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HEPATITIS B: SCIENCE & TREATMENT 2005
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Ira Jacobson, MD
Vincent Astor Professor of Clinical Medicine
Chief, Division of Gastroenterology & Hepatology
Weill Medical College of Cornell University
NY, NY Editorial additions by Jules Levin
KEY CLINICAL MANAGEMENT POINTS
1. long-term viral suppression is the key to improving virologic, histologic, and clinicaloutcomes in patients with chronic hepatitis B (HBV).
2. HBeAg-positive (hepatitis B ‘e’ antigen positive) patients should continue antiviral therapy for at least 6-12 months after HBeAg seroconversion, while HBeAg-negative patients require long-term therapy.
3. Oral antiviral therapy should be geared toward a combination of antiviral potency & minimal long-term resistance, as the advantages of therapy are diminished or lost with the emergence of resistance.
4. The field of HBV therapy is moving toward an expansion of the spectrum of patients who are considered treatment candidates.
INTRODUCTION
Despite the major medical advance represented by the widespread availability of hepatitis B vaccine, over 350 million people worldwide still have chronic infection with hepatitis B virus, and HBV-associated liver disease remains a major cause of morbidity & mortality. Even in an area of “low endemicity” like the USA, there are about 1.25 million carriers. In addition to the magnitude of hepatitis B as a worldwide public health problem, several factors are related to the current high level of interest in the treatment of chronic hepatitis B: (1) Many clinicians in the USA have an impression they are seeing more patients with HBV, perhaps as a result of immigration patters. (2) It is increasingly clear that therapeutic efficacy should not be measuredwithin the temporal framework that has traditionally been the foundation of clinical trials, e.g. 1 year. Instead, for the majority of patients who fail to achieve endpoints that signal a long-term “switching off” of viral replication, particularly HBeAg seroconversion, the emphasis increasingly is on achieving long term viral suppression with minimal possible incidence of emergent resistance. (3) There is compelling evidence that long term viral suppression translates into improvement in histology and clinical outcomes. This recognition places a premium on the utilization of maximally sensitive assays for HBV DNA such as PCR, which is 3-4 logarithmic orders of magnitude more sensitive than the hybridization asays used in earlier years. (4) The therapeutic armamentarium is steadily expanding, with potent new drugs on the horizen. This will increase the choices available to the clinician, and mau broaden the spectrum of patients considered to be “treatment candidates”.
VIROLOGY
Hepatitis B is a member of the hepadnavirus family. Its DNA genome, which contains one complete and one incomplete strand within the virion, replicates via an RNA intermediate, with the reverse transcriptase function served by the HBV DNA polymerase. A critical feature of the viral life cycle is the production of a number of copies of covalently closed circular DNA (cccDNA) which exist within the hepatocyte nucleus and serve as the template for viral replication and translation via pregenomic and mRNAs which are exported to the cytoplasm, where viral assembly occurs. In addition, viral DNA integrates into the host cell chromosome, which may play a role in the hepatocarcinogenesis of which HBV is capable.Thus, the viral life cycle of HBV is complex, and the cccDNA in particular accounts for the capacity of the virus to persist in “inactive carriers” with the potential for reactivation of viral replication in the future. None of the treatments for hepatitis B is tailored specifically toward eradication of cccDNA, although a nearly one log reduction in the quantity of cccDNA has been demonstrated with a year of adefovir(1).
Recently, hepatitis B viral genotypes have been defined. These are designated by letter (genotypes A through G). There is considerable geographic diversity of HBV genotypes, with genotype A found predominantly in the USA, northwest Europe and central Africa, and genotypes B & C in Asia, and genotype D in the Mediterranean, Middle East & India. Several studies have evaluated the relationship of HBV genotype to the spontaneous course of disease or response to therapy. Genotype C has been suggested to be associated with higher ALT, an increased prevalence of cirrhosis (2) and greater resistance to interferon therapy than genotype B (3). The latter has been associated with earlier spontaneous HBeAg seroconversion (2,4), but also a higher rate of HCC in young persons (5). Genotype D has been associated with a high prevalence of precore mutations (2). At present, the role of HBV genotype Unlike HCV genotyping) requires further evaluation before it can be incorporated into practice algorithms.
