Non-responders

                              48 weeks - ETR

RBV (n=30)                  25%

MMF (n=29)                 28%

AMA (n=28)                 11%  

RBV + AMA                 40% 

(n=31)

Relapsers:

                               48 weeks-ETR

RBV (n=32)                     61 %

MMF (n=29)                    72%

AMA (n=31)                     42%

RBV + AMA                    71% 

(n=31)

This ongoing study indicates that some patients who failed to respond to standard interferon/ribavirin may benefit from an additional course of therapy with pegylated interferon plus other agents. However, these results must be viewed with several caveats. First, it is anticipated the approximately 20% of EOT responders will experience a virologic relapse after a course of interferon plus ribavirin. Thus, the sustained response rates will be considerably lower for all treatment groups. In addition, ribavirin prevents relapse and there is little reason to believe that MMF or AMA will prevent relapse in a similar manner. Consequently, one may expect the sustained response rates to be considerably lower in the MMF and AMA groups than in the groups that received ribavirin. Furthermore, the medical rationale for the use of either MMF or AMA is dubious at best and, while new and better therapies are urgently needed, it remains doubtful that these agents will have any role in the future management of chronic HCV infections.

Abstract 279. Retreatment of Interferon And Interferon-Ribavirin Non-Responders with Peginterferon-alpha-2a (Pegasys) And Ribavirin: Initial Results from the Lead-In Phase of the Halt-C Trial

The HALT-C trial was designed to determine if long term maintenance interferon therapy, administered over 4 years, could prevent histologic progression, reduce the development of hepatocellular carcinoma and the need for hepatic transplantation in patients with chronic HCV and advanced fibrosis or cirrhosis who remain HCV-RNA (+) despite therapy. Since peginterferon plus ribavirin is more effective than standard interferon/ribavirin for treatment of chronic HCV all patients enrolled in the HALT-C trial were first treated with peginterferon plus ribavirin during the lead-in phase of this trial.

This study enrolled patients with advanced liver disease (Ishak Fibrosis stage ³ 3) and no evidence of hepatic decompensation. All patients had previously failed to respond to interferon-based therapy administered for at least 12 weeks. After screening, all patients received pegylated interferon alfa-2a (180 mcg weekly) plus ribavirin (1 - 1.2 grams/day).

Dr. Adrian Di Bisceglie presented on-treatment virologic response data on the first 268 patients who completed at least 20 weeks of therapy within this ongoing study. For the purpose of this presentation, viral response was defined as an undetectable HCV-RNA level at treatment week 20. 15 (5.6%) patients discontinued therapy prior to week 20. At week 20, 107 of 268 patients (40%) (based on an intention-to-treat analysis) had an undetectable HCV RNA level. These patients will continue therapy for an additional 28 weeks and, per protocol, will not enter the "maintenance" phase of the study. There were several important "sub-group" analysis presented. Persons who had only failed prior interferon monotherapy were much more likely to achieve a response than those who failed prior interferon/ribavirin combination therapy (53% > 21%) and African-Americans were significantly less likely to respond than Caucasians (10% < 41%).

In addition, a large number of patients had dose reductions of the PEG-interferon (53%), ribavirin (44%) or both (47%). Thus, while the discontinuation rate was quite low (~5%), it remains uncertain if such dose reductions will impair the overall effectiveness of the therapy. Nonetheless, these results are encouraging and suggest that persons with advanced liver disease who failed to respond virologically to prior therapy may benefit from a course of pegylated interferon/ribavirin.

Abstract 987. Peg-Interferon alpha-2b Plus Ribavirin for Treatment of Patients with Chronic Hepatitis C Who Have Previously Failed to Achieve A Sustained Virologic Response Following Interferon alpha-2b or Interferon alph-2b Plus Ribavirin Therapy

In a poster session, Dr. Mark Sulkowski and colleagues presented preliminary data from an ongoing multicenter study of pegylated interferon alfa-2b (weight-based 1.5 mcg/kg weekly or fixed dose 100 mcg < 80 kg and 150 mcg > 80 kg weekly) plus ribavirin 800mg/day in patients who failed to achieve a sustained response following interferon-based therapy ("non-responders" and "relapsers").

