Status of Infection in Young Hemophilia Patients in Münster

At one time, the hemophiliac faced four hazards: bleeding to death, crippling, poverty, and isolation. The disease had a serious detrimental impact on quality of life-not even royalty was spared from these severe consequences. The existence of the illness within the Russian czar's family even influenced world history. Although the disease ``hemophilia'' had been known for centuries, there was no effective treatment before the 1960s. It was not until 1964 that Pool et al[1] developed cryoprecipitate. Special freezing techniques enabled the concentration of factor VIII and the production of the first factor concentrates. However, these forerunners of today's coagulation preparations had only a low factor VIII content and, as a result, they had to be administered frequently and in large quantities. This often led to a distortion of blood components, with subsequent circulatory failure.

During the years that followed, further improvements in the production process enabled highly concentrated factor concentrates to be manufactured commercially. The blood plasma required as the raw material was supplied from large plasma pools, obtained in some cases from more than 1000 blood donors. For the first time in history, these preparations made it possible not only to arrest acute bleeding effectively, but also to prevent the crippling that had been inseparably associated with hemophilia for centuries.

Unhappily, at the very moment when patients and those treating hemophilia were anticipating the prospects of a better life, a new menace threatened-a fifth scourge-viral infections. For some years, these infections were accepted as the inevitable ``price'' of successful treatment; to live with an infection was always better than bleeding to death or crippling. In the period before these highly concentrated (but also highly infectious) preparations were developed, the mean life expectancy of a patient with hemophilia was limited to 16.5 years.[2]

High infection rates with hepatitis viruses were observed in the 1980s. For many years, only hepatitis A and hepatitis B could be attributed with certainty to the respective pathogens because methods of detection were available only for these two viruses. If a test for these two species of virus failed in the case of a patient with elevated liver enzymes (glutamic-oxaloacetic transaminase [GOT], glutamate pyruvate transaminasse [GPT]), the case was described as ``non-A, non-B'' (NANB) hepatitis. It was not until 1988 that the identification of a third species of virus became possible, known today as hepatitis C. In recent years, further causative agents of hepatitis have been classified, designated as forms D, E, F, and G.

Hepatitis A is one of the most common infectious diseases in the world, and is by no means confined to recipients of blood products. In southern countries (e.g., in the Mediterranean region), its prevalence in the normal population is as high as 80%. Even in central European countries with a high standard of hygiene, such as Belgium, however, a prevalence of more than 30% is expected in individuals age 20 and older.[3] The primary route of transmission is fecal-oral infection with contaminated foods or polluted water, although epidemics have been described in nursery schools and similar institutions. Infection leaves a legacy of life-long immunity, and patients almost always recover completely. Persisting damage is very rare. Active inoculation has been available since 1993.

Some authors have reported that only a few patients exhibited no signs of having had a hepatitis B infection after treatment with non-virus-inactivated coagulation preparations.[4] Lechner[5] put the level of hepatitis B infection among hemophiliacs at 70 to 90% when non-virus-inactivated preparations were used. As early as 1972, the Food and Drug Administration (FDA) in the United States stipulated that all blood donors whose plasma was intended for the manufacture of factor VIII concentrates should be tested for hepatitis B.[5] In addition to parenteral transmission via blood or blood products, sexual relations and perinatal infections are regarded as primary routes of transmission.

Table [1] gives further information on the prevalence of hepatitis B among hemophiliacs in the 1970s and 1980s in various countries.[4] [6] [7] [8] [9] [10] The first hepatitis B vaccines were developed in 1983[5] and are also used today in many hemophiliacs to prevent infection.

The causative agent of hepatitis C was discovered in 1988. It is an RNA virus belonging to the genus Flavivirus. A high incidence of cirrhosis of the liver has been observed in patients with hepatitis C infection. The routes of transmission and risk groups are the same as for hepatitis B infection.

A retrospective Australian study at the end of the 1980s found that 75% of hemophiliacs tested had an earlier hepatitis C infection.[11] High rates of infection were also found in other countries, as shown in Table [2].[11] [12] [13] [14]

The published figures for rates of infection of hemophiliacs who were infected with human immunodeficiency virus (HIV) after treatment with non-virus-inactivated coagulation preparations reveal a wide range of variation of between 1 and 90%.