For clinicians, the most important points to understand about HBV virology are the mutations associated with HBeAg-nagative chronic hepatitis b and the mutations, located in entirely different portins of the genome, associated with prolonged oral antiviral therapy. Patients with HBeAg-negative chronic HBV are distinguished from HBeAg-negative inactive carriers by the usual presence of over 104 HBV DNA copies/ml (10,000), elevated ALT, and necroinflammatory liver disease. In contrast, inactive carriers usually have either undetectable HBV DNA or levels <103 copies/ml (1,000), normal ALT, and inactive liver histology. The explanation for HBeAg-negative chronic hepatitis B is rooted in mutations in the precore or core promoter portions of the genome. Translation of HBeAg begins at the initiation site of the precore portion of the genome and extends to the end of the portion, following which a cleavage process results in HBeAg. In contrast, initiation od core protein translation occurs downstream of the precore portion even though the two are connected. Since HBeAg is a secretory protein and not an essential structural protein as is hepatitis B core antigen, HBV replication and virion production may continueto occur in the presence of mutations which interfere with HBeAg synthesis but not HBcAg synthesis. Some literature suggests that HBeAg-negative chronic hepatitis B entails a particularly high risk of progressive hepatic fibrosis.
Although the prevalence of precore mutant HBV has been recognized in the past to be higher in some regions than others, particularly Mediterranean countries like Greece & Italy, an increasing proportion of patients with chronic hepatitis B present with HBeAg-negative virus in many regions, including the USA. This is likely related to aging of the existing HBV-infected population. Because of the shift in prevalence, the near exclusive performance of pivotal trials in HBeAg-positive patients that characterized the landmark interferon & lamivudine trials, are no longer appropriate, Appropriately, both the adefovir & entecavir development programs entailed the performance of parallel pivotal trials in HBeAg-positive & HbeAg-negative patients. (Peginterferon studies have examined HBeAg-negative patients).
SUSTAINED RESPONSE TO PEGASYS IN HBeAg-NEGATIVE CHRONIC HEPATITIS B
http://www.natap/2005/EASL/easl_18.htm
Pegasys for HBV, 72 Weeks: HBsAg Seroconversion Response
http://www.natap.org/2005/EASL/easl_20.htm
Pegasys was just approved by the FDA for hepatitis B in the USA.
Equally important, but entirely distinct in terms of the involved portions of the HBV genome from precore & core promotor mutations, are the mutations in the DNA polymerase that confer resistance to the oral agents in current use. The loci within the HBV DNA polymerase that confer resistance are different with lamivudine & adefovir, with long term resistance to adefovir being far less frequent. (see below). The resistance profile of HBV drugs is a major concern because long term therapy is usually required in patients treated with oral agents & the emergence of virologic resistance results in increased ALT levels & histologic worsening. Thus resistance ranks with potency as a determinant of treatment choices in HBV therapy.
TREATMENT OF HEPATITIS B
The three approved drugs in the USA are interferon (Pegasys received approval yesterday), lamivudine, & adefovir; (entecavir received approval for HBV therapy from the FDA very recently). Interferon exerts its effect via a constellation of immunomodulatory and antiviral effects, while lamivudine (3TC) & adefovir work via chain termination during the process of viral replication. We will briefly review each of these drugs, followed by a discussion of treatment guidelines & future horizons.
INTERFERON
Interferon alpha was introduced for the treatment of hepatitis B over 20 years ago, & interferon alfa-2b at a dose of 5 MU daily or 10 MU tiw for 16 weeks was approved in the USA 15 years ago. A meta-analysis of 15 studies devoted to HBeAg-positive patients revealed a pooled rate of HBeAg loss of 33% & HBV DNA clearance in 37% as measured by hybridization tests (6). Similar rates of ALT normalization were found. HBsAg clearance at the end of therapy occurred in about 89% of patients. However, over the years after HBeAg seroconversion is achieved with interferon therapy, many more patients eventually clear HBsAg (7).
