|
Hepatitis C Associated with Immunoglobulin
Quote: "Since the 1940s, immune globulin products licensed in the United States have
been
safely administered; these products previously have not been known to be
associated
with the transmission of bloodborne agents, including HIV. Cases of non-A, non-B
hepatitis (of which HCV is the primary etiologic agent) have been previously
associated
with an unlicensed IGIV product used in a clinical trial in the United States
and
with IGIV products manufactured and distributed abroad; however, reasons for
these
episodes of transmission ( 2 ) and the episodes described in this report have
not been
determined. Since mid-May 1994, the approved manufacturing process for both Gammagard
® and Polygam® includes a solvent-detergent treatment designed to inactivate
contaminating viruses. Products manufactured with this treatment should not pose
a
risk for HCV transmission to recipients."
Outbreak of Hepatitis C Associated with Intravenous
Immunoglobulin Administration —
United States, October 1993–June 1994
On February 21, 1994, the Food and Drug Administration (FDA) was notified of
14 possible cases from three different countries of acute hepatitis C among
persons
who had received Gammagard®*, an intravenous immunoglobulin (IGIV) product
manufactured by Baxter Healthcare Corporation (Glendale, California). The
company
removed Gammagard® from the worldwide market on February 23, 1994. The American
Red Cross removed Polygam® (IGIV manufactured by Baxter Healthcare from
American Red Cross plasma) from the market on the same date. This report
presents
preliminary findings of an evaluation of transmission of hepatitis C virus (HCV)
infection
from these products and guidelines for monitoring patients who may have
received them.†
As of July 19, 1994, CDC had received 112 reports from 24 states and Puerto Rico
of
possible cases of acute HCV infection in recipients of IGIV; 111 were in persons
who
received Gammagard®, and one was in a person who received Polygam®. Medical
and epidemiologic information and serum samples for HCV serologic testing are
being
collected from each person. The dates of onset (defined by occurrence of
symptoms or first abnormal alanine aminotransferase [ALT] value) for suspected
cases were from October 1993 through June 1994 (Figure 1). Of 74 reported
persons
with possible HCV infection for whom risk factor data (e.g., blood transfusion
or
injecting-drug use) were available, 68 (92%) had receipt of IGIV as the only
risk factor
for infection.
The median age of persons with reported cases was 37 years (range: 2–84 years);
52% were female, and 63% received IGIV for treatment of a primary immuno-deficiency disorder (e.g., hypogammaglobulinemia). Of 62 persons tested at CDC
for
serologic markers of viral hepatitis, 42 (68%) were positive for antibody to HCV
(anti-HCV), and none were positive for serologic markers of acute hepatitis A or
hepatitis B
virus infection. Anti-HCV was detected in 20 (53%) of 38 patients with a
diagnosis of
primary immunodeficiency and in 21 (95%) of 22 patients with other diagnoses. In
blinded testing of serum specimens from 36 persons with suspected cases, none
were
positive for antibody to human immunodeficiency virus (HIV)-1 or HIV-2.
To assess the risk for HCV infection among persons who received IGIV and to
identify
risk factors for infection, a cohort study among persons exposed to different
IGIV
products at one hospital and a case-control study of persons from throughout the
United States have been initiated. Lot-specific denominator data needed to
complete
these analyses are not yet available from the manufacturer. Preliminary analysis
of the
cohort study found 16 (7%) cases of HCV infection among 245 recipients of
Gammagard
® (three persons with HCV infection had also received other IGIV products within
6 months of onset). However, no cases of HCV infection were found among 55
recipients
who had received only other IGIV products (p<0.05, two-tailed Fisher exact
test).
Additional laboratory testing for HCV will be performed on serum samples from
infected
persons and on samples of implicated and nonimplicated lots of IGIV. Other
cohort studies will examine any association between HCV infection and receipt of
other IGIV products or intramuscular immune globulin (IGIM). In one of these
studies
FIGURE
1. Possible cases* of hepatitis C virus infection reported among persons
receiving GammagardÒ or PolygamÒ — United States, October 1993–June 1994
506 MMWR July 22, 1994
*Of 112 reported possible cases, the date of illness onset or
date of first abnormal alanine
aminotransferase level was available for 81 cases.
involving persons who received IGIM in 1993, no anti-HCV seroconversions were
found among 513 persons tested at least 6 months after IGIM administration (95%
confidence interval=0–0.7%).
Reported by: L Schneider, R Geha, Harvard Medical School, Boston. Walter Reed
Army Institute
of Research, Washington, DC. Div of Transfusion Transmitted Diseases and Div of
Hematology,
Office of Blood Research and Review, Center for Biologics Evaluation and
Research, Food and
Drug Administration. Div of Digestive Diseases and Nutrition, National Institute
of Diabetes and
Digestive and Kidney Diseases; Dept of Transfusion Medicine, Warren G. Magnuson
Clinical
Center, National Heart, Lung, and Blood Institute, National Institutes of
Health. Hepatitis Br and
Epidemiology Activity, Div of Viral and Rickettsial Diseases, National Center
for Infectious
Diseases, CDC.
