serologic markers,Hbs,Hcv

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Slide 1 : HEPATITIS B VIRUS   The hepatitis B virus (HBV) is a double-stranded DNA virus belonging to the family of hepadnaviruses, which include duck hepatitis virus, woodchuck hepatitis virus, and ground squirrel hepatitis virus
Slide 2 : HBV has traditionally been classified into eight genotypes (A to H). The prevalence of specific genotypes varies geographically. Furthermore, genotypes may correlate with clinical course and response to interferon. Genotype testing is not necessary in routine clinical practice, but it may be indicated for HBeAg-positive patients who are considering interferon therapy since patients with genotype A have a more favorable response.
Slide 3 : EPIDEMIOLOGY Hepatitis B virus infection is a global public health problem. It is estimated that there are more than 300 million HBV carriers in the world, of whom approximately 500,000 die annually from HBV-related liver disease. Despite the availability of HBV vaccines, the rate of HBV-related hospitalizations, cancers, and deaths in the United States have more than doubled during the past decade
Slide 4 : The spectrum of clinical manifestations of hepatitis B virus (HBV) infection varies in both acute and chronic disease. During the acute phase, manifestations range from subclinical or anicteric hepatitis to icteric hepatitis and, in some cases, fulminant hepatitis; during the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Extrahepatic manifestations can also occur with both acute and chronic infection.
Slide 5 : SEROLOGIC MARKERS  Hepatitis B surface antigen and antibody  It can be detected by radioimmunoassays (RIA) or enzyme immunoassays (EIA). HBsAg appears in serum 1 to 10 weeks after an acute exposure to HBV, prior to the onset of hepatitic symptoms or elevation of serum alanine aminotransferase (ALT) . In patients who subsequently recover, HBsAg usually becomes undetectable after four to six months. Persistence of HBsAg for more than six months implies chronic infection. It is estimated that less than 1 percent of immunocompetent adult patients with acute hepatitis B progress to chronic infection. Among patients with chronic HBV infection, the rate of clearance of HBsAg is approximately 0.5 percent per year.
Slide 6 : The disappearance of HBsAg is followed by the appearance of hepatitis B surface antibody (anti-HBs). In most patients, anti-HBs persists for life, thereby conferring long-term immunity. In some patients, however, anti-HBs may not be detectable until after a window period of several weeks to months during which neither HBsAg nor anti-HBs can be detected. At this time, the serologic diagnosis may be made by the detection of IgM antibodies against hepatitis B core antigen (IgM anti-HBc)
Slide 7 : Coexistence of HBsAg and anti-HBs has been reported in approximately 24 percent of HBsAg positive individuals. In most instances, the antibodies are unable to neutralize the circulating virions . These individuals should therefore be regarded as carriers of the hepatitis B virus.
Slide 8 : Hepatitis B core antigen and antibody   Hepatitis B core antigen (HBcAg) is an intracellular antigen that is expressed in infected hepatocytes. It is not detectable in serum. Anti-HBc can be detected throughout the course of HBV infection. During acute infection, anti-HBc is predominantly of IgM class. IgM anti-HBc is the sole marker of HBV infection during the window period between the disappearance of HBsAg and the appearance of anti-HBs. The detection of IgM anti-HBc is usually regarded as an indication of acute HBV infection.
Slide 9 : However, IgM anti-HBc may remain detectable up to two years after the acute infection. Furthermore, the titer of IgM anti-HBc may increase to detectable levels during exacerbations of chronic hepatitis B. This can present a diagnostic problem, incorrectly suggesting acute hepatitis B, particularly in endemic areas in which many patients presenting with HBsAg-positive acute hepatitis have exacerbations of chronic hepatitis B.
Slide 10 : IgG anti-HBc persists along with anti-HBs in patients who recover from acute hepatitis B. It also persists in association with HBsAg in those who progress to chronic HBV infection
Slide 11 : Isolated anti-HBc — The isolated presence of anti-HBc in the absence of HBsAg and anti-HBs has been reported in 0.4 to 1.7 percent of blood donors in low prevalence areas and in 10 to 20 percent of the population in endemic countries.
Slide 12 : Isolated detection of anti-HBc can occur in three settings: during the window period of acute hepatitis B when the anti-HBc is predominantly IgM class; many years after recovery from acute hepatitis B when anti-HBs has fallen to undetectable levels; and after many years of chronic HBV infection when the HBsAg titer has decreased below the cutoff level for detection.
