1 department of health and human services




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19 DR. KOERPER: I would just like to comment on your

20 slide about improving product safety for HAV for hemophilia

21 patients. First of all, the Medical and Scientific Advisory

22 Committee of the National Hemophilia Foundation has strongly

23 recommended that all hemophilia patients be vaccinated for

24 hepatitis A, and that is currently being implemented and the

25 effectiveness of the vaccine is being tested in a nationwide


78 1 study.

2 Secondly, while in the early '80s, when heat

3 treating Factor VIII and IX was first proposed, there were

4 concerns about the possibility that Factor VIII and Factor

5 IX would lose some of their potency and that neoantigens

6 would be exposed, resulting in increased inhibitor

7 formation. Those concerns have been negated. In other

8 words, the Factor VIII and IX are still completely active

9 and we are not seeing an increase in inhibitor formation due

10 to the heat treatment process. So, that was universally

11 recognized as a first approach toward eliminating viruses in

12 factor concentrates. It has been supplemented by such

13 things as solvent-detergent and column chromatography, but

14 heat treating is an important adjunct to eliminate some of

15 the viruses that are not eliminated by solvent-detergent,

16 and most manufacturers include that in their processing of

17 product that does come from plasma.

18 Thirdly, with regards to the recombinant factor

19 products, while most of the Factor VIII products do contain

20 albumin, to my knowledge, there has been no transmission of

21 hepatitis A from albumin --

22 DR. FARSHID: Yes, I mentioned that actually there

23 has not been any report of transmission of hepatitis A by

24 any of the fractionated product except for Factor VIII and

25 Factor IX, which was from the U.S.


79 1 DR. KOERPER: Right, by not from albumin --

2 DR. FARSHID: Not from albumin.

3 DR. KOERPER: So, the feeling is that the use of

4 albumin as an excipient in Factor VIII is probably okay,

5 although the manufacturers are moving away from that. So, I

6 feel that we have taken many steps to help eliminate this

7 problem in our hemophilia patients.

8 DR. HOLLINGER: Yes, Dr. Chamberland?

9 DR. CHAMBERLAND: Could you please review one more

10 time -- I didn't quite get it all -- your estimate of the

11 number of donations per year that might be captured in that

12 formula? You might want to put it back up.

13 [Slide]

14 DR. FARSHID: The 67 percent of the population

15 basically are not positive for anti-HAV. So, these are all

16 anti-HAV negative. They have never been exposed to

17 hepatitis A. This is the notification rate as determined by

18 the CDC per 100,000 per year. I think that was given from

19 1994 or '92. Maybe Dr. Feinstone will clear that estimate

20 up. It is important to determine that not all cases of HAV

21 are reported to CDC, and they estimate that probably the

22 actual number will be 4-5 times what we see here. The

23 average incubation period for hepatitis A is estimated to be

24 3 weeks. As I mentioned, this is a very crude estimation

25 and hopefully the other speakers will give us a more


80 1 accurate estimate, but I put it here basically to stimulate

2 more discussion, and that what we are dealing with is a very

3 rare event.

4 DR. HOLLINGER: Yes, Mr. Rice?

5 MR. RICE: I just have a question. I know that

6 HAV vaccinations have been recommended for persons with

7 hemophilia, but I was wondering if there was any difference

8 in that recommendation for persons -- and this would be for

9 Marion probably -- who have HIV chronic infection and

10 exacerbated HAV status as to whether or not they are also

11 recommended also to get the HAV vaccination basically

12 because this risk of the lower purity products from

13 recombinant bearing some risk of transmitting HAV is

14 becoming to be more of a possibility in recent guidelines on

15 reimbursement from DOJ. It has actually forced some people

16 on Medicaid to have to now not take recombinant product and

17 have to go to some lower-level purity product which

18 conceivably, if that person has HIV infection and is not

19 vaccinated against HAV, that puts that person at risk. That

20 is the real world coming in, basically now forcing people

21 back from the highest technology for other considerations.

22 DR. FARSHID: If I may defer that question to Dr.

23 Steve Feinstone, he will talk about the pathology of the

24 virus and he is more qualified to answer that question.

25 DR. HOLLINGER: Yes, Kenrad?


81 1 DR. NELSON: I think the 9 per 100,000 estimate

2 has to be taken with a huge grain of salt. You don't get 33

3 percent prevalence of antibody with 9 per 100,000 attack

4 rate. It is much higher than that because most infections

5 are asymptomatic, and asymptomatic infections may easily

6 transmit.

7 DR. FARSHID: That is true.

8 DR. NELSON: I realize it was an estimate --

9 DR. FARSHID: Actually, as I mentioned, the number

10 is probably five times what we saw here, but the CDC

11 estimate is that the rate of infection is between 80,000 to

12 120,000 per year for HAV infection, and that will not come

13 out to 9 per 100,000; it would be much higher. But, I

14 thought I would put a number where I have some documentation

15 for that and, as I mentioned, it is much higher. But even

16 if we say five times what is there, still the rate would be

17 very low.

18 DR. HOLLINGER: Yes, Dr. Mitchell?

19 DR. MITCHELL: I wasn't clear about the relative

20 risk of HAV between blood components -- whole blood versus

21 fresh-frozen plasma versus Factor VIII and Factor IX.

22 DR. FARSHID: Certainly, there is no data to show

23 what is the rate. I mean, the risk is so small and probably

24 approaching zero. If you look at transmission by blood from

25 1981 until today, I think the total report is probably 13 or


82 1 14 cases that have been reported. In case of the factor

2 concentrates, from late 1980 until today there were about

3 116 reported transmissions, with some of them maybe even

4 questionable by factor. So, the incidence is very small,

5 extremely small.

