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58th Annual Meeting of the American Association for the Study of Liver Diseases

Boston, Massachusetts / November 2-6, 2007

Up to 5% of adults and almost all children fail to clear the hepatitis B virus (HBV) infection, and chronic disease, marked by the continued presence of HBV surface antigen (HBsAg), high levels of serum HBV DNA and the presence of hepatitis B e-antigen (HBeAg), sets in. In adults, the early phase of infection is frequently accompanied by marked disease activity and increased alanine aminotransferase (ALT) levels.

Although mean HBV DNA levels are lower in HBeAg-negative (e-antigen-negative) patients, spontaneous remission is uncommon in this patient group and their long-term prognosis is reportedly poorer than that for HBeAg-positive (e-antigen-positive) patients.

The goal of anti-HBV therapy is thus to eliminate all evidence of HBV DNA from the serum if possible, or at least to suppress it to the lowest possible level. This in turn should lead to histologic improvement in the liver, normalization of ALT and, ultimately, prevention of disease progression to cirrhosis or hepatocellular carcinoma, as noted by Dr. Douglas Dieterich, Professor of Medicine and Liver Diseases, Mount Sinai Medical Center, New York. For patients who are HBeAg-positive prior to therapy, an additional goal is to induce the loss of HBeAg and have patients seroconvert to anti-HBe.

“The biggest challenge for many patients with hepatitis B is that they have to be treated for life,” stated Dr. Stefan Zeuzem, Professor and Chief, Department of Medicine, Johann Wolfgang Goethe University, Frankfurt, Germany. “We would like to be able to cure patients, but with currently available drugs, this is achievable only in a small fraction of patients. In Europe and western countries, we have an emerging number of e-antigen-negative patients. They still have a reasonably high rate of viral replication and have disease progression, and there is very little to offer these patients in a confined treatment duration. They must be treated for years.”

GLOBE Trial Results

Dr. Dieterich discussed results from the GLOBE study, a large, international multicentre trial comparing telbivudine (TVD) with lamivudine (LVD) in 1367 patients with chronic hepatitis B. Entry criteria included serum levels of HBV DNA of >106 copies/mL, ALT ³1.3 x the upper limit of normal (ULN) and <10 x ULN with clear signs of liver disease on biopsy.

According to final data from the two-year study presented by Dr. Dieterich, TVD was more effective than LVD by every measure (Table 1). The average decline in HBV DNA from baseline among the 458 e-antigen-positive individuals was 5.7 log10 compared with 4.4 log10 in the LVD arm. HBV DNA was undetectable by PCR assay in 56% of e-antigen-positive patients in the TVD group vs. 39% of those on LVD. ALT normalization rates for the two arms were 70% and 62%, respectively. Among patients who were originally e-antigen-positive, HBeAg loss was 35% and 29% in those on TVD and LVD, respectively; 30% and 25% of patients, respectively, seroconverted.

Table 1. GLOBE: Efficacy at Year 2, HBeAg-Positive Patients ITT Population

For e-antigen-negative patients, the differences between the two agents were similar but the numbers were considerably better for both.

In turn, Dr. Yves Benhamou, Services d’hépato-gastroenterologie, Groupe hospitalier Pitié-Salpêtrière, Paris, France, and colleagues identified previously elusive on-treatment predictors of liver disease progression based on responses in the GLOBE cohort.

At week 52, patients who had progressed despite either therapy had either a 1-unit increase in the Ishak Fibrosis Score or a 2-unit increase in the Knodell Necroinflammatory Score but no decrease in the Ishak Fibrosis Score. Both histology scores at baseline turned out to be the only significant predictors for disease progression (P<0.0001 for both), with lower scores being more predictive of progression than higher scores, possibly because patients with higher values on both scores responded better to treatment, investigators speculate.

“The only significant on-treatment predictor of progression was failing to achieve a decline in HBV DNA of >5 log10 copies/mL by week 24 (P=0.008) which increased the likelihood of progression by 57%,” they added.

