Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases

Abstract

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.

Conflict of interest statement

Conflict of Interest: D.R.K. is a consultant to and has received honoraria from Abbott, Boehringer - Ingelheim, Bristol-Myers Squibb, Celera, Gilead, Glaxo Smith Kline, Inno VirVax, Koronis, Merck, Roche, Sangamo and ViiV; he has received grant support from Gilead and Merck, and speaking honoraria from Gilead and ViiV. M.A. has received speaking honoraria from Gilead and Merck.

Figures

Figure 1. Detection of HIV-1 and Clinical Course Following Analytical Treatment Interruption

Panel A shows results from clinical monitoring of quantitative HIV-1 plasma RNA and qualitative whole blood HIV-1 DNA testing for patient A. Open circles or minus signs (-) denote samples in which no HIV-1 was detected. Shaded areas represent the use of combination antiretroviral therapy (ART). HIV-1 was first detected 12 weeks after ART interruption (+). Clinical symptoms of acute retroviral syndrome followed a rapid rise in plasma viral load, and resolved at the time of active ART re-initiation. A plasma RNA level of 20, 202 copies/ml was recorded 226 days after treatment interruption (*), 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. Panel B shows results for patient B. HIV-1 was first detected 32 weeks after ART interruption. In addition, no HIV-1 DNA or plasma RNA was detected by sensitive research assays 38 and 129 days after ART discontinuation. Clinical symptoms of acute retroviral syndrome occurred approximately 7 days after the last negative viral load test. Symptoms resolved with prompt initiation of ART and subsequent viral suppression. TDF denotes tenofovir; FTC emtricitabine, EFV efavirenz, RAL raltegravir, DRV/r ritonavir boosted darunavir, DTG dolutegravir, ATI analytical treatment interruption.

Figure 3. Anti-HIV-1 Antibody Avidity by Limiting-Antigen Assay Before and After Analytical Treatment Interruption

HIV-1 antibody levels and avidity declined in both patients during the period of virologic suppression post-allogeneic stem cell transplantation [including pre-ATI time-points as previously reported (15)]. Antibody levels measured by the less sensitive (LS) VITROS Anti-HIV- 1+2 assay increased in both patients shortly after viral rebound. Antibody avidity increased slightly following viral rebound in patient A, in whom virologic control was not immediately reestablished, but continued to decline in patient B, who promptly resumed ART after the first detectable VL measurement. O Dn denotes normalized optical density measured by limitingantigen avidity (LAg) enzyme immunoassay, S/C signal to cutoff ratio of the VITROS assay, HSCT hematopoietic stem cell transplantation, and ATI analytical treatment interruption.