The Berlin Patient

Feb. 27, 2015

By Medical Discovery News

Millions of people around the world are infected with HIV, the virus that causes AIDS, but only one has ever been cured. Known as the “Berlin Patient,” Timothy Ray Brown is a 48-year-old American living in Germany. Scientists and physicians have wondered how he was cured, and some recently published studies in monkeys have provided one clue.

Brown had been HIV positive since 1995. When HIV infects the body’s cells, it integrates its genetic information into cells, making the virus a permanent part of the host’s genetic information. Brown’s HIV was held at bay by antiretroviral drugs that have made this infection survivable.  However, in 2006 he was diagnosed with acute myeloid leukemia (AML), a cancer unrelated to HIV. AML affects a group of blood cells in bone marrow called the myeloid cells. Brown underwent grueling chemotherapy that failed. In the hope of saving his life, he received two bone marrow transplants. The year of his first transplant, he stopped taking the antiretrovirals, which would normally cause a patient’s HIV levels to skyrocket.

Yet, years later, there is no sign of the virus returning. Only traces of HIV’s genetic material have been found in his blood, and those pieces are unable to replicate. The big question now is: how was this accomplished?

His treatment for AML included three different factors that could have individually or collaboratively resulted in curing his HIV infection. First, in preparation for a bone marrow transplant, a patient is treated with a combination of chemotherapy and whole body radiation to eliminate the entire immune system in preparation for receiving a new one. Second, Brown received blood stem cell transplants from a person with a defective cell surface protein, CCR5, which is what HIV uses to enter cells. People with a CCR5 mutation are resistant to HIV infection. Third, his new immune system may have eliminated the virus and remnants of his old immune system that harbored it in something called a graft versus host reaction.

In an experiment to determine how Brown was cured of HIV, scientists isolated blood stem cells from three Rhesus Macaque monkeys and put them into cold storage. They then infected those monkeys as well as three control monkeys with an engineered version of HIV. Soon after infection, all six monkeys were treated with a cocktail of drugs, and just like in humans, the levels of the virus soon declined. A few months later, the first three monkeys underwent radiation treatments to eliminate their immune systems, and then their immune systems were restored using their own stem cells from storage. Months later, the antiretroviral drugs were withheld from all six monkeys, and the virus came roaring back in five of them. One of the monkeys who underwent the stem cell transplant did not have the virus return in its blood, but it was detected in some tissues.

This experiment established that the destruction of immune system prior to bone marrow transplant was not sufficient to eliminate the virus, so the selection of bone marrow cells resistant to HIV infection and/or the graft versus host reaction may be the reason Brown was cured of HIV. Further studies are needed before we will know exactly how HIV can be cured.

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Thalidomide: A Nightmare Revisited

Spet. 20, 2013

By Medical Discovery News

While thalidomide is now being tapped for its cancer-fighting properties, it has a more notorious history. Starting in 1957, doctors recommended thalidomide as a mild over-the-counter sleeping pill supposedly safe enough for even pregnant women. That it also reduced morning sickness made it even more popular. The company that made thalidomide aggressively marketed the drug in 46 countries even after the wife of an employee who took the drug before its release gave birth to a child with no ears. Within two years, an estimated 1 million people in West Germany were taking the drug daily. However, thousands of babies born with severely malformed limbs revealed that this drug was not safe, but that connection was not made until 1961.

German pharmaceutical company Chemie Grünenthal GmbH originally developed thalidomide to treat convulsions, but users reported feeling sleepy. During testing, the company discovered that it was almost impossible to take enough thalidomide to be fatal. The company did not test the drug’s effects during pregnancy. Though approved for use in Germany and elsewhere in Europe, a U.S. Food and Drug Administration medical officer named Frances Oldham Kelsey denied its license because there was insufficient clinical evidence about its side effects. This decision limited the impact of the drug in America. In 1962, President John F. Kennedy awarded Kelsey the President’s Medal for Distinguished Federal Civilian Service. 

Warnings of the drug’s possible toxicity began to emerge in 1959. Adults taking the drug reported peripheral neuritis or inflammation of the nerves and the resulting nervous system damage. Even after an Australian and a German physician independently linked thalidomide to birth defects in 1961, it was four months before the company withdrew the drug from the market, and it was banned even later in some countries. It is thought that at least 100,000 pregnant women were affected by the drug leading to more than 90,000 miscarriages. Even a single dose of thalidomide during early pregnancy may cause severe birth defects. About 40 percent of babies exposed to the drug die before or soon after delivery. Over 10,000 children were born with thalidomide-related birth defects such as missing or shortened limbs. Still others were born deaf and blind, some had curved spines and some had damaged hearts and brains and many other abnormalities.

The company refused to pay compensation for many years until 1970 when they established a $28 million fund in return for legal immunity. When those funds were depleted, the German government paid compensation to victims. In 2009, Grünenthal provided another $63 million in compensation. The company did not publicly apologize for its actions until August 2012.  However, dissatisfaction with that statement and the level of compensation by the company continues.

Researchers are actively seeking drugs that work similarly to thalidomide but without the side effects. The thalidomide tragedy prompted creation of and reforms in the laws and policies that govern drug testing and approval, reducing the chances of another such incident, but it must not be forgotten lest history repeats itself.

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