icon star paper   Articles  
Back grey_arrow_rt.gif
 
 
The Hepatitis D Virus
 
Reported by Jules Levin
 
  The hepatitis D virus (also called delta virus) is a small circular RNA virus. The hepatitis D virus is replication defective and therefore cannot propagate in the absence of another virus. In humans, hepatitis D virus infection only occurs in the presence of hepatitis B infection.
 
Hepatitis D virus infection is transmitted by blood and blood products. The risk factors for infection are similar to those for hepatitis B virus infection. The hepatitis D virus most often infects intravenous drug users.
 
A patient can acquire hepatitis D virus infection at the same time as he/she is infected with the hepatitis B virus. This is called co-infection. A patient with hepatitis B can be infected with hepatitis D virus at any time after acute hepatitis B virus infection. This is called super-infection.
 
Hepatitis D virus super-infection should be suspected in a patient with chronic hepatitis B whose condition suddenly worsens. There is usually an obvious history of continued exposure to blood or blood products (eg. an active intravenous drug user). A particularly aggressive acute hepatitis B infection could suggest hepatitis D co-infection. Co-infection or super-infection with hepatitis D virus in a patient with hepatitis B is diagnosed by the presence of antibodies against the hepatitis D virus. IgM antibodies indicate acute infection.
 
HDV Fact Sheet
 
Virus: Incomplete RNA virus, dependent on HBV envelope proteins.
 
Disease: Coinfection: acute infection with hepatitis B virus.
 
Superinfection: acute HDV infection on chronic hepatitis B.
 
Outcome: May cause persistent infection (80% as superinfection, <10% with coinfection). Long-term sequella as with HBV, but more severe/accelerated.
 
EPIDEMIOLOGY:
 
Transmission: bloodborne and sexual.
 
Risk groups: as with HBV.
 
Endemic to Mediterranean regions.
 
Case Management: Diagnosis: anti-HDV and as with HBV.
 
Hepatitis Delta Virus
 
In 1977, Dr. Mario Rizzetto and associates discovered in Italy, in patients affected by Hepatitis B a new antigen different than surface, core and e systems that they called "delta antigen". (Gut 18:997-1003,1977). This antigen was detected by immunofluorescence in the nuclei of liver cells in patients infected with hepatitis B and looked similar to hepatitis B core antigen. Delta, however was not present in cases positive for core; was not present in cases negative for s antigen and was present in only some cases positive for s antigen. Therefore came the suspicion that the new antigen might belong to a different virus. This hypothesis, tenaciously postulated by Dr. Rizzetto, was confirmed some years later by experimentally infecting chimpanzees and obtaining a new viral particle which was given the name of Hepatitis D Virus (HDV).
 
The virus is an incomplete viral particle resembling a viroid of the plant world 36 nm in diameter containing:
 
--a HBS Ag envelope from hepatitis B virus.
--a delta Antigen predominantly found in the nuclei and in small amounts in the cytoplasm of hepatocytes.
--a single stranded circular RNA, with 1636 bases, a segment of which has a plant viroid sequence and does not encode any protein while another segment is dissimilar and encodes the delta antigen. The virus, therefore, operates with the help of HBV which makes its capsule. It is the only viroid-like agent so far known to infect humans.
 
Clinical Course:
 
Transmission is by blood. Infection may occur simultaneously with Hepatitis B virus (coinfection) or it may be acquired after B (superinfection). In the case of coinfection the patient displays two transaminases peaks, the first apparently due to hepatitis B and the second, which occurs weeks later, due to hepatitis D infection. The acute infection is bifasic. -- Most cases of coinfection resolve. Only 2.4-4.7% become chronic carriers. This course is apparently due to the fact that HDV seems to suppress HBV eplication and does not have optimal conditions for its own replication. --Most cases (50-70%) of superinfection develop a severe form of acute hepatitis and 90% of them become chronic carriers. This course is due to the fact that the D virus infects hepatocytes heavily colonized by B viruses which provide the D with excellent help for replication. With both infections there is more incidence of fulminant hepatitis and the mortality rate is 5% versus 1% with hepatitis B alone. Hepatitis D does not increase the incidence of extrahepatic disease hepatocellular carcinoma over hepatitis B infection. --Delta hepatitis is considered to be the most severe viral hepatitis. In acute forms it produces more fatalities. In chronic forms it produces more cirrhoses even in children. However it has marked geographical variations. While it is very frequent and lethal in the Amazonian basin with peculiar microvesicular fatty infiltration of hepatocyte it is very benign in Greece and south Pacific.
 