Editorial Note: The temporal association of acute hepatitis C with Gammagard®
administration
and the absence of other risk factors among these patients indicate that
HCV was most likely transmitted by administration of Gammagard®. The report of
one
possible case in a person who received only Polygam® and had no other risk
factors
suggests that Polygam® also may be associated with transmission of HCV.
Preliminary
analysis of data from epidemiologic studies suggests that HCV transmission is
not related to the administration of other IGIV products or IGIM, and there is
no need
for change in the use of these products.
Since the 1940s, immune globulin products licensed in the United States have
been
safely administered; these products previously have not been known to be
associated
with the transmission of bloodborne agents, including HIV. Cases of non-A, non-B
hepatitis (of which HCV is the primary etiologic agent) have been previously
associated
with an unlicensed IGIV product used in a clinical trial in the United States
and
with IGIV products manufactured and distributed abroad; however, reasons for
these
episodes of transmission ( 2 ) and the episodes described in this report have
not been
determined. Since mid-May 1994, the approved manufacturing process for both
Gammagard
® and Polygam® includes a solvent-detergent treatment designed to inactivate
contaminating viruses. Products manufactured with this treatment should not pose
a
risk for HCV transmission to recipients.
Chronic hepatitis develops in more than 60% of persons infected with HCV ( 3 ).
All
patients who received Gammagard® or Polygam® since April 1, 1993 (6 months
before
the first reported case), should be screened for evidence of HCV infection and
the
results interpreted according to the algorithm established by the Public Health
Service
(PHS) (Table 1). Initial screening of these patients should include a test for
ALT activity
and an FDA-licensed enzyme immunoassay (EIA) for anti-HCV. All specimens
repeatedly
(two or more times) reactive for anti-HCV should be tested using an FDA-licensed
supplemental anti-HCV assay to reduce the likelihood of false-positive EIA
results.
Because some patients will have a prolonged interval between exposure and
seroconversion
to anti-HCV, patients who are anti-HCV–negative but have abnormal ALT
levels should be retested for anti-HCV 3–6 months later. In most patients with
normal
immune status, seroconversion occurs within 6 months after infection ( 3,4 ).
However,
approximately 10% of HCV-infected patients with normal immune status will be
persistently
negative for anti-HCV, even after prolonged follow-up ( 3 ). Persons with
immunodeficiency disorders may be less likely to seroconvert or may have longer
intervals between infection and seroconversion than persons with normal immune
function.

For anti-HCV–negative persons with elevated ALT levels, the diagnosis of
hepatitis
C is possible with the use of polymerase chain reaction (PCR) for the detection
of
HCV RNA. However, PCR assays, which are difficult and expensive to perform,
should
be done only by experienced laboratories using specimens that have been properly
collected, stored, and handled. These assays are not licensed by FDA.
Patients aged ³18 years with chronic hepatitis C (abnormal ALT levels for more
than
6 months) should be evaluated for possible therapy with alpha interferon by a
physician
experienced in its use ( 5 ). Patients should be informed that the proportion of
adults with chronic hepatitis C who sustain a long-term response to alpha
interferon
is low (approximately 20%). Although FDA has not licensed alpha interferon for
patients
aged <18 years, they can be considered for therapy if entered into an approved
study protocol.
All patients with hepatitis C should be considered potentially infectious.
However,
because of limited data on the risk of household, sexual, and perinatal
transmission
and because testing cannot determine infectivity, PHS does not recommend
substantial
changes in behavior based on knowledge of infection status ( 1 ). PHS recommends
that household articles such as toothbrushes and razors that could become
contaminated with blood should not be shared, and cuts or skin lesions should be
covered to prevent the spread of infectious secretions or blood ( 1 ). HCV
transmission
by sexual contact appears to occur, but this route of transmission is much less
efficient than that for other bloodborne sexually transmitted diseases ( 3 ).
Although
anti-HCV–positive persons should be informed of the potential for sexual
transmission,-

there are insufficient data to recommend changes in current sex practices for
persons with one steady sex partner. To prevent many sexually transmitted
diseases,
including hepatitis and HIV infection, persons with multiple partners should
follow
safer sexual practices, including reducing the number of sex partners and using
barriers
(e.g., latex condoms) to prevent contact with body fluids. No evidence supports
advising against pregnancy based on anti-HCV status or using any special
treatments
or precautions for pregnant women or their offspring.
References
1. CDC. Public Health Service inter-agency guidelines for screening donors of
blood, plasma,
organs, tissues, and semen for evidence of hepatitis B and hepatitis C. MMWR
1991;40(no.RR-4):6–17.