Of 511 enrolled subjects, viral response data after 12-weeks of therapy was available on 481 patients. Overall, 35% of patients had an undetectable HCV RNA level after 12 weeks of therapy and no significant difference was observed in viral response or adverse events between patients who received fixed versus weight-based PEG-interferon dosing. The week 12 viral response rate was 26.5% among "non-responders" and 55.2% among "relapsers." As has been observed in other studies, persons with HCV genotype 1 and African-Americans were less likely to respond virologically. In this study patients will remain on therapy for an additional 36 weeks. It is anticipated that approximately 15-20% of the end-of -treatment viral responders will experience a "relapse." Thus, while the sustained viral response data is not yet available, it is likely that the observed rates will be lower than on-treatment results.

Conclusions:

Based on this and other data, persons who failed to achieve a sustained viral response to interferon alfa/ribavirin may consider a course of pegylated interferon alfa/ribavirin with the expectation of a response rate in the neighborhood of 20% for "non-responders" and 50-60% for relapsers. The response rates anticipated for "non-responders" is somewhat higher than might have been predicted and may reflect the increased effectiveness of pegylated interferon as well as dramatic improvements in the skill and expertise of the medical professional, who have learned how to use interferon/ribavirin more effectively since the introduction of combination therapy in 1998.

While encouraging, these data clearly indicate that many patients, particularly those with HCV genotype 1 and African-Americans, will not achieve HCV eradication with currently available treatments; new drugs are urgently needed for such patients.

Editorial note: 2 additional studies, one presented by ira Jacobson, MD, at Cornell-NY Hospital in NYC, reported similar findings.

Written for NATAP by Douglas T. Dieterich, MD Cabrini Hospital and NYU Medical Center, NYC

The therapy of hepatitis B is becoming almost as complicated as the disease itself. It is suffering from the success of all the new therapies coming as well as some information on the older therapies. I will attempt to keep this as uncomplicated as possible and have been debating how to organize this, alphabetical order or order of likely approval and I think it would be better to put this in historical perspective to build on the base and educate those still confused by the field.

The first treatment approved by the FDA for HBV was alfa interferon 2b at a disabling dose of 10 MIU thrice weekly or 5 MIU daily for 4 months. This resulted in about a 25% HbeAg to HbeAb seroconversion rate and a histological benefit on liver biopsy. In late 1998 3TC or lamivudine was approved at a dose of 100 mg per day, considerably less than the HIV dose of 300 mg per day. One years' treatment resulted in a seroconversion rate of about 25%, like interferon and a histological benefit on biopsy similar to interferon's. The difference in this therapy was that HBV resistance developed in nearly as many patients who seroconverted per year. The good news was that the resistant virus was seen as more benign than the wild type virus and even though the virus was still replicating, the seroconversion rate was significantly higher if the patients continued taking 3TC. News from this meeting however suggested that the early biopsy benefit is lost after 4 years on 3TC and the biopsies start to worsen again. This is beginning to sound like the HIV story where sequential nucleoside analogue therapy resulted in sequential nucleoside resistance and I believe that is clearly the case.

Why not combine the two therapies? Well there were several combination trials presented here in Dallas. They, unlike the first study performed a few years ago, showed that combination 3TC and interferon is better than either alone and that interferon prevents the development of 3TC resistance mutations. There was even a combination trial of famciclovir and interferon, which showed some benefit. Famciclovir is approved for the treatment of herpes virus infections but not for hepatitis B. It does however have some activity against hepatitis B albeit slightly less than 3TC. Famciclovir and 3TC share some resistance mutations as well, but not all and there is one paper from 2000 at least that demonstrates synergy between the two. In my practice, for patients not on clinical trials, I always use the combination of famciclovir and 3TC.

The advances in interferon technology to pegylate it and lengthen the half life so that it can be administered weekly, have spread to hepatitis B treatment as well. One study showed that pegylated interferon alfa 2 a is clearly superior to plain alfa 2a interferon thrice weekly in the treatment of hepatitis B. Clearly the next step is to combine pegylated interferon and 3TC in a trial. That trial is now in progress, but has no results to date.

