive chronic hepatitis developed with readily detectable HBV DNA. All sera collected after acquisition of HBV, which tested negative for HCV RNA by standard laboratory assay, were positive for HCV genomes when analysed by PCR/NAH. Peripheral lymphoid cells carried HBV DNA and covalently closed circular DNA, but were negative for HCV. CONCLUSIONS: This is the first reported case of profound suppression of chronic hepatitis C after superinfection with HBV and establishment of chronic hepatitis B. It is hypothesized that HBV infection precipitated generalized and/or virus-specific cellular immune responses that profoundly suppressed HCV replication and yet failed to inhibit progression to chronic hepatitis B.     

Chronic evolution of acute hepatitis B: the significance of simultaneous infections with hepatitis C and D. Copenhagen Hepatitis Acuta Programme

Seventy-six of 77 consecutive patients with hepatitis B surface antigen (HBsAg)-positive acute hepatitis were reevaluated using anti-hepatitis C virus (HCV), anti-hepatitis D virus (HDV), and IgM anti-hepatitis B core (HBc) testing. Anti-HCV and/or anti-HDV was found in 32 patients (42%). The presence of these markers was significantly associated with intravenous drug abuse (p less than 10(-6). Sixty-nine patients were IgM anti-HBc-positive, of whom two (3%) (95% confidence limits, 1-12%) became chronic HBsAg carriers with histologically verified chronic liver disease; both were anti-HCV and anti-HDV-negative. Among the remaining 67 IgM anti-HBc-positive patients 8 had HBV and HDV co-infection, 3 had HBV and HCV co-infection, and 1 had HBV, HCV, and HDV co-infection. Twenty-two had evidence of preceding or past HCV infection; two developed chronic active hepatitis in spite of HBsAg clearance. Seven patients with IgM anti-HBc negative. One was a chronic HBsAg carrier with HDV superinfection. One had subclinical acute HBV infection and became a chronic HBsAg carrier. In a further two patients reactivation of replication in a chronic HBV infection could not be disregarded. Three patients could not be classified; all had acute recent onset of symptoms, cleared HBsAg within 6 months, but lacked IgM anti-HBc. It is concluded that HCV and HDV superinfections in HBV carriers mimicking acute HBV infection with chronic evolution are rarely encountered in the present population in spite of high frequency of both HCV and HDV markers.     

Coinfection with hepatitis B and C or B, C and δ viruses results in severe chronic liver disease and responds poorly to terferon-a treatment

SUMMARY. Chronic coinfection with the hepatitis B (HBV) and hepatitis δ (HDV) viruses is known to cause severe liver disease, but the importance of coinfection with hepatitis C virus (HCV) and HBV has not been well documented. In the present study, the clinical and pathological severity of liver disease among patients with hepatitis resulting from multiple viruses was examined and an open trial of the efficacy of interferon-α2b (IFN-α) treatment was conducted. Nineteen patients with chronic HBV and HCV infection and 17 with HBV, HCV and HDV infection were studied: 12 in each group underwent liver biopsy. For each coinfected patient, two patients infected with HCV alone were selected as controls, and these were matched for age and risk factor and were estimated to have been infected for a similar duration. Coinfection with HBV and HCV or HBV, HCV and HDV was associated with more severe liver disease than HCV alone (P < 0.01); total Scheer score, portal and lobular inflammation and fibrosis were all worse in coinfected subjects. Eight patients with chronic HBV and HCV were treated with recombinant IFN-α2b [3 million units (MU), thrice weekly for 6 months]. Liver function tests normalized in two patients and one lost hepatitis B surface antigen (HBsAg). Seven patients with hepatitis B, C and δ coinfection were treated with the same regimen and only one normalized serum alanine aminotransferase (ALT) during (and after) treatment. It is concluded that coinfection with multiple hepatitis viruses is associated with histologically more severe liver disease than HCV alone. Short-and long-term responses to doses of IFN-α that are used to treat HCV are infrequent, but further studies are required to determine whether higher-dose IFN-α may benefit patients with combined hepatitis virus infections.     

Impact of comorbidities on the severity of chronic hepatitis B at presentation

AIM: To evaluate the clinical relevance of each cofactor on clinical presentation of chronic hepatitis B.METHODS: Out of 1366 hepatitis B surface antigen (HBsAg) positive subjects consecutively observed in 79 Italian hospitals, 53 (4.3%) showed as the only cofactor hepatitis D virus (HDV) infection [hepatitis B virus (HBV)/HDV group], 130 (9.5%) hepatitis C virus (HCV) (group HBV/HCV), 6 (0.4%) human immunodeficiency virus (HIV) (group HBV/HIV), 138 (10.2%) alcohol abuse (group HBV/alcohol); 109 (8.0%) subjects had at least two cofactors and 924 were in the cofactor-free (CF) group.RESULTS: Compared with patients in group CF those in group HBV/alcohol were older and more frequently had cirrhosis (P < 0.001), those in group HBV/HDV were younger (P < 0.001), more frequently resided in the south of the country and had cirrhosis (P <0.001), those in group HBV/HCV were older (P < 0.001) and more frequently had cirrhosis (P < 0.001). These cofactors were all independent predictors of liver cirrhosis in HBsAg positive patients. Multivariate analysis showed that an older age [odds ratio (OR) 1.06, 95% CI: 1.05-1.08], alcohol abuse with more than 8 drinks daily (OR 2.89, 95% CI: 1.81-4.62) and anti-HDV positivity (OR 3.48, 95% CI: 2.16-5.58) are all independently associated with liver cirrhosis. This association was found also for anti-HCV positivity in univariate analysis, but it was no longer associated (OR 1.23, 95% CI: 0.84-1.80) at multivariate analysis.CONCLUSION: Older age, HDV infection and alcohol abuse are the major determinants of severe liver disease in chronic HBV infection, while HCV replication plays a lesser role in the severity of hepatic damage.