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Treatment
Aims, Objectives and Strategies
Although a rare event, HBsAg seroconversion is the ultimate goal of anti-HBV therapy as it corresponds to the disease state achieved in patients who spontaneously resolve HBV after acute infection. It indicates that the immune system has successfully overcome the infection, and therefore may be regarded as the closest outcome to a ‘cure’ (Figures 3-1, 3-2). However, because the HBV genome integrates into the host genome, complete eradication of HBV is unlikely, even in patients achieving HBsAg seroconversion.
Figure 3-1. Treatment objectives
In HBeAg-positive CHB, the recommended measurable surrogate marker of treatment efficacy is HBeAg seroconversion,1 since this is ultimately associated with disease remission and increased survival. This marker cannot be used in HBeAg-negative CHB, where other markers, such as reduction in HBV DNA levels and normalisation of ALT levels are used. The long-term goal of therapy is to prevent, stop, or reduce liver necrosis, progression to cirrhosis and/or liver cancer and thereby prolong patient survival.
The primary objective of therapy for chronic HBV is to achieve control of viral replication and halt disease progression/improve liver histology. This will decrease pathogenicity and infectivity and thereby stop or reduce hepatic necroinflammation. Based on the objectives described above two treatment goals emerge:
- off-therapy sustained response with immunological control – achieved with a course of treatment of finite duration (ie IFNα-based therapy), with the following possible outcomes:
- in HBeAg-positive CHB: HBeAg seroconversion (lasting remission) and HBsAg seroconversion
- in HBeAg-negative CHB: HBV DNA reduction, ALT normalisation (lasting remission) and HBsAg seroconversion
- on-therapy maintained response – achieved during antiviral treatment (ie nucleoside/tide analogue therapy or NA), that leads to viral suppression with HBV DNA reduction and ALT normalisation. High rates of rebound can occur both once the treatment is stopped, however. Furthermore, long-term use increases the risk of the development of resistance to the drug, which can have serious clinical consequences.
The long-term goals of therapy are prevention of hepatic decompensation, progression to cirrhosis or HCC and, ultimately, prolonged survival.3
Figure 3-2. Therapeutic endpoints over time
Measuring response to therapy
The primary efficacy endpoint used to assess off-therapy sustained response in HBeAg-positive CHB is HBeAg seroconversion (ie clearance of HBeAg and development of anti-HBe antibodies). Other short-term efficacy endpoints include normalisation of serum ALT levels, suppression of HBV DNA, and improvement in liver histology.1,3 In HBeAg-negative CHB suppression of HBV DNA to below 10,000 copies/mL (2,000 IU/mL) is considered an appropriate virological endpoint.1-3
Treatment guidelines
Currently available therapies for the management of CHB can be divided into two classes: IFNs (conventional or peylated - PEGASYS®), with dual immunomodulatory and antiviral mode of action; and antivirals, the NAs.
At present, several recognised treatment guidelines and algorithms for the treatment of CHB have been published by different organisations around the world. These all recommend use of PEGASYS® as a first-line option in the treatment of patients with HBeAg-positive or HBeAg-negative CHB.4-7
- PEGASYS® achieves durable off-treatment serological, virological and biochemical response8
- No viral resistance has been observed with PEGASYS® 9
In the United Kingdom (UK), the National Institute for Health and Clinical Excellence (NICE), which provides national guidance on use of new therapies, concluded that Pegasys should be used as first line treatment in CHB. This was regardless of whether patients were HBeAg-positive or not. This finding was based on the fact that PEGASYS® therapy was more cost effective than adefovir or lamivudine as it is given for a fixed duration.
The Asian Pacific consensus statement makes a distinction when specifying treatment duration with PEGASYS® between patients with HBeAg-positive and HBeAg-negative disease: 6 months of therapy for patients with the ‘easier-to-treat’ HBeAg-positive CHB, and 12 months for those patients with the more ‘difficult-to-treat’ HBeAg-negative CHB. All treatment guidelines also make this distinction for treatment duration with conventional IFNα.
The current treatment guidelines all agree that factors that should be taken into consideration when deciding upon the most appropriate treatment include the needs of the individual patient, duration of therapy, cost of treatment, potential for drug resistance development, adverse events profile, monitoring tests/clinic visits required and patient/provider preferences. The advantages and disadvantages of the currently available anti-HBV therapies are outlined in Table 3-1, which can be viewed by clicking here. Figures 3-3 to 3-5 compare the efficacy of IFNα-based therapy compared with nucleos(t)ide analogue antivirals (NAs), as well as cost considerations .