The next drug likely to be approved in the US for HBV is adefovir. It is a nuceotide analogue similar to tenofovir which just arrived on pharmacy shelves in early November for the treatment of HIV. Adefovir was studied in HIV patients and had little activity and quite a bit of kidney toxicity at 120 mg and 60 mg per day. The HBV dose is fortunately only 10 mg and so far has demonstrated very little toxicity and a great deal of efficacy. Long-term data were presented up to 136 weeks for adefovir, which showed a seroconversion rate of 21% and only 3/39 patients discontinued drug for toxicity. Also encouraging was the loss of e Ag in 39% and the HBV DNA < 400 copies of 61% at week 48 and 70% at week 100 demonstrating a 3.75 log drop in HBV DNA. One of the biggest advantages of adefovir was that over 2 years no resistance developed! There were some mutations found in the HBV genome, but they did not confer resistance to adefovir. That is very promising and encouraging. HIV HBV infection is becoming a bigger problem each year because after 4 years of 3TC treatment over 90% of HIV HBV infected patients demonstrate 3TC resistant HBV. An abstract from Paris clearly showed in 35 HIV HBV co-infected patients with 3TC resistant HBV that adefovir reduced HBV DNA by 4.74 logs. This was accompanied by 3/33 patients seroconverting from e Ag to e Ab. This demonstrates the efficacy of adefovir in 3TC resistant virus even in HIV patients. There was no change in HIV RNA or CD4 count in these patients. Combinations of adefovir and 3TC were studied for drug-drug interactions and there appear to be none, paving the way for a combination adefovir 3TC trial, which is ongoing now. There is every reason to believe that this drug will be licensed in the US by this time next year for the treatment of hepatitis B and 3TC resistant hepatitis B

Next in the arena is FTC, a close cousin of 3TC. There was originally no real reason to suspect that this would be any better than 3TC. However in a large multiple dose trial presented here the highest dose 200 mg resulted in 61% of patients with <4700 copies of HBV DNA, but even more impressive was the e Ag loss of 50% and the eAb seroconversion rate of 23%. Only 2 patients developed the classic 550 and 526 mutations, which are the same as the 3TC resistant ones. There were no serious side effects noted in this trial. From the same company, Triangle, another drug clevudine or L-FMAU was studied first in an animal toxicology study and shown to be safe in animals. Then it was studied in a 28 day trial in man . The results were somewhat surprisingly good. All three doses showed as much as a 3 log drop in HBV DNA in the 28 days, but what was surprising was that HBV DNA stayed down by as much as 2 logs even 5 months after stopping clevudine!. The highest dose resulted in some ALT elevations, but that just may mean that it is working well. The obvious next step is to combine these two agents and the results of that trial will be really interesting.

editorial notes: Entecavir is a new hepatitis B drug. A study was presented on entecavir vs 3TC resistance-

New Hepatitis B Drugs at AASLD (LDT, adefovir, entecavir)
http://www.natap.org/2001/aasld2/day13.htm

One study of entecavir in transplant patients clearly showed activity of about a 1.5 log drop in HBV DNA in heavily pre treated patients suggesting that entecavir may indeed be active in 3TC resistant patients.

LDT is another nucleoside made by Novirio which has good activity against HBV and HIV and the phase I dose escalation results were presented here which showed linear pharmacokinetics, a good thing to have. A large combination trial with 3TC is due to get started in the US any day now and it should be exciting. The trial design is very intriguing and adventurous and should look immediately for synergies between the two drugs.

D4C is the Achillion addition to the hepatitis B nucleoside pool. A phase I trial in healthy volunteers was presented which revealed good absorption and good half-life. In vitro this drug shows activity against both wild type and 3TC resistant hepatitis B. This is also a promising new agent for which trials are presently underway.

There is much progress in the world of hepatitis B now and much of it is proceeding in the direction of combination therapy based on the building blocks of 3 TC and perhaps pegylated interferon. Nucleoside only combinations, of course have fewer side effects and appear to be the wave of the future.

Reported by Jules Levin

After I sent out the report on the TMA ultrasensitive viral load test reported on here at AASLD, I received this note from LabCorp. I thought you would like to see it.

The information below (the TMA study I reported toy you that was presented here at AASLD) compared a highly sensitive TMA qualitative test to LabCorp/NGI's highly sensitive quantitative test (apples/oranges) Our HCV quantitative test (HCV SuperQuant) has a sensitivity of 100 copies / 39 IU's w/ a dynamic range to 5 million copies / 2 million IUs. Our HCV qualitative RNA test (HCV UltraQual) has a sensitivity of 5-8 copies / 2 IU's. The UltraQual test is the most sensitive qualitative test commercially available in the world. I'm surprised this test was not compared to TMA since it to is an ultra sensitive qualitative test.

In fact, on September 21st LabCorp's National Genetics Institute announced the FDA approval of the HCV and HIV UltraQual tests for use in the screening of source plasma. This is the same HCV UltraQual test that we offer diagnostically. Because this was FDA approved in the screening market it has been scrutinized heavily by the FDA and its claims and purpose have been upheld/endorsed.

