Do we need to determine viral genotype in treating chronic hepatitis B?

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J Viral Hepat. 2010 May 31. [Epub ahead of print]

Do we need to determine viral genotype in treating chronic hepatitis B?

Cooksley WG.

Discipline of Medicine, University of Queensland, Royal Brisbane Hospital,
Brisbane, QLD, Australia.

Abstract
Summary. Many studies have attested that not only does HBV genotype influence
the outcome of the disease but it also influences the outcome of therapy with
interferons and pegylated interferons, with genotype A doing better than
genotype D in Caucasians and genotype B better than genotype C in Asians.
However, the guidelines from three regional bodies - AASLD, APASL and EASL -
all stop short of recommending genotyping as part of the management of chronic
hepatitis B. The recommendations, however, from several national organizations
as well as from individual reviewers suggest that genotyping is essential to
detect patients in whom the use of pegylated interferon will give a high
likelihood of response with a finite course of therapy and avoid the
disadvantages of nucleoside analogues with their viral resistance. It is
concluded that determination of HBV genotype should form part of the
management in treating chronic hepatitis B.
PMID: 20529201 [PubMed - as supplied by publisher]
_________________________________________________________________

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From Journal of Viral Hepatitis
Do we Need to Determine Viral Genotype in Treating Chronic Hepatitis B?
W. G. E. Cooksley
Authors and Disclosures
Posted: 02/21/2011; J Viral Hepat. 2010;17(9):601-610. © 2010 Blackwell Publishing

Abstract and Introduction

Abstract

Many studies have attested that not only does HBV genotype influence the outcome of the disease but it also influences the outcome of therapy with interferons and pegylated interferons, with genotype A doing better than genotype D in Caucasians and genotype B better than genotype C in Asians. However, the guidelines from three regional bodies – AASLD, APASL and EASL – all stop short of recommending genotyping as part of the management of chronic hepatitis B. The recommendations, however, from several national organizations as well as from individual reviewers suggest that genotyping is essential to detect patients in whom the use of pegylated interferon will give a high likelihood of response with a finite course of therapy and avoid the disadvantages of nucleoside analogues with their viral resistance. It is concluded that determination of HBV genotype should form part of the management in treating chronic hepatitis B.

Introduction

When conventional interferon was first used in the treatment of chronic hepatitis B in the 1980s, it became apparent from multinational studies[1] that response was more frequent in Caucasians who had been infected usually as an adult compared with Asians who had been infected perinatally. Although it was thought that the response in Asians was reduced in those with a normal ALT and that patients with an elevated ALT had a response similar to that in Caucasians, it was subsequently found to be more complex. Caucasians with genotype A were more likely to respond than Caucasians with genotype D[2] and that in Asia patients with genotype B were more likely to respond than genotype C.[3,4]

When the first study[5] with pegylated interferon was carried out (this being in the Asian Pacific region), one-third of the patients had genotype B and two-thirds had genotype C. The response rate in those with genotype B (31%) was higher than in those with genotype C (17.5%). Within the next 3 years, five randomized controlled trials had been published[5–9] using pegylated interferon alfa 2a or pegylated interferon alfa 2b. Four of the studies[5–8] were in HBe antigen-positive patients, and one[9] was in HBe antigen-negative patients. In two[6,7] of these studies, patients with genotype A were involved and patients with this genotype did best of all confirming earlier studies with conventional interferon. In the last few years, there has been considerable interest in the geographical distribution of HBV genotypes and subgenotypes and the difference in the severity of the liver disease and frequency of HCC with the genotypes, drawing attention to the role of the genotypes in the clinical importance of the liver disease.

