Editor’s note: Soon after this article was posted to AIDSmeds and POZ, the editorial staff discovered that the long-anonymous Berlin Patient has decided to come forward, for the first time ever, in a profile published in the December 9 issue of Stern magazine. He is 44-year-old Timothy Ray Brown. (Click here for an approximate English translation of the profile teaser posted to stern.de.)
The “Berlin Patient”—a man living with HIV who underwent a transplant involving HIV-resistant stem cells in 2007 for the treatment of leukemia—has been classified as cured of his HIV, according to an update of the patient’s experience published online, ahead of print, on December 8 by the journal Blood. The man has remained off HIV treatment for three-and-a-half years with normal CD4 counts and no evidence of HIV replication.
Though it was initially suspected that HIV archived in the man’s cells would begin proliferating once his immune system began to recover from pre- and post-transplantation treatment, this was not observed and the team monitoring the patient now conclude, “our results strongly suggest that cure of HIV has been achieved in this patient.”
The intriguing case, first reported at 15th Conference on Retroviruses and Opportunistic Infections (CROI) in 2008, involved a 40-year-old American HIV-positive man living in Berlin with a relapse of acute myeloid leukemia—a potentially fatal cancer of the immune system—in February 2007. Rather than simply performing a transplant that would increase the patient’s chance of cancer survival, Gero Huetter, MD, of the University Medicine Berlin and his colleagues opted to perform a transplant that might also increase the patient’s chance of surviving HIV.
Huetter asked the blood and tissue bank if any of its stem cell donors had a particular genetic defect, called the CCR5 delta-32 deletion. This defect prevents CD4 cells from developing a receptor, called CCR5, on their surfaces. People who inherit this genetic mutation from both parents have CD4 cells that lack the CCR5 entirely and, as a result, are highly resistant to HIV. People who inherit the mutation from one parent can be infected, but because they have fewer CCR5 receptors on their CD4 cells, tend to have slower disease progression.
Huetter scored an excellent match—a suitable donor with the delta-32 deletion from both parents.
As is standard in stem cell transplants, Huetter’s team prepared the patient to receive the cells by first ablating, or destroying, most of his immune cells. This process, also called conditioning, is usually performed using intensive chemotherapy and radiation. The patient also began taking a number of immune-suppressive drugs to reduce the risk of graft-versus-host disease (GVHD) following the transplant.
On the day of his transplant, he discontinued his antiretrovirals.
About 13 months after receiving the transplant, the patient’s leukemia relapsed yet again. A second round of conditioning, followed by another transplant with stem cells with the CCR5 delta-32 deletion, was performed. This led to a complete remission of the cancer.
At no point during the initial 20-month follow-up period did the Berlin Patient’s HIV rebound, as highlighted during the initial CROI presentation and in a detailed case report published in a February 2009 issue of The New England Journal of Medicine.
However, uncertainty remained over whether a bona fide cure for HIV infection had been achieved in this patient. First, it was assumed that traces of HIV remained in the patient’s body, despite intensive pre-transplant conditioning. Second, CXCR4-targeting HIV—virus capable of using another receptor on CD4 cells—was found in the patient’s blood before conditioning and transplantation. In turn, it was suggested that archived CXCR4-targeting HIV would proliferate and become detectable, especially with the discontinuation of immune-suppressive drugs potentially keeping existing cellular reservoirs of HIV in check.
According to the December 8 report, written three-and-a-half years following the initial transplant and several months after the discontinuation of immune-suppressive treatment, the patient’s CD4 count has returned to normal—it is well within the range of HIV-negative, immune-competent individuals. What’s more, HIV remains continuously undetectable, not only in blood plasma but also in blood cells. As the article states: “Today, by monitoring the most common prognostic markers, i.e., plasma viral load and CD4+ T cell counts in the peripheral blood, HIV disease cannot be assessed in this patient.”
Additional findings used by Huetter’s team to bolster the claim that this patient has, in fact, been cured—earlier reports by Huetter and his colleagues were resistant to use the term “cure” as an outcome, based on lingering concerns—were also published. First, the researchers demonstrated successful reconstitution of CD4s throughout the body, notably in the gut, which is a common site of infection and cellular depletion in people with active HIV infection. Second, many of the HIV-negative cells collected post-transplantation were activated “memory” CD4 cells, which are the preferential targets of HIV and susceptible to infection with CXCR4-targeting virus. Lastly, during the process of immune reconstitution, Huetter’s team found that long-lived cells belonging to the patient were gradually replaced with the donor’s cells, suggesting that the any lingering population of HIV-infected cells was continuing to decrease in size.
“In summary,” the authors write, “our results demonstrate successful CD4+ T cell reconstitution at the systemic level as well as in the [gut] following [transplantation], and additionally provide evidence for the reduction in the size of the potential HIV reservoir overtime. Although the recovered CD4+ T cells are susceptible to infection with X4 HIV infection, the patient remains without any evidence for HIV infection since more than 3.5 years after discontinuation of ART. From these results, it is reasonable to conclude that cure of HIV infection has been achieved in this patient.”