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Interferon Treatment of Hepatitis B and C In ??-Thalassemia
... This drug should be used for one year. During this period the goal of therapy should be the complete clearance of HBV 142,143 . Unfortunately, only 25%-40% of patients are noted to have a good response and the use of other antiviral drugs (adefovir, tenofovir, lamivudine, telbivudine, and entecavir) is often necessary 142 . ...
The clinical approach to thalassemia and hemoglobinopathies, specifically Sickle Cell Disease (SCD), based on transfusions, iron chelation and bone marrow transplantation has ameliorated their prognosis. Nevertheless, infections still may cause serious complications in these patients. The susceptibility to infections in thalassemia and SCD arises both from a large spectrum of immunological abnormalities and from exposure to specific infectious agents. Four fundamental issues will be focused upon as central causes of immune dysfunction: the diseases themselves; iron overload, transfusion therapy and the role of the spleen. Thalassemia and SCD differ in their pathogenesis and clinical course. It will be outlined how these differences affect immune dysfunction, the risk of infections and the types of most frequent infections in each disease. Moreover, since transfusions are a fundamental tool for treating these patients, their safety is paramount in reducing the risks of infections. In recent years, careful surveillance worldwide and improvements in laboratory tests reduced greatly transfusion transmitted infections, but the problem is not completely resolved. Finally, selected topics will be discussed regarding Parvovirus B19 and transfusion transmitted infections as well as the prevention of infectious risk postsplenectomy or in presence of functional asplenia.
... Another study was excluded because its subjects were co-infected with HBV [5] and one other study was also excluded because it included patients after bone marrow transplantation [6]. Five additional studies were excluded because of low sample size of 2, 3, 4, 7 and 8 subjects respectively [7][8][9][10][11][12]. One study was excluded because it did not provide enough information on methodology and outcome [13], one further study was excluded because it just reported early viral response [14] and two other studies were excluded because they did not report SVR [15,16]. ...
Hepatitis C virus (HCV) infection is a major cause of liver-related morbidity and mortality among thalassaemic patients. In order to analyse the effect of the current anti-HCV treatment in this subset of HCV-infected patients, we conducted a systematic review with meta-analysis of the available literature. The outcome was sustained viral response. Both comparative [odds ratio (OR)] and non-comparative indeces (success rate) were used to run the meta-analytical procedure. Data encompassing 429 thalassaemic HCV-infected patients treated with conventional or pegylated interferon monotherapy or combination therapy with ribavirin were collected from 13 articles (10 prospective cohort studies, 1 randomized-controlled trial and 2 controlled trials). Pooled sustained viralogical response (SVR) was 44.7% (34.6-54.9). Pooled ORs of SVR for Genotype 1 vs non-Genotype 1 infected thalassaemic patients were 0.46 (95% CI: 0.22-0.95) in IFN monotherapy and 1.7 (95% CI: 0.46-6.04) in ribavirin combination therapy. Our meta-analysis shows that thalassaemic patients with Genotype 1 infection significantly benefit from the addition of ribavirin to their therapeutic regimen. It seems that using ribavirin in thalassaemic patients increases transfusion need by a median of 30-40%, but does not increase major adverse events or treatment withdrawal. Current literature is lacking sufficient evidence about the use of PEG-IFN as monotherapy or in combination with ribavirin in thalassaemic patients.
... Indeed, HBV infection is still common in Bangladesh 80 and India. 72 Interestingly, Singh and colleagues 81 In those thalassaemic patients with progressive chronic hepatitis B, interferon therapy should be tried, 82 although appropriate trials are lacking and no data are available on the use of pegylated interferons. ...
Infections are major complications and constitute the second most common cause of mortality and a main cause of morbidity in patients with thalassaemia, a group of genetic disorders of haemoglobin synthesis characterised by a disturbance of globin chain production. Thalassaemias are among the most common genetic disorders in the world. Predisposing factors for infections in thalassaemic patients include severe anaemia, iron overload, splenectomy, and a range of immune abnormalities. Major causative organisms of bacterial infections in thalassaemic patients are Klebsiella spp in Asia and Yersinia enterocolitica in western countries. Transfusion-associated viral infections (especially hepatitis C) can lead to liver cirrhosis and hepatocellular carcinoma. A unique and challenging infection detected in Asian patients is pythiosis, caused by a fungus-like organism, the mortality rate of which is very high. Because the prognosis for thalassaemia has much improved, with many patients surviving to the fifth decade of life in developed countries, it is mandatory to reduce mortality by recognising and presumptively treating infections in these patients as quickly as possible.