Nevertheless, the guidelines for the management of chronic hepatitis B published by the American Association for the Study of Liver Diseases (AASLD),[10] the European Association for the Study of the Liver (EASL)[11] and the Asian Pacific Association for the Study of the Liver (APASL)[12] suggest that genotyping the virus is not a recommended part of the management and is best regarded as a research tool. In contrast, individual reviews[13,14] cite the same evidence and recommend that therapy be based on genotyping, and the German guidelines[15] for the management of hepatitis B virus infection strongly support this position. The rationale for this position is because interferon alpha therapy should be evaluated first because it is for a finite duration, and the aim is a sustained success of therapy. Because genotype A is likely to achieve this outcome, it is important to identify such patients. The Dutch guidelines[16] maintain pegylated interferon should be considered for initial therapy particularly with genotypes A and B, and the Swedish guidelines[17] recommend pegylated interferon as first-line treatment, in particular for genotypes A and B. In contrast, the guidelines published by the major regional organizations tend to be fairly broad. Because they deal with a complex disease, they take the view that, as only a minority of patients are treated with interferons, the role of genotypes is specialized. Furthermore, unlike in hepatitis C where patients with different genotypes have different durations of therapy, in hepatitis B patients still receive the same treatment protocol with interferon regardless of the genotype.

In this review, the genotypes and the subgenotypes including mixtures and recombinations and their geographical distribution will be described. The results of the four large studies[5–7,9] where the genotype has been ascertained will be discussed. We will then try to explain and reconcile the different points of view and then indicate those circumstances where genotyping appears to be important.

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Genotypes and Their Geographical Distribution

Shortly after the discovery of the Australia antigen by antigen antibody precipitation lines on agar gel diffusion plates, it was recognized that the precipitin lines on the agar gel plate had spurs, indicating a further antigen antibody system 'd' and 'y' and subsequently a second system 'w' and 'r', and together with the common antigen determinant 'a' there were four serotypes, adw, adr, ayw and ayr.*

These were recognized as having different distribution around the world. Subtypes were soon added, and on viral sequencing, it was recognized that a single point mutation could change the serotype, so that serotypes can change from d to y and w to r by a single point mutation at nt 365 and nt 479 which converts codons 122 and 160 from lysine to arginine.[20] In 1988, four genotypes were proposed by Okamoto and colleagues[21] based on sequence divergence of more than 8% in the entire HBV genome, and in 1994,[22] another two genotypes were added using the same criteria and a further two subsequently.[23,24] More recently another two have been added provisionally,[25,26] and it is recognized that there are some nosological problems with the inclusion of new genotypes[27] and the most recent genotype, J, was discovered in an 88-year-old Japanese male stationed in Borneo during the Second World War whose viral sequence positions it phylogenetically between human and ape viral genotypes.[26]

The HBV genotypes have distinct locations[28,29] (Table 1). In brief, genotype A occurs in Africa, Europe and India, genotype B occurs in east and southeast Asia, genotype C occurs in East Asia and the Pacific Islands and genotype D occurs in the Mediterranean region, Middle East, central Asia and India and can be used to study anthropological migration patterns in the past.[30,31] Because of recent migration patterns, genotypes A, B, C and D may occur in Europe, North America and Australasia. Genotype E occurs in West Africa and genotypes F and H in central and South America. The genotype G appears partially defective and invariably occurs together with another genotype, which provides transcription factors necessary for replication.[32] In areas of high endemicity, mixes of genotypes may occur in about 10% of HBsAg-positive carriers[33] and may be responsible for intertypic recombination.[34] Hybrids of B and C are found in Asian countries, A and D in Italy and C and D in Tibet and China.[35]

The natural history may differ between genotypes and best shown in studies where multiple genotypes occur in the same country such as Spain,[36] Alaska,[37] Japan,[38] China and Taiwan.[39] Many studies have shown that genotype C is associated with more severe liver disease and more HCC,[35,38–40] probably partly related to later HBe antigen seroconversion.[41] There are multiple subgenotypes that may also have clinical significance. For example, B1 (Bj for Japan) occurs in Japan, whereas B2 (Ba for Asia) occurs in Taiwan, China and Vietnam and appears to be a recombination of genotype B and C and has a different natural history from genotype B1. Again, in India,[42] genotype D was more likely to be associated with severe liver disease and HCC than genotype A.

