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Management of Hepatitis B Infection

Stefan Zeuzem, MD
Program Director
Harry L. A. Janssen, MD, PhD
Milan J. Sonneveld, MD, PhD, MSc
Released: June 17, 2019

On-Treatment Management of HBV–Infected Patients Receiving Peginterferon Therapy

Endpoints of Peginterferon Therapy

Peginterferon is typically administered for a finite, 1-year course, after which therapy is discontinued (Table 9). A subset of patients will achieve an off-treatment sustained response after finishing the treatment course (as assessed at 6 months posttreatment) and will require no further therapy.

In patients with HBeAg-positive chronic HBV infection treated with peginterferon, a sustained response is frequently defined as an off-treatment sustained loss of HBeAg accompanied by the appearance of anti-HBe (HBeAg seroconversion), as these parameters are associated with an increased survival rate.[2,4,15,,173] However, a subset of these patients will have persistently high HBV DNA levels after HBeAg seroconversion, that is, they will progress to HBeAg-negative chronic HBV infection, and will require retreatment.[109,110] Using a combined serologic and virologic endpoint (HBeAg loss or seroconversion with concomitant HBV DNA < 2000 IU/mL), therefore, seems preferable, as this combined endpoint reduces the risk of relapse[174] and development of HCC,[14,175] and has a high probability of subsequent HBsAg loss and seroconversion.[176]

In HBeAg-negative chronically HBV–infected patients, the optimal response to peginterferon is prolonged suppression of HBV DNA to low levels (typically < 2000 IU/mL), combined with normalization of ALT levels.[177] Late relapse beyond 6 months post-treatment has been described, but a sustained response at 1 year post-treatment appears to be durable through long-term follow-up.[4,177]

Monitoring Patient Response to Peginterferon

Different patterns of HBV DNA decline have been described during peginterferon alfa-2b therapy in HBeAg-positive patients, but even patients with a late decline in HBV DNA have a considerable chance of response (~ 38%).[178] Furthermore, the predictive properties of HBV DNA levels are strongest after at least 24 weeks of treatment,[179] although the negative and positive predictive values are still limited. Indeed, one study found that, of 21% of 265 patients with HBV DNA > 9.0 log10 copies/mL after 24 weeks of treatment, only 14% (8/56) achieved HBeAg seroconversion at Week 72, which correlated to a negative predictive value of 86%.[180]

Quantitative serum HBsAg levels may help to predict response to peginterferon in HBeAg-positive chronic HBV infection and correlate with intrahepatic HBV DNA and active covalently closed circular DNA, 2 powerful predictors of off-treatment sustained response.[181,182] The pattern of HBsAg decline during peginterferon therapy for HBeAg-positive chronic HBV infection is strongly associated with response, and an absence of a decline in HBsAg levels at Week 12 of treatment reduced the probability of response to < 5% in one study (Table 12).[183] In another study, patients with HBsAg levels < 1500 IU/mL at Week 12 had a 51% chance of sustained off-treatment HBeAg seroconversion compared with only 16% of those with HBsAg levels > 20,000 IU/mL.[184] These findings were subsequently confirmed in another cohort of mostly Asian patients, where 58% and 57% of patients with HBsAg < 1500 IU/mL at Week 12 and 24, respectively, achieved HBeAg seroconversion 6 months posttreatment.[104] Nevertheless, it has become increasingly clear that HBsAg-based prediction rules are inconsistent in performance,[183,185] which may be explained by the differences in HBV genotype distribution across patient populations.[174] However, the EASL guidelines state that HBeAg-positive patients who do not achieve serum HBsAg levels < 20,000 IU/mL or any decline in HBsAg levels from baseline by Week 12 of therapy may be considered for discontinuation of treatment.[4]

A pooled analysis of 803 HBeAg-positive patients treated with peginterferon alfa in 3 global cohorts evaluated the application of a stopping rule based on a lack of HBsAg decline from baseline, rather than a prediction rule.[186] The presence of both an HBsAg level > 20,000 IU/mL and an HBsAg decline from baseline < 2000 IU/mL at Week 12 of treatment may serve to identify nonresponders to peginterferon therapy. However, the predictive value of these markers at Week 12 was highly variable based on HBV genotypes. Evaluations at Week 24 of therapy found that the same parameters had a high negative predictive value across HBV genotypes (Figure 5).

Predicting a patient’s response to peginterferon using HBV DNA levels is as difficult in HBeAg-negative patients as in HBeAg-positive cohorts.[128] However, a combination of on-treatment HBV DNA and HBsAg levels could accurately identify genotype D patients unlikely to achieve a response (Table 12),[113] and the EASL practice guidelines state that genotype D, HBeAg-negative patients who do not achieve any decline in HBsAg levels and fail to achieve a ≥ 2 log10 IU/mL decline in HBV DNA levels after 12 weeks of therapy may be considered for discontinuation of treatment.[4]

Figure 5. HBsAg levels at Week 24 of peginterferon therapy and response to treatment in HBeAg-positive patients, stratified by HBV genotype.[186]


Table 12. HBsAg Levels at Week 12 of Peginterferon Therapy and Response to Treatment in HBeAg-Negative Patients


Add or Switch to Peginterferon Therapy to Increase Success of Nucleos(t)ide Analogue Therapy

Given the limited chances of successful discontinuation in patients treated with nucleo(s)tide analogues, various studies have investigated the feasibility of using peginterferon-alfa-2a switch or add-on strategies to increase the chances of off-treatment success. In one proof-of-concept trial in HBeAg-positive disease, 175 patients were randomized to either entecavir with subsequent peginterferon alfa-2a add-on from Week 24-48 (n = 85) or entecavir alone.[187] At Week 48, patients with a response (HBeAg clearance with HBV DNA < 200 IU/mL) discontinued peginterferon alfa-2a, followed by 24 weeks of additional entecavir consolidation treatment. Entecavir was discontinued by all responders at Week 72. Off-treatment follow-up continued for another 6 months (through Week 96). At Week 48, response was achieved in 19% of patients treated with add-on therapy compared with 10% of patients treated with entecavir alone (P = .095). Of those patients who discontinued entecavir, a sustained response was observed in 79% of the patients who discontinued entecavir therapy after peginterferon alfa-2a add-on therapy compared with 25% of those who discontinued after a response induced by entecavir alone (P = .014).

In another study in HBeAg-negative disease, 183 patients with undetectable HBV DNA for at least 1 year during treatment with nucleo(s)tide analogues were randomized to continue monotherapy or to add peginterferon alfa-2a for 48 weeks.[188] At Week 96, HBsAg clearance was achieved in 7 patients (8%) treated with peginterferon alfa-2a compared with 3 patients (3%) who continued the nucleo(s)tide analogue (P = .15).

Switching from entecavir to peginterferon alfa-2a has also been evaluated. HBeAg-positive patients (n = 200) who had received entecavir for 9-36 months and had HBeAg level < 100 PEIU/mL and HBV DNA < 1000 copies/mL were randomized to 48 weeks of entecavir or a switch to peginterferon alfa-2a.[189] At Week 48 (end of treatment), HBeAg seroconversion was achieved in 14.9% of patients who switched to peginterferon alfa-2a vs 6.1% of those who continued entecavir (P = .0467).

Despite the limited increases in off-treatment sustained response rates with peginterferon add-on or switch treatment, such strategies are currently not recommended by EASL.[4]

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