Hepatitis B viral infection: Questions and comments

1-A 22-year-old man diagnosed with hepatitis B on routine blood tests. He is asymptomatic and has no past medical history of note. He is not currently on any medications and drink alcohol only socially. Clinical examination is normal. He has the following serology:

HBsAg (+),

HBeAg (+),

anti-HBe (-).

HBV DNA : 71.5 million copies/mL (approximately 14 million int. unit/mL)

Serum ALT is persistently in the range of 20 to 30 int. unit/L (upper limit of normal 40 int. unit/L).

Liver biopsy is essentially normal.

What is the best course of action?:

1-commence on PEG INF and RBV

2-Tenofovir

3-Enticavir

4-No treatment

5-F/U

Comment — Immune-tolerant phase 1. I would not treat this patient at this time although his HBV DNA level is high. He is very young, has no significant inflammation on liver biopsy and serum ALT that is normal (which predicts low probability of HBeAg seroconversion to both peginterferon and nucleos/tide analog).

Although antiviral therapy can decrease serum HBV DNA level in this patient, there is no evidence that treating this patient at this stage will improve clinical outcome. Given the low rate of HBeAg seroconversion (less than 5 percent after one year of treatment), this patient will need to receive treatment for many years and even decades to derive a clinical benefit.

The feasibility of achieving this goal must be balanced against the risk of drug resistance. It is also possible that this patient may undergo spontaneous HBeAg seroconversion during the next few years. Thus, I would follow this patient and recheck ALT every three to six months. If his ALT becomes more than two times normal, I would monitor him more frequently and recommend treatment if he does not spontaneously seroconvert after three to six months. I would biopsy this patient if he was 45 years old with similarly high HBV DNA level and consider treatment if HBV DNA level is persistently high or if there is moderate/severe inflammation and/or advanced fibrosis on biopsy.

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2- A 25-year-old Asian man presented unwell to his GP. Hep serology was done:

HBsAg (+)

HBeAg (+)

Serum HBV DNA of 700 million copies/mL (140 million int. unit/mL).

Liver Bx mild inflammation.

Serum ALT is 100 int. unit/L (upper limit of normal 40 int. unit/L).

What is the best course of action?:

1-Adenovir

2-Tenofovir

3-Entecavir

4-No treatment

5-F/U

Comment — This patient should be considered for therapy with entecavir, tenofovir, or pegylated interferon alfa. Lamivudine or telbivudine should not be used unless cost is a limiting factor. Adefovir at the approved dose has weak antiviral activity and has been superseded by tenofovir.

The degree of elevation of the serum ALT is particularly important in influencing the decision to treat HBeAg positive patients since it has proven to be one of the most important predictors of HBeAg seroconversion. In one study on lamivudine, for example, the rates of HBeAg seroconversion for patients with pretreatment ALT levels within normal, one to two times normal, two to five times normal, and more than five times normal were 2, 9, 21, and 47 percent, respectively.

As a general rule, we consider the degree of elevation of the serum ALT in three categories: normal, between one to two times normal, and more than two times normal. Treatment with any of the approved therapies is unlikely to be successful in achieving HBeAg seroconversion in those with normal or minimally elevated serum ALT. The degree of liver inflammation on liver biopsy is also useful in predicting treatment related HBeAg seroconversion. Increasing data indicate that presence of HBeAg and high serum HBV DNA, lasting four decades or longer, are associated with increased risks of cirrhosis, hepatocellular carcinoma, and liver-related deaths. As a result, treatment may also be considered in patients who remain HBeAg positive after the age of 40, regardless of ALT level.

For patients who are contemplating interferon treatment, a test for HBV genotype can be performed. Patients with HBV genotype A are more likely to achieve HBeAg as well as HBsAg seroconversion.

The pros and cons of various treatment options should be discussed with the patient. The main advantages of nucleos/tide analogues are their side effect profile and ease of administration.

The disadvantages of interferon are costs, side effects, and need for parenteral administration but the duration of treatment is finite and interferon is not associated with drug-resistant mutations. All of the oral agents can be considered as a first line therapy.

In a young patient like this, the concern is the adverse consequences of drug-resistant mutants and the possibility of more restricted treatment options in the future. Entecavir, despite its higher cost, may be a better first line therapy. Tenofovir would be a reasonable alternative in countries in which it has been approved. It is less expensive than entecavir but there is a small risk of nephrotoxicity. Given the young age of the patient, peginterferon should also be considered because of the finite duration of treatment.