2. Lever AML, Webster ADB, Brown D, Thomas HC. Non-A, non-B hepatitis occurring
in agammaglobulinaemic
patients after intravenous immunoglobulin. Lancet 1984;2:1062–4.
3. Alter MJ. The detection, transmission, and outcome of hepatitis C virus
infection. Infectious
Agents and Disease 1993;2:155–66.
4. Vallari DS, Jett BW, Alter HJ, Mimms LT, Holzman R, Shih JW. Serological
markers of posttransfusion
hepatitis C viral infection. J Clin Microbiol 1992;30:552–6.
5. Hoofnagle JH. Therapy of acute and chronic viral hepatitis. Adv Intern Med
1994;39:241–75.
Vol. 43 / No. 28 MMWR 509
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http://www.dallasnews.com/sharedcontent/dallas/tsw/stories/102703dntexsoldierstory.1b17f.html
Soldier
contracts Sporadic Creutzfeldt-Jakob disease (the human form of Mad
Cow Disease)-was it From the fetal calf serum used in vaccines?
A quote from the article:
"In 2001, certain vaccine manufacturers admitted
that they were using
fetal calf serum and other materials from cattle raised in countries
at high risk for mad cow disease, in spite of years of warnings from
the Food and Drug Administration. The vaccines include those to
prevent polio, diphtheria, tetanus and anthrax."
***************************************
A soldier's tale: military misdiagnosis
He was a decorated Green Beret, but when his performance faltered,
the Army gave him the boot - not medical treatment for his deadly
disease
Dallas Morning News, Monday, October 27, 2003
By NANCY BARR CANSON / Special Contributor to The
Dallas Morning News
KARNACK, Texas - Staff Sgt. James Alford can't
talk. He doesn't recognize his wife. His head shakes, his hands
tremble.
He is agitated, restless, diapered and helpless,
requiring round-the-clock care from his family. Unable to coordinate
his fingers and hands, the former marathon runner can still walk,
with assistance, and his daily ritual is to unsteadily "walk the
floor," as his wife, Army Spec. Amber
Alford, describes it.
In April, the Green Beret and Bronze Star
recipient was sent home from Iraq by the Army. But it wasn't because
he badly needed medical care.
"They sent him home to be court-martialed," said
his mother, Gail Alford, a former Army nurse. "They wanted to strip
him of his Special Forces tab. They wanted him out of the Army."
Army officials say they did not realize the
24-year-old soldier's increasingly erratic behavior was an early
symptom of the difficult-to-diagnose Creutzfeldt-Jakob disease. CJD
is a fatal, degenerative brain disorder that attacks the human brain
in the same way that "mad cow" disease attacks cattle.
Staff Sgt. Alford was disciplined and demoted.
Although the Army has restored his rank and corrected what it admits
was a mistake, the Alfords -a family in which many members have
served in the armed forces - question how this could have happened.
"I don't blame the Army for this disease," said
his father, retired Army Command Sgt. Maj. John Alford, who was in
the service 34 years. "I blame them for how they treated my son.
They treated him like yesterday's garbage. They reduced his rank.
They called him an idiot, called him
stupid - this is a wounded soldier. It's no different than if he had
taken a bullet to the brain."
The family has asked for and received
acknowledgement that commanders in the 5th Special Forces Group
erred.
"It's a terrible thing that happened," said Maj.
Robert E. Gowan, public affairs officer for the Special Forces.
"Everyone is deeply sorry for Sergeant Alford and his family. I
think personal apologies, apologies that really mean something, will
happen in time."
During his first six years in the Army, Staff Sgt.
Alford was ranked an "excellent" soldier in every evaluation. He was
awarded two Army Commendation medals, five Army Achievement medals,
an Army Good Conduct Medal, numerous division ribbons and, in May
2002, the Bronze Star for
"peerless expertise" in Afghanistan.
Changing behavior
But four months later, changes in his behavior were
noted. He went from being lauded for his "exceptionally meritorious
service," "gallant conduct" and "incisive competence" to being
called an irresponsible failure. In September 2002, he was
disciplined for losing his assault vest and
other military items. He was AWOL for several days from his post in
Fort Campbell, Ky., and later demoted from staff sergeant to
sergeant.
"In retrospect, when he got back from Afghanistan,
there were signs," his mother said. "But we thought it was combat
stress. We didn't know what it was."
No one knew that the changes in Staff Sgt.
Alford's personality -forgetfulness and impaired judgment - were
early symptoms of CJD.
Staff Sgt. Alford's wife, who was working with
Army intelligence before her husband's illness, was training in
California during this period, and his parents saw him only briefly
at Christmas before he was deployed to Kuwait in January.