Most of the studies on therapy for chronic hepatitis B have involved patients with the four genotypes A, B, C and D but a small number of patients with the genotypes E, F, G and H as well as genotype mixtures have also been shown to respond to interferon therapy.[43] Whether there are differences between the subgenotypes or mixtures in response to antiviral therapy remains to be seen. For a detailed understanding of the origin and evolution of the hepatitis B virus and its genotypes, one is referred to several recent reviews.[44,45]

* le Bouvier[18] gave the initials 'd' or 'y' after the college football teams, Dartmouth and Yale, whose play he was listening to on the radio while working in the laboratory. The second system was designated 'w' and 'r' after Walter Reed Hospital in Washington, DC.[19]

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Response to Conventional Interferon

In 1993,[46] a meta-analysis of conventional interferon treatment with injections given for 12–24 weeks showed that interferons lead to HBe antigen seroconversion in 33% of treated patients compared with 12% of untreated controls. A subsequent analysis[47] 10 years later of 24 randomized controlled trials showed a risk difference of 24.3% in favour of interferon with respect to loss of HBe antigen. However, the response amongst Asian patients was perhaps less satisfactory. In a retrospective analysis of 48 patients treated with interferon alpha 2b from Taiwan,[3] the response rate was 41% and 15% in genotype B and C patients, respectively (P = 0.025). In a further study[4] from Asia of 73 patients, the response rate was 39% in genotype B and 17% in genotype C. A European study[48] found a sustained response to alpha interferon was better for genotype A than genotype D (46%vs 24% in HBeAg-positive patients and 59%vs 29% in HBeAg-negative patients). Other European studies have shown similar results. A systematic review[49] of 20 interferon trials up to 2007 found HBV genotypes produced better responses to interferon with genotype A vs D and in HBe antigen-positive patients with genotype B vs C.

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Response to Pegylated Interferon

Pegylated interferon is likely to replace conventional interferon worldwide. In 2003, the first study of pegylated interferon alfa 2a in chronic hepatitis B was published with almost 200 patients in the Asian Pacific region. Over the next few years, a total of five randomized controlled trials involving 100 patients or more were reported, four of these being in patients with HBe antigen-positive disease and one study being carried out in HBe antigen-negative patients (Table 2). Although most of these studies were multinational, the majority of the patients had genotypes B and C.

In the first study, Cooksley et al.,[5] data on HBV genotype were available on 96% of all 194 patients. The HBV genotypes were C 66% and B 32%. The rate of combined response (HBe antigen seroconversion, HBV DNA <500 000 copies/mL and ALT normalization) was 31% in patients with genotype B compared with 17.5% in those with genotype C (P < 0.05). For those receiving conventional interferon, the figures were 25% and 6% for genotypes B and C, respectively.

In study two, the largest study, Lau et al.,[6] 814 patients participated worldwide. Again, genotypes B and C were predominant, and there were also 56 patients with genotype A and 37 patients with genotype D. The HBe antigen seroconversion rate in those receiving pegylated interferon plus placebo was 52% (12/23) in genotype A and 22% (2/9) in genotype D. The results were virtually identical for both genotypes B and C with 30% and 31%, respectively, undergoing HBe antigen seroconversion. Multivariate logistic regression analysis failed to show a significant role for genotype even though patients with genotype A had nearly twice the HBe antigen seroconversion rate (52%) and 22% HBsAg seroconversion, probably because of a lack of statistical power, as only 7% of patients in the study had genotype A. The odds ratio for genotype A response compared with the genotype D response was 2.0 (P = 0.21).