Slide 13 : The clinical significance of isolated anti-HBc is unclear. Although HBV DNA has been detected in the serum of individuals with isolated anti-HBc when tested by PCR assays, the frequency of detection varies from 0 to 20 percent. HBV DNA can be detected in the liver of most (more than 70 percent) persons with isolated anti-HBc. Transmission of HBV infection has been reported from blood and organ donors with isolated anti-HBc but the incidence ranged widely from 0.4 to 78 percent. The risk is highest when liver from anti-HBc positive donors are transplanted.
Slide 14 : The evaluation of individuals with isolated anti-HBc should include repeat testing for anti-HBc, HBsAg, anti-HBe, and anti-HBs. Those who remain isolated anti-HBc positive should be tested for the presence of IgM anti-HBc to rule out recent HBV infection. The presence of anti-HBe indicates that the individual had prior exposure to HBV. Individuals with evidence of chronic liver disease should be tested for HBV DNA to exclude low level chronic HBV infection.
Slide 15 : Hepatitis B e antigen and antibody  Hepatitis B e antigen (HBeAg) is a secretory protein that is processed from the precore protein. It is generally considered to be a marker of HBV replication and infectivity. The presence of HBeAg is usually associated with high levels of HBV DNA in serum and higher rates of transmission of HBV infection from carrier mothers to their babies and from patients to health care workers.
Slide 16 : HBeAg to anti-HBe seroconversion occurs early in patients with acute infection, prior to HBsAg to anti-HBs seroconversion. However, HBeAg seroconversion may be delayed for years to decades in patients with chronic HBV infection. In such patients, the presence of HBeAg is usually associated with the detection of high levels of HBV DNA in serum and active liver disease. However, HBeAg-positive patients with perinatally acquired HBV infection may have normal serum ALT concentrations and minimal inflammation in the liver.
Slide 17 : Seroconversion from HBeAg to anti-HBe is usually associated with decrease in serum HBV DNA and remission of liver disease. However, some patients continue to have active liver disease after HBeAg seroconversion. Such individuals may have low levels of wild type HBV or HBV variants that prevent or decrease the production of HBeAg.
Slide 18 : SERUM HBV DNA ASSAYS  Qualitative and quantitative tests for HBV DNA in serum have been developed to assess HBV replication. The sensitivity limit of these assays depends upon the techniques used. The range of linearity also varies. Currently, most HBV DNA assays use real-time PCR techniques, report results in IU/mL, have lower limit of detection around 10 IU/mL and a range of linearity up to 8 log(10) IU/mL
Slide 19 : Recovery from acute hepatitis B is usually accompanied by the disappearance of HBV DNA in serum as determined by hybridization or bDNA assays. However, HBV DNA may remain detectable in serum for many years if tested by PCR assays. This observation suggests that the virus persists after "recovery" but is controlled by the immune system.
Slide 20 : Similar findings have been noted in patients with chronic HBV infection. Spontaneous or treatment-induced HBeAg seroconversion is usually accompanied by the disappearance of HBV DNA from serum by hybridization methods but PCR assays usually remain positive except in patients with HBsAg seroconversion
Slide 21 : In fact, many patients receiving nucleos/tide analogue therapy remain HBeAg positive despite having undetectable serum HBV DNA for months or years.
Slide 22 : HBV DNA levels are also detectable in patients with HBeAg negative chronic hepatitis, although levels are generally lower than in patients with HBeAg positive chronic hepatitis. A serum HBV DNA level of >10(5) copies/mL has been proposed as a cutoff level to differentiate patients with HBeAg negative chronic hepatitis from those in an inactive carrier state (ie, HBeAg negative, persistently normal ALT) Some studies propose lower cutoffs, around 10(4) copies/mL or 2000 IU/mL.
Slide 23 : Clinical use — The major clinical role of serum HBV DNA assays in patients with chronic HBV infection is to assess HBV replication and candidacy for antiviral therapy. Indication for HBV treatment is based on the presence of active liver disease and high HBV DNA levels. A cutoff of 100,000 copies/mL or 20,000 IU/mL has been proposed for treatment initiation in HBeAg positive patients, and a lower threshold (2000 IU/mL) for HBeAg negative patients
Slide 24 : Suppression of serum HBV DNA is also used as one of the end-points in assessing response to antiviral treatment and to detect virologic breakthrough Rarely, tests for HBV DNA in serum help to identify HBV as the etiology of liver disease in HBsAg negative patients
Slide 25 : DIAGNOSTIC ALGORITHMS  Acute hepatitis — The diagnosis of acute hepatitis B is based upon the detection of HBsAg and IgM anti-HBc. During the initial phase of infection, markers of HBV replication, HBeAg and HBV DNA, are also present. Recovery is accompanied by the disappearance of HBV DNA, HBeAg to anti-HBe seroconversion, and subsequently HBsAg to anti-HBs seroconversion.
