Securing the International Blood Supply Against HIV

The modern pandemic known as AIDS continues to spread at an alarmingrate, with approximately 5,000 people becoming infected with HIVdaily.[1] The World Health Organization estimated in 1995 that20 million people worldwide were HIV infected, and that therewere more than 4 million cases of AIDS.[1]

Among the international population of HIV-positive adults, approximately5% have been infected through blood and blood products, whichprovide the most efficient mode of HIV transmission.[1]

The majority of HIV infection through blood and blood productsoccurred in the early to mid-1980s, reflecting a period in whichinternational bureaucracy and national attitudes of protectionismcaused unconscionable delays in the implementation of measuressuch as donor screening and viral inactivation that could haveprevented the spread of HIV to thousands of individuals.

Infections in Hemophiliacs

The worldwide hemophiliac population, in particular, was devastatedby the use of contaminated blood products. Although rates varysignificantly by country, more than half of the hemophiliac populationsof many countries, including the US, France, Denmark, and Japan,were infected with HIV in the 1980s.[2,3]

The US Centers for Disease Control and Prevention published itsfirst reports of AIDS in homosexual men in June, 1981.[4] In January,1982, the AIDS death of a hemophiliac was reported. As more casesof hemophiliacs with AIDS began to surface in 1982, the safetyof the US blood supply was called into question.

Of particular concern was the use of plasma pooled from thousandsof donors in the manufacture of clotting factor concentrates usedby hemophiliacs. This created the means by which one infecteddonor could contaminate an entire supply of blood products andinfect hundreds of individuals.

In the January 13, 1983, issue of The New England Journal of Medicine,associate editor Jane Desforges addressed this potential hazard,urging that therapy with clotting factor concentrates for hemophiliacsbe replaced with the more cumbersome, outdated therapy using cryopre-cipitate,which is manufactured from a single donor.[5]

At the time, there was no conclusive evidence for AIDS transmissionthrough blood, and HIV had yet to be discovered. An article inthe April 2, 1983, Lancet responded to Desforges' claim that hemophiliacswere being infected through blood products, stating that "therecognition of disease in a few hemophiliacs does not necessarilyreflect the tip of an iceberg . . . Whilst careful surveillancemust continue, the reported cases do not constitute a strong argumentfor a change in treatment policy."[6]

Acknowledging the Risk

As research progressed and more AIDS cases were documented, itbecame apparent that there was a risk of infection from bloodand blood products. By the end of 1983, most countries had officiallyacknowledged that risk and had begun to examine ways of increasingthe safety of their blood supply.

The screening of donors was begun in most countries; however,many policies were premised on donor self-deferral based on questionsabout health status rather than on questions regard-ing the knownhigh-risk factors.[7] Homosexuals were the highest risk group,but questions regarding sexual orientation were omitted from donorscreening for fear of civil claims for human or civil rights violationsor invasions of privacy.

There was also the notion that much of the risk of HIV blood contaminationcould be avoided by relying solely on voluntary donors; however,many countries, including the United States, relied heavily onpaid donors, and the need to keep up with the demand for bloodproducts precluded the adoption of an exclusively voluntary donorsystem.

The risk of using paid donors was propagated throughout the worldby countries that imported blood products from the United States,where 80% of blood plasma donors were remunerated.[8] Countriesusing large quantities of American blood products reported highrates of HIV infection in hemophilia patients, a trend seen inCanada (40% of hemophiliacs infected), the United Kingdom (39%),France (50%), Germany (53%), and the US (50%).[9,10]

In contrast, countries that manufactured blood products from localdonors through a voluntary system, such as Belgium (7%), Norway(8%), the Netherlands (17%), and Finland (1%), all showed muchlower HIV infection rates among their hemophilic populations.[9]

The development of virally inactivated blood products played thegreatest role in curbing the spread of HIV. As early as 1980,Behringwerke, a German pharmaceutical company, showed that factorVIII, a blood product for hemophiliacs, could be safely heat treatedto kill the hepatitis B virus.[11] Similar heat treatment methodswere later found to inactivate HIV, and the FDA began licensingheat-treated products in March, 1983.

