HTB

UK patient likely to be the second person cured of HIV: two further cases at CROI 2019 of HIV remission after allogenic stem cell transplants

Simon Collins, HIV i-Base

One of the headline reports from CROI 2019 will be a case where a stem cell transplant is likely to have cured a second person of HIV.

Although the results were due to presented on the first day of the conference, other publications, including Nature made details available before the CROI presentations. The New York Times notably published their article before the CROI presentations without contacting people who had contributed to the article. As a result the study was reported before the study has even been presented.

Lead author Ravindra Gupta from the University of Cambridge is also interviewed in the NYT article and the study is on behalf of an international team from the Netherlands, Spain and the UK. [1] Further details of the UK case are included from the paper that is due to be published in Nature, but which has also had a broken embargo. [2]

The results reproduce the circumstances that cured Timothy Ray Brown (the Berlin patient) ten years ago [3] but are notable for achieving HIV remission with less aggressive treatment.

The UK case is an HIV positive man with CCR5-tropic HIV who was diagnosed in 2003 and who started HIV treatment (efavirenz/TDF/FTC) in 2012. Shortly after starting ART he was also diagnosed with advanced Stage IVB Hodgkin’s Lymphoma (HL) that failed to respond to either first line chemotherapy (ABVD) or several salvage combinations.

This patient underwent allogenic hematopoietic stem cell transplantation (HSCT, 3.6 million CD34+ cells/kg) as treatment for advanced HL using cells from a donor from an international registry who was also homozygous for the CCR5 delta-32 deletion. The donor was a close but not complete match (9/10 – with one allelic mismatch at HLA-B). Induction therapy continued with lomustine, cyclophosphamide, cytarabine and etoposide (LACE) and T cells were depleted with reduced intensity conditioning using anti–CD52 (alemtuzumab). Cyclosporine-A and short-course methotrexate were used as prophylaxis for graft versus host disease (GvHD).

During chemotherapy, ART was switched to raltegravir/TDF/FTC and then to rilpivirine/dolutegravir/3TC (after K65R and M184V developed during a short period of viral rebound).

Unlike the Berlin patient, the UK patient did not undergo full body irradiation but he also experienced only mild GvHD (grade 1), in this case fever and gastrointestinal symptoms at day 77. ART was maintained throughout and continued for 16 months post-transplant. Following detailed consultations with the patient including ethical approval and informed consent, the decision was made to stop HIV treatment.

Viral load was monitored weekly for the first three months then monthly and HIV has remained undetectable HIV DNA (< 1 copy/mL) in peripheral T-cells for 18 months. No reactivatable HIV has been recovered from more than 24 million cells using viral outgrowth assay. Post-transplant, total PBMC associated HIV DNA dropped to below the limit of detection after transplant and total DNA in CD4 T cells was undetectable at 29 months by ultra-sensitive qualitative PCR. Ex vivo, CD4 cells could be infected by CXCR4- but not CCR5-tropic HIV.

Similar to reports with the Berlin patient, a single low level signal was reported in one sample – cellular DNA from blood – which was interpreted as a likely false-positive DNA result.

Both antibody and T cell responses were similar to that reported for the Berlin patient, leading the investigators to tentatively suggest that this might be a second case of HIV remission, while emphasising that this can only be confirmed with longer follow-up.

Also at CROI 2019, a third case of HIV remission/cure following HSCT was reported in a late-breaking poster, but with much less follow-up off-ART.

This case was presented by Björn-Erik Jensen from Heinrich Heine University Hospital, Düsseldorf and colleagues and involved HSCT to treat relapsed AML in February 2013, again using a matched donor (10/10) that was homozygous for CCR5 delta-32. [4]

AML relapsed for a second time in June 2013 and remission was reachieved after eight courses of 5-azaC chemotherapy and 4 donor lymphocyte infusions.