Prevention and treatment
 
All measures that prevent hepatitis B will prevent HDV, including HBV vaccine. Treatment will alpha -interferon is not successful. Liver transplantation is to be considered in fulminant cases. Five year survival after liver transplantation is around 70%. For the fact that HDV has a suppressive effect on HBV replication, the recurrence of accelerated disease after transplantation is less frequent than in hepatitis B alone
 
Hepatitis Delta Virus
 
Hepatitis D can damage the liver: through direct liver cell damage, through inflammation, which is caused by the immune system attacking the virus. Someone who does not have hep B or who is immune to the B virus is protected from the hepatitis D virus.
 
Hepatitis D virus infection is often severe if it occurs in someone who already has chronic hepatitis B. This acute fulminant form of hepatitis involves severe liver cell destruction and loss of liver function. It can be fatal. Symptoms include: an enlarged, painful liver, enlarged spleen, severe jaundice, susceptibility to bleeding, encephalopathy, a disorder in the functioning of the brain, aplastic anemia in rare cases. Aplastic anemia is a condition in which the bone marrow cannot make enough red and white blood cells.
 
Chronic liver disease, which may occur with hepatitis D, often has minimal symptoms. At times there may be mild flare-ups with jaundice, nausea, fatigue and weight loss.
 
Hepatitis D and hepatitis B are spread through exposure to infected blood and by sexual intercourse. People at risk include those who: puncture themselves with contaminated needles and syringes, such as intravenous drug abusers or healthcare workers, are stuck with contaminated needles during tattooing, acupuncture, or body piercing - are sexually promiscuous, whether homosexual or heterosexual - have had an organ transplant or blood transfusion, though blood is now screened for hepatitis B to prevent this form of transmission.
 
PREVENTION
 
Each year, fewer cases are reported due to use of the hepatitis B vaccine. Those who receive the hepatitis B vaccine do not usually catch hepatitis D, even if exposed to it.
 
The best way to prevent the D virus is to prevent hepatitis BThis can be done by getting the hepatitis B vaccine, avoiding unsterile needles, and following safer sex guidelines.
 
How is the infection diagnosed?
 
The healthcare provider may suspect hepatitis D after doing a physical examination and checking liver function tests. Another blood test, often drawn at the same time as the liver function tests, can confirm that hepatitis D is the cause of the symptoms.
 
Chronic hepatitis can be diagnosed with a liver biopsy. Liver biopsy specimens can be graded in terms of severity. Liver biopsies may have to be done repeatedly to detect progression of the disease or response to therapy.
 
What are the long-term effects of the infection?
 
Rarely, chronic liver disease and cirrhosis an occur. Cirrhosis is a serious disease that causes scarring of the liver. Severe hepatitis and cirrhosis may require a liver transplant and can result in death.
 
What are the risks to others?
 
A person with the hepatitis D virus can usually transmit both hepatitis B and hepatitis D. The viruses have been found in blood, saliva, semen, and vaginal secretions of infected individuals. They can be spread through sexual contact with an infected person, passed on to a newborn from an infected mother during childbirth, or transmitted by contact with infected blood or bodily fluids.
 
What are the risks to others?
 
A person with the hepatitis D virus can usually transmit both hepatitis B and hepatitis D. The viruses have been found in blood, saliva, semen, and vaginal secretions of infected individuals. They can be spread through sexual contact with an infected person, passed on to a newborn from an infected mother during childbirth, or transmitted by contact with infected blood or bodily fluids.
 
What are the treatments for the infection?
 
Treatment of hepatitis D includes: - bed rest - drinking extra fluids to prevent dehydration - avoiding unnecessary medications - avoiding alcohol - eating a well balanced diet for liver disease - taking antinausea medications as needed
 
For sudden, severe hepatitis D, treatment takes place in the hospital. A person may require antibiotics, vitamin K injections, blood and plasma transfusions, and fluids.
 
