Saudi Journal of Gastroenterology
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Year : 2003  |  Volume : 9  |  Issue : 3  |  Page : 129-134
Interferon-ribavirin therapy for chronic hepatitis C: Efficacy in Saudi patients


1 Department of Gastroenterology, Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia
2 Department of Pathology, Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia

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Date of Submission06-Oct-2002
Date of Acceptance09-Apr-2003
 

   Abstract 

Background: Hepatitis C affects 2% of Saudi population. Previous local trials showed low response to interferon monotherapy for six-months. Aim: To evaluate biochemical and virological response of interferon-ribavirin combination on naive Saudi patients infected with HCV. Methods: A prospective single armed study was conducted at Riyadh Armed Forces Hospital from July 1999 to July 2002 for fifty patients who have hepatitis C virus (HCV-PCR) positive and chronic hepatitis on liver biopsy were started on the combination therapy for one­year. All had HCV-PCR at the end of therapy and at six months follow-up. Results: Thirty-one patients (62%) normalized their ALT levels, and 25 patients (50%) became HCV-PCR negative achieving end-of-treatment response (ETR). The sustained virological response (SR) was achieved in 19 patients (38%) at six months follow-up after stopping the treatment. Side effects were mainly flu like syndrome in 36 patients (72%). Conclusion: Combination therapy of interferon alfa-2b plus ribavirin is an effective treatment modality for HCV infected Saudi patients, with tolerable side effects. Our virological response rates are compatible with international published literatures

Keywords: Chronic hepatitis C, interferon, ribavirin.

How to cite this article:
Sandokji AM, Sanai FM, Al-Ajlan AA, Al-Karawi MA. Interferon-ribavirin therapy for chronic hepatitis C: Efficacy in Saudi patients. Saudi J Gastroenterol 2003;9:129-34

How to cite this URL:
Sandokji AM, Sanai FM, Al-Ajlan AA, Al-Karawi MA. Interferon-ribavirin therapy for chronic hepatitis C: Efficacy in Saudi patients. Saudi J Gastroenterol [serial online] 2003 [cited 2020 Oct 23];9:129-34. Available from: https://www.saudijgastro.com/text.asp?2003/9/3/129/33354


Hepatitis C is an important cause of chronic hepatitis and continues to dominate current issues of evolving therapy. Almost 200 million people worldwide are affected by hepatitis C virus (HCV) infection, which is one of the main causes of chronic liver diseases. Chronic liver disease secondary to HCV is currently the most common indication for liver transplantation [1] . Approximately 80% of patients infected with this virus will develop chronic hepatitis [2] . Presence of chronic hepatitis is associated with a progressive liver disease that may evolve insidiously to cirrhosis and carries an increased risk of hepatocellular carcinoma. Interferon-alpha is the first drug approved for treatment of patient with HCV.

Hepatitis C is common in the Saudi population, with almost 2% of the population being infected with the virus [3],[4],[5] . Epidemiological surveys have shown that genotype 4 is the most common HCV genotype prevalent amongst the Saudi carriers [6] .

Previous local study showed poor biochemical response to interferon alpha Monotherapy at 3million units three times a week for 24 weeks [7] . In another trial by Al-Faleh et al using interferon alpha at higher dose 5 million units three times a week for 24 weeks in HCV genotype 4 patients, the sustained response rate was 16% [8] .

In a meta-analysis of interferon-alpha-2b trials, it is been noted that the higher the dose and the longer the duration of treatment the higher the sustained response [9] . In vitro studies by Hayden and colleagues [10] suggest that ribavirin combined with interferon-alpha have additive or synergistic antiviral effect on RNA virus replication. Clinical trials on this combination were undertaken and has showed an improvement in the rate of sustained virological response and the associated long-term benefits. [11],[12],[13],[14]

On this background, we undertook a study to determine the efficacy and safety of combined interferon alpha and ribavirin therapy in patients infected with hepatitis C virus.


