Hepatitis B viral breakthrough associated with inappropriate preservation of entecavir.

If virologic breakthrough is observed during chronic hepatitis B treatment, drug resistance or compliance problem should be considered. But in some cases, breakthrough depends on drug preservation conditions. We report the case of a 30-years-old man, who experienced viral breakthrough due to wrong preservation conditions of the drug.

Introduction

Hepatitis B virus (HBV) is a partially double spiral type DNA membrane virus. Globally, approximately over 400 million individuals are infected with hepatitis B. HBV is known as one of the most important carcinogens. Every year, over one million individuals die due to HBV-related causes.[1]

Primary objective in hepatitis B treatment is to improve clinical and histological progression and to provide virus eradication. For many years, interferon, lamivudine, adefovir, telbevudine, entecavir and tenofovir were used in treatment of hepatitis B. Entecavir and tenofovir are potent antiviral drugs. The treatment with these drugs leads to normalization in liver enzymes, improvement in liver histology, HBsAg and HBeAg loss and undetectable HBV DNA levels.[2-4] Elevation of the decreased HBV DNA during treatment is attributed to drug resistance or noncompliance.[5]

Case Report

A 30-years-old man, a marketer by profession, had been diagnosed with hepatitis B infection for 10 years. His laboratory values were HBsAg (+), HBeAg (-), Anti-HBe (+), HBV-DNA: 123.000.000 IU/ml, ALT:160 U/L,AST:120 U/L. In liver biopsy with modified Ishac scoring system,[67] hepatitis activity index was 13 and fibrosis score was 5. According to those findings, entacavir 0.5 mg 1×1/ day was initiated.

In the third month of the treatment, HBV DNA levels declined at 1200 IU/ml, ALT was 44 U/L, AST was 48U/L. In the ninth month of the treatment, HBV DNA levels were increased to 26,000 IU/ml, ALT was 61 U/L. In this period, patient's compliance was investigated. It was observed that the patient had taken the drugs regularly in recommended dose and duration. Entecavir resistance can be investigated by molecular methods.[8] In this patient, it was investigated by determination of surface and polymerase gene mutations method. No mutation was found. The test was repeated twice. Patient's compliance was investigated once more. The patient was requested to inform how and under which conditions he has taken the medication and where the drugs were preserved. The patient was a marketer by profession and used to spend 2/3 part of the day in his car. To avoid missing the medication dose, he had preserved the drug in the car. In the month of August, the atmospheric temperature was high (40–50°C) and therefore the drug was degenerated and lost its activity as a result of inappropriate preservation. It was recommended to continue the therapy with appropriate drug preservation. After three months of following this recommendation, patient's HBV DNA levels were regressed to 200 IU/ml ALT: 26 U/L and AST:26 U/L’ [Table 1].

Table 1

Follow-up laboratory results of patient suffering from hepatitis B viral breakthrough

Discussion

In some cases treated with hepatitis B treatment even though ALT level are found to be normal, resistance is considered if one log elevation is observed in HBV DNA levels. Hence, treated cases were recommended to be followed up with estimation of HBV DNA. Hence, regular HBV DNA follow-up is required during antiviral therapy. If one log elevation is observed in HBV DNA levels, this should be confirmed by repeating the test. In those cases, if treatment compliance was found and the doses were appropriate, anti-viral resistance should be examined.[9]

In this case, we could detect neither noncompliance nor drug resistance. Despite this, there were elevations in the HBV DNA level and in ALT, AST levels. Because of the negative results of the compliance and resistance tests, alternative etiologies were searched. Further investigation showed that the patient failed to preserve the drug in appropriate conditions. Proper preservation of the drugs is as important as taking them in suitable doses and at appropriate time in terms of treatment outcome.[10] According to the manufacturing firms, the drug requires to be preserved under 35°C, away from excess heat, light and moisture.[11] Our patient preserved the drug in the car. In summer, heat levels inside waiting cars probably exceed the prescribed limits for preservation and therefore the drug degenerates. This may lead to viral breakthrough. Entecavir should not be preserved at very low or high temperature and should be avoided from exposure to moisture and direct sun light.[12]

The author therefore suggests that when the response to antiviral treatment is not obtained, patient compliance as well as drug preservation conditions should be examined, and patient should be counseled to preserve the drug at requisite temperatures at all times.