Loss of intrahepatic HBsAg expression predicts sustained response to peginterferon and is reflected by pronounced serum HBsAg decline.

There is a lack of knowledge regarding the effect of peginterferon (PEG-IFN) on the expression of intrahepatic hepatitis B core and surface antigen (HBcAg and HBsAg) in chronic hepatitis B (CHB) and its relation with response to therapy. Fifty-two HBeAg-positive and 67 HBeAg-negative CHB patients with paired liver biopsies taken at baseline and after 1 year of PEG-IFN therapy were studied. After PEG-IFN therapy, HBeAg-negative patients showed a significant reduction in both intrahepatic HBcAg (P = 0.04) and HBsAg expression (P < 0.001). In contrast, a reduction in intrahepatic HBcAg expression was not observed in HBeAg-positive patients, while a trend in reduction of intrahepatic HBsAg staining was found (P = 0.09). Post-treatment, 7 (13%) HBeAg-positive and 9 (14%) HBeAg-negative patients had no expression of intrahepatic HBsAg. Patients without any intrahepatic HBsAg expression post-treatment were more likely to achieve a combined response (HBeAg loss with hepatitis B virus (HBV) DNA <2000 IU/mL for HBeAg -positive and HBV DNA <2000 IU/mL and normal alanine aminotransferase for HBeAg-negative CHB): 71% vs 5% for HBeAg-positive (P < 0.001) and 60% vs 16% for HBeAg-negative patients (P = 0.004), respectively. Moreover, a more profound decline of serum HBsAg was observed in patients with absence of intrahepatic HBsAg staining (3.1 vs 0.4 log IU/mL, P < 0.001 and 1.7 vs 0.4 log IU/mL, P = 0.005 for HBeAg-positive and HBeAg-negative CHB, respectively). In conclusion, PEG-IFN reduces expression of intrahepatic HBsAg. Loss of HBsAg as assessed by immunohistochemistry from the liver predicts a sustained response and is reflected in a pronounced serum HBsAg decline.

Treatment of chronic hepatitis B virus infection - Dutch national guidelines.

The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of national standards in the evaluation and antiviral treatment of patients with chronic hepatitis B virus (HBV) infection. This includes recommendations on the initial evaluation of patients, choice and duration of antiviral therapy, follow-up after antiviral therapy and monitoring of patients not currently requiring antiviral therapy. The initial evaluation of chronic HBV-infected patients should include testing of liver biochemistry, virus serology and abdominal imaging. In patients without cirrhosis, antiviral treatment is recommended for those with a serum HBV DNA of at least 1.0 x 105 c/ml (>or=2.0 x 10(4) IU/ml) in combination with: a) elevation of serum alanine aminotransferase (ALAT) level above twice the upper limit of normal during at least three months, and/or b) histological evidence of porto-portal septa or interface hepatitis on liver histology. In patients with cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1.0 x 10(4)c/ml (>or=2.0 x 10(3) IU/ml) or higher, independent of ALAT levels or histological findings. If the patient has decompensated cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1000 c/ml (>or=200 IU/ml) or higher. Patients who do not have an indication for antiviral treatment should be monitored because there is a risk of (re)activation of disease activity. Monitoring every three to six months is recommended for HBeAg-positive and HBeAg-negative patients with high viraemia (HBV DNA >or=1.0 x 10(5) c/ml or >or=2.0 x 10(4) IU/ml) and normal ALAT levels. For patients with serum HBV DNA below 1.0 x 10(5) c/ml (<2.0 x 10(4) IU/ml) the recommended frequency of monitoring is every three to six months for HBeAg-positive patients and every six to 12 months for HBeAg-negative patients. Peginterferon (PEG-IF N) therapy should be considered as initial therapy in both HBeAg-positive and HBeAg-negative patients without contraindications for treatment with this drug because of the higher chance of achieving sustained response compared with nucleos(t)ide analogue therapy. In patients starting nucleos(t)ide analogue therapy, the use of lamivudine is not preferred if long-term antiviral treatment is expected due to the high risk of antiviral resistance against this drug. Of the currently licensed nucleos(t)ide analogues, entecavir has the lowest risk of antiviral resistance (compared with lamivudine, adefovir and telbivudine), while suppression of viral replication seems most profound with either entecavir or telbivudine. The recommended duration of treatment with PEG-IF N is one year for both HBeAg-positive and HBeAg-negative patients. In HBeAg-positive patents, nucleos(t)ide analogue therapy should at least be continued until HBeAg seroconversion and a decline in HBV DNA to below 400 c/ml (80 IU/ml) has been achieved and maintained for six months during therapy. Whether nucleos(t)ide analogue therapy can be safely discontinued in HBeAg-negative patients is unknown; usually prolonged or indefinite antiviral treatment is necessary. Patients receiving PEG-IF N should be monitored once a month, while three monthly monitoring suffices for those receiving nucleos(t)ide analogues. Genotypic analysis of the HBV polymerase is indicated if an increase in serum HBV DNA of at least 1 log(10) c/ml (IU/ml) compared with the nadir value is observed during nucleos(t)ide analogue therapy. Antiviral therapy should be changed as soon as possible in case of confirmed genotypic resistance. Adding a second antiviral agent seems beneficial over switching to another agent. With the availability of multiple new antiviral drugs for the treatment of chronic hepatitis B, effective treatment is now possible for more patients and for longer periods. However, the complexity of HBV therapy has also increased. Nowadays, virtually all chronic HBV-infected patients can be effectively managed, either by inducing sustained off-treatment response or by maintaining an on-treatment response.