Slide 26 : Rarely, patients present during the window period when HBsAg has become negative but anti-HBs is not yet positive. In this setting, which is more common in patients with fulminant hepatitis B in whom virus clearance tends to be more rapid, IgM anti-HBc is the sole marker of acute HBV infection.
Slide 27 : Past HBV infection — Previous HBV infection is characterized by the presence of anti-HBs and IgG anti-HBc. Immunity to HBV infection after vaccination is indicated by the presence of anti-HBs only.
Slide 28 : Chronic HBV infection — The diagnosis of chronic HBV infection is based upon the persistence of HBsAg for more than six months. Additional tests for HBV replication — HBeAg and serum HBV DNA — should be performed to determine if the patient should be considered for antiviral therapy. All patients with chronic HBV infection should be regularly monitored because HBV DNA and ALT levels vary during the course of infection to monitor for progression of liver disease.
Slide 29 : HBeAg-negative patients who have normal serum ALT and low or undetectable HBV DNA are considered to be in an inactive carrier state. These patients generally have a good prognosis and antiviral treatment is not indicated. However, serial tests are necessary to accurately differentiate them from patients with HBeAg-negative chronic hepatitis. Thus, it is recommended that these patients have repeat ALT +/- HBV DNA tests at three-month intervals during the first year
Slide 30 : . Patients who are truly inactive carriers should continue to be monitored but at less frequent intervals. HBeAg-negative patients with elevated serum ALT concentrations should be tested for serum HBV DNA to determine if the liver disease is related to persistent HBV (wild type or mutant) replication. Additional tests for hepatitis C and hepatitis D should also be performed to rule out superinfection with other hepatitis virus(es).
Slide 31 : Occult HBV infection — There exists a subset of patients with occult HBV infection defined as the presence of detectable HBV DNA by PCR in patients who are negative for HBsAg. Such patients have been further subclassified as having "seropositive" or "seronegative" HBV depending upon whether they are positive or negative for other HBV markers, most commonly anti-HBc.
Slide 32 : Most of these patients have very low or undetectable serum HBV DNA levels accounting for the failure to detect HBsAg. HBV DNA is often detected in the liver and transplantation of livers
Slide 33 : WHO SHOULD BE TESTED  Testing should include HBsAg and anti-HBs. Patients who are negative for these markers should be vaccinated.
Slide 34 : Liver biopsy may be considered for patients who meet criteria for chronic hepatitis (ie, HBsAg positive for >6 months, serum HBV DNA >10(5) copies/mL or >20,000 IU/mL, persistent or intermittent elevation in ALT/AST levels). Liver biopsy is most important for patients who do not meet current criteria for treatment but have serum HBV DNA 10(4) to 10(5) copies/mL (2000 to 20,000 IU/mL) and ALT/AST levels that are normal or mildly elevated (<2x upper limit); patients with histologically active or advanced liver disease may benefit from treatment. A normal serum ALT level alone in patients with active viral replication does not predict mild or normal histologic findings.
Slide 35 : WHO SHOULD BE TREATED AND HOW  We recommend that treatment be considered in patients with HBeAg positive or HBeAg negative chronic hepatitis. Patients with compensated cirrhosis and HBV DNA >2,000 IU/mL and those with decompensated cirrhosis and detectable HBV DNA by PCR assay should be considered for antiviral therapy, regardless of the serum ALT level
Slide 36 : Patients in whom therapy is indicated: acute liver failure, clinical complications of cirrhosis, cirrhosis or advanced fibrosis with high serum HBV DNA, or reactivation of chronic HBV after chemotherapy or immunosuppression. Patients for whom therapy may be indicated: patients in the immune-active phase who do not have advanced fibrosis or cirrhosis (HBeAg-positive or HBeAg-negative chronic hepatitis). Patients for whom immediate therapy is not routinely indicated: (1) Patients with chronic HBV in the immune tolerant phase (with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy); (2) Patients in the inactive carrier or low replicative phase (with low levels of or no detectable HBV DNA in serum and normal serum ALT levels); (3) Patients who have latent HBV infection (HBV DNA without HBsAg).
