The San Francisco Chronicle - Monday, May 31, 1999
Tom Abate, Chronicle Staff Writer

Right now, the tests theoretically miss just 1.5 HIV and 10 hepatitis C viruses in every million pints, but safety regulators say that isn't good enough.

In response, U.S. blood banks launched a new genetic test this spring that promises to make the slim odds of infection even slimmer. This new technique, called nucleic acid testing, or NAT, is supposed to be sensitive enough to detect the earliest traces of HIV or hepatitis C viruses that can slip through current blood tests.

Although current tests already have made infection from donated blood exceedingly rare, NAT could reduce the risk 80 to 90 percent for hepatitis and somewhat less for HIV.

"The new test is a dramatic improvement in the safety of the blood supply," says professor Pearl Toy, who heads the blood bank at the University of California at San Francisco.

But some experts have questioned whether the cost of the new test --it could add 5 percent to the overall cost of a pint of blood -- is worth the slim improvement in safety margins.

Jim AuBuchon, a pathology professor at Dartmouth Medical Center in New Hampshire, says NAT should reduce the statistical probability of transfusion-caused HIV from 24 cases a year at present to 16 a year. But he notes that there hasn't been a single real case of HIV-infected blood reported in five years -- which makes him wonder whether there actually would be an increased safety margin for HIV.

"This is the least cost-effective medical procedure I have ever seen," he says.

But with safety regulators requiring NAT tests by July 1, it seems that cost may be no object when it comes to the public's perception of the safety of the blood supply.

"To add a new technology that might increase the cost by several percent might be regarded as onerous by the blood banks that operate on a slim cash flow," says Rajen Dalal, president of the blood test division at Chiron Corp. in Emeryville. "But I, for one, find it hard to say that is too high a price for the societal good."

Chiron is one of two Bay Area corporations vying for the potential $200 million business of selling the equipment and chemicals to do NAT tests. Its rival is Roche Molecular Systems in Pleasanton.

Both companies already are players in the huge, global business of testing or manufacturing blood products -- most importantly, the clear liquid component of blood called plasma, which accounted for $5 billion in medical byproducts last year.

The safety push is coming from European regulators, who issued the July 1 deadline. "About 80 percent of the plasma collected by the American Red Cross or independent blood banks is made into products, and many of these products are sold in Europe," said Jim MacPherson, executive director of America's Blood Centers.

ABC is the trade association of independent blood banks, which collect half the nation's blood supply. The Red Cross collects most of the rest. Because any viral infection in donated blood potentially could get into the plasma-manufacturing pipeline, protecting the purity of this clear liquid is a global priority.

The FDA has supported the European initiative by allowing Roche and Chiron to install NAT systems in blood testing and production facilities. These NAT systems are running in experimental mode, but all parties expect the FDA to approve the commercial use of NAT next year.

The blood-safety push on both sides of the Atlantic results from lessons learned during the early 1980s, when less-sophisticated tests, designed mainly to detect syphilis, allowed HIV and new strains of hepatitis to infiltrate the world blood supply and infect thousands of people who received transfusions or plasma byproducts.

"We've come a long way in terms of blood safety since then," said Mike Fulwider, spokesman for the American Red Cross. "The very sophisticated tests we see today all ensued after the AIDS crisis."

The first HIV blood test went into effect in the mid 1980s. Since then, blood banks have added other tests. Today, each donated pint of blood is given seven tests to look for HIV or other blood-born viruses. Any pint that tests positive is withdrawn before it can pollute the blood supply.

Each pint must be screened within a day or two at most, lest short- lived blood components like platelets -- which are good only for five days -- get wasted.

Although current tests seem to have virtually eliminated blood- borne HIV infections, they have proven less effective at detecting hepatitis. MacPherson, the ABC executive, explained the shortcomings in current tests and how NAT should increase blood safety.

Current tests mainly look for the antibodies that our immune systems produce to fight off viruses. But there is a lag between infection and immune response. The time varies for each disease. For hepatitis, it can be more than 45 days. If a person donates blood during the lag time before antibodies are present, current tests won't find the virus.

Blood banks, which will continue doing the seven current tests indefinitely, will add NAT as an eighth check for hepatitis C and HIV.

NAT involves two basic steps, MacPherson explained. First, NAT employs genetic techniques to find any viral particles in the sample and to replicate them millions of times over. At that point, standard chemical tests can detect any infection that might be present.

"The antibody test can't detect hepatitis C until about 45 days after infection," says Dartmouth's AuBuchon. "With NAT, we can cut that down to 25 days."

Shortening this blind spot should mean that instead of the 160 hepatitis C infections a year, we might expect to slip through current tests, we're more likely to see just 32 misses per year in the United States, AuBuchon says. Although Roche and Chiron both use a two-step technique -- replication then testing -- their NAT technologies differ, according to Mike Busch, research director at Blood Centers of the Pacific.

