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Stem-cell transplants may purge HIV..... Post-Transplant and Off Drugs, H.I.V. Patients Are Apparently Virus-Free
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Everyone with HIV could benefit from this work, researchers say, because it could yield valuable information about how to eliminate the HIV reservoir, Heinrich said ....The value of the study might be in what it tells researchers about the reductions in HIV DNA that might need to be achieved in order to control HIV off treatment. "How low do we need to go - what level of reduction of the reservoir do you need in order to achieve a lasting impact? We hope our study will shed light on this important question".
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Post-Transplant and Off Drugs, H.I.V. Patients Are Apparently Virus-Free
By DONALD G. McNEIL Jr.
NY Times Published: July 3, 2013
Two H.I.V.-infected patients in Boston who had bone-marrow transplants for blood cancers have apparently been virus-free for weeks since their antiretroviral drugs were stopped, researchers at an international AIDS conference announced Wednesday.
The patients' success echoes that of Timothy Ray Brown, the famous "Berlin patient" who has shown no signs of resurgent virus in the five years since he got a bone-marrow transplant from a donor with a rare mutation conferring resistance to H.I.V.
The Boston cases, as with Mr. Brown's, are of no practical use to the 34 million people in the world who have H.I.V. but neither blood cancer or access to premier cancer-treatment hospitals.
But AIDS experts still find the Boston cases exciting because they are another step in the long and so-far-fruitless search for a cure. They offer encouragement to ambitious future projects to genetically re-engineer infected patients' cells to be infection-resistant. At least two teams are already experimenting with variants on this idea, said Dr. Steven G. Deeks, an AIDs researcher at the University of California at San Francisco Medical School.
Dr. Francoise Barre-Sinoussi, a discoverer of the virus that causes AIDS and the president of the International AIDS Society meeting now in Kuala Lumpur, Malaysia, called the findings about the Boston patients "very interesting and very encouraging." The announcement about the cases was made at the society's annual conference.
Mr. Brown is sometimes referred to as the "first H.I.V. cure."
But there are important differences between his case and those of the Boston patients. For example, no AIDS expert, including the doctors from Brigham and Women's Hospital in Boston following the two patients, is using the word "cured" to describe their status.
The technique used on them involves severely weakening the immune system before a marrow transplant. It is so dangerous that it is unethical to perform it on anyone not already at risk of dying from cancer, especially because most people with H.I.V. can live relatively normal lives by taking a daily antiretroviral cocktail.
"But we cannot speak about 'cure,' " she added. "The follow-up has been very short."
One patient stopped taking antiretroviral drugs seven weeks ago. For the other, it has been 15 weeks. No virus or antibodies to the virus have been found in their blood or other tissues since.
Normally, when a patient stops the drugs, the virus bounces back in less than a month, but each person is different.
"It could come back in a week, or in six months," said Dr. Timothy Henrich, a doctor overseeing the two patients. "Only time will tell."
The process the two patients underwent is risky - a third patient in the study died when his cancer returned - but somewhat less so than the procedure done on Mr. Brown.
Mr. Brown had leukemia. The three Boston patients had lymphoma.
The Boston patients' bone marrow, where new blood cells are made, was only partially destroyed by drugs before they were given new marrow from matching donors - a process that carries a 15 to 20 percent risk of death, Dr. Henrich said.
Mr. Brown's marrow was completely obliterated by drugs and whole-body radiation, a procedure that kills 40 percent of the patients, and he had it done twice.
Mr. Brown's new marrow came from a donor who was a close genetic match and had a rare mutation that makes a person virtually impervious to infection with H.I.V.
The mutation, known as delta 32, creates CD4 cells - the white blood cells that the virus attacks - lacking a CCR5 surface receptor, the "door" that the virus uses to enter the cell.
The donors for the Boston patients did not have the delta 32 mutation.
Unlike Mr. Brown, the Boston patients stayed on antiretroviral therapy throughout the lengthy transplant process and for years afterward. The drugs prevent the virus from replicating itself.
"The idea was to protect the new donor cells from becoming infected," Dr. Henrich explained.
During that time, in a phenomenon known as graft-versus-host disease, the new cells were attacking their old, chemotherapy-weakened counterparts and clearing them from the body, a process that takes about nine months, Dr. Henrich said.
Because only the old cells were infected with H.I.V., the hope was that graft-versus-host disease would "mop up" all the viral reservoirs.
But runaway graft-versus-host disease can be fatal, so the two patients were intermittently on and off immunosuppressive drugs and steroids to control it.
One immunosuppressive drug, sirolimus, may also have helped kill off H.I.V., he said.
It is known to prevent retroviruses like H.I.V. from replicating.
