HTB

London patient is second person to be cured of HIV from allogeneic stem-cell transplant

Simon Collins, HIV i-Base

The second day of the virtual CROI 2020 was due to start with a press conference at 7.30 am that included details on the London Patient – now officially the second person to be cured of HIV by allogeneic haematopoietic stem cell transplantation (HSCT).

Even though the press conferences are no longer part of the virtual conference, the embargo for the presentation later today was still lifted early. This was largely because the case was also just published in the Lancet HIV. [1, 2]

The headline news story from CROI 2020 about HIV cure is important for several reasons.

Firstly, the early reports from CROI 2019 on the results of the HSCT in a London patient have reached and passed the two-year target that researchers set last year for the remission to be called a cure. [3, 4]  This case is now supported by extensive tissue sampling using ultrasensitive tests that still show no evidence of active HIV infection.

Secondly, the London Patient has shared his personal experience in an interview in the New York Times yesterday, planned to coincide with the presentation at CROI 2020. [5]

This disclosure – neither easy nor straightforward – is partly a way to acknowledge and thank the many doctors, nurses and other health workers that have contributed to his care over the last eight years – and who also protected his anonymity throughout. It is partly to support Tim Brown (aka the Berlin Patient) who as the first person cured by similar HSCT treatment 12 years ago, has been the only public face of an HIV cure. And it is partly to give other people hope – not just for HIV but also for cancer – that such successes are possible.

For all the complexity the scientific research is perhaps the easiest data to report. After 30 months since the transplant, HIV viral load has remained undetectable using ultrasensitive tests in blood plasma and CSF (<1 copy/mL) and in semen plasma (<12 copies/mL, at 25 months) and cells (<10 copies/million cells, at 21 months). (See Table 1).

HIV DNA by droplet digital PCR was negative in rectum caecum sigmoid and terminal ileum tissue. Lymph node tissue from the axilla was positive for LTR and Env at around 30 copies/million cells but negative for packaging signal and integrase. These remnants of HIV-1 sequences, also reported for the Berlin Patient, were present at levels low enough to be false-positive or may have survived HSCT but are unlikely to be replicant competent and are regarded as so-called fossil virus.

The intact proviral DNA assay (IPDA) was negative.

Plasma HIV antibodies have remained undetectable by western blot except low level Env reactivity.  Donor chimerism has been maintained at 99% in T cells.

The CD4 count, CD4% and CD4:CD8 ratio at 28 months post-transplant were 430 cells/mm3, 23·5% and 0.86 which are close to pretransplant levels.

There have been no further episodes of graft versus host disease (GvHD) since gut GvHD at 2 months post-transplant, and donor chimerism has also been maintained at 99% in peripheral CD4 T cells.

The researchers also undertook mathematical modelling to firstly simulate the expected distribution of rebound times as a function of reservoir size for latent and active HIV in someone off-ART and secondly to interpret the outcomes from the London Patient. Results were adjusted for the reduced CD4 cell pool.

This was to look at the likelihood of a rebound sometime in the future (compared to lifetime remission) based on 29 months without viral rebound and no viral outgrowth seen in 24 million CD4 cells at 18 months

The models estimates that with 50% and 80% chimerism, the likelihood of full remission is 87% and 98%. For 90% or higher reduction in susceptible cells, that cure is almost certain.

The authors concluded that this represents HIV cure and that this is not affected by low level defective HIV genomes in lymphoid tissue.

The interview in the NYT also included many remarkable personal aspects of this case.[6, 7]

Table 1: Summary of evidence support HIV cure

Test and tissue sample Lower limit of detection / test sensitivity Results Time since transplant and ATI (months)
VL in blood plasma <1 copy/mL Negative 30 mo
VL in CSF <1 copy/mL Negative 25 mo
VL semen plasma <12 copy/mL Negative 21 mo
Semen cells <10 c/million cells Negative 21 mo
HIV-1 DNA in peripheral CD4 memory cells Weakly positive * 28 mo
HIV DNA in rectum, caecum, sigmoid and terminal ileum tissue (150,000 to 300,000 cells tested for each site) <10 c/million cells Negative 22 mo
Long-terminal repeat (LTR) in axilla lymph node tissue 33 c/million cells Positive * 28 mo
Env in axilla lymph node tissue 26 c/million cells Positive * 24 mo
Intact packaging signal and integrase in lymph node 30 c/million cells Negative 24 mo
Proviral DNA (IPDA) in axilla tissue <0·5 intact proviral DNA c/million Negative 27 mo
Antibody responses western blot Negative (low level positive in Env but persistent loss of bands * 27 mo

* Remnants of HIV-1 sequences were present at levels low enough to be false-positive, and in tissue samples are unlikely to be capable of producing virus and are regarded as so-called fossil virus.

References

  1. Gupta RK et al. Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report. Lancet HIV 2020. March 10, 2020 https://doi.org/10.1016/ S2352-3018(20)30069-2
    http://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(20)30069-2/fulltext
  2. Gupta RK et al. Sustained HIV remission in the London Patient: the case for an HIV cure. CROI 2020. Late breaker poster abstract 346LB.
    http://www.croiconference.org/sessions/sustained-hiv-remission-london-patient-case-hiv-cure
  3. 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)
  4. Collins S. 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. HTB (12 March 2019).
    https://i-base.info/htb/35767
  5. Collins S. The London Patient tells his story as second person cured of HIV. HTB (9 March 2020).
    http://i-base.info/htb/3729
  6. Mandavilli A. The London Patient, cured of HIV, reveals his identity. New York Times. (9 March 2020).
    https://www.nytimes.com/2020/03/09/health/hiv-aids-london-patient-castillejo.html

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