American Association for the Study of Liver Diseases (AASLD), 50th Annual Meeting, Dallas

NATAP at Dallas Liver Conference: PEG IFN; HCV Dynamics
Jules Levin, NATAP

Selected Highlights:
I had one of my famous refrigerator from hell experiences here in Dallas as I did recently in Lisbon. I reserved my room at the Wyndam Anatole Hotel 2 months ago and requested a refrigerator for my interferon and insulin. When I checked in today at 2:30 pm they said a refrigerator was on the way up to the room. About 4-5 hours later there was still no refrigerator. The manager took me on a tour to try and locate one without luck. Finally Valerie, the front-desk clerk, located a refrigerator on her own in a room and brought it to my room.

In Lisbon I had to purchase a refrigerator in an appliance store and install it in the Sheraton Hotel because they could not offer me one. I spent half the day trying to locate a hotel with a frig and after giving up I bought this one. I have a story like this in many different cities as I’ve traveled to conferences. First is was associated with ritonavir but now it doesn’t have to be refrigerated. And now its related to interferon and insulin. 

Following are some summaries of the first day’s proceedings and discussion of new preliminary data being presented here on Roche's Pegysis (pegylated interferon).


Ray Koff, University of Massachusetts, Screening for Liver Disease
Screening for liver disease has not been generally accepted by doctors and health care organizations. The purpose of screening for liver disease is to detect liver disease in either selected or unselected populations of asymptomatic individuals, or to detect liver disease complications in selected populations with known liver disease, in order to intervene. 

(JML- At risk populations are good candidates for screening. People with HIV should be tested.) An example of the former is HBsAG screening of pregnant women in order to immunize the newborn infants of such mothers with HBIG and hepatitis B vaccine to prevent maternal-neonatal infection. This recommendation has been endorsed by the US Preventive Services Task Force and given a grade of A indicating that there is good evidence to support the recommendation. 

An example of the use of screening in populations with established liver disease, a selected population, is screening for hepatocellular carcinoma in patients known to have cirrhosis. Screening for liver disease in average-risk adults as part of a periodic health exam, with the exception of HbsAg screening of pregnant women, has not received the blessing of the US Preventive Services Task Force.

With regard to routine screening of the general population for HBV infection, the Task Force recommends against such screening. The Task Force felt that there was insufficient evidence to recommend for or against routinely screening asymptomatic high-risk individuals for HBV to determine eligibility for vaccination unless the prevalence of HBV markers was likely to succeed 20%, a point at which a recommendation for screening could be made on the basis of cost-effectiveness analysis.

Koff discussed the hazards of screening for the individual. These include direct complications of the screening test, which may involve an invasive procedure (e.g. venipuncture), medical-legal issues such as possible loss of insurance coverage and loss of employment, social and familial disruption, and increased health care costs. Psychological issues include changes in self-perception, family interactions, and in risk-taking behaviors resulting from disease detection. Additionally, the implications of the possibility of false-positives and false-negatives are to be considered.


HCV Dynamics, Alan Perelson, Los Alamos National Lab
Perelson talked about a study he initiated wherein patients received 5, 10, or 15 MIU of interferon alone for 14 days and thereafter 5 MIU per day. In a first study a single injection of interferon was given at a dose of either 3 MIU, 5 MIU, or 10 MIU. This lead to a decline in serum HCV RNA at 24 hours but by 48 hrs the viral load began increasing for all 3 doses. The decline in viral load seen at 24 hrs was greater for the 5 MIU and 10 MIU doses than for the standard 3 MIU dose.

Because of the observed increase in viral load at day 2, a second study was designed in which high dose interferon was given daily for 14 days to three groups of patients. The groups received either 5, 10 or 15 MIU daily and the serum levels of HCV RNA were monitored frequently. At the end of the 14 days all patients were switched to a regimen of 5 MIU daily. After the initiation of therapy there was a delay of 7 to 10 hrs before any reduction in HCV RNA was seen. After the delay, the serum HCV RNA levels fell. At the higher doses, 10 and 15 MIU, the fall was dramatic and on average encompassed a decline of 1.6 logs. In some patients the decline was even greater. At 24 hrs the declines of the 10 and 15 MIU doses were comparable but bothwere significantly greater than the 5 MIU dose. By comparison, in chronic HIV-1 infected patients, declines of 1.5 to 2 logs are at best only seen after 2 weeks of potent antiretroviral therapy. Here a single dose of IFN can give the same decline in HCV RNA in 1-2 days. 

When the same patients were followed for the full 14 days of high dose therapy, a two-phase decline in serum HCV RNA became apparent. Perelson estimates that % MIU daily causes about an 80% block, while doses of 10 MIU or 15 MIU daily cause about a 95% block. Following the acute phase of serum HCV RNA decline there is a slower second phase; patients with the highest values of decline were HCV RNA negative at 12 weeks, while those with low values of decline were PCR positive. This suggests the measurements of the second-phase slope may be predictive of the response to IFN therapy. This prediction still needs to be verified by larger prospective studies. 

During the Q&A some panelists said it is too soon to say that such early viral load declines will predict long term sustained responses. And research is mixed on whether high dosing will result in longer term sustained response. It appears to me that HCV disease and its kinetics may be very different than HIV. Certainly, we are at much earlier stages of understanding and research in HCV than we are in HIV. We are in experimental stages of understanding when to begin therapy and with what dosing. Is it worth tolerating the side effects of high dosing (5 –10 MIU) or is it preferable to use more tolerable lower dosing (3 MIU)? Is daily dosing preferable to 3 times per week. My impression is that daily dosing is preferable. But there appear to be a number of questions about whether higher dosing will be more effective in the long run. Possibly a lead-in induction dosing period may be helpful followed by a reduced dosing. It appears so far that study results are mixed on these questIons.

In the Bayer Diagnostics symposium they talked about several HCV viral load tests they are developing. They’re developing one of which measures down to 50 copies/ml. It appears to me that all current HCV viral load tests are very variable at this point and that further refinement will be necessary for FDA approval.

Combination Therapy with PEG Interferon and Ribavarin in chronic HCV (phase II open-label study). Here is an advance peak at results in abstract book. If they are different at tomorrow's poster I'll inform you. At week 24, 18/20 had normalization of serum ALT and 16/19 had HCV undetectable (below 100 copies/ml) or unquantifiable (below 1000 copies/ml).