The two patients had transplants between two and five years ago. They had months of tests on their blood and tissues to make sure no H.I.V. or antibodies to it were found, before Dr. Henrich and his research partner, Dr. Daniel Kuritzkes, proposed stopping the antiretroviral treatment.
For such tests, doctors remove immune cells and "activate" them with chemicals to make them reproduce. If any virus is hiding in the cells' DNA, it is "spit out" and can be detected.
But doctors can never be sure that they have tested all the reservoirs where dormant virus might hide. It is relatively easy, for example, to sample rectal but not brain tissue.
Since the patients stopped taking antiretrovirals, they "feel great and are leading completely normal lives," Dr. Henrich said.
That distinguishes them from Mr. Brown, who has survived virus-free for more than five years but still has weakness and pain from his grueling anticancer regimen.
AIDS specialists are interested in the Boston patients because they offer new insights into how the immune system can be used to attack the virus.
Dr. Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Diseases, said it was "conceivable and maybe even likely" that their H.I.V. was permanently gone.
If so, he said, it would show that it is not necessary to find a matching donor who also had the delta-32 mutation.
Dr. Deeks, the AIDS researcher in California, said the cases raise the question of when to say an H.I.V. patient has been "cured."
"Should we wait six months to see if the virus rebounds?" he asked. "Or will we have to wait up to five years, as oncologists tend to do with cancer?"
Dr. Barre-Sinoussi said she might eventually prefer to adopt the term oncologists use: "in remission."
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Stem-cell transplants may purge HIV.....
Two men with HIV may have been cured after they received stem-cell transplants to treat the blood cancer lymphoma, their doctors announced today at the International AIDS Society Conference in Kuala Lumpur.
WELBA05 - Oral Abstract Session
In depth investigation of peripheral and gut HIV-1 reservoirs, HIV-specific cellular immunity, and host microchimerism following allogeneic hematopoetic stem cell transplantation
Presented by Timothy Henrich (United States).
T. Henrich1,2, E. Hanhauser1, M. Sirignano3, B. Davis2,3, T.-H. Lee4,5, S. Keating4,5, M. Busch4,5, F. Marty1,2,6, A. LaCasce2,6, P. Armand2,6, R. Soiffer2,6, M. Altfeld2,3,7, D. Kuritzkes1,2
1Brigham and Women's Hospital, Boston, United States, 2Harvard Medical School, Boston, United States, 3Massachusetts General Hospital, Boston, United States, 4Blood Systems Research Institute, San Francisco, United States, 5University of California, San Francisco, San Francisco, United States, 6Dana-Farber Cancer Institute, Boston, United States, 7Ragon Institute of MGH, Harvard & MIT, Cambridge, United States
Background: We previously reported the loss of detectable peripheral blood HIV-1 reservoirs in 2 individuals following reduced-intensity conditioning allogeneic hematopoetic stem cell transplantation (RIC-alloHSCT) from wild-type CCR5 donors. To understand further the impact of alloHSCT on viral reservoirs, we studied the longitudinal effects of HSCT on host microchimerism and HIV-specific cellular immunity, and tested rectal tissue and peripheral blood mononuclear cells (PBMCs) obtained by leukapheresis for evidence of residual HIV-1 DNA or replication-competent proviruses up to 4.3 years post-transplantation.
Methods: The following experiments were performed: 1) collection of PBMCs by leukapheresis for large-scale HIV-1 quantification of genomic DNA and viral co-culture from purified CD4+ T lymphocytes (assays using 5 million PBMCs were repeated up to 30 times for each patient), 2) HIV-1 DNA PCR on rectal tissue (one patient), and 3) microchimerism studies of residual donor PBMCs. We also investigated HIV-specific cellular immune function by ELISpot IFN-gamma screenings of total PBMCs involving comprehensive HLA-specific peptide panels on the above patients in addition to a third RIC-alloHSCT patient that died 6 months post-transplantation from recurrent lymphoma; a fourth patient who received an autologous HSCT served as a control.
Results: No HIV-1 DNA was detected from PBMCs from both previously-reported RIC-alloHSCT patients indicating at least a 3 to 4 log10decrease in peripheral viral reservoir size post-transplantation. No HIV-1 p24 antigen was detected by viral co-culture from purified CD4+ T cells, and no HIV-1 DNA was detected in rectal tissue. Residual host cells constituted less than 0.001% of PBMCs post-HSCT and may have represented circulating non-hematopoietic cells. No HLA-specific or pooled HIV-1 peptides elicited a strong HIV-specific immune response from all patients either before or after allogeneic or autologous HSCT.