Is it possible to reconcile the difference in response rates in genotypes B and C in the two studies? The demographics were similar in both the Cooksley and Lau studies[5,6] as most Asian patients came from Hong Kong, Guangzhou province in China, Taiwan and Thailand and, in the Lau study, also from Korea. The B genotype was probably B2(Ba) in these patients. In the study by Cooksley et al.,[5] patients were treated with conventional interferon alpha 2a or one of three doses of pegylated interferon alpha 2a – 90, 180 or 270 μg – weekly for 24 weeks. The combined response for all pegylated interferon-treated patients – 24% (loss of HBe antigen, normalization of ALT and DNA <500 000 copies/mL.) was significantly better than for conventional interferon-treated patients 12% (P < 0.05). However, quantitative HBe antigen declined rapidly in all pegylated interferon arms, and HBe antigen loss and seroconversion were slightly higher in the 90 μg arm than in the 180 μg am at 37% and 37%vs 35% and 33%, respectively (P = NS) and higher than those in the 270 μg arm. The decision to use 180 μg in the second study[6] rather than 90 μg was made because the mean HBV-DNA curve with time was slightly lower than in the 90 μg arm, although it is now known that HBe antigen decline is a better prediction for HBe antigen loss than HBV DNA decline.[50] The different duration of therapy and the different doses of pegylated interferon in the two studies, however, have led to the suggestion[12] that a longer duration of therapy and/or higher dose may be required to enhance the response of patients with a more difficult to treat genotype such as genotype C compared with genotype B which only required 6 months treatment with 90 μg.

A recent open-label study (n = 230) was conducted in China[51] to examine the clinical relevance of low-dose interferons in HBe antigen-positive patients for 24 weeks as an effective, alternative and cheaper form of therapy in a region where the cost of a drug may have to be borne by the individual. Patients received either pegylated interferon alfa-2b 1 μg per kilogram body weight or conventional interferon alfa 2b 3M IU three times a week, both drugs being used in lower doses than in the five randomized controlled trials. Multivariate statistical analysis revealed that HBV genotype B and patient age (25 years or less) were two independent factors associated with sustained combined response. A total of 40% of patients with HBV genotype B aged 25 or less achieved a sustained combined response to short-course, low-dose treatment. Prospective studies, however, would be necessary to answer the question whether different genotypes required differences in dose and duration of therapy. However, as a result of the first study,[5] the APASL[12]recommended 90–180 μg for a duration of at least 6 months (rather than 180 μg for 12 months), because many patients in the Asian region have to purchase the drugs themselves.

The third study, Janssen et al.,[7] was a European study and 34% of patients were genotype A and 39% genotype D, 9% had genotype B and 15% had genotype C and utilized 100 μg for 52 weeks. Response rates (HBe antigen loss) varied by HBV genotype using univariate analysis (P = 0.01): genotype A n = 42 patients (response rate 47%); B n = 10 (44%); C n = 11 (28%); and D n = 26 (25%). Using multivariate analysis, patients infected with genotype A were more likely to respond than those with genotype D (odds ratio 2.4, P = 0.01) or genotype C (3.6, P = 0.006). Patients infected with genotype B were slightly but not significantly more likely to respond compared with those with genotype C (odds ratio 2.2, P = 0.18).

Both of the studies (Lau[6] and Janssen)[7] with genotypes A, B, C and D had shown the best response in genotype A and the lowest response in genotype D, and the numbers in these two groups was great enough in the study by Janssen but not Lau to show a significant difference. The responses in genotypes B and C were intermediate, and neither study[6,7] showed a significant difference even though the first study (Cooksley et al.)[5] had. In both Janssen[7] and Cooksley[5] studies, patients with genotype B have almost twice the response than occurs with genotype C, but in the Lau study[6] that had the greatest numbers the responses were virtually identical.

The fourth study[8] in the HBe antigen-positive disease was carried out in Hong Kong with 100 patients. Twenty-four weeks after the end of treatment, 36% in the combination treatment group of pegylated interferon and lamivudine compared with 14% in the lamivudine monotherapy group had a sustained virological response(P = 0.011). However, the response by genotypes was not analysed except to show that the rate of lamivudine-resistant mutants was not influenced by genotype (P > 0.2).

