| Abstract|| |
Background: Chronic hepatitis B (CHB) in Oman is similar to the Mediterranean Region with significant number of HBeAg negative patients. Interferon therapy is less effective in these patients and lamivudine is an alternative treatment. Patients and Methods: Thirty patients (16 HBeAg positive), who received lamivudine were studied retrospectively over 27 months. End of treatment (after 52 weeks) and sustained responses were analyzed for both HBe-antigen positive and negative patients. Results: Of the thirty patients, who received lamivudine, 22 patients (73%) completed 52 weeks therapy. Eight patients had previously received interferon treatment. The overall end-of-treatment (ET) biochemical response was 81.8% and virological response was 45%. Among patients who were HBeAg positive and HBeAg negative, similar proportion of patients achieved end-of-treatment biochemical responses (80% Vs 83.3%) and virological responses (40% Vs 50%) respectively. Sustained biochemical and virological response was achieved in four patients, two each in both groups. Of the nine patients currently receiving treatment, six of them had normalization of ALT and two had undetectable HBV DNA. Conclusion: Almost 50% of patients with CHB in Oman have HBeAg negative hepatitis. Therapy with lamivudine is effective in both HBeAg positive and negative cases
Keywords: Chronic hepatitis B, therapy and lamivudine
|How to cite this article:|
Upadhyay Dip AP, Radhakrishnan SP, Dhar A, Khashoub MB, Al Busaidi SM, Mohan AN, Al Zubaidi G. Treatment of chronic hepatitis B in Oman experience with lamivudine. Saudi J Gastroenterol 2003;9:69-74
|How to cite this URL:|
Upadhyay Dip AP, Radhakrishnan SP, Dhar A, Khashoub MB, Al Busaidi SM, Mohan AN, Al Zubaidi G. Treatment of chronic hepatitis B in Oman experience with lamivudine. Saudi J Gastroenterol [serial online] 2003 [cited 2020 May 31];9:69-74. Available from: http://www.saudijgastro.com/text.asp?2003/9/2/69/33366
Chronic infection with hepatitis B virus (HBV) is estimated to affect 350 million people worldwide and is a major public health issue  . The prevalence of HBeAg positivity is 5% among healthy blood donors in Oman and it was 7% in a sample of 605 women visiting antenatal clinics in six health institutions in the year 2000. Among those only 0.5% were positive for hepatitis Be Antigen (HBeAg)  .
Chronic hepatitis B (CHB) in the Mediterranean Asian region is characterized by predominance of HBeAg negative CHB where the infection is acquired at birth or early childhood leading to chronic sequelae in adulthood , . The disease pattern of HBeAg negative CHB compared with the HBeAg positive CHB seen in the West is different, with a poor response and greater relapse after treatment with interferon  . Response to therapy with lamivudine, a nucleoside analogue, approved for treatment of CHB in 1998, is encouraging although, several issues regarding duration of treatment, drug resistance and relapse need to be clarified  . In this report we present our experience in treating chronic hepatitis B with lamivudine in Oman, with particular emphasis on the comparison of HBeAg positive and HBeAg negative patients.
| Patients and methods|| |
This is a retrospective study and data were collected from the computerized hospital records of adult patients treated for chronic hepatitis B, from May 2000 to August 2002 in Oman. Royal Hospital is a tertiary referral center, and patients were referred after initial assessment by general physicians. All patients were evaluated and treated in accordance with the protocol adopted by our department [Figure - 1] based on standard guidelines and common practice , . Briefly, the inclusion criteria were adults between 16 and 60 years of age, seropositive for HBsAg for at least six-months period before enrollment, serum alanine aminotransferase (ALT) values more than 1.3 upper limit of normal (ULN), and measurable HBV-DNA in the serum by hybridization/ quantitative PCR/ branched chain DNA assay. Patients were excluded from treatment if they were aged less than 16 or over than 60 years, had advanced liver disease (Child's class B or C), had co-infection with HIV or HCV, ongoing alcohol abuse, pregnancy, hepatocellular carcinoma (HCC), or autoimmune disease.