HIV remained undetectable throughout post-transplant period, with ART maintained for more than 5.5 years. Proviral DNA was not detected by qPCR in PBMCs at different time points in plasma, CSF, rectal tissue, ileum and bone marrow. Low signals failed to confirm HIV replication.

After discussions on risk and with informed consent, ART was stopped as part of an analytic treatment interruption in November 2018 and HIV has remained undetectable in plasma for the last three months.

While concluding that the results were optimistic for this to be another case of HIV remission, the researchers emphasised that longer follow-up was still essential.

Table 1: Summary regimens of UK, Dusseldorf and Berlin patients

UK patient Dusseldorf patient Berlin patient
Underlying condition HL AML AML
ASCT, donor CCR5-d32/d32 Once Once Twice
Conditioning reduced intensity: anti–CD52 (alemtuzumab) reduced intensity: fludarabine/ treosulfan Total body irradiation (twice)
GvH disease Grade 1 Grade 1 Grade 1
ART post-transplant 16 months 66 months None
Time with HIV remission 18 months 3 months > 10 years

comment

These optimistic results provide hope to millions of people globally – even though this is only a modification of last-stage treatment for advanced cancer.

Previous attempts to reproduce the Berlin patient were not successful, often due to rebound with CXCR4-tropic virus that was later found to have been present at baseline. [5, 6, 7]

Although other cases of HSCT in HIV positive patients have been reported, many are still on ART and the UK case is the longest reported remission after a treatment interruption.

The results are also optimistic for these HIV remission cases at CROI 2019 being achieved with a less aggressive treatment compared to the Berlin patient, whose treatment included total body radiation twice and two courses of HSCT to treat acute myeloid leukaemia; and a less than perfectly matched donor.

The way that such important scientific research was released by mainstream media before presentation at a peer reviewed scientific conference undervalues the work of the researchers and of the individuals in these two studies.

References

Unless mentioned otherwise, references are to the programme and abstracts of the Conference on Retroviruses and Opportunistic Infections, 4–7 March 2019, Seattle.

  1. Gupta RK et al. Sustained HIV-1 remission following homozygous CCR5 delta32 allogenic HSCT. CROI 4 – 7 March 2019, Seattle. Late breaker oral abstract 29 LB.
    http://www.croiconference.org/sessions/sustained-hiv-1-remission-following-homozygous-ccr5-delta32-allogenic-hsct (abstract)
    http://www.croiwebcasts.org/console/player/41065 (webcast)
  2. Gupta RK et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem cell transplantation. Nature. DOI: 10.1038/s41586-019-1027-4.
    https://www.nature.com/articles/s41586-019-1027-4
  3. Hutter G. et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 360, 692-698, doi:10.1056/NEJMoa0802905 (2009).
    https://www.nejm.org/doi/full/10.1056/NEJMoa0802905
  4. Jensen B-E O et al. Analytic treatment interruption (ATI) after allogeneic CCR5-d32 HSCT for AML in 2013. CROI 4 – 7 March 2019, Seattle. Late breaker oral abstract 394 LB.
    http://www.croiconference.org/sessions/analytic-treatment-interruption-ati-after-allogeneic-ccr5-d32-hsct-aml-2013 (abstract)
  5. Hayden EC. Hopes of HIV cure in ‘Boston patients’ dashed. Nature. doi:10.1038/nature.2013.14324 (6 December 2013).
    https://www.nature.com/news/hopes-of-hiv-cure-in-boston-patients-dashed-1.14324
  6. Henrich TJ et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med 161, 319-327, doi:10.7326/M14-1027 (2014).
    https://annals.org/aim/article-abstract/1889547/antiretroviral-free-hiv-1-remission-viral-rebound-after-allogeneic-stem
  7. Kordelas L. et al. Shift of HIV tropism in stem-cell transplantation with CCR5 Delta32 mutation. N Engl J Med 371, 880-882, doi:10.1056/NEJMc1405805 (2014).
    https://www.nejm.org/doi/10.1056/NEJMc1405805

 

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