   Patients and Methods Top


Adult patients with ages rangel8-60 years, who received no prior therapy and had been infected with Hepatitis C virus (HCV) have been enrolled in the study. All patients were positive to anti-HCV antibodies as determined by enzyme linked immunosorbent assay second generation (ELISA II) and confirmed by recombinant immunoblot assay third generation (RIBA III). All patients had detectable levels of HCV RNA in the serum by reverse transcription polymerase-chain-reaction (PCR) (Roche Amplicor®) with a lower limit of HCV-RNA detection of 100 copies/mL, and had elevated levels of alanine aminotransferase (>40 IU/L). HCV genotyping and viral load were not performed because of technical reasons. Liver biopsy was done prior to initiation of treatment. The minimum hematological values (hemoglobin > 12 gm/dL for females, > 13 gm/dL for males; white blood cells count > 3,000/mm 3, neutrophil count > 1,500/mm 3 , platelets > 100,000/mm 3 ) and biochemical values correlating with normal bilirubin, albumin and creatinine levels were considered as strict inclusion criteria. All patients were evaluated for the presence of antinuclear antibodies (ANA) and criterion for inclusion included titers of < 1:160. Patients were excluded from the study if there was evidence of decompensated cirrhosis, serum α-fetoprotein concentration of more than 50µg/L, HIV, HBV infection, previous organ transplantation, psychiatric disease, seizure disorder, serious cardiovascular disease and other co-morbid diseases like uncontrolled diabetes or autoimmune disease, ongoing substance abuse and when the patients were unable to use contraception. Patients were also excluded if they had evidence of other causes of liver disease.

This was a prospective single armed study undertaken at the Riyadh Armed Forces Hospital, Saudi Arabia. The ethics committee of the hospital approved all aspects of the study and all patients provided informed consent. The patients were given Interferon-alfa-2b (Intron A®) 5 million units three times a week (TIW) subcutaneously and oral ribavirin (rebitol®) at 1000mg ( < 75 kg body weight) or 1,200mg ( > 75 kg body weight) in two divided doses a day for a 12-month period. Ribavirin dosages, which have been adopted based on international recommendation [15] . Hepatitis C virus, polymerase-chain reaction has been performed pre treatment and during the treatment period at 6 t1i 12th and 18th month. Biochemical, hematological and virological testing was performed at the study center. All patients had initiation of treatment as in­patients and discharged home after 24 hours observation. Then subsequent followed-up in the outpatient clinics has been scheduled at 1 st , 2 nd and 4 th week after initiation of treatment within which 4­weekly intervals have been scheduled until treatment was discontinued and then 24 weeks thereafter. Each visit involved hematological and biochemical assessment including liver function tests (LFT). Thyroid function testing (TFT) was performed at baseline, 3rd 6th and 12th month of treatment.

Non-hematological and non-biochemical toxicity were graded according to W.H.O. toxicity grading scale [16] as mild, moderate, severe and life threatening. For severe events, the dose of interferon alfa-2b and ribavirin was decreased by 50%. The original doses were restarted once the adverse event remitted. If the event persisted in spite of dose reduction, then the medications were permanently discontinued. Therapy was permanently discontinued for life-threatening events.

Hematological and biochemical toxicities were monitored according to W.H.O. toxicity grading scale [16] . Interferon-alpha was reduced by 50% if white blood cell (WBC) < 1.5x109/L or granulocytes < 0.75x109/L or plate lets < 50x109/L and discontinued if WBC < 1x109L or granulocytes < 0.5x109/L or platelets < 25x109/L. Ribavirin dose was reduced by 50% if hemoglobin levels < 10 g/dL and discontinued if the hemoglobin levels < 8.5 g/dL.

The primary end point was sustained virological response (SR) defined as undetectable HCV RNA in serum at the end of the follow-up period of six months. Secondary end points were the normalization of serum ALT levels and the absence of detectable serum HCV RNA levels at the end of therapy, termed as end-of-treatment response (ETR). Analyses have been performed on the whole treatment group irrespective of their duration of treatment, using SPSS 10.0 statistical program.


