A new case of HIV remission may become the sixth example of an HIV cure.
The 2020s have proven to be a remarkable decade for HIV cure advancements, with several significant cases. The Dusseldorf Patient has been declared cured, the New York Patient achieved remission through an innovative haplo-cord transplant, and the City of Hope Patient became the oldest patient in HIV remission. This comes just after the 2010s wrapped up with The London Patient being declared cured in 2019. This month, researchers reported on the Geneva Patient, who is now in HIV remission, thus opening the possibility for a sixth HIV cure case. Within three years into the decade, there have been three confirmed cases of an HIV cure and another three patients in HIV remission who are being observed for “cure” status.
HIV can be cured, and the cure cases show us how it’s done — but the Geneva Patient’s case doesn’t seem to play by the rules. In the other HIV remission/cure cases, when a patient living with HIV also developed certain types of blood cancer, doctors performed a bone marrow or stem cell transplant with a twist:
- Use radiation and chemotherapy to decimate the cancerous and HIV-infected blood cells. This essentially wipes out the immune system, so you need to replace it.
- Give the patient the stem cells / bone marrow they need to create a new immune system via transplant. Make sure those cells have the CCR5Δ32/Δ32 genotype so that the new immune system will be HIV-resistant.
- During recovery, the patient generates a new HIV-resistant immune system which can suppress any remaining HIV in the body without becoming infected.
The Geneva Patient did not receive HIV-resistant stem cells; yet, they still seem to be in remission, even without HIV-resistant stem cells. This is very exciting news for researchers, since CCR5Δ32/Δ32 stem cells have been instrumental in all the previously mentioned HIV remission cases.
Researchers are cautiously optimistic about this unique case
Of all the HIV remission cases being observed for cure status, the Geneva Patient is undoubtedly the most mysterious. While the patient has remained off antiretroviral therapy (ART) for over 20 months without a viral rebound, doctors are puzzled and cannot pinpoint why this patient has experienced such positive results without CCR5Δ32/Δ32 stem cells. Despite the presence of many unknowns, the case of the Geneva Patient was reported on during the International AIDS Society’s (IAS) 12th conference on HIV science, IAS 2023.
What we know
Doctors are working to piece together the mystery by starting with what we do know about the Geneva Patient. The details, as reviewed by AIDSMap, are:
- The study involves a Caucasian male in his 50s who was diagnosed with HIV in 1990.
- Since 2005, he has been on continuous ART, and despite effective treatment, before transplant, he had detectable HIV RNA and HIV DNA using ultrasensitive tests.
- For his rare form of sarcoma, the man underwent chemotherapy and radiation, followed by a stem cell transplant in 2018. Since no matching CCR5Δ32/Δ32 donors could be found, the transplanted cells were “normal.”
- The new bone marrow successfully engrafted into the patient, reaching full chimerism, but the patient also experienced acute and chronic graft-versus-host disease (GvH). Doctors prescribed various immunosuppressant drugs to combat this immune reaction.
- After three years, the patient went on a monitored treatment interruption, discontinuing his ART in November 2021.
- Now, 20 months later in July 2023, the patient is still off ART and has not had a viral rebound. Even his ultrasensitive tests have turned negative, and no HIV-specific T cell response has been detected, indicating that the immune system can’t find HIV either.
Scientists and doctors are continuing to study the Geneva Patient to search for answers, which may provide a mechanism behind this unexpected outcome. The potential influence of the GvH disease that evolved after transplant, or the associated immunosuppressant drugs used to treat it, have been identified as areas of interest.
What we don’t know
Despite good record keeping and scores of tests, there are still many unanswered questions in the case of the Geneva Patient. Since HIV infects immune cells, which can migrate throughout the body, as well as some other scattered cell types, researchers are working to confirm that HIV is not present in the various anatomical sites that could possibly harbor replication-competent HIV. So far, laboratory testing on gut biopsies has not yielded viral outgrowth and intact HIV DNA has not been detected. Step by step, confidence is building atop the cautious optimism. Dr Asier Sáez‐Cirión of Institut Pasteur