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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2006  |  Volume : 17  |  Issue : 3  |  Page : 338-343
Tolerance and Efficacy of Interferon-alpha in Hemodialysis Patients in Tripoli


Department of Infectious Diseases, Tripoli Medical Center, Tripoli, Libya

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   Abstract 

A prospective non-randomized study was conducted at the Department of Infectious Diseases at Tripoli Medical Center. We evaluated the tolerance and efficacy of interferon-alpha (IFN) monotherapy in our hemodialysis (HD) patients with chronic hepatitis C virus (HCV) infection. Patients with evidence of active viral infection i.e. positive polymerase chain reaction (PCR) results and who were potential transplant candidates were included in the study. They received three million units of IFN-alpha, administered subcutaneously, three times a week for 12 months. The treatment was discontinued in 12 out of the 35 treated patients (i.e drop out rate 34.2%). Among the 23 patients who completed the treatment course, 14 (60.8%) became PCR negative, and by the end of eighteen months, nine of the patients maintained PCR negativity (39%). Thus, a sustained virological response was observed in nine (25.7%) of the 35 enrolled patients. Our study suggests that the efficacy of IFN-alpha in our patients was less than anticipated and the tolerance to the drug was poor. However, studies involving larger numbers of patients are required to optimize the treatment protocol.

Keywords: Hepatitis C Virus, Hemodialysis, Interferon.

How to cite this article:
Buargub M, El Huni S, Tagdi M. Tolerance and Efficacy of Interferon-alpha in Hemodialysis Patients in Tripoli. Saudi J Kidney Dis Transpl 2006;17:338-43

How to cite this URL:
Buargub M, El Huni S, Tagdi M. Tolerance and Efficacy of Interferon-alpha in Hemodialysis Patients in Tripoli. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2021 Mar 6];17:338-43. Available from: https://www.sjkdt.org/text.asp?2006/17/3/338/35765

   Introduction Top


The prevalence of hepatitis C virus (HCV) infection in patients undergoing hemodialysis (HD) is high; in our dialysis unit, rates are greater than 60%. This can be attributed to several risk factors. Nosocomial transmission due to poor adherence to infection control measures is probably the most important factor.

The goals of treating HCV infection are to: a) prevent long-term complications such as chronic hepatitis, cirrhosis and hepato­cellular carcinoma, b) reduce its extra-hepatic manifestations and, c) prevent spread of infection to other patients.

In patients with normal kidney function, the treatment of choice for chronic HCV infection is a combination of ribavirin and pegylated-interferon, administered for a total of 6-12 months with an expected response rate of up to 88% for genotypes two and three and 48% for genotypes one, four, five and six. [1]

Monotherapy with pegylated-interferon may be used if ribavirin is not tolerated or contraindicated, with an expected sustained virological response (SVR) of 39%. [2] In patients with normal renal function, the response to interferon (IFN) monotherapy is much lower with the reported SVR being 13-25% after 12 months of treatment. [3]

Ribavirin is relatively contraindicated in patients with end-stage renal failure on maintenance HD, due to its prolonged half­life. [4] Ribavirin, a poorly dialyzable drug, can cause severe hemolysis and life threatening anemia in dialysis patients and, thus, IFN monotherapy is used.

Interferon may increase the risk of graft rejection after transplantation. Therefore, the treatment of potential renal transplant reci­pients with chronic HCV infection should be considered before kidney transplantation. [5],[6]

Analysis of the literature on efficacy and safety of IFN monotherapy in dialysis patients has shown a pooled sustained response rate of 33 to 37% and a drop-out rate of 17 to 29.6%, [7],[8],[9] suggesting that it is more effective in dialysis patients than patients with normal renal function, and that it has a larger side­effect profile.

This study was conducted to evaluate the effectiveness and tolerance of IFN-alpha in our HD patients.


