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Antiretroviral-Free HIV-1 Remission and Viral Rebound After Allogeneic Stem Cell Transplantation: Report of 2 CasesHIV-1 Remission and Viral Rebound After Allogeneic HSCT

Timothy J. Henrich, MD; Emily Hanhauser, BS; Francisco M. Marty, MD; Michael N. Sirignano, BS; Sheila Keating, PhD; Tzong-Hae Lee, MD, PhD; Yvonne P. Robles, BA; Benjamin T. Davis, MD; Jonathan Z. Li, MD; Andrea Heisey, BS; Alison L. Hill, PhD; Michael P. Busch, MD, PhD; Philippe Armand, MD, PhD; Robert J. Soiffer, MD; Marcus Altfeld, MD, PhD; and Daniel R. Kuritzkes, MD
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 22 July 2014.

From Brigham and Women's Hospital, Harvard Medical School, and Dana-Farber Cancer Institute, Boston, Massachusetts; Heinrich-Pette-Institut, Leibniz-Institut für Experimentelle Virologie, Hamburg, Germany; Blood Systems Research Institute and University of California, San Francisco, San Francisco, California; and Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts.

This paper was published to coincide with the 20th International AIDS Conference held in Melbourne, Australia, 20–25 July 2014.

Note: Dr. Henrich had full access to all of the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.

Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation or the National Institutes of Health.

Acknowledgment: The authors thank Athe Tsibris and Steven Deeks for helpful discussions, Mila Lebedeva for performing the antibody quantitation, Li Wen for performing the microchimerism testing, Ann LaCasce for helping with the initial study design, and Christine Palmer for helping with the flow cytometry and immune assays.

Grant Support: By the Foundation for AIDS Research (amfAR Research Consortium on HIV Eradication grant); National Institute of Allergy and Infectious Disease, National Institutes of Health (1K23AI098480-01A1); AIDS Clinical Trials Group Virology Support Laboratory (UM1 AI068636); Harvard University Center for AIDS Research Therapeutics Program (P30 AI060354); Delaney AIDS Research Enterprise Collaboratory (U19 AI096109); and Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University. This article is also based on research funded in part by the Bill & Melinda Gates Foundation (Global Health grant OPP1017716).

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1027.

Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Dr. Henrich (e-mail, thenrich@partners.org).

Requests for Single Reprints: Timothy J. Henrich, MD, Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139; e-mail, thenrich@partners.org.

Current Author Addresses: Drs. Henrich, Li, and Kuritzkes; Ms. Hanhauser; and Ms. Heisey: Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139.

Dr. Marty and Ms. Robles: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Mr. Sirignano and Dr. Altfeld: Abt 8, Heinrich-Pette-Intitut, Leibniz-Institut f|$$|Adur Experimentelle Virologie (HPI), Martinistrasse 52, 20251 Hamburg, Germany.

Drs. Keating, Lee, and Busch: Blood Systems Research Institute, 270 Masonic Avenue, San Francisco, CA 94118.

Dr. Davis: Massachusetts General Hospital, 55 Fruit Street, Boston, MA 0 2114.

Dr. Hill: Harvard University, One Brattle Square, Cambridge, MA 02139.

Drs. Armand and Soiffer: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215.

Author Contributions:Conception and design: T.J. Henrich, M.P. Busch, M. Altfeld, D.R. Kuritzkes.

Analysis and interpretation of the data: T.J. Henrich, E. Hanhauser, F.M. Marty, M.N. Sirignano, S. Keating, J.Z. Li, A.L. Hill, M.P. Busch, M. Altfeld, D.R. Kuritzkes.

Drafting of the article: T.J. Henrich, M.P. Busch, R.J. Soiffer, D.R. Kuritzkes.

Critical revision of the article for important intellectual content: T.J. Henrich, F.M. Marty, M.N. Sirignano, B.T. Davis, J.Z. Li, M.P. Busch, P. Armand, R.J. Soiffer, D.R. Kuritzkes.

Final approval of the article: T.J. Henrich, F.M. Marty, M.N. Sirignano, B.T. Davis, J.Z. Li, M.P. Busch, P. Armand, M. Altfeld, D.R. Kuritzkes.

Provision of study materials or patients: T.J. Henrich, F.M. Marty, R.J. Soiffer.

Statistical expertise: A.L. Hill, M.P. Busch.

Obtaining of funding: T.J. Henrich, D.R. Kuritzkes.

Administrative, technical, or logistic support: T.J. Henrich, E. Hanhauser, F.M. Marty, Y.P. Robles, B.T. Davis, M.P. Busch.

Collection and assembly of data: T.J. Henrich, E. Hanhauser, M.N. Sirignano, S. Keating, T.H. Lee, Y.P. Robles, B.T. Davis, J.Z. Li, A. Heisey, M.P. Busch, P. Armand, M. Altfeld.

Ann Intern Med. 2014;161(5):319-327. doi:10.7326/M14-1027
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Background: It is unknown whether the reduction in HIV-1 reservoirs seen after allogeneic hematopoietic stem cell transplantation (HSCT) with susceptible donor cells is sufficient to achieve sustained HIV-1 remission.