Roche uses a replication technique called polymerase chain reaction to grow the tiny viral particles. During PCR, a sample must be heated and cooled 35 to 40 times, a process that is cumbersome and time-consuming compared with Chiron's replication technology, Busch said.

Chiron's NAT grows viruses using a process called transcription mediated amplification, which operates at a constant temperature and grows viral samples more quickly, Busch said.

Chiron didn't develop TMA, but licensed the technique from San Diego's Gen-Probe Inc., its partner in the battle to conquer the NAT niche. Douglas Lind, a Morgan Stanley analyst who follows the testing market, thinks Chiron and Gen- Probe have the only NAT system fast enough to process the 40,000 donations that flow through blood banks each day.

In addition to a speed advantage, Lind believes that Chiron eventually will beat Roche in their patent wars.

Chiron, which discovered hepatitis C in 1987, has used its patents on the virus to control the sale of tests for the bug. But Roche has been selling tests for hepatitis C in defiance of Chiron's patents. Roche argues that it purchased the technology to do hepatitis C tests in 1991, when it bought certain patent rights from Cetus, a now-defunct biotech firm.

Chiron bought the rest of Cetus at the same time, and ever since, Roche and Chiron have been fighting in court over who got what from Cetus' carcass. Lawyers for the two firms actually sparred over this patent issue Friday before Oakland Federal Judge Claudia Wilken.

Lind considers the hepatitis C test the most important function for NAT test. He thinks the courts eventually will stop Roche from selling NAT systems that screen for hepatitis C, leading him to say, "Without the ability to test for hepatitis C, Roche's NAT system could not be competitive."

Martin Madaus, vice president for Roche's blood-screening business unit in Pleasanton, calls the patent dispute "a business risk for us but not an unsurmountable issue." He maintains that one manufacturer has never been allowed to control a vital process "when the nation's blood supply is at stake."

Busch, the San Francisco blood expert, is glad Roche is in the NAT race. "During the initial period, Chiron was talking about charging $10 a sample to screen for HCV," says Busch, adding that Roche's competition already has brought the projected cost down to $6 or $7 per NAT test.

Even a $7 charge makes blood banks wince. It costs $150 to acquire a pint of donated blood. Less than $25 of that amount covers all seven current tests. So far, blood banks haven't experienced the full cost of NAT. During the experimental phase, FDA rules only let Roche and Chiron recover actual costs. But once they gain commercial approval, they can charge "whatever the market will bear," Busch says.

Blood banks aren't yet testing each pint of blood using NAT. Instead, they're pooling about 20 samples for one test -- and one charge. Part of the issue is that current NAT systems can't handle the 40,000 pints that are donated every day. But FDA officials have signalled that as soon as the equipment can handle the load, they want each pint individually NAT tested. Multiply the 14 million pints of blood collected annually in the United States by whatever the final price per test and it becomes clear that NAT safety comes at a cost.

Whatever the price, the medical system eventually will have to pay it.

"We're ready to do whatever it takes to make the blood supply as safe as it can possibly be," said the Red Cross' Fulwider.

MAKING THE BLOOD SUPPLY SAFER

U.S. blood labs have added a new test to screen out blood infected with viral diseases such as Hepatitis and HIV. Each donated pint of blood is already tested for specific antigens or viruses. Others look for antibodies which signal the presence of disease. (1) Blood is drawn and packaged. (2) Antibody-antigen blood test. (3) Blood is separated into 3 components Plasma is a clear liquid that can be transfused into patients to help maintain blood pressure. But more often than not, plasma is processed and manufactured to create a host of life-giving medicinal products.

Platelets are small cells that help blood clot. They must be used within five days. Platelets transfusions help keep chemotherapy patients alive. . Fresh red blood cells must be used within 42 days. But red blood cells can be frozen and saved for years.

NUCLEIC ACID TESTING (NAT)

4. New blood test

Current blood tests have dramatically reduced the chance of contracting HIV from a blood traansfusion from one in 100 in the early 1980s to one in 676,000 today. But the new, nucleic acid tests should cut these odds another 50 percent to 100 percent, by detecting minute amounts of virus particles that slip through current screening techniques.

How Nucleic Acid Testing (NAT) works.

NAT testing involves two steps. First, a blood sample is put through a process that replicates certain viruses -- HIV and Hepatitis C -- that might be there. After this replication process, the sample is subjected again to the same sorts of tests that are given to blood earlier in the process. If the test detects a virus, the sample is withdrawn from the blood supply.

(5) Blood and plasma by products used in surgery or drugs

About 40,000 units of blood are used each day in the U.S. Treating auto accident victims could consume 50 pints of blood. Bone marrow transplant patients can get 120 units of platelets. Plasma and its byproducts are the most widely used blood components. Plasma derivatives are used to treat hemophilia, low blood pressure and a growing array of neurological and immune conditions.

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