   Patients and Methods Top


During the period from 1st January 2002 to 30 th December 2004, all HCV antibody positive HD patients who were referred to the infectious diseases department at Tripoli Medical Center were examined. The HCV antibody positive status was confirmed with a third generation ELISA test. Qualitative polymerase chain reaction (PCR) tests were performed using Combas Amplicor Roche reagent with a sensitivity threshold of 100 HCV RNA copies/ml. Quantitative PCR tests were completed using Versant HCV-RNA 3 with a sensitivity threshold of 3200 HCV RNA copies/ml and genotyping was done by Roche-Combas-Amplicor HCV version 2. All PCR tests were carried out at the Merieux laboratory, France.

Anti-HCV antibody positive patients were assessed for the possibility of IFN therapy. Treatment was considered if the patient met the following criteria:

a) HCV infection documented with a positive PCR test.

b) The patient was a potential candidate for transplantation.

c) The patient wanted to undergo treatment. Liver transaminase levels were noted although they could be normal (< 30 IU/l) or high at the start of the treatment. Transaminase levels are now considered poor markers of the severity of the liver disease and the argu­ment to limit the therapy only to patients with increased levels is no longer valid. [10]


   Treatment Protocol Top


To every patient, we administered three million units of IFN-alpha subcutaneously, three times a week, for 12 months. Doctors at the infectious diseases department conducted monthly follow-up visits. Regular biochemical and hematological blood tests were done during each visit and side effects, if any, were noted.


   Definitions Top


A responder was defined as a patient with negative PCR result at the end of treatment i.e. at 12 months; a non-responder was a patient with positive PCR at 12 months, a relapser was an initial responder, but with a positive PCR at the end of follow-up (i.e. >18 months), while a patient with a negative PCR at the end of the follow-up was con­sidered to have a sustained response.


   Statistical analysis Top


Results are expressed as mean +/- SD, the association between the risk factor and the response was assessed by the odds ratio (OR) with 95% confidence interval. P was considered significant if below 0.05.


   Results Top


A total of 104 anti-HCV positive HD patients were referred to the infectious diseases depart­ment. Of them, 23 (22%) had negative PCR results. In 81 patients, the PCR test was positive confirming active infection. The most prevalent genotype was genotype four detected in 50 patients (61.7%), followed by genotype one in 22 patients (27%), geno­type three in seven patients (8.6%), while genotype two was the least common and found in only two patients (2.2%).

Therapy with IFN was initiated in 35 patients, all of whom were negative for markers of hepatitis B virus (HBV) and human immuno­deficiency virus (HIV). Also, none of them had clinical evidence of chronic liver disease or neuropsyciatric illness, and none received IFN therapy in the past. In 12 of them, the treatment course was not completed; two male patients died, one due to myocardial infarction and the other due to sepsis. One female patient developed severe dermatitis, which improved after treatment with IFN was discontinued. In the remaining nine patients, treatment was stopped because of poor com­pliance. The overall drop out rate was 34.2%.

Twenty-three patients completed the one­year treatment and six-month post-treatment follow-up course [Table - 1],[Table - 2]. They included 13 males and 10 females. Their mean age was 39.5 years and the mean duration on HD was two years. Their mean pre-treatment HCV viral level in logs was 5.95.Genotype four was the most prevalent (present in 12 out of 23 patients), followed by genotype one (7 patients).

By the end of one year, 14 patients responded to IFN treatment (60.8%), while the other nine patients did not. Among the responders, nine (40%) maintained a negative PCR status until the end of follow-up. Thus, a sustained response was detected in 25.7% of the 35 enrolled patients. Flu like symptoms, asthenia and depression were the most frequently reported side effects.


   Discussion Top


Therapeutic decisions in patients with chronic HCV infection have been difficult. The disease usually has a sub-clinical course, and most patients are asymptomatic until the development of cirrhosis and end-stage liver disease. Management of HCV in dialysis patients is even more controversial; clini­cians argue that the long-term consequences of chronic HCV may not become apparent in these patients, who already have reduced survival without transplantation.

