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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


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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