SUMMARY OF THE AASLD MEETING, DALLAS, OCTOBER 2000
   Hepatology, October 2000 supplement
      Written for NATAP by Ray Chung, MD, Director of Liver Transplantation, Massachusetts General Hospital, Boston

The recently concluded AASLD meeting in Dallas was noteworthy for several new developments in the arena of HCV treatment, along with presentations on drug hepatotoxicity in coinfected individuals, experience with treatment in decompensated cirrhotics and other special groups, along with updates on newer forms of therapy.

Perhaps the most eagerly awaited data was from the trial of PEG-IFN-alfa-2b (PEG-INTRON, PEG-IFN) + Ribavirin (RBV) (abstract number 552). Because earlier studies demonstrated significant improvement in efficacy (by about 2-fold) using PEG-INTRON (PEG-IFN) versus conventional INTRON (IFN) in monotherapy trials, it has been strongly felt that combining PEG-IFN with RBV would provide the best available therapeutic combination. In this vein, patients from 62 sites worldwide with previously untreated chronic HCV were randomized to treatment with 48 weeks of IFN 3MU tiw +RBV 1000-1200 mg/d (Rebetron), 48 weeks of PEG-IFN 1.5 ucg/kg/wk + RBV 800 mg/d (PEG-RBV 1.5), or 4 weeks of PEG-IFN 1.5 mcg/kg/wk + RBV 1000-1200 mg/d followed by 44 weeks of PEG-IFN 0.5 mcg/kg/wk + RBV 1000-1200 mg/d (PEG-RBV 0.5).

In short, the news is reassuring. PEG-RBV 1.5 arm demonstrated superior end-of-treatment and sustained virologic response rates when compared with either of the other two arms, achieving 54% SVR in all patients on an intent-to-treat analysis. When broken down by genotype, non-genotype 1 SVR was 82%, and genotype 1 SVR was 42%. The combination was equally well-tolerated compared with the Rebetron arm, and the overall completion of therapy rate was 80%. Further, when subgroup analysis was performed, it appeared that RBV at 800 mg/d was as effective as the higher doses in subjects under 65 kg, whereas 1000 mg/d appeared to be effective for those patients between 65 and 75 kg, and 1200 mg/d was required for maximal efficacy in those over 75 kg.
      (Editorial note from Jules Levin: in the Peg-Intron study, the IFN+RBV arm had a sustained virologic response of 47%, which is higher than the previously seen of 40% in large studies. In this study, discontinuations were 14% in the Peg 1.5 hi-dose arm vs 21% in previous US study of IFN+RBV).

These data strongly support that PEG + RBV will eventually become the standard of care in the HCV singly-infected population, especially for patients with genotype 1 disease. It is somewhat disappointing that the tolerability rate was not significantly improved on this regimen compared with Rebetron. The potential for more protracted hematologic adverse events (leukopenia/neutropenia) can not be understated for application to the coinfected population. (Editorial note from Jules Levin: Neutropenia Grade 3 was 18% vs 11% vs 7% in thePeg-Intron 1.5 ug/kg hi-dose arm, Peg Intron 0.5 ug/kg lo-dose arm, and in the regular interferon arm, respectively. Grade 4 was 2% in IFN and Peg 0.5 and 4% in Peg 1.5. Discontinuation rate for neutropenia was 0.2%, 0.4%, and 1% in IFN, Peg 0.5 and Peg 1.5 arms, respectively).
It should still be cautioned, then, that these findings are not immediately extendable to HCV/HIV coinfection, and that patients with coinfection should continue to be treated in the context of clinical trials.

Tolerability and Effect on Quality of Life Measures

With regard to tolerability and effect on quality of life measures, two presentations addressed the tolerability of PEGylated IFNs. The first (abstract #590) found that health related quality of life measures were significantly better using the 0.5 mcg/kg/wk dose compared with conventional INTRON. Quality of life scores were comparable between PEG 1.0 and slightly worse with 1.5. The second abstract (#591) examined PEG-IFN-a-2a (Pegasys) given at a dose of 180 mcg/wk for 48 weeks compared with the conventional Roferon regimen of 12 weeks of 6 MU tiw followed by 36 weeks of 3 MU tiw. Fatigue and quality of life indices were significantly better for Pegasys at weeks 2 and 12 but not statistically different 24 weeks after completion of therapy. These data suggest that the side effect profile in the early going of therapy, usually the most difficult period of patients, will be better-tolerated. Nonetheless, if patients can negotiate the first 12 weeks, these differences tend to even out. We await further long-term data regarding the efficacy of Pegasys with RBV in terms of tolerability and efficacy.

