Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients?

Chronic hepatitis B(CHB) remains a challenging global health problem, with nearly one million related deaths per year. Nucleos(t)ide analogue(NA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus(HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen(HBs Ag), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated NA therapy discontinuation after several years of NA treatment and before HBs Ag loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBs Ag seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure aclose follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host's immune system. Viral parameters that have been described as good predictors of response in HBe Ag(+) cases, have proven useless in HBe Ag(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe NA discontinuation in both groups.     

Effect of switching from treatment with nucleos(t)ide analogs to pegylated interferon α-2a on virological and serological responses in chronic hepatitis B patients

AIM To investigate the efficacy of switching to pegylated interferon-α-2a(Peg IFNα-2a) treatment in nucleos(t)ide analog(NA)-treated chronic hepatitis B(CHB) responder patients. METHODS A 48-wk prospective and retrospective treatment trial of NA-treated CHB patients who had received entecavir(ETV) for at least 48 wk and had serum hepatitis B virus(HBV)-DNA 500 IU/m L, serum hepatitis B envelope antigen(HBe Ag) 100 S/CO, serum alanine aminotransferase, and aspartate aminotransferase levels 2 × the upper limit of normal of 40 IU/L was performed. The effects on virological and serological responses and adverse reactions to 0.5 mg daily ETV for 48 wk vs switching to Peg IFNα-2a were compared. Forty-four patients were randomized to be switched from NA treatment to the Peg IFNα-2a group, and 44 patients were simultaneously randomized to the ETV group. RESULTS After 48 wk of therapy, the decrease in hepatitis B surface antigen(HBs Ag) levels was greater in the Peg IFNα-2a group than in the ETV group(3.1340 log10 IU/m L vs 3.6950 log10 IU/m L, P = 0.00). Seven patients who were anti-HBs-positive at baseline achieved HBs Ag loss when switched to Peg IFNα-2a(15.91% vs 0%,P = 0.018). The HBe Ag serological conversion rate was higher in the Peg IFNα-2a group than in the ETV group; however, the difference was not significant because of the small sample sizes(34.38% vs 21.88%, P = 0.232). In the Peg IFNα-2a group, patients with HBs Ag levels 1500 IU/m L at baseline had higher HBe Ag seroconversion and HBs Ag loss rates at week 48 than those with HBs Ag levels ≥ 1500 IU/m L(HBe Ag seroconversion: 17.86% vs 62.5%, P = 0.007; HBs Ag loss: 41.67% vs 6.25%, P = 0.016). Moreover, patients with HBs Ag levels 1500 IU/m L at week 24 had higher HBs Ag loss rates after therapy than those with HBs Ag levels ≥ 1500 IU/m L(36.84% vs 0%, P = 0.004). However, there were no statistically significant differences in HBe Ag seroconversion rates(47.06% vs 25.93%, P = 0.266). CONCLUSION NA-treated CHB patients switched to sequential Peg IFNα-2a achieved highly potent treatment termination safely.     

A comparison of 4-year entecavir efficacy in nucleos(t)ide analog-naïve and -experienced adult Taiwanese chronic hepatitis B patients

Purpose

To compare the efficacy of entecavir (ETV) monotherapy up to 4 years in nucleos(t)ide analog (NA)-experienced and -naïve subjects.

Methods

One hundred sixty NA-experienced and 282 naïve chronic hepatitis B patients who were treated with ETV were enrolled. Of the 160 NA-experienced patients, 49 had prior lamivudine (LAM)-resistant mutants, 18 had resistant mutants to LAM followed by adefovir (ADV) after switching to ADV sequential therapy (LAM/ADV resistance), and 9 had prior ADV-resistant mutants. NA-resistant mutants were detected by line probe assay.

Results

Four years of ETV therapy resulted in virological response (VR, HBV DNA < 300 copies/ml), HBeAg seroconversion, and ETV-resistant mutants development in 98.2, 45.2, and <1 % of naïve patients, respectively. LAM- and ADV-experienced patients who never developed LAM-resistant mutants had similar VR and ETV-resistant mutant rates to NA-naïve patients. In contrast, prior LAM-resistant mutants were significantly associated with higher ETV-resistant mutants development and reduced VR rates. Patients with prior LAM-resistant mutants but not at baseline had a lower rate of ETV-resistant mutants compared to those with baseline LAM-resistant mutants [hazard ratio (HR): 0.58, 95 % confidence interval (CI): 0.35–0.95] and those who had LAM/ADV resistance (HR:0.16, 95 % CI:1.0.03–0.76). Early add-on ADV achieved VR in eight of nine patients with ETV-resistant mutants when HBV DNA was <2 × 10⁵ copies/ml.