There is a single study[9] in HBe antigen-negative patients using pegylated interferon or pegylated interferon with lamivudine or lamivudine monotherapy involving 530 patients in Europe and Asia. Patients received pegylated interferon alfa 2a 180 μg for 48 weeks. Genotype was available for 346 patients in the two arms containing PEG interferon, and the largest group was genotype C, then genotypes D and B. Only 6% had genotype A. The combined response (normalization of ALT and DNA <20 000 copies/mL) was 44% for genotype B, 49% for genotype C and 16% for genotype D in patients receiving PEG interferon only. Six months after the end of therapy, approximately 3% of patients in the two PEG interferon groups had lost HBs Ag vs 0% in the lamivudine group. Two hundred and thirty patients from the two groups who received PEG interferon then entered a long-term follow-up study for 5 years. After 5 years, 22% of patients still had ALT normalization, 17% had undetectable DNA (<400 copies/mL) and 12% had lost HBsAg.[52]

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Response to Nucleos(t)ides

Most studies[49,53,54] conclude that there is no difference in the response in different genotypes to treatment with nucleoside analogues in loss of HBe antigen and HBV DNA suppression, a view shared by the EASL.[11] However, the loss of HBsAg, which is a rare event with nucleos(t)ide analogues, seems to occur more frequently with genotype A, where in four clinical trials with adefovir, six of nine patients who lost HBsAg were genotype A.[55]

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HBsAg Loss and Seroconversion

In Caucasian patients with HBe antigen-positive chronic hepatitis B treated with conventional interferon, it was found that those who lost HBe antigen also lost HBsAg in about 50% of cases by 3 years.[56] The loss of HBsAg is the most important end point but occurs rarely in practice and only occasionally or rarely with nucleoside analogues.

In the pegylated interferon HBeAg-positive trials, 3% of patients had lost HBsAg 24 weeks after the end of therapy with a2a (Genotype A in 7% of patients)[6] and 6–9% with a2b (genotype A in 34% of patients).[7] This increased to 8% for a2b and 14% for a2b with lamivudine at 3 years after the end of therapy.[57] In the alpha 2b study,[57] HBsAg loss at 6 months post treatment was highest in genotype A at 14% and lowest in genotype D at 2%. A similar gradient was noted in the alpha 2a study,[6] although the number of patients with genotypes A and D was small.

Although the numbers are small, the percentage of patients with HBsAg loss 5 years after the end of therapy by genotype in the HBeAg-negative study was genotype A 20%, B 6%, C 16% and D 11%.[52] A study in Italian HBe antigen-negative patients (all genotype D) had an HBsAg loss of 11% 3 years after the end of pegylated interferon.[58]

It is clear that the loss of HBsAg, although uncommon, is a very important end point and occurred most often in patients with genotype A. It is uncommon in patients treated with nucleoside analogues, and when it does occur again it is usually genotype A.

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The Recommendations by AASLD, APASL and EASL

The guidelines for the management of chronic hepatitis B have been published by three regional organizations for the study of the liver, AASLD, APASL and EASL[10–12] (including an unchanged update for the AASLD)[59] (Table 3). None of these have a recommendation to perform genotype before commencing treatment despite discussing the influence of genotypes on natural history and response to treatment in the background. Furthermore, many of the authors of the three panels have an interest in genotypes and have published in the field of genotypes. This would therefore seem to refute the suggestion that we need to determine viral genotype in treating chronic hepatitis B. However, there are reasons for not accepting this statement.