An important subject is that of early predictors of response to therapy. In this vein, data presented in abstract 633 by Neumann et al suggesting that accomplishment of 2 log declines within the first 4 weeks followed by another 2 log decline in the second 4 weeks of therapy (rapid virologic response) is the best predictor of sustained virologic response. Pegasys appears to be superior to conventional Roferon in accomplishing this RVR. The large majority of these individuals (68%) accomplishing RVR achieved SVR. None of those failing to achieve RVR accomplished SVR. These promising data suggest that within the first 1-2 months of therapy, those individuals destined not to obtain an SVR can be identified. Other abstracts confirmed that early non-SVR response determinations may be made by 12 weeks of therapy. These findings have obvious implications for the enhancement of cost-effectiveness and limitation of adverse effects attributable to therapy.

Another subject of ongoing debate is that of the value of so-called induction therapy. It is based on the premise that the offering of higher doses of therapy in the initiation phase of treatment will reduce the emergence of interferon-resistant quasispecies by bringing about steep viral load declines. Several abstracts in the meeting addressed the value of induction dosing, and the take-home message appears to be that induction dosing brings about higher early virologic responses, but does not appear to affect overall SVR. Thus, there is little rationale to introduce induction dosing. Nonetheless, it should be noted that Roferon dosing is currently approved at 6MU tiw for 12 weeks followed by 3MU tiw for 36 weeks in Europe and has been used in most clinical trials at these doses, in large measure because of likely differences in unit strengths between Roferon and Intron-A.

The pharmacokinetics of PEGylated interferons are also an important area of investigation, given the potential for more prolonged toxicities with these agents. Two abstracts (#842 and 848) confirm that the metabolism of Pegasys is primarily hepatic and, further, that dose adjustments of this agent are not necessary in subjects with renal impairment. Thus, one important group of patients, those with renal failure who may be on dialysis, can benefit from monotherapy with PEGylated interferon. Given that this group has not been able to benefit from the addition of RBV, which can not be cleared by dialysis, the introduction of PEGylated interferons represents a significant step forward.

The response rates to antiviral therapy in African-Americans and Hispanic-Americans has been further examined, in view of clear data showing that response rates to interferon monotherapy are lower in these two groups, even after corrections for genotype distribution are applied. Abstracts 753 and 756 addressed responses to newer forms of therapy in these groups. In African-Americans, responses to Pegasys and Roferon were compared between Caucasian (n=1208) and African-American (n=55) patients. The SVRs in African-American patients (80% genotype 1) was 0 and 15% in those treated with Roferon and Pegasys 180, whereas the same regimens produced SVRs of 13% and 35% for Caucasians, respectively. Thus, while PEGylated IFN represents a step forward, the limited response rates in African-Americans continues to be problematic. Similarly, the SVR in Hispanic subjects was evaluated with Rebetron in Puerto Rico. The SVR was 23% for naïve subjects, 45% for relapsers, and 8% for previous IFN nonresponders. These figures confirm lower response rates in Hispanic subjects when compared with multicenter efficacy data for Rebetron. Further study is clearly warranted to determine the host factors that limit responsiveness in these groups. To this end, the NIH will be sanctioning a multicenter clinical and scientific initiative aimed at addressing this important topic over the next several years.
    (Editorial Note from Jules Levin: Pegasys study investigators reported comparable adverse event and discontinuation profiles in Black and White groups. They concluded that this indicated that the lower response rates in Black patients cannot be a result of a higher incidence of side effects and/or discontinuation rate).

The treatment of HCV-infected patients with compensated cirrhosis has been an important area of investigation. An analysis of subjects included in a Pegasys treatment trial (abstract 1131) revealed that 30% of those individuals treated with Pegasys 180 for 48 wks experienced SVR compared with 6% of those cirrhotics treated with conventional Roferon monotherapy. Genotype analysis revealed that genotype 1 SVRs were 16% and 3% in the two groups, respectively, while genotypes non-1 experienced 49% and 12% SVRs with the two regimens. These data show that PEGylated IFN represents a particularly hopeful option for those individuals with established cirrhosis. Further examination of PEGylated interferons with ribavirin in this important treatment group will be eagerly awaited.

The treatment of those individuals with objective evidence of clearcut liver dysfunction (jaundice, low albumin, ascites, encephalopathy, and coagulopathy) has been hazardous, and in general recommendations have been not to treat these so-called decompensated cirrhotics with IFN-based regimens. Two abstracts (#594, 595) addressed the treatment of these groups with lower-dose or escalating regiments of IFN + RBV. Both demonstrated that these drugs were poorly tolerated, with dropout rates of 40% and serious adverse events, including mortality, reported. In those capable of completing therapy, SVRs were about 17%. Thus, the treatment of decompensated cirrhosis with IFN and RBV regimens can not be routinely recommended.

