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Keywords:

  • antiviral treatment;
  • chronic hepatitis B

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References

Summary.  Chronic hepatitis B infection is a significant health problem throughout the world, and particularly in China. It is estimated that more than half a million Chinese people die annually from end-stage hepatitis B complications, which is associated with huge healthcare costs and a heavy socioeconomic burden. In China, the implementation of a hepatitis B vaccination programme has come into effect, and there has been a one-third decrease of the hepatitis B virus (HBV) carrier population since 1992. This great achievement changes China from a highly endemic area for HBV infection to an intermediate one. The predominant HBV genotypes in China are B and C, which might predispose patients to a poor antiviral response. Patients and physicians from China have been actively involved in the global research into and development of new antiviral agents. Patients have been recruited for global and domestic clinical trials on antiviral agents, including lamivudine, adefovir dipivoxil, entecavir, telbivudine and two pegylated interferon-α. In the future, more important data, focussing on optimization of the efficacy of antiviral agents, will be released from China, based on the newly launched National Eleven Five Plan Project on Hepatitis Research. Both economic development and healthcare system reform, including a new reimbursement policy, will make antiviral agents more accessible to Chinese patients. Ultimately, this will allow physicians greater opportunities to follow international and Chinese treatment recommendations.


Abbreviations:
ADV

adefovir dipivoxil

ALT

alanine aminotransferase

CHB

chronic hepatitis B

ETV

entecavir

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

IFN

interferon

PCR

polymerase chain reaction

SOC

standard–of-care

ULN

upper limit of normal

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References

Despite the increasing use of highly effective prophylactic vaccines, eradication of hepatitis B virus (HBV) infection remains an unfulfilled global health goal, and the end-stage sequelae of chronic HBV infection – cirrhosis-related liver failure and hepatocellular carcinoma (HCC) – are responsible for one million deaths each year worldwide [1]. More than one-third of the world’s 350–400 million chronic HBV carriers live in China, which means that China has the biggest HBsAg carrier population [2–4]. In Chinese patients with chronic HBV infection, the infection leads to a striking increase in the risk of cirrhosis, hepatic decompensation, HCC, and liver-related premature mortality [5]. It is estimated that more than half a million Chinese people die annually from end-stage liver diseases [6]. In China, as in other countries in the Asia–Pacific region, progression to end-stage disease is associated with increased healthcare costs and other socioeconomic burdens. However, the implementation of a hepatitis B vaccination programme significantly decreased the prevalence of HBV infection in the general population.

The prevalence of HBV genotypes in China differs from that observed in Western countries, and might contribute to differences in disease manifestation and progression [7–9]. Chinese HBV carriers are infected almost exclusively with genotypes C or B, while Western patients of non-Asian ethnicity display an array of HBV genotypes; primarily A, D, E and F. Patients with genotypes A and B but not genotypes C and D have a higher rate of HBeAg seroconversion with interferon (IFN) therapy [10].

New antiviral agents are needed to maximize sustained suppression of HBV replication and to improve therapeutic outcomes. Clinical studies in China are essential for understanding the potential benefits and risks of new antiviral agents in this large hepatitis B patient population. Recently, Chinese hepatologists have been actively involved in the global development of new antiviral agents. They have made major contributions in recruiting patients for global and domestic clinical trials on antiviral agents, including lamivudine, adefovir dipivoxil, entecavir (ETV), telbivudine and pegylated IFN-α. Not surprisingly, the international publications from mainland China have also increased dramatically during the past decade [11].

Prevalence changes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References

According to the national survey carried out between 1992 and 1995, the prevalence of HBsAg in the general population was 9.75%. Fortunately, this figure has declined steadily since the implementation of universal HBV vaccination of neonatal babies in 1992 [12]. On 21 April 2008, the Ministry of Health in China released new statistical data from a national seroprevalence survey on HBV carried out at the end of 2006 [13]. The adjusted prevalence of HBsAg in the general population (aged 1–59 years) was 7.18%, being lowest in children 1–4 years of age (0.96%), intermediate in children 5–14 years of age (2.42%) and highest in people 15–59 years of age (8.57%). The almost one-third decrease in HBsAg prevalence is mainly attributed to the high HBV vaccination coverage rate (81.56%) in the younger age group (1–14 years). This great achievement changes China from a highly endemic area for HBV infection to an intermediate one.

Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References

Hepatitis B is the leading cause of chronic hepatitis, cirrhosis and HCC in China. As hepatitis B progresses from a self-limited acute infection to chronic disease, cirrhosis and HCC, there is increasing use of healthcare resources and costs associated with the sequelae of the disease. In China these costs are significant. A survey on disease burden carried out in Shanghai revealed that the annual direct and indirect medical cost for each patient with chronic hepatitis B (CHB) was US$3000, while the cost for a patient with compensated or decompensated liver cirrhosis was US$5100 and US$5200, respectively [14]. A major portion of the indirect costs was associated with reduced work-related productivity caused by patients taking time off to receive treatment or for hospitalization, a large number of patients leaving or losing their jobs, and premature death. Many patients with HBV-related diseases were men of working age, resulting in a considerable impact on families in which these individuals were the sole income earner. The high costs associated with CHB highlight the importance of disease prevention and treatment. Successful prevention of HBV infection and the prevention or delay of disease progression will offer considerable socioeconomic savings in the future.

Geographical distribution of HBV genotypes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References

The most prevalent HBV strains in China are genotypes B and C, which are distributed unevenly. We analyzed 1096 chronic HBV carriers from nine provinces in mainland China by either nucleotide sequencing or polymerase chain reaction (PCR)–restriction fragment length polymorphism RFLP [15]. Four genotypes – A, B, C and D – were found, and their prevalence was 1%, 41%, 53% and 4%, respectively. The remaining 1% of patients was co-infected with genotypes B and C. Genotypes E, F, G and H were not found in China. Genotype C was predominant in northern China, present in approximately 77% of patients, while genotype B was more prevalent in southern China (59%). Genotype D was mainly found in north-western China. Investigations by Ding et al. [16] indicated the presence of genotypes A, B and C in Shanghai, eastern China. Other regional studies confirmed the presence of genotypes B and C as the most prevalent HBV strains in northern and southern China [17,18].

In Tibet and Gansu provinces of western China, two types of genotype C/D hybrid were recently identified [19,20]. One hybrid has recombination over the S gene (nt 10–799) with genotype D, and its genome has approximately 25% of genotype D and 75% of genotype C. The other hybrid shows recombination with genotype D over a larger part of the HBV genome (nt 10–1499) and its genome has approximately 46% of genotype D and 54% of genotype C.

Taken together, genotypes B and C are the most common HBV strains and account for approximately 95% of HBV infections in China. Genotype D mainly prevails in some populations of north-western China. HBV C/D recombinant hybrids have been found only in western China. Studies have shown that patients with genotype B tend to be younger and have a lower prevalence of HBeAg positivity than patients with genotype C [15]. The distribution of HBV genotypes in patients being followed by those authors was consistent with previous reports. However, the severity of liver disease (determined by liver function test or histology) did not differ significantly between patients infected with genotypes B or C.

Guideline for HBV management in mainland china

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References

The Chinese Society of Hepatology and the Chinese Society of Infectious Diseases jointly published an evidence-based guideline for the prevention and management of CHB in Chinese in 2005 and subsequently in English in 2007 [21]. This guideline distinguishes chronic HBV carriers from inactive HBsAg carriers. Chronic HBV carriers are defined as being HBsAg positive with active viral replication but normal transaminase levels. Inactive HBsAg carriers are defined as being HBsAg positive without active viral replication and significant liver disease. In this guideline, conventional IFN, pegylated IFN, lamivudine, adefovir dipivoxil and ETV are all first-line antiviral therapies for CHB. Telbivudine and pegylated IFN-α2b were not included in the version of the guideline as it was marketed in China in 2007 (Fig. 1).

image

Figure 1.  Timeline of the State Food and Drug Administration (SFDA)-approved therapy for chronic hepatitis B in China.

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Reimbursement for treatment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References

Despite the wide availability of treatments for hepatitis B, the proportion of patients actually receiving treatment is frequently low in China. The main obstacle to treatment in China is the cost. A standard course of pegylated IFN-α costs almost ten times that of a 12-month course of lamivudine. In the past, only government employees in China receive reimbursement for hepatitis B treatment and reimbursement is available only for lamivudine. Therefore, the majority of patients have to fund their own treatment; only a very small minority of patients have private health insurance. For example, in western China it is estimated that <5% of patients in rural communities can afford treatment for 1 year compared with approximately 40% of patients in developed areas (such as Guangzhou). In addition, poorer patients may not be able to afford the initial diagnostic tests needed to confirm a diagnosis of hepatitis B.