Elucidating Other Trial Data

Dr. Zeuzem also referred to entecavir registration data (ETV-022 and ETV-027). He noted that although undetectable viral load findings from these data appeared more favourable than those for TVD in the GLOBE study, no head-to-head comparison is available, and that unlike the GLOBE study, the entecavir registration data were not analyzed on the basis of intent to treat.

That also might have caused the resistance levels in the entecavir trials to be understated, remarked Dr. Thomas Berg, Head, Division of Hepatology and Gastroenterology, Charité Hospital, Berlin, Germany. Resistance was measured at 1%, in contrast to the GLOBE study, in which TVD resistance in HBeAg-positive and -negative patients reached 21.6% and 8.6%, respectively. However, as Dr. Berg explained, “The former trials stopped treatment in those patients who had not had a virologic response, and those are the ones who are most likely to develop resistance.” Nonetheless, he added that resistance to entecavir was still quite low.

Close Monitoring Critical

Regarding optimal time to initiate treatment, consensus suggests that HBeAg-positive patients should be considered for therapy when they have HBV DNA levels of 20,000 IU/mL or higher and elevated levels of ALT or evidence of hepatitis on liver biopsy. Therapy for e-antigen-negative patients may in turn be considered for patients with lower serum levels of HBV DNA. Importantly as well, speakers here agreed that it is vital to monitor patient response to therapy very soon after initiation of therapy to ensure patients are responding to treatment and HBV DNA loads are indeed being suppressed.

Currently approved antivirals for the initial treatment of chronic HBV infection include adefovir, entecavir, interferon, LVD and peginterferon alfa-2a (PEG-IFN alfa-2a). While new and improved drugs are critical to improving treatment for hepatitis, the themes of close monitoring and advances in treatment strategies loomed equally large at AASLD. As Dr. Zeuzem emphasized, it is critical not to let virus burdens get out of control. For example, on LVD, “If you wait until a patient with virological breakthrough has gained levels of HBV DNA above 8 logs, and you add on adefovir only then, you are only going to rescue 50% of your patients,” he cautioned. “However, if you add on adefovir [before the burden has risen beyond 6 logs], you can actually rescue all the patients.”

Dr. Zeuzem monitors his patients every three to six months, depending on the particulars of the case. Yet it is not enough to catch a viral breakout in time to rescue the patient. Dr. Dieterich elaborated, “Sustained suppression of HBV—this is the major point, because we can change this—may reduce long-term risk of cirrhosis and hepatocellular carcinoma.”

Thus, rather than waiting for obvious symptoms to arise, suggesting changes in treatment, or letting excessive time to pass between HBV DNA monitoring, Dr. Zeuzem asserted that virus burden should be watched enough so that physicians can re-evaluate treatment at the first sign of a rise. He also urged physicians to counsel patients to maintain their compliance.

Achieving Undetectable Viral Load

The most important single take-home message—a result in the GLOBE study, among others—was the importance of achieving an undetectable viral load by week 24. “If patients were undetectable at week 24, they remained undetectable at two years out,” confirmed Dr. Dieterich (Figure 1). That is true regardless of e-antigen status or genotype, he added. And among HBeAg-positive patients, “[Low] viral load at week 24 was the strongest predictor of e-antigen seroconversion.” This would suggest that TVD patients with undetectable viral load at 24 weeks display remarkably low resistance at two years.

Figure 1
sistance at 24 Weeks

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Conversely, viral burden heralded less encouraging outcomes. In the REVEAL study, a landmark trial that began in 1991, with a cohort of 90,000 Taiwanese patients, serum HBV DNA levels correlated closely with histologic necroinflammation (0.78), noted Dr. Dieterich. Higher baseline HBV DNA levels were associated with progression to cirrhosis, the relative risk ranging from 1.0 for those with <300 copies/mL to 2.2 for those with 104 to 105, to 8.6 for those with ³1011 copies/mL (P<0.001), according to Dr. Dieterich. Outcomes were even worse for progression to hepatocellular cancer (HCC), with a relative risk of 2.4 for those with 104 copies/mL. More generally, “Anything over 300 copies/mL HBV DNA has a significant increased relative risk for mortality,” he stated. Dr. Dieterich indicated that the impact can be seen in the “dramatically different” survival curves over 14 years of follow-up for HBV DNA burdens ranging from 104 to 106 copies/mL.