Table 3-1. Advantages and disadvantages of current HBV therapies
Figure 3-3: Treatment for 1 year withIFN/PEG-IFN achieves higher rates of HBeAg seroconversion compared with NAs
PGS:Pegasys / PGN: Peglntron / IFN:Conventional interferon / LAM:Lamivudine / ETV:Entecavir / ADV:Adefovir / TLV:Telbivudine / TNV:Tenofovir
* Collation of Currently available data not from head-tohead studies
** Antivrals achieve higher rates of seroconversion on longer term treatment - LAM:36% (Yr5), ADV:48% (Yr5), ET V:39% (Yr3), TLV:30% (Yr2)
***Average of the results of 2 clinical trials (Range 22-36%)
****Average of the results of 8 clinical trials (Range 12-44%)
Figure 3-4: Rates of HBsAg clearance with interferons and nucleosides/tides
PGS:Pegasys / PGN: Peglntron / IFN:Conventional interferon / LAM:Lamivudine / ETV:Entecavir / ADV:Adefovir / TLV:Telbivudine / TNV:Tenofovir
1.Collation of current available data: not from head-to-head studies; 2. 3 year follow-up after EOT; 3. 0% HBsAg clearance reported by Lampertico et al, 2003 (figure 1): 7.8% HBsAg loss reported on AASLD guidelines 2007 4. On-therapy result at teh end of 72 weeks; 5. 4 year follow up after EOT; 6. No results reported; 7.Marcellin et al. NEJM 2004; 8. Janssen et al. Lancet 2005; 9. Lampertico et al, 2003, AASLD Guidlienes; 10. Hoofnagle et al. Gepathology 2005; 11. Marcellin EASL 2008; 12. Piratvisuth APASL 2007, Marcellin EASL 2008
Figure 3-5: Rates of resistance with IFNs and NAs in naïve and LAM-R patients
- of clinical benefits (e.g., virologic / histologic improvement)
- Co-resistance hinders efficacy of NA therapy for NA-pretreated patients, whereas pretreatment with NAs is not a limiting factor for interferon therapy
LAM:Lamivudine / ETV:Entecavir / ADV:Adefovir / TLV:Telbivudine / TNV:Tenofovir
*Pegasys, Pegintron and conventional interferon
Cost-effectiveness analyses
A recent analysis of life expectancy and cost-effectiveness in patients with HBeAg-negative CHB suggested that a 48-week course of PEGASYS® remained cost effective compared with either 48 weeks or 4 years of lamivudine therapy, despite variations in assumptions regarding the treatment effectiveness, disease progression rates and costs.10 A systematic review in the Journal of Viral Hepatitis published in 2007 noted that the treatment was ”within the range considered by NHS decision-makers to represent good value for money.11 An cost-effectiveness comparison for IFNα-based therapy versus NAs is shown in Figure 3-6.
Figure 3-6: Comparison of costs: IFNα-based therapy versus NAs**
† Including China, the European Union, Switzerland, and the US
References:
1. Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology 2004;39(3):857–61 and
2. de Franchis R, Hadengue A, Lau G, et al. EASL International Consensus Conference on Hepatitis B. 13–14 September, 2002 Geneva, Switzerland. Consensus statement (long version). J Hepatol 2003;39 (Suppl 1) :S3–25.
3. Liaw YF, Leung N, Guan R, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver International 2005;25:472–89.
4. Lok ASF, McMahon BJ. AASLD Practice Guidelines update 2007: chronic hepatitis B. (Accessed March 2007 at: www.aasld.org/eweb/docs/chronichep_B.pdf).
5. Liaw Y-F et al. Liver International 2005: 25:472-489.
6. Keeffe EB et al. Clin Gastroenterol Hepatol 2006;4:936-62.
7. National Institutes for Health and Clinical Excellence Guidelines: www.nice.org.uk/TA096
8. Marcellin P et al. Hepatology 2006;44(4 Suppl 1):550A.
9. PEGASYS® Summary of Product Characteristics, revised 2005.
10. Veenstra D, Sullivan SD, Lewis G, Green J, Patel K. Cost-effectiveness of peginterferon alfa-2a (40KD) compared to lamivudine for the treatment of HBeAg-negative chronic hepatitis B in the UK. Presented at the ISPOR meeting, May 15–18 2005, Washington DC.
11. A. Takeda, J. Jones, J. Shepherd, P. Davidson and A. Price. A systematic review and economic evaluation of adefovir dipivoxil and pegylated interferon-alpha-2a for the treatment of chronic hepatitis B. Journal of Viral Hepatitis 2007 Feb;14(2):75-88.