Treatment of chronic hepatitis C virus infection - Dutch national guidelines.

The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of practical guidelines in the evaluation and antiviral treatment of patients with chronic hepatitis C virus (HCV) infection. This includes recommendations for the initial evaluation of patients, the choice and duration of antiviral therapy and the follow-up after antiviral therapy. Hepatitis C is a slowly progressive disease. The initial evaluation of chronically HCV-infected patients should include liver biochemistry testing, virological testing and abdominal ultrasound imaging. Liver biopsy is no longer a routine procedure. Antiviral treatment should be considered for all HCV-infected patients. Current antiviral treatment is a long-term process and is associated with substantial side effects. When deciding whether to start treatment or not, the chance of successful treatment (80% with hepatitis C genotype 2 and 3 and 50% with hepatitis C genotype 1 and 4), the fibrosis stage, the expected side effects and the compliance of the patient should be taken into consideration. In the absence of significant fibrosis and necroinflammation in liver biopsy, postponing treatment is an option. Current antiviral treatment is contraindicated in patients with Child-Pugh-class B or C cirrhosis. The possibility of a liver transplantation should be investigated in these patients. Significant comorbidity with a limited life expectancy is an absolute contraindication for antiviral treatment Treatment of chronic hepatitis C consists of administration of peginterferon and ribavirin for 24 or 48 weeks. Patients with hepatitis C genotype 1 or 4 are treated for 48 weeks. Patients with hepatitis C genotype 2 or 3 are treated for 24 weeks. In patients with undetectable HCV RNA after four weeks (28 days) of treatment, a shorter treatment is equally effective (12 to 16 weeks for hepatitis C genotype 2 or 3; 24 weeks for hepatitis C genotype 1 or 4). Outpatient clinic visits are recommended at the start and after 2, 4, 8, and 12 weeks of treatment, and thereafter every four to six weeks until the end of treatment. It is recommended to stop treatment if the HCV RNA level has not decreased by at least 2 log10 IU/ml (c/ml) after 12 weeks of treatment or when HCV RNA is still detectable after 24 weeks of treatment. The recommended frequency of outpatient clinic visits for patients who are not being treated is once every six months in patients with cirrhosis, otherwise every 12 months. It is expected that new anti-HCV-medication (STAT-C, specifically targeted antiviral therapy for HCV) will become available in the near future. Therefore treatment of chronic HCV infection will probably be more effective in the future.

[The practice guideline 'Viral hepatitis and other liver diseases' (second revision) from the Dutch College of General Practitioners; a response from the perspective of gastroenterology]. / De standaard 'Virushepatitis en andere leveraandoeningen' (tweede herziening) van het Nederlands Huisartsen Genootschap; reactie vanuit de maag-darm-levergeneeskunde.

The treatment of chronic viral hepatitis B and C is now so effective that the efforts of health care workers should now be concentrated on tracing infected persons and determining antiviral therapies. It is for these reasons in particular that this revision from the Dutch College of General Practitioners' practice guideline 'Viral hepatitis and other liver diseases' is so necessary. It is estimated that there are 46 patients with chronic viral hepatitis in each general practice of 2300 people, and that only 1 in 64 is registered as such. This calls for active case finding. If a risk factor is present, a feasible approach might be to ask about symptoms and complaints and to establish serum transaminase levels.

Antiviral treatment for chronic hepatitis B virus infection--immune modulation or viral suppression?

The availability of nucleoside analogues has broadened treatment options for chronic hepatitis B virus (HBV ) infection. Registered treatment for chronic hepatitis B currently consists of (pegylated) interferon, lamivudine and adefovir, while entecavir is expected to be licensed in the short term. Treatment is generally recommended for patients with high serum HBV DNA and elevated ALAT, indicating the host's immune response against HBV. Induction of an HBV -specific immune response seems crucial for persistent control of HBV infection. Currently available treatment strategies can be differentiated into those that provide sustained off-treatment response and those that provide therapy maintained response. A finite treatment course with immunomodulatory agents (interferon-based therapy) results in sustained response in about one third of patients, while nucleoside analogue treatment generally requires indefinite therapy without a clear stopping point. Since nucleoside analogues are well tolerated, prolonged therapy is feasible, but a major drawback is the considerable risk of developing antiviral resistance, which occurs most frequently in lamivudine treated patients and to a lesser extent during adefovir or entecavir therapy. In our opinion, treatment with peginterferon should therefore be considered first-line therapy in eligible patients with a high likelihood of response based on serum HBV DNA, ALAT and HBV genotype. Patients not responding to PEG-IF N therapy or not eligible for peginterferon therapy should be treated with nucleos(t)ide analogues.