In patients with HBeAg-negative chronic hepatitis B, 4-6 months courses of recombinant interferon alfa-2b 5MU daily or 10 MU tiw resulted in substantial rates of ALT normalization & HBV DNA clearance, as measured by hybridization, but responses were much less durable than in the HBeAg-positive population, resulting in low rates of sustained ALT normalization or DNA clearance. However, studies in Greece & Italy, where infection with HBV precore mutants has long been prevalent, revealed that prolongation of interferon treatment to 12 & even 24 months appears to significantly improve rates of sustained response (8,9). In a long term followup from the study in Greece, 27% of patients had sustained normalization of ALT & 13% cleared HBsAg, the latter mostly in those with sustained biochemical response (10).
In a long term study of patients with & without HBeAg seroconversion in response to interferon, Niederau & colleagues showed significant reductions in mortality & liver-related complications after a mean of six years (11). However, hepatocelluar carcinoma was not assessed independently, presumably because few or no such tumors occurred. Favorable long term benefits in long term interferon responders have been reported by others (12). In contrast, a study from Asia by Yuen et al showed that at 6 & 24 months of followup, treated patients had significantly higher rates of HBeAg loss but over a mean of 9 years there was no significant difference in rates of HBeAg negativity, HBV detectability, and clinical complications (13). This study notwithstanding, most experts continue to believe that HBeAg seroconversion after interferon therapy confers a more favorable prognosis on patients with chronic hepatitis B.
Interferon is associated with a variety of toxicities which are fimilar to the gastroenterologist & hepatologist. As a result of its side effects profile, interest in the USA shifted dramatically to the use of oral agents after lamivudine was introduced. The subsequent addition of adefovir to the available therapies, with its much lower rate of resistance, contributed further to the preponderant interest in oral therapy. Recently, however, with the introduction of pegylated interferons there has been renewed interest in the use of interferon. In addition to the much greater convenience of once weekly injections, factors invoked by proponents of interferon include the following: (1) interferon therapy is self-limited in time with a clearly defined endpoint; (2) the absence of resistant mutations; (3) the apparently higher rates of HBsAg clearance associated with interferon compared with oral agents. The latter putative advantage has not, however, been demonstrated conclusively in comparative trials.
Peginterferon alfa-2a (40KD) (PEGASYS) Monotherapy and in Combination with Lamivudine is More Effective than Lamivudine Monotherapy in HBeAg-positive Chronic Hepatitis B: Results from a Large, Multinational Study
http://www.natap.org/2004/AASLD/aasld_11.htm
Long-term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B (PegIntron)
http://www.natap/2005/HBV/050905_03.htm
Pegasys Receives Positive Opinion for HBV in Europe; HBV/HIV Coinfection Medical Management
http://www.natap.org/2005/HBV/012405_01.htm
LAMIVUDINE
The efficacy of lamivudine, a nucleoside analogue also effective against HIV, in treatment naïve patients with chronic HBV was established in three pivotal one year trials. These studies demonstrated HBeAg seroconversion rates of 17-18% (14,15). Long term treatment with lamivudine results in progressively increasing rates of HBeAg clearance to 40% after 3 years (16,17). As with interferon, higher ALT levels are associated with higher rates of HBeAg seroconversion (18). Lamivudine is also associated with significant improvement in histology compared with placebo. Results in HBeAg-negative patients with chronic hepatitis B showed two thirds or more of patients having normalization of ALT at 12 months and, similarly, at least 65% of patients having a decline in HBV DNA to less than detectable by hybridization (19-21). Relapse after discontinuation of lamivudine at one year generally occurs, but in a recent report in HBeAg negative patients, nearly 50% had sustained clearance of HBV DNA after cessation of therapy following a two year course of lamivudine (22).
The main limitation of lamivudine, applying both to HBeAg-positive & HBeAg-negative patients, is the high rate of resistance associated with its use beyond six months. The HBV DNA polymerase has 7 domains, A through G. The predominant mutation in the patients with lamivudine resistance which increases from 15-25% after one year to about 70% after 4 years, is the YMDD mutation, representing a switch from methionine to valine or isoleucine in the C domain (M204I or M204V). A second mutation associated with lamivudine resistance is a leucine to methionine substitution in the B domain (L180M). The risk of developing lamivudine resistance has been shown to be inversely related to the degree of viral decline at 24 weeks of therapy (23).
Unfortunately, lamivudine resistance leads to recurrence of elevated ALT & histologic worsening (17). Therefore, at present the emergence of resistance on lamivudine is a strong indication for switching to another drug. Adefovir has potency against YMDD mutant HBV similar to its potency in patients with wild-type virus, and thus far at least an equally good resistance profile.