6 DR. MITCHELL: I am still not clear. Are you

7 saying that it is higher in the factor concentrates than in

8 other products?

9 DR. FARSHID: Your question is, is it higher in

10 Factor VIII compared to other fractions in a product? There

11 is no report of transmission -- is that the question?

12 DR. MITCHELL: No, that is not the question. The

13 question is compared to whole blood does Factor VIII, Factor

14 IX, those types of components, do they have a higher rate of

15 transmission of HAV?

16 DR. FARSHID: Actually, I don't know based on what

17 I see and the number of outbreaks, most likely there would

18 be more in Factor VIII concentrate because you start from

19 the pooled source. If you compare the number of years and

20 the number of infections, you have a much higher level of

21 infection through clotting factor than you have through

22 blood transfusion. Through blood transfusion mostly occurs

23 in neonates, and there have not been that many.

24 DR. HOLLINGER: Thank you. Our next speaker is

25 Dr. Stephen Feinstone, who is going to talk on the


83 1 epidemiology, clinical implications, prophylaxis of

2 hepatitis A virus. You are going to do that in a short

3 time. How can you do that, Steve?

4 DR. FEINSTONE: Well, actually I wasn't planning

5 on taking a short time!

6 DR. HOLLINGER: Oh, good! I don't think you

7 should.

8 [Laughter]

9 Hepatitis A Virus:

10 Epidemiology/Clinical/Implications/Prophylaxis

11 DR. FEINSTONE: Actually, there is almost no

12 reason for me to be doing this with Dr. Hollinger and Dr.

13 Koff here who are world experts in this problem, but I will

14 try to just go through this very quickly because there is a

15 lot to cover.

16 [Slide]

17 So, as you see, hepatitis A is one of the five

18 well-recognized hepatitis viruses and it is classified as a

19 picorna virus, which are a group of viruses that have

20 single-stranded RNA genomes.

21 [Slide]

22 This is a list of picorna viruses. It includes

23 the enteroviruses, the rhinoviruses, cardeo viruses and

24 apthoviruses of animals. Hepatitis A is not classified as

25 an enterovirus; due to some of its unique features, it is in


84 1 its own genus.

2 [Slide]

3 This is the virus itself. It has a small non-

4 enveloped di-icosa hedral structure of about 17-28 nm in

5 diameter. Morphologically, it is virtually

6 indistinguishable from any of the other viruses that you saw

7 in that list of picorna viruses. But the important aspect

8 from this is that it is non-enveloped and, therefore, it is

9 not sensitive to lipid solvents.

10 [Slide]

11 I just want to make one point from this slide on

12 acid stability and heat stability. This virus is relatively

13 heat stable, even relative to many of the other picorna

14 viruses, and heating the virus to 60 degrees for one hour

15 would not be expected to eliminate total infectivity. So,

16 the processes that have been used to inactivate, say, HIV,

17 HCV and HBV have not been validated to inactivate hepatitis

18 A virus completely.

19 [Slide]

20 This is hepatitis A in cell culture. The point I

21 want to make here is that the virus grows in the cytoplasm.

22 I don't know if you can see from this immunofluorescence

23 study but the fluorescence appears as cytoplasmic granules.

24 [Slide]

25 We think what these granules represent are small


85 1 vesicles inside the cell that contain the virus, here

2 stained by peroxidase in a study done by Yoko Shimizo. We

3 never actually see the virus free in the cytoplasm of the

4 cell. We only see it inside these vesicles.

5 [Slide]

6 I must tell you this is only my conjecture, there

7 is no real hard data for this but the virus replicates by

8 the same general mechanism of the other picorna viruses. It

9 enters the cell. The RNA genome functions both as a message

10 molecule and a template for new RNA virus production, and it

11 goes through a series of steps and virus maturation but

12 inside these vesicles. I think what may be happening is

13 that these vesicles themselves are extruded from the cell

14 and typically into the bile where the action of the bile

15 salt and detergents break down the vesicle and release free

16 virus particles.

17 [Slide]

18 However, in this picture, by Lucy Asher, in the

19 serum of a primate with hepatitis A we see virus contained

20 still within a vesicle. So, this is free virus in the

21 serum.

22 [Slide]

23 This picture, by Yoko Shimizo, is of virus

24 contained within a vesicle in a stool sample. So, the virus

25 may be contained, at least at times, within these vesicle


86 1 structures.

2 [Slide]

3 Now, the epidemiology of this of virus -- and

4 first I want to thank Miriam Alter, from the CDC, for

5 sending me some updates on these epidemiology slides -- this

6 virus has a worldwide distribution but parts of the world,

7 obviously, have much higher rates of infection than other

8 parts. Generally tropical countries but also some northern

9 countries, such as Greenland, have very high rates of

10 hepatitis A prevalence. Then there are intermediate

11 countries such as Asia, most of the former Soviet Union and

12 southern Europe, and then the low prevalence areas such as

13 the United States, western Europe and Australia.

14 [Slide]

15 So, what has been seen worldwide are different

16 disease rates but also different types of disease. Where

17 the endemicity is very high, the infections, as most enteric

18 viruses, are in early childhood. Transmission is primarily

19 person to person and we rarely see outbreaks amongst the

20 indigenous populations in those situations. Then, if you go

21 to areas where there are moderate rates of infection, the

22 age of typical infection usually increases and we see

23 actually more disease because the disease in young children

24 is usually in a parent. Then, you go to low and very low

25 areas of the world and there, again, the age of infection


87 1 usually increases to young adults. In the very low rates

2 there is virtually no transmission within those countries

3 and most of the infections we see are imported or in

4 travelers. The disease burden in these countries is not

5 very great because of the low rates.
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