Conclusions

Entecavir was highly efficacious and low resistance in NA-naïve, LAM-, or ADV-experienced patients without LAM-resistant mutants. Patients with prior LAM-resistant mutants but not at baseline had lower ETV-resistant mutant rates compared to those with baseline LAM-resistant mutants or LAM/ADV resistance.     

Potent hepatitis B surface antigen response to treatment of hepatitis-B-e-antigen-positive chronic hepatitis B with α-interferon plus a nucleos(t)ide analog

Background and Aim: Hepatitis B surface antigen (HBsAg) clearance is the closest cure outcome in hepatitis B. The goal of this study was to investigate clinical features in chronic hepatitis B patients achieving seroconversion of HBsAg after treatment with α‐interferon (IFN‐α) and a nucleos(t)ide analog. Methods: This retrospective study enrolled 38 chronic hepatitis B patients treated with IFN‐α plus a nucleos(t)ide analog who achieved HBsAg seroconversion during the period from June 2001 to May 2009. Clinical and laboratory data of the patients were collected before and after treatment every 3 months. All patients with HBsAg seroconversion in this study were followed up for at least 12 months post‐treatment. Results: A total of 38 out of 142 patients achieved HBsAg seroconversion after treatment with IFN‐α and a nucleos(t)tide analog for a prolonged period of time (medium 31 months). The median time to hepatitis B e antigen seroconversion and to HBsAg seroconversion was 19.5 months (range 3–60 months) and 25.5 months (range 9–63 months), respectively. Thirty‐six patients (95%) sustained HBsAg seroconversion during the post‐treatment follow up. Three different HBsAg response patterns were observed with classical model accounting for 57.9% (22/38 cases), simultaneous transition mode accounting for 23.7% (9/38 cases), and HBsAg prior transition model accounting for 18.4% (7/38 cases). Conclusions: Extended treatment with IFN‐α in combination with a nucleos(t)ide analog in patients with hepatitis‐B‐e‐antigen‐positive appears to be a promising approach for achieving a high rate of HBsAg clearance—the closest outcome to cure.     

When to stop nucleos(t)ide analogues treatment for chronic hepatitis B? Durability of antiviral response

Introduction of nucleos(t)ide analogues (NAs) for oral antiviral therapy has dramatically improved the clinical outcome in patients with chronic hepatitis B (CHB). Although current international guidelines for the management of CHB provide information regarding when to begin the antiviral therapy with NAs, there is no clear consensus on when to stop the treatment, especially for those who respond to the therapy. Hepatitis B surface antigen loss has been regarded as an ideal endpoint of oral antiviral therapy with NAs, however since this is rarely achieved, practical endpoints have been suggested by the international guidelines. Despite the stopping rules recommended by the international guidelines, whether oral antiviral therapy with NAs can be safely discontinued is of major concern. While attention has been drawn to whether antiviral treatment with NAs can be a finite therapy, there is lack of sufficient data on off-treatment durability of highly potent NAs. Based on the available evidences, current guidelines for stopping NA therapy seems to be inadequate in terms of off-treatment durability, with relapse rates of more than 40% for both hepatitis Be antigen (HBeAg)-positive and HBeAg-negative patients. Therefore, further studies are required to accumulate data on off-treatment durability of highly potent NAs, and future studies are warranted to identify adequate predictive markers that could provide supplementary information to guide the timing of stopping NA therapy.     

Entecavir and interferon-α sequential therapy in Japanese patients with hepatitis B e antigen-positive chronic hepatitis B

Background

The outcomes of sequential therapy with lamivudine followed by interferon have been unsatisfactory in Japanese patients with hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B. However, the efficacy of sequential therapy with entecavir and interferon remains unclear.

Methods

Twenty-four HBeAg-positive patients (23 men and 1 woman; mean age 39 ± 7 years) received entecavir 0.5 mg alone for 36–52 weeks, followed by entecavir plus interferon-α for 4 weeks, and lastly by interferon-α alone for 20 weeks. Twenty-three patients had genotype C infection, and one had genotype A infection.

Results

No entecavir-resistant mutant variants emerged in any patient. Hepatitis flare occurred in three patients during interferon-α treatment after the withdrawal of entecavir, but none had hepatic decompensation. Serum hepatitis B surface antigen levels did not change during or after therapy. Serum hepatitis B core-related antigen levels were significantly decreased at the start (P < 0.0001) and at the end of interferon-α treatment (P < 0.0001), but returned to baseline levels after treatment. Twenty-four weeks after the completion of the sequential therapy, a sustained biochemical, virological, and serological response was achieved in 5 (21 %) patients. The proportion of patients in whom HBeAg was lost during entecavir treatment was significantly higher among those with a sustained response than among those with no response (P = 0.015).