In the pivotal US lamivudine trial, patients who failed to clear HBeAg after one year & continued for 2 more years accrued significant histologic benefit, which was attenuated in those who developed YMDD mutation (24). Indeed, histologic benefit, as well as late HBeAg seroconversion, were impaired most in patients who developed YMDD early in their treatment course. Moreover, patients with advanced fibrosis had significant regression fibrosis, especially if viral suppression was not compromised by the development of YMDD mutant virus. Cirrhosis regressed in 8 of 11 patients, and the three patients in whom bridging fibrosis progressed all had YMDD mutations.
In a landmark trial published recently, lamivudine was compared with placebo in a large multicenter study in the Asian-Pacific region (25). Patients could be either HBeAg-positive or negative and had Ishak fibrosis scores of >4 on entry. After a mean of 32 months, a significant advantage for lamivudine was demonstrated in clinical outcomes, increase in CPT score, and even HCC. The study was stopped by its monitoring board because it was considered untenable to continue patients on placebo. Notably, the development of YMDD resistance was associated with partial loss of the benefits of lamivudine (25).
ADEFOVIR
The introduction of adefovir, a nucleotide analog, in 2002, was based upon parallelpivotol studies in HBeAg-positive & negative patients. Adefovir added to the armamentarium a drug that conferred substantial potency with markedly less resistance than lamivudine. Adefovir was studied for HBV & approved at a dose of 10mg daily, which was less potent than doses of >30mg but unassociated with the nephrotoxicity marking the use of the higher doses. With 48 weeks of treatment, mean HBV levels declined by 3.5 to 3.9 logs in HBeAg-positive & HBeAg-negative patients, respectively (26,27). HBeAg seroconversion occurred in 12% of adefovir recipients compared with 6% in placebo recipients, and the drug conferred significant histologic improvement compared with placebo (26). These were the first pivotal HBV trials utilizing PCR to measure HBV DNA. The rate of PCR negativity (<400 copies/ml) was 21% in the HBeAg-positive patients at 48 weeks & 51% in the HBeAg-negative patients. In the HBeAg-positive study, patients who had HBeAg seroconversion after one year & came off treatment had highly durable responses—only 9% (6 patients) lost their seroconversion, of whom 2 patients had disappearance of anti-HBe and 4 had reappearance of HBeAg (28). In the HBeAg-negative study, most patients who became PCR negative during one year of therapy had recurrent viremia if adefovir was stopped, while viral suppression was maintained in patients randomized to receive treatment for a second year. In HBeAg-positive patients, long term studies with adefovir have shown increased rates of HBeAg loss & seroconversion with two or three years of treatment (29). In a study of HIV/HBV coinfected patients by Benhamou etal, viral load progressively declined over 4 years of treatment by a mean 5.5 logs, without the emergence of any drug resistance (30). In another study in pre- & post-liver transplant patients, 144 weeks of adefovir treatment resulted in significant reductions in HBV DNA, ALT normalization, stabilization or improvement in liver function as reflected by CPT scores, and an apparently favorable impact on survival experience.
The excellent resistance profile of adefovir is the main feature distinguishing it from lamivudine. From a rigorous resistance surveillance program built into the pivotal adefovir trials, 192 weeks results were reported at this year’s EASL: for eAg(-), week 48: 0%; week 96: 3%; week 144: 11%; week 192: 18%. Resistance in eAg(+) appeared to be much less. You can read the NATAP report:
Adefovir Resistance report: 4 years update
http://www.natap.org/2005/EASL/easl_14.htm
As well, you can read 4 years efficacy data reported at EASL:
Adefovir Week 144 Efficacy in HBeAg+
http://www.natap.org/2005/EASL/easl_13.htm
The dominant mutation, when mutations do occur, is an N236T substitution, which is a different domain of the DNA polymerase than that in which the YMDD mutation occurs.