Recently it has been announced that all available antiviral agents have been entered into the candidate list for inclusion in the Chinese National Reimbursement Drug List (NRDL). Physicians are very hopeful that they can work together to make these medicines more accessible to Chinese patients. Ultimately this would allow physicians greater opportunities to follow international and Chinese treatment recommendations; that is, to initiate treatment with potent antiviral agents having low resistance or high HBeAg seroconversion rate, and to ensure adequate treatment duration and compliance.

Key clinical studies in naive patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References

The management of CHB has improved dramatically over the past decade with the development of newly developed antiviral drugs. In addition to the standard IFN-α therapy, four nucleotide/nucleoside analogues (lamivudine, adefovir dipivoxil, ETV and telbivudine) and two pegylated IFN (Pegasys and Pegintron) have been approved for treatment of CHB. Long-term therapy with nucleoside/nucleotide analogues, both in HBeAg-positive and HBeAg-negative CHB, showed the most favourable effect on patient outcome, provided that virological and biochemical responses were maintained without development of viral resistance. However, drug resistance has become increasingly challenging to the clinical management of patients with CHB. Below, we review the efficacy data of some important global and domestic trials.

Efficacy in global trials: 1-year data

In the global Phase III clinical trials for HBeAg-positive patients, the virological response rate at 1 year (undetectable HBV DNA; defined variously in the different trials and differently from the present guidelines) was 25%, 10%, 40%, 21%, 67%, 60% and 76% with pegylated IFN-α2a, pegylated IFN-α2b, lamivudine, adefovir, ETV, telbivudine and tenofovir, respectively [10,22–26]. The HBeAg seroconversion rate at 1 year was 27–32%, 22–29%, 16–21%, 12%, 21%, 22% and 21% with pegylated IFN-α2a, pegylated IFN-α2b, lamivudine, adefovir, ETV, telbivudine and tenofovir, respectively. ([10,22–26]).

In HBeAg-negative patients, the virological response rate at 1 year (undetectable HBV DNA; defined variously in the different trials and differently from the present guidelines) was 63%, 72%, 51%, 90%, 88% and 93% with pegylated IFN-α2a, lamivudine, adefovir, ETV, telbivudine and tenofovir, respectively [25–29]. Loss of HBsAg rates after 1 year were 3% with pegylated IFN-α and 0% with lamivudine, adefovir, ETV, telbivudine or tenofovir.

Efficacy in domestic trials: 1-year data

Apart from the global trials in which many Chinese patients have participated, there have been some local trials for lamivudine, adefovir, ETV and telbivudine enrolling only Chinese patients. The efficacy of these drugs has been assessed in randomized controlled trials after 1 year (2 years for telbivudine). Long-term results are available for lamivudine, adefovir, ETV and telbivudine in patient subgroups. These trials used different HBV DNA assays and they are not head-to-head comparisons for all of the drugs (Fig. 2).

image

Figure 2.  One-year efficacy data of domestic trials in China. The rate of HBeAg seroconversion, ALT normalization and undetectable HBV DNA after 1 year of treatment with lamivudine (LAM), adefovir (ADV), entecavir (ETV) and telbivudine (LdT) in HBeAg-positive compensated chronic hepatitis B patients in different randomized domestic clinical trials is shown. These trials used different HBV DNA assays and they were not head-to-head comparisons for all drugs, so the data should be considered with caution.

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Lamivudine

Yao et al. reported the first randomized, double-blind, placebo-controlled study of lamivudine in China in 1999 [30]. Four hundred and twenty-nine HBeAg-positive CHB patients were randomized into lamivudine and placebo groups. Three hundred and twenty-two patients received lamivudine 100 mg daily and 107 patients received placebo treatment for the first 12 weeks. All patients were then offered a further 9-month open-label lamivudine treatment. During the 12-week treatment period, 92.2% of lamivudine-treated patients became HBV DNA negative (below 1.6 pg/mL) compared with only 14.1% of those receiving placebo (< 0.01). Patients with elevated alanine aminotransferase (ALT) levels at baseline became normal in 60.3% of the lamivudine-treated group compared with 27.5% in the placebo group (P < 0.01).

