Chronic hepatitis B virus (CHB) infection still remains a global public health concern with an estimated 350 million people chronically infected worldwide, the majority of whom acquire infection at birth or in early childhood. It is estimated that 50% of male and 14% of female carriers will die from CHB-related complications such as hepatocellular carcinoma (HCC) or cirrhosis. Since the global introduction of routine vaccination against hepatitis B virus (HBV) in newborns in countries where the incidence of HBV-related complications are high, such as in the Asia-Pacific region, there has been a significant and gratifying decline in rates of CHB and HCC.[3, 4]
In the last decade, we have developed a better appreciation of the natural history of CHB—it appears that the progression to cirrhosis and HCC in these patients is associated with persistently high serum HBV DNA levels over time. The other major risk predictors of progression to HCC and cirrhosis include age, male gender, hepatitis B e antigen (HBeAg) status, serum alanine aminotransferase (ALT) levels and HBV genotype. Two recent landmark clinical trials in Asia (Taiwan) clearly demonstrate the dramatic improvement in survival, reduced risk of HCC and advanced fibrosis/cirrhosis with the use of antiviral therapy.[5, 6] Where treatment options are concerned, we have come a long way in the last decade—complete suppression, or elimination of HBV is now eminently feasible and well-tolerated, and should be the key management goal in the treatment of CHB. The major strides in therapy lie in the introduction of newer oral nucleos(t)ide agents with higher genetic barrier to drug resistance.
There are currently seven antiviral agents that are commonly used in HBV infection. These include interferon-α, pegylated interferon α-2a, lamivudine, adefovir, entecavir, tenofovir and telbivudine. Interferon, which has both antiviral and immunomodulatory properties was the first agent used in the management of CHB. Despite long term data showing an improvement in overall survival and a reduction in the incidence of hepatic decompensation, the use of interferon has been limited due to its major side effects such as flu-like symptoms, bone marrow suppression, depression and autoimmune disorders, such as autoimmune thyroiditis. Thus, it is not surprising that the use of conventional and pegylated interferon-α has now been largely superseded by the introduction of other potent oral antiviral agents that can effectively suppress viral replication, reduce hepatic inflammation and halt disease progression.[8, 9]
Lamivudine, (2′,3′-dideoxy-3′-thiacytidine, commonly known as 3TC) was the initial oral nucleoside analog reverse transcriptase inhibitor, used in CHB to inhibit HBV DNA synthesis. Lamivudine is phosphorylated to active metabolites, which compete for incorporation into viral DNA; it is rapidly absorbed with an excellent bioavailability of > 80%.[9, 10] This drug has been reported to effectively prevent disease progression in patients with high HBV DNA levels and cirrhosis. The major drawback of this agent lies with its high rates of drug resistance; this typically develops at a rate of up to 25% of patients per year and reaching 80% by 4 years.[12, 13] Lamivudine resistance is related to the emergence of mutations in the YMDD motif (rtM204V/I) (tyrosine, methionine, aspartate, aspartate) of HBV DNA polymerase domain C as well as in (upstream) compensatory mutations in the polymerase domains A and B, that collectively limit the drug's clinical efficacy. The rate of genotypic resistance is reported to increase from 14% to 32% at 1 year, to 70% at 5 years.[9, 14]
Antiviral resistance can manifest in manifold ways, most commonly as virological breakthrough (> 1 log10 increase in HBV DNA level from nadir in a medication compliant patient). This scenario is usually followed by biochemical breakthrough (elevated ALT), and in some instances acute hepatitis flare and/or liver failure[9, 14] However, in select groups of HBV-infected patients, successful long-term viral suppression has been achieved using lamivudine with low treatment failure rates. With strict dosing adherence and monitoring for virological breakthrough, sustained virological suppression can still be reliably achieved with this agent. Because of cross-resistance between several oral antiviral agents and the emergence of lamivudine resistance, switching to alternative agents such as telbivudine and entecavir, would be imprudent. Of greater concern is the emergence of drug-resistant strains, which can significantly put global hepatitis B immunization initiatives at risk. Mutations associated with drug treatment can cause changes to the hepatitis B surface antigen (HBsAg) protein, the component of the virus that the hepatitis B vaccine mimics. Despite its limitations, lamivudine remains the mainstay treatment of CHB in many developing countries because of its safety, efficacy and affordability.