Objective: To characterize HIV-1 reservoirs in blood and tissues and perform analytic antiretroviral treatment interruptions to determine the potential for allogeneic HSCT to lead to sustained, antiretroviral-free HIV-1 remission.

Design: Case report with characterization of HIV-1 reservoirs and immunity before and after antiretroviral interruption.

Setting: Tertiary care center.

Patients: Two men with HIV with undetectable HIV-1 after allogeneic HSCT for hematologic tumors.

Measurements: Quantification of HIV-1 in various tissues after HSCT and the duration of antiretroviral-free HIV-1 remission after treatment interruption.

Results: No HIV-1 was detected from peripheral blood or rectal mucosa before analytic treatment interruption. Plasma HIV-1 RNA and cell-associated HIV-1 DNA remained undetectable until 12 and 32 weeks after antiretroviral cessation. Both patients experienced rebound viremia within 2 weeks of the most recent negative viral load measurement and developed symptoms consistent with the acute retroviral syndrome. One patient developed new efavirenz resistance after reinitiation of antiretroviral therapy. Reinitiation of active therapy led to viral decay and resolution of symptoms in both patients.

Limitation: The study involved only 2 patients.

Conclusion: Allogeneic HSCT may lead to loss of detectable HIV-1 from blood and gut tissue and variable periods of antiretroviral-free HIV-1 remission, but viral rebound can occur despite a minimum 3-log10 reduction in reservoir size. Long-lived tissue reservoirs may have contributed to viral persistence. The definition of the nature and half-life of such reservoirs is essential to achieve durable antiretroviral-free HIV-1 remission.

Primary Funding Source: Foundation for AIDS Research and National Institute of Allergy and Infectious Diseases.


Grahic Jump Location
Figure 1.

Detection of HIV-1 and clinical course after ATI.

Results from clinical monitoring of quantitative HIV-1 plasma RNA and qualitative whole-blood HIV-1 DNA testing for both patients. Open circles or minus signs denote samples in which no HIV-1 was detected. Shaded areas represent the use of combination ART. In patient A, HIV-1 was first detected 12 wk after ATI (+). Clinical symptoms of the acute retroviral syndrome followed a rapid increase in plasma viral load and resolved at the time of active ART reinitiation. A plasma RNA level of 20 202 copies/mL was recorded 226 d after ATI (*), but this may have been due to sample switching in the clinical laboratory. CD4+ T-cell counts transiently declined during the time of peak viremia. In patient B, HIV-1 was first detected 32 wk after ATI (+). In addition, no HIV-1 DNA or plasma RNA was detected by sensitive research assays 38 and 129 d after ART discontinuation. Clinical symptoms of the acute retroviral syndrome occurred approximately 7 d after the last negative viral load test result. Symptoms resolved with prompt initiation of ART and subsequent viral suppression. ART = antiretroviral therapy; ATI = analytic treatment interruption; DRV/r = ritonavir-boosted darunavir; DTG = dolutegravir; EFV = efavirenz; FTC = emtricitabine; PBMC = peripheral blood mononuclear cell; RAL = raltegravir; TDF = tenofovir disoproxil fumarate.

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Appendix Figure.

Phylogenetic relationships between peri-HSCT HIV-1 DNA and rebound HIV-1 plasma RNA.

Phylogenetic trees of near–full-length, single-genome HIV-1 envelope sequences for patient A (left) and patient B (right) are shown. Compared with an outgroup of HIV-1 subtype B sequences from the Los Alamos National Laboratory HIV Sequence Database Compendium, rebound HIV-1 envelope sequences were highly related to peri-HSCT cell-associated viral DNA. Rebound HIV-1 envelope sequences were monophyletic with a very high degree of intrasample sequence homology, suggesting that viral reseeding occurred from only one or a few cells or proviruses. Maximum likelihood trees were constructed using a general time-reversible model after stripping gaps and ambiguous alignment regions. Distance scale bars denote nucleotide substations per site. HSCT = hematopoietic stem cell transplantation.

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Grahic Jump Location
Figure 2.

Anti–HIV-1 antibody avidity by LAg assay before and after ATI.

HIV-1 antibody levels and avidity decreased in both patients during virologic suppression after allogeneic HSCT (including time points before ATI, as previously reported [15]). Antibody levels measured by the LS Vitros Anti-HIV-1+2 assay (Ortho Clinical Diagnostics) increased in both patients shortly after viral rebound. Antibody avidity increased slightly after viral rebound in patient A, in whom virologic control was not immediately reestablished, but continued to decrease in patient B, who promptly resumed ART after the first detectable viral load measurement. ART = antiretroviral therapy; ATI = analytic treatment interruption; HSCT = hematopoietic stem cell transplantation; LAg = limiting antigen; LS = less sensitive; ODn = normalized optical density measured by limiting-antigen avidity enzyme immunoassay; S/C = signal–cutoff ratio of the Vitros assay.

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