   Results Top


Initial evaluation was carried out on 52 patients who tested positive for anti-HCV antibodies, with detectable level of HCV-RNA and had raised liver enzymes. From this one patient tested positive for HBsAg. One patient failed to follow-up after satisfying initial screening tests before starting treatment. Subsequently, 50 patients were included in the study after satisfying all screening and inclusion criteria. Enrollment began in July 1999 and the trial ended in June 2002. The efficacy and safety analyses have been determined on the 50 patients on intent to treat basis i.e. on those who received at least one dose of the medication. [Table - 1] shows the patient's characteristics. Of these 29 were male and 21 female and the age range was 27-60 years (mean 46 years). None of the patients have ANA titer > 1:160. One pathologist reviewed the liver biopsies using Ishak scoring system [17].

[Table - 2] shows the number of patients in different stage and grade. In stage 1 and 2 (minimal fibrosis) there were 37/50 (74%), and there were three patients with cirrhosis.

The spectrum of side effects is shown in [Table - 3]. There were no cases of deterioration in synthetic liver function during the course of the therapy or in the follow-up period. There was no significant decrease in the platelet count during the therapy of the 50 patients studied on an intent-to-treat basis, but three patients were dropped from the study because of side effects encountered during the first four weeks of therapy.

One patient developed severe neutropenia after the 2nd interferon dose and his treatment had to be discontinued. Another patient developed skin necrosis at the injection site within the first four weeks and after discontinuation of therapy, the lesion rapidly healed. The last patient developed schizophrenic symptoms and required termination of therapy. His behavioral symptoms improved with treatment withdrawal and commencement of anti­psychotic medication.

Thyroid function was monitored and 2/50 (4%) developed hypothyroidism required thyroid replacement, and 1/50 (2%) developed hyperthyroidism required therapy with anti-thyroid medication, discontinuation of combination therapy was not required. Therapy was otherwise well tolerated in all other patients who continued on the treatment. None of the 47 patients who completed therapy required a dose modification.

At the end of follow-up, SR was seen in 19/50 (38%). There were no cases of late virological response and all the patients that showed response did so in the first six months. ETR was seen in 25/50 (50%). Whereby four patients relapsed on follow-up, one patient had break-though- i.e. initially became HCV RNA negative at six months but regained the virus at the end of a 12-month of therapy, and one patient who was cleared of the virus at 12 months died in a car accident soon after. The calculated relapse rate was 10% (5/50). [Table - 4] shows the biochemical and hematological effects. The mean ALT levels were 120 before treatment and 40 at the end of treatment with P value <0.005.Thirty-one/50 (62%) normalized their ALT levels at the end of follow up. Seventeen /19 patients (89.5%) with SR had normalization of serum ALT levels.

The liver biopsy scoring for the responders is shown in [Table - 5]. There were 15/19 SR (78.9%) having minimal fibrosis.


   Discussion Top


Interferon-alpha has become the cornerstone in the management of HCV infection. There are host factors and treatment factors influencing the SR in HCV population. The host factors include age <40, female gender, low HCV-RNA viral load, genotype 2 and 3, minimal fibrosis on liver biopsy and short duration of infection. The treatment factors include higher dose interferon, combination with ribavirin, longer duration of treatment and longer interferon half life [18] .

The current treatment standard for chronic HCV infection is interferon-alpha in combination with ribavirin. The over all rates of SR with this regimen in international trials are approximately 43­ 47% [19],[20] . However, studies in Saudi Arabia, has shown a low response rate to interferon monotherapy. The possible reasons for this low response are the high percentage of patients with cirrhosis in these trials, long infection interval, high percentage of patients with genotype 4, poor drug compliance and using monotherapy [7],[8] . In general these factors are well known to predict low SR. In our prospective study, using combination therapy (interferon-ribavirin) for one-year, we report a sustained virological response of 38%, which is higher than the reported local trials. Among the reasons for this result is the lower number of cirrhotics in our patient population (74%) having minimal fibrosis.

