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Viral Load Undetectable 288 Days Without ART After Stem Cell Transplant
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Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle
Mark Mascolini
HIV RNA in plasma remained undetectable for 288 days after antiretroviral therapy (ART) stopped in a man who had undergone allogeneic peripheral blood stem cell transplant (PBSCT) more than 2 years earlier [1]. Then HIV rebounded, although several measures showed waning viral reservoirs after the transplant.
The Berlin patient—the only verified HIV cure case—is a man who underwent allogeneic stem cell transplantation for acute myeloid leukemia with cells from a donor homozygous for the CCR5 delta32 deletion [2]. This man has remained free of HIV replication without ART for nearly a decade.
The new case reported from the Mayo Clinic involves a 55-year-old man diagnosed with HIV in 1990, who began ART in 1999, stopped between 2004 and 2009, then restarted. Diagnosed with B-lineage acute lymphoblastic leukemia with myeloid features in April 2013, he switched regimens to tenofovir/emtricitabine plus raltegravir and etravirine because of persistent low-level viremia (90 to 107 copies) and anticipating myeloablative therapy. The man underwent reduced-intensity conditioning in October 2013 followed by allogeneic PBSCT from a CCR5 wild-type, HLA-matched related donor.
At the time of the transplant, the patient's viral load measured 25 copies and his CD4 count stood at 288. The man remained on his stable antiretroviral regimen after PBSCT. Four days after the transplant his viral load lay below 10 copies, then bounced into a low detectable range through posttransplant day 91, when it again fell below 10 copies. During this time E coli septicemia and Pneumocystis jirovecii pneumonia developed. Colon biopsy-proved grade 1 graft-versus-host disease (GVHD) developed 4 months after PBSCT and was not treated with augmented immunosuppression.
More than 2 years (784 days) after PBSCT, the man agreed to an analytic treatment interruption, during which clinicians monitored his HIV RNA every 2 weeks for 12 week then every 4 weeks. After 9 months (288 days) the man's viral load rebounded asymptomatically to 60 copies then climbed to 1640 copies 5 days later. He resumed ART at that point, denying any HIV exposure that could explain a new infection. Genotyping revealed no emergent resistance mutations, and HIV RNA became undetectable after 4 weeks of treatment.
After PBSCT several measures of peripheral blood proviral DNA indicated significant reductions in that reservoir. In situ hybridization detected no HIV RNA in 105 colon biopsy sections collected 133 days after PBSCT to evaluate GVHD-associated diarrhea. Single-genome sequencing and phylogenetic analysis detected identical viral clones 142 days after PBSCT, which the researchers suggest could be "consistent with homeostatic proliferation of latently infected cells" after the transplant. From 199 days before the transplant until 888 days afterwards, western blot showed decreasing number and intensity of anti-HIV bands, indicating devolution of anti-HIV antibodies.
The Mayo Clinic team concludes that allogenic PBSCT in HIV patients may significantly reduce HIV reservoir size and allow prolonged ART-free remission. PBSCT during suppressed viral replication, they propose, may lead to loss of HIV-specific immunity. And they hypothesize that immune activation during GVHD without anti-HIV-specific immunity "may cause homeostatic proliferation of latently infected cells, decreasing the chance of HIV eradication."
References
1. Cummins N, Rizza S, Baker J, et al. Two hundred eighty-eight–day drug-free remission from HIV rebound by allogeneic PBSCT. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 319.
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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