The antiviral activity of adefovir is fully preserved in patients with lamivudine resistance (33). In light of the loss of virologic & histologic benefit of lamivudine once resistance develops, switching to adefovir is appropriate. The combination of adefovir with lamivudine has not been shown to confer a greater degree of viral suppression than adefovir alone. (however, data suggests that the combination may prevent or slow resistance). Abrupt cessation of lamivudine and initiation of adefovir in lamivudine-resistant patients has been associated with a risk of hepatitis flare (33), leading many clinicians to prefer an overlap period, e.g. three months, before lamivudine is discontinued.
Tenofovir is a nucleotide analog which represents the addition of a methyl group to adefovir. It is licensed for use in HIV infection at a dose of 300mg daily, and observations in HBV-HIV coinfected patients have established its potency against HBV as well. At this dose it has been shown to have greater potency than adefovir 10mg against lamivudine-resistant HBV (34,35). Although not labled for use in HBV & awaiting further trials for this indication, many clinicians appear anecdotally to be using tenofovir in selected patients who fail to suppress HBV DNA to a desired level on other oral drugs (36).
NEW HBV DRUGS FOR HEPATITIS B
With the current availability of peginterferon there has been renewed interest in the use of interferon-based therapy for hepatitis B. In a comparison of peginterferon alfa-2a at doses of 90, 180, & 270 ug with IFN 4.5 MU tiw for 24 weeks, response (defined as HBV DNA clearance, HBeAg loss & ALT normalization) occurred in 12% of the standard IFN recipients & 24% of the PegIFN recipients when the results of the 3 PegIFN arms were pooled (37). However, the dose of standard IFN used in this study was roughly half that used in most of the older studies establishing the role of IFN, a meta-analysisof which revealed HBeAg loss in 33% of patients (6). There have been several recent trials combining PegIFN alfa-2a or 2b with lamivudine compared with PegIFN alone and/or lamivudine alone, all with duration of 1 year. (38-41). Three trials were in HBeAg-positive patients, while the fourth was in HBeAg-negative patients. Despite heterogeneity in study design, the results of these studies can be distilled into the conclusion that peginterferon monotherapy & combination therapy induce similar rates of sustained response, (although with a suggestion that end of treatment response is superior with combination therapy than with peginterferon monotherapy), and that either regimen is superior to lamivudine alone. In the HBeAg-negative study, at 24 weeks of followup lamivudine monotherapy had a lower rate of HBV DNA <400 copies/ml (7%)than PegIFN alfa-2a or combination therapy (19-20%) (41). Limitations of these studies include heterogeneity in the HBV DNA assays used, and most importantly the discontinuation of lamivudinetherapy at one year, which is not how oral agents are currently used for this disease. Consequently, they do not answer the question of whether superior long term results would be achievable with a finite course of PegIFN followed by a much longer course of oral nucleos(t)ide therapy.
Two potent nucleoside analogues have either completed with phase III trials or are in phase 3 trials: entecavir (recently approved by the FDA for HBV treatment in chronic infection) & telbivudine (LdT), currently in phase III trials. In a very large trial, entecavir 0.5mg provided a 1.5 log greater mean log reduction than lamivudine (7 logs vs 5.5, p<0.001) after 48 weeks of therapy in an HBeAg-positive population (42). HBeAg seroconversion occurred in 21% & 18% of patients with entecavir & lamivudine, respectfully. By PCR, 69% of patients receiving entecavir were negative for HBV DNA at 48 weeks compared with only 38% with lamivudine (p<0.0001). Histologic improvement was more frequent with entecavir than lamivudine (72% vs 62%, p=0.0085). In a parallel HBeAg-negative study, fully 91% of entecavir-treated patients became negative by PCR (<400 copies/ml) after 1 year compared with 70% with lamivi=udine (43). In a third trial in lamivudine resistant (or refractory) patients utilizing entecavir 1 mg daily, the mean reduction in HBV DNA was 5 logs, indicating less potency (though still considerable) of the drug against YMDD mutants than against wild-type HBV (44). The resistance profile of entecavir thus far appears excellent, with no resistance reported after one year for wild-type virus and a low incidence for lamivudine-resistant HBV (45). Longer term resistance data with entecavir are awaited.
