London patient in long-term HIV remission after stem cell transplant

Ravindra Gupta presenting at CROI 2019. Photo by Liz Highleyman.

A London man has no remaining detectable HIV a year and a half after undergoing a bone marrow stem cell transplant to treat lymphoma, according to a presentation at the Conference on Retroviruses and Opportunistic Infections (CROI 2019), taking place this week in Seattle.

Professor Ravindra Gupta of University College London presented the case on Tuesday, but after a premature embargo break the day before, many media outlets reported the findings in advance, with some suggesting that the case represents a second HIV cure, similar to that of Timothy Ray Brown, known as the 'Berlin patient'.

Brown – the first and so far only person known to have been cured of HIV – received two stem cell transplants to treat leukaemia in 2006. The donor had double copies of a rare gene mutation known as CCR5-delta-32 that results in missing CCR5 co-receptors on T cells, the gateway most types of HIV use to infect cells. He underwent intensive conditioning chemotherapy and whole-body radiation therapy to kill off his cancerous immune cells, allowing the donor stem cells to rebuild a new HIV-resistant immune system.

Glossary

stem cells

Cells from which all blood cells derive. Bone marrow is rich in stem cells.

CCR5

A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.

remission

The disappearance of signs and symptoms of a disease, usually in response to treatment. The term is often used in relation to cancer, indicating that there is no evidence of disease, although the possibility of cancer remaining in the body cannot be ruled out. In HIV, remission is an alternative term for ‘functional cure’. A sustained ART-free remission would boost the immune system to induce long-term control of HIV, allowing a person living with HIV to maintain an undetectable viral load without daily medication.

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

chemotherapy

The use of drugs to treat an illness, especially cancer.

As described at the 2007 CROI, Brown stopped antiretroviral therapy at the time of his first transplant but his viral load did not rebound. Researchers extensively tested his blood, gut, brain and other tissues, finding no evidence of replication-competent HIV anywhere in his body. This week Brown celebrated 12 years free of HIV and was at CROI to hear about the 'London patient'.

Other attempts to discontinue antiretroviral therapy in HIV-positive bone marrow transplant recipients have been less successful. Dr Timothy Henrich, now at the University of California at San Francisco, and colleagues attempted to reproduce Brown's cure in two cancer patients in Boston, but in those cases the donors had normal or 'wild-type' stem cells that remained susceptible to HIV, they received less intensive chemotherapy and they stayed on antiretroviral therapy.

After no HIV could be detected in their blood and tissues for years, the men underwent closely monitored treatment interruptions. Although their HIV remained in remission longer than expected – for three and eight months – eventually their virus returned, Henrich reported at CROI 2014. More recently, researchers reported that a bone marrow transplant recipient in Minnesota had viral remission lasting nearly 10 months after an analytic treatment interruption, but he too ultimately experienced viral rebound.

"The work we did involved cells that were susceptible to HIV, but even then we saw a dramatic reduction in the size of the HIV reservoir and a prolonged rebound time, suggesting that the transplant itself can reduce the burden of HIV," Henrich told aidsmap. "But adding this piece where the cells are resistant to the patient's strain of HIV really makes the difference to go the whole hundred yards."

The so-called 'London patient', who remains anonymous, underwent stem cell transplantation to treat Hodgkin lymphoma in May 2016. Like Brown, his donor had a double CCR5-delta-32 mutation.

The man continued on his antiretroviral regimen of dolutegravir (Tivicay), rilpivirine (Edurant) and lamivudine. He also received less aggressive conditioning chemotherapy (lomustine, cyclophosphamide, cytarabine and etoposide), alemtuzumab (Campath, a monoclonal antibody that targets CD52 on malignant B and T cells), and cyclosporine-A and methotrexate, immunosuppressive drugs used to prevent graft-versus-host disease (when transplanted immune cells attack the recipient's body).

The transplant led to complete lymphoma remission. About 10 weeks post-transplant the man developed mild graft-versus-host disease, which resolved on its own. He also experienced reactivation of pre-existing Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection, which were treated. Tests showed that his CD4 T cells now lacked CCR5 receptors. Extensive testing of blood plasma and T cells revealed undetectable HIV and his HIV-specific antibody levels also dropped.

The man stopped antiretroviral therapy in an analytic treatment interruption 16 months after the transplant. His blood viral load remains undetectable 18 months later using a sensitive assay with a 1 copy/ml limit, no HIV DNA can be found in peripheral CD4 cells and tests showed no "reactivatable" virus in 24 million resting T cells. One blood sample revealed bits of viral genetic material, which may reflect laboratory contamination or defective virus that is unable to replicate, Gupta suggested. Unlike Brown, the London patient has not yet undergone testing for residual HIV in his gut, brain and other tissues.

These findings demonstrate that "the Berlin patient was not an anomaly," Gupta said. What's more, this case shows that remission can happen without harsh conditioning chemotherapy or radiation therapy. While this appears to be the second longest adult HIV remission yet observed, the researchers acknowledge that "it is premature to conclude that this patient has been cured."

Gupta noted that the man's HIV viral load could still rebound. He suggested that two or three years without detectable virus would be enough time to speak of a cure, saying he was "highly confident this will be achieved."

A poster presented at CROI described another case of long-term HIV remission after a stem cell transplant from a donor with a double CCR5-delta-32 mutation. This patient, treated in Dusseldorf, underwent the procedure in February 2013 to treat acute myeloid leukaemia. The man remained on antiretroviral therapy with undetectable viral load until November 2018. Extensive testing showed no viral DNA in his bone marrow, gut tissue samples, rectal tissue samples or lymph nodes. The Dusseldorf patient stopped antiretroviral therapy in November 2018, still has undetectable HIV and is undergoing continued monitoring.

Experts caution that even if CCR5-delta-32 stem cell transplantation can lead to a functional cure of HIV, this high-risk procedure will not be an option for most people.

"This is not a treatment appropriate for people with HIV who do not have cancer," the Treatment Action Group said in a statement. "The hope is that lessons can be learned to help develop more widely applicable therapeutic approaches for attaining HIV remissions or cures."

Stem cell transplantation is life-threatening, with a mortality rate of 10 to 25%. Brown nearly died during the process and was left with lasting side-effects. However, this new case adds to the evidence that using gene therapy to delete CCR5 receptors from T cells may be a feasible approach.

"I think it's getting close to something that should be called a cure," Brown told aidsmap. "I consider him my sibling and I can't wait to meet him."

This report, originally posted on 4 March 2019, has been updated to reflect new information presented at CROI on 5 March.

References

Gupta RK et al. Sustained HIV-1 remission following homozygous CCR5 delt32 allogeneic HSCT. Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 29 LB, 2019.

View the abstract on the conference website.

Watch the webcast of this presentation on the conference website.

Gupta RK et al. HIV-1 remission following CCr5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature, 2019.

Jensen BO et al. Analytic treatment interruption (ATI) after allogeneic CCR-D32 HSCT for AML in 2013. Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 394 LB, 2019.

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