Adefovir

To date, the longest well-designed clinical trial to evaluate the long-term efficacy and safety of 10 mg adefovir for treating HBeAg-positive CHB patients has been conducted in China [31]. Four hundred and eighty Chinese subjects with HBeAg-positive CHB were enrolled in this multicentre, double-blind, randomized, placebo-controlled study. Eligible patients were randomly assigned to receive either adefovir dipivoxil (ADV) 10 mg once daily (QD) or matching placebo tablets in a 3:1 ratio for 12 weeks to evaluate the initial antiviral response. At Week 12, all subjects started open-label ADV 10 mg QD for 28 weeks. After this, subjects who had received ADV in the first 12 weeks were re-randomized to receive either ADV or placebo in a 2:1 ratio for 12 weeks to evaluate the effect of discontinuing therapy. Subjects who had received placebo in the initial 12 weeks continued to receive open-label ADV. The 1-year data showed that there was a significant difference in the reduction of HBV DNA after 12 weeks between subjects who received ADV and those who received the placebo (3.4 and 0.1 log10 copies/mL, respectively; P < 0.001). Further reductions in serum HBV DNA and increases in the proportion of subjects with undetectable HBV DNA and ALT normalization were observed in ADV-treated subjects at Week 52 (28% with undetectable HBV DNA and 79% with ALT normalization). The study continued for an additional 4 years and the 5-years data is discussed below.

Entecavir

The first Chinese study of entecavir (ETV) was to evaluate its antiviral efficacy and safety in nucleoside-naive Chinese CHB patients treated with ETV or lamivudine [32,33]. It was a randomized, double-blind, double-dummy and control design. Five hundred and nineteen nucleoside-naive CHB patients were treated with a daily dose of ETV 0.5 mg (258 patients) or lamivudine 100 mg (261 patients) for at least 52 weeks. The primary end-point was a composite end-point of HBV DNA <0.7 mEq/mL by branched (b)DNA assay and ALT <1.25 × the upper limit of normal (ULN) at Week 48. The primary end-point was achieved in 90% of ETV-treated patients compared with 69% of lamivudine-treated patients (P < 0.0001). The mean HBV DNA level decreased by 5.9 lg copies/mL from the baseline in the ETV group vs 4.3 lg copies/mL in the lamivudine group (P < 0.0001). The serum HBV DNA become undetectable (<300 copies/mL by PCR) in 76% of the ETV group vs 43% of the lamivudine group (P < 0.0001). The normalization of ALT was 90% in the ETV group vs 78% in the lamivudine group (P = 0.0003). Compared with lamivudine, ETV achieves better virological and biochemical improvements in nucleoside-naive Chinese patients with CHB.

Telbivudine

In a Phase III, double-blind, multicentre trial conducted in China, 332 patients with compensated HBeAg-positive or HBeAg-negative CHB were randomly assigned to treatment with 600 mg of telbivudine or 100 mg of lamivudine daily for 104 weeks [34]. The primary efficacy end-point was reduction in serum HBV DNA levels at Week 52 of treatment. At Week 52, among 290 HBeAg-positive patients, mean reductions of serum HBV DNA were significantly greater in telbivudine recipients than in lamivudine recipients (6.3 log10vs 5.5 log10; P < 0.001) and the HBV DNA-negative rate was significantly higher in telbivudine recipients than in lamivudine recipients (67%vs 38%; P < 0.001). ALT normalization was 87%vs 75% (P = 0.007) and HBeAg loss was 31%vs 20% (P = 0.047) in the telbivudine and lamivudine recipients, respectively. Treatment effects showed similar patterns in the smaller HBeAg-negative group (n = 42). Viral resistance in the telbivudine recipients was approximately half that observed in the lamivudine recipients. In Chinese patients with CHB, telbivudine treatment for 52 weeks provided greater antiviral and clinical efficacy than lamivudine, with less resistance.

