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CATIE-News: Bite-sized HIV/AIDS news bulletinsBone marrow transplants to cure HIV—a long and troubled historyWidely available in most high-income countries, highly active antiretroviral therapy (HAART) can put AIDS into remission and greatly prolong the life of HIV positive people. However, HAART has not cured HIV infection. Despite this setback, researchers struggle to find a cure. When AIDS was first recognized in the 1980s, researchers noted that many patients had a profound weakness in their immune system because of the presence of overwhelming infections. In that decade, many studies were done with so-called immune boosters but none proved to provide consistent benefit. Still, at least the recognition of the immune deficit meant that researchers knew the immune system needed help. This led some scientists to consider transplanting bone marrow from healthy HIV negative people into HIV positive people. The hope was that the transplanted tissue would form new blood and immune cells and restore the health of the recipient, whose immune cells were depleted. In 1983, researchers attempted the first bone marrow transplant (BMT) to help restore immunity in a man with HIV-related illness. Sadly, the attempt failed and so did a subsequent try in another man with HIV. A BMT in 1984 in another HIV positive man resulted in a brief improvement before he died. Add AZTBy 1989, with more tools at their disposal, researchers were becoming more creative in trying to cure HIV/AIDS. One team tested its idea on an HIV positive man who had cancer. Researchers would first wipe out the patient’s bone marrow with radiation and, in subsequent experiments on other people, sometimes also chemotherapy. This would then be followed by intravenous doses of the first anti-HIV drug, AZT (zidovudine, Retrovir), prior to transplantation. Unfortunately, the first patient died from a relapse of cancer nearly two months after the transplant. Using the technology available at the time, researchers could not detect any HIV in the man. This stimulated further research using BMT in an attempt to cure HIV. In an experiment on 16 HIV positive people without cancer, American researchers used intensive doses of AZT combined with bone marrow transplants and regular infusions of lymphocytes from their HIV negative twins. This failed to rebuild the recipients’ immune systems and cure them of HIV. The big pictureBetween 1982 and 1996, at least 32 attempts to cure HIV infection or restore immunity with BMT were reported. In only two cases (of all those for which detailed reports and long-term monitoring were available) did researchers claim that HIV could not be detected. ( However, both patients subsequently died from either recurring cancer or from a complication called graft versus host disease (GVHD). This latter condition sometimes occurs when transplanted tissue attacks the recipient’s body. Technique is everythingThe rigour of technique and technology used in the previously mentioned studies to try to find HIV would be considered weak by today’s standards. In the present era, a few research laboratories have specialized in finding HIV in patient samples collected during eradication trials. These labs conduct immense and time-consuming efforts to find HIV, sometimes culturing millions of CD4+ T cells over months at a time. Using state-of-the-art techniques, in every case in recent eradication experiments HIV has eventually been found. It is in this context that future reports of a so-called cure must be evaluated. The Berlin patientA recent story in the Wall Street Journal written by award-winning author Mark Schoofs told the tale of an HIV positive cancer patient in whom, after a BMT, doctors could no longer find HIV. Newspaper headlines around the world interpreted this to mean that his HIV infection had been cured. We urge our readers to be cautious when reading about this case and we will explain why later in this report. Case detailsIn 2006, a 40-year-old HIV positive man sought care at Berlin’s Charité Medical University because of a diagnosis of leukemia. Despite taking HAART, his initial chemotherapy regimen failed to cure the leukemia. So for their second attempt at cancer treatment, his doctors tried something novel. Before we explain their idea, some background information is necessary. A rare mutationHIV needs at least two receptors to enter and infect a cell. One receptor is called CD4+ and the other is CCR5. Both of these receptors are commonly found on cells of the immune system. In people of European ancestry, sometimes a rare mutation occurs whereby a person’s immune system apparently lacks the CCR5 receptor. This mutation is called delta-32. In Central Europe, this mutation occurs in about 1% of people. And in northern Europe, this mutation is slightly more common. However, in people whose ancestors came from Africa, Asia or South America, this mutation is extremely rare. So, the Berlin doctors undertook an experiment and recommended a BMT from a donor whose cells lacked the CCR5 receptor. This meant that once the donated immune system grew in the recipient, he too would have cells that did not have CCR5 receptors, at least in theory. The transplantThe man’s doctors blasted his body with intensive chemotherapy and radiation to try to wipe out his bone marrow