Slide 37 : Recommendations from the American Association for the Study of Liver Diseases: HBeAg-positive patients — Treatment is recommended for those with HBV DNA >20,000 IU/mL and ALT >2 x ULN in patients without cirrhosis. As noted above, patients with compensated cirrhosis and HBV DNA >2,000 IU/mL and those with decompensated cirrhosis and detectable HBV DNA by PCR assay should be considered for antiviral therapy, regardless of the serum ALT level
Slide 38 : Treatment should be delayed for three to six months in newly diagnosed HBeAg positive patients with compensated liver disease to determine whether spontaneous HBeAg seroconversion will occur.
Slide 39 : HBeAg-negative patients — Treatment may be initiated immediately once a diagnosis of HBeAg negative chronic hepatitis (ALT >2 x ULN and HBV DNA >2000 IU/mL) is established because sustained remission is rare in the absence of treatment. Liver biopsy should be considered in HBeAg negative patients who have serum HBV DNA levels >2000 IU/mL and normal or mildly elevated ALT to determine if treatment is warranted.
Slide 40 : Treatment strategies for chronic HBV Choosing among the available options — Treatment strategies for chronic HBV include interferon (standard and pegylated), lamivudine, adefovir dipivoxil, telbivudine, entecavir, and tenofovir (in countries in which it is approved).
Slide 41 : Interferon  The advantages of interferon compared to the other options are its finite duration of treatment, the absence of selection of resistant mutants, and a more durable response. On the other hand, side effects from interferon are troubling for many patients, and (less commonly) can be severe. Furthermore, interferon cannot be used in patients with decompensated disease.
Slide 42 : The main role of interferon is primarily treatment of young patients with well compensated liver disease, who do not wish to be on long-term treatment or are planning to be pregnant within the next two to three years, and in whom drug resistance may limit their treatment options in the future. Interferon is also an attractive option for patients with HBV genotype A infection
Slide 43 : Lamivudine  The main advantages of lamivudine are its lower cost compared to the other oral agents and the many years of experience confirming its safety, including its use during pregnancy. Compared to adefovir, lamivudine has more rapid and more potent virus suppression, but entecavir, telbivudine, and tenofovir are superior to lamivudine in suppressing viral replication
Slide 44 : The main disadvantage of lamivudine is the high rate of drug resistance. Lamivudine may still have a role in patients coinfected with HIV.
Slide 45 : Adefovir  The main advantage of adefovir is its activity against lamivudine-resistant HBV and a lower rate of drug resistance compared to lamivudine. However, virus suppression is slow . Adefovir at high doses has been associated with nephrotoxicity.
Slide 46 : Adefovir resistance was not detected after one year of treatment but the rate of drug resistance has been reported to be as high as 29 percent after five years of treatment. The most important role of adefovir is in the treatment of patients with lamivudine-resistant HBV, preferably in combination. With the approval of tenofovir, which is more potent, the role of adefovir is rapidly diminishing.
Slide 47 : Entecavir — The main advantages of entecavir are its potent antiviral activity and a low rate of drug resistance. Entecavir may also have an important role in patients with decompensated cirrhosis because of its potent antiviral activity and low rate of drug resistance but its safety in this patient population has not been well studied.
Slide 48 : Resistance to entecavir is rare (approximately 1 percent with up to five years of treatment). By contrast, resistance has been observed in up to 50 percent of lamivudine-refractory patients after five years of treatment.
Slide 49 : Telbivudine  appears to have slightly more potent antiviral effects compared with lamivudine and adefovir but it selects for the same resistant mutants as lamivudine and is more expensive. Thus, its role as primary therapy is limited. Furthermore, there have been rare cases of myopathy and peripheral neuropathy
Slide 50 : Tenofovir  Tenofovir has more potent antiviral activity than adefovir and is effective in suppressing wild-type as well as lamivudine-resistant HBV. Tenofovir may be used as first line treatment , and in patients with lamivudine, telbivudine or entecavir resistance, preferably as additional treatment in these patients.
Slide 51 : Prediction of response HBeAg positive patients — For HBeAg positive patients,  depends upon the degree of elevation of the serum aminotransferases. As a general rule, treatment with any of these drugs does not result in higher rates of HBeAg seroconversion compared to no treatment in those who have a serum ALT =2 X the upper limit of normal.