The first infection of a hemophiliac with HIV was found in 1982. In the same year, the transmission of the infection by blood transfusions was confirmed by the Centers for Disease Control. Since the risk of HIV infection has become known, many studies have been published on the rate of infection of hemophilia patients with HIV (Table [3]).[11] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]

When the various countries are compared, the main point that becomes apparent is that the ``Iron Curtain'' was not only impassable for people, but also for HIV. In contrast to western Europe, where the infection rates were coming close to those of the United States, in eastern Europe HIV infections hardly occurred at all among either the normal population or hemophiliacs.

However, in the early 1980s, cirrhosis of the liver as a consequence of therapy-related hepatitis B and C (still called non-A, non-B at that time) became increasingly prominent as a cause of death among hemophiliacs. It was not until the increased incidence of HIV infections among hemophilia patients was first described some years later, however, that the need for virus inactivation of coagulant preparations as an essential routine step became apparent. According to the statistics for causes of death in West Germany from 1980 to 1989, 188 of 283 hemophiliacs (66.1%) died from autoimmune deficiency syndrome (AIDS) or as a consequence of a hepatitis infection, and therefore from the consequences of replacement therapy that had been so successful initially.

At first various steps were taken to reduce the risk of infection from plasma concentrates. Thus, people belonging to certain risk groups (e.g., homosexuals, drug addicts, and male and female prostitutes and their sexual partners) were and are still excluded from donating blood. Once the HIV antibody test was developed, the test was also performed in order to exclude infected blood donors from donating blood. However, complete protection from the transmission of infection cannot be guaranteed by these measures. Only the direct virus inactivation of the concentrates was able to break the fateful chain of infection.

The first factor VIII preparation to offer adequate viral safety was Haemate HS^℗ (formerly Behringwerke, today Aventis Behring, Marburg, Germany) in 1980.[25] [26] [27] Pasteurization of the concentrate, in other words, heating to 60°C in an aqueous solution for 10 hours, was the first successful method to achieve effective virus inactivation of a factor VIII concentrate.[28] [29] In Münster, all newly diagnosed hemophiliacs and all hemophiliacs still seronegative were treated with the new pasteurized factor VIII concentrate from 1980 onwards, and all hemophiliacs were treated with it from 1982 onward. The authors produced records of 218 patient years for the period between 1980 and 1994 for a group of 41 hemophilia patients who had received Haemate HS exclusively or, from 1990 on, the more highly purified, but also virus inactivated Beriate HS^℗; the patients were given no other factor VIII preparations or other blood products such as red cell concentrates, for example. All the patients included in this study were suffering from severe hemophilia A with a residual factor VIII:C level of <0.01 IU/mL. The diagnosis and treatment of all patients were conducted exclusively in the Münster Hemophilia Center. Tests for infections were carried out by means of viral serology and liver enzyme tests up to four times a year. In 1984, when the first hepatitis B vaccine became available, all patients were inoculated against hepatitis B. In the course of the study, the patients received a total of 6,863,250 units of Haemate HS or Beriate HS from more than 50 batches. No side effects of the treatment were observed. The conclusions of this study are summarized in Table [4].

In contrast, of the patients belonging to a historical reference population who had still been treated with non-virus-inactivated factor VIII concentrates before 1982, 30% were hepatitis A positive, 92% were hepatitis B positive, 85% were hepatitis C positive, and 54% were HIV positive.

Among the patients in a third group who came to us from eastern Europe after 1990 and who had been treated predominantly with cryoprecipitates in their native country, the picture was similar: 42% were hepatitis A positive, 75% were hepatitis B positive, and 67% were hepatitis C positive. Thus, nonpooled cryoprecipitate could not be shown to present a lower risk of viral transmission than large-pool preparations. However, one major difference from our historical reference population was that the patients who had to live behind the ``Iron Curtain'' were evidently spared from infection with HIV.

The data presented impressively demonstrate the effectiveness and reliability of pasteurization as a method of virus inactivation that was achieved as long ago as 1980 in the case of Haemate HS^℗ and later with Beriate HS^℗. However, the inclusion of a virus inactivation step in the production process of factor VIII concentrates was not made a requirement in western countries until 1985.

Under treatment with virus-inactivated factor VIII concentrates since then, no new infection with HIV has been observed.

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