We evaluated the antiviral response of patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as having hepatitis B virus (HBV) DNA ≥9 log10 copies/mL, after 240 weeks of tenofovir disoproxil fumarate (TDF) treatment. A total of 641 hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients (129 with HVL) received 48 weeks of TDF 300 mg (HVL n = 82) or adefovir dipivoxil (ADV) 10 mg (HVL n = 47), followed by open-label TDF for an additional 192 weeks. Patients with confirmed HBV DNA ≥400 copies/mL on or after week 72 had the option of adding emtricitabine (FTC). By week 240, 98.3% of HVL and 99.2% of non-HVL patients on treatment achieved HBV DNA <400 copies/mL. Both groups had similar rates of histologic regression between baseline and week 240. Patients with HVL generally took longer to achieve HBV DNA <400 copies/mL than non-HVL patients, but by week 96, the percentages of patients with HBV DNA <400 copies/mL were similar in both groups. Among HVL patients, time to achieving HBV DNA <400 copies/mL was shorter among those initially receiving TDF, compared to ADV. No patient with baseline HVL had persistent viremia at week 240 or amino acid substitutions associated with TDF resistance. Conclusion: CHB patients with HVL can achieve HBV DNA negativity with long-term TDF treatment, although time to HBV DNA <400 copies/mL may be longer, relative to patients with non-HVL. (Hepatology 2013;58:505–513)
Chronic hepatitis B (CHB) patients with high pretreatment viral load (HVL) represent a clinical challenge. Higher levels of hepatitis B virus (HBV) DNA are associated with an increased risk for hepatocellular carcinoma (HCC) and cirrhosis. In addition, available evidence suggests that CHB patients with HVL are less likely to respond to interferon (IFN)-based regimens than those with lower viral load. In hepatitis B e antigen (HBeAg)-positive patients, having baseline HBV DNA <2 × 108 IU/mL is a positive predictor of sustained response to pegylated interferon alpha (Peg-IFN-α). Furthermore, having HBV DNA levels ≤109 copies/mL is predictive of HBeAg seroconversion with Peg-IFN-α2a treatment. Baseline HBV DNA level is also a predictor of response in HBeAg-negative patients treated with Peg-IFN-α2a with or without lamivudine.
A similar trend with baseline HBV DNA level and virologic response (VR) has been observed with nucleos(t)ide analog treatment. Mean baseline HBV DNA has been indicated as a factor influencing likelihood of VR with entecavir therapy. In a study of treatment-naïve HBV patients who received entecavir for 3 years, 100% of patients with baseline HBV DNA <8 log10 copies/mL had undetectable HBV DNA (<12 IU/mL), whereas only 75% of patients with baseline HBV DNA ≥8 log10 copies/mL did. Of the patients who did not have HBV DNA undetectability, many had relatively low HBV DNA levels (≤3 log10 copies/mL), and it is not known whether these patients may have achieved further reductions in HBV DNA with longer treatment.
The nucleotide analog tenofovir disoproxil fumarate (TDF) was approved in 2008 for the treatment of CHB. In two phase III studies, which included a total of 641 patients, TDF suppressed viral replication in both HBeAg-positive and -negative patients. In these studies, 240 weeks of TDF-based therapy led to significant histologic regression, including reversal of cirrhosis in 74% of patients that had cirrhosis at baseline. Within this analysis, we examined whether HBeAg-positive and -negative patients with HVL, defined as pretreatment levels of HBV DNA ≥9 log10 copies/mL, responded as well to long-term TDF-based treatment as patients without pretreatment HVL (non-HVL).
Data from this 240-week study of the nucleotide analog, TDF, suggest that CHB patients with HVL can achieve VR at similar rates as patients with lower viral loads, but VR tends to take longer in HVL patients. Previous studies of the nucleoside analog, entecavir, suggested that HVL was a negative predictor of response, defined either as HBV DNA <400 copies/mL during on-treatment follow-up or HBV DNA being undetectable at year 3 of treatment[7, 8]; however, the analyses were conducted in smaller patient populations treated for shorter time courses. In this study, by the end of 240 weeks, neither persistent viremia nor TDF resistance were observed in any patient, regardless of baseline viral level.