In Kuwait, as his condition worsened, his conduct
became more erratic. He received a written order to carry a note pad
"to write instructions down to ensure they are not forgotten." His
records show he was placed on probation, accused of "dereliction of
duty" and "larceny," of losing his
protective mask, stealing another soldier's mask, failing to report
for duty four times and lying to superiors.
His commander wrote on April 10 that he would
initiate action to revoke Staff Sgt. Alford's Special Forces
designation.
Critical comments
"Your conduct is inconsistent with the integrity
and professionalism required by a Special Forces soldier," wrote Lt.
Col. Christopher E. Conner of the 2nd Battalion, 5th Special Forces
Group Headquarters in Kuwait. "I do not believe you are suitable for
further Special Forces duty."
The Alfords were later told that Staff Sgt. Alford had been seen by
a doctor in Kuwait, who reportedly said nothing was wrong with him.
A psychiatrist in Kuwait reportedly said that he was "faking it."
"Jamie was a good soldier," said his mother, who
has left her job to care for her son. "When all this started
happening, anyone should have known he was sick."
The cause of Staff Sgt. Alford's disease,
diagnosed as "sporadic" CJD, is unknown.
CJD is a fatal degenerative brain disease in which
early symptoms of behavioral changes and memory loss lead to severe
mental impairment, dementia, loss of coordination, involuntary
jerking movements, loss of speech, loss of vision, coma and death.
Sporadic CJD is said to occur
spontaneously, while new variant CJD is caused by eating beef
contaminated with mad cow disease.
Sporadic CJD usually affects elderly patients, who
often die within six months of the onset of symptoms. The duration
of new variant CJD symptoms is often 18 months or more, and the
median age of death is 28.
Staff Sgt. Alford showed clinical symptoms of new
variant CJD, but his brain pathology was consistent with sporadic
CJD. The Alfords suspect he might have contracted the disease by
eating contaminated beef somewhere. During the past six years, he
was deployed to Iraq, Kuwait, Jordan, Oman, Uzbekistan, Afghanistan,
Thailand, France and England.
But they also see another possibility.
Staff Sgt. Alford told his doctors and his family
that he ate sheep's brain when serving in Oman two years ago.
"As a Green Beret, he lived among the people,"
said his wife, Spec. Alford. "He said the locals served him the head
of a sheep. It was considered an honor."
But while experts say cattle in Great Britain
contracted mad cow disease from eating scrapie-infected sheep parts,
they don't believe the disease is transmissible from sheep to people
- no human has been proved to have contracted "mad sheep disease."
It's also theoretically possible that the soldier
was given a contaminated vaccine.
In 2001, certain vaccine manufacturers admitted
that they were using fetal calf serum and other materials from
cattle raised in countries at high risk for mad cow disease, in
spite of years of warnings from the Food and Drug Administration.
The vaccines include those to prevent polio, diphtheria, tetanus and
anthrax.
"Jamie was given all those," his father said.
No one has been known to have contracted the
disease from a contaminated vaccine, and the FDA puts the odds of a
vaccine being tainted with mad cow disease at 1 in 40 million doses.
But the odds of Staff Sgt. Alford getting CJD
"spontaneously" are one in 100 million, according to the Centers for
Disease Control and Prevention.
His family realizes that the cause of his disease
is likely to remain a mystery.
Now, in the final months of his illness, Jamie is
fed intravenously and sedated to help him sleep. He stares blankly
and doesn't recognize his family. His wife, brother, parents and
grandparents help him in his walking ritual.
"We walk the floor," his wife said. "I hold onto
him so he won't fall down. We just walk across the living room and
back and forth. He'll do that for hours and hours. It's like he
can't be still."
The family knows it is only a matter of days or
weeks before he may go blind and lapse into a coma.
He is expected to die before Christmas.
Soldier sent home On April 22, Staff Sgt.
Alford was sent home to Big Rock, Tenn., near
his Army post at Fort Campbell. "His hands were
shaking," said his neighbor Justin Hawkins, 23. "He couldn't turn
his keys. He wasn't able to talk right. Something was really wrong
with him, but we didn't know what. He just seemed really shook up
and frightened."
The utilities were disconnected. Mr. Hawkins said
he unlocked the house and called the power company. His mother,
Beverly Hawkins, contacted the Alfords in Texas on April 26.
Neither they nor their daughter-in-law had had any
communication with Staff Sgt. Alford for months.
"I had a 24-year-old son I thought was fighting a
war in Iraq, and I find out from his neighbor that he's sick in
Tennessee," Mrs. Alford said.
The Alfords drove about 600 miles to see their son
that night.
"He had lost 30 pounds," his mother said. "He
looked like a skeleton. ...He couldn't drink from a glass. He
couldn't hold a pen or eat with a fork. He couldn't button a shirt,
couldn't drive, couldn't say his wife's name- how could anyone not
have known he was sick?"