For chronic hepatitis D, treatment includes the antiviral drug alpha interferon, which can help if cirrhosis has not developed. It is more effective in the early stage of the disease.
 
Some people with severe hepatitis or end-stage liver disease may need a liver transplant. Hepatitis can recur in the transplanted liver, but it is rare.
 
What are the side effects of the treatments?
 
Side effects will depend on the treatments used. Side effects of interferon include a flu-like illness, with fever and body aches.
 
A liver transplant can cause many problems, including failure or rejection of the new liver. After a liver transplant, a person will need to take powerful antirejection medications for the rest of his or her life. Side effects of these medications increase the person's risk for infections, certain cancers, and other problems.
 
What happens after treatment for the infection?
 
A person with hepatitis D will be monitored for side effects and benefits during and after interferon treatment. Alpha interferon treatment might be repeated if the disease flares up again.
 
How is the infection monitored?
 
Periodic visits to the healthcare provider and liver function tests will be used to monitor the hepatitis and to see how the liver is working. The status of the liver may require repeated liver biopsies. Decisions about further treatment or liver transplantation are frequently made based on these tests. Any new or worsening symptoms should be reported to the healthcare provider.
 
STUDIES OF TREATMENT FOR HDV
 
Chronic Hepatitis D: A Vanishing Disease? An Italian Multicenter Study

 
Abstract: Hepatitis delta virus (HDV) was responsible for a high proportion of cases of acute and chronic liver disease in Southern Europe during the 1970s. Some data suggest that by the 1990s HDV circulation had substantially declined. We have assessed the prevalence of HDV infection and its clinical impact in 834 Italian hepatitis B surface antigen (HBsAg) carriers in 1997. Anti-HDV antibodies were sought in all consecutive chronic HBsAg carriers observed in 14 referral liver units throughout Italy. Risk factors for anti-HDV positivity were evaluated. Anti-HDV antibodies were found in 69 of 834 (8.3%) HBsAg-positive patients. Cohabitation with an anti-HDV-positive subject, intravenous drug addiction, residence in the South of the country, and the presence of cirrhosis were independently associated with the presence of anti-HDV antibodies. Typically, the spread of hepatitis B virus (HBV) and HDV infections in the south, as in other endemic areas, was mainly associated with intrafamily and environmental factors, whereas illicit drug abuse was the most common source of infection in the north. The overall prevalence of anti-HDV antibodies was lower than those observed in 2 multicenter surveys performed in 1987 and 1992 (23% and 14%, respectively). By 1997, the percentage of anti-HDV-positive subjects had sharply decreased in the 30 to 50 years age group, whereas it was almost unchanged in subjects over 50 years of age. The highest prevalence of anti-HDV antibodies (11.7%) was found in patients with cirrhosis. This prevalence was as high as 40% in the 1987 study. The circulation of HDV sharply decreased in Italy, by 1.5% per year, from 1987 to 1997. This decrease resulted mainly from the reduction in chronic HDV infections in the young, for whom high morbidity and mortality rates were recorded in the past. The results anticipate the almost complete control of HDV infection in the near future.
 
A spontaneous down-trend of hepatitis B has been noted in Italy since the end of the 1980s and has been accelerated by the introduction of universal HBV vaccination in newborns and adolescents in 1991 and by the impact of the educational measures taken to contain the epidemic of AIDS.
 
The decreased circulation of HBV is depleting the HBsAg carrier reservoir, thus rarefying the network of susceptible subjects to HDV infection and depriving the defective virus of the biological substrate necessary for it to thrive. The data of the Italian surveys indicate that the drop in the circulation of HDV is not colinear with that of HBV but exponential, so that the decrease in hepatitis delta has been much more profound than in hepatitis B.
 
In conclusion, the spectacular epidemiologic changes of the last few years herald an almost complete control of HDV infection in Italy in the near future. Although hepatitis delta could be newly introduced by immigrants from areas of the developing world where HDV infection is still endemic, the epidemiologic impact would appear to be minor given the solid nation-wide protection built up against HBV. (Hepatology 2000;32:824-827.)
 