Conclusions

The rate of response to sequential therapy with entecavir and interferon-α in Japanese patients with HBeAg-positive chronic hepatitis B was not higher than the rate in previous studies of lamivudine followed by interferon.     

Current treatment of hepatitis B infection: where do the new nucleos(t)ide analogues fit in?

One of the most important advances made in the treatment of chronic hepatitis B infection has been the development of nucleos(t)ide analogues. The first antiviral agents used had limited efficacy due to the high resistance rate. However, in the last few years, new agents (tenofovir, entecavir) have been developed with greater antiviral potency and a lower resistance rate. Consequently, these agents are considered to be the treatment of choice in the most recent clinical guidelines. Nevertheless, interferon may still play an important role in the treatment of hepatitis B in selected patients. Moreover, in some contexts, such as renal insufficiency, pregnancy or immunosuppression, the role of the new oral antiviral agents has not been precisely defined. The present review analyzes these aspects, as well as some of the particular features of the management of patients treated with nucleos(t)ide analogues.     

Interferon-α improves bone resorption and osteopenia in patients with chronic hepatitis C

Background

Interferon (IFN)-β is known to be involved in the regulation of bone homeostasis. As IFN-α and -β share the same receptor complex and signaling pathway, we speculated that treatment with IFN-α for chronic hepatitis C (CHC) may provide a beneficial effect on bone loss.

Methods

Urinary deoxypyridinoline (uDPD) of 41 patients with CHC who had been receiving IFN-α for 24 weeks was examined during the period of observation. Among them, eight patients showed a bone mineral density (BMD) of less than 0.850 g/cm² before IFN therapy and they were examined a BMD again after completion of IFN administration. Relationships between the percentage difference of uDPD after discontinuation of IFN and various factors related to CHC were also examined.

Results

A mean uDPD of 7.1 ± 3.4 nM/mM creatinine before IFN therapy decreased to 4.5 ± 2.4 in the 4th week and 4.2 ± 2.7 in the 24th week of IFN therapy, respectively (p < 0.0001). The reduction in uDPD was more prominent in cases with a lower viral load (p = 0.0266). The BMD of the eight patients, which was less than 0.850 g/cm² before IFN therapy, showed significant increase after the end of therapy (p = 0.0172).

Conclusion

IFN-α can improve bone resorption in CHC patients, especially in those with a lower viral load, and increased BMD. These effects are thought to be a result of direct action of IFN on bone homeostasis.     

Effects of interferon-α therapy on serum and liver HBV DNA in patients with chronic hepatitis B

The aim of this study was to evaluate the effect of interferon- therapy on serum and liver HBV DNA in 20 patients with chronic hepatitis B and to correlate the presence or absence of HBV DNA with the clinical response. There were 11 responders and all lost HBV DNA from the serum. Ten of the 11 were followed for 36 months following IFN treatment and remained well with absence of HB_eAg and HBV DNA from the serum and with normal ALT. Five also lost HB_sAg. HBV DNA became undetectable in the liver of nine of 10 of these patients in whom liver tissue was available for study. HBV DNA persisted in the liver of seven of nine nonresponders and was not detected in two in spite of the presence of HBV DNA and HB_eAg in the serum of these two patients. We conclude that IFN may induce long remissions in patients with chronic hepatitis B with loss of HBV DNA from the serum and that occasionally HBV DNA may persist in the liver of such patients.This work was supported in part by Health and Welfare Canada Grant 6606-2435-52.     

Effects of interferon-α therapy on cardiac function in patients with chronic hepatitis B infection

Various types of cardiovascular complications, such as myocardial infarction, cardiac arrhythmias, cardiomyopathy, and myocarditis attributed to interferon therapy have been reported. The aim of this study was to evaluate the cardiac effects of interferon- (IFN-) in patients with chronic hepatitis B infection. Forty-five patients with chronic hepatitis B infection (41 men and 3 women; mean age 34.2 ± 11.5 years) were included in the study, and 10MU IFN- 2b was administered three times a week for 6 months to the patients. Cardiac evaluation (detailed medical history, physical examination, electrocardiography, systolic and diastolic function parameters by echocardiography) was performed at the beginning, and at the 1st, 3rd, and 6th months of therapy. No patients had any cardiac symptoms during interferon therapy, and systolic and diastolic blood pressure and heart rate were not significantly affected (P > 0.05). None of the patients revealed cardiac rhythm disturbance on electrocardiography before or during the therapy period. No significant changes were detected in systolic (ejection fraction, fractional shortening, pre-ejection period, left ventricular ejection time, the ratio of pre-ejection period/ejection time, Q-V peak) and diastolic (E peak, A peak of transmitral flow velocity, E/A ratio, deceleration time, isovolumic relaxation time by conventional echocardiography, and E peak, A peak, deceleration time of E wave at the medial and lateral corners of the mitral annulus by tissue Doppler echocardiography) left ventricular function parameters between the beginning and the 1st, 3rd, and 6th months of therapy. The results of this study suggest that IFN- therapy does not cause a significant deterioration in cardiac function in patients with chronic hepatitis B infection, and it may be used safely in patients without cardiac disease.     