The Alfords took their son to the hospital
emergency room, then to an Army medical clinic. From the Blanchfield
Army Hospital, he was sent to the veteran's hospital in Nashville,
where Dr. Steve J. Williams, clinical fellow in the Division of
Infectious Diseases at Vanderbilt University
Medical Center, eventually diagnosed CJD.
"I was very struck by Jamie's symptoms," Dr.
Williams said. "I had never seen a patient like Jamie before."
Dr. Williams said Jamie's superiors might not have
realized he was ill because Jamie tried so hard to hide his
symptoms.
"Jamie was very smart," Dr. Williams said. "He was
tremendously resourceful. He tried to hide his disease as long as he
could. He tried to compensate. When I asked him his birth date, he
glanced at his nametag. He wanted so much to get it right."
A brain biopsy was performed May 29, and the
sporadic CJD diagnosis was confirmed at the Armed Forces Institute
of Pathology two weeks later. The National Prion Disease
Surveillance Center also examined the brain tissue, to confirm it
was not a case of new variant CJD.
In May, Staff Sgt. Alford was still able to recall
and describe, in broken sentences, how he was treated by his
superiors in Kuwait.
"They called him stupid, called him lazy," his
father said. "It made him so angry and there was nothing he could
do."
Mr. Alford's other son, Billy, is in the National
Guard. Both of Jamie Alford's grandfathers and two great-uncles
fought in World War II. Mr. Alford says he still loves the military.
"But we need to remove cruel commanders," he said.
Doctors who treated Staff Sgt. Alford wrote
letters supporting the family's efforts to correct his record and
restore his rank.
The Alfords filed paperwork to challenge the
demotion. And they asked for apologies from 12 individuals in the
5th Special Forces Group who they say were "involved in the
persecution both verbally and physically" of their son.
U.S. Rep. Max Sandlin, D-Marshall, intervened on
the Alfords' behalf and received a reply from the Army on July 30.
'Deepest concerns'
"The 5th SFG(A) would like to express its deepest
concerns to Sergeant Alford and his family," wrote Lt. Col. Johan C.
Haraldsen from the Office of Special Inquiries at Fort Campbell.
"His disease was not known prior to or during his [Uniform Code of
Military Justice] proceedings. All
actions taken by the 5th SFG(A) involving Sergeant Alford were
appropriate based on the best information available at that time."
The Alfords received no reply to their application to correct Staff
Sgt.Alford's record, and so they sought help from the Army Review
Boards Agency. That request was denied in August in a letter stating
the Alfords had not exhausted other remedies.
Spec. Alford, said her husband's Green Beret
teammates had been helpful
and supportive during this ordeal.
"His team has been fantastic," she said. "They
call when they can and ask how he's doing. They helped me move all
our stuff out of our house in Tennessee.
"That was hard," she said. "That's when it hit me
that he'd never be
coming back."
Mr. Sandlin's office and The Dallas Morning News
made further inquiries, and the Alfords were informed Sept. 24 that
the Army had reinstated Staff Sgt. Alford's rank.
"The Army tries to take care of its people as best
it can," said Maj. Gowan of the Special Forces. "Getting things done
like this often takes a long time. They're trying to do the right
thing and act with compassion in light of Sergeant Alford's
misfortune."
Surrounded by his family, Staff Sgt. Alford was in
the hospital with a kidney infection when his father received the
news in a phone call from the major who is second in command of the
battalion.
"He's a good man," Mr. Alford said. "He asked
about Jamie. He assured us that everything had been corrected. ...
It took too long. But we're glad it's finally done."
Staff Sgt. Alford is unable to comprehend that
he's been vindicated.
But his father confessed that he told a white lie
to his son three months ago, when Jamie was still able to
understand.
"I told him they'd already corrected it," Mr.
Alford said. "I wanted him to know that. If I had waited 'til now it
would have been too late."
Nancy Barr Canson is a Marshall-based freelance
writer.
Same Doctor that did the study the CDC based
the safety of Immune Globulins
Immunoglobulin Transmits Hepatitis C. True or False? Intramuscular immunoglobulin
preparations are prepared according to the Cohn fractionation
process, which separates the fraction containing antibodies that
neutralize various infectious agents. The resulting preparations are
highly concentrated (16% in solution and containing 160 mg of
protein/mL).