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 3-A 20-year-old woman has the following hep B serology results:

HBsAg (+),

HBeAg (-).

HBV DNA is 1.2 million copies/mL (approximately 250,000 int. unit/mL).

Liver Bx mild portal inflammation, no fibrosis.

Serum ALT is 60 int. unit/L (upper limit of normal 40 int. unit/L).

What is the best course of action?:

1-commence on PEG INF and RBV

2-Tenofovir

3-Enticavir

4-No treatment

5-F/U

Comment — I would follow this patient without recommending treatment at this time. Although she has high HBV DNA, she is HBeAg negative, and is likely to be infected with a precore variant. All approved treatments: interferon, lamivudine, telbivudine, adefovir, entecavir, and tenofovir have a low rate of sustained response in such patients. Because she is young and has only mild histologic changes on liver biopsy, I think it is reasonable to observe her for the time being. A reasonable approach may be to repeat liver function tests every three to six months and consider performing a repeat liver biopsy in a few years.

The situation might be different if the patient is 60 years old, repeatedly had a serum ALT that is more markedly elevated or if she had moderate to severe inflammation or bridging fibrosis or cirrhosis on liver biopsy. Because HBeAg negative chronic hepatitis tends to run a fluctuant course, serial testing is needed and treatment should be recommended if she subsequently develops more marked ALT elevation. Entecavir, tenofovir, or interferon should be considered. Longer duration of treatment will be needed but the optimal duration is unknown as the end-point of treatment has not been defined. Because of the need for long-term treatment, lamivudine and telbivudine are less desirable. Tenofovir has replaced adefovir because of its more potent antiviral activity.

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4-A 24-year-old who has recently been admitted to dental school. He is HBsAg (+),

Full serology:

HBeAg (+),

anti-HBe (-).

HBV DNA is 400 million copies/mL (approximately 80 million int. unit/mL)

Serum ALT is 45 (upper limit of normal 40 int. unit/L).

Liver biopsy shows macrovesicular fat, no portal fibrosis.

The Dean of the dental school has denied his matriculation pending your advice.

 What is your advice:

1-commence on PEG INF and RBV

2-Tenofovir

3-Enticavir

4-No treatment

5-Advice career change

Comment — Recommendations are periodically issued by the Centers for Disease Control and Prevention (CDC) in the United States, the most recent of which were updated in 2012 . The CDC recommends that chronic HBV infection in itself not preclude the practice or study of medicine, surgery, dentistry, or allied health professions provided that the following criteria are met:

•               Healthcare providers and students who perform invasive exposure-prone procedures have oversight from an expert panel. The expert panel should include one or more persons with expertise in the provider's specialty, infectious disease and hospital epidemiology, liver disease, the infected provider's occupational health, student health or primary care clinicians, ethicists, human resource professionals, hospital or school administrators, and legal counsel.

•               HBV-infected providers can conduct exposure-prone procedures if a low or undetectable HBV viral load is documented by regular testing at least every six months. A threshold of 1000 int. unit/mL (5000 GE/mL) or its equivalent is an appropriate threshold. The assay used should have a detection capability as low as 10 to 20 int. unit/mL. Spontaneous fluctuations above this level may occur and should prompt the HBV-infected provider to abstain from performing exposure-prone procedures while awaiting subsequent re-testing, changing drug therapy, or other reasonable steps.

•               Standard precautions should be rigorously adhered to in all settings.

Based on the above, I would advise this patient to reconsider his plans to enter dental school. Because he has high HBV DNA and low ALT levels, the likelihood of him responding (HBeAg loss) to current treatment is low and the chance of him clearing HBsAg is even more remote. He will likely need long-term if not lifelong treatment and be subjected to frequent monitoring throughout his career. The impact of chronic HBV infection with high level viremia on career paths of dental students is different from medical students who can choose career paths that do not involve performance of invasive procedures.

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5- A 50-year-old Asian man has the following hep B serology.

HBsAg (+),

HBeAg (-).

Serum ALT is 75 int. unit/L (upper limit of normal 40 int. unit/L).

Liver biopsy moderate hepatitis with bridging fibrosis.

What is the best course of action?:

1-commence on PEG INF and RBV

2-Tenofovir

3-Entecavir

4-No treatment

5-F/U

Comment — Although this patient has only a mildly elevated serum ALT, I would recommend treatment based upon the advanced histologic features on his liver biopsy if his serum HBV DNA level is more than 10,000 copies/mL (>2000 int. unit/mL). The threshold HBV DNA level for initiating treatment in HBeAg negative patients is unclear because these patients tend to have lower HBV DNA levels than HBeAg positive patients. The benefit of antiviral therapy in preventing adverse clinical outcome: progression to cirrhosis, hepatic decompensation and hepatocellular carcinoma is not as clear in patients with low HBV DNA levels.

