Spontaneous or treatment induced flares of inflammation are frequently observed in CHB. These abrupt elevations in serum ALT are the result of an increase in intrahepatic necroinflammation associated with expanded numbers of intrahepatic lymphocytes, in particular cytotoxic T lymphocytes. Cytotoxic T lymphocytes are important to control HBV but can also induce liver damage, depending on the environment and functional capability.10–15
Therapy with IFN is based on its stimulating effect on cytotoxic T lymphocyte and natural killer cell function. Flares during standard IFN treatment occur typically during the second and third month, and are thought to herald virological response and disease remission.2–5,16
Probably, these flares represent an attempt of the immune system to clear the HBV infection.
In the current study, 29% of patients experienced a flare during therapy (n
34) or follow up (n
33). We did not find a significant difference between the number of flares in patients treated with Peg-IFN α-2b alone versus those treated with Peg-IFN α-2b in combination with lamivudine. Patients with low baseline ALT or pre-existing cirrhosis were more prone to having flares. Cirrhotics tended to experience flares with high ALT values. These patients should be monitored carefully during treatment with Peg-IFN α-2b, not only because of their increased risk of flares but also because of their diminished residual liver function and the consequent risk of developing decompensated liver disease. In the current study, no permanent or life threatening signs of liver failure were encountered.
Overall, flares were not associated with response to therapy. However, flares during treatment were more often associated with response than flares after treatment (fig 1). In addition to the timing of flares, response was dependent on HBV genotype and the magnitude of the flare. Previously, a strong association between the severity of flares and HBsAg seroconversion was found both in the natural history of CHB and in the setting of IFN therapy.16,17
In these studies, different definitions of flares were used. Nair and Perrillo16
defined a flare as an increase in ALT of at least twice the ULN compared with baseline values while Yuen and colleagues17
defined a flare as elevated transaminases above twice the ULN. As our patients already had high baseline serum ALT levels (ALT levels above twice the ULN was used as an entry criterion in this study population), these definitions were less suitable. For a clear distinction between flares and relative mild elevations in serum ALT, we based our definition on our previous experience, in which a threefold increase in serum ALT from baseline was used.7
An important finding of the current study was the distinct patterns of flares occurring, with stable viral load followed by a decrease in viral load (host induced flares) versus flares preceded by an increase in viral load and variable viral loads afterwards (virus induced flares). Patients with host induced flares responded significantly better to therapy than those with a virus induced flare. Multivariate analysis revealed host induced flare as the only independent factor predicting treatment response. Interestingly, all patients undergoing HBsAg seroconversion had a host induced flare. This further supports the hypothesis that full control and elimination of the virus, as indicated by clearance of HBeAg and HBsAg, is achieved by a vigorous host immune response rather than by direct suppression of the virus. Previous studies have shown that both spontaneous or IFN-α induced exacerbations of hepatocellular necrosis in CHB are associated with induction of a virus specific CD4+
T cell response.18,19
Under IFN-α therapy such a hepatitis flare preceding sustained HBeAg seroconversion requires a substantial increase in IL-12 production, along with induction of the Th1 cytokines IFN-α and IL-2.20
Virus induced flares, which emerged after increasing levels of HBV DNA, were related to treatment with the combination with lamivudine, and more frequently seen after therapy. These flares were attributed to reactivation of HBV after withdrawal of lamivudine. In general, they did not lead to disease remission but have been associated with clinical exacerbation and disease progression.7
In our study, virus induced flares did not usually lead to response, and even appeared to be detrimental rather than beneficial for treatment response. Virus induced flares are not restricted to CHB patients treated with IFN and or lamivudine, but also occur during the natural history of the disease. Liu et al
described several patients in whom significant flares were preceded by an increase in HBV DNA.21
Studies in anti-HBe positive patients also showed episodes of flares as a result of sudden reactivation of HBV.22–24
In general, flares during treatment with IFN or Peg-IFN should not be treated with nucleoside analogues, and IFN should only be discontinued in case of impending liver failure. Particular care should be taken in patients with cirrhosis who have the highest risk of developing liver failure. On-treatment flares are likely to be host or IFN induced flares, and could well herald loss of HBeAg or even HBsAg. In contrast, flares after treatment, especially after lamivudine, are in general detrimental flares. These flares are typically seen after an increase in HBV DNA and seldom lead to treatment response. Retreatment with a nucleoside analogue should then be considered.
In conclusion, flares play an important role in the treatment with Peg-IFN α-2b alone or in combination with lamivudine, and patients with pre-existing cirrhosis are at greater risk for experiencing a flare. Furthermore, host induced flares but not virus induced flares may herald a response to therapy. For optimisation of treatment, it remains to be investigated which virological and immunological mechanisms induce the specific flare patterns described in our study.