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Two Boston Stem-Cell Transplant Patients Stop Antiretrovirals With No Rebound
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
Two HIV-positive Boston men who had stem-cell transplants for lymphoma stopped their antiretrovirals 2 to 5 years after the transplants and have not had viral load rebounds after 7 and 15 weeks without therapy [1]. The two Boston men differ from the cured Berlin patient in several ways. It remains too early to tell whether the Boston transplant approach can result in years of HIV-free life without antiretroviral therapy, as in the Berlin patient.
The Boston men had taken antiretroviral therapy for several years when they were diagnosed with lymphoma. Both underwent reduced-intensity conditioning allogeneic hematopoetic stem cell transplantation (RIC-alloHSCT) with stem cells from donors who did not have the CCR5 delta 32 mutation that largely shields T cells from HIV infection [2]. They continued antiretroviral therapy during and after the transplants for 2 and 5 years. After the stem-cell transplants, host cells made up less than 0.001% of their peripheral blood mononuclear cells (PBMCs), a finding indicating that cells generated by the transplants accounted for virtually all PBMCs in these men.
At that point Timothy Henrich, Daniel Kuritzkes, and colleagues asked the men to try a closely monitored antiretroviral interruption. Both agreed. Seven and 15 weeks after treatment stopped, HIV did not reappear in PBMCs, according to a study summary posted online by Uriel Moreno-Nieves, writing for the meeting organizer, the International AIDS Society [3]. HIV p24 antigen, a signal of viral replication, could not be spotted by viral coculture in purified CD4 cells. One man had no HIV DNA detectable in rectal tissue. And neither man had detectable HIV-specific immune responses [3].
These two men differ from the Berlin patient in several notable ways. First, the Berlin patient underwent pretransplant obliteration of bone marrow cells, while the "reduced-intensity conditioning" in the Boston men only partially destroyed their bone marrow. The approach with the Berlin patient carries a 40% risk of death, according to the New York Times [4], while the Boston tactic carries a 15% to 20% death risk. The Berlin patient had leukemia; the Boston men had lymphoma.
The Berlin patient received a transplant from a donor carrying the rare CCR5 delta 32 mutation, while the Boston donors had wild-type (unmutated) CCR5. Unlike the Berlin patient, the Boston men kept taking their antiretrovirals throughout their transplants and for years afterwards. The Boston strategy aimed to let antiretroviral therapy protect newly minted cells from becoming infected with HIV. As antiretroviral therapy continued, the Boston clinicians counted on graft-versus-host disease to kill the men's old, possibly still-infected cells [4]. They also surmised that one of the immunosuppressive drugs the men took, sirolimus, may have helped kill HIV-positive cells [4].
Together, these differences between Berlin and Boston suggest a type of gene therapy (via the CCR5 delta 32 transplant) cured the Berlin patient, while ongoing antiretroviral therapy plus graft-versus-host disease deserve credit for banishing HIV (so far) from the Boston men.
Because antiretroviral-free follow-up has continued for only 7 and 15 weeks, it is impossible to say whether the Boston approach will ultimately work as well as the Berlin strategy. If it does, it would not be a practical--or ethical--way to rid bodies of HIV. Stem cell transplantation is hugely expensive and so risky that it cannot be considered for anyone not at risk of dying from their cancer [4].
References
1. Henrich T, Hanhauser E, Sirignano M, et al. In depth investigation of peripheral and gut HIV-1 reservoirs, HIV-specific cellular immunity, and host microchimerism following allogeneic hematopoetic stem cell transplantation. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract WELBA05.
2. Henrich TJ, Hu Z, Li JZ, et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis. 2013;207:1694-1702.
3. Moreno-Nieves U. Late breaker track A. Rapporteur report. IAS 2013. http://pag.ias2013.org/session.aspx?s=75
4. McNeil DG Jr. Post-transplant and off drugs, H.I.V. patients are apparently virus-free. New York Times. July 3, 2013. http://www.nytimes.com/2013/07/04/health/post-transplant-and-off-drugs-hiv-patients-are-apparently-virus-free.html
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