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Personalized genetic medicine already offers tests designed to prevent dangerous drug reactions — but doctors are reluctant to use them

Reciprocal reactions between drugs and the patients' genes may have a negative effect on the effect of the drugs and even endanger the patients' lives. Genetic testing may prevent this and help find an alternative drug. Illustration: National Human Genome Research Institute.
Reciprocal reactions between drugs and the patients' genes may have a negative effect on the effect of the drugs and even endanger the patients' lives. Genetic testing may prevent this and help find an alternative drug. Illustration: National Human Genome Research Institute.

By Dina Payne Maron, the article is published with the approval of Scientific American Israel and the Ort Israel Network 15.12.2016

  • About half of the patients every year receive a drug that may react with one of their genes and cause serious side effects.
  • Inexpensive genetic tests, currently available in only a few hospitals, may prevent these problems, some of which are life-threatening.
  • However, the lack of coverage by insurance companies and the embarrassment of doctors regarding the question of how and when to change a prescription, hinder the widespread use of the new tests.

Corey Parker is a cheerful seven-year-old girl with an infectious smile, who loves to improvise her own songs and play them out loud to others. One day in April two years ago, in her hometown of Memphis, Tennessee, Corey came home from kindergarten with strange bruises. She said she bumped into some furniture, maybe a table, but not hard, not enough to cause deep marks. Her mother, Rhonda, called the pediatrician and made an appointment for a few more days. But the next morning Corey woke up covered in new spots that covered one arm and her forehead. And when she brushed her teeth, the gums began to bleed.

The mother and daughter went to St. Jude Children's Hospital, a research hospital close to their home. Doctors diagnosed Corey with a deficiency in the production of new red and white blood cells, a condition that causes uncontrollable bleeding, bruising and infections. It is a disease called by name Severe acquired aplastic anemia.

The girl was immediately prescribed several medications designed to increase her blood cell production and improve her ability to resist infections. But the doctors at the hospital did something else, not acceptable: they tested about 230 of Corey's genes, which affect her response to drugs and determine which drugs, and in what doses, will work optimally in her body. Different versions of certain genes can cause enzymes in the body to break down drugs very quickly. In such cases, even high doses of the drug will not help.

The tests revealed that because of Corey's unique genetic makeup, her body was breaking down the drug Voriconazole, which was prescribed to her in the first place to prevent fungal infections, very quickly. "She was on an adult dosage and it didn't seem to help her at all," says Rhonda, Corey's mother. Her daughter was not infected with any dangerous fungus, but she became vulnerable to such an infection, and if she had been infected her body would not have been able to fight off the fungus. That's why the doctors decided to replace the drug with another one, which reacts with enzymes encoded by other genes. Corey's body responded to the alternative medicine normally, it did not break down too quickly and Corey did not contract the fungus.

Matching treatments to the patient's genetic makeup is part of the futuristic vision of personalized medicine, in which each treatment will be matched to the patient's DNA. Part of this vision is already beginning to be realized in the form of genetic matching of drugs - the so-called procedure Pharmacogenomics. Corey Parker got to enjoy it. Although finding the complete sequence of a person's genome costs $1000, finding the connection between a drug and several hundred genes in St. Jude's laboratories costs about half that amount per patient. "We are standing at the threshold of the era of precision medicine," he says Dan Roden, Deputy Head of the Medical Center at Vanderbilt University. "And the most readily available fruit is pharmacogenomics."

Unfortunately, only a few hospitals are willing to reap this fruit. The lack of coverage by insurance companies for the tests, along with embarrassment among doctors who do not know what to do with genetic data, all prevent the widespread use of these tests.

The sad result is that people get sick unnecessarily, so claim the adherents of the approach. Thus, for example, according to estimates, between 5% and 30% of the total population in the world carry the same problematic version of the gene that Corey Parker has, and it affects their reactions to various drugs, not just voriconazole. According to analyzes done at St. Jude and Vanderbilt, roughly 50% of hospital patients each year receive a drug that may cause serious side effects due to the patient's individual genetic makeup. According to an estimate of one study done at Vanderbilt and looking at only six drugs, tests of the gene-drug relationship could prevent about 400 adverse events in a population of 52,942 patients. If such tests are carried out for more than six drugs in the entire US population, the number of health damages that will be avoided may reach hundreds of thousands.

Shots in the dark

Doctors are not used to choosing drugs relying on genetics. Over decades, they are used to looking at relatively prominent factors such as the patients' age and weight, kidney and liver functions. They also take into account additional medications that the patients receive, as well as additional relevant information according to their preferences.