and immune system. Several days later he received the BMT, at which point he stopped taking HAART because doctors were concerned that these drugs might affect the growth of the new bone marrow. The patient also received transplant drugs to further suppress any remnants of his immune system and to prevent the transplanted cells from attacking his body. ResultsAfter the transplant, technicians regularly tested his blood using a research assay that could assess viral load with a lower limit of quantification of 15 copies. That is, the test could accurately count down to as low as 15 copies/mL of blood. Two months after the man’s BMT, the test could no longer detect HIV. And five months after the BMT they could not detect HIV in samples from his rectum. Note that antibodies to HIV were initially not detected in his blood after his BMT but became intermittently detectable several months later. It is possible that the intensive chemotherapy and radiation could have wiped out HIV-infected cells. However, the Berlin doctors did not apparently conduct the extensive tests that are used by laboratories that study HIV eradication. What does it all mean?The Berlin results are scientifically interesting and raise the possibility that one day, perhaps using genetic therapy, HIV might be cured. However, for now it is far too early to describe this case as cured. HIV could still be lurking deep inside the man’s body, finding sanctuary in some cell that perhaps has both CCR5 and CD4+ or even another receptor such as CXCR4. This other co-receptor can be used by HIV to enter cells. So researchers need to be vigilant against the possibility that the man has HIV-infected cells that have both CD4+ and one of these two receptors: CCR5 or CXCR4. That will require much testing. Note that BMTs in HIV do not usually have a good long-term outcome—historically most patients died from complications of the transplant or HIV, or, if they had cancer, the cancer returned, causing death. The Berlin researchers need to monitor this man extensively for many years before they can be certain about his HIV status. The French outcome—HAART + BMTLast year, French researchers reported the results of a BMT in an HIV positive teenager. He was symptom-free with moderately elevated CD4+ counts until 2003, when he developed lymphoma. He then began taking HAART and recovered from lymphoma, but in 2005 he developed another cancer—leukemia. Chemotherapy for this second cancer worked for a few months before he relapsed. So his doctors proposed a BMT (from a donor without the rare delta-32 mutation). Like many of the other cases we have described, his immune system was first wiped out with intensive chemotherapy, followed by a BMT accompanied by transplant drugs to suppress any attacks his new immune system might mount against his body. He continued to take HAART after the transplant, except for brief periods of suspected toxicity. Tests several months after the BMT showed that he had recovered from leukemia. After the BMT, tests for HIV and infected cells in samples of tissue taken from the man’s rectum, throat and lymph nodes suggested that the virus had been cleared there. However, four months after the transplant he had to interrupt HAART, and HIV and HIV-infected cells became detectable again. This development suggests that HIV had not been eradicated. He later developed intensive graft versus host disease as his new immune system attacked the skin and intestines, despite the extensive use of transplant drugs to suppress such attacks. He then developed complications from several infections and died six months after his transplant. The French report is notable because unlike previous reports from the 1980s or early 1990s, when AZT was the only anti-HIV agent used, the French used combination therapy or HAART. Implications for people with HIVThe German findings are scientifically interesting yet not practical. People who have the delta-32 mutation are rare, and even more so among potential donors of bone marrow. So there is no way that the German results will be repeated on a large scale and certainly not in low-income countries where the HIV pandemic rages. The good news is that the results of the German experiment provide hope that one day HIV might be cured. It will certainly stimulate other researchers to try to repeat the experiment to confirm the results. And one day, scientists might develop a genetic therapy that could make a person’s immune system resist HIV. It might also prompt other researchers to study wider use of drugs, such as maraviroc (Celsentri, Selzentry), that block the CCR5 receptor, preventing HIV from infecting cells. Maraviroc is approved for use as part of combination therapy for treatment-experienced patients in Canada and other high-income countries. Our next CATIE News story examines another potential therapy that claims to have wiped out HIV. AcknowledgementWe thank Andrew Badley, MD, PhD, (Mayo Clinic College of Medicine) for helpful discussions. —Sean R. Hosein REFERENCES:
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Created on: 12/12/2008 |
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Decisions about particular medical treatments should always be made in consultation with a qualified medical practitioner who is knowledgeable about HIV-related illness and the treatments in question. MORE | |