At the time, it was not known that heat-treated products couldprevent the spread of AIDS; however, it was known that many viruseswere susceptible to the heating process.

In retrospect, it may seem like the most prudent move by governmentagencies at that time would have been to recall any non-heat-treatedproducts and then to distribute products that had been heat treated.However, financial and political considerations delayed the distributionof heat-treated products for years in some countries.

A protectionist attitude prevailed in countries that sought topreserve their own markets for heat-treated products. France wasoffered heat-treated factor VIII by an American company as earlyas May, 1983. France's National Center for Blood Transfusionswas in the process of constructing a new fractionation plant,and in the interest of preserving a national market, heat-treatedproducts were not imported from the United States, despite thefact that France's central fractionation plant did not acquireheat treatment technology until November, 1985.

In March, 1985, the French government was unequivocally informedthat its blood products were contaminated with HIV, but unheatedproducts were not withdrawn from the French market until October,1985, when the Social Securities Office stopped reimbursing bloodtransfusion centers for their expenses in manufacturing non-heat-treatedblood products. It is estimated that this 7-month delay in actionby the government resulted in the HIV-infection of 1,500 Frenchhemophiliacs.[7,12]

Canada is another example of a country whose decisions regardingthe blood supply were influenced by a protectionist attitude.In the 1980s, the Canadian Blood Committee, responsible for directingthe Canadian blood collection, processing, and distribution system,attempted to preserve its markets by developing Canadian self-sufficiencyin blood products through several fractionation plants.

None of these proposed plants, however, produced any of the majorcategories of fractionated products, and in 1987 the fractionationindustry was abandoned in Canada, despite the expenditure of millionsof dollars of government subsidies.

In November, 1984, Cutter Biologic in North Carolina was licensedto heat treat Canada's blood products; however, Connaught Laboratories,still in operation producing non-heat-treated products in Toronto,continued to distribute its product in Canada until the end ofMarch, 1985, under the terms of an existing contract. In July,1985, a voluntary withdrawal and exchange of all non-heat-treatedproducts was undertaken by the Canadian Red Cross Society.[13]

Perhaps the worst example of blood product mismanagement occurredin the 1980s in Japan. Heat-treated blood products were availableto Japan from the United States as early as March, 1983, but theywere not approved for sale in Japan until July, 1985. During thattime, Japan increased imports of non-heat-treated US products,and US companies were only too happy to comply.

The price of concentrates was much higher in Japan than in theUnited States, and when the United States began withdrawing untreatedproducts in 1984, companies were faced with the dilemma of cleaningout their old stocks, which conveniently could be exported toJapan.

Within Japan, the move toward heat-treated products was extremelyslow. One company, Midori Juji, left non-heat-treated productson the market until 1988, two years after the company had reportedto the Ministry of Health and Welfare that withdrawal had beencompleted.[14-16]

Screening Test Becomes Available

The licensing of a screening test for HIV in March, 1985, by AbbottLaboratories in the United States marked another turning pointin ensuring the safety of the blood supply. Most US blood banksbegan using Abbott's ELISA test in March, 1985, and on July 1,1985, the American Association of Blood Banks formally requiredanti-HIV testing.[17]

The international distribution of the ELISA test, as with heat-treatedproducts, was delayed in some countries in the interest of marketpreservation. The French National Laboratory did not approve theELISA test until June 24, 1985, three days after the French Pasteuranti-HIV kit was approved.[18]

Great Britain did not implement mandatory testing at RegionalTransfusion Centers until October 14, 1985, deciding to use recentlydeveloped British and Dutch tests. The delay in implementationwas attributed to the need to determine the most accurate test;however, Abbott Laboratories accused Britain of delaying approvalof their test until a British one became available.[19]

In the late 1980s, governments began to determine a means of compensationfor people infected with HIV via contaminated blood products.Many countries (France, Canada, Great Britain, Switzerland, Germany,Japan, the Netherlands and Australia) have set up compensationfunds.[20] Infected family members are, in most cases, also eligiblefor compensation. If the claimant is deceased, the remaining familymembers are eligible.

