1 department of health and human services




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18 DR. HOLLINGER: Yes, Dr. Chamberland?

19 DR. CHAMBERLAND: Perhaps the presentations later

20 on will help address this point but I wanted a

21 clarification. Can we assume that the manufacturer who has

22 approached FDA with his application for HAV NAT testing is

23 really only providing the agency with data that addresses

24 the sensitivity, the specificity, the accuracy of the test

25 itself and has not provided or is intending to provide the


69 1 agency with data about the donor notification? We are all

2 in the middle of this giant IND trial, if you will, for HIV,

3 HCV NAT testing that includes not just how good the test

4 works but this whole notification process etc. So, are

5 there any data that are going to come now or at a later

6 date?

7 MS. KOCH: I think some of the future speakers are

8 going to address that a little more.

9 DR. CHAMBERLAND: Okay, because to me that would

10 be a big consideration as to how frequently donor

11 notification might happen and how timely that might occur

12 because all of that will impact on whether or not the

13 potential preventive measures for secondary transmission

14 could be practical or effective.

15 DR. BISWAS: Mary, what we got was basically like

16 the B19 NAT.

17 DR. CHAMBERLAND: Okay.

18 DR. HOLLINGER: And the agency will probably have

19 a standard for HAV for sensitivity that can be utilized in

20 these tests, because that will be critical.

21 DR. BISWAS: That is certainly something that we

22 will do. You know, we haven't got there yet but that is

23 something we will do.

24 DR. HOLLINGER: Just in case this goes into the

25 record down the line, on your slide 11 for the de novo


70 1 classification you had testing of plasma pools for presence

2 of HAV DNA and it should be HAV RNA.

3 MS. KOCH: Oh, I am sorry.

4 DR. HOLLINGER: If there are no further questions,

5 we will go on to the next speaker, and this is a review of

6 history of hepatitis A transmitted by transfusion. Dr.

7 Farshid?

8 Review of History of Hepatitis A Transmitted by Transfusion

9 DR. FARSHID: Thank you.

10 [Slide]

11 Hepatitis A virus, as we have heard already, is a

12 non-enveloped RNA virus, and it is almost always transmitted

13 by the fecal-oral route through person to person contact or

14 ingestion of contaminated food or water. However, rare

15 cases of transmission by blood and blood products have been

16 reported, as we will see in the next few slides.

17 Hepatitis A virus causes only acute infections. In certain

18 rare cases there is some prolonged and relapsing infection

19 which Dr. Feinstone will probably discuss those with you.

20 [Slide]

21 As mentioned earlier, the blood-borne transmission

22 of hepatitis A is very rare. This is based on the absence

23 of documented cases of hepatitis A in studies of post-

24 transfusion hepatitis. These are studies which were

25 performed in the '70s and '80s to assess post-transfusion


71 1 hepatitis due to non-A/non-B. In those studies, which were

2 large studies, no cases of hepatitis A were detected. Also,

3 there were studies in the '70s and '80s which showed a lack

4 of any differences between serological prevalence in rate of

5 hepatitis A in a transfused and non-transfused population.

6 [Slide]

7 What are the causes of rare transmission by blood

8 transfusion? There are a number of factors involved. There

9 is a short viremic period and absence of n HAV carrier state

10 or persistent infection, and also low concentration of HAV

11 in the blood and overall low incidence of HAV infection.

12 Also, we need to consider that almost 50 percent of the

13 population is already immune to HAV.

14 [Slide]

15 As mentioned earlier, there are cases in the

16 literature which indicate transmission by blood by either

17 packed cells of fresh-frozen plasma. This is not all that

18 are reported. I think there are probably three excellent

19 reports which I did not include here. But overall as we

20 see, the number is not large. The striking feature that we

21 see here is that large number of the newborn or neonates and

22 also the large number of the secondary infections.

23 The report in 1983 by Dr. Hollinger and his

24 colleagues is particularly important because it represents

25 the first clear demonstration that hepatitis A virus from a


72 1 donor sample can produce post-transfusion hepatitis A. This

2 is the case, right here, where a 10-year old child developed

3 acute hepatitis A, as indicated by jaundice and also by IgM

4 anti-HIV and the infection was traced back to a donor who

5 donated and also developed acute hepatitis 7 days after

6 donation, and died of hepatic failure. HIV antigen was

7 detected in the plasma from the original samples and also in

8 the liver of the donor. There were also chimp studies where

9 the chimpanzees were transfused with the plasma from the

10 original sample and they developed hepatitis A and

11 seroconverted 3 weeks after infusion.

12 The other interesting case which underscored the

13 importance of secondary infections, by Noble, were packed

14 cells were given to a number of neonates and 11 of them

15 developed acute hepatitis A. Also, the studies showed that

16 the first case that actually came to attention was when one

17 of the nurses developed acute hepatitis A. Further

18 investigation showed that 16 percent of nursery personnel

19 had hepatitis A as the result of this one particular case,

20 and 4 percent of the physicians who were in contact with the

21 patient also developed hepatitis A, and 25 percent of the

22 family members. That 25 percent rate of secondary infection

23 among family members has also been reported by others.

