Researchers report case of bone marrow transplant patient off ART for 288 days without HIV rebound

An HIV-positive bone marrow transplant recipient at the Mayo Clinic experienced prolonged viral remission lasting nearly 10 months – longer than the so-called Boston patients – after interrupting antiretroviral therapy (ART), according to a report at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) last month in Seattle. Although his viral load eventually rebounded, his HIV reservoirs appeared to be reduced.

The only person known to be cured of HIV – Timothy Ray Brown, known as the 'Berlin Patient' – stopped ART when he received a bone marrow transplant to treat leukaemia and has not had detectable virus for ten years. Brown received a transplant from a donor with a double CCR5-delta-32 mutation, meaning they lack the CCR5 co-receptors most types of HIV use to enter T-cells. It is unclear whether his sustained remission is attributable to the donor's CCR5 mutation, the strong chemotherapy conditioning regimen used to kill off cancerous blood cells, a graft-versus-host reaction or multiple factors.

Bone marrow transplantation is apparently not sufficient to eradicate HIV. A few years ago, Timothy Henrich reported on two HIV-positive bone marrow transplant patients in Boston who got stem cells from 'wild-type' donors without the CCR5-delta-32 mutation, received a milder conditioning regimen and experienced acute graft-versus-host disease (GVHD). Both men maintained undetectable viral load longer than expected after interrupting ART, but eventually they experienced viral rebound at three and eight months after stopping HIV treatment.

Glossary

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.

stem cells

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

bone marrow

Cells in the middle of bones which are responsible for producing blood cells.

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.

 

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.

The latest case, presented by Nathan Cummins of the Mayo Clinic in Rochester, Minnesota, and colleagues, involved a 55-year-old man who was diagnosed with HIV in 1990 and started combination ART in 1999 with a CD4 T-cell count of 300 cells/mm3. He stopped treatment between 2004 and 2009 for unexplained reasons, then restarted ART consisting of ritonavir-boosted atazanavir (Prezista) plus tenofovir disoproxil fumarate (DF) and emtricitabine (the drugs in Truvada).

In April 2013 the man was diagnosed with B-cell acute lymphoblastic leukaemia. In anticipation of chemotherapy, his ART regimen was switched to raltegravir (Isentress), etravirine (Intelence), and tenofovir DF/emtricitabine. In October 2013 he underwent reduced intensity conditioning followed by an allogeneic stem cell transplant from a CCR5 'wild-type' donor.

At the time of transplantation the man had an HIV viral load of 25 copies/ml and a CD4 count of 288 cells/mm3, and he stayed on ART without interruption. After the transplant he developed opportunistic infections (E. coli septicaemia and pneumocystis pneumonia) and experienced GVHD at four months post-transplant.

The man continued on ART for more than two years after transplantation, mostly with detectable plasma viral load levels. HIV RNA was also undetectable in gut biopsy samples. HIV DNA in his peripheral blood cells became undetectable by day 56, and repeated leukapheresis procedures showed significant reductions in HIV RNA and DNA reservoir size.

In addition, that man's HIV antibody levels decreased, as indicated by weaker Western blot bands. However, single genome sequencing and phylogenetic analysis identified identical HIV clones at day 142, possibly due to homeostatic proliferation, or replication of latently infected cells, while he had GVHD.

After having such low HIV levels for a prolonged period, the man underwent an analytic treatment interruption, or carefully monitored discontinuation of ART. His plasma HIV RNA levels were tested every two weeks for the first 12 weeks of ART interruption, then every four weeks.

At day 288 – 9.6 months after stopping ART – he was found to have low-level viral rebound to 60 copies/ml. This rose to 1640 copies/ml by day 293, requiring that he restart HIV treatment. The man had no evidence of drug resistance and his viral load was re-suppressed within a month.

"Allogeneic peripheral blood stem cell transplantation in the setting of HIV is associated with significant reductions in HIV reservoir size by multiple measures, including prolonged combination ART-free remission," the researchers concluded.

They added that stem cell transplantation in the setting of suppressed viral replication may be associated with loss of HIV-specific immunity, and hypothesised that "immune activation in the setting of GVHD without anti-HIV specific immunity may cause homeostatic proliferation of latently infected cells, decreasing the chance of HIV eradication."

References

Cummins N et al. Two hundred eighty-eight-day drug-free remission from HIV rebound by allogeneic PBSCT. Conference on Retroviruses and Opportunistic Infections (CROI 2017), Seattle, abstract 319, 2017.

View the abstract on the conference website.

Download the poster from the conference website.