If doctors consider using genetics, here's what they could learn about using the common pain reliever Codeine, for example In most people, the body produces an enzyme called CYP2D6 that breaks down the drug into the active ingredient, morphine, relieve the pain. But about 10% of patients have another genetic variant that produces too small amounts of the enzyme, so very little codeine breaks down into morphine. These people do not feel any pain relief under the influence of codeine. On the other hand, about 2% of the population has the opposite problem. They have too many copies of the gene, which leads to a large excess production of the enzyme. In their bodies, a small dose of codeine can quickly turn into a large dose of morphine, which can be fatal. Genetic influences of this type on how drugs work explain some of the oldest mysteries of medical science. Already in 510 BC, the Greek mathematician Pythagoras (who formulated the famous theorem in geometry) noticed that when certain people eat a certain type of legume, they suffer from a serious illness that manifests itself in increasing weakness, and ends in death. Today it is known that this disease is Hemolytic anemia (blood coagulation), which manifests itself in the continuous destruction of red blood cells (first observed in the 17th century, 2,100 years after Pythagoras). And 2,500 years after Pythagoras, researchers discovered what causes the disease: the people who contracted it due to eating pulses, carry versions of genes that lead subtract in the production of an enzyme called Glucose-6-phosphate dehydrogenase (G6PDD). In a normal state, the enzyme prevents the destruction of red blood cells. The problematic genetic version, which can be identified today through genetic testing, means that people who carry it tend to suffer from hemolytic anemia not only as a result of eating pea, but also due to the effect of several drugs currently on the market, including Rasburicase, given to leukemia patients.

Many of these interactions between drugs and genes, severe or mild, can be prevented by changing the dosage of the drugs or replacing them with others. In the October 2015 issue of the journal Nature wrote researchers 800 drugs are known that are affected by interactions with about 20 genes, and they have suitable alternatives.

She is the one who achieved some of the most outstanding achievements in the contemporary research of the relationship between drugs and genes Mary Relling, Head of the Department of Pharmaceutical Sciences at St. Jude Hospital. Many children with cancer come to this hospital, and since many of the drugs that may be problematic are the drugs used in chemotherapy, a concern arose in the hospital that some of the children might be harmed by interactions between the drugs and the genes. For years, Relling and her colleagues conducted tests for interactions between drugs and genes on a modest scale, and starting in May 2011, Relling promoted conducting tests for all new patients admitted to the hospital.

Genetic differences are responsible for the fact that codeine, a common pain reliever, does not work the same way in the body of all people. An enzyme found in the liver cells usually converts codeine into morphine, which is the pain reliever (a). But some people have a defective version of the gene, and therefore also of the enzyme (b). or they have no active enzyme at all. In others, excessive amounts of enzyme (c) are produced. DNA tests can find out which version each person carries, and help doctors adjust the dose of the drug to the patient. Illustration for illustration only: ZngZng / Wikimedia.
Genetic differences are responsible for the fact that codeine, a common pain reliever, does not work the same way in all people's bodies. An enzyme found in the liver cells usually converts codeine into morphine, which is the pain reliever (a). But some people have a defective version of the gene, and therefore also of the enzyme (b). or they have no active enzyme at all. In others, excessive amounts of enzyme (c) are produced. DNA tests can find out which version each person carries, and help doctors adjust the dose of the drug to the patient. Illustration for illustration only: ZngZng / Wikimedia.

St. Jude's also has a distinct advantage over others: It is not limited by the need to receive reimbursement from insurance companies for these tests, nor does it force patients to pay themselves. The payment for the treatment of patients is primarily covered by donations and grants. Thanks to the financial security that the hospital enjoys, whenever a new patient is admitted, the hospital takes blood from him to test and detect more than 200 genes.

In March 2016, the hospital had medical data of more than 3,000 patients, relating to seven genes and 23 well-known drugs that affect the patients. One record in the database is that of Eden Brewer, a five-year-old girl who was diagnosed last year as suffering fromAcute lymphoblastic leukemia. Fortunately, her genetic testing did not reveal any mutations that might require the doctors to change her treatment plan. But the tests revealed that she may have had problems with other drugs over the years. One medicine named Simvastatin Used to treat high cholesterol levels. It turns out that Aden carries a version of the gene called SLC01B11, which prevented her body from using the drug. For reasons that are still unclear, this problem sometimes leads to muscle destruction that can be fatal. Simvastatin is a commonly used drug, but Eden will be prohibited from using it.

"This knowledge is really exciting," says Nicole, Eden's mother. "We have a new tool like this in our toolbox not just while we're receiving care here at St. Jude, but for Eden's entire life — forever." If a doctor at St. Jude's ever tried to prescribe her this drug, an alert would pop up in her computerized medical record.

A warning is in order

Vanderbilt University Medical Center is one of the few institutions in the US that uses pharmacogenomics to help its patients. Rodan, who heads the field of personalized medicine, likes to tell about the center's first patient who benefited from it in 2010. The woman, who was 68 at the time, came to the center for treatment following a heart transplant, and her doctor inserted a stent to support the walls of one of her blood vessels. After that he tried to prescribe her medicine and name it Clopidogrel that it is acceptable to give it to prevent the formation of blood clots inside the stent. As he typed the name of the drug into her computerized medical file, an alert popped up on the screen, informing him that the woman's genetic tests indicated that she was unable to process the drug. The alert was part of Vanderbilt's new project, conducting pharmacogenic experiments. The alert that came up also included a suggestion for another drug, pressurgirl, which does not react negatively with the patient's genes.

