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Keywords:

  • Adefovir;
  • chronic hepatitis B;
  • entecavir;
  • lamivudine;
  • nucleoside analogues;
  • nucleotide analogues;
  • telbivudine;
  • tenofovir

Abstract

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References

HBeAg seropositivity is a marker for active viral replication. In the natural history of chronic hepatitis B infection, HBeAg marks the first two of the four phases, namely the immune tolerant phase and the immune clearance phase, and is associated with highly replicative activity of the hepatitis B virus (HBV). Most HBV consensus reports and guidelines recommend antiviral therapy if the immune clearance phase is prolonged and if there is evidence of significant necroinflammation and fibrosis. Two main types of antiviral agents have been approved for treating patients in the immune clearance phase: interferon and nucleos(t)ide analogues (NUCs). The endpoints of therapy are viral suppression with HBeAg seroconversion, undetectable serum HBV DNA, normalization of serum alanine transaminase and improvement in the histological necroinflammatory and fibrosis scores. The ultimate goal of therapy is to obtain clinical benefit for the patient by reducing complications including hepatocellular carcinoma (HCC). The choice between interferon-based immune modulators or NUCs that target the HBV DNA polymerase must be carefully weighed on an individual basis. Therapy with NUCs is often preferred by doctors and patients because it is easy to administer, with predictable efficacy and minimal side-effects. In specific patient subgroups such as those with decompensated disease, poor predictors of response or lack of response to interferon-based therapy and/or significant comorbidities that cannot tolerate interferon-induced side effects, NUCs therapy is the obvious choice. Entecavir and tenofovir are the treatments of choice because their efficacy and safety profile are better than lamivudine, adefovir and telbivudine. More importantly, there is a minimal risk of drug resistance during long-term therapy with these agents.

Abbreviations
CHB,

chronic hepatitis B;

HBV,

hepatitis B virus;

HCC,

hepatocellular carcinoma;

NUCs,

nucleos(t)ide analogues.

Chronic hepatitis B (CHB) infection affects over 400 million individuals worldwide. Three quarters of them are Asians who are mostly infected with wild-type hepatitis B virus (HBV) from vertical transmission from CHB mothers or early childhood horizontal transmission. Non-Asian CHB patients may be infected later in life. The natural progression of the disease in individual patients varies according to the pace at which they go through the four phases of CHB infection, namely immune tolerant, immune clearance, inactive and reactivation phases. This is largely determined by the HBV genotype and host immune characteristics. Patients with positive HBeAg serology are either in the immune tolerant or in the immune clearance phase. Assessment of these patients includes regular monitoring of HBeAg and anti-HBe, serum HBV DNA levels, alanine transaminase (ALT) levels and imaging of the liver. Liver histology may or may not be useful when determining the treatment strategy. Most HBV consensus reports and guidelines recommend antiviral therapy for the immune clearance phase, especially when there is significant necroinflammatory activity and advanced fibrosis. Personal factors such as gender, age and family history often influence the decision. The appropriate choice of antiviral therapy is also important. Theoretically, the current available therapeutic options can treat all chronic HBV-infected patients. A sustained response is more likely to be achieved with interferon-based therapy, while a maintained response can be achieved with long-term nucleos(t)ide analogue (NUCs) therapy. The choice between interferon treatment and NUCs must be carefully considered in the individual patient. It should be based on the patient's profile and viral characteristics. The goal of antiviral therapy is to resolve individual disease activity and to reduce the burden of the disease in the community with a cost-effective strategy.

Disease spectrum in HBeAg-positive chronic hepatitis B

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References

The disease spectrum is very wide in patients with HBeAg-positive CHB. Patients go through the immune tolerant and immune clearance phases at different paces, which are largely determined by the interaction between the virus and the host immune response. Around a quarter of Asian CHB patients have a prolonged immune clearance phase or evolve to HBeAg-negative CHB and die from complications such as liver failure because of acute exacerbation, chronic insidious deterioration, bleeding oesophageal or gastric varices, spontaneous bacterial peritonitis and hepatocellular carcinoma (HCC). It is important to closely monitor serum HBV DNA and ALT levels monthly for three to six months to determine whether the patient is in the immune tolerant or the immune clearance phase and to monitor disease progression. Doctors and clinics in highly endemic regions are often overwhelmed by a large number of patients. They must stratify the monitoring schedule to treat patients with an indication for therapy at the appropriate time. Imaging with ultrasound or computed tomography scan and liver biopsy to identify patients with significant necroinflammatory activity and advanced fibrosis are essential in the management of CHB patients. A fibroscan examination of liver stiffness may provide additional information for decision-making.