LabCorp purchased NGI last fall and we have been making these exquisite tests available to all clinicians. NGI has completed the clinical trial work for all HCV drugs w/ the exception of one using these highly sensitive qualitative and quantitative RNA tests. We also announced yesterday the availability of the most sensitive HCV RNA quantitative test (HCV QuantaSure) w/ a sensitivity of 5-8 copies / 2 IU's to 5 million copies / 2 million IUs.

PERFORMANCE OF TRANSCRIPTION MEDIATED AMPLIFICATION (TMA) IN THE DETERMINATION OF VIROLOGICAL RESPONSE TO TREATMENT IN PATIENTS WITH CHRONIC HEPATITIS C

abstract 207

This is the program abstract, I will check tomorrow to see if poster is different. Remember, this test is in clinical development and not yet FDA approved. But its my understanding that the test can be accessed through certain commercial labs and may be reimburseable: Quest - order code 37273N; Specialty Labs - order code 7516

Emilia Hadziyannis, Fotini Spanou, Aggeliki Kostamena, Savvas Savvas, Stephanos J Hadziyannis, Acad Dept of Medicine, Hippokration Gen Hosp, Athens Greece

A sensitive qualitative HCV RNA assay based on transcription mediated amplification (TMA) has recently been introduced in research and clinical laboratories. TMA has a sensitivity level of 25-50 HCV RNA copies/ml, 2-3 times lower than other widely used assays. We evaluated the performance of TMA (VersantTM , Bayer) in the determination of long term response to therapy (monotherapy or combination therapy) in patients with chronic hepatitis C (CHC) at the end of treatment (ET). Materials and Methods: 47 treated patients, 10 sustained responders, 29 relapsed responders and 8 non responders, were included. Sera from all of them were obtained at the end of treatment and were tested with a sensitive PCR assay, either in house by AmplicorTM, Roche or at National Genetics Institute (NGI). Aliquots, stored at 70o were thawed before tested with TMA. TMA was performed according to the manufacturers instructions. The results were compared. Results:TMA classified 21% of relapsed responders as non responders at the end of therapy. There was 100% concordance between the results of TMA and PCR for the groups of non responders and long term responders to treatment. The results were further analyzed in relationship to baseline viral levels, HCV genotype and type of therapy. Conclusions: 1)The results of this study indicate that the virological response at the end of treatment should be determined by the TMA assay which reclassifies approximately 1/5 of relapsed virological responders to non responders 2) These findings have practical application in monitoring and tailoring therapy in chronic hepatitis C.

Reported by Jules Levin

The authors performed biopsies after an average 16 years of having HCV, the 2nd biopsy an average of 3.5 years later, and the third biopsy an average of 2.77 years later. The authors conclude progression seems to accelerate in later stages. While the optimal interval has yet to be defined, it is likely to be at least five years. My reading of this abstract is that waiting 5 years may be too long for a percentage of people particularly if you've had HCV for a long time.

editorial note: for persons with HCV/HIV coinfection, HIV accelerates HCV and although there are no studies I know of looking at this question, you may want to consider rebiopsy after 1 or 2 years if you have postponed therapy.

DEFINING THE OPTIMAL INTERVAL BETWEEN LIVER BIOPSIES FOR CLINICAL DECISION MAKING REGARDING INITIATING HCV THERAPY : RATE OF DISEASE PROGRESSION IN HCV DISEASE

abstract 212

Jean-Pierre Zarski, Ctr Hospitalier Univ de Grenoble, Grenoble France; Richard Garcia-Kennedy, Pacific Med Ctr, San Francisco; Jean-Pierre Bronowicki, Ctr Hospitalier Univ, Nancy France; John Mac Hutchinson, Scripps Clinic, San Diego; Enkelejda Hodaj, Ctr Hospitalier Univ, Grenoble France; Truta Brandusa, Teresa Wright, Veteran's American Hosp, San Francisco; Robert Gish, Pacific Med Ctr, San Francisco

Background : In clinical practice, treatment is often deferred in patients with mild disease, yet the interval at which liver biopsy should be repeated is not defined.

Aims : In order to address this issue, we examined the rate of fibrosis progression in patients in whom two or more liver biopsies were available for review in the absence of therapy. Methods : Two hundred and twenty patients (131 M, 89 F, mean age : 42 ± 12 years) with histologically proven chronic hepatitis C were selected in 5 hospital centers (3 in USA and 2 in France), having at least 2 liver biopsies and no treatment. Liver histology was assessed according to the Metavir scoring system by a single pathologist.