In the quest for an undetectable burden by 24 weeks, Dr. Zeuzem urged clinicians to “assess for primary nonresponse after 12 weeks of therapy. If the patient has seen more than a log drop in viral burden, continue as is. If not, you assess whether they are compliant, and react accordingly.”

If viral DNA remains detectable at 24 weeks, then it is important to act quickly to switch strategies, he stressed. Although simply switching medications can be an effective way to rescue patients, Dr. Zeuzem said that adding a second non-cross-reactive medication to the therapy was the better option. “In patients who have developed resistance to LVD, if you follow on with adefovir monotherapy, emergence of resistance is incredibly high,” he reported. Even drugs with high genetic barriers are going to evoke resistance quickly, “and only the continued combination therapy, adefovir and LVD, enables you to keep this patient at low HBV levels without virological breakthrough.”

The downside of combination therapy is cost, acknowledged Dr. Zeuzem. But in patients with an inadequate drug response by week 24, it is inconsequential compared to the risk of “lower chances of seroconversion, PCR negativity, [and] a very high potential for emergence of a resistant strain.”

Hepatitis C: New Interferon Strategies

One of the problems in treating patients for hepatitis C with PEG-IFN alfa-2a/ribavirin (RBV), the current standard of care, has been the low quality of life they face due to that drug’s side effects, noted Dr. Stephen Pianko, Monash Medical Centre, Victoria, Australia, at a poster session. These typically are worse in the day or two after dosing.

Dr. Pianko, Dr. Zeuzem and others conducted a phase IIb study comparing a new compound, albinterferon (alb-IFN) alfa-2b in IFN-naive patients, in combination with RBV, with PEG-IFN alfa-2a/RBV as the control arm. Over 400 patients (N=458) at 82 centres in eight countries took part in the study.

Alb-IFN is a genetic fusion of IFN with human serum albumin. The latter, a highly durable molecule, confers a substantial half-life upon the compound. That, in turn, makes it possible to give the drug every two weeks, or possibly only every four weeks, instead of weekly, as in the case of PEG-IFN.

In the study, patients on alb-IFN/RBV received 1200-µg doses either biweekly (q2wk), or every four weeks (q4wk), or 900 µg q2wk. PEG-IFN alfa-2a/RBV was given weekly. The primary end point was SVR at 24 weeks’ post-treatment follow-up. There was no significant difference in SVR between PEG-IFN/RBV and the three alb-IFN/RBV groups (P=0.64). About 58% of both PEG-IFN alfa-2a/RBV and alb-IFN alfa-2b/RBV 900 µg q2wk patients achieved SVR.

One of the two secondary end points was health- related quality of life. In this category, those on alb-IFN/RBV fared best, reported Dr. Pianko. He added, “More importantly, that correlated with the mental health scores.”

Of the three alb-IFN/RBV arms, the 900-µg biweekly arm excelled, particularly with respect to mental health. Mental health was evaluated using the short form (SF)-36 v.2, a generic health survey, and with the Hospital Anxiety and Depression Scale (HADS). At 12 and 24 weeks, the 900-q2wk arm of alb-IFN/RBV scored above the PEG-IFN/RBV cohort on all 10 domains of the SF-36. The 900-µg arm also showed markedly less decline in social functioning and vitality as compared with the PEG-IFN/RBV group, while the other two alb-IFN/RBV groups also scored better than the PEG-IFN/RBV arm. Both the 900-µg, q2wk arm and the q4wk arm of alb-IFN/RBV scored a mean decline of <4 points on the SF-36, while the PEG-IFN/RBV cohort declined by more than 10 points. All three alb-IFN/RBV groups scored markedly better than PEG-IFN/RBV in bodily pain.