Doctor to patient transmission of hepatitis B virus: implications of HBV DNA levels and potential new solutions.

Hepatitis B virus (HBV)-infected health care workers (HCWs) can infect patients undergoing exposure prone procedures. Until now reviews have focused on the problem of the HBeAg-positive HCWs. After transmission of HBV by HBeAg-negative surgeons, the focus of Public Health Policy in the UK and the Netherlands has changed from HBeAg status to serum HBV DNA level. Viral load and the volume of blood transmitted determine the transmission risk of HBV. We have estimated the number of infectious particles transmitted by needlesticks, in comparison with those attributed in maternal-fetal transfusion. The blood volume transmitted by needlestick is roughly 1-30% of that of delivery. As vertical transmission with maternal HBV DNA levels below 10(7) g Eq./ml is rarely documented, HBV transmission by needlesticks is, according to our assumptions, unlikely to occur with HBV DNA levels below 10(7) g Eq./ml. Sera of transmitting HCWs contained HBV DNA levels between 5.0 x 10(9) and 6.35 x 10(4) g Eq./ml. Interpretation of these levels is hampered as the sera were taken at least 3 months after transmission. To prevent both loss of expertise and nosocomial infection, highly viremic HCWs can be offered antiviral therapy. Lamivudine and alpha-interferon can now be complemented with adefovir, tenofovir and entecavir to provide effective new therapies for chronic HBV-infected HCWs.

Doctor-to-patient transmission of hepatitis B virus: the potential of antiviral therapy for prevention.

Hepatitis B virus (HBV)-infected health-care workers (HCWs) have infected patients during medical procedures. In many countries HBV-infected HCWs are restricted in performing exposure prone procedures based on either HBeAg status or serum HBV DNA level. To prevent loss of skilled HCWs and to minimize transmission risk, highly viraemic HCWs can be offered antiviral therapy. Nucleoside analogues have proven to be effective in reducing transmission of HIV and HBV in the setting of vertical mother-to-infant transmission. Following the same rationale, suppression of viral load in HBV-infected HCWs could minimize the risk of doctor-to-patient transmission to such an extent that job modifications are no longer indicated. To limit the risk of drug resistance, the use of combination therapy is advocated. We describe two chronic HBV-infected HCWs treated with antiviral therapy, eventually leading to well-tolerated and highly effective combination therapy with lamivudine and tenofovir, with continuation of medical practice.

The 2012 revised Dutch national guidelines for the treatment of chronic hepatitis B virus infection.

In 2008, the Netherlands Association of Gastroenterologists and Hepatologists (Nederlands Vereniging van Maag-Darm-Leverartsen) published the Dutch national guidelines for the treatment of chronic hepatitis B virus infection. New insights into the treatment of chronic hepatitis B with relevance for clinical practice have been adopted in these concise, revised guidelines. The most important changes include the choice of initial antiviral therapy, licensing of tenofovir for the treatment of chronic hepatitis B and the management of antiviral resistance.

Prolonged antiviral therapy for hepatitis B virus-infected health care workers: a feasible option to prevent work restriction without jeopardizing patient safety.

To prevent transmission of hepatitis B virus (HBV) from health care workers (HCWs) to patients, highly viraemic HCWs are often advised to restrict performing exposure prone procedures (EPPs). To prevent loss of highly qualified medical personnel and simultaneously minimize transmission risk to patients, we offered highly viraemic HCWs antiviral therapy and evaluated the effects of this strategy. Eighteen chronic HBV-infected HCWs have been monitored every 3-6 months for a median period of 5.6 years (range 1.1-12.5 years). Antiviral therapy was offered if HBV DNA was above 10(5) copies/mL and EPPs were performed or active liver disease was present. Median HBV DNA levels, the percentage of days with HBV DNA above 10(3), 10(4) and 10(5) copies/mL, and reduction of HBV DNA during antiviral treatment have been analysed for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative HCWs separately. Prolonged viral suppression was achieved in both HBeAg-positive, as well as HBeAg-negative HCWs. In HBeAg-negative HCWs treatment with interferon or lamivudine maintained HBV DNA levels below 10(5) copies/mL. For HBeAg-positive HCWs continuous treatment with tenofovir or entecavir was essential for reaching low viraemia persistently. In 2004, median HBV DNA levels in both HBeAg-negative and HBeAg-positive HCWs were below 10(3) copies/mL and all HCWs executed their professional work full-range. For both HBeAg-positive and HBeAg-negative HCWs, antiviral treatment is effective in persistent suppression of virus levels below 10(5) copies/mL. This observation supports antiviral therapy as a viable management option instead of work restriction, with the provision of regular expert monitoring including quantification of HBV DNA.