Slide 52 : Prediction of response in HBeAg negative patients — For HBeAg negative patients, prediction of response is less precise. Because of the need for long-term treatment, Interferon, adefovir, entecavir, or tenofovir are generally preferred because long-term treatment with lamivudine or telbivudine is associated with diminishing response due to selection of drug-resistant mutants. Advantages of entecavir and tenofovir are more potent antiviral activity and lower rate of drug resistance compared with adefovir.
Slide 53 : Failed prior interferon therapy — Patients who failed to respond to prior interferon therapy can be treated with lamivudine, adefovir, telbivudine, entecavir, or tenofovir.
Slide 54 : Compensated cirrhosis — In patients with clinically and biochemically compensated cirrhosis, interferon may be used with caution but nucleosides/nucleotides are safer. Because of the need for long-term treatment, entecavir or tenofovir is preferred. Decompensated cirrhosis —Interferon is contraindicated in these patients.
Slide 55 : DOSES — Standard interferon For adults: 5 MU daily or 10 MU three times a week For children: 6 MU three times weekly with a maximum of 10 MU Treatment duration for HBeAg positive chronic hepatitis is 16 to 32 weeks Treatment duration for HBeAg negative hepatitis is 12 to 24 months
Slide 56 : Peginterferon alfa-2a For adults: 180 microG once weekly For children: Not approved The manufacturer recommends 48 weeks of treatment for HBeAg positive or negative chronic HBV. The Asian-Pacific guidelines recommended 24 weeks treatment for HBeAg positive.
Slide 57 : Lamivudine — Lamivudine is administered orally. The recommended dose for adults with normal renal function without concomitant HIV infection is 100 mg daily. Dose adjustment is required in those with decreased renal function. The recommended dose for children is 3 mg/kg per day with a maximum of 100 mg/day The recommended dose for those who are coinfected with HIV is 150 mg twice daily (along with other anti-retroviral drugs).
Slide 58 : Adefovir — Adefovir is administered orally. The dose is 10 mg daily. Patients with impaired renal function should have the dosing interval adjusted Entecavir — Entecavir is administered orally. The recommended dose is 0.5 mg once daily for adults and adolescents older than 16 while it is 1 mg daily for those who have lamivudine resistance. The dosage should be adjusted in patients with a creatinine clearance of <50 mL/min.
Slide 59 : Telbivudine — Telbivudine is administered orally. The recommended dose is 600 mg once daily. Tenofovir — Tenofovir is given at a dose of 300 mg daily; the dose needs to be adjusted in renal impairment.
Slide 60 : DURATION OF TREATMENT EN  The optimal duration of therapy for the oral drugs is not well-established. Most patients receiving nucleos/tide analogue therapy will require at least four to five years of treatment, and some may require indefinite treatment.
Slide 61 : HBeAg-positive chronic hepatitis — The endpoint of treatment is HBeAg seroconversion. Patients in whom HBeAg seroconversion has occurred and serum HBV DNA has become undetectable should be treated for at least 12 more months after HBeAg seroconversion has been confirmed (by testing on two occasions at least two months apart) to reduce the rate of relapse.
Slide 62 : HBeAg-negative chronic hepatitis — The endpoint of treatment has not been established. Treatment may be discontinued in patients who have confirmed loss of HBsAg (by testing on two occasions at least two months apart).
Slide 63 : Compensated cirrhosis — The aim of treatment is to prevent liver failure and HCC. Thus, life-long treatment is generally recommended. It is possible that treatment may be discontinued in those who have lost HBsAg. Decompensated cirrhosis — Life-long treatment is recommended
Slide 64 : ACUTE INFECTION  Treatment is mainly supportive and should include appropriate measures to prevent infection in exposed contacts. However, there are known subgroups of patients whose prognosis is relatively worse. These include patients who are immunocompromised, have concomitant infection with hepatitis C virus, have preexisting liver disease, or are elderly. The role of antiviral therapy for such patients remains unsettled since few studies have addressed its benefits during acute infection.
Slide 65 : Most experience has been in patients who developed reactivation while receiving immunosuppressive therapy. In this setting, prophylaxis with antiviral treatment can help prevent severe reactivation of hepatitis. 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 acute liver failure due to hepatitis B to reduce the likelihood of reinfection post-liver transplant.