Another reason is using higher dose of interferon at 5MU, in fact the effect of different doses of interferon was assessed in four studies, and among the patients, who had received higher than 3MU ETR was 61% compared to 52% in those received 3MU, and SR was 28% compared to 19% [9] . The third reason for having this result is the use of combination therapy with ribavirin, in the first randomized, double blind, placebo-controlled study of interferon/ribavirin versus interferon/placebo, the SR was 45% versus 23%, this was confirmed with several trials [21],[22] .

In our study we noted that the longer duration of therapy may not be a factor to achieve a better response because the patients who did not respond by six months of treatment did not respond later on, but it may be a factor in conjunction with ribavirin to achieve low relapse rate, which was about 10% in this study.

Side effects are more frequent among patients who receive the combination therapy for which treatment has to be monitored very carefully. Ten per cent of patients receiving ribavirin will develop a dose­dependent, reversible, intravascular, hemolytic anemia, with an average fall in hemoglobin of 2-3 g/dl in the 1 st 4 -8 weeks of therapy [23] , in our study this was encountered in 4%, which was transient and did not require dose modification.

Interferon-alpha is known to cause significant side effects; the estimated common side effect of interferon at > 5MU is flu-like symptoms 76%, leucopenia 13%, depression 10%, discontinuation of therapy 5% and thyroid abnormality 2% these estimated side effects are more or less equal when interferon dose is 3MU except for the flu like symptoms, which is 41% [24],

Fortunately, tachyphylaxis develops after the first or second injection, and these symptoms abate within the first and the second weeks of therapy. Although our side effect profile is within the acceptable range, drug induced toxicity is a major concern in the short and long-term safety and cost. In view of the low rate of cure of HCV infection, the pharmaceutical industries have provided us with several types of interferon (alpha-2a, alph-nl, consensus interferon) and for each one several clinical trials have been conducted. The most recent development in this field is the formulation of the long acting pegulated-interferon, which has very promising results in achieving higher response rate with less relapses [25].

There are on going multicenter trials comparing the efficacy of combination interferon ribavirin versus the combination of PEG-interferon/ribavirin in patients infected with HCV in Saudi Arabia

Until these trials are over we recommend the use of interferon/ribavirin combination therapy for patients with chronic HCV.

Acknowledgement: We would like to thank Schering Plough Co. for supporting by research grants and Miss Thelma Monserate for participating in data collection.

