Hepatitis B: Modern End Points of Treatment and the Specter of Viral Resistance

The ultimate goal of treating a chronic infectious disease is the eradication of the infectious agent to prevent organ damage or death. The natural history of untreated chronic hepatitis B may result in the development of cirrhosis, followed by hepatic decompensation and death. Hepatocellular carcinoma (HCC) can also occur in patients with chronic hepatitis B virus (HBV) infection, with or without the presence of cirrhosis. Antiviral therapy with oral nucleos(t)ide analog (NUC) agents suppress viral replication but do not directly act on the covalently closed circular DNA that resides within infected hepatocytes; thus, current oral therapy rarely eradicates HBV infection. Although these oral antiviral agents are well-tolerated with minimal side effects, prolonged viral suppression runs the risk of selecting for antiviral drug–resistant mutations and causing virologic breakthrough; decreased patient adherence with antiviral treatment may also be associated with breakthrough. Therefore, routine “cure” or eradication of HBV infection is unrealistic, at least with current therapy. Nevertheless, preventing the clinical outcomes, or end points, of this disease remains important and are likely achievable with available treatment.

The development of complications of chronic hepatitis B occur over the long natural history of HBV infection, but are not necessarily uniform as demonstrated by the occurrence of HCC in patients without cirrhosis. Furthermore, cirrhosis may take from years to decades to develop, and patients with chronic HBV infection are often asymptomatic before these clinical end points of cirrhosis or HCC are discovered. Judging the efficacy of antiviral therapy by waiting to see if these clinical end points are avoided is neither practical nor ethical. To satisfy the need to assess the impact of antiviral therapy, reliable intermediate or surrogate end points have been used as therapeutic goals with the treatment of chronic hepatitis B. According to the National Institutes of Health, surrogate end points are “biomarkers intended to substitute for a clinical endpoint.” These surrogate end points should occur on the causal pathway of disease, be highly associated with the long-term clinical end point of interest, and be easier to assess than the ultimate outcome. Furthermore, the effect of an intervention upon the surrogate end point should also have a downstream effect on the prevention of the clinical end point.

The National Institutes of Health–proposed surrogate end points for chronic HBV infection include histologic criteria [decrease in histology activity index (HAI) by ≥2 points with no worsening of fibrosis], biochemical changes [normalization of alanine aminotransferase (ALT)] levels, virologic response (maintained suppression of serum HBV DNA to undetectable levels by a sensitive assay), and serologic changes [loss of hepatitis B e antigen (HBeAg), with or without seroconversion to antibody to HBeAg (anti-HBe), and potentially loss of hepatitis B surface antigen (HBsAg); Table 1 ]. Although these surrogate end points are used to assess the efficacy of antiviral therapy, particularly during phase III clinical trials of HBV treatment and by regulatory authorities for licensing new treatments, they do not evaluate the various aspects of disease status associated with chronic hepatitis B. Therefore, such end points may not be sufficient in individual patients for determination of the overall course of treatment such that combination of end points may be necessary. Given their intermediate status along the causal pathway of disease, these surrogate end points may still require further clarification of their pathogenic role and impact on ultimate outcomes, although much information has been learned from cohort studies involving both treated and untreated patients. In addition, these surrogate end points could be subject to confounding owing to undefined interactions between each other. Last, cost-effectiveness analyses of these various end points are currently unavailable.

Table 1

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