One of the conditions of applying for compensation in most countriesoffering it is the renouncement of all civil rights actions. Therebygovernments can appease the people infected as a result of theirnegligence without having to openly accept responsibility fortheir actions.

Lobbying efforts are currently being conducted in the United Statesto establish a compensation scheme. A legal battle over accountabilityand compensation from private companies is currently in the settlementstage. Armour Pharmaceutical, Rhône-Poulenc Rorer, Baxter,Bayer Corp., and Alpha Therapeutic have agreed, without admittingliability, to a classwide settlement paying $100,000 to hemophiliacsinfected with HIV and to those that they, in turn, infected.[21]

On November 25, 1996, the settlement will be considered in USDistrict Court. A similar out-of-court settlement for a plaintiffgroup in Japan on March 29, 1996, awarded a lump sum of 45 millionyen ($405,400) and 150,000 yen/month for life to cover medicalexpenses.[22] Many US claimants feel that the $100,000 offer isan insult, and point out the monetary discrepancies between theirproposed settlement and the Japanese one.

Criminal Trials

The mismanagement of blood products has resulted in criminal trialsin several countries. In February, 1994, the director and fourstaff members of UB Plasma in Koblenz, Germany, were charged withgrievous bodily harm (maximum 5-year prison sentence) for sellingproducts inadequately tested for HIV between 1987 and October,1993.[23]

In France, blame has been cast at a more national level. In October,1992, Michael Garretta, former head of France's National Centerfor Blood Transfusions, and Jean-Pierre Allain, former head ofresearch at the center, were given 4-year prison sentences forsupplying hemophiliacs with clotting factors they knew were infectedwith HIV.

Jacques Roux, former director general of the Health Ministry,was charged with "non-assistance to persons in danger"and given a 4-year suspended sentence.[12]

The indictments in France sparked controversy and accusationsof scapegoat-ing, particularly in the case of Allain, who triedto go public about his knowledge of the dangers of France's bloodsupply in the first 6 months of 1985, although the newspaper LeMatin did not publish his findings.[24] The allegation is thatAllain did not do enough to inform the public and influence thepoor decision made by the National Center for Blood Transfusionsto continue using unheated blood products for 7 months despiteknowledge of their inherent dangers.

The scientific community responded to the indictments by signinga petition asking President Francois Mitterrand to pardon thoseconvicted, which hemophiliac groups claimed was an insult to thevictims of the blood scandal.[25] Allain's conviction, in particular,prompted more than 30 Nobel prize winners to write to Mitterrandpleading Allain's case. The French judiciary itself was criticizedin July, 1994, by the Paris bar association for allowing publicopinion to influence the legal process.[26]

More recently, Japan has begun its probe into allegations of professionalnegligence for distribution of unheated blood products. In September,1996, Takeshi Abe, former head of the government AIDS study group,was arrested on charges of professional negligence resulting inthe death of a hemophilia patient.[27]

Also in September, Takehiko Kawano, current president of MidoriJuji, and two of his predecessors, Renzo Matsushita and TadakazuSuyama, were arrested on suspicion of negligence in promotingthe sale of non-heat-treated blood products in 1986 and for notcompleting the recall of such products until 1988.[16]

Akihito Matsumura, a former official in the Ministry of Healthand Welfare, was indicted in October, 1996, for his involvementin the blood scandal, marking the first criminal prosecution ofa bureaucrat for alleged inaction while in office.[28]

Lessons to Learn

If there is one thing governments could learn from the blood debacleof the 1980s, it is that more effective measures need to be developedto ensure the safety of the world's blood supply. Progress appearsto have been made. For example, in October, 1996, the US Foodand Drug Administration's special advisory panel voted unanimouslyto withdraw any blood products from donors found to have contractedCreutzfeldt-Jacob disease (CJD).[29] This marked the first decisionto withdraw blood products based on theory rather than conclusiveevidence that CJD is transmitted by blood.

The importance of the FDA's decision, however, is undermined bythe fact that implementation of the withdrawal is extremely difficultand slow due to the lack of a computerized national tracking system.