Other manufacturing procedures do not ensure the same safety.
| United States Patent
Application |
20020028214
|
| Kind Code
|
A1 |
| PIAZZA, MARCELLO
|
March 7, 2002 |
METHOD OF PRODUCING SPECIFIC IMMUNOGLOBIN TO
BLOCK HCV INFECTION
Abstract
A drug which protects individuals against hepatitis C virus
(HCV) is made of HCV hyperimmune globulins, which guarantee a
substantial hyperimmunity against HCV thanks to a substantial
hyperconcentration of virus C neutralizing antibodies. This
hyperconcentration is obtained from blood of a large number of
antiHCV positive blood donors. The material used for the
preparation of the HCV hyperimmune globulins is made of up to
100 % of antiHCV positive blood units.
| Inventors: |
PIAZZA, MARCELLO;
(NAPOLI, IT)
|
| Correspondence
Name and Address: |
OBLON SPIVAK MCCLELLAND
MAIER & NEUSTADT
1755 JEFFERSON DAVIS HIGHWAY
FOURTH FLOOR
ARLINGTON
VA
22202
|
| Serial
No.: |
117292 |
| Series Code:
|
09 |
| Filed: |
August 26, 1998 |
| PCT Filed:
|
February 24, 1997 |
| PCT NO: |
PCT/IT97/00037 |
| U.S.
Current Class: |
424/228.1;
424/149.1; 424/161.1; 424/189.1 |
| U.S. Class
at Publication: |
424/228.1;
424/149.1; 424/161.1; 424/189.1 |
| Intern'l
Class: |
A61K 039/29;
A61K 039/42 |
Foreign Application Data
| Date |
Code |
Application Number |
| Feb 26, 1996 |
IT |
PN-96-A/000013 |
Claims
1. Drug containing immune globulin against hepatitis C virus,
adapted to protect individuals against the viral hepatitis C
infection and/or to cure individuals affected by said infection,
characterised by a substantial hyperconcentration of HCV
neutralizing antibodies, such as anti-gpE1/gpE2 and/or other
types of HCV neutralizing antibodies which can be present in
anti HCV positive blood units.
2. Drug according to claim 1, wherein said hyperconcentration is
obtained from blood units of a very large number of anti HCV
positive blood donors such that a wide range of heterogeneous
neutralizing antibodies to the different HCV strains is
obtained.
3. Drug according to claim 1 or 2, wherein said HCV hyperimmune
globulin is produced from up to 100% of anti HCV positive blood
units containing high titers of HCV neutralizing antibodies.
4. Method for producing a drug according to anyone of the
preceding claims, wherein blood units of a very large number of
anti HCV positive donors is used,
5. Method according to claim 4, wherein even only those anti HCV
positive blood units containing substantially very high titer of
HCV neutralizing antibodies are used.
6. Method according to claim 4 or 5, wherein the hyperimmune
serum globulin is prepared by an alcohol fractionation (Cohn
method) and/or other virucidal treatments and/or additional
methods for inactivating HCV and other infectious agents.
Description
[0001] The present invention relates to a drug adapted to
protect individuals against the viral hepatitis infection.
[0002] It was only in the early 40's, in the U.S.A., that
viruses (designated "hepatitis A and hepatitis B viruses")
capable of causing hepatitis were detected in samples of human
blood. Individuals invariably recover from viral hepatitis A,
whereas 5-10% of patients affected by viral hepatitis B do not
recover, but go on to develop chronic hepatitis or become
asymptomatic chronic carriers of the disease. The serum of
patients who recover from viral hepatitis infection contains
antibodies that neutralize the effect of the virus.
[0003] Consequently, in an attempt to protect individuals
at-risk of contracting the infection, researchers began first to
produce immune serum globulins and later vaccines.
[0004] When only hepatitis A and B viruses were known, all viral
hepatitis infections not attributable to these viruses were
called "nonA-nonB hepatitis". It is important to note that the
hepatitis C virus (HCV) was discovered only about seven years
ago and that it is the cause of the majority (80%) of
parenterally transmitted nonA-nonB hepatitis cases.
[0005] Hepatitis C infection can be very severe because of its
fatal sequelae, i.e., chronic hepatitis, liver cirrhosis and
hepatocellular carcinoma. Only about 20-30% of infected
individuals recover from the disease. Furthermore, infected
subjects can transmit the infection to other individuals by
means of their blood, the sexual route, etc.
[0006] It should be noted that most HCV-infected individuals are
asymptomatic. Therefore, they are often unaware they have the
infection and can transmit it to others.
[0007] While vaccines and specific immune preparations are used
for the prevention of hepatitis A and B infection, there are at
present no measures to protect all the many subjects exposed to
the risk of acquiring HCV infection.
[0008] At present, HCV affects about 300 million people
worldwide. Given the lack of effective protective measures,
these infected individuals are a potential danger because they
can spread this scourge through the world with devastating
human, social and economic consequences.
[0009] The drug according to the present invention intends to
make available to mankind a product that can effectively protect
from HCV infection and is characterized by a substantial
hyperimmunity against HCV, said hyperimmunity being due to a
substantial hyperconcentration of virus C neutralizing
antibodies.
[0010] Furthermore the drug according to the invention would be
produced from blood units collected from HCV-infected
individuals that contain a substantially high concentrations of
HCV neutralizing antibodies. The final product would be safe
because any HCV or any other possible infectious agents, that
could be present in the blood units used for preparing the drug
according to the invention, are inactivated by the Cohn method
(alcohol fractionation) and/or by other possible virucidal
treatments and/or additional methods capable of inactivating
infectious agents.
