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HIV Rebounds Detailed in Two Boston Stem Cell Transplant Patients
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CROI 2014, March 3-6, 2014, Boston
Mark Mascolini
Three and 8 months after HIV in blood and cells remained undetectable off treatment in two Boston men who underwent hematopoietic stem cell transplantation (HSCT), HIV did rebound in both men [1]. Timothy Henrich and Brigham and Women's Hospital colleagues proposed that "long-lived tissue reservoirs, including host macrophages that may be replaced more slowly than T lymphocytes following HSCT, may have contributed to viral rebound."
At the July 2013 International AIDS Society meeting, Henrich made headlines with the news that 2 men who underwent reduced-intensity conditioning allogeneic HSCT for lymphoma and stopped their antiretrovirals 4.3 years (patient A) and 2.6 years (patient B) after transplantation did not have viral rebound or detectable HIV DNA in peripheral blood mononuclear cells (PBMCs) after 7 to 15 weeks without therapy [2]. Patient B had no HIV DNA detectable in rectal tissue. But by the end of 2013, HIV rebounded in both men. At the 2014 CROI Henrich offered details on virologic changes in these men.
Before treatment suspension, patient A had HIV DNA detectable at a level below 1 copy in short-lived terminally differentiated T-cell subsets and was negative in all other subsets. Patient B had no detectable HIV DNA in any T-cell subset. Two to 4 years after HSCT, the men's own PBMCs made up less than 0.001% of all PBMCs measured. All other PBMCs came from the donors during transplantation.
The investigators planned to perform large-volume blood sampling 6 to 12 weeks after antiretroviral therapy stopped and every 3 months after that. They decided they would resume treatment with a confirmed rebound above 200 copies in plasma or a single viral load above 1000 copies.
Patient A had rebounding viremia 12 weeks after treatment interruption, first at 900 copies than spiking to 127,000 copies 3 to 4 days later and peaking at several million copies per cell (including "low level CSF viral load detected"). Acute retroviral syndrome developed then resolved with resumed antiretroviral therapy. This man's CD4 count dropped when virus rebounded and rose again when treatment resumed.
For 8 months off treatment patient B had no detectable HIV RNA in blood or HIV DNA in PBMCs ("CSF viral load was detectable"), and his CD4 count remained stable. Symptoms of acute viral infection emerged 7 to 8 days after the last negative viral load tests. PBMC testing a few days later detected nearly 2 million copies per cell. Viral loads fell when patient B resumed therapy, and the CD4 count remained stable. Viral sequencing in both men indicated that HIV superinfection did not cause their rebounds.
The investigators detected no HIV cellular immune responses before or during treatment interruption in either man. Testing after viral rebound detected PBMC activation 108 days after rebound in patient A and 13 days after rebound in patient B.
Henrich concluded that allogeneic HSCT with CCR5 wild-type donor cells can lead to loss of detectable HIV RNA and DNA in blood and gut tissue that persists after antiretroviral therapy stops. Although PBMC DNA dropped at least 1000-fold in these men, viral rebound did occur off treatment. With a post-HSCT HIV-naive immune system, both men had rebounds that resembled acute HIV infection, with moderately severe symptoms and rapid HIV replication.
The researchers suggested "long-lived tissue reservoirs inaccessible to sampling may have contributed to viral persistence" in these men. Because assays to detect residual virus remain limited, they proposed that "analytical treatment interruption," as in these men, "remains the most reliable measure of viral persistence despite potential risks to patients and the potential need for long-term clinical monitoring." ("as reported by Hill & Rosenblum at CROI 2013 that it could take up to 2-3 years for virus to rebound in particular situations of reservoir reduction"); "defining the nature and half-life of HIV-1 reservoirs is essential in order to achieve durable antiretroviral-free remission".
Reference
1. Henrich TJ, Hanhauser E, Sirignano MN, et al. HIV-1 rebound following allogeneic stem cell transplantation and treatment interruption. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 144LB.
http://www.croiwebcasts.org/console/player/22281?mediaType=audio&
2. 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.
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