Despite the lessons of the 1980s, many governments continue tobe reticent about potential hazards in their blood supply. InApril, 1996, the Chinese government ordered state medical institutionsto stop using a serum albumin blood product manufactured by amilitary factory without offering an explanation for the action.

In October, 1996, the government finally acknowledged that theproduct was contaminated with HIV, marking the first time Chinapublicly recognized an HIV contamination crisis and the possibilityof official negligence in the handling of blood products.[30]

That such a crisis could happen in 1996 suggests that the safetyof the international blood supply can still not be guaranteed,and governments may be well served by coordinating efforts toreact to potential hazards in the blood supply.

References:

1. World Health Report 1996--Executive Summary. World Health Organization.

2. Grmek MD: History of AIDS: Emergence and Origin of a ModernPandemic. Princeton, NJ, University Press 1990.

3. Acquired Immunodeficiency Syndrome--Data as of 31 Dec 1993.World Health Organization.

4. Morbidity and Mortality Weekly Report: Centers for DiseaseControl. June 5, 1981.

5. Desforges JF: AIDS and preventive treatment in hemophilia.N Engl J Med 308:94-95, 1983.

6. Acquired Immunodeficiency in hemophilia. Lancet 1(April 2):745,1983.

7. Trebilcock M, Howse R, Daniels R: Do institutions matter? Acomparative pathology of the HIV-infected blood tragedy. VirginiaLaw Review, in press.

8. Feldschuh J, Weber D: Safe Blood: Securing the Nation's BloodSupply in the Age of AIDS, p 50. New York, Free Press, 1990.

9. Rosendaal FR, Smit C, Briet E: Hemophilia treatment in historicalperspective: A review of medical and social developments. AnnHematol 62:5-15, 1991.

10. Mickleburgh R: End to Red Cross' blood rule urged. The Globeand Mail February 9, 1994, p A3.

11. Lohmann W, Scheu G, Schmidbauer G: Zweite BeschulBempfehlungund SchluBbericht des 3. Untersuchungsausschusschusses nach Artikel44 des Grundgesetzes. Bonn; October 21, 414, 1994.

12. Butler D: Verdict in French blood trial shames science. Nature359(Oct 29):764, 1992.

13. Picard A: The Gift of Death: Confronting Canada's TaintedBlood Tragedy. Toronto, Harper Collins, 1995.

14. Swinbanks D: American witnesses testify in Japan about AIDSrisks. Nature 364(July 15):181, 1993.

15. Swinbanks D: Japan faces new questions on HIV in blood. Nature367(Feb 17):584, 1994.

16. Swinbanks D: Japan's HIV blood scandal broadens out. Nature383(Sept 26):291, 1996.

17. US Institute of Medicine: HIV and the blood supply. NationalAcademy Press, Washington DC, 1995.

18. Anderson C: AIDS scandal indicts French government. Nature353(Sept 19):197, 1991.

19. Ministers delayed launch of AIDS test. New Scientist 107:16,1985.

20. World Federation of Hemophilia Information Clearinghouse.HIV Financial Assistance--Update. May, 1996.

21. Hutchcraft C: Judge ok's pact to pay hemophilia AIDS victims.Chicago Tribune. August 15, 1996, business section, p 1.

22. Shimbun Y: HIV plaintiffs say yes; 7-year court battle over.The Daily Yomiuri March 22, 1996, p 1.

23. Abbott A: . . . as German executives are charged. Nature 367(Feb17):584, 1994.

24. Bader JM: France: Prison sentences for doctors. Lancet 340(Oct31):1087, 1992.

25. Butler D: Petition prompts backlash against scientists. Nature367(Jan 27):304, 1994.

26. Butler D: Judiciary criticized over French blood trial. Nature370(Aug 4):319, 1994.

27. Blood scandal scientist arrested. Nature 383(Sept 5):9, 1996.

28. Japanese official indicted in HIV scandal. Reuters HealthInformation Services, Inc. October 28, 1996.

29. S 343 will imperil the safety of America's blood supply. Committeeof Ten Thousand, press release.

30. HIV-contaminated serum albumin acknowledged by China. ReutersHealth Info Serv, 10/28/96.