Advances in hepatitis B.

Hepatitis B virus (HBV) remains an important public health issue in South Africa. Prior to the incorporation of HBV vaccination into the Expanded Programme of Immunisation (EPI) more than a decade ago, prevalence rates of HBV were estimated at between 0.3% and 15%. (1) However, the potential benefits of introducing the vaccine have not yet been accurately assessed and may not be fully realised without complete vaccination coverage. A further potentially negative factor in HBV control is the burgeoning HIV/AIDS epidemic as the natural history of HBV is altered in those who are coinfected. (2) The long-term risks of chronic HBV infection include chronic hepatitis, which may evolve to cirrhosis and the risk of hepatocellular carcinoma is significantly increased, irrespective of the presence of cirrhosis.

Highlighting the advances in the understanding of HBV is that in the past 2 years four major groups, viz. the American Association for the Study of Liver Diseases (AASLD), the European Association for Study of the Liver (EASL), the Asia-Pacific Association for the Study of the Liver (APASL) and the World Gastroenterology Organisation (WGO), have updated their guidelines on the management of HBV infection. (3-6)

Knowledge and understanding of both the natural history of HBV and therapeutic advances have significantly increased over the last decade. Key among several factors that explain the predilection of HBV to persist has been the understanding that the virus remains within the nucleus of infected hepatocytes. It achieves this through covalently closed circular DNA (cccDNA) that forms the template upon which viral particles can be replicated. During transcription, cccDNA is replenished by returning to the hepatocyte nucleus. An insight in the virus' ability to persist is that patients who have cleared HBV surface antigen continue to harbour cccDNA. This may allow for so-called occult HBV infection that is clinically defined as detectable HBV DNA in the serum of those previously exposed to HBV, i.e. HBsAg negative and HBcore antibody (IgG) positive. To date no discernable liver disease is associated with occult HBV infection; however, the risk of reactivated disease exists in those who are immunocompromised.

Natural history

Intrinsic to defining an appropriate management strategy for patients with chronic HBV infection is determining in which phase of the natural history of chronic infection they are in. In those with chronic infection, an initial immune tolerant phase is characterised by the presence of HBeAg, high HBV DNA levels while transaminase levels are normal. Histologically there is minimal or no necroinflammation or fibrosis.

It is followed by a phase of immune clearance that is similar to the immune tolerant phase. However, transaminases are now elevated and histologically there is increased necroinflammatory activity. This phase may last for several weeks to years and if successful, HBeAg seroconversion will occur with the development of sustained HBe-antibody titres.

The next phase of HBV latency (also called inactive HBV carrier state) is characterised by loss of HBeAg, normal transaminases and low or undetectable HBV DNA levels. HBsAg loss during this phase may occur spontaneously but does so in <1% of individuals.

The HBV latent phase may persist lifelong, but in about 5-15% of patients HBeAg-negative chronic HBV hepatitis can occur. This phase, more common in older men, is due to patients harbouring HBV variants with nucleotide substitutions in the precore and/or basal core promoter regions of the HBV genome, resulting in the inability to express HBeAg while being able to avidly replicate. The phase is thus characterised by undetectable HBeAg, fluctuating transaminases and HBV DNA levels. Invariably, there is significant necroinflammatory activity with progressive fibrosis. The concern with this particular phase is the propensity to develop more rapidly progressive fibrosis and cirrhosis.

Data published in the last 2 years and, most notably, the REVEAL-HBV study, strongly suggest that suppressing HBV DNA levels reduces the risk of cirrhosis and/or hepatocellular carcinoma. (7) However, an important consideration in this particular study is that 85% of patients were HBeAg negative and hence findings may not be applicable to all patients with chronic HBV infection.

Management strategies

Key to choosing a specific therapy for a patient with chronic HBV infection is deciding who actually warrants therapy. Firstly, as indicated, patients need to be categorised in terms of which phase of chronic infection they are in. Treatment should be considered in those in the immune clearance and HBeAg-negative phase of chronic HBV infection. Treatment should also be considered in patients with established cirrhosis, especially decompensated cirrhosis. Furthermore, a useful clinical point to remember is that HBV causes liver disease and liver biopsy remains an important adjunctive clinical tool in deciding who warrants therapy.

Goals of therapy differ depending on HBeAg status. In HBeAg-positive patients the primary goal is sustained HBeAg seroconversion, while in HBeAg-negative patients the goal is sustained HBV DNA suppression. Secondary goals in both scenarios are normalisation of transaminases that invariably follows HBeAg seroconversion in HBeAg-positive and HBV DNA suppression in HBeAg-negative patients. Improvement in liver histology is probable if these endpoints are achieved. HBsAg loss and seroconversion is the ultimate goal of HBV therapy but remains distinctly elusive with currently available therapies.