Role of hepatitis B, C, and D viruses in dual and triple infection: Influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference
 
The interactions among hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) were studied by measuring HBV-DNA and HCV-RNA levels and by determining the influence of viral genotypes and mutations in HBV basal core promoter (BCP) and precore regions. We included 65 consecutive patients, 25 HBV/HCV, 18 HBV/HDV, and 22 HBV/HCV/HDV. Controls consisted of 55 patients with chronic HBV and 55 with chronic HCV infection. HBV-DNA and HCV-RNA levels were lower in coinfections than in single infections (P < .05). HBV/HCV coinfection was associated with lower HBV viremia (8.2 104 copies/mL) and lower HCV-RNA levels (7 105 IU/mL), than the corresponding control group (P < .05), with more marked decrease in HBV replication (P < .05). Moreover, in HBV/HCV coinfection and in triple coinfection we observed an inverse relationship between HBV-DNA and HCV-RNA levels (P < .05). HBV/HDV coinfection was associated with lower HBV viremia (2.5 104 copies/mL) than that found in HBV infection (P < .05). Patients with triple coinfection showed lower HBV-DNA and HCV-RNA levels than control groups (P < .05). Prevalence of precore mutations was lower in HCV coinfections (P < .05). No significant association was observed between HCV-RNA levels and HBV precore mutations, BCP mutations or HBV genotypes, or between HBV-DNA levels and HCV genotypes (P < .05). In conclusion, HCV exhibited stronger inhibitory action in the reciprocal inhibition seen in HBV/HCV coinfection. HDV was the dominant virus in HBV/HDV coinfection and in triple coinfection, and had a greater unfavorable influence on HCV than on HBV replication. The reciprocal inhibition of viral replication seemed to be little influenced by the inherent genomic factors studied. (HEPATOLOGY 2001;34:404-410.)
 
Lamivudine for Chronic Delta Hepatitis
 
Chronic delta hepatitis is a severe form of chronic liver disease caused by hepatitis delta virus (HDV) infection superimposed on chronic hepatitis B or the hepatitis B surface antigen (HBsAg) carrier state. Therapy of delta hepatitis is currently unsatisfactory. We have evaluated lamivudine (3-thiacytidine), an oral nucleoside analogue with marked effects against hepatitis B, as therapy in 5 patients with chronic hepatitis D. Five men, ages 38 to 65 years, were treated. All had HBsAg, antibody to HDV, and HDV RNA in serum, as well as persistent elevations in alanine aminotransferase (ALT) levels and liver histology showing severe chronic hepatitis with fibrosis or cirrhosis. Lamivudine was given in a dose of 100 mg orally daily for 12 months. Patients were monitored carefully and tested for HBsAg, HBV-DNA and HDV-RNA levels serially during the year of treatment and for 6 months thereafter. Liver biopsies were performed before therapy and repeated after 1 year. Serum levels of HBV DNA fell rapidly in all 5 patients, becoming undetectable even by polymerase chain reaction (PCR) in 4. However, all 5 patients remained HBsAg- and HDV-RNA-positive, and serum ALT levels and liver histology did not improve. All patients tolerated therapy well. When lamivudine was stopped, HBV-DNA levels returned to pretreatment values without a change in disease activity. Lamivudine is a potent inhibitor of HBV-DNA replication, but does not improve disease activity or lower HDV-RNA levels in patients with chronic delta hepatitis.
 
Editorial from Hepatology (Malik & Lee): A related question is whether lamivudine has any role in management of hepatitis delta (HDV). Lau et al. have examined this with 5 patients, 4 of whom had previously seroconverted to anti-HBe and had HBV DNA detectable by polymerase chain reaction only and 1 who had positive serum HBeAg and detectable HBV DNA by hybridization assay. All patients had hepatitis B surface antigen (HBsAg), evidence of chronic HDV infection on biopsy, and elevated transaminase levels. Despite all exhibiting a marked drop in HBV DNA with lamivudine treatment, 4 becoming negative by polymerase chain reaction, all remained positive for HBsAg and HDV RNA, and there was no improvement in serum ALT or histology. HDV activity paralleled changes in HBsAg titers in 1 patient. Although this is a small series, the results confirm that HDV RNA levels will not improve with lamivudine. HDV is not dependent on DNA polymerase for replication but replicates via the cccDNA; like HBsAg, it remains unaffected by lamivudine. One might have hoped that HBeAg-negative patients with very low levels of HBV DNA might seroconvert, but this was not the case after 1 year of lamivudine for the 4 HBeAg-negative patients. There is little hope that lamivudine will be effective for HDV. (Hepatology 1999;30:546-549.)
 