24 [Slide]

25 This table shows transmission into clotting


73 1 factor. There has not been any report of transmission by

2 clotting factor until the late '80s where outbreaks were

3 reported from Europe, in Italy, Germany and Ireland, and

4 other places like South Africa and later, in 1994, in the

5 U.S.A. and also the latest one from Germany.

6 Because time is short, I will not go through these

7 one by one, but overall the common feature among all of them

8 is that all the patients received highly purified solvent-

9 detergent treated clotting factor concentrate. The earlier

10 reports from Italy and Germany and Ireland relied primarily

11 on epidemiological evidence to indicate transmission. All

12 the product was manufactured by one single manufacturer in

13 the corresponding countries. There were no other risk

14 factors for hepatitis A among patients, and the patients

15 were geographically dispersed. There was also a correlation

16 between the quantity of Factor VIII concentrate received by

17 the patient and the HAV infections. There was very little

18 sequence analysis in the early cases, but in the most recent

19 ones, the ones from South Africa, the U.S.A. and Germany, in

20 addition to epidemiological studies that I mentioned there

21 were also some sequence analyses. Viral sequence analysis

22 was done from samples from the patient, from the product and

23 also from the plasma source, and the sequence identity was

24 determined in these three samples.

25 [Slide]


74 1 Basically, I just want to say that the sequence

2 analysis was done in different regions of the HAV genome

3 including the VP1 and VP2 and, in addition, in the VP1 and

4 2A region which are variable regions of the genome. It is

5 important that the sequencing be done in different parts.

6 In all those studies, it was shown that there were

7 identical strains in the patient product and the source

8 plasma. Also, there were some laboratory studies, done by

9 Stanley Lemon, which basically looked for the fate of HAV

10 during the manufacturing process. This is the process which

11 uses ion chromatography and solvent detergent treatment. He

12 has shown that neutralization reduced the viral load by two

13 logs and as a result of the cryoprecipitation almost 99

14 percent of the virus will remain in the supernate and only

15 one percent will go to the cryoprecipitate. The supernate

16 will be used to develop Factor IX concentrate and the

17 cryoprecipitate will be for Factor VIII. Solvent-detergent

18 treatment basically showed no reduction. However, it is

19 important to mention that he also found that solvent-

20 detergent did not interfere with the neutralization, as has

21 been suggested by some investigators. In fact, it may even

22 enhance the neutralization to a certain degree, probably by

23 stripping the virus of some of the host lipids. Subsequent

24 steps in the manufacturing process had little or no effect

25 on overall viral reduction. The conclusion from his study


75 1 is that the margin of safety provided by this manufacturing

2 process is not sufficient to prevent HAV infection if one or

3 two HAV-contaminated units get into the plasma pool.

4 [Slide]

5 Then the question is what is the cause of these

6 outbreaks? Overall, it can be summarized as simultaneous

7 changes in the purification process, change in viral

8 inactivation techniques, and change in epidemiology of HAV.

9 The purification process to provide low purity and

10 intermediate purity product contain sufficient amounts of

11 HAV to confer immunity to the recipient. However, in the

12 highly purified product by high purification you actually

13 remove the antibody so there is no more passive protection.

14 As we saw in the viral inactivation technology, the solvent-

15 detergent had no effect on viral reduction. As far as

16 epidemiology, there seems to be a shift toward the older

17 population and the donor age group also. Overall, the

18 prevalence of HAV is declining which indicates that there is

19 less antibody in the plasma pool. Since the donor age is

20 more vulnerable, it is more likely that they will get

21 infected, and if they are a donor they can pass on the

22 infection.

23 [Slide]

24 What will be the implication? This also will most

25 likely be covered by Dr. Feinstone, but just to mention that


76 1 HAV is a mild infection, however, in those who already have

2 preexisting chronic liver disease it may exacerbate the

3 problem and in certain cases cause death. It has been

4 reported that 95 percent of U.S. hemophilia patients between

5 the age of 20 to 40 are already infected with HCV, and 8

6 percent are chronically infected with hepatitis B.

7 [Slide]

8 Then the question is what should be done about it.

9 There are a number of suggestions. There is vaccination

10 against HAV in anti-HAV negative hemophilia. The experts

11 agree that using vaccination is cheap, inexpensive and very

12 effective in preventing infection. Also, terminal heat

13 treatment for Factor VIII has been suggested. I should

14 mention that although HAV is relatively heat stable, heating

15 may reduce effectiveness of Factor VIII and may cause

16 denaturation and also produce inhibitor perhaps as a result

17 of formation of new antigen. So, it is more complicated

18 than simple heating. Also, the use of recombinant Factor

19 VIII without use of plasma derived product has been

20 suggested. I should mention that in some of the recombinant

21 factor they use albumin as a stabilizer and that

22 theoretically will produce risk for HAV. Therefore, it is

23 suggested that vaccination should be done in this group of

24 recipients as well.

25 [Slide]


77 1 Also, screening of plasma pools for HAV has been

2 suggested, and that is what we are discussing here. I tried

3 to come out with a rough and crude estimate, and 0.67 is the

4 fraction of the population that is not infected with HAV,

5 and 9 is the prevalence of HAV. This is the notification

6 rate for HAV by CDC, 9 per 100,000 per year. If we estimate

7 the average window period to be 3 weeks in a year, the rate

8 will be 0.35 per year. So, it will be 3-4 units per million

9 per year. I must mention that the numbers that are there

10 may change, especially the one that says 9 per 100,000 per

11 year. It is fluctuating, and I think I got this from 1994

12 estimates by CDC.

13 Finally, development and implementation of viral

14 inactivation are steps that are effective in removal of non-

15 enveloped viruses, and there are a number of methods which

16 are currently being investigated. Thank you.

17 DR. HOLLINGER: Thank you, Dr. Farshid. Any

18 questions? Yes, please, Dr. Koerper?
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