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HIV rebound and meningoencephalitis following ART interruption after allogeneic
hematopoietic stem cell transplant: an investigation of the source of HIV rebound
8th IAS Conference on HIV Pathogenesis, Treatment and PreventionVancouver, British Columbia, Canada
July 20th, 2015
-No Disclosers-
Adam Capoferri
Johns Hopkins University School of Medicine, Baltimore, MD, United StatesHoward Hughes Medical Institute
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• Allogeneic hematopoeitic stem cell transplant (alloHSCT)
• ‘Berlin Patient’, received alloHSCT for AML treatment1
– Donor was homozygous CCR5Δ32
• ‘Boston Patients’, identified 5 and 3 years after alloHSCT 2,3
– Donors were wild-type for CCR5– HIV-1 not found in multiple compartments; donor chimerism
>99.99%– Analytical treatment interruption; delayed rebound, 12 and
32 weeks– Both patients with symptoms of acute retroviral syndrome
• One patient also had HIV-associated meningitis– Source of rebound unclear
1 Hütter, G., et al. (2009) NEJM; 2 Henrich, T., et al. (2013) JID; 3 Henrich, T., et al. (2014) Annals of Internal Medicine
Study Background
•At Johns Hopkins, we are conducting a clinical trial of optimized ART in HIV+ patients undergoing alloHSCT
– Optimized ART includes: avoiding ritonavir-boosted PIs, ART changes as needed, and administration of Enfuvirtide (ENF)
•Within this study, we present the case of a patient who had HIV viral breakthrough and experienced acute retroviral syndrome and meningoencephalitis after self-discontinuing ART post-alloHSCT
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• 2004: Diagnosed with chronic HIV-1 infection and AML
– Unstable VL and CD4 counts; multiply-relapsed AML
– Lack of ART adherence and lost to follow-up
– Drug resistance history with K103N and M184V
– Virus Tropism determined R5
• 2013: Re-engaged in care for multiply-relapsed AML
– Optimized ART regimen: RAL, ABC/3TC, MVC
– Became virally suppressed on his optimized ART regimen
– Reduced intensity conditioning match related alloHSCT
Background Patient History•BMT Clinical Course:
– Engrafted by day 20
– >95% donor chimerism measured in peripheral blood
– Day 84, HIV RNA was <20 c/mL
– Patient began missing clinic appointments
– Day 100, developed fevers; recommended HIV-1 VL--not done
– Day 146, admitted to hospital, lumbar puncture with CSF analysis:
• Protein 150 [range 15-45 mg/dL], WBC 28 [range 0-3 cells/uL] • CSF microbiology studies negative for VZV, EBV, CMV, HSV,
JCV, cryptococal, VDRL, West Nile, parvovirus; blood tests negative for histoplasma, syphilis, Hepatitis B and C, adenovirus; and bacterial, fungal, and AFB stains
• HIV plasma VL= 25,518 c/ml• HIV CSF VL= 17,000 c/ml
What is the source of viral rebound?
•Other reservoirs (e.g. CNS)?
•Persistent circulating resting memory CD4+ T cells?
Henrich, T., et al. (2014) Annals of Internal Medicine
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• 31 distinct sequences VOA• 55 sequences rebound CSF• 92 sequences rebound plasma
Methods
•Limiting-dilution viral outgrowth assay (VOA)– Resting memory CD4+ T cells obtained 100 and 25 days pre-
alloHSCT•Sequencing of RT region of pol
– Sanger sequencing of supernatant from p24+ viral outgrowth wells from VOA
– Deep sequencing (Roche 454) of rebound virus from peripheral blood (PB) and cerebrospinal fluid (CSF)
• Sequence reads: CSF= 14,645; PB= 5,003• Consensus sequences using cut-off of >0.2% of total sequence
reads
•Phylogenetic analysis of final sequence alignment using maximum likelihood (ML) in PAUP*v.4b
– Model of evolution selected using jModelTest– Bootstrapping of 1,000 replicates
– Finzi D et al, 1997; Siliciano JD et al, 2005
Conclusions
•In this case:
– Rebound virus is consistent with virus found in resting memory CD4+ T cells isolated from multiple pre-transplant time-points
– Rebound virus appears to be consistent with virus from the circulating peripheral blood
– Interruption of ART post-alloHSCT can lead to severe symptoms consistent with those of HIV-1 acute infection
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Thank you
Questions?
Special Thanks
Dr. Christine DurandDr. Richard F. Ambinder
Dr. Mark LevisDr. Robert F. Siliciano
Dr. Thomas QuinnDr. Andrew Redd
Dr. Steven F. PorcellaMatthew Sievers
Ayla CashDaniel Xu