A randomized controlled trial of a 12-month course of recombinant human interferon-alpha in chronic delta (type D) hepatitis: A multicenter Italian study
 
To determine whether long-term therapy with recombinant interferon-alpha can improve the course of chronic delta hepatitis, 61 Italian patients with this disease were randomly assigned to receive either interferon-alpha-2b three times a week (5 MU/m2 for 4 mo and then 3 MU/m2 for another 8 mo) or no treatment. At the end of the 12-mo study, all patients were followed-up for 12 additional months. Normalization or decrease of more than 50% from baseline of serum ALT levels occurred in 42% of treated patients the fourth month of therapy, 26% the twelfth month and 3% the twenty-fourth month vs. 7%, 7% and 0%, respectively, in the control group. However, relapses occurred in 7 of 8 (87.5%) responders 1 to 10 mo (mean = 3.5 mo) after cessation of therapy. Liver biopsies were carried out at baseline and during the twelfth month of treatment. Histological improvement, mostly caused by decrease of portal inflammation, was observed in 57% of treated and 36% of untreated patients. Measures of antiviral activity (serum hepatitis delta virus RNA and intrahepatic hepatitis delta antigen) showed similar levels in treated and control patients. In treated patients the percentage of patients who were negative for HDV RNA never exceeded that of baseline. Although interferon-alpha in the dosage given in this study had no antiviral effect on patients with chronic hepatitis D, it reduced hepatic inflammation as measured by ALT levels. Whether a longer duration or reinstitution of interferon-alpha therapy would achieve long-term control of ALT levels and prevent chronic liver damage is not known. (Hepatology 1991 Jun;13(6):1052-6)
 
Treatment of chronic hepatitis D with interferon alfa-2a
 
BACKGROUND AND METHODS. Chronic hepatitis D is a severe and rapidly progressive liver disease for which no therapy has been proved effective. To evaluate the efficacy of treatment with interferon, we studied 42 patients with chronic hepatitis D who were randomly assigned to receive either 9 million or 3 million units of recombinant interferon alfa-2a (three times a week for 48 weeks) or no treatment. RESULTS. By the end of the treatment period, serum alanine aminotransferase values had become normal in 10 of 14 patients receiving 9 million units (71 percent), as compared with 4 of 14 treated with 3 million units (29 percent, P = 0.029) and 1 of 13 untreated controls (8 percent, P = 0.001). Seven patients treated with the higher dose of interferon (50 percent) had a complete response (normal levels of alanine aminotransferase and no detectable serum hepatitis delta virus [HDV] RNA), as compared with three of those who received the lower dose (21 percent, P = 0.118), and none of the controls (P = 0.004). Treatment with 9 million units of interferon was associated with a marked improvement in the histologic findings (reduced periportal necrosis and portal and lobular inflammation), whereas in the untreated controls there was considerable histologic deterioration. In 5 of the 10 patients treated with 9 million units of interferon whose alanine aminotransferase values became normal, the biochemical responses persisted for up to 4 years (mean, 39 months), but the effects of treatment on viral replication were not sustained. In contrast, none of those who received 3 million units and none of the untreated controls had a sustained biochemical or virologic response. CONCLUSIONS. In about half the patients with chronic hepatitis D treated with high doses of interferon alfa-2a (9 million units three times a week for 48 weeks), the serum alanine aminotransferase level becomes normal, HDV RNA becomes undetectable in serum, and there is histologic improvement. However, a relapse is common after treatment has been stopped. N Engl J Med 1994 Jan 13;330(2):88-94
 
The French experience of treatment of chronic type D hepatitis with a 12-month course of interferon alpha-2B. Results of a randomized controlled trial
 