[0011] At last, the use of the drug according to the invention
is directed to substantially protect the individuals against HCV
infection, such as, for example:
[0012] sexual partners of HCV-infected patients,
[0013] patients undergoing hemodialysis,
[0014] patients undergoing dental therapy or chiropodistry,
[0015] drug abusers,
[0016] patients affected by HCV-related fulminant hepatitis,
liver cirrhosis or hepatocellular carcinoma undergoing liver
transplantation,
[0017] etc, etc..
[0018] Additionally, the use of the drug according to the
invention is also directed to substantially block HCV infection
in all other possible conditions.
[0019] These and further features of the drug according to the
invention will be apparent from the following description.
DESCRIPTION
[0020] The proposal of the drug according to the invention arose
from an informed intuition later confirmed by experiments
performed both in animals and in humans.
[0021] It is well known that blood is used also for the
production of immune serum globulins (ISG or standard polyvalent
ISG), that are present in plasma (the liquid part of blood) and
are effective in preventing one or more infectious diseases. The
starting material for the preparation of ISG is generally blood
collected from at least 10,000 blood donors.
[0022] The mechanism of prevention obtained with ISG is the
following: individuals affected by one or more infectious
diseases (which can be clinically apparent or not) produce
antibodies against those infectious agents and these antibodies
are present in their blood. Some of these antibodies are defined
"infection-related", because their presence is evidence of the
infection, whereas other antibodies are defined "neutralizing",
because they are able to destroy the agents that cause the
infection.
[0023] For example, subjects infected by hepatitis A virus
recover because they produce hepatitis A virus antibodies (i.e.
hepatitis A virus neutralizing antibodies), that destroy the
infectious agent. After recovery from the illness, the "memory"
of this experience (infection) remains in the blood because
hepatitis A virus neutralizing antibodies persist throughout the
subject's life.
[0024] If the plasma of a subject who has recovered from
hepatitis A infection (and which thus contains hepatitis virus A
neutralizing antibodies) is administered to person who has never
been exposed to hepatitis A virus and hence is susceptible to
infection, the latter will be protected against this virus by
virtue of these passively administered antibodies. Because
hepatitis A virus neutralizing antibodies, like most
neutralizing antibodies against other infectious agents, are
present only in a limited percentage of the population, the
starting material for producing ISG, which is effective against
several infectious agents, must be blood pooled from at least
10,000 blood donors. Protection from infection can also be
obtained with "hyperimmune globulins" (i.e., specific immune
globulins) that contain the same antibodies as ISG, except that
the antibody against one particular infectious agent is present
in high concentration (i.e., at least five-fold the
concentration present in standard polyvalent ISG).
[0025] Hyperimmune globulin preparations are produced from the
blood of donors specifically immunized with the relative vaccine
or from blood donors who have recovered from the natural
infection.
[0026] HCV infection is one of the most pressing health problems
facing mankind today. About 300 million individuals worldwide
are infected by this virus, many of whom die from liver
cirrhosis or liver cancer. A fundamental problem in the fight
against HCV infection is the existence of asymptomatic infected
subjects, who are unaware they are affected and who are a
potential source of infection for others.
[0027] Seven years ago Dr.M.Houghton and his research team
(Chiron Corp., Emeryville, Calif., USA) identified the
etiological agent of hepatitis C infection. This led to a
breakthrough and for the first time a serological test became
available that identified individuals infected by HCV. The
diagnostic test is based on the detection of the antibodies
induced by the virus (i.e., HCV antibodies). As mentioned above,
these antibodies are infection-related antibodies and their
presence in serum is merely a demonstration that the subject is
HCV-infected.
[0028] Generally, the percentage of HCV-infected subjects varies
from country to country and from continent to continent. In
Italy the mean prevalence of HCV infection in the population is
about 2%, it is lower in the USA and about 4.5% in Africa. It is
important to emphasize that about 50% of the pooled blood
samples used worldwide come from developing countries. Untill
1993 blood pooling centers did not discriminate HCV-infected
blood donors from other donors. After 1993 most healthy
authorities worldwide decreed that the anti-HCV positive blood
units (i.e., blood containing infection-related antibodies)
collected from HCV-infected donors should not to be used in
pooled blood samples.
[0029] Thus, about 2% of blood units collected in Italy and 4.5%
of blood units collected in Africa, etc., are discarded because
they are anti-HCV positive. In Italy the law according to which
all anti-HCV positive blood units are discarded came into effect
in March 1993. After this date only anti-HCV negative blood
units are used to prepare ISG.