During the first 48 weeks of therapy, HBV DNA declines in a biphasic pattern (Fig. 2) similar to what has been reported on previously with ADV therapy. In the HVL group, HBV DNA continued to decline from week 48 through 88, whereas, in the non-HVL group, many patients achieved HBV DNA <400 copies/mL by week 56. By week 96, the proportions of patients who had HBV DNA <400 copies/mL was similar between the groups.
Our results are in contrast with perceptions in the clinical setting that HVL patients are challenging to treat. These perceptions have been, at least in part, caused by experience with earlier antivirals, such as lamivudine and telbivudine, to which some patients had minimal or no VR and others experienced breakthrough. With lamivudine monotherapy, 76% of patients develop resistance after 5 years, and with telbivudine, approximately 25% of HBeAg+ and 11% of HBeAg− patients had resistance after 2 years. ADV, though effective against lamivudine- and telbivudine-resistant mutants, has limited potency and is generally used as add-on therapy.
Given the concern for development of resistance with earlier antivirals, this study of TDF monotherapy was designed such that FTC could be added to patients with HBV DNA ≥400 copies/mL at 72 weeks. However, add-on therapy with FTC appeared to be unnecessary, even in patients with HVL, because it did not provide further benefit over TDF alone regarding VR or suppression of resistance. In a recent study, combination entecavir and TDF therapy conferred an incremental benefit over entecavir monotherapy for reaching HBV DNA <50 IU/mL in HBeAg-positive patients with high baseline viral loads after 96 weeks of treatment. Our results suggest that TDF monotherapy is effective in patients with high baseline viral levels, with 98.3% of HVL and 99.2% of non-HVL patients achieving HBV DNA <400 copies/mL and no persistent viremia detected by week 240.
Rate of ALT normalization was high in both HVL and non-HVL groups, although the rate was higher in the non-HVL group. The majority of patients in both HVL and non-HVL groups had regression of histological cirrhosis. HBsAg loss and HBsAg seroconversion were higher among patients with HVL versus non-HVL. No obvious differences in patient or disease characteristics accounted for the differential rates of HBsAg loss and seroconversion. More research is needed to determine whether and how viral load might affect HBsAg loss and seroconversion in patient populations outside of this study.
From the outset of HBV antiviral therapy, it has been conventionally accepted that patients with lower baseline viral levels and higher baseline serum ALT values are more responsive than patients with higher viral levels and/or lower ALT values. In 2010, Wu et al. found that among HBeAg-negative patients, those with minimally raised serum ALT values had similar antiviral responsiveness as patients with higher values. In the present analysis, we have explored the prognostic significance of baseline serum HBV DNA levels; our finding of equal virologic responsiveness, regardless of baseline viral load, now confirms that these earlier perceptions are no longer applicable in the current antiviral arena.
This study only included patients in the immune clearance phase of HBV infection, and therefore the results cannot be extrapolated to immunotolerant patients, who likewise generally have HVL, but who do not have elevated ALT, and therefore may have little evidence of histologic inflammation. The effectiveness of TDF and TDF plus FTC is currently being evaluated in CHB patients with normal ALT levels. Additionally, the normal ALT levels associated with the immunotolerant population make direct analyses of ALT and comparisons between the two groups difficult.
In conclusion, our results suggest that long-term TDF monotherapy can lead to virologic suppression in the vast majority of CHB patients with HVL, regardless of HBeAg status. The extent of virologic suppression and absence of resistance with TDF in this study is indicative of a shifting HBV treatment landscape in which risk of nonresponse or development of resistance is declining with the adoption of newer, more-potent antivirals. Accordingly, HVL should not be a deterrent for treatment. For patients with CHB with HVL treated with TDF, our findings offer the reassurance that the long-term VR should prove excellent.