HIV eradication unlikely following bone marrow transplantation

The first published report of the HIV eradication potential of a bone marrow transplant in an individual on highly active antiretroviral therapy (HAART) has concluded that eradication is unlikely utilising this method. The report is published as a letter in the March 30^th issue of the journal AIDS.

Currently available anti-HIV drugs may be able to reduce HIV to 'undetectable' levels in the blood, but they cannot remove HIV's genes that are integrated in the DNA of our own cells. Although scientists have been working on eradicating HIV from the body for more than two decades, and knowledge is increasing incrementally, their work has ultimately been disappointing.

One possible avenue considered promising in the pre-HAART era was bone marrow transplantation. 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 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 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. It suggested that utilising more potent anti-HIV drugs alongside pre-transplant chemo- or radiation therapy might provide a more satisfactory outcome, since AZT monotherapy had been used in most cases (Huzicka 1999).

Since then, however, other less toxic and/or invasive methods of HIV eradication have been attempted, and many different kinds of studies are ongoing.

French investigators have now reported the first case of a bone marrow transplant in an HIV-positive individual on HAART. The individual, a young man who required a transplant to treat monocytic acute myeloid leukaemia (AML) had achieved an undetectable viral load for 18 months before the transplant, and remained on HAART – with a short interruption – following the transplant until his death 191 days post-transplant.

The investigators used ultra-sensitive methods to measure HIV DNA levels in the man’s peripheral blood mononuclear cells (PBMC). Before transplantation, HIV DNA was at 2.76 log₁₀ copies/10₆ PBMC. After undergoing bone marrow ablation chemotherapy – which destroyed his own marrow – and then a bone marrow transplant, the procedure was considered a success with full restoration of blood cells after 19 days, and remission from AML confirmed at day 124.

Following the bone marrow transplant, blood plasma HIV RNA remained undetectable and HIV DNA levels examined in more than a million PBMCs became undetectable (<2 log₁₀ copies/10₆ PBMC), which, write the investigators, “gave hope of a significant reduction of the reservoir, indeed HIV remission.”

However, the man experienced severe graft-versus-host disease (which is when the immune cells from the donated marrow attack the body of the transplant patient, often affecting skin, eyes, stomach and intestines) which was only partially controlled via immunosuppressive drugs.

At 114 days post-transplant, HAART was interrupted for three weeks due to suspected toxicity, and sixteen days after HAART interruption both HIV RNA (4.61 log₁₀ copies/ml) and HIV DNA (2.50 log₁₀ copies/10₆ PBMC) became detectable again.

Phylogenetic analysis of four plasma viral strains (two in 2003, and two after the transplant) suggested that two totally different HIV quasispecies were in circulation before and after the bone marrow transplant, which, write the investigators, “confirmed that the viral reservoir previously constituted was not eradicated... Unfortunately the HIV-1 replication recovery a few days after HAART interruption unambiguously showed the persistence of an infectious viral residual reservoir.”

They conclude, “despite the use of intensive pretransplant cytoablative conditioning with chemotherapy combined with 18 months of potent effective HAART before [bone marrow transplant] (contrary to zidovudine alone used in cases described before 1996), the goal of HIV eradication was not achieved for this patient.”