Slide 66 : Treatment can be stopped after confirmation (two consecutive tests four weeks apart) that the patient has cleared HBsAg. Interferon should be avoided because of the risk of infection and a further increase in hepatic necroinflammation in patients with severe hepatitis or acute liver failure
Slide 67 : CASE ONE, YOUNG ASIAN WITH ACTIVE REPLICATION  The patient is a 25 year old Asian man who is HBsAg (+) and HBeAg (+) with serum HBV DNA of 700 million copies/mL (140 million IU/mL). He has mild inflammation on biopsy. His serum ALT is 100 IU/L (upper limit of normal 40 IU/L).
Slide 68 : 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.
Slide 69 : 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.
Slide 70 : CASE TWO, PRESUMED PRECORE VARIANT The patient is a 20 year old woman who is HBsAg (+), HBeAg (-). Her HBV DNA is 1.2 million copies/mL (approximately 250,000 IU/mL). She has mild portal inflammation, no fibrosis. Her serum ALT is 60 IU/L (upper limit of normal 40 IU/L).
Slide 71 : Comment — I would follow this patient without recommending treatment at this time. 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.
Slide 72 : 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.
Slide 73 : CASE THREE, CHRONIC CARRIER, NORMAL ALT, NORMAL LIVER BIOPSY  The patient is a 22 year old man who is HBsAg (+), HBeAg (+), anti-HBe (-). His HBV DNA is 71.5 million copies/mL (approximately 14 million IU/mL) and serum ALT is persistently in the range of 20 to30 IU/L (upper limit of normal 40 IU/L). His liver biopsy is essentially normal.
Slide 74 : Comment — 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).
Slide 75 : 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.
Slide 76 : CASE FIVE, CHRONIC CARRIER, ADVANCED HISTOLOGIC FEATURES  The patient is a 50 year old Asian man who is HBsAg (+), HBeAg (-). His serum ALT is 75 IU/L (upper limit of normal 40 IU/L). He has moderate hepatitis with bridging fibrosis on liver biopsy.
Slide 77 : 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 IU/mL)
Slide 78 : CASE SIX, DECOMPENSATED CIRRHOSIS  The patient is a 75 year old woman who is HBsAg (+) HBeAg (+), and has a serum ALT of 50 IU/L (upper limit of normal 40 IU/L). Her HBV DNA is 8000 copies/mL (approximately 1600 IU/mL). She has ascites and known esophageal varices. She is not considered to be a candidate for liver transplantation.
Slide 79 : but I would treat her 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. With these considerations in mind, entecavir or tenofovir is preferred.
Slide 80 : CASE SEVEN, AWAITING TRANSPLANT  The patient is a 44 year old with decompensated cirrhosis who is on the transplant waiting list. He is HBsAg (+), HBeAg (+), and has a serum ALT of 100 IU/L (upper limit of normal 40 IU/L).
Slide 81 : Comment — The optimal approach for patients with chronic HBV who are awaiting liver transplantation has not been established. The greatest experience in this setting has been with lamivudine but it is associated with a high rate of drug resistance. Adefovir and probably tenofovir can also be used but renal function needs to be monitored closely. Although experience with entecavir in this setting is limited, it is probably the best option. Experience with telbivudine is also limited, but due to the high rate of drug resistance, it is not an optimal treatment. The antiviral effect of adefovir 10 mg is less consistent than lamivudine or entecavir, and may be slow or suboptimal in some patients. De novo combination treatment has not been studied in this patient population but may be a reasonable option if lamivudine or telbivudine are used.
Slide 82 : CASE EIGHT, REMAINS HBeAg POSITIVE DESPITE LAMIVUDINE FOR ONE YEAR  The patient is a 40 year old man with pretreatment ALT 129 IU/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.
Slide 83 : Comment — 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.
Slide 84 : 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.
Slide 85 : CASE NINE, BREAKTHROUGH INFECTION WHILE ON LAMIVUDINE  The patient is 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.
Slide 86 : 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 tenofovir 300 mg daily (while continuing lamivudine). 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.
Slide 87 : CASE TEN, ACUTE INFECTION  — The patient is a 68 year old man who is hospitalized with low grade fever, abdominal pain, anorexia, and jaundice. Serologic evaluation reveals that he is HBsAg positive, IgM anti-HBc positive, with serum HBV DNA level of 1.5 million copies/mL (approximately 300,000 IU/mL). Serum ALT is 2000 U/L, total bilirubin is 8.0 mg/dL, and 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.
Slide 88 : 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 Treatment would be reasonable given this patient's advanced age and coagulopathy.

 


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