The mean duration of disease at the first biopsy was 15 ± 9 years. The mean delay between the biopsies was 3.51 ± 2.06 years [median : 3 (1 - 8)], and 2.77 ± 1.60 [median : 2 (1 Ð 6)] in the 18 patients having 3 biopsies. Fourteen variables were included in a uni and multivariate analysis in order to determine factors associated with liver fibrosis progression.

Results : At the first biopsy, the distribution was F0 32 %, F1 33 %, F2 19 %, F3 10 %, F4 6 %. The mean fibrosis progression rate per year was 0.10 ± 0.18 [median 0.07 (0 Ð 0.57)] at the first biopsy, 0.07 (0 - 0.57),0.07 ± 0.40 [median : 0.00 (- 81 - + 0.95)] between the first and the second biopsy and 0.36 ±0.45 [median : 0.17 (0 - 1.5)] (p = 0.07) between the second and the third biopsy. The difference was not statistically significant. In univariate analysis, age at infection, age at biopsy, mode of contamination, alcohol consumption, BMI, high viral load, log AST and log ALT were associated with severe fibrosis (F3 Ð F4). However, in multivariate analysis, only age at the first biopsy > 40 years (OR = 5) (2 Ð 12) and alcohol consumption : 1 to 50 g per day (OR = 4) (2 Ð 12) and more than 50 g per day (OR = 8) (3 Ð 23) were associated with severe fibrosis (F3 Ð F4). Between the 2 biopsies only 16 (8.%) patients achieved "clinically significant fibrosis progression defined as an increase in fibrosis stage 2 (62.5 % at 5 years, 87.5 % at 6 years). However no variable was associated with this worsening. 2 / 16 patients worse between first and third biopsy. AST (p < 0.02) was the only variable associated with this worsening.

Conclusions : The interval of 3 years may be inadequate to measure disease progression. This progression seems to accelerate in later stages. While the optimal interval has yet to be defined, it is likely to be at least five years.
 

Interferon Improves Risk for Death and Cancer
New Ribavirin in Early Development

Interferon Improves Risk for Death and Cancer
New Ribavirin in Early Development
Normal ALT in African-Americans
Fats, Overweight, Diabetes in HCV
How Often Should You Do a Biopsy in HCV/HIV Coinfection

A Japanese research group reported that interferon therapy improves the risk for developing HCC and death. This is not a new finding. Several studies have reported this. But this study was a large one. The study measured ALT response. Authors reported therapy was 4-12 months & presumably interferon alone. Responders and transient responders improved risk but non-responders did not compared to untreated patients. One of the key questions is if you take IFN+RBV therapy and are a partial responder, relapser or nonresponder how long will improved histology last after stopping therapy? I don't think we know but anecdotal opinion is that histology can improve while on IFN even if you're a nonresponder. After stopping therapy progression starts up again but it may take a year to get back to where you were before therapy. Opinion is that by staying on interferon histology improvement is continued. Two large studies in HCV monodisease are ongoing to prove this.

Levovirin is a second generation ribavirin being made by ICN Pharmacueticals. In a poster today they reported that in monkeys they found Levovirin gets into the red blood cell less than ribavirin. This would suggest perhaps less side effects. RBV can lead to reduced hemoglobin and fatigue. A study in HCV-infected patients is planned and required to see if this new version of RBV has antiviral activity as RBV does in combination with IFN.

A study reported today by Thelma Wiley from the University of Illinois, Chicago reported finding that in African-Americans compared to non-AAs cirrhosis was as likely to occur whether ALT is normal or abnormal (25%). Among the general population, normal ALT implies less progression in general. Although ALT is not a predictor of non-progression. You could have nomal ALT and have moderate or more advance liver disease. Wiley said African-Americans with normal ALT are as likely to develop significant histologic disease as whites with abnormal ALT.

Several posters associate overweight, elevated fats (cholesterol, triglycerides), and sugar with HCV and progression. This is not new information but is worth reporting because these are things that patients can have some control over with dietm, exercise, and medical intervention for lipids.

One poster suggested in HCV monodisease a follow-up biopsy should be done 3-5 years after the first to evaluate progression. Since HIV accelerates HCV perhaps a followup biopsy should be considered 1-2 years after the first, if HCV therapy was not started.

A San Diego group reported that HCV/HIV patients treated with HAART & for HCV have better survival if they are compliant with taking meds, participating in support groups, and in stopping alcohol. In other words, good support systems are important.