Important advances have been made in understanding the events that lead to successful clearance of acute HCV infection. These studies have been conducted in the only viable animal model for the disease, the chimpanzee. After inoculation with HCV, the immune response to HCV was compared in the blood and liver between animals that cleared HCV successfully from those that did not. Interestingly, while all animals were able to mount vigorous cellular immune responses, only those animals with vigorous responses within the liver were able to clear infection, suggesting that persons whose lymphocytes are capable of homing in to the liver appear to have the best outcome. The factors that determine the immune response within the liver will no doubt be the focus of continued intensive investigation.

Two studies addressed particular aspects of antiretroviral drug toxicity. One study (abstract 611) identified a distinctive form of hepatic injury identified on liver biopsies examined retrospectively in individuals on HAART who had developed increases in liver enzymes. This pattern of injury, seen in 26% of biopsies, has features of fibrosis mixed with cell damage, and did not appear to correlate with HBV or HCV infection, nor did it correlate with any particular antiretroviral agent. Withdrawal of HAART appeared to lead to reversal of liver enzyme abnormalities in some but not all of these patients. These findings, while not definitive, suggest a possible distinct histologic pattern associated with HAART. Further prospective studies will be necessary to determine whether this correlation holds.

The second study (abstract 610) examined the effects of the newer non-nucleoside RTIs found that the risk of delavirdine, efavirenz, and nevirapine for grade 3 or higher elevations of LFTs was 2.4%-3.6%, lower than that reported for the protease inhibitors. The only grade 4 toxicity was seen with nevirapine in one case. Further, the study did not find that HBV or HCV coinfection increased the risk of grade 3-4 toxicities, suggesting that this class of compounds can be used safely in the coinfected population. However, these otherwise sanguine findings must be tempered by occasional reports from other sites of serious hepatotoxicity with nevirapine. These findings should still not steer us away from exercising caution and monitoring of liver function tests in all individuals receiving HAART, irrespective of regimen.

It is quite clear that thorough assessment and investigation of preexisting liver disease is paramount for those individuals about to undertake a course of antiretroviral therapy. The optimal nature of this assessment awaits further definition from prospective studies of HIV-infected persons with and without coinfection.

Clearly, the floor is being lifted for all patients with chronic HCV, insofar as promising data for PEGylated interferons in combination with RBV suggest that sustained responses can be obtained in over half of singly-infected patients. However, there is still considerable cost (toxicity) associated with these regimens. Thus, further work in the development of virus-specific agents against HCV along with adjunctive agents in the treatment of coinfected patients is of critical importance.

Ribozymes

The use of ribozymes (RNA molecules with enzymatic ability to clip other RNA sequences specifically) is one area of potential promise. Phase I studies of ribozymes targeted against the key regulatory region of HCV RNA governing protein synthesis are now underway and suggest that the drug can be given safely (abstract 1136). We now await the results of dose-finding and efficacy studies for this highly specific agent that is capable of interrupting the viral lifecycle (abstract 902). (Editorial note: Study of ribozyme in combination with Peg IFN will begin next Spring).

HCV-specific Protease, Helicase, and Polymerase Inhibitors

In addition, the development of HCV-specific protease, helicase, and polymerase inhibitors are the subject of intensive programs by both small and large pharma. We can look forward to introduction of agents specific for these viral enzymatic targets in the next 2-3 years. The screening of agents directed at HCV replication generally will be aided by the development of surrogate model systems such as a novel system that is capable of recapitulating the early events in the HCV lifecycle (abstract 261).

Alternate Ribivarins

Because of RBV’s often dose-limiting toxicity, work has also commenced on the development of alternative ribavirins. One such candidate is the mirror image of ribavirin, called levovirin. Early work (abstract 849) suggests that this compound possesses similar immunomodulatory activity to RBV, but does not have its toxicity and its broad antiviral activity against other RNA viruses. Because RBV is likely to be inhibiting HCV through indirect, immunomodulatory means, levovirin may still have anti-HCV activity. Of course this awaits further testing in surrogate and animal models, and, ultimately humans. (Editorial note: VX-497 is a second alternate ribivarin and is in phase 2/3 clinical studies).

Maxamine

Another agent of interest is a histamine analogue that may also have immunomodulatory capacity. Preliminary studies using combination therapy of IFN with varying dose ranges with this agent, MAXAMINE, also given as a subcutaneous injection, suggested high week 24 virologic response rates could be achieved (64% all subjects). However, only 47% of the cohort was genotype 1. (These data were first presented at the International Symposium on Hepatitis Viruses, Atlanta in April 2000 and in Dallas, abstract 1134). The combination appeared to be well-tolerated. Sustained VR rates are awaited. Further, because these studies were conducted without a RBV-based comparison group, the recommendation of this therapy for all naïve HCV patients would appear to be limited. Nonetheless, we can also look forward in the near-future to further combination trials with this agent, especially in RBV-intolerant patients.