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ART Feasible During Bone Marrow Transplant--Enfuvirtide a Safe Option
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IDSA/IDWeek 2015, October 7-11, San Diego
Mark Mascolini
Continuing antiretroviral therapy (ART) proved feasible during bone marrow transplant (BMT), though side effects and drug interactions required antiretroviral switches in a 7-person US study [1]. Enfuvirtide, the injected HIV fusion inhibitor, was a safe and well-tolerated alternative to oral ART.
The only established cure of HIV infection came after stem-cell transplantation for acute myeloid leukemia, in which donor cells protected from HIV infection by the CCR5delta32 deletion replaced the patient's T cells [2]. Because stem-cell donors homozygous for the delta32 deletion are rare, researchers from Johns Hopkins and collaborators who reported the new case series observed that maintaining effective ART throughout BMT might protect donor cells from HIV until full donor chimerism is achieved. They hypothesized that in HIV patients needing BMT for cancer, "the combination of continuous ART and the allogeneic or graft versus host effect can reduce or completely eradicate HIV reservoirs."
Continuing ART during BMT raises several challenges, the researchers noted, including drug-drug interactions, renal or liver side effects, and intolerance of oral medications due to nausea, vomiting, or mucositis. Because of this last factor, they decided to assess the injected fusion inhibitor enfuvirtide as part of an optimized ART regimen during BMT. Other facets of the optimized regimen were avoiding ritonavir-boosted protease inhibitors (because of potential interactions) and ongoing antiretroviral changes as needs arose.
The 7 study participants, all men, ranged in age from 32 to 53 (median 50). All 7 had a viral load below 200 copies, and CD4 counts ranged from 57 to 547 (median 227). Three men needed BMT for acute myelogenous leukemia, 2 for non-Hodgkin lymphoma, and 2 for Hodgkin lymphoma. Six men had reduced-intensity conditioning and 1 had myeloablative conditioning.
Two men died 49 and 64 weeks after BMT, both because of liver failure, one probably because of graft-versus-host disease. One man had survived 4 weeks after BMT at the time of this report, and the other 4 were in remission for 29 to 120 weeks. One man who died had poor antiretroviral adherence, while the other who died had 73% adherence. All other men had 95% or better antiretroviral adherence. Everyone tolerated enfuvirtide well with no adverse events.
Among the 5 men who survived, antiretroviral switches ranged from 0 to 2. Five of 6 men had to switch from tenofovir disoproxil fumarate (TDF) because of rising serum creatinine. Other reasons for switches were interactions with azole antifungals, insurance issues, and concern about a possible abacavir hypersensitivity reaction.
Among 4 men who received BMT from matched donors, 2 achieved 100% donor chimerism (full replacement of original host cells by donor cells). The other 2 men had about 70% and 80% donor chimerism. In 3 men with mismatched donors, all had 100% donor chimerism at early follow-up points. In the 2 men who did not achieve full chimerism, HIV remained detectable in resting CD4 cells at about 0.18 and 0.45 per million cells. Among 3 men who achieved full chimerism and had post-BMT reservoir measurements, HIV could be detected in less than 1 per 10 million cells in 2 men and in fewer than 4 per 100 million cells in 1 man.
The researchers concluded that it is feasible to maintain ART during BMT, though antiretrovirals may have to be changed frequently, often because of renal dysfunction. They added that enfuvirtide proved a safe and well-tolerated alternative to oral ART in their patients. The investigators cautioned that interrupting ART after BMT can lead to severe retroviral syndrome, including meningoencephalitis, probably because HIV-naive donor cells lack any immune response.
References
1. Cash A, Capoferri A, Xu D, et al. Safety of optimized antiretroviral therapy during allogeneic matched and haploidentical bone marrow transplant in HIV+ individuals. IDWeek 2015, October 7-11, San Diego. Abstract 730.
2. Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. N Engl J Med. 2009;360:692-698. http://www.nejm.org/doi/full/10.1056/NEJMoa0802905
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