This patient highlights the importance of liver biopsy in patients with normal or mildly elevated ALT, particularly older patients and those who have been infected for many years. Assuming he has no comorbid conditions or evidence of hepatic decompensation, adefovir, entecavir, tenofovir, or interferon would be reasonable options. Interferon should not be used in patients with decompensated cirrhosis, but it may be used cautiously in patients who have bridging fibrosis and no evidence of clinical or biochemical decompensation. Because of the need for long-term treatment, entecavir or tenofovir is preferred if oral treatment is desired.

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6- A 75-year-old woman presented with Juandice and ascites. She drinks I bottle of whisky per day.

Her Hep B serology as follow:

HBsAg (+)

HBeAg (+),

Serum ALT of 50 int. unit/L (upper limit of normal 40 int. unit/L).

HBV DNA is 8000 copies/mL (approximately 1600 int. unit/mL).

She has ascites and known esophageal varices. She is not considered to be a candidate for liver transplantation.

What is the best course of action?:

1-commence on PEG INF and RBV

2-Tenofovir

3-Entecavir

4-No treatment

5-F/U

Comment — Treatment with interferon is not an option for this patient because she has decompensated cirrhosis. I would treat this patient because there is little to lose and suppression of HBV DNA and any accompanying inflammation may be of benefit in a patient with very little hepatic reserve.

Given the need for long-term treatment, the risk of lamivudine or telbivudine resistance and the possibility of clinical deterioration due to breakthrough infection must be considered in a patient who is not a transplant candidate. I would also not use adefovir because of its inconsistent antiviral effects.

An important question is whether these patients should receive de novo combination oral antiviral therapy. A trial comparing de novo entecavir monotherapy with a combination of entecavir and tenofovir found no difference in virologic and serologic responses overall, but combination therapy resulted in more rapid viral suppression and a higher percent with HBV DNA less than 50 unit/mL at week 96 among the subset of patients with baseline HBV DNA more than 108 int. unit/mL. None of the patients had evidence of genotypic resistance up to week 96. These data indicate that de novo combination therapy is not necessary in most patients but may have a potential benefit in patients with high baseline HBV DNA.

With these considerations in mind, entecavir or tenofovir is preferred. Entecavir may be a better choice because patients with decompensated cirrhosis are at risk of renal failure and because this patient is 75. As an alternative, lamivudine or telbivudine can be used in combination with adefovir or tenofovir for rapid viral suppression and to reduce risk of drug resistance. Available data showed that entecavir and tenofovir are well tolerated in this patient population, although one case series reported the occurrence of lactic acidosis in patients with severe liver dysfunction receiving entecavir.

Recommendations would be the same if this patient is a 44-year-old and is currently on the liver transplant waiting list. Suppressing HBV DNA to undetectable at the time of transplantation will reduce the risk of HBV recurrence post-transplant.

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7- A 40-year-old man with pretreatment ALT 129 int. unit/L and moderate inflammation on liver biopsy. He remains HBeAg positive but HBV DNA is undetectable by PCR after one year of therapy with lamivudine.

What is the best course of action:

1-continue lamividine

2-stop treatment

3-switch to Entecavir

4-switch to Tenofovir

5-switch to PEG INF

Comment — It is important to think through the treatment plan and all its contingencies prior to beginning any type of therapy for HBV. It is reasonable to continue treatment since longer duration of treatment is associated with an increased probability of HBeAg seroconversion. A problem with longer duration of therapy is the selection of resistant mutants (M204V/I mutants). These mutants can be detected in 15 to 30 percent of patients at the end of one year of treatment, and in 70 percent of patients at the end of four years of treatment.

Alternative options include switching to drugs that are more potent or have lower rates of resistance such as entecavir or to add a drug that is not cross-resistant such as adefovir or tenofovir since it is possible that resistant mutants may already be selected after one year of lamivudine treatment.

Patients who have been on lamivudine and have had undetectable serum HBV DNA for many years can continue on lamivudine, especially if virus was suppressed to undetectable levels within 6 to 12 months of initiation of treatment. Patients who have only been on lamivudine for one to two years should be switched to other drugs that have lower risk of resistance. Entecavir may be used in patients who had been exposed to lamivudine for a short time and in whom serum HBV DNA is undetectable. Tenofovir would be a better option for patients who have been on lamivudine for more than one to two years.