On the other hand, data from several published papers have shown the following:

a) Patients with chronic HCV infection who are on dialysis or status post kidney transplantation may have significant liver disease and liver biopsy may show chronic hepatitis despite normal blood liver enzyme levels. [11]

b) There is an increased risk of death among long-term HD patients infected with HCV compared with HCV-negative patients. [12]

c) Patient and graft survival rates are lower in HCV-positive renal transplant patients when compared with HCV-negative patients. [13]

d) The treatment of HCV-positive HD patients with IFN can induce a complete and sustained clearance in almost 29% of the patients. Additionally, no relapse has been seen in these patients following renal trans­plantation despite subsequent immuno­suppressive therapy [14],[15]

Renal transplantation is associated with worsening of liver disease and treatment of HCV positive HD patients with IFN is associated with lesser degree of progre­ssion of chronic liver disease after trans­plantation even in the absence of HCV clearance. [15]

e) Pre-transplant IFN may prevent HCV­associated glomerulopathy in the renal allograft. [5]

f) After transplantation, there is no effective and safe treatment available for HCV infection. Interferon therapy is associated with a high rate of acute rejection in renal transplant patients. [5],[6]

Not all patients on dialysis with chronic HCV infection are candidates for therapy.

Treatment is recommended in carefully selected patients such as those waiting for transplantation and those with advanced fibrosis. [14],[15],[16],[17]

Results from our patients revealed the following:

a) 22% of patients with positive anti-HCV antibodies had a negative PCR result. Possible explanations could be false positive serologic test, spontaneously cleared infection, very low viral titer undetected by the PCR test or a fluctuating pattern of viremia with virus free intervals. [18] It is unfortunate that we were not able to repeat the test in these patients.

b) The most prevalent genotype was geno­type four detected in 61.7% of patients, a result similar to the previous reports from other Middle East countries. [19] Genotype four is considered to have a favorable response to treatment. [16]

c) The drop out rate was 34%. This high rate could be partly explained by the intolerance of patients to the side effects of IFN. By the end of 12 months of treat­ment and six months of follow-up, only nine patients were PCR negative, i.e. the SVR was 25.7%. This result is comparable to previous reports; when compared to patients with normal renal function, dialysis patients show a higher response to IFN monotherapy. [7],[8] As most of our patients were infected with genotype four, we anticipated a better response rate and the possible explanation for this poorer result may be the higher blood viral levels in our patients.

d) Factors that were reported in earlier studies to be associated with favorable response to IFN therapy are: recent onset of infection, lower levels of viremia and genotypes other than type one. [3],[4] Upon statistical analysis of our data using an odds ratio with a 95% confidence interval, the only significant association detected was in younger patients <40 years of age. Our data did not demonstrate any signi­ficant association with gender, increased ALT levels or genotype four [Table - 3].


   Conclusion Top


Use of IFN has been limited by its cost, high incidence of side effects and variable response rates. In our study, the SVR was comparable to earlier reports, which demon­strated a relatively higher effectiveness of this therapy in dialysis patients. The drop out rate was high. There are several limitations to our study including the small number of treated patients, the absence of a control group, and the absence of histopathologic evidence to support the good response. The durability of the viral response also needs to be followed. Recently, there have been reports of a more efficient response in end-stage renal disease patients to pegylated interferon-alpha­ 2a.[20] We hope that, in the near future, clear guidelines about the optimal dose, duration and type of IFN therapy in dialysis patients will be established.

