HepB Forum : Unofficial Research Thread (URT) Tx info

[stevenNYer]

I am reposting articles / summaries on the treatment management of chronic HepB.  "cajim" located these articles which are quite informative.  I thought about putting them on a seaprate Health Page but didn't think it was appropriate since we didn't write them.

Let's make this a sort of "Unofficial Research Thread" or "URT" for this type of information.  Let's keep this URT free of comments.  For comments, start a new thread indicating that it's in reference to URT.

We'll see how it goes.

[cajim]

TABLE 4

Clevudine (CLV or L-FMAU) is a nucleoside analog which is unique in having a very long half-life (>40 hours). Figure 3 shows the results of a phase 2 clinical trial, evaluating 4 different doses of CLV (10, 50, 100, and 200 mg/day). After 4 weeks of treatment, all 4 doses produced HBV DNA decreases, ranging from 2.5 logs (with the 10 mg dose) to 3 logs (with the 100 mg dose). When treatment was stopped, HBV DNA remained suppressed for up to 6 months.10

This sustained effect suggests that a short course of CLV may produce long-term suppression. However, the optimal dose, dosing interval, and treatment duration have not yet been determined.

FIGURE 3

Tenofovir, a nucleotide analog similar to adefovir, has been approved for HIV treatment. It has in vitro and in vivo activity against both wild-type and lamivudine- resistant HBV, but has not been thoroughly evaluated as a therapy for hepatitis B. Limited clinical evidence suggests that TFV (300 mg/day) decreases serum HBV DNA levels by a mean of 4.5 logs (range, 3.4 to 7.3 logs)11-a greater degree of suppression than that observed with adefovir (10 mg/day). It also appears to have less potential for nephrotoxicity than adefovir. TFV therefore deserves further study as a hepatitis B treatment.

In a much earlier stage of development are two new antiviral agents, LB 80380 and ACH-126,433 (Beta-L-FD4C). LB 80380 is a nucleoside phosphonate prodrug with in vitro activity against wild-type and lamivudine-resistant HBV. In vitro studies also suggest that it is less nephrotoxic than adefovir. Preliminary data are available from a phase 2A dose-finding trial. After 4 weeks of treatment, the higher doses of LB 80380 produced a 3- to 4-log decrease in serum HBV DNA, and were well tolerated.12

ACH-126,443 has been shown to have in vitro activity against wild-type and lamivudine-resistant HBV. Preliminary data from a phase 2A clinical trial were recently presented. Three different doses (5, 20, and 50 mg/day) were evaluated. After 12 weeks of therapy, pooled data from all patients showed an approximately 3-log decrease in serum HBV DNA.13 However, there are concerns about bone marrow toxicity at the higher doses.

Summary

Many new antiviral agents are on the horizon. Of the new agents discussed, ETV and LdT (particularly entecavir) appear to produce the most potent viral suppression and the least drug resistance compared to lamivudine. Comparative data with adefovir are not available.

LdT, FTC, and CLV are cross-resistant with lamivudine. Entecavir, LB 80380, and ACH-126,433 have in vitro activity against lamivudine-resistant HBV, but in vivo activity has been confirmed only for entecavir.

For many years, a need for combination therapy has been recognized; however, the promise of combination therapy has not yet been fulfilled. For example, in one study the combination of LdT and lamivudine appeared to be less effective than LdT alone, suggesting a possible antagonistic effect between the two drugs. However, further research may yet discover combinations that will improve the rate of sustained viral suppression in chronic hepatitis B patients.

[cajim]

Notes on “ New Antiviral Therapies for Hepatitis B,” Anna S. F. Lok, MD

This section focuses on new treatments in development for chronic hepatitis B. After a brief discussion of treatment goals and the efficacy of currently approved medications, new therapeutic agents and combination therapies that are now in clinical trials will be reviewed.

The goals of treatment in chronic hepatitis B are to 1) achieve sustained suppression of viral replication; 2) induce remission of liver disease (ie, reduce hepatic necroinflammation and fibrosis); and 3) prevent progression to cirrhosis, liver failure, and hepatocellular carcinoma.