Six drugs are currently available in South Africa for the treatment of hepatitis B. These include standard and pegylated alpha interferon, lamivudine and entecavir. Not registered in SA but available for off-label use, is tenofovir (alone or in fixed combination with emtricitabine). Tenofovir was registered for chronic HBV infection by both the European regulatory authority as well as the FDA in 2008. Ordinarily, tenofovir alone, or in a fixed-dose combination with emtricitabine, is used in the treatment of HIV/AIDS.

Patient selection for a given treatment modality is vital. Ideal patients for alpha interferon include HBeAg-positive patients with elevated transaminases, an HBV DNA viral load (<[10.sup.7] IU/ml) and high necroinflammatory activity scores on liver biopsy. Patients also need to be motivated. Existing data suggest that HBV genotype A and B is more responsive to interferon that genotypes C and D. However, genotyping is not routinely available in South Africa and genotype alone should not singularly direct the choice of treatment. Six to 12 months of standard or 48-52 weeks' pegylated interferon are both effective in HBeAg-positive patients. If interferon is to be used in HBeAg-negative patients, pegylated interferon should be used, as standard alpha interferon has poor sustained efficacy in this group. While on treatment, factors such as an HBV DNA decrease to <20 000 IU/ml at 12 weeks of therapy predict for a sustained response when using interferon. Benefits of pegylated interferon over standard interferon include improved efficacy and the convenience of once-weekly dosing. However, the side-effect profile is similar with both standard and pegylated interferon. Contraindications to interferon remain decompensated cirrhosis, autoimmune disease and uncontrolled severe depression or psychosis. The overwhelming benefit of interferon-based therapy includes a finite course of treatment, immune-mediated containment of HBV infection and the absence of resistance.

Compelling indications for oral antiviral therapy are contraindications to interferon, cirrhosis or as primary therapy in HBeAg-negative patients. The major concern with antivirals remains the development of resistance. In drugs with a low genetic barrier to resistance such as lamivudine, resistance can exceed 70% after 5 years. The newer agents have greater efficacy and have higher genetic barriers to resistance. Existing data for entecavir and emerging data for tenofovir suggest a very low rate of resistance developing with sustained long-term use. (8) Preferentially agents such as lamivudine should be avoided but given the cost differentials between lamivudine and some of the newer agents this is not always possible. Fortunately tenofovir remains very affordable in South Africa. When using antivirals, in particular lamivudine, monitoring for genotypic and phenotypic resistance is required. An incomplete or failing response to an antiviral warrants an appropriate intervention that is beyond the scope of this review. Endpoints in patients on antiviral therapy differ somewhat to those using interferon. In HBeAg-positive patients antiviral therapy should continue beyond HBeAg seroconversion for approximately 1 year before considering stopping antiviral therapy. However, this should be carefully considered and dictated by the clinical scenario. HBeAg seroconversion with antivirals will occur in approximately 20% of patients after 1 year of treatment. In the absence of HBeAg seroconversion therapy should continue indefinitely. In HbeAg-negative patients the aim of therapy is prolonged HBV suppression. Therapy, therefore, once initiated, is continued indefinitely. Given the issue of resistance, combination antiviral therapy has been an attractive option. Evidence in favour of de novo combination therapy remains limited and current guidelines suggest de novo combination therapy in cirrhotics and post liver transplantation for HBV.

Conclusion

Chronic HBV remains a public health issue in South Africa. Prevention with the continued widespread implementation of HBV vaccination remains the cornerstone of management. In those with chronic HBV infection careful evaluation of who actually warrants and would benefit from treatment is as important as tailoring a therapeutic modality to a patient. Practitioners should have a low threshold for referral of patients to specialist centres for expert opinion and advice.

References

(1.) Vardas E, Mathai M, Blaauw D, et al. Preimmunization epidemiology of hepatitis B virus infection in South African children. J Med Virology 1999; 58:111-115.

(2.) Puoti M, Torti C, Bruno R, et al. Natural history of chronic hepatitis B in co-infected patients. J Hepatology 2006; 44: S65-S70.

(3.) Lok ASF, McMahon BJ. American Association for the Study of Liver Diseases (AASLD) Practice Guidelines: Chronic hepatitis B. Hepatology 2007; 45(2): 507-539.

(4.) European Association for Study of the Liver. EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatology 2009; 50: doi:10.1016/ j.jhep.2008.10.001 (in press)

(5.) Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update--AsiaPacific Association for the Study of the Liver (APASL). Hepatol Int 2008; 2: 263-283.

(6.) World Gastroenterology Organisation Practice Guideline: Hepatitis B. http://www. worldgastroenterology.org/hepatitis-b.html

(7.) Chen CJ, Iloeje UH, Yang H. Long-term outcomes in hepatitis B: The REVEAL-HBV Study. Clin Liver Dis 2007; 11: 797-816.

(8.) Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008; 359(23): 2442-2455.

MARK SONDERUP, FCP (SA)

Senior Specialist, Division of Hepatology, University of Cape Town and Groote Schuur Hospital