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8- A 56-year-old woman with HBeAg positive HBV and early cirrhosis on liver biopsy. Treatment with lamivudine was associated with an initial decline in HBV DNA titers to undetectable levels by PCR assay and normalization of serum aminotransferases. However, after 18 months of treatment, she developed a flare in serum aminotransferases with increasing levels of HBV DNA. She remains HBeAg positive.

What is the best course of action:

1  1- add adefovir

2  2- add entecovir

3  3- add PEG INF

4  4- continue lamividine

Comment — It is likely that this patient has developed breakthrough infection with a lamivudine resistant mutation. If possible, specific testing to confirm resistance should be performed, as breakthrough infection may also be due to medication non-compliance. It is important to differentiate hepatitis flares associated with HBeAg seroconversion (which is accompanied by decrease in HBV DNA level) versus flares associated with emergence of drug resistance (which is accompanied by increase in HBV DNA level).

In this case, the patient was compliant with medication and had increasing HBV DNA level. Given that she has advanced histologic features, it would be reasonable to add adefovir 10 mg daily or switch to tenofovir 300 mg daily. Adefovir or tenofovir is preferred to entecavir because mutations to lamivudine decrease susceptibility to entecavir and increase the risk of entecavir resistance. In countries where tenofovir is available, tenofovir is preferred to adefovir.

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9- A 68-year-old man who is hospitalized with low grade fever, abdominal pain, anorexia, and jaundice. Serologic evaluation reveals:

HBsAg positive,

IgM anti-HBc positive,

Serum HBV DNA level of 1.5 million copies/mL (approximately 300,000 int. unit/mL).

Serum ALT is 2000 unit/L, total bilirubin is 8.0 mg/dL,

INR is 1.5.

Other causes of liver disease are excluded. The patient is not known to be a carrier for HBV; however, he is bisexual and thus has potential risk factor for HBV carriage. His aminotransferases, INR and total bilirubin rise slightly during the first two days of hospitalization while awaiting the results of the above serology.

What is the best course of action:

1- commence on PEG INF

2- commence on tenofovir

3- He will need prolong treatment

4- treatment should commence within 2 week

Comment — It would appear that this patient has acute HBV, although reactivation of chronic HBV infection is also possible. It can sometimes be difficult to distinguish acute HBV from exacerbation of chronic hepatitis B based upon serology alone (unless there are previous laboratory tests available). The diagnosis of acute hepatitis B is based upon the detection of HBsAg and IgM anti-HBc .However, IgM anti-HBc can also be seen during severe exacerbation of chronic hepatitis B. This patient is more likely to have exacerbation of pre-existing chronic hepatitis B if he has cirrhosis at diagnosis, a family history of HBV, or past history of liver disease. By contrast, acute infection is more likely in patients with a known recent exposure and no prior history of liver disease.

A question is whether the patient should be treated with antiviral therapy. The prognosis with acute infection is relatively worse in patients who are immunocompromised, have concomitant infection with hepatitis C virus, have preexisting liver disease, or are elderly. Thus, the patient's advanced age is a risk factor for morbidity (and possibly mortality) from acute infection.

Few studies have addressed the benefits of antiviral therapy during acute infection. There are relatively more data with reactivation of infection in patients receiving immunosuppressive therapy. In this setting, prophylaxis with antiviral treatment can help prevent severe reactivation of hepatitis. We do not believe that all patients with acute HBV require antiviral treatment since the likelihood of fulminant hepatitis B is less than 1 percent, and in immunocompetent adults the likelihood of progression to chronic HBV infection is less than 5 percent. As a general rule, we treat patients with a severe (such as those who develop a coagulopathy [INR >1.5]) or a protracted course (such as persistent symptoms or marked jaundice [bilirubin >10 mg/dL] for more than four weeks after presentation). We also recommend treating patients with fulminant hepatitis B to reduce the likelihood of reinfection post-liver transplant. These recommendations are consistent with a 2009 guideline issued by the American Association for the Study of Liver Diseases.

Treatment would be reasonable given this patient's advanced age and coagulopathy. Interferon should be avoided because of the risk of infection and further increase in hepatic necroinflammation. In patients suspected to have protracted or severe acute hepatitis, telbivudine, lamivudine, adefovir, tenofovir, or entecavir would all be acceptable options given as monotherapy as the duration of treatment should be short. Treatment can be stopped after confirmation (two consecutive tests four weeks apart) that the patient has cleared HBsAg.