Context:
Hepatitis C virus (HCV) infection is a major cause of liver-morbidity and mortality among patients with thalassemia. Peginterferon plus ribavirin is currently the recommended therapy for hepatitis C infection in patients do not have thalassemia, but using ribavirin in patients with thalassemia is restricted due to its hemolytic effect. To evaluate the efficacy and safety of adding ribavirin to peginterferon or interferon, authors performed a systematic review on the available literatures.
Evidence acquisition:
Trials were identified through electronic database, manual searches of journals and bibliographies and approaching authors of trials. Randomized trials that enrolled patients with a diagnosis of thalassemia and chronic hepatitis C infection treated with interferon or peginterferon with or without ribavirin were included. Two investigators independently evaluated the trials for inclusion criteria, risk of bias and data extraction. The primary outcomes were sustained virological response (SVR), liver-related morbidity, mortality and adverse events. The odds ratios from each trial were calculated individually and in the subgroup analysis of trials. Data were analyzed with fixed-effect model.
Results:
Three randomized clinical trials with 92 patients were included. All three trials had unclear risk of bias. Compared with peginterferon monotherapy, adding ribavirin to peginterferon had significant beneficial effect on sustained virological response (OR = 3.44, 95% CI: 1.18 - 10.06). There was no significant difference between combination therapy and monotherapy in the end of treatment achievement response. Other than about 30% increase in blood transfusion due to anemia that returned to normal level 2 - 3 months after treatment, there was no significant increase in side effects followed by adding ribavirin to pegylated interferon (Peg-IFN). Data were insufficient to determine the impact of genotype, viral load and age on the response to treatment.
Conclusions:
Compared with monotherapy, adding ribavirin to treatment is more effective in removing hepatitis C virus from the bloodstream in patients with thalassemia, it is also more effective in reducing the relapse rate after treatment. Except the increase in blood transfusion, there was no significant increase in side effects followed by adding ribavirin.
Acute hepatitis B virus (HBV) infection is typically distinguished from chronic disease by a positive IgM anti-hepatitis B core antigen (anti-HBc) test. Patients with chronic hepatitis B remain hepatitis B surface antigen (HBsAg) positive, often with raised serum alanine aminotransferase (ALT) activities, for more than six months. The presence of hepatitis B e antigen (HBeAg) and HBV-DNA correlates with infectivity (although patients infected with the pre-core mutated virus may be HBeAg negative). Immunity after HBV infection is characterised by the presence of anti-HBs and anti-HBc antibodies. Patients who respond to interferon alfa treatment lose HBV-DNA and HBeAg from serum and their ALT values return to normal; some also lose HBsAg and acquire anti-HBs. Diagnosis of acute hepatitis C virus (HCV) infection remains largely dependent on history and exclusion, as anti-HCV antibodies may appear late or never at all, although HCV-RNA may be detectable on polymerase chain reaction (PCR) within days of infection. Second generation ELISAs detect a range of anti-HCV antibodies in chronic infections, and confirmatory RIBAs have reduced the incidence of false-positive results. Direct tests for HCV antigens in serum are not yet available, although PCR testing for HCV-RNA can be used to confirm viraemia. Patients who respond to interferon alfa treatment show continuous normalisation of serum ALT values, and some lose HCV-RNA. Relapse occurs in about half of all those who respond.
In this open, pilot study, interferon (IFN) alpha-2b seemed effective in the treatment of hepatitis C virus (HCV) infection in patients with beta-thalassaemia. In seven of nine patients who completed the study alanine aminotransferase activities returned to normal, and a completely stable response 24 months after treatment was seen in five. Liver biopsy specimen showed a clear reduction in portal, periportal, and lobular necroinflammation in all five cases. Three patients stopped treatment early because of side effects.