Conclusion: HIV-1 remained undetectable from peripheral blood and rectal tissue after RIC-alloHSCT in patients on ART despite the testing of very large numbers of PBMCs or CD4+ T cells. The lack of detectable HIV-1 was in the setting of full donor chimerism and weak HIV-specific cellular immunity. Analytical treatment interruption remains the definitive experiment to test the full impact of RIC-alloHSCT on HIV-1 persistence.
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Nature | News
http://www.nature.com
Stem-cell transplants may purge HIV
But treatment is too risky for most people infected by the virus.
By Erika Check Haden
03 July 2013
Daniel Kuritzkes, a researcher working with two 'Boston patients' who may have been cured of HIV, speaks at an AIDS conference in Kuala Lumpur, Malaysia.
International AIDS Society/Steve Forrest/Workers' Photos
Two men with HIV may have been cured after they received stem-cell transplants to treat the blood cancer lymphoma, their doctors announced today at the International AIDS Society Conference in Kuala Lumpur.
One of the men received stem-cell transplants to replace his blood-cell-producing bone marrow about three years ago, and the other five years ago. Their regimens were similar to one used on Timothy Ray Brown, the 'Berlin patient' who has been living HIV-free for six years and is the only adult to have been declared cured of HIV. Last July, doctors announced that the two men - the 'Boston patients' - appeared to be living without detectable levels of HIV in their blood, but they were still taking antiretroviral medications at that time.
Timothy Henrich, an HIV specialist at Brigham and Women's Hospital in Boston, Massachusetts, who helped to treat the men, says that they have now stopped their antiretroviral treatments with no ill effects. One has been off medication for 15 weeks and the other for seven. Neither has any trace of HIV DNA or RNA in his blood, Henrich says.
If the men stay healthy, they would be the third and fourth patients ever to be cured of HIV, after Brown and a baby in Mississippi who received antiretroviral therapy soon after birth.
But Henrich and Daniel Kuritzkes, a colleague at Brigham who also worked with the men, caution that it is still too early know whether or not the Boston patients have been cured. For that, doctors will need to follow the men closely for at least a year, because the virus may be hiding out in 'reservoirs' - parts of the men's bodies, such as their brain or gut, that can harbour the virus for decades.
"We're being very careful not to say that these patients are cured," Kuritzkes says. "But the findings to date are very encouraging."
HIV researcher Steven Deeks of the University of California, San Francisco, says that doctors might need to wait at least two years before declaring that a cure has been achieved. "Any evidence that we might be able to cure HIV infection remains a major advance," Deeks says. But, he adds, "there have been cases of patients who took many weeks off therapy before the virus took off".
Exciting news
Still, researchers and doctors are excited about the news, especially because the Boston patients' treatment differed from the Berlin patient's regimen in one key way. Brown was given stem cells that were predisposed to resist HIV infection, because the donor happened to have a mutated version of a key protein - CCR5 - that is needed for HIV to infect cells. So Brown's transplant was akin to gene therapy with HIV-resistant cells.
But the Boston patients received stem cells without the protective mutation. The transplanted cells must therefore have been protected from infection by the antiretroviral drugs taken during cancer treatment. Their doctors think that an immune response called graft-versus-host disease - a post-transplant reaction in which donated cells kill off a patient's own cells - may have then wiped out the patients' HIV reservoirs, potentially curing the men.
Transplant specialist Christine Durand of Johns Hopkins University School of Medicine in Baltimore, Maryland, says that the case of the Boston patients may show that current antiretroviral drugs are powerful enough, on their own, to protect the transplanted cells. "If cure has been achieved in the Boston patients, then it was the antiretroviral therapy, not gene therapy, that protected the donor cells," she says.
The finding is very important for people with HIV who also need blood-cell transplants, but the treatment is unlikely to be used more generally because the risks from transplants are high. Durand says that Johns Hopkins is now revising its transplant procedures to keep people with both cancer and HIV on antiretroviral drugs during the transplant regimen.
Separately, the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group, based in Silver Spring, Maryland, is trying to replicate the Berlin patient's cure by giving CCR5-mutated HIV-resistant blood from umbilical cords to children and adults with HIV and cancer.
Everyone with HIV could benefit from this work, researchers say, because it could yield valuable information about how to eliminate the HIV reservoir, Heinrich said ....The chief value of the study will be in what it tells researchers about the reductions in HIV DNA that might need to be achieved in order to control HIV off treatment. "How low do we need to go - what level of reduction of the reservoir do you need in order to achieve a lasting impact? We hope our study will shed light on this important question".
"We are still a long way off from a viable cure option for most patients," Durand says. "But every step counts, and these cases can teach us important lessons."
Kuritzkes said the patients will be put back on the drugs if there is a viral rebound.
A rebound will show that other sites are important reservoirs of infectious virus and new approaches to measuring these reservoirs will be needed in developing a cure, Henrich said.
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