Efficacy in domestic trials: 3–7-years data

Lamivudine

A Chinese study evaluated the long-term efficacy and safety of lamivudine treatment for CHB and the impact of the emergence of the YMDD mutation of the HBV [35] (Fig. 3). A total of 429 HBeAg-positive CHB patients were randomized to receive either lamivudine 100 mg daily or a placebo in a 3:1 ratio for the first 12 weeks. Thereafter, all patients received lamivudine 100 mg/day for 5 years and were followed up for 2 years. At the end of the 5 years, the loss of HBeAg and seroconversion were significantly correlated with baseline ALT levels in patients with baseline ALT >2 × ULN: the loss of HBeAg was 54% and the seroconversion rate was 50%. The tyrosine-methionine-aspartate-aspartate (YMDD) mutation had developed in 70.8% of the patients at Year 5. In patients with the YMDD mutation, HBV DNA levels were increased moderately and there were mild to moderate increases of ALT. ALT flares (ALT >5 ULN) occurred in 22 patients – 16 with YMDD HBV variants and six with non-variants. The 1-year durability of seroconversion after stopping lamivudine was 80%.

image

Figure 3.  Long-term (3–5 years) efficacy data of domestic trials in China. The rate of HBeAg seroconversion, ALT normalization and undetectable HBV DNA after 3–5 years of treatment with lamivudine (LAM), adefovir (ADV), entecavir (ETV) and telbivudine (LdT) in HBeAg-positive compensated chronic hepatitis B patients in different randomized domestic clinical trials is shown. These trials used different HBV DNA assays and they were not head-to-head comparisons for all drugs. Some of the data are cumulative results. These data should be considered with caution.

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Adefovir

Four hundred and eighty HBeAg-positive CHB subjects were randomized in an initial 52-week controlled ADV study. The subjects were then offered open-label ADV treatment for a further 208 weeks. Four hundred and eighty subjects were enrolled in the first year of the study, and a total of 474, 456,443, 421 and 390 subjects completed the first, second, third, fourth and fifth year of the study, respectively. At the end of each year, samples were analyzed from those subjects with protocol-defined HBV DNA breakthrough (an increase ≥1.0 log10 copies/mL from the nadir) for the rtN236T or rtA181V ADV mutations. The cumulative ADV resistance rate was 0%, 1.3%, 5.4%, 10.4% and 14.6% after 1, 2, 3, 4 and 5 years, respectively. Data showed that treatment with ADV in Chinese HBeAg-positive CHB subjects for up to 5 years resulted in a cumulative rate of 14.6% (70/480) ADV resistance-associated mutations with HBV DNA breakthrough. At 5 years, the median HBV DNA reduction was 5.5 log10 and the proportion of subjects achieving undetectable HBV DNA, ALT normalization, HBeAg loss and seroconversion was 55%, 77%, 50% and 29%, respectively [36].

Entecavir

Entecavir has shown superior efficacy over lamivudine in Chinese nucleoside-naive CHB patients over 48 weeks, with continued clinical benefit to 96 weeks [33,37]. A study evaluated the long-term efficacy of ETV in Chinese patients with CHB who continued ETV treatment for 144 weeks [38]. Patients receiving either ETV 0.5 mg/day (n = 258) or lamivudine 100 mg/day (n = 261) entered the initial 96-week randomized, double-blind, controlled efficacy study. Those not achieving a consolidated response (HBV DNA <0.7 MEq/mL; ALT <1.25 ULN; and if HBeAg positive at the baseline, a loss of HBeAg for ≥24 weeks) or who experienced viral breakthrough or relapse, entered a 48-week ETV rollover study. A total of 160 patients received continuous ETV for 144 weeks: 89% had undetectable serum HBV DNA, 86% showed ALT normalization, 20% reported HBeAg loss and 8% experienced HBeAg seroconversion. Cumulative rates of HBeAg loss and seroconversion at Week 144 were 36% and 27%, respectively. The development of resistance was low, with three patients up to Week 96 and an additional two patients in Weeks 96–144 showing evidence of associated genotypic mutations. This study demonstrates that ETV provides durable, long-term suppression of HBV DNA and ALT normalization in Chinese CHB patients, and is associated with low rates of emerging resistance. The results are consistent with the findings in global and Japanese studies of ETV.

