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Hepatitis B

Background


Hepatitis B is endemic in New Zealand with an estimated 90,000 individuals with chronic infection. The National HBV screening programme confirmed highest rates in Chinese (9.1%), Pacific Islander (8.5%) and Maori (5.8%). Although Europeans were not specifically targeted in this programme, of a prevalence rate of 1% which is higher than in Australia, North America and Europe, reflecting the risk of early horizontal transmission. Although new childhood infections have been largely eradicated by the introduction of neonatal vaccination, the numbers of chronic infections are projected to climb steadily from increased immigration for high-prevalence countries throughout the Asia-Pacific region (see Department of Statistics website Census data and projections).

Chronic hepatitis B remains the leading and leading cause of hepatocellular carcinoma (75%), liver-related mortality (63%) and liver transplantation (32%) in this country.

The two major advances in management of chronic HBV infection in New Zealand were the introduction of national screening programme for HBV in 1998 and of lamivudine in 2000. 

Although the screening programme was limited to 3 years and only screened one third of  the targeted at-risk population (Maori, Pacific Islanders and Asian New Zealanders >15 years old), almost 13,000 carriers were identified, most of whom have entered a long-term follow-up programme, designed to facilitate early diagnosis and treatment of both hepatocellular carcinoma and chronic liver disease. The follow-up programme is now managed through the Hepatitis Foundation (www.hepfoundation.org.nz), who co-ordinate blood tests through primary care providers, store results and ensure appropriate referrals to secondary care for consideration of antiviral therapy or investigation for hepatocellular carcinoma. The Foundation also follows up referrals to ensure timely assessment. They collect and archive all screening results (ALT, AFP) for later audit of outcomes of the programme. The NZLTU has been contracted by the Ministry of Health to perform this analysis. To-date, NZLTU has analysed the effect of screening on the outcome of HBV-related hepatocellular carcinoma in 120 cases detected through the screening programme compared to 220 detected in the unscreened population between 2000 and 2007. This demonstrated a significant improvement in survival, even correcting for a 3 year lead-time bias (5 year survival of 40% vs. 2%). The NZLTU are currently analysing the ALT data to determine the impact of antiviral therapy on survival.

Drug treatments


Lamivudine was approved and funded for the management of chronic hepatitis B in May 2000 and since that time almost 2,500 have been treated. Initial funding criteria were ALT>2xULN, HBV DNA >5logs, with maximum duration of 3 years. In recognition of new data, these have been widened to include all advanced liver disease with ALT <2xULN, all HBsAg receiving chemotherapy, and duration is now life-long.

Most clinicians follow the published APASL guidelines and monitor patients for lamivudine resistance with 3 monthly ALT and HBV DNA. In most other countries in Asia-Pacific including Australia viral load monitoring is not funded. We are fortunate in that 3 monthly HBV DNA measurements are fully funded in New Zealand.
With increasing numbers and duration of lamivudine therapy, lamivudine resistance has become a major issue. Data from over 1000 patients receiving long-term lamivudine demonstrate rate of >50 after 4 years. Adefovir was approved by the FDA for rescue of lamivudine resistance in September 2002. In Early 2003, Gilead Sciences began compassionate access scheme in New Zealand, into which 160 patients were enrolled. Adefovir was finally funded by PHARMAC in May 2006 for the rescue of established lamivudine resistance (with evidence of biochemical, virologic and genotypic resistance).

As for lamivudine monotherapy, adefovir monotherapy is associated with significant resistance (29% after 5 years in treatment naïve, and >50% after 4 years in lamivudine resistant patients). Two controlled studies published in recent issues of Hepatology (Lampertico et al and Rapti et al) clearly demonstrate the benefit of combination therapy in preventing adefovir resistance and complications. New Zealand is the only country where combination lamivudine and adefovir therapy is funded (for patients with lamivudine resistance and advanced fibrosis – F3/F4). Currently discussions are underway with PHARMAC to access combination therapy for all patients with lamivudine resistance.

During the last 2 years, Pegylated Interferon, Entecavir and Telbivudine have been approved by the FDA for treatment of CHB, all of which are registered in New Zealand, but only Pegylated Interferon approved by PITAC and still unfunded. Over the next 12 months, other agents likely to gain FDA approval include tenofovir, the combination Truvada (tenofovir plus emtracitabine) and clevudine. The Asia-Pacific Association of Study of Liver will update the regional guidelines on management of chronic hepatitis B in November this year. It is likely that lamivudine will be removed from first-line therapy. The “Roadmap” concept will also be recommended, where treatment algorithms are indivualised according to early on-treatment responses - the degree of viral suppression at 24 weeks therapy dictates change in therapy and monitoring practice. This is supported by data from lamivudine, adefovir, entecavir and telbivudine registration studies which correlate early viral suppression with long-term efficacy and risk of resistance.

Current treatment trials include:


(1)    Phase III study of Tenofovir versus Adefovir in both eAg positive and eAg negative CHB. This is in the extension phase (long-term open-labelled tenofovir).
(2)    Phase III study of Clevudine versus Adefovir in both eAg positive and eAg negative CHB. About to commence the active recruiting phase.
(3)    Phase III study of Telbivudine versus Pegylated Interferon versus combination in eAg positive CHB. This is in the active recruiting phase.
(4)    Phase III study of four different regimens of Pegylated Interferon in eAg positive CHB. This is in the active recruiting phase.
(5)    Phase II study of long-term tenofovir versus Truvada in immunocompetent HBV infection. Aim is to suppress HBV to PCR nondetectability and prevent complications in high-risk patients. About to commence the active recruiting phase

Middlemore Hepatitis Clinic was one of the 4 global sites chosen for complete FDA inspection of the Telbivudine registration studies last year. This is only the third FDA visit to these shores and went extremely well with no major findings.

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