Currently, there are three approved treatments: interferon, lamivudine, and adefovir. Table 1 summarizes the efficacy of these drugs in achieving HBeAg seroconversion (in HBeAg-positive patients) or viral suppression (in HBeAgnegative patients).

TABLE 1

Clinical studies have shown that, after a finite course of interferon or a year of lamivudine or adefovir, responses are achieved in approximately 10% to 20% of HBeAg-positive patients and 50% to 70% of HBeAg-negative patients. But when post treatment relapses are taken into account, <15% of HBeAg-positive patients (50% to 80% of initial responders) and <10% of HBeAg-negative patients achieve a sustained response with lamivudine or adefovir. The percentage of interferon treated patients achieving a sustained response appears to be somewhat higher, but is still 1 year. These mutations differ from those associated with lamivudine or adefovir resistance.6

TABLE 3

Figure 1 illustrates results of a phase 2 trial of ETV (0.01 mg/day, 0.1 mg/day, or 0.5 mg/day) versus lamivudine (100 mg/day) in 169 nucleoside-naïve patients. The two higher ETV doses were significantly more potent than lamivudine in decreasing serum HBV DNA levels.5

FIGURE 1

Figure 2 shows results of a clinical trial of ETV (0.1, 0.5, or 1.0 mg/day) versus continued lamivudine (100 mg/day) in 181 patients who had previously failed lamivudine therapy. Mutations in the YMDD motif were detected in 87% of the patients. All three ETV doses were significantly more effective than lamivudine in suppressing HBV DNA. The two higher ETV doses decreased HBV DNA levels by 4 to 5 logs after 48 weeks of treatment.7

FIGURE 2

Another new antiviral is emtricitabine (FTC), a synthetic nucleoside analog that was recently approved for HIV treatment. It also has potent activity against HBV. FTC is structurally related to lamivudine, and like lamivudine, it selects for mutations in the YMDD motif. However, in a 96-week clinical trial, these mutations occurred at a lower rate (19% after 2 years), while the HBeAg seroconversion rate was similar (29% after 2 years) to that with lamivudine. FTC was well tolerated at the optimally-effective dose of 200 mg/day.8 Phase 3 trials in hepatitis B are ongoing.

Telbivudine (LdT) is a natural, HBV-specific nucleoside. In animal experiments (woodchucks), LdT produced marked viral load reduction (8 to 10 logs). In a phase 2 clinical trial, LdT was more potent than lamivudine in suppressing HBV replication, but the combination of LdT and lamivudine was not superior to LdT alone. The results of that trial are summarized in Table 4. Patients who received LdT (either alone or in combination with lamivudine) had a 6.1-log decrease in HBV DNA, compared to a 4.6-log decrease in the group that received only lamivudine-a statistically significant difference. The LdT-only group also had a significantly higher rate of ALT normalization than the lamivudine-only group. However, more potent viral suppression did not translate into a higher rate of HBeAg loss. YMDD mutations occurred in all three groups, with the lowest rate in the LdT-only group (5%, compared to 16% with lamivudine only). All three treatments had similar side effect profiles.9

[cajim]

FIGURE 15

Reminiscent of the study in HBeAg-positive patients, there was a greater decline of serum HBV DNA in the combination therapy group than in either of the monotherapy groups (Fig. 16).14 Lamivudine monotherapy initially seemed to cause more rapid HBV DNA decline compared to interferon monotherapy; however, the difference between the two monotherapies was no longer evident at the end of treatment, possibly due to emergence of lamivudine-resistant mutants in the lamivudine monotherapy limb. In this study, the end-of-treatment difference in viral suppression was on the order of 1 log greater with combination therapy (in contrast to the 3-log difference seen in the study of HBeAg-positive patients).

