Examining the excitement over a bone marrow transplant that ‘eradicated’ HIV, by Edwin J Bernard.
Last month, the world’s press reported that a 42-year-old American man living in Berlin had been ‘cured’ of his HIV infection following a bone marrow transplant two years earlier.
We last examined the elusive ‘cure’ for HIV almost three years ago, following media reports of so-called “miracle man” Andrew Stimpson and his premature claims that he was ‘cured’ of HIV in November 2005.1
Is this latest case just another example of media hype?
A tantalising possibility?
Between 1982 and 1996, reports of over 30 bone marrow transplants in HIV-positive individuals with advanced disease were published. In some cases, individuals required chemotherapy and radiation and subsequent bone marrow transplants for non-Hodgkin’s lymphoma. In other cases, researchers actively enrolled individuals with AIDS at a time when there appeared to be no other options and replaced their bone marrow with those from healthy transplanted donors - in some cases these were not humans, but baboons - in order to attempt to repopulate the individual’s immune system with healthy, HIV-free blood cells.
Although most died due to HIV - or transplant-related complications soon after the procedures - two individuals were found to have undetectable HIV RNA and DNA levels in the weeks and months following the procedures. A review of these reports, written in 1997 and published in 1999, suggested that bone marrow transplantation offered the tantalising possibility of a “cure” for HIV.2
Then, last year, French researchers reported on the case of an HIV-positive individual who had required a bone marrow transplant to treat acute myeloid leukaemia. As well as experiencing severe graft-versus-host disease (which is when the immune cells from the donated marrow attack the body of the transplant patient), the man was found to still have detectable viral load following a post-transplant treatment interruption, and he died 191 days post-transplant. Doctors concluded that eradication of HIV from the body was unlikely utilising this method.3
A promising approach
Unlike the previously reported cases, the most recent case differs in two important ways:
unusually, despite the high-risk nature of the procedure, the patient is still alive two years following the transplant.
a transplant donor was sought who specifically had two copies of the natural genetic mutation (also known as a polymorphism) delta32 CCR5.
People who have acquired two copies of this mutation (from both parents) are usually protected against infection with HIV, although there have now been at least eight case reports where infection occurred in people with two mutant CCR5 genes.4
The case was first reported in February 2008 as a poster presentation at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston. The poster described an HIV-positive individual who had achieved an undetectable viral load on antiretroviral therapy for several years before being diagnosed with acute myeloid leukaemia. After radiation treatment and chemotherapy failed to successfully treat the leukaemia, he underwent stem cell therapy by having a bone marrow transplant.
Out of a total of 232 potential donors with the same HLA type (genetic markers that identify cells as ‘self’ and prevent the immune system from attacking them), one donor was also found to have two copies of delta32 CCR5.
The man was asked to stop his antiretroviral therapy the day before his bone marrow transplant, since doctors were concerned it might have interfered with his recovery from the procedure. However, 68 days following the transplant, he was found to still have an undetectable viral load in his blood and bone marrow. Follow-up tests 285 days later also found no virus in rectal fluids, where the virus is often present.
The investigators were careful not to call this a ‘cure’ in their poster presentation, instead suggesting that “this finding... encourages further investigations of the development of CCR5-targeted treatment options.” 5
A ‘functional cure’
In September this year, the Foundation for AIDS Research (amfAR) arranged a meeting between German haematologist, Dr Gero Hütter - who had found the donor and performed the stem cell transplant - and ten experts in clinical AIDS, stem cell transplantation and HIV virology. Further details of the case were reported in an article published on the amfAR website on 5 November. 6
The man had suffered a relapse of his leukaemia following his initial transplant and had required a second transplant using the same donor. However, he continued to have no detectable signs of HIV in his blood, bone marrow and rectum, and further investigations found no HIV in his lymph nodes or brain.
“To the limits of our ability to detect HIV,” wrote amfAR’s senior scientific consultant, Dr Jeffrey Laurence, “it appears that the virus has been eradicated from his body. At the very least this patient represents a functional cure: he is off all anti-HIV meds, has a normal T-cell count, and exhibits no evidence of virus.” 7 However, the amfAR experts have arranged to examine further specimens from the patient, since they believe the distinct possibility remains that HIV has not been totally eradicated from his body.
The story was then picked up in the Wall Street Journal 8 on 7 November, and press interest grew so great that Dr Hütter and his colleagues at the Charité Clinic for Haematology and Oncology in Berlin held a press conference on 12 November, resulting in global coverage of the case.
There is no doubt that the case is remarkable, even if experts are not satisfied that HIV has been completely and permanently eradicated. However, it is unlikely to be repeatable due to several important limiting factors:
The number of potential donors is limited, since less than 1% of individuals in parts of the Middle East, Europe and Asia (and none in Africa, Asia and South America) have two copies of delta32 CCR5.9 In addition, there are more than 100 HLA types. Taken together, the pool of potentially matching donors is very shallow indeed.
Bone marrow transplants are expensive (costing up to US$250,000 according to amfAR), and result in a 10 to 30% mortality rate. Even Dr Hütter admits that they are so dangerous that "they can't be justified ethically" in anything other than life-threatening situations like late-stage leukaemia. 10
The patient received immunosuppressive treatment for two years after the transplant. Some experts think this has played a role in the failure of HIV to return.
However, this case report may aid ongoing research into treatments, such as gene therapy, that seek to eradicate HIV - although cost and safety issues are likely to continue to be limiting factors for the foreseeable future.
1. Can HIV be cured? ATU 153, January/February 2006.
2. Huzicka I Could bone marrow transplantation cure AIDS? Medical Hypotheses 52 (3): 247-257, 1999.
3. Avettand-Fenoel V et al. Failure of bone marrow transplantation to eradicate HIV reservoir despite efficient HAART. AIDS 21 (6):775–786, 2007.
4. Sheppard HW HIV-1 infection in individuals with the CCR5-Delta32/Delta32 genotype: acquisition of syncytium-inducing virus at seroconversion. JAIDS 29(3):307-13, 2002.
5. Hütter G et al. Treatment of HIV-1 infection by allogeneic CCR5-Δ32/Δ32 stem cell transplantation: a promising approach. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 719, 2008.
6. Laurence J A First Step Toward a Cure for AIDS? Novel Procedure Appears to Have Eliminated HIV. The Foundation for AIDS Research. 5 November, 2008. http://www.amfar.org/cgi-bin/iowa/programs/resrch/record.html?record=71
7. Laurence J A first step toward a cure for AIDS? Novel procedure appears to have eliminated HIV. amfAR, November, 2008. http://www.amfar.org/cgi-bin/iowa/programs/resrch/record.html?record=71
8. Schoofs M A doctor, a mutation and a potential cure for AIDS. Wall Street Journal. 7 November, 2008. http://online.wsj.com/article/SB122602394113507555.html
9. Martinson JJ et al. Global distribution of the CCR2-64I/CCR5-59653T
HIV-1 disease-protective haplotype. AIDS 14:483-489, 2000.
10. Harrell E Can a bone-marrow transplant halt HIV? Time, 13 November 2008. http://www.time.com/time/health/article/0,8599,1858843,00.html?imw=Y