Analytical epidemiological data from Taiwan and Hong Kong have shown that delayed HBeAg clearance increases the risk of progression to the reactivation phase, cirrhosis and HCC. HBV genotypes B and C predominate in Asian CHB patients. A study in Taiwan included 483 CHB patients with no evidence of cirrhosis or HCC at HBeAg seroconversion. They were subgrouped according to the age of HBeAg seroconversion: (group A, n=218) occurred before 30, (group B, n=199) between 31 and 40 and (group C, n=66) after 40. The older the patient was when HBeAg seroconversion occurred the more the 15-year cumulative incidences of progressive disease and complications increased. Patients who underwent HBeAg seroconversion after the age of 40 had a significantly higher risk of disease progression than those who seroconverted before the age of 30. The risk of evolving to HBeAg-negative CHB was 66.7 vs 31.2%, respectively (P<0.0001), with a hazard ratio of 2.95. The risk of progressing to cirrhosis was 42.9 vs 3.7%, respectively, (P<0.0001), with a hazard ratio of 2.95. The risk of HCC was 7.7 vs 2.1%, respectively (P=0.29), with a hazard ratio of 5.22 (1).

A study from Hong Kong used transient elastography, which was performed in 1315 unselected CHB patients. A liver stiffness score of <8.1 kPa was used as a cut-off for the presence of severe fibrosis or cirrhosis. Nine hundred and fifty-one (72%) were treatment-naïve and 34% of these had severe fibrosis. A higher prevalence was found in men than in women (39 vs 24% respectively, P<0.01). Severe fibrosis increased with age, 20% in patients <25 years and 81% in those >65 years. Like in the Taiwanese data, the prevalence of severe fibrosis was higher in HBeAg-positive patients than in HBeAg-negative patients >45 years old (58 vs 43% respectively, P=0.03), and multivariate analysis showed that male gender, advanced age and high ALT levels were significantly associated with severe fibrosis (2).

Indications for antiviral therapy in HBeAg-positive patients

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References

Most HBV management consensus reports and guidelines recommend appropriate assessment and monitoring of individual patients before considering therapy. Treatment is indicated in HBeAg-positive patients if serum HBV DNA is above 5 log10 IU/L and ALT has been shown to be over twice the upper limit of normal at least once. Other important factors when deciding to treat are age, especially age over 40 years, male gender, evidence of significant fibrosis and a family history of HCC. Patients with cirrhosis and detectable HBV DNA should be treated whatever the ALT results. The choice between interferon-based or NUCs therapy in compensated liver disease is discussed with the patient. However, in HBeAg-positive patients with established cirrhosis, interferon-based therapy has potentially serious complications such as neutropenia, sepsis, coagulopathy and bleeding. Thus, therapy with NUCs is more appropriate. Interestingly, a recent survey showed poor compliance to HBV management guidelines in 124 respondents from 12 Asian countries. Detectable HBV DNA was either the first or the second most important factor when deciding whether to initiate therapy. Many physicians were unsure about initiating treatment in patients >40 years old when ALT levels were within the normal range. Oral antiviral drugs were the most frequently prescribed medication because of their effectiveness, safety and ability to provide maintained viral suppression. Interferon therapy was only used in a minority of cases and was chosen because of its effectiveness, fixed treatment duration and lack of drug resistance (3).

Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References

The initial goal of therapy is virological response defined as HBeAg loss or seroconversion with HBV DNA below 1000 IU/L. ALT normalization and improvement in histological necroinflammation usually follows a virological response. Maintained virological response can lead to the regression of fibrosis. The essential question that must be answered is whether the ultimate goal of sustained viral response (SVR) is possible after treatment is stopped. The overall SVR when NUCs therapy is discontinued is not satisfactory. Viral rebound and relapse of hepatitis is well documented in lamivudine responders. In a single-center cohort study from Europe, 132 HBeAg-positive patients were treated with NUCs therapy and 35% achieved HBeAg seroconversion. During a median off-treatment follow-up period of 59 months (range, 28–103 months) after HBeAg seroconversion, only 31% had a sustained remission. HBeAg seroconversion during NUCs treatment does not seem to be sustained in most CHB patients (4). Long-term NUCs treatment may be necessary while continuing the search for markers of SVR such as quantitative HBsAg or hepatic covalently closed circular DNA (cccDNA).

Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References

Lamivudine

Lamivudine 100 mg daily was the first FDA-approved NUCs for CHB therapy (5–7). The HBeAg seroconversion rate was approximately 15–20% after 1 year of lamivudine and reached around 50% at the end of 5 years. However, lamivudine resistance also increased from approximately 30% after year 1 to 70% in year 5. A viral breakthrough is usually followed by hepatitis relapse and histological deterioration. Treatment of patients with lamivudine resistance includes the addition of adefovir or tenofovir. Patients who achieve HBeAg seroconversion may terminate therapy after one more year therapy for consolidation. The SVR is not satisfactory.

Adefovir dipivoxil

A daily dose of 10 mg of adefovir dipivoxil is not an ideal first-line NUCs therapy because of low potency and because a sizable proportion (20–50%) of patients fail to achieve even a 2 log10 reduction in serum HBV DNA. HBeAg seroconversion after 1 year of therapy is 12% and reliable longer term data in HBeAg-positive patients are lacking. The adefovir resistance rate is nearly 30% at the end of 4 years of therapy. In a small proportion of treated patients, adefovir also causes renal tubular acidosis with hypophosphataemia when treatment is prolonged. Creatinine increased in 3% of these patients after 4–5 years of therapy requiring a dose reduction (8, 9).

Entecavir

The long-term efficacy of entecavir therapy was published recently. The results in 146 patients from clinical trials with up to 5 years (240 weeks) of continuous entecavir 0.5 or 1.0 mg therapy showed 94% (88/94) with HBV DNA <300 copies/ml and 80% (78/98) with normalization of ALT levels. However, the HBeAg seroconversion rate was only 23% (33/141). HBsAg was lost in 1.4% of patients (2/145). The major advantage of entecavir therapy is the significantly low development of resistance. Over 5 years, entecavir resistance emerged in one patient and the good safety profile of entecavir was consistent with previous reports (10). Long-term therapy also led to significant histological improvement. Liver biopsy performed after a median of 6 years (range, 3–7 years) showed improvement (≥2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) in 96% of patients, and an improvement of at least1 point in the Ishak fibrosis score in 88% of the patients. There was also a significant improvement in 10 patients with advanced fibrosis or cirrhosis (11).

Telbivudine

Telbivudine is as potent as entecavir. A median decrease in serum HBV DNA of approximately 6 log10 is observed after 48–52 weeks of therapy and 68% of patients achieve undetectable HBV DNA. In the 2-year GLOBE study, HBeAg-positive patients treated with telbivudine had better outcomes than those with lamivudine for undetectable viraemia (<300 copies/ml), which was 55.6% compared with 38.5% (P<.001), respectively, HBeAg loss: 35.2 vs 29.2% (P=.056), respectively, and HBeAg seroconversion, which was 29.6 vs 24.7% (P=.095) respectively. However, although viral resistance was lower than with lamivudine, 25.1 vs 39.5% (P<.001), respectively, this is still unacceptably high compared with other available NUCs. The indication for this agent may need to be further refined for patients with baseline ALT level ≥2 times normal and lower baseline HBV DNA to obtain higher HBeAg seroconversion rates (12). There is also a risk of myopathy and neuropathy with telbivudine. Although this has been reported in a small percentage of patients after 1 or 2 years of therapy, doctors should be aware of early symptoms and appropriate tests should be performed so that treatment can be stopped promptly (13).