FIGURE 16

Summary

Pegylated interferon appears to be more potent than conventional interferon in the treatment of chronic hepatitis B. Combined use with nucleoside analogue therapy is associated with greater viral suppression than either agent given alone; however, sustained virologic responses have not been shown to occur any more frequently with combination therapy than with either agent alone. Future studies should address ways of maximizing sustained virologic response. Consideration should probably be given to higher and more consistent interferon dosing and possibly to altering the way in which the two drugs are combined. Theoretically, simultaneous administration of the two drugs might abrogate the immunologic response to interferon; therefore, it is possible that a lead-in phase with pegylated interferon followed by nucleoside analogue therapy might be more effective than giving the two drugs simultaneously. Finally, different dosage recommendations should be investigated for patients with unfavorable viral genotypes.

The take-home message is that interferons and nucleoside analogues work through different mechanisms of action. Although two large-scale trials have failed to show sustained differences between combination therapy and interferon monotherapy, further research is needed before discounting the possibility that combined therapy may lead to a higher rate of more lasting response.

[cajim]

Figure 5 shows 52-week results from two trials of combined lamivudine and conventional interferon therapy. In the study from Solko Schalm's group, all patients were treatment-naïve, and received either interferon monotherapy for 6 months, lamivudine monotherapy for 1 year, or combination therapy (lamivudine for 6 months plus interferon for 4 months). The solid-colored bars represent an intent-to-treat analysis, which showed no significant differences in HBeAg seroconversion among the three treatment limbs. In contrast, the diagonallymarked bars represent a per protocol analysis of patients who met virologic criteria at baseline rather than at initial screening. The per protocol analysis revealed a significantly greater response rate with combination therapy versus lamivudine monotherapy.11

FIGURE 5

In the study by Schiff et al all patients were interferon nonresponders. There were no statistical differences in HBeAg seroconversion between patients receiving combined therapy versus lamivudine monotherapy.12

FIGURE 6

More recently, Harry Janssen and colleagues from Rotterdam reported the results of a large trial in which 266 patients with HBeAg-positive hepatitis B were randomized to treatment with either 52 weeks of pegylated interferon alfa-2b or a combination of pegylated interferon and lamivudine. Pegylated interferon was given in dosages of 100 µg/week until week 32, when the dosage was reduced to 50 µg/week (considerably less than the dose used to treat hepatitis C). Patients were followed for a 26-week posttreatment interval. The primary endpoint was HBeAg loss; secondary endpoints included HBV DNA <200,000 copies/mL, ALT normalization, and HBsAg loss.13 The study design is summarized in Figure 6.

FIGURE 7

Figure 7 shows that HBeAg loss, evaluated after 1 year of treatment, occurred significantly more frequently in patients treated with combination therapy. However, at the end of posttreatment followup, the percentage of patients with a sustained HBeAg response did not differ between the two treatment groups.13

The HBV DNA response is shown in Figure 8. Patients receiving combined therapy achieved HBV DNA <200,000 copies/mL by the end of treatment significantly more frequently than the interferon monotherapy group. However, this difference was not sustained to the end of the posttreatment followup.13 An even more important indicator of the level of viral suppression is the number of individuals whose HBV DNA became negative as measured by PCR. Figure 9 shows that this occurred by the end of treatment significantly more frequently in the combined therapy group. Again, the response was not sustained through the end of followup.13

FIGURE 8

The serum HBV DNA curves are shown in Figure 10. Combined therapy resulted in a consistently greater degree of HBV DNA suppression throughout the treatment cycle. This became evident as early as week 8 and, by the end of treatment, the difference in viral suppression was nearly 3 logs.13

FIGURE 9

Consistent with the greater viral suppression, patients treated with combination therapy exhibited a greater decline in serum ALT. Figure 11 suggests absence of an ALT flare in the combination therapy group, with ALT levels rebounding only after withdrawal of treatment in both groups.13 The incremental change after drug discontinuation is more noticeable in the combined group, and it is unclear whether this was influenced by lamivudine withdrawal.

FIGURE 10

As mentioned before, one of the major advantages of interferon versus nucleoside analogue therapy is the early HBsAg loss that occurs with interferon. In Dr Janssen's study this occurred in 5% to 7% of patients receiving interferon, and was sustained through the end of followup (Fig. 12).13

FIGURE 11

A second large multicenter trial was conducted by Marcellin and colleagues. In this study, 537 patients with HBeAg-negative chronic hepatitis B were randomized to receive 48 weeks of either pegylated interferon alfa-2a monotherapy (180 µg/week), lamivudine monotherapy (100 mg/day), or combined therapy. Followup was continued until 24 weeks after the end of treatment.14 The study design is summarized in Figure 13.