HBV DNA was defined as positive if the following values were obtained: >105 copies/ml by quantitative PCR; values > 2.5 pg/ml by hybridization method; values > 0.7 meq/ml by branched DNA assay. Pretreatment liver biopsy was done in 15 patients.
All patients were treated with lamivudine 100 mg daily for 52 weeks. Patients who had earlier failed or relapsed after treatment with IFN were also included. Patients who did not respond to the standard duration of treatment with lamivudine or those who relapsed after stopping the 52-week course, were offered long-term treatment for periods up to 48 months ,, . Exceptions were made for one post liver transplant patient, one patient who had HBV induced polyarteritis nodosa (PAN), and one with HBV related vasculitis who received long-term therapy on a continuous basis.
Patients were assessed every 8-12 weeks till week 52 and thereafter every 3-6 months; liver function tests were carried out at each visit, and serological and virological assays were carried out at week 52 and week 76. Liver biopsy was done for all patients who agreed for the same but assessment of histological response by follow-up liver biopsy was not a part of this study.
All patients were evaluated for biochemical response (normalization of ALT), serological response (loss of HBeAg; where applicable) and virological response (DNA undetectable by hybridization method or < 10' copies/ml by quantitative PCR). Responses were designated as end-of-treatment (at week 52), or sustained (at week 76). Breakthrough infection for those receiving lamivudine is defined as reappearance of HBV DNA after its initial disappearance. Recurrence of rise in ALT or flares of ALT while on active treatment may serve as markers for breakthrough infection and this was monitored in all patients , Genetic analysis for YMDD mutation is not available in Oman.
| Results|| |
Thirty patients were evaluated and their demographic profile is shown in [Table - 1]. Of these 22 patients (73%) completed 52 weeks of treatment with lamivudine and were included for analysis. Eight patients had received Interferon and either did not respond, or suffered a relapse.
They received lamivudine and are included in this study. Overall, at the end of treatment normalization of ALT was observed in 18/22 (81.8%) patients and a virological response was noted in 10 (45%) patients.
Of the tern patients, who had adequate length of follow-up after end of treatment, six (60%) suffered a relapse (elevation of ALT and detectable HBV DNA). Four (40%) patients had sustained biochemical and virological response. Nine patients are currently receiving ongoing long-term treatment (6 relapsers, 3 naive); six (66.6%) have a normal ALT and two have undetectable viral DNA. None of these patients have so far been noted to have a breakthrough rise of ALT on continued treatment of duration up to 48 months. One patient with cirrhosis (Child's A), decompensated while on therapy. Sixteen patients were HBeAg positive, of which ten (62.5%) completed 52 weeks treatment. At the end of treatment eight (80%) had normal ALT and four (40%) had loss of DNA. One patient had loss of HBeAg and seroconverted. Sustained biochemical and virological response was noted in two patients.
Fourteen patients were HBeAg negative and 12 (85.7%) had completed the course of treatment. End of treatment biochemical response was noted in ten (83.3%) and virological response in 6 (50%). Two patients had a sustained biochemical and virological response.
Lamivudine was well tolerated by all patients without any serious adverse effects. There were no deaths during the study and no patient discontinued the drug on account of side effects. There was no ALT flare up during the use of lamivudine, although one patient had development of ascites on treatment; this was recorded as decompensation.