In the treatment of chronic hepatitis C, a large randomized controlled study[60] showed that 24 weeks treatment with pegylated interferon is sufficient in treating genotypes 2 and 3, whereas 48 weeks treatment is necessary in treating genotype 1. As this is the only form of treatment currently available for chronic hepatitis C, the genotype must be established before treatment is commenced to know the duration of therapy. Although it has been suggested that, in chronic hepatitis B, treatment with 24 weeks may be sufficient in the more responsive genotypes A and B but 48 weeks may be necessary for genotypes C and D, no randomized controlled trial has been carried out to support this contention. Furthermore, as treatment with nucleoside analogues is also available, treatment with one of these agents will obviate the issue.
Because of the complexity of chronic hepatitis B, guidelines have been constructed for the clinicians who treat the majority of patients. Most of the experts who comprised the three regional panels have published and presumably have considerable expertise in the use of interferons in this area. However, they also recognize that the great majority of the prescriptions written for the treatment of this disease prescribe nucleoside analogues so the guidelines are directed to this form of treatment and they must arrive at a consensus. Their views on treatment may differ considerably from those of the practicing gastroenterologists. For example, 50% of members of an international panel of experts[61] rejected 'that a nucleoside analogue with low resistance was the initial choice in HBe antigen-negative chronic hepatitis B' compared with only 7% of members of the AASLD whose opinion was sought. In the discussion of interferons, the question of influence of genotype may seem to be outside the scope of the guidelines in the absence of an unambiguous trial of different treatments in different genotypes. Usually, a comment is simply made referring to the importance of certain genotypes in influencing the decision to use interferons. For example, the two authors of the AASLD guidelines both have an interest in genotypes[41,62] but suggest this may be a research tool. Fourteen North American centres participated in the trials with pegylated interferon. A recent review by an American author[13] advocates the use of pegylated interferon in patients with genotype A. He also points out that recent studies (which would not have been available to the AASLD, EASL or APASL guidelines committees) have shown that changes to HBsAg and HBeAg concentrations during treatment predict sustained virological response, and serial monitoring of HBsAg is helpful in predicting HBsAg loss enabling treatment to be terminated if the patient is unlikely to respond. Other publications emphasize nucleotide analogues and a roadmap for their use. It has been emphasized[15] that the number of nucleoside analogues now available and the proportion of patients with viral resistance mean that a knowledge of mutants and resistance is a pre-requisite for anyone using nucleoside analogues. This was demonstrated recently by a hepatitis B viral sequencing study in Australia where about 8% of patients were found to be receiving suboptimal nucleoside analogues.[63] It is not the role of this review to list the advantages and disadvantages of interferons and antiviral agents, but several recent reviews have discussed this subject.[13,14]
The published guidelines for the EASL are in conflict with recently published guidelines from three national associations in Europe – Germany, Sweden and the Netherlands. The German guidelines (2008)[15] recommend that when choosing drugs for the treatment of hepatitis B, the first step is to check whether an alfa interferon therapy is possible as the duration is finite and the aim is a sustained success of therapy. An interferon-based therapy can be especially recommended for genotype A so genotyping should be performed as part of the diagnosis. The Dutch guidelines (2008)[16] also state that pegylated interferon should be considered as initial therapy for HBeAg-positive patients and HBe antigen-negative patients without contraindications because of the higher chance of achieving sustained response. The Swedish national guidelines (2008)[17] recommend pegylated interferon for first-line treatment, in particular for HBe antigen-positive patients with HBV genotype A or B. They recommend HBV genotype being ascertained prior to treatment.
In Asia, the conflicting results from the pegylated interferon trials on the role of genotypes B and C have meant that the recommendations in the last 2 years on dose and duration of therapy mention uncertainty. It has been suggested, however, that the explanation lies in genotype C requiring longer duration (48 weeks) of treatment.[12]
Recent studies have emphasized the importance of genotype in treatment. In the last few years, there has been a plethora of small studies published on the response to both pegylated interferon and nucleoside analogues broken down by genotypes. An explorative analysis of published evidence (2008)[49] of abstracts from PubMed, EASL and AASLD with at least 30 patients and reporting treatment results by genotypes produced 20 reports. Treatment response to nucleoside analogues was not significantly influenced by HBV genotype in HBeAg-positive or HBeAg-negative individuals. In contrast, HBV genotypes were informative concerning responses to interferon treatment in all patients with genotype A vs D and in HBeAg-positive patients with genotype B vs C. They concluded that if no contraindications are present, interferon may be considered as first-line therapy in all patients with genotype A and in patients with genotype B who are HBe antigen positive.
Analysis of the effects of HBV genotypes on the treatment outcome in the pooled analysis[64] of three large cohorts of hepatitis B patients both HBeAg positive and HBeAg negative treated with interferon alpha produced 1229 patients and included two clinical trials[6,9] as well as a collaborative European study. There were 174 patients with genotype A, 245 genotype B, 464 genotype C and 346 genotype D, and treatment was standard interferon or pegylated interferon with or without lamivudine. Multivariate analysis examined genotypes, HBeAg status, cirrhosis, ethnicity and treatment regimen and found that genotype was the strongest predictor for SVR. Overall, sustained virological response was greatest for genotype A (P < 0.001) (with 36% and 34% having a sustained virological response for HBeAg positive and negative, respectively). The rates of sustained virological response for HBe antigen-positive patients were 21%, 19% and 15% for genotypes B, C and D, respectively, and in the negative patients 32%, 50% and 21%.