FIGURE 12

FIGURE 13

When measured at the end of followup, ALT normalization occurred in approximately 60% of both groups receiving interferon versus 44% of the lamivudine monotherapy group (Fig. 14). The differences between each interferon-containing difference between the two interferon-containing regimens.14

FIGURE 14

Figure 15 depicts the percentage of individuals achieving HBV DNA suppression to a level <20,000 copies/mL at the end of followup. Again, both groups receiving interferon fared better than the lamivudine monotherapy group, with no difference between the two interferon-containing regimens.14

[cajim]

Notes on “ Interferon Therapy for Chronic Hepatitis B,” Robert P. Perrillo, 2005

Alpha interferon was licensed for hepatitis B in 1992. In the past several years its use has been eclipsed by nucleoside analogue therapy; however, evidence suggests that it continues to bear promise as a treatment for hepatitis B, either alone or in combination with nucleoside analogue therapy. From a theoretical perspective, the different mechanisms of action of interferon and nucleoside analogues should make them complementary to each other. Furthermore, there has been a recent resurgence of interest in interferon with the development of the more potent and longer-acting pegylated forms.

Figure 1 illustrates the life cycle of the hepatitis B virus (HBV).1 The dark and white circles indicate the mechanisms of action of interferon and nucleoside analogues, respectively. Interferon activates intracellular enzymes such as 2`5 oligoadenylate synthetase, resulting in the degradation of HBV mRNA; it also bolsters the cell-mediated immune response to HBV by augmenting expression of HLA class I antigen-presenting molecules on the surfaces of infected hepatocytes. The immunologically relevant viral peptides are located in a peptide-binding cleft on the HLA molecule. In contrast, nucleoside analogues competitively inhibit HBV DNA polymerase, interfering with the synthesis of the first and/or second HBV DNA strand.

FIGURE 1

Table 1 lists the advantages and disadvantages of interferon therapy. Several of the beneficial properties (in italics) deserve further comment. First, interferon results in the disappearance of hepatitis B surface antigen (HBsAg) in 5% to 8% of patients within 6 months of treatment. Furthermore, several studies have documented that the frequency of HBsAg clearance in interferon responders increases over time,2 in one study reaching rates of >50% within 5 years.3 In contrast, nucleoside analogue therapy has to be prolonged for several years before HBsAg loss is observed. During the first year or two of nucleoside analogue therapy, the rate of HBsAg loss is comparable to that observed in untreated controls (approximately 1% to 2% per year) (eg, a recent study demonstrated HBsAg loss in 1.6% of patients after 72 weeks of adefovir treatment).4

TABLE 1

Second, drug-resistant mutants have not been described with interferon and, indeed, there are a number of published reports indicating that extension of treatment or retreatment can lead to higher response rates.5,6

Third, interferon is immunomodulatory. Interferon-induced cellular immune responses are thought to result in apoptosis of the infected cell and, although direct evidence is lacking, this probably leads to more effective elimination of the highly resistant closed circular covalent template of HBV DNA (CCC DNA).

A number of studies have shown that the best independent predictors of a response to interferon therapy are the serum HBV DNA and alanine aminotransferase (ALT) levels at baseline. Figure 2 shows data from 41 patients treated with interferon alfa-2b (5 million units/day for 16 weeks). Virologic response (defined as sustained disappearance of HBV DNA and hepatitis B envelope antigen [HbeAg] seroconversion) occurred in only 17% of patients with baseline ALT values 200 pg/mL by solution hybridization assay.7 (This corresponds roughly to 56 million copies by polymerase chain reaction (PCR) assay.)