Adefovir dipivoxil is another antiviral agent available in the drug armamentarium; however, its utility has been limited by the development of significant drug resistance, reported at 30% by the end of 4 years. It has also lost appeal by virtue of poorer potency and slower rates of HBV DNA suppression. Based on smaller studies, adefovir has unfortunately (and perhaps, unfairly) acquired a reputation of the antiviral “least likely” to induce HBeAg seroconversion and one that is most likely to result in “primary non-response” (defined as failure to achieve a reduction in the HBV DNA level of < 2 log10) in 20–50% of patients[17-19]
Other second-line agents such as entecavir and tenofovir have emerged in the past 5 years with superior genetic barrier to HBV resistance; these agents have revolutionized CHB treatment with higher likelihood of viral load suppression, ALT normalization and HBsAg loss.[18, 19] Several trials report the use of nucleos(t)ide analogs in HBeAg positive patients at 1 year can result in undetectable levels of HBV DNA in up to 75% of treated patients, and that 40–77% patients normalize their ALT. It is also important to note, in these cohorts 12–22% developed HBeAg seroconversion and approximately 3% lost HBsAg. In patients with HBeAg-negative CHB, a one-year course of nucleos(t)ide analogs led to undetectable levels of HBV DNA in 50–90% of patients, and promising rates of HBsAg loss (1%). By extending the duration of nucleos(t)ide analog treatment to 5 years, such a strategy was associated with a progressive increase in the rate of HBeAg seroconversion, up to 48%; however, the rate of HBsAg loss remained low (0–10%)[7, 12, 18] While these newer agents are more potent and effective, they are unfortunately, more costly and thus, less accessible.
In this issue of the Journal, Kim and colleagues, retrospectively reviewed patients with CHB who were treated with lamivudine or second line nucleos(t)ide analogs from 1999 and 2009, and compared them with historical controls naïve to drug treatment (1991 to 1999). The authors observed that patients on antiviral treatment with “successful” viral suppression (defined as serum HBV DNA < 105 copies/mL at last follow-up) carried a better long-term prognosis and were less predisposed to hepatic decompensation, HCC and death. For those who had “suboptimal” viral suppression (HBV DNA > 105 copies/mL), this proved to be an independent risk factor for hepatic failure and death. Most notably, suboptimal viral suppression was significantly linked with an increased risk of HCC. These observations echo those of the “Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus” (REVEAL-HBV) study which showed a strong association between “low” HBV DNA levels of < 104 copies/mL (equivalent to < 2000 IU/mL) and a significantly reduced incidence of cirrhosis, liver-related mortality and HCC.
Both the REVEAL and current study highlight the vexing issue of elevated HBV DNA levels over time, and the highly plausible contribution of persistently high HB viral replicative activity to accelerated progression of fibrosis to cirrhosis and HCC. Interestingly, Kim and his co-authors note that the Child–Pugh scoring system used in their study to grade the severity of liver disease was suboptimal at predicting poorer survival in those with HBV-related liver cirrhosis. In their cohort of patients treated with nucleos(t)ide analogs, there appeared to be no significant difference in the survival rates between Child–Pugh grade B and C patients. It is also unclear in this study whether patients were able to reverse their degree of liver function impairment and perhaps, pro-inflammatory hepatic milieu, when treated successfully with antiviral agents to attain “undetectable” HBV DNA levels, or to a criteria they believed to be adequate viral suppression (HBV DNA < 105 copies/mL [< 20 000 IU/mL]).
While not entirely novel, the work of Kim et al. still adds to the literature by reinforcing the effectiveness of oral antiviral agents in mitigating the development of complications associated with CHB, especially those related to cirrhosis. We should not be satisfied with a HBV DNA level < 105 copies/mL (< 20 000 IU/mL), nor be lulled into a false sense of security that “lower” levels are optimal enough in minimizing the pro-inflammatory consequences of any viral replicative activity. There is now enough convincing evidence to support the ultimate treatment goal of an “undetectable” viral load in all patients with CHB, in order to derive the greatest benefit in risk reduction of HCC and liver-related mortality. The European Association for the Study of the Liver (EASL), Asia Pacific Association for Study of the Liver (APASL) and American Association for the Study of Liver Diseases (AASLD) guidelines on the management of CHB uniformly stipulate the major aim of treatment using a nucleos(t)ide analog is to achieve “virological response” that is, to reduce HBV DNA levels to “as low as possible”, ideally below the lower limit of detection of real-time polymerase chain reaction (PCR) assay (10–15 IU/mL), by 48 weeks. Long-term maintenance of sustained “low” to “undetectable” HBV DNA levels in such patients is also important in reducing the risk of resistance to antiviral agents.[7, 20, 21] It is sobering to note that despite the proven efficacy of nucleos(t)ide analogs in achieving viral suppression, they do not cure CHB infection and such agents alone will not be sufficient to reduce the global burden of HBV. Such therapeutic strategies must be combined with coordinated efforts from government, policy makers and health care providers in driving education programs to increase public awareness of hepatitis B, and when treatment is indicated, to improve accessibility, affordability and compliance in the use of antiviral agents against CHB.