March 5, 2019

expert reaction to HIV-1 remission in a second patient

Reactions to claims that a second HIV-1 patient is in remission as published in Nature.

Prof Sarah Fidler, Professor of HIV Medicine at Imperial College London, said:

“The report of a second case of HIV remission is of great interest but does not move the scientific field forward very significantly over the Berlin patient. Rather, it reinforces the science that this is rare but feasible. The treatment this patient received is not safe, and not scalable. It is certainly not an option to be recommended for people living with HIV who are doing well on antiretroviral therapy.

“However, the main important message from this report is that dCCR5 homozygous bone marrow donors should be specifically selected where possible for people living with HIV on ART, who develop cancer and require this treatment. This work was made possible through a unique NHS research collaboration (called CHERUB), and represents a world-class UK contribution to cutting edge clinical science.”

Prof Jane Deayton, Clinical Senior Lecturer in HIV at Barts and the London School of Medicine and Dentistry, Queen Mary University of London and honorary consultant at Barts Health NHS Trust, said:

“HIV-1 is now considered a chronic treatable condition for those who can access combination antiretroviral therapy (ART). Successful ART can maintain or restore normal immunological function and may be associated with normal life expectancy. However, HIV cure, the sustained remission of HIV viraemia in the absence of therapy, remains a priority for many researchers and patients. There is one documented case of HIV-1 cure, that of the “Berlin Patient”, who remains virus-free more than 10 years after discontinuation of ART and in whom numerous investigations have failed to demonstrate replication – competent HIV-1. This was achieved by conducting two allogenic haemopoietic stem cell transplantations (HSCT) for leukaemia using a donor homozygous for the ∆32 mutation in the HIV co-receptor CCR5 gene, which confers cellular resistance to infection by CCR5-tropic virus. Three subsequent cases of HSCT using CCR5 wild-type donors demonstrated viral suppression after ART discontinuation and initially raised hopes that this approach was reproducible. Extended follow-up of those cases revealed recurrent HIV viremia, albeit delayed, suggesting that the presence of the CCR5 ∆32/∆32 mutation is required to protect against HIV rebound.

“This case replicates that of the Berlin Patient and reports sustained absence of HIV-1 plasma RNA and pro-viral DNA 18 months after discontinuation of ART following allogenic HSCT from a CCR5 ∆32/∆32 donor for Hodgkin’s lymphoma. There are important similarities and differences between the cases, which serve to enhance understanding of the underlying mechanisms. Most obviously, both cases employed donors homozygous for the CCR5 ∆32 mutation; further evidence that this is required for sustained viral suppression. Both patients were shown to harbour only CCR5-tropic HIV-1. In both cases there was clinical graft-versus-host disease, managed in comparable ways; both achieved full-donor chimerism to become CCR5 ∆32/∆32 after HSCT. In both cases, specific anti-HIV-1 antibody and T-cell responses became negative post-transplant. Both patients remain in complete remission of haematological malignancy.  There are significant differences in the regimens used to achieve remission. The Berlin Patient received two HSCTs with a more intensive conditioning regimen and total body irradiation with each transplant in contrast to this case, where remission was achieved after one HSCT without irradiation. Finally, the Berlin Patient has now been followed-up for 12 years and this case is reported at 18 months after ART discontinuation.

“This case is important in robustly reproducing the findings of the Berlin Patient whilst demonstrating that a single HSCT and less intensive and toxic regimen can achieve this. Although HSCT is not a viable strategy for HIV cure and will be unavailable to all but a tiny minority of individuals, the case enhances understanding and informs research. In particular, CCR5 which has long been of interest in HIV cure research, appears key. It seems likely that future strategies will include CCR5 modification or knock-out. Further follow-up of this case is required.”

Prof Áine McKnight, Professor of Viral Pathology at Queen Mary University of London, said:

“The [Nature] press release accurately reflects the science. This is good quality research and the authors used the best available technology to demonstrate with the highest degree of certainty currently possible that the patient is free of the virus. 

