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No Viral Load Rebound Off-ART Following Stem Cell Transplant: Two "Cure" Cases Using Reduced Intensity Conditioning Chemotherapy and CCR5 d-32 Negative Donors

By Simon Collins

August/July 2013

Three cases of HIV positive people, who underwent stem cell transplant (HSCT) to treat leukemia, were presented by Timothy Henrich of Harvard Medical School as a late-breaker. 1

After intensive tests failed to show evidence of ongoing viral replication, two of the three patients stopped HIV treatment as part of an analytic treatment interruption. Follow-up to week 8 and 15 has failed so far to isolate evidence of viral load rebound.

Unlike the widely reported case of Timothy Brown who has remained off treatment for more than five years without viral rebound following myeloablative chemotherapy, these patients did not use a donor with CCR5-delta-32 genetic deletion that protects against HIV infection and which was attributed to the functional cure in that case. 2 They also continued ART before, during and after the transplant with follow-up prior to stopping treatment of 4.5 and 2.7 years.

The two patients that have responded successfully underwent reduced intensity conditioning (RIC) chemotherapy post-transplant that involves non-ablative slightly milder chemotherapy without total body irradiation (therefore retaining some of the patients own immune cells) or antithymocyte globulin (which also clear host immune cells). This is considerably less aggressive that the procedures undertaken by Timothy Brown but it is still associated with an approximately 15% two-year mortality.

Both patients are male but with very different HIV histories.

The first was infected perinatally and had been on long-term ART. In 2006, he was diagnosed with stage 4 Hodgkins disease that relapsed following standard chemotherapy and he underwent autologous RIC HSCT in 2007 with a partially mismatched donor and response included graft versus host disease (GVHD) that subsequently worsened.

The second patient was sexually infected in the mid 1980s and had remained off-treatment until 2003 when he was diagnosed with a diffuse large B-cell lymphoma that responded to chemotherapy and ART. In 2006, he developed stage 4 Hodgkins lymphoma and following disease recurrence after chemotherapy and salvage chemotherapy, he underwent autologous HSCT in 2007. In 2010, he developed a myelodysplastic syndrome, likely related to previous chemotherapy, and underwent an RIC matched HSCT which also resulted in complicated GVHD response.

GVHD in both patients was managed by sirolimus and tacrolimus, with prednisone used when initial GVHD response worsened. Both patients are currently stable. The difficulty of recovering HIV DNA in PBMCs at 8-17 months post-transplant was reported in detail at the IAS conference in Washington in 2012 and was published this year as an open access article in JID. 3,4

In both patients, HIV DNA was detected in PBMCs prior to and 2-3 months after transplant but not following full engraftment. An updated summary this year on the attempts to recover HIV DNA now covers assays using 5 million PBMCs that have been repeated up to 30 times for each patient or in rectal tissue (for one patient), prior to the decision to stop ART.

Residual pre-transplant cells now constitute less than 0.001% of PBMCs post-HSCT and may represent circulating non-hematopoietic cells but donor cells now clearly constitute the majority population. Also, no strong HIV-specific immune responses were generated from HLA-specific or pooled HIV-1 peptides before or after transplant.

HIV has so far failed to be detected in plasma (using less than 1 copy/mL assays), in cells (in millions of cells with sensitive testing), or in gut tissue (which is one of the compartments that cure researchers believe is a sanctuary site).

The researchers suggested that two aspects of their protocol may be important. Firstly, that the role of GVHD may be critical in clearing host cells post-transplant, especially as host cells are not cleared by irradiation or antithymocyte globulin, and secondly, that continuing on ART for several years after the transplant may also have prevented reinfection while allowing clearance of any residual reservoir of HIV-infected cells.

Unfortunately, a third patient enrolled in the study protocol died from recurrent lymphoma six month after HSCT, highlighting the seriousness risk of the complications for any patient considered suitable for this type of treatment.

Further details on this presentation are limited, as neither the webcast from this session nor the presentation slides have yet been posted to the conference website. This article will be updated when these become available. 5

In the press conference, Henrich emphasised the importance of continue careful follow-up in these patients and that the potential for very delayed rebound, even out to 1-2 years, was supported by modeling studies presented at CROI 2013. 6,7 Also, that while this is not a realistic option for most people, this research may inform cure research on how low viral suppression needs to go and for further understanding the innate immune responses that are likely to be needed for functional cure in chronic HIV infection.

Comment

Although currently off-ART for only 15 and 7 weeks, if these results are sustained this would make the chance to cure HIV a more realistic possibility for HIV positive patients requiring HSCT as it removes the need to source and match CCR5-d32 deleted donors.

While these cases seem very promising, even with the RIC chemotherapy this remains a complex procedure and a salvage response to previously non-responsive or relapse first-line chemotherapy.

Viral dynamics of untreated HIV suggest that four months would be sufficient in most cases to detect new viral replication. However, researchers in this case are cautious about suggesting that these patients are functionally cured. Individual cases – not in the context of HSCT – include later rebound when virus is detectable in less than 1.7 billions cells, following more than ten years of viral suppression and starting ART during primary infection. 8

References

Unless stated otherwise, references are to the Programme and Abstracts for the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 30 June – 3 July 2013, Kuala Lumpur.

  1. Henrich T 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.Oral late breaker abstract WELBA05.
  2. Hütter G et al.Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation.N Engl J Med 2009; 360:692-698. DOI: 10.1056/NEJMoa0802905. (12 February 2009).
  3. Henrich T et al.Long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation in two HIV-positive individuals. 19th International AIDS Conference, 22-27 July 2012. Oral abstract THAA0101.
  4. Henrich T et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation.J Infect Dis. (2013) 207 (11): 1694-1702. doi: 10.1093/infdis/jit086.
  5. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June – 3 July 2013, Kuala Lumpur. Link to session for slides and webcast.
  6. Ya-Chi H et al. Characterisation of non-induced HIV-1 proviruses dampens the hope for HIV-1 eradication.20th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013. Oral abstract 43.
  7. Webcast from the Track A Late Breaker press conference.
  8. Chun, T-W et al. Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS. 24(18):2803-2808, (27 November 2010). doi: 10.1097/QAD.0b013e328340a239.
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