To assess the effect of interferon therapy on posttransfusion non-A, non-B acute hepatitis, we examined the appearance of serum hepatitis C virus antibody (anti-HCV) and abnormal serum aminotransferase levels after the onset of hepatitis in 12 patients treated with interferon and in 46 patients treated conservatively. Eleven patients were given 3 million units of human fibroblast beta-interferon three times weekly for 4 wk and 1 was given one million units of human lymphoblastoid alpha-interferon daily for 3 months. In the interferon-treated patients, the effect of therapy on hepatic histology was also assessed. Detection of anti-HCV within 6 and 12 months after the onset of hepatitis was less common in interferon-treated patients than in control patients (6/12 vs 35/46 and 5/12 vs 35/46, both p = NS). At 24 months after the onset of hepatitis, anti-HCV levels were significantly lower in interferon-treated patients (0/10, p less than 0.05), but had not changed significantly in control patients (34/46). Abnormal serum aminotransferase levels at 6, 12, and 24 months after the onset of hepatitis were significantly less common in interferon-treated patients than in controls (25% vs 78.3%, p less than 0.005; 25% vs 71.7%, p less than 0.01; and 0% vs 67.4%, p less than 0.001). The percentage of abnormal serum aminotransferase levels at 6, 12, and 24 months after onset of hepatitis was also less in interferon-treated patients than in control patients, both among anti-HCV-positive patients (50% vs 85.7%, p = NS; 50% vs 80%, p = NS; and 0% vs 77.1%, p less than 0.01) and among anti-HCV-negative patients (0% vs 54.5%, p = NS; 0% vs 45.5%, p = NS; and 0% vs 27.3%, p = NS). Immediately after interferon therapy, the histological activity index dropped from 6.0 +/- 4.2 to 4.8 +/- 2.5 in anti-HCV-positive patients (p = NS) and from 4.2 +/- 4.3 to 2.6 +/- 1.7 in anti-HCV-negative patients (p = NS). Biopsy specimens obtained from four patients 12-23 months after interferon therapy revealed normal histology in one anti-HCV-positive patient and two anti-HCV-negative patients, and marked improvement in the other anti-HCV-positive patient. These results indicate that short-term, low-dose interferon therapy may be effective for posttransfusion non-A, non-B acute hepatitis (both anti-HCV-positive and anti-HCV-negative).
We studied the clinical course and the effect of alfa interferon treatment in sixty-six patients of Southern Italy suffering from chronic hepatitis C virus. The patients were randomly assigned to the control group (33 patients without treatment) or to the group treated with 3MU of interferon three times a week for six months. Alanine transaminase (ALT) levels normalized in 17 of the 33 treated subjects (52%) within two months of treatment. Seven of these "responders" relapsed at the end of the six-month treatment period, but ALT normalized in these patients after resumption of interferon at the same dosage. None of the non responders on 3MU for four months showed improvement even when the dose was increased to 6MU. Our results coincide with other reports on interferon treatment in hepatitis C virus. Further studies are required to clarify whether or not higher doses at the onset of treatment increase the number of responders and decrease the frequency of relapses.
This paper reviews the results of recent studies carried out in the USA on the treatment of chronic hepatitis B with interferon alfa-2b. In the US multicentre trial, 37% of patients lost hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV)-DNA when treated with 5 million units (MU) daily for 16 weeks, compared to 42% in the US National Institutes of Health (NIH) trial treated with 10 MU thrice weekly for 16 weeks. In both studies, the loss of HBeAg and HBV-DNA was associated with virological, biochemical, histological, and clinical improvement. Long term follow up in the National Institutes of Health study showed that 65% of responders had disappearance of HBsAg over a mean of four years, suggesting that termination of the HBV carrier state may be possible.
Hepatitis C virus (HCV) is responsible for the majority of cases of post transfusion non-A non-B (NANB) hepatitis in thalassaemia major (TM). Fifteen multi-transfused TM patients with serological, biochemical, histological and molecular biological evidence of HCV infection have been treated for six months with recombinant alpha interferon (IFN). Eleven (73%) responded, 8 (53%) had complete response (CR), 3 (20%) partial response (PR) and 4 (27%) did not respond (NR) to IFN. Natural killer (NK) cell activity 24 hours after the first dose of IFN was significantly increased in responders as compared to non-responders. Liver histology showed an overall reduction of portal inflammation and periportal necrosis in the responding patients. HCV RNA disappeared from serum in 8 (15) responders and partial responders. Non responders remained positive. HCV RNA was tested and found to be positive in liver tissue material in 7 patients, five of those were re-tested after IFN treatment. Two became negative (both CR) 3 remained positive despite biochemical response to IFN. The degree of induction of peripheral blood mononuclear cell 2'5' oligoadenylate synthetase messenger RNA (2-5 OAS mRNA), an enzyme induced by IFN, after the first dose of IFN did not correlate with response neither was any significant interaction with cytokines observed; tumour necrosis factor (TNF), interleukin-1. (IL-1) and CD4:CD8 ratios did not change. We conclude that IFN should be given to all TM patients with chronic active hepatitis due to HCV.