[0030] On the intuition that ISG contain HCV neutralizing
antibodies, before the tests to detect said HCV neutralizing
antibodies were available, Piazza and co-workers, in a research
that started in 1991 and ended in 1993, found that ISG produced
from blood units, which were not screened for anti-HCV,
protected the sexual partners of HCV-infected patients from the
infection in a statistically significant fashion. Later in an
experimental study on chimpanzees Houghton et al. showed that
HCV induced the appearance of neutralizing antibodies, defined
anti-gpE1/gpE2, that protected the chimpanzees from the
infection. The neutralizing activity of these antibodies was
confirmed by a reliable specific test (neutralization of binding
assay).
[0031] The unscreened ISG used by Piazza in his clinical study
and some lots of screened ISG produced after 1993 were tested to
verify if they contained the anti-gpE1/gpE2 neutralizing
antibodies.
[0032] The results of this study were striking:
[0033] a) all the lots of ISG produced from blood units pooled
from donors unscreened for anti-HCV contained high titers of HCV
neutralizing antibodies;
[0034] b) no HCV neutralizing antibodies were detected in any of
the lots of screened ISG currently on the market, which are
produced exclusively from anti-HCV negative blood units.
[0035] Piazza then asked to himself which was the difference
between the unscreened ISG preparations which contain HCV
neutralizing antibodies and the screened ISG preparations which
do not contain said HCV neutralizing antibodies.
[0036] Piazza intuited that the difference consists only in the
fact that the unscreened ISG contain a small (about 2%)
percentage of anti-HCV positive blood units, whereas the
screened ones do not contain said anti-HCV positive blood
percentage. Thus it is logical, as Piazza intuited, that the HCV
neutralizing antibodies are contained only in that small aliquot
of anti-HCV positive blood units (2%) which are now, by law,
discarded.
[0037] Piazza then asked to himself: "If said anti-HCV positive
blood units, which are now discarded, were utilized for the
preparation of immune globulins, would the HCV neutralizing
antibodies (anti-gpE1/gpE2 and/or other type of HCV neutralizing
antibodies) contained in said immune globulins be substantially
hyperconcentrated?"
[0038] The hypothesis and the intuition prompted the idea of
producing hyperimmune globulins against the hepatitis C virus
using as source material only the anti-HCV-positive blood units,
which at present are discarded. HCV hyperimmune globulins that
are produced from up to 100% of anti-HCV-positive blood units
will contain an even higher titer of HCV neutralizing antibodies
than the pre-1993 immune serum globulins, which were produced
from blood units containing only 2% of anti-HCV positive blood
units.
[0039] HCV hyperimmune globulins so produced would contain a
mean HCV neutralizing antibody titer about fifty-fold higher
than that present in the pre-1993 immune serum globulins that
were effective in preventing HCV infection in sexual partners of
HCV-infected patients. In order to obtain HCV hyperimmune
globulins with even higher HCV neutralizing antibody titers,
only those anti-HCV positive blood units containing very high
titers of HCV neutralizing antibodies should be utilized as
starting material.
[0040] Obviously hyperimmune globulins against HCV should be
prepared from blood of a very large number of anti-HCV positive
blood donors in order to obtain a wide range of heterogeneous
neutralizing antibodies to the different strains of HCV.
[0041] Besides protecting from infection sexual partners of
HCV-infected patients, these HCV hyperimmune globulins could be
used in many other situations in which individuals are exposed
to the risk of acquiring HCV infection, e.g. patients undergoing
hemodialysis, patients undergoing dental therapy or
chiropodistry, drug abusers, etc.
[0042] Finally, HCV hyperimmune globulins would be of great
benefit in preventing HCV reinfection after liver
transplantation in patients affected by HCV-related fulminant
hepatitis, liver cirrhosis or hepatocellular carcinoma. In fact,
a major complication in these patients is given by the
reinfection of the transplanted liver by HCV.
[0043] Additionally, HCV hyperimmune globulins could also be
used to substantially block HCV infection in all other possible
conditions.
[0044] Other important advantages, which should be taken into
account, are that anti-HCV positive blood donors, who are now
excluded from donating their blood, will feel in the future
socially useful. In addition, the HCV-infected patients
themselves will be able to enjoy a social life unconditioned by
the thought they may affect their partners. The drug according
to the invention, herein referred to as HCV hyperimmune
globulins, will cost much less to produce than other hyperimmune
globulins currently used for other infectious agents. Moreover,
the costs of disposing of anti-HCV positive blood units
represent a further saving.
[0045] At last, the drug according to the invention is safe. In
fact, immune serum globulins prepared for intramuscular use by
Cohn method (alcohol fractionation, which inactivates both HCV
and other infectious agents) have been safely used throughout
the world for over 50 years. Virucidal treatments and/or
additional methods capable of inactivating infectious agents can
also be added to production process, in order to assure further
the safety of the final product. HCV hyperimmune globulin
preparations are intended not only for intramuscular use but
also for intravenous use.
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