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Will the London patient be cured of HIV?

At the annual Conference on Retroviruses and Opportunistic Infections held earlier this year in Seattle, doctors from London, England, reported details from the case of an HIV-positive man with life-threatening cancer who received a series of treatments, including complex chemotherapy and a stem cell transplant.

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In particular, the man received a transplant of stem cells from a donor who had a rare genetic mutation called delta-32. People with this mutation lack a co-receptor called CCR5 (R5), which is needed by many strains of HIV to infect cells. The stem cells successfully grew in the man’s bone marrow and formed a new immune system free from HIV. The man is now in remission both from cancer and HIV. In this article we will report his case details.

The London patient

Doctors in London, England, reported case details of a man of unknown age who was diagnosed with HIV in 2003. His lowest-ever CD4+ count was 290 cells/mm3 and his highest recorded viral load was about 180,000 copies/mL. He declined to initiate treatment until 2012 and this consisted of the following combination:

  • efavirenz + TDF + FTC

In December 2012 he was diagnosed with life-threatening Hodgkin’s lymphoma. His cancer did not respond to several different combinations of chemotherapy or to the anti-cancer antibody brentuximab. During his chemotherapy, his HIV combination therapy (ART) was changed to the following regimen:

  • raltegravir (Isentress) + TDF + FTC

This raltegravir-based regimen was thought unlikely to interact with the drugs used for his chemotherapy.

For undisclosed reasons, there was a five-day interruption of ART and his viral load rose to 1,500 copies/mL. Analysis found that his HIV was now resistant to TDF and FTC, so doctors prescribed a new regimen, as follows:

  • dolutegravir (Tivicay) + rilpivirine (Edurant) + 3TC

On this new regimen his viral load became suppressed.

Additional chemotherapy resulted in the man’s lymphoma going into remission by March 2016, as CT and PET (positron emission tomography) found no evidence of residual cancer.

A conditioning regimen

In the meantime, doctors found a donor with the rare delta-32 mutation. To prepare the man’s immune system to receive a stem cell transplant, they gave him what oncologists call a “conditioning regimen” consisting of the following drugs:

  • lomustine
  • cyclophosphamide
  • ara-C
  • etoposide

The purpose of a conditioning regimen is two-fold: to significantly weaken his immune system (so that it would not attack the stem cells) and to wipe out some of his bone marrow so that there was space for the stem cells to grow.

The man was also treated with intravenous infusions of the monoclonal antibody alemtuzumab. This antibody binds to mature T lymphocytes and targets them for destruction. Thus, residual HIV-infected cells (many of which are lymphocytes) would be destroyed. He continued to take ART.

GvHD

After the stem cell transplant, he was given low doses of drugs such as cyclosporine and methotrexate. These drugs are commonly used in transplant patients, as they weaken the recipient’s new immune system and reduce the ability of this new immune system (formed from the transplanted stem cells) to attack the tissues of the recipient. These attacks are called graft vs. host disease (GvHD) and can cause serious and even life-threatening complications. However, the man was sufficiently well enough to leave the hospital a month after the stem cell transplant.

On the 77th day after transplantation, he sought care because of fever and unspecified gastrointestinal symptoms. Biopsies of his intestines revealed that he had injury arising from GvHD. However, this resolved without the need to intensify his dose of transplant medicines.

Six months after transplantation, doctors discontinued cyclosporine as they were no longer concerned about GvHD.

Immunological and other tests

One month after the transplant, tests showed that the man’s new immune system was derived from the stem cell transplant. Also, his new immune system, particularly CD4+ and CD8+ cells, did not have CCR5 co-receptors. Overall, his white blood cells as well as his lymphocytes were generally within the normal range. However, his CD4+ cell count remained low, and at his last test it was about 300 cells/mm3.

His HIV viral load tests after transplantation were undetectable, using an ultrasensitive test with a lower limit of less than 1 copy/mL.

In September 2017, the man and his doctors decided to stop his use of ART.

Therapy interrupted

Upon interrupting ART, the patient underwent weekly blood tests to check his viral load. During the first three months of treatment interruption, researchers found that it was less than 1 copy/mL (the lower limit of the research assay that they used). Three months after interrupting ART, his viral load was checked once monthly. It has continued to remain less than 1 copy/mL.