Telbivudine

In a large 2-year Phase III trial in China, telbivudine demonstrated significantly greater efficacy than lamivudine in adults with CHB. Most of the telbivudine-treated patients (137/167) continued treatment in a 2-year extension trial. Efficacy and safety results for 3 years of telbivudine treatment are presented here [39]. One hundred and thirty-seven out of 167 patients from the telbivudine arm of study 015 were enrolled, which required rollover into the extension trial (2303) without study drug interruption/discontinuation. Patients with genotypic resistance at the baseline were excluded from analysis. Of 137 Chinese patients (111 HBeAg positive, 26 HBeAg negative) analyzed, 99 completed 3 years of telbivudine treatment. At the end of the 3 years, among the HBeAg-positive patients, 70% had undetectable HBV DNA (<300 copies/mL), 85% had HBV DNA <5 log10 copies/mL, 89% had ALT normalization, 62% had HBeAg loss, 42% had HBeAg seroconversion, and one patient lost HBsAg. The cumulative HBeAg seroconversion rate over 3 years was 60%. Among the HBeAg-negative patients, 83% had undetectable HBV DNA, 100% had HBV DNA <5 log10 copies/mL and 90% had ALT normalization. Telbivudine treatment was well tolerated. The safety profile was similar to the 2-year results. In Chinese patients, telbivudine treatment achieves a high cumulative seroconversion rate and provides highly effective viral suppression and ALT normalization over 3 years while maintaining a favourable safety profile.

Management of patients with resistance to nucleos(t)ide analogues: data from china

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References

The management of patients who have developed resistance to nucleos(t)ide analogues can be challenging as cross-resistance can develop between individual nucleos(t)ide analogues. Therefore, although adefovir has been shown to be effective in lamivudine-resistant patients, there is a degree of cross-resistance [40,41]. Patients with resistance to lamivudine have an increased risk of developing resistance to ETV: 15% developed resistance to ETV after 2 years of continuous treatment [42]. With its dual mechanism of action, Pegasys provides an alternative treatment regimen for lamivudine-resistant patients, and data from pilot studies have suggested that a finite course of Pegasys could be effective in achieving sustained antiviral efficacy in this population [43].

To compare the efficacy and safety of Pegasys with that of adefovir in HBeAg-positive patients with lamivudine-resistant CHB, patients from 13 centres across China were included in a randomized, open-label study. Patients with documented lamivudine-resistant CHB were randomized 2:1 to receive Pegasys (180 μg/week) for 48 weeks or adefovir (10 mg/day) for 72 weeks. Pegasys-treated patients were followed up for an additional 24 weeks after the end of the treatment. All patients continued lamivudine treatment (100 mg/day) for the first 12 weeks of the study. Of the 251 patients with documented lamivudine resistance randomized to therapy, 235 received either Pegasys (n = 155) or adefovir (n = 80) for the agreed duration (48 weeks and 72 weeks, respectively). Results showed that HBeAg seroconversion at Week 72 was significantly higher in the Pegasys arm (11.6%vs 3.8%; P = 0.045). Three of the 18 patients treated with Pegasys who achieved HBeAg seroconversion also achieved HBsAg seroconversion. No adefovir-treated patients cleared HBsAg. HBsAg decline from the baseline was more pronounced in the Pegasys-treated patients. At Week 24, 31% of the Pegasys-treated patients with available data had HBsAg levels <1500 IU/mL compared with 14% of those treated with adefovir. The rate of HBeAg seroconversion 6 months post-treatment was twice as high in Pegasys-treated patients with HBsAg <1500 IU/mL at Week 24. There was no association between HBsAg level at Week 24 and response to adefovir. Pegasys is a viable treatment strategy for difficult-to-treat patients who bear lamivudine-resistant mutations, and it was superior to adefovir in achieving HBeAg seroconversion within 72 weeks. Quantification of HBsAg level at Week 24 may help to identify those patients most likely to benefit from Pegasys [44].

Ongoing clinical studies: optimization of current antiviral agents

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References

The antiviral efficacy of current drugs is far from satisfactory as the durable response after cessation is still very low. For nucleoside or nucleotide drugs, long-term therapy is indicated, which may result in drug resistance. Hepatologists all over the world are trying to design new strategies to improve the efficacy of standard-of-care treatment. In the next 3–5 years, some important data from China will meet the objective. After searching in the clinical trials centre, we found several important trials being carried out in China trying to improve efficacy and/or decrease resistance based on different optimization strategies.