All these factors correlated with fewer missed workdays in the three alb-IFN/RBV arms and markedly fewer in the 900-µg arm. Over the course of the study, mean missed workdays among patients working for pay was 12.6 in the PEG-IFN/RBV arm, 9.7 in the 1200-µg biweekly arm, 6.7 in the q4wk arm and 4.0 in the 900-µg q2wk arm. Thus, biweekly dosing of alb-IFN/RBV appeared to provide better quality of life than PEG-IFN/RBV and an improved dosing schedule, without sacrificing efficacy, concluded Dr. Pianko.

There were more advantages for the alb-IFN/RBV arms in hematological measurements. “Absolute neutrophil counts were pretty equal between active controls and q2wk alb-IFN/RBV doses,” reported Dr. Zeuzem, “but there was tremendous advantage with respect to neutrophil counts for patients dosed with alb-IFN/RBV 1200 µg only every four weeks, with half the rate of grade 3 neutropenia compared to the other groups.”

The 1200-µg biweekly arm had the highest rate of discontinuing therapy, he added. Potentially, the results could have been improved by allowing those 1200-µg patients who could not tolerate the dose to reduce it, as per protocol. Nonetheless, he noted that overall, 80% of alb-IFN/RBV patients adhered to treatment more than 80% of the time.

After safety data were evaluated, two further cohorts of nonresponders to earlier regimens of alb-IFN/RBV were treated with higher doses of alb-IFN/RBV 1500 µg q2wk and 1800 µg q2wk. Patients tolerated both doses well, and 50% of the 12 genotype 1 null-responders to the previous regime achieved early virologic response at week 12. “Alb-IFN was well tolerated at high doses and able to cure a limited group of previous nonresponders,” stated Dr. David R. Nelson, Associate Professor of Medicine, Director of Hepatology and Liver Transplantation, University of Florida, Gainesville. “These data are very similar to other non-responder trials that show that one can get patients virus-negative with higher doses of IFN, but high relapse rates lead to relatively low SVR rates. However, the 1500-µg and 1800-µg dosing groups were able to convert prior null-responders into partial responders, which may have important implications for future small-molecule treatment paradigms.”

Currently, the 900-µg and 1200-µg q2wk regimens are being evaluated in phase III trials. According to Dr. Zeuzem, “Every-four-week dosing deserves further evaluation, not only in genotype 1 but in other genotypes, and perhaps in hepatitis B.”

Questions and Answers

This question-and-answer section is based on interviews with Dr. Douglas Dieterich, Professor of Medicine and Liver Diseases, Mount Sinai Medical Center, New York and Dr. Stefan Zeuzem, Professor and Chief, Department of Medicine, Johann Wolfgang Goethe University, Frankfurt, Germany.

Q: What do you think were among the most important findings from the GLOBE study?

Dr. Dieterich: The GLOBE study showed that if patients were undetectable at week 24, they remained undetectable at two years. This was true regardless of e-antigen or genotype status. Among HBeAg-positive patients, a low viral load at week 24 was the strongest predictor of e-antigen seroconversion as well.

Q: What do you think the clinical implications of GLOBE might be for practicing physicians?

Dr. Zeuzem: I think what it is telling us is to make sure we assess patients for primary non-response after 12 weeks of therapy. If there has been more than a log drop in viral burden, we should continue as is, but if not, we need to assess whether or not patients are compliant and react accordingly.

Q: How has the management of chronic HBV infection changed in the past few years?

Dr. Zeuzem: Typically, we used to wait until patients developed clear resistance to a drug and had increasing viral loads before we made any further treatment decisions. Now, the concept is to evaluate early how well the viral load is suppressed, and if it is not maximally suppressed, you can anticipate that this patient is going to develop resistance, and you don’t want to wait for resistance to develop. So we now make decisions at predefined time points and optimize the treatment schedule and not wait until treatment fails.

Note: At the time of printing, albinterferon alfa-2b is not available in Canada.