Doctors also analysed the man’s blood several times and did not detect any traces of ART.

Nearly 1,000 days after transplantation, technicians could not find any of HIV’s genetic material in his cells. Furthermore, in one analysis using ultrasensitive methods, they received a positive signal that suggested the possible presence of HIV-infected cells. However, the doctors cautioned that such tests are research tools only and when a brief positive signal is reached at the outer limits of these assays, it requires interpretation, and they listed the possible meaning of such a test result as follows:

  • the signal was incorrect; that is, it was falsely positive
  • the sample being tested may have been contaminated with trace amounts of HIV from another source in the lab
  • there may be an extremely low level of HIV-infected cells that produce infectious virus

However, if such HIV-infected cells exist, they are either quickly controlled by his new immune system or produce HIV that does not infect the new cells of his immune system.

Bear in mind that in their search for trace amounts of HIV, researchers will likely have screened millions of the man’s cells.

Tests of his CD4+ cells in the lab found that they could become infected with HIV that uses the X4 co-receptor. Analysis of his old immune system, prior to the transplant, found that it harboured HIV that used the R5 co-receptor.

Technicians have also found that the man has gradually diminished levels of HIV antibodies in his blood. Furthermore, his T-cells have no immunological memory of encountering HIV. The researchers stated that these findings—diminishing antibody levels and lack of immunological memory—are “highly similar” to what happened with the Berlin patient after his second stem cell transplant.

Compare and contrast

There are both similarities and differences between the Berlin and London patients. Perhaps the most interesting difference is that the London patient had a less intensive (and debilitating) round of conditioning therapy than the Berlin patient. This is encouraging for potential volunteers who may undergo a similar course of therapy as the London patient in the future. Until the case of the London patient, researchers thought that an immense degree of immune suppression was necessary for a possible cure of HIV to occur in the setting of a delta-32 stem cell transplant.

The London researchers also credit the development of mild GvHD in their patient with helping to clear his immune system of residual HIV-infected cells and his prolonged remission from the virus.

Notes on a potential cure

Overall, the findings from the London patient are encouraging and further experiments with HIV-positive people who have leukemia or lymphoma and who need a stem cell transplant from a donor with delta-32 mutation will likely occur in the future. However, the preparation for stem cell transplants (conditioning regimens, additional suppression of the immune system) can be deadly in the context of life-threatening cancer. Doctors at the Mayo Institute conducted a review of stem cell transplants done in HIV-positive people with cancer between 2002 and 2017. They found that nearly half of 49 patients died over the short- and long-term. The majority of deaths occurred because of a recurrence of cancer (60%) and other causes of death included severe infections, complications of GvHD and organ failure.

It is important to note that doctors in the UK have not judged the patient to be cured of HIV. In theory, it is possible that there still may be a few HIV-infected cells deep within his body, such as in the lymph nodes or brain. It will take several more years of assessments before they would feel confident in declaring him cured.

Resources

The Canadian HIV Cure Enterprise (CanCURE)

—Sean R. Hosein

REFERENCES:

  1. Gupta RK, Abduljawad S, McCoy L, et al. Sustained HIV-1 remission following homozygous CCR5 delta-32 allogenic HSCT. In: Program and abstracts of the Conference on Retroviruses and Opportunistic Infections, 4–7, March 2019, Seattle, Washington. Abstract 29.
  2. Gupta RK, Abdul-Jawad S, McCoy LE, et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature. 2019 Apr;568(7751):244-248.
  3. Arslan S, Litzow MR, Cummins NW, et al. Risks and outcomes of allogeneic hematopoietic stem cell transplantation for hematologic malignancies in patients with HIV infection. Biology of Blood and Bone Marrow Transplantation. 2019; in press.
  4. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014 Jul 17;124(3):344-53.
  5. Baker KS, Leisenring WM, Goodman PJ, et al. Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation. Blood. 2019; in press.
  6. Hütter G. More on shift of HIV tropism in stem-cell transplantation with CCR5 delta32/delta32 mutation. New England Journal of Medicine. 2014 Dec 18;371(25):2437-8.
  7. Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. New England Journal of Medicine. 2009 Feb 12;360(7):692-8.