FIGURE 2

These results suggest that interferon is more effective in patients who have a relatively well preserved cellular immune response to HBV. This conclusion is further supported by a study in which high necroinflammatory scores on liver biopsy correlated with higher rates of virologic response.8

Higher rates of response to interferon have also been shown to correlate with ALT flares during therapy. The relationship between virologic response and the magnitude of ALT flares was evaluated in a cohort of patients with high-level viremia (serum HBV DNA levels >100 pg, or roughly 28 million copies, per mL). Figure 3A shows that, by multivariate analysis, the best independent predictors of response were baseline ALT and severe flares (defined as an increase of >8 times the ULN above baseline). Figure 3B illustrates the virologic response frequencies according to the degree of ALT flare. A striking relationship was observed between the height of the ALT flare and the virologic response.9 These data suggest that robust flares are capable of overcoming the effects of high-level replication and provide some optimism should pegylated interferon prove to have greater immunomodulatory action compared to standard interferon.

FIGURE 3A

FIGURE 3B

That pegylated interferon is more potent than conventional interferon has been shown in a large randomized trial in Asian patients. Three different doses of pegylated interferon (90, 180, or 270 µg once weekly) were compared with standard interferon (4.5 MIU three times weekly). After 24 weeks of therapy, the patients were followed for 24 weeks off treatment. Endpoints included HBeAg loss, suppression of HBV DNA to <500,000 copies/mL, and ALT normalization. At the end of followup, rates of HBeAg loss were highest in patients receiving the 90-and 180 µg dosages of pegylated interferon (Fig. 4). The percentage of patients achieving all three endpoints was twice as great in all of the pegylated interferon groups combined compared to the group receiving standard interferon.10

FIGURE 4

As mentioned above, interferon and nucleoside analogues have different mechanisms of action. This should, in theory, lead to additive or synergistic effects on viral suppression. There are now two lines of evidence to support this theory:
· Higher rates of virologic response have been observed both in woodchucks and in small clinical trials when conventional interferon was combined with lamivudine, compared to either agent alone.
· Greater HBV DNA suppression has been reported with combination therapy in two large-scale trials of pegylated interferon and lamivudine.

The studies conducted prior to the two large-scale trials have several limitations. First, they used conventional rather than pegylated interferon. Second, interferon was given for relatively brief periods of 4 to 6 months. Third, they used an inadequate design in which treatment periods with lamivudine were shorter in the combined limb than in the lamivudine monotherapy limb and, therefore, the end-of-treatment responses were assessed at different time points. Finally, they collected limited data on sustained virologic response rates.

[cajim]

38. What are the advantages and disadvantages of the current approved hepatitis B treatments?
To summarize what I've reviewed with you, and this is what I try to talk about with my patients, there's advantages and disadvantages of our three therapies. I've only highlighted a few of them here. Interferon, and I haven't discussed this, but there is about a 5%-8% chance with interferon you actually will lose the surface antigen, that's higher than the other two therapies. It's only a short duration of therapy, 4-6 months on average, it has to be given by shots and there are a lot of side effects. Both of the oral agents, they're oral, there's good tolerance you can use it in end stage liver disease, whether it's cirrhosis or liver failure, and you use lamivudine in adefovir failures and adefovir in lamivudine failures. The disadvantages are that drug resistance is common, about 20% per year, where here you also have drug resistance but it's less common. Now there are new studies from Berlin, they showed here loss of surface antigen in 2% of patients at one year, not bad. It's not as high as interferon but it's reasonable.
39. Are there new treatments on the horizon for treatment of chronic hepatitis B?
The other thing to be encouraged about, is that hepatitis B is actually a rich area of ongoing studies. These are abbreviations of drugs that are in various stages of study. Entecavir, that will be out by Bristol Myers Squibb will probably be on the market in about a year or a year and a half, it's in the latest stages of study. They all have different characteristics. What encourages me is that some of my patients, when they have e-Negative chronic hepatitis B, we say we're going to start adefovir and you're going to have to take this for a long time, that creates an anxiety because there will be a certain amount of resistance. But I know that lamivudine is effective against the A181V mutation and I suspect that some of these agents will also be active against other mutations. So the bottom line is that we're going to have a whole shelf-full of drugs over the next five years, and probably more use of interferon, so that there will be lots of treatment options as we go down the road.