Telbivudine: effort study

To optimize the efficacy of antiviral agents, an investigator-initiated study was started in China in August 2009. This is a 2-year, randomized, controlled, open-label, virological response adaptive design, multicentre study to optimize antiviral efficacy of telbivudine in adult patients with HBeAg-positive CHB. The purpose of this trial is to prove that the strategy of treatment adjustment at Week 24 according to virological response based on the ROADMAP concept is better than the standard–of-care (SOC) strategy. Six hundred HBeAg-positive compensated CHB patients will be randomized into two arms: ROADMAP and SOC. Patients in the ROADMAP arm will receive telbivudine treatment for 24 weeks, then will be randomized into two groups based on HBV DNA level lower or higher than 300 copies/mL at Week 24: (i) continuing telbivudine monotherapy for additional 80 weeks or (ii) add on adefovir therapy from Weeks 28 to 104. Patients in the SOC arm will receive telbivudine treatment for 104 weeks. For patients on telbivudine monotherapy, adefovir will be added if HBV DNA breakthrough is confirmed. The primary end-point is to demonstrate the percentage of patients achieving HBV DNA <300 copies/mL at Week 104 in the ROADMAP group is greater than that in the SOC group. (ClinicalTrials.gov identifier: NCT00962533.)

Pegasys

Another two clinical trials in progress in China regard the efficacy optimization of pegylated IFN-α2a. The first trial is a randomized, open-label study to assess the effect of Pegasys + ETV combination therapy on quantitative changes in HBeAg in treatment-naive patients with HBeAg-positive CHB. More than 200 HBeAg-positive, non-cirrhotic patients will be randomized to three arms: (i) Pegasys 180 μg/week for 48 weeks; (ii) Pegasys 180 μg/week for 48 weeks + ETV 0.5 mg daily from Weeks 13 to 36; and (iii) ETV 0.5 mg daily for 24 weeks + Pegasys 180 μg/week from Weeks 21 to 68. Treatment will be followed by 24 weeks of treatment-free follow-up. The primary end-point is log change in quantitative HBeAg from the baseline to 24 weeks after the end of treatment. (ClinicalTrials.gov identifier: NCT00614471.)

The second trial is a study on optimizing HBeAg seroconversion in HBeAg-positive CHB patients with combination or sequential treatment of pegylated IFN-α2a and ETV. This two-arm study will assess the efficacy and safety of Pegasys in combination or sequential treatment with ETV in patients with HBeAg-positive CHB. Two hundred patients who have been pretreated with and responded to ETV for approximately 1 year were randomized to two groups: (i) Pegasys 180 μg/week for 48 weeks + ETV 0.5 mg daily for the first 8 weeks or (ii) ETV 0.5 mg daily for 48 weeks. The primary outcome measure includes HBeAg seroconversion at Week 48. (ClinicalTrials.gov identifier: NCT00940485.)

Adefovir

One study from China regarding optimization of antiviral efficacy of adefovir treatment was started in July 2008. It is a comparative study of the Week 12 antiviral efficacy and safety of switching to ETV vs continuing adefovir treatment in adults with CHB and suboptimal response to adefovir. The purpose is to prove that switching to ETV will result in superior antiviral efficacy as compared with continuing adefovir in patients with suboptimal response to adefovir. One hundred and sixty compensated CHB patients with suboptimal response to adefovir treatment were randomized to ETV treatment for 52 weeks or to adefovir treatment for 12 weeks, followed by ETV treatment until 52 weeks. The primary outcome measure was percentage of patients with HBV DNA <50 IU/mL at Week 12. (ClinicalTrials.gov identifier: NCT00718887.)

As hepatitis B is not a curable disease for most CHB patients, there is a long way for hepatologists and patients to go to defeat the virus. More and more hepatologists from China will be actively involved in this battle. In the next 5–10 years, more important data from China will be published. We are very confident and pleased to share our experience of management of CHB with the rest of the world.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence changes
  5. Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society
  6. Geographical distribution of HBV genotypes
  7. Guideline for HBV management in mainland china
  8. Reimbursement for treatment
  9. Key clinical studies in naive patients
  10. Management of patients with resistance to nucleos(t)ide analogues: data from china
  11. Ongoing clinical studies: optimization of current antiviral agents
  12. Acknowledgement
  13. References