 
   References Top

1.Poynard T, Yuen MF, Ratzin V, Lai CL. Viral hepatitis C. Lancet 2003;362:2095-100.  Back to cited text no. 1    
2.Zeuzem S, Feinman SV, Rasenaek J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C.N Engl J Med 2000;343:1666-72.  Back to cited text no. 2    
3.Feitelson MA. Hepatitis C virus, from laboratory to clinic. Cambridge. 2002; 9101-9102.  Back to cited text no. 3    
4.Liang TJ, Hoofngle JH. Hepatitis C. Biomedical research reports 2000.Acadamic press.  Back to cited text no. 4    
5.Magnone M, Holly JL, Shapiro R, et al. Interferon-alpha induced acute renal allograft rejection. Transplantation 1995;59:1068-70.  Back to cited text no. 5    
6.Rostaing L, Izopet J, Baron E, Duffaut M, Puel J, Durand D. Treatment of chronic hepatitis C with recombinant interferon alpha in kidney transplant recipients. Transplant­ation 1995;59:1426-31.  Back to cited text no. 6    
7.Fabrizi F, Dulai G, Dixit V, Bunnapradist S, Martin P. Meta-analysis: interferon for the treatment of chronic hepatitis C in dialysis patients. Aliment Pharmacol Ther 2003;18: 1071-81.  Back to cited text no. 7  [PUBMED]  
8.Russo MW, Goldweig CD, Jacobson IM Brown RS Jr.Interferon monotherapy for dialysis patients with chronic hepatitis C: an analysis of the literature on the efficacy and safety. Am J Gastroenterol 2003;98(7):1610-5.  Back to cited text no. 8    
9.9. Degos F, Pol S, Chaix ML, et al. The tolerance and efficacy of interferon-alpha in haemodialysis patients with HCV infection: a multicentre prospective study. Nephrol Dial Transplant 2001;16(5):1017-23.  Back to cited text no. 9    
10.Editorial. Chronic hepatitis C and normal ALT, consideration for treatment .Am J Gastroenterology 2004;99:1706-7.  Back to cited text no. 10    
11.Roth D. Hepatitis C Virus: the nephrologist's view. Am J Kidney Dis 1995;25:3-16.  Back to cited text no. 11  [PUBMED]  
12.Espinosa M, Martin-Malo A, Alvarez de Lara MA, Aljama P. Risk of death and liver cirrhosis in anti-HCV positive long-term haemodialysis patients. Nephrol Dial Transplant 2001;16(8):1669-74.  Back to cited text no. 12    
13.Morales JM, Campistol JM. Transplantation in the patient with hepatitis C. J Am Soc Nephrol 2000;11:1343-53.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Kamar N, Toupance O, Buchler M, et al. Evidence that clearance of Hepatitis C Virus RNA after alpha interferon therapy in dialysis patients is sustained after renal transplant­ation. J Am Soc Nephrol 2003;14: 2092-8.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Casanovas-Taltavull T, Baliellas C, Benasco C, et al. Efficacy of interferon for chronic hepatitis C virus -related hepatitis in kidney transplant candidates on hemo­dialysis: results after transplantation. Am J Gastroenterol 2001;96(4):1170-7.  Back to cited text no. 15    
16.Huraib S, Tanimu D, Romeh SA, et al. Interferon-alpha in chronic hepatitis C infection in dialysis patients. Am J Kidney Dis 1999;34(1):55-60.  Back to cited text no. 16    
17.Daugirdas JT, Blake PG, Ing TS. Handbook of Dialysis. 3 rd Edition. Lippincott Williiams&Wilking. Page 504.  Back to cited text no. 17    
18.Umlauft F, Gruenewald K, Weiss G, et al. Pattern of hepatitis C vireamia in patients receiving hemodialysis. Am J Gastroenterol 1997;92(1):73-8.  Back to cited text no. 18    
19.Huraib S, Al-Rashed R, Aldrees A, Aljefry M, Arif M, al-Faleh FA. High prevalence of and risk factors for hepatitis C in hemodialysis patients in Saudi Arabia: a need for new dialysis strategies. Nephrol Dial Transplant 1995;10:470-4.  Back to cited text no. 19    
20.Teta D, Luscher BL, Gonvers JJ, Francioli P, Phan O, Burnier M. Pegylated interferon for the treatment of hepatitis C virus in haemodialysis patients. Nephrol Dial Transplant 2005;20:991-3.  Back to cited text no. 20    

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Correspondence Address:
Mahdia Buargub
Consultant Physician, Tripoli Central Hospital, P.O. Box 83478, Tripoli
Libya
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PMID: 16970253

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    Tables

  [Table - 1], [Table - 2], [Table - 3]

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    Abstract
    Introduction
    Patients and Methods
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    Definitions
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