| Discussion|| |
The prevalence and pattern of chronic HBV infection in Oman seems to be similar to that observed in the Mediterranean-Asian region, with intermediately high carrier rates of 2%-7% in the population  . HBeAg negative hepatitis constitutes the major part of CHB in Oman. A survey of 605 pregnant women seen in antenatal clinics of six health institutions in Oman in the year 2000, showed a 0.5% HBeAg positivity among those positive for HBsAg  . Recent reports from the Far-East estimate that prevalence of HBsAg negativity in chronic HBV infection ranges between 70% and 100% ,,,,, However, only a minority (15% to 30%) among these will have elevation of ALT, suffer from CHB and require antiviral treatment, while an elevated ALT is seen in 80% of HBeAg positive patients ,, In the present report 46.6% of those who received treatment were HBeAg negative. As in other reports from the region, patients with HBeAg negative CHB are older compared to those with HBeAg positive CHB with male preponderance ,, Most of the patients were asymptomatic and were detected incidentally during blood donation or routine medical check-ups. The source of HBV infection was unknown for the majority 19/22 (86.3%) cases and this is most likely to be due to intrafamilial acquisition of HBV in early life 
The choice of therapy in CHB needs to be tailored to the individual patient and either interferon or lamivudine can be used as the first line of therapy  .
Treatment should therefore be guided by factors such as likelihood of response to therapy, compliance, cost and ease of follow up. The advantages of interferon-alpha are that it is given for a limited period, antiviral resistance does not develop, and quality and durability of response are excellent. However, it is expensive, has significant side effects, requires uncomfortable injections, needs to be stored under specified conditions and may not be appropriate in certain subgroups of patients such as pre-core mutant virus infection, recipients of solid organ transplants, and immunosuppressed patients ,, . Lamivudine is easy to administer, safe and effective in subgroups where IFN is either ineffective, unsuccessful or contraindicated 
In this study, eight patients had received IFN- alpha initially without sustained response, while 22 were naive. The overall end-of-treatment biochemical response rate was 81.8%. Lowering of HBV DNA levels to <105 copies/ml was seen in 45% at end-of treatment evaluation. Sustained biochemical and virological response was noted in 40%, while there was a 60% relapse after a mean follow-up of 10.66 months. Histological response was not studied. Responses were similar for both HBeAg positive and HBeAg negative patients. Our results are similar to the recent literature, where treatment with lamivudine is associated with a median 4-log decrease of HBV DNA (with undetectable levels in 44%) followed by improvement in ALT (in approximately 41 %) after one year of therapy. However, relapse rates of up to 50% have been reported ,. Response is sustained in those who either develop HBeAb (73%), or those who lose HBeAg (81%-86% in the west, 73% in Asia),In HBeAg positive patients, a high ALT level and histological activity index are predictors of a good response to lamivudine, including loss of HBeAg. In a recent study, the loss of HBeAg was highest with pretreatment ALT values >5 times ULN and it was moderate for ALT values between 2-5 times ULN; in our study, eight of 16 HBeAg positive patients had ALT values <2 times ULN and therefore a low loss of HBeAg is expected  . In patients with HBeAg-negative CHB, 65% of patients are reported to have normal ALT and undetectable DNA after one year of therapy, but relapses are common and majority of the patients (74%) have elevated ALT with resurgence of HBV DNA after long term follow-up ,,,. Thus the pattern of response to lamivudine appear to be similar for both the groups of patients and, while most patients respond to treatment, relapse on long term follow up is a common occurrence.
Several factors have been identified that help predict a response to lamivudine. High levels of ALT at the beginning of treatment, duration of therapy. low DNA levels predict a response while high levels of DNA correlate with increased rates of resistance ,, Lamivudine is effective even in patients with co-morbid conditions like HIV co-infection, chronic renal failure, post-renal and liver transplant,
In conclusion, we have found that in the Middle Eastern population in Oman, lamivudine is a safe and effective treatment for both HBeAg positive and HBeAg negative patients with CHB, over 52 weeks.
However, several issues remain to be studied further and the cohort of CHB patients is now being prospectively followed up for durability of response, relapse rates, YMDD mutants and histological improvement.
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Ghazi Bin Omer Al Zubaidi
Department of Gastroenterology, Royal Hospital, P O. Box 1331, PC 111, Seeb, Sultanate of Oman
Source of Support: None, Conflict of Interest: None
[Figure - 1]
[Table - 1], [Table - 2]