Six years later, Vanderbilt continues to focus on heart patients, because the center was able to document some genetic effects on drugs to treat heart problems. One analysis done at the hospital, during which 9,500 of the patients were tested, found that 91% of them carried at least one genetic variant that would lead the doctors to recommend changing the dose or replacing the drug itself. A subset of these patients, about 5% of them, carried two copies of genes that increase their chances of disorders such as stroke or heart attack due to the formation of a blood clot, if they receive one of the standard-dose drugs.

Like St. Jude Hospital, the Vanderbilt center bears the vast majority of the costs associated with these tests itself, due to insurance issues. The insurance companies say that they are willing to cover only some of the tests because not all of them make an unequivocal contribution to improving medical results. "Insurance coverage varies for these tests because of the limited clinical evidence as to their effectiveness for patients," says Claire Krassing, spokeswoman for America's Health Insurance Plans - the national association of health insurers.

There are signs that this skepticism is softening. Managers at Vanderbilt say that in recent years, a policy of reimbursing expenses has begun to develop in some insurance companies, and they have begun to cover a small percentage of the costs. Other hospitals are following the developments. A few years after Vanderbilt began conducting tests, the University of Maryland Medical Center also began offering them, although as at Vanderbilt, the tests there are usually performed on patients with cardiovascular disease. This institution uses medical research grants received from the federal government to cover the costs of testing more than 600 patients. But according to Amber Beetles, which is one of the leaders of this move, Maryland hopes that it will soon be able to start charging the insurance companies with expenses.

Still, the number of hospitals in the US that allow pharmacogenomic testing for certain patients is less than ten, including Maryland, Vanderbilt and St. Jude. Next to covering expenses, the second major obstacle facing the widespread use of tests is the lack of clear guidelines for doctors who prescribe drugs. Most doctors were educated at a time when such tests were not available and they do not even think of using them. And it is likely that many of them lack the knowledge that would allow them to understand the results. "The doctor needs something more than the raw information; We need to build tools for him to use the information, systems that will support decision-making based on the information," says Rodan. A busy doctor needs someone to tell him that the patient has undergone a genetic test to identify certain variants, and what is found in the test. And he needs clear instructions regarding the changes requested in the patient's drug prescription due to the test results.

A doctor tried to prescribe the patient clopidogrel, a drug that prevents the formation of blood clots. When she typed the name of the drug into her computerized medical file, an alert appeared on the monitor announcing that genetic testing showed that she would not process the drug in her body.

The pharmacists at St. Jude work to make doctors aware of the existence of alternative drugs to the drugs they are used to prescribing. The hospital has produced information sheets on the meaning of specific genetic variants, and these are given to patients alongside the test results.

The degree of accuracy of the tests is also an important issue. The US Food and Drug Administration, the FDA, has taken steps to regulate genetic testing when offered directly to consumers. In 2013, for example, the FDA ordered a genetic testing company named 23andMe Stop selling the test kit that was its flagship and was called Personal Genomic Service. The authority claimed that the company failed to provide enough evidence that the test results were accurate. Since this product was taken off the shelves, other products have appeared that are supposed to fill this slot, with a special emphasis on pharmacogenomics. Society for Genetic Testing DNA4LIFE For example, it began marketing a DNA test to consumers at a price of $249, the purpose of which is to predict reactions to drugs. But in November 2015, the FDAA sent the company a stern warning letter saying that the company was required to obtain marketing approval or convince the administrator why it should be exempted from the approval process. The FDA says it cannot comment on the ongoing discussions between it and the company. However, he notes that in general he maintains close supervision of the tests because there is a fear of customer fraud, or worse, there is a fear that people will receive wrong information that could harm their health.

What is not subject to the supervision of the FDA, is the tests developed by hospitals like St. Jude. In the 70s, when the rules governing the development of tests in hospitals were first formulated, such diagnostic measures were relatively simple, and it was sufficient to explain that the tests were done in laboratories subject to federal licensing. Today, as genetics has become more complicated and the use of tests more common, the FDA is considering increasing its oversight. However, so far he has not published a timetable for implementing the required changes.

The situation may be changing slowly, as is the case in the insurance sector. These days, Relling leads with others an NIH-funded research group designed to rigorously document any new drug-gene interactions well supported by evidence from new studies. With the help of this information, the researchers formulate criteria that will be the basis for deciding which genes should be tested, and will clarify what changes should be made in prescribing drugs based on the results of these tests. The standards they formulate will be transferred to other laboratories in other hospitals.

As the number of tests increases and as the benefit to patients becomes clearer, the experts hope that the various obstacles and objections will diminish and eventually disappear altogether. Relling believes that as more doctors learn about the interactions between genes and drugs, they will prefer to avoid prescribing drugs without the results of such tests, and this will force research institutions to conduct more tests. "If a doctor knows that this genetic information exists and he does not rely on it," she says, "he is not providing proper medical care."


2 תגובות

  1. We must do such a test in every hospital for every patient who comes, and adjust individual medicines to him! Otherwise they do blind experiments on people and kill them too.

  2. It's all a matter of money, the interests of pharmaceutical companies, the authorities' financial position, policies of health funds, and insurance companies...
    The welfare of the patient is the last in the order of priorities.

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