Hepatitis due to hepatitis delta virus (HDV) infection is generally associated with severe histological abnormalities and rapid progression of the disease. To assess the efficacy of recombinant interferon-a2b in treatment of chronic delta hepatitis, 22 patients were entered into a randomized controlled trial: 11 received interferon-a2b subcutaneously three times weekly for 12 months (5 MU/m2 for 4 months and then 3 MU/m2 for a further 8 months) and 11 were untreated. All patients were followed up for 6 months after the completion of therapy. Nine treated patients completed the trial: one was withdrawn with hyperthyroidism and one committed suicide. Serum ALT levels were normalized or significantly reduced, always within 3 months of initiating treatment, and remained so in 73% of treated patients at the 4th month and in 54.5% at the 12th month, compared with 18% and 18%, respectively, in the untreated group. Moreover, in seven of nine treated patients, interferon was associated with the clearance of serum HDV-RNA, associated with amelioration of the histological picture, whereas this occurred in only four of 11 untreated patients. On cessation of therapy, all patients but one experienced a biological and/or virological relapse over the 6-month follow up. In conclusion, our data confirm that HDV is sensitive to inhibition by interferon-a2b, although the schedule used did not achieve permanent control of the disease. The adverse effects of interferon require consideration; in particular, care will be needed to avoid serious psychiatric side effects. Liver 1995 Feb;15(1):45-52
 
Elimination of hepatitis delta virus infection after loss of hepatitis B surface antigen in patients with chronic delta hepatitis.
 
Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892. The aim of this study was to evaluate whether patients with chronic hepatitis delta virus (HDV) infection treated with alpha interferon and subsequent loss of hepatitis B surface antigen (HBsAg) eliminate HDV. HDV RNA was detected in 26 of 28 patients with chronic delta hepatitis using the polymerase chain reaction. Seventeen patients in whom HDV RNA was detected were treated with alpha interferon; in 65%, HDV RNA remained detectable during treatment or reappeared after stopping therapy whereas in three patients HDV RNA remained absent (17.5%). HDV RNA became and remained undetectable in serum and liver of two of these three patients who lost HBsAg from serum and in one patient who was intermittently HBsAg negative during therapy. After loss of HBsAg, hepatitis B virus (HBV) DNA was still detectable in the liver, but not HBV RNA, indicating absent or very low HBV replication. Three patients were lost to follow up (17.5%). Two nontreated patients with chronic HDV infection also lost HBsAg during follow up; HDV RNA also became undetectable in their serum. Thus, HDV replication does not persist after the loss of HBsAg. Clearance of HBsAg may be a useful guide to when therapy can be stopped. J Med Virol 1994 Dec;44(4):389-92
 
Serum Immunoglobulin M Antibody to Hepatitis D As a Surrogate Marker of Hepatitis D in Interferon-Treated Patients and in Patients Who Underwent Liver Transplantation
 
The kinetics of the immunoglobulin (Ig) M type antibody to the hepatitis D virus (IgM anti-HD) were investigated in hepatitis B surface antigen (HBsAg) carriers with chronic hepatitis D treated with interferon (IFN) and in patients with terminal hepatitis delta virus (HDV) cirrhosis who underwent liver transplantation. The IgM antibody disappeared in each of 8 patients who responded to IFN therapy with the persistent normalization of aminotransferases and with the clearance of serum HBsAg and HDV-RNA. The IgM reactivity did not decline in the 45 treated patients who did not respond to the cytokine or who experienced a relapse after responding while on therapy. The antibody rapidly disappeared from serum post-transplantation in each of 10 examined patients with HDV who underwent transplantation. In 5 patients who underwent transplantation and who became reinfected with HDV, the antibody remained undetectable during the early reinfection phase, as marked by HDV replication and by the absence of liver damage; however, it rapidly raised to pre-transplantation levels with the recurrence of hepatitis D (HD) in the liver graft. Monomeric 7S IgM anti-HD predominated over pentameric 19S antibody in each of the two patients examined for IgM anti-HD molecular species. The IgM antibody to HDV raises in response to HDV-induced damage and represents a valid surrogate marker of liver damage which is immunopathologically related to HDV infection. Besides providing diagnostic information, it provides the best predictor of impending resolution of chronic HDV disease, whether spontaneous or IFN-induced. (Hepatology 1998;27:873-876.)
 
 
 
  icon paper stack View Older Articles   Back to Top   www.natap.org