Telbivudine is another potent nucleoside analog with 1.5 log greater potency than lamivudine, with a 6.1 log decline at 52 weeks with telbivudine compared with a 4.6 log decline with lamivudine (46). HBeAg seroconversion occurred in 31%, 22%, and 15%, and undetectable HBV DNA (<200 copies/ml) in 61%, 32%,, and 49% of those receiving telbivudine, lamivudine, or combination therapy. Studies thus far indicate a resistance rate of about 5% after one year of therapy with telbivudine (46a). Other drugs being developed include clevudine, a nucleoside analog which suppressed HBV DNA a mean of 2 logs over 12 weeks & prolonged time to recurrence of viremia (47). Another nucleoside analogf, emtricitabine (FTC), the 5-flourinated derivative of lamivudine, has shown antiviral potency in its own right and additive effects on suppression of HBV replication when added to adefovir: at 48 weeks there was a 3.9 log decline in HBV DNA with combination versus 2.2 log with adefovir.
GUIDELINES FOR TREATMENT OF CHRONIC HEPATITIS B
The most widely quoted guidelines for the treatment of chronic hepatitis B are those put forth by the American Association for the Study of Liver Diseases (AASLD), which have been reissued twice since their inception (49). These guidelines are intended to be strictly evidence-based. An HBV DNA level of 100,000 copies/ml is emphasized as the basis for treatment candidacy, as most of the pivotal trials in the field were done with hybridization assays which had 100,000 to 1 million as the lower limit of quantification. Similarly, treatment is recommended only for patients with elevated ALT—actually, twice the upper limit of normal in the latest version of the guidelines—because (a) this was the requirement in many of the studies with IFN & oral agents, (b) normal or minimally elevated ALT is often associated with minimally active liver disease and, (c) with HBeAg seroconversion as the definition of primary serologic endpoint in nearly all historic trials, it was established that patients with normal or minimally elevated ALT had very low rates of response.
From the viewpoint of evidence-based guidelines, the rationale for the ALT requirement is clear but has recently been questioned. Many clinicians report that some patients who they biopsy with normal ALT levels have significant liver disease, including fibrosis, a contention supported by a recent large study on liver biopsy in HBV infected Chinese patients with persistently normal ALT (50). High grade viremia with normal ALT arises with particular frequency in HBeAg-positive patients. These are patients who have historically been designated as being in the “immunotolerant” phase of their chronic infection. With the increased emphasis on long term viral suppression as a principal goal of therapy, it can be argued that this is more readily achievable than HBeAg clearance and may still translate into improved clinical outcomes, although with oral therapy this has been rigorously demonstrated only in compensated cirrhotics (25). In particular, there is concern that high levels of viral replication for many years in patients who do not necessarily develop cirrhosis may still result in excessive risk for hepatocellular carcinoma, a concern that has substantial basis in studies showing a relationship beyween viral DNA levels & HCC risk (51), even in patients with normal ALT at the onset of a 10 year observation period (52). The proposition that long term viral suppression with current or soon-to-be-available drugs can reduce the risk in viremic patients with mild disease, with acceptable long term safety & resistance profiles & cost effectiveness, requires further evaluation. This will be a major challenge because of the large cohort & long period of time that would be required to demonstrate such a benefit, and it is not clear that such studies are feasible.
Recently, attempts have been made to formulate strategies that address the large number of patients encountered in practice who do not meet the criteria for treatment outlined in the guidelines. Underlying these attempts are the shift in testing for HBV DNA to PCR based assays, with far lower limits of detectability than hybridization. In a paper by Keefe (53), it was proposed that 100,000 viral copies/ml is a reasonable cutoff for HBeAg-positive patients, since most such patients have viral levels above this figure. Patients with elevated ALT to any degree are considered candidates for antiviral therapy, with IFN, lamivudine & adefovir all being first-line options. Keefe et al stated that patients with normal ALT may be considered on an individualized basis for further evaluation with liver biopsy & consideration of antiviral therapy, recognizing that HBeAg seroconversion usually does not occur and that therefore long term therapy is likely to be needed. For patients with HBeAg-negative disease, the frequency with which such patients have viral levels between 10,000 & 100,000 copies/ml (54) led this panel to downgrade the level of virus defining treatment candidacy to 10,000. HBeAg-negative patients with normal ALT may be considered for therapy on an individualized basis, as for HBeAg-positive patients. However, for HBeAg-negative patients, in whom IFN is more commonly associated with relapse even if a viral & biochemical response is obtained, oral therapy was considered preferable to IFN and long term therapy is required even if HBV DNA is negative after one year, given the likelihood of virological relapse in these patients if treatment is stopped.