Intraocular complications of IFN-α and ribavirin therapy in patients with chronic viral hepatitis C

We report a panel of severe inflammatory and vascular intraocular disorders occurring during interferon-alpha (IFN-α) treatment in eight hepatitis C virus (HCV)-infected patients. These events include three cases of Vogt-Koyanagi-Harada like (VKH) disease (an association of panuveitis, retinal detachment, ear and meningeal detachment and skin and hair changes), two cases of central retinal vein occlusion, one case of central retinal artery occlusion, one case of severe hypertensive retinopathy and one case of bilateral ischemic optic neuropathy with severe visual impairment. Rare as they are, such severe ophthalmological complications require a close follow-up of HCV-infected patients under IFN-α treatment with ophthalmological monitoring if any ocular manifestation occurs.     

Intraocular complications of IFN-α and ribavirin therapy in patients with chronic viral hepatitis C

We report a panel of severe inflammatory and vascular intraocular disorders occurring during interferon-alpha (IFN-a) treatment in eight hepatitis C virus (HCV)-infected patients. These events include three cases of Vogt-Koyanagi-Harada like (VKH) disease (an association of panuveitis, retinal detachment, ear and meningeal detachment and skin and hair changes), two cases of central retinal vein occlusion, one case of central retinal artery occlusion, one case of severe hypertensive retinopathy and one case of bilateral ischemic optic neuropathy with severe visual impairment. Rare as they are, such severe ophthalmological complications require a close follow-up of HCV-infected patients under IFN-a treatment with ophthalmological monitoring if any ocular manifestation occurs.     

New developments in therapy of chronic hepatitis B. When are nucleoside analogs indicated?

Nucleoside analogues are promising agents for the treatment of chronic hepatitis B infection (HBV-DNA-positive by hybridization assay). The drug being studied most intensively is Lamivudine (Zeffix) which has recently been approved in Germany. When given orally once daily (100 mg) Lamivudine is well-tolerated and suppresses HBV-DNA to undetectable levels in the majority of patients. Since relapse is frequent when medication is stopped long-term treatment (at least until seroconversion of HBeAg) is warranted. Indications for lamivudine monotherapy are patients with chronic hepatitis B in which interferon (IFN) is contraindicated or patients who did not respond to a previous course of interferon. Further indications are the HBV-DNA-positive cirrhosis prior to liver transplantation (OLT) and the HBV-reinfection after OLT. The main problem of long-term monotherapy with lamivudine is viral resistance. The clinical impact of the resistant mutants is often not clear. Withdrawal or even continuation of the medication may be acceptable approaches. Other nucleoside analogues like Entecavir or Adefovir are currently being tested in clinical studies. Famciclovir was investigated preferably in patients with decompensated liver disease or HBV-reinfection after OLT. Because of conflicting results the drug should only be used under study conditions. In IFN-naive patients with chronic hepatitis B (and compensated liver disease) alpha-interferon is still the first-line therapy. With a standard course of interferon 30-40% of the patients become seronegative for HBeAg as compared with 16-17% when treated with lamivudine for twelve months. Combination of lamivudine and interferon is not more effective than IFN alone. In the future combined antiviral treatment is likely to replace monotherapy.     

Pegylated IFN-α2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B

AIM: To investigate the role of pegylated-interferon (IFN)α-2b in the management of patients with lamivudine-resistant chronic hepatitis B. METHODS: Twenty consecutive anti-HBe positive patients were treated with pegylated IFNα-2b (100μg sc once weekly) for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry, serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison. RESULTS: Nine patients (45%) had a partial viro-logical end-treatment response; seven patients (35%) showed complete virological end-treatment response. Eight patients (40%) showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders (four out of seven patients vs none out of six patients, respectively; P=0.1). Patients without virological end-treatment response showed significant worsening of fibrosis [median score 2 (range, 1 to 3) vs median score 3 (range, 1 to 4)], in the first and second biopsy respectively (P=0.014), whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies (n = 5). Nevertheless, after 12 mo of follow-up, only one patient (5%) showed sustained virological response and only 2 patients (10%) showed sustained biochemical response. Two patients (10%) discontinued pegylated IFN both after 6 mo of treatment due to flu-like symptoms. CONCLUSION: Pegylated IFNα-2b, when added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B, induces sustained responses only in a small minority of cases.