Tenofovir

Double-blind phase 3 clinical trials in HBeAg-positive CHB patients have shown that tenofovir disoproxil fumarate (DF) 300 mg daily is significantly more effective than 10 mg adefovir dipivoxil per day. At week 48, 76% of HBeAg-positive patients receiving tenofovir DF reached virological and histological endpoints, which is significantly better than the 13% of patients receiving adefovir dipivoxil (P<0.001). Significantly more patients treated with tenofovir DF had normalized alanine aminotransferase levels (68 vs 54% respectively, P=0.03) and loss of HBsAg (3 vs 0% respectively, P=0.02) than those treated with adefovir dipivoxil. Resistance to tenofovir DF did not develop in any of the patients. The HBV DNA response to tenofovir DF was similar in patients who had previously received lamivudine to those who had not. The safety profile of tenofovir was similar and renal toxicity was minimal (14).

Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References

The HBV vaccination programme was begun for newborns in endemic regions in the mid 1980s. The prevalence of HBsAg in children and young adults has decreased significantly. In Taiwan and Hong Kong, universal HBV vaccination for all newborns and additional HBIg for newborns of CHB mothers was begun in 1988. The impact of this programme is immense and HBsAg prevalence among children and young adults is now less than 1% compared with the previous peak of 10–15%. However, many other Asian countries or regions have incomplete HBV vaccination coverage. In China, the coverage is nearly 100% since a catch-up programme was begun in 2005. There are still many young adults in the immune tolerant phase. There are no data to support the clinical benefit of treating these young immune tolerant patients. Ongoing clinical trials evaluating potent NUCs such as entecavir or tenofovir monotherapy or in combination with another NUCs may provide further results on achieving treatment endpoints.

Young adults in the immune clearance phase with ALT two to 10 times the upper limit of normal and relatively low serum HBV DNA levels below 8 log10 IU/L have a 30–40% chance of responding to pegylated interferon and achieving HBsAg loss. However, in the clinical setting, the proportion of patients in this subgroup with these positive predictors of response is relatively small. Intensive monitoring of ALT may be needed to identify the best moment for treatment. However, the question of how to manage the 60–70% of non-responders with significant disease activity remains. Often, the pros and cons of longer duration NUCs therapy have to be discussed thoroughly. The decision requires careful and detailed counselling of patients, especially if they are in their childbearing years. The chance of achieving HBeAg loss or seroconversion can be achieved in 30–40% of patients with more potent NUCs such as entecavir, tenofovir or telbivudine after 3–5 years of therapy. Data on SVR are being gathered. Additional markers such as quantitative HBsAg or hepatic cccDNA may help make the decision to stop therapy and achieve an SVR.

Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References

As mentioned above, data from Taiwan and Hong Kong where genotypes B and C predominate show that delayed HBeAg clearance increases the risk of progression to the reactivation phase, cirrhosis and HCC. Whether all patients should be treated for the rest of their life is debatable and controversial. One argument is that the indication should still be based on the degree of fibrosis on liver biopsy or liver stiffness on fibroscan examination. Another argument is that evidence showing that NUCs treatment in this group can significantly reduce the risk of HCC only applies to lamivudine therapy in patients with advanced fibrosis or cirrhosis (15, 16). A meta-analysis of randomized trials, case–control and cohort studies over the past 10 years has shown that the risk of HCC after interferon treatment was reduced by 34% [risk ratio (RR): 0.66, 95% confidence interval (CI): 0.48–0.89]. The benefit is more significant in patients with early cirrhosis than in those without cirrhosis. Five studies compared patients treated by NUCs with control patients. The risk of HCC after treatment was reduced by 78% (RR: 0.22, 95% CI: 0.10–0.50). The risk of HCC was the lowest in HBeAg-positive patients. Patients without cirrhosis benefited more from NUCs than those with cirrhosis. It is important to note that resistance to NUCs has limited the benefit of the treatment (17). The REVEAL study has clearly shown that a longer duration of high viral replication increases the risk of HCC. Normograms for assessing the risk of HCC in patients with CHB virus infection have been published. The independent predictors of risk are gender, age, a family history of HCC, high alcohol consumption, serum ALT levels, HBeAg serostatus, serum HBV DNA levels and HBV genotype (18).

Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References

The role of NUCs therapy is well established in specific patient subgroups such as treated HCC, in organ transplant recipients receiving immunosuppressant therapy and cancer patients receiving chemotherapy. NUCs therapy in the last trimester of pregnancy for CHB mothers with a high viral load is controversial and may do more harm than good to the mothers because the decision to treat will not be based on her disease activity but on an entirely different biological situation. It will be difficult to stop therapy after delivery without a risk of having a flare of hepatitis.

Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References

A Systematic Review and Bayesian Meta-Analyses evaluated the relative efficacies of the first 12 months of lamivudine, pegylated interferon, adefovir, entecavir, telbivudine and tenofovir, as monotherapies and combination therapies, in treatment-naïve HBeAg-positive patients and HBeAg-negative patients. Tenofovir was found to be the most effective in inducing undetectable HBV DNA (predicted probability=88%), in normalization of ALT (66%), in HBeAg seroconversion (20%) and HBsAg loss (5%) in the HBeAg–positive patients. Entecavir was most effective in improving liver histology (56%) and only second to tenofovir for inducing undetectable HBV DNA levels (61%) and normalization of ALT levels (70%) (19). In most countries in North America and Europe, the recommended first-line NUCs therapy is either tenofovir or entecavir. The picture is very different in Asia. The limited government subsidies mean that patients are treated late in the disease so that therapy seems to have made little impact on morbidity and mortality in CHB patients. Because of the strict budget controls, alternative management and therapeutic strategies must be developed. The Roadmap is one of them. The Roadmap facilitates the use of other cheaper NUCs such as lamivudine and telbivudine to adapt to the cost barrier while minimizing the risk of having large numbers of drug-resistant patients. Patients with drug-resistant HBV are often left untreated because neither the patient nor the healthcare system can afford the expensive add-on therapy. The Roadmap models with a switch-to tenofovir if HBV is detectable at week 24 or add-on tenofovir if resistance develops at year 1 were compared with tenofovir and entecavir monotherapy. The primary measure of effectiveness was undetectable HBV DNA at year 2. In the US and Germany, the costs of the reference arms were US$14 486 and US$9998 for HBeAg-positive and US$11 398 and US$7531 for HBeAg-negative patients respectively. In HBeAg-positive patients, the lamivudine roadmap was the most cost effective (ICER US$15 260 in the US and US$29 113 in Germany) and the strategy was as effective (75.1%) as other strategies. In Asia, where telbivudine costs less, both telbivudine and lamivudine roadmaps were cost effective in HBeAg-positive patients. Tenofovir would be the most cost-effective treatment in HBeAg-negative patients if it cost the same as telbivudine in Asia (20).

Conclusion

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References

The decision to treat HBeAg-positive CHB patients with one of the NUCs must be individualized. Choosing the appropriate NUCs in the first intention is vital to a good clinical outcome. Patients must be made aware of the importance of drug compliance and the possible prospect of lifelong therapy. The emergence of HCC is a major source of morbidity and mortality, and therefore, of anxiety for individual CHB patients. The psychological burden is even greater in patients with family members or close relatives who have succumbed to the disease. A sound healthcare strategy requires good epidemiological data and detailed cost-effective analysis.

References

  1. Top of page
  2. Abstract
  3. Disease spectrum in HBeAg-positive chronic hepatitis B
  4. Indications for antiviral therapy in HBeAg-positive patients
  5. Endpoints for treatment with nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B
  6. Choice of nucleos(t)ide analogue in the treatment of HBeAg-positive chronic hepatitis B patients
  7. Why do I treat a young HBeAg-positive chronic hepatitis B patient with nucleos(t)ide analogues?
  8. Why do I treat older HBeAg-positive chronic hepatitis B adults with nucleos(t)ide analogues?
  9. Why do I treat other HBeAg-positive chronic hepatitis B patients with nucleos(t)ide analogues?
  10. Roadmap concept in the treatment of HBeAg-positive chronic hepatitis B patients
  11. Conclusion
  12. Conflicts of interest
  13. References