 
   References Top

1.Detre KM, Belle SH, Lombardero M. Liver transplantation for chronic viral hepatitis. Viral Hepatitis Rev 1996; 2: 219-28.  Back to cited text no. 1    
2.National Institutes of Health. Consensus Development Conference Panel statement: management of Hepatitis C. Hepatology 1997; 26: 2­-10.  Back to cited text no. 2    
3.Saeed AA, Fairclough D, Al-Adamawi AM, et al. Hepatitis C virus in Saudi Arabia: A preliminary survey. Saudi Med J 1990; 11: 331-32.  Back to cited text no. 3    
4.Al-Faleh FZ, Ramia S, Arif M, et al. Profile of Hepatitis C virus and the possible modes of transmission of the virus in the Gizan area of Saudi Arabia: a community-based study. Ann Trop Med Parasitol 1995; 89: 43 1-7.  Back to cited text no. 4    
5.Al-Faleh FZ. Hepatitis C infection: An update. Saudi J Kidney Dis Transplant 1995; 6: 118-21.  Back to cited text no. 5    
6.AI-Faleh FZ, Huraib S, Sbeih F, et al. Hepatitis C virus genotypes in chronic liver disease and hemodialysis patients from Saudi Arabia. J Viral Hepatitis 1995; 2: 293-6.  Back to cited text no. 6    
7.Al-Karawi MA, Ahmed AM, Yousuf M, et al. alfa­interferon in the treatment of chronic hepatitis C viral infection (CHCV): a pilot study of 18 patients. Ann Saudi Med 1994; 14: 464-6.  Back to cited text no. 7    
8.Al-Faleh FZ, Sbeih F, Al-Karawi MA, et al. Treatment of chronic hepatitis C genotype 4 with alfa interferon in Saudi Arabia: a multicenter study. Hepato-Gastroenterology 1998, 45: 488-91.  Back to cited text no. 8    
9.Carithers R.jr and Emerson S. Therapy of Hepatitis C: Meta-analysis of Interferon Alfa-2b Trials. Hepatology 1997; 26: 83-8.  Back to cited text no. 9    
10.Hayden FG, Schlepushkin AN, Pushkarshava NL. Combined interferon alfa, rimantidine hydrochloride, and ribavirin inhibition of influenza virus replication in vitro. Antimicrob Agents Chemother 1984: 25: 53-­7.  Back to cited text no. 10    
11.Reichard O, Yun ZB, Sonnerborg A Weiland O. Hepatitis C viral RNA titers in serum prior to, during and after oral treatment with ribavirin for chronic hepatitis C. J Med Virol 1993; 41: 99-102.  Back to cited text no. 11    
12.Brillanti S, Garson J, Foli M, et al. A pilot treatment of combination therapy with ribavirin plus interferon for interferon alfa resistant chronic hepatitis C. Gastroenterology 1994; 107: 812-17.  Back to cited text no. 12  [PUBMED]  
13.Schalm SW, Hansen BE, Chemello L, et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C: meta-analysis of individual patient data from European centers. J Hepatol 1997; 26: 961-6.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339: 1485-92.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Olle R. Robert S. Ola W. Therapy of Hepatitis C: Alpha Interferon and Ribavirin. Hepatology 1997; 26: 108-11.  Back to cited text no. 15    
16.World Health Organization. W.H.O. Handbook for reporting results of cancer treatment. Geneva: WHO publication 1979: 38.  Back to cited text no. 16    
17.Ishak K, Baptista A, Bianchi L et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696-9.  Back to cited text no. 17    
18.Sleisenger & Fordtran's Gastrointestinal and Liver Disease 6` h Edition. In Viral hepatitis A through G. edited by M. Feldman, B. F. Scharschmidt, M. H. Sleisenger, Pennsylvania, W. B.Saunders press 1998: 1123-70.  Back to cited text no. 18    
19.Chemello L, Cavaletto L, Bernardinello E, Guido M, Pontisso P, Alberti A. The effect of interferon alfa and ribavirin combination therapy in naive patients with chronic hepatitis C. J Hepatol 1995; 23: 8-12.  Back to cited text no. 19    
20.Lai M, Kao J, Yang P, et al. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology 1996; 111: 1307-12.  Back to cited text no. 20    
21.Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352: 1426-32.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Reichard O, Norkran G, Fryden A et al. Alfa­interferon and ribavirin versus Alfa-interferon alone as therapy for chronic hepatitis C: A randomized, double-blind, placebo-controlled study (Abstract). Hepatology 1996; 24: 356.  Back to cited text no. 22    
23.McHutchiaon JG, Hoofnagle JH. Biomedical research reports I st edition. In Hepatitis C. edited by TJ Liang and JH Hoofnagle. London.; Academic Press, 2000: 203-39.  Back to cited text no. 23    
24.Poynand T, Leroy V, Cohard M et al. Meta-analysis of interferon randomized trial in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996; 24: 778-89.  Back to cited text no. 24    
25.Mann MP, McHutchinson KG, Gordon SC, et al. Peginterferon alfa-2b in combination with ribavirin compared to interferon alfa-2b plus Ribavirin for initial treatment of chronic hepatitis C: results of randomized trial. Lancet 2001; 358: 958-65.  Back to cited text no. 25    

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Correspondence Address:
Abdulkareem Mohammad Sandokji
Department of Medicine, Riyadh Armed Forces Hospital, P 0. Box 7897, Riyadh 11149
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


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