“There are two known varieties of HIV:  One uses the CCR5 co-receptor and the other uses the CXCR4 co-receptor.  The vast majority of infections are due to the first of these.  The difficulty in treating HIV stems from the fact that the virus specifically targets cells of the immune system itself that use these co-receptors.  The previous successful study with the ‘Berlin patient’ employed a technique which can be thought of as an immune system transplant.  The infected patient’s immune cells were replaced by corresponding ones from an individual resistant to the infection by virtue of the fact that the donor had a mutated form of the CCR5 co-receptor.   People with this mutated form of CCR5 are very rare and, as a consequence, this is only the third study that has attempted to exploit this technique.  This article describes the second successful application of this technique.    In all three studies the donor immune cells were of the mutated CCR5 variety.  However, in the case where the treatment was unsuccessful the recipient was infected with both the CCR5 and CXCR4 strains of the virus. This work is consistent with previous studies.

“The authors clearly point out that the technique will not necessarily be effective for all HIV infected individuals, specifically those infected with CXCR4 viruses.  However, the principal of targeting co-receptors may be of universal benefit. 

“There is no overspeculation in the publication:  indeed the authors advise caution.  Although the authors show beyond reasonable doubt, using the latest state of the art technology, that the patient no longer has replication competent virus, the authors advise that it would be prudent to allow more time to definitely state the patient is virus free.  The conclusions of the study are that therapies exploiting genetic mutations of co-receptors used by HIV have the potential to cure the disease.

“Due to the rarity of suitable donors, this precise approach will not be available to all HIV patients. However, this work has the potential to stimulate research into more generally applicable therapies.

“This is a highly significant study. After a ten year gap it provides important confirmation that the ‘Berlin patient’ was not simply an anomaly.”

Prof Graham Cooke, NIHR Research Professor and Reader in Infectious Diseases, Imperial College London, said:

“This second “London patient”, whose HIV has been controlled following bone marrow transplantation, is encouraging. Other patients treated in a similar way since the “Berlin patient” have not seen similar results. This should encourage HIV patients needing bone marrow transplantation to consider a CCR5 negative donor if possible. If we can understand better why the procedure works in some patients and not others, we will be closer to our ultimate goal of curing HIV. At the moment the procedure still carries too much risk to be used in patients who are otherwise well, as daily tablet treatment for HIV is usually able to maintain patient’s long-term health.”

Dr Andrew Freedman, Reader in Infectious Diseases and Honorary Consultant Physician, Cardiff University, said:

“This an interesting and potentially significant report of a second patient whose HIV infection has gone into remission after receiving a stem cell transplant as part of treatment for a haematological malignancy. As with the ‘Berlin patient’ who remains free of all traces of the virus more than 10 years later, this patient received stem cells from a donor with a specific genetic mutation rendering them resistant to HIV.

“As the authors caution, it is still too early to be certain that this second patient has been cured of HIV. Much longer follow-up will be needed to ensure the virus does not re-emerge at a later stage.

“While this type of treatment is clearly not practical to treat the millions of people around the world living with HIV, reports such as these may help in the ultimate development of a cure for HIV.  This is likely to be many years away and until then, the emphasis needs to remain on prompt diagnosis of HIV and initiation of life-long combination antiretroviral therapy (cART).  cART is highly effective both in restoring near normal life expectancy and preventing onward transmission to others.”

‘HIV-1 remission following CCr5Δ32/Δ32 haematopoietic stem-cell transplantation’ by Ravindra K Gupta et al. was published in Nature on Tuesday 5th March.

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/tag/hivaids/

Declared interests

Prof Jane Deayton:  I have no conflicts of interest except that I am co-investigator on a different study with Prof Gupta.

Prof Sarah Fidler: Sarah is co-lead of the CHERUB Collaboration, who were involved in this work – though she was not directly involved in this research

Prof Graham Cooke: No declarations

Dr Andrew Freedman: No declarations

None others received.