Combination of the data[65] from the two largest trials[6,7] using pegylated interferon in HBe antigen-positive chronic hepatitis B produced 542 patients treated with alfa 2a and 266 treated with alfa 2b. Logistic regression analysis was performed to identify predictors of a sustained virological response (HBe antigen loss and HBV DNA <10 000 copies/mL at 6 months post treatment). Seven hundred and twenty-one patients had genotype A, B, C or D. Models based on genotype, gender, age, baseline ALT, baseline DNA and previous treatment were produced for each HBV genotype separately and showed that genotype A, together with baseline ALT and baseline DNA, was the most important predictor of response.

Comments[66] on the EASL practice guidelines challenged recommendations on interferon-based therapies. They disagreed with the assertion 'that HBV genotype has a poor individual predictive value and that genotype alone should not override choice of treatment'. They listed many previous studies that have shown the importance of HBV genotypes for interferon-based therapy and noted that the two largest studies conducted so far showed that genotype was the most important predictor of response in both HBe antigen-positive and HBeAg-negative patients in addition to ALT and HBV DNA. They emphasized it is important in all patients to identify good candidates for pegylated interferon therapy.

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Conclusions

The earlier data with conventional interferon and the recent data with pegylated interferon provide compelling evidence that, of the genotypes, A responds best to treatment with a third to a half expecting a sustained response in HBeAg-positive disease. The advantages of interferons are their finite treatment duration, the absence of viral resistance and the potential loss of HBsAg. In the absence of contraindications, interferons should be considered for initial therapy. Testing should therefore be carried out in those regions with genotype A including Europe, North and South America, India, Australia and recently Japan. The argument for differentiating between genotypes B and C is less clear with suggestions that the response in genotype B may be better than in C and that testing should be carried out in Asia and in Asians who have migrated. Cross-sectional analysis of large centres will then confirm or refute this speculation. In addition, randomized studies to examine different doses or duration of therapy may lead to genotype specific guidelines.

In HBeAg-negative disease, genotype A again gives the best response although it is an uncommon genotype in this disease. It is important to ascertain genotypes where genotype A is found. However, in patients with HBeAg-negative disease, sustained virological response occurs in about 25% of patients and about half of these will lose HBsAg 5 years after treatment. This may occur because of a lower viral load. However, even in genotype D, 5 of 47 patients (11%) cleared HBsAg 5 years after treatment. If it was intended to treat all patients with HBeAg-negative disease with interferons, then to test for genotypes could be regarded as superfluous.

What will be the outcome if genotyping is carried out in HBe antigen-positive patients prior to treatment? Patients with genotype A and B will be offered pegylated interferon as first line of therapy as it offers the likelihood of HBeAg seroconversion with a finite course of therapy. If cost is a factor, then a lower dose and duration of pegylated interferon should be offered, e.g. 90 μg of a2a or 1 μg per kilogram of a2b for 6 months. Alternatively, utilization of HBe antigen and HB surface antigen quantitative measurements to monitor the response could be employed. A study to compare low-dose pegylated interferon with standard-dose pegylated interferon and 24 or 48 weeks will enable treatment selection on a more assured basis. In HBe antigen-negative patients, the same recommendations with respect to genotypes A and B at least will apply. As a result, about a third of patients will be successfully treated, and the disadvantages of nucleoside analogues will be avoided.

In summary, genotyping should be carried out in HBeAg-positive disease to influence choice of treatment and in HBeAg-negative disease where decision to treat depends on genotype.

lyq2003526

文章没看，不过目前中国基本都是b和c，应该没必要查。