Continuation of oral antiviral therapy in patients with HBeAg-positive disease is recommended for as long as HBV levels are decreasing until HBV DNA is undetectable by PCR, after which treatment should be continued for another 6 months. In patients who have had HBeAg seroconversion & in whom HBV DNA levels are detectable & stable, treatment should be continued for six months after which consideration can be given to stopping except in cirrhotics (53). Although there is scant evidence that HBeAg loss alone has inferior durability to HBeAg seroconversion, most experts feel more confident in seroconversion. There is some evidence that if oral therapy is stopped relatively soon after seroconversion the response is less likely to be durable (55). For HBeAg-negative patients IFN, when used, appears to be associated with more durable response when given for 12-24 months than for shorter periods of time. Oral therapy in these patients is, as previously noted, associated with a high rate of relapse even if PCR negativity is achieved after one year, and at present oral therapy is considered to require indefinite therapy unless evidence emerges that there is a finite stopping point associated with highly durable response, whether with existing or future drugs.
Several special populations deserve mention. To prevent potentially life-threatening flares of liver disease, patients who are inactive HBsAg carriers must be given prophylaxis with oral therapy prior to initiation of chemotherapy or immunosuppressive. Some experts even advocate such prophylaxis for patients with HBV antibodies (53). It seems unlikely that widespread screening for HBV is being performed with sufficient frequency in oncology patients.
Pregnancy is another situation warranting consideration. Women who are HBsAg carriers can be given lamivudine without well documented adverse effects in late pregnancy with further reduction in the risk of vertical transmission beyond the high, but not complete, level of protection conferred by perinatal administration of HBIg & vaccination. In women who become pregnant on oral HBV therapy, the clinician must decide whether to stop treatment, at least during the first trimester, thereby risking a hepatic flare, or whether to continue given the exiting databases, particularly with lamivudine in both HIV & HBV infected patients, indicating no clear association with adverse outcomes. A decision to continue treatment in this setting warrants careful and well documented discussion with the patient and about the benefits & risks.
The emerging evidence that HIV/HBV coinfected persons have a significant risk of progressive liver disease warrants strong consideration of therapy in all such patients. If HIV therapy is not being given, lamivudine or tenofovir must be avoided. Adefovir monotherapy is more feasible because the dose of adefovir in current use is not active against HIV (ed note: you can consider entecavir, which does not have activity against HIV). Usually, anti-HBV therapy in coinfected patients should be in context of antiviral treatment for HIV.
FUTURE DIRECTIONS
The two predominant developments in HBCV therapy in the foreseeable future are likely to be the availability of additional, potent drugs, and the widening spectrum of patients who are considered treatment candidates. These two developments are linked in that the availability of more potent drugs with much less resistance than that associated with lamivudine will make long term suppression of HBC replication increasingly attainable at diminished “virologic cost” (if not financial cost). The trial of entecavir versus lamivudine reported recently suggests that the enhanced antiviral potency of entecavir translated into superior histlogic outcomes after one year of therapy, with no demonstrated resistance in treatment naïve patients. Ongoing study will be required to assess the impact of enhanced antiviral potency on clinical outcomes & the long term resistance profiles of the new drugs, with adefovir having a demonstrated “track record’ of low long term resistance rates. A special need is for more data on the impact of therapy on clinical outcomes in patients with mild disease, including those patients who hitherto have been labeled as being “immunotolerant” (HBeAg-positive, high HBV DNA, normal ALT). Until more evidence based guidelines applicable to these patients can be developed (which will be a major challenge), there is likely to be significant variability among experts in the use of antiviral therapy for patients who fall outside the criteria for treatment in the current guidelines.
Another factor which will influence therapeutic choices is the advent of peginterferon. Although recent studies have been flawed by the cessation of the oral component of combination regimens at one year, these studies do re-emphasize the capacity to achieve meaningful long term response rates in HBeAg-positove & even HBeAg-negative patients. There is likely to be significant variability in the enthusiasm for use of IFN in the next several years, but it will continue to have its proponents. In the longer term, there should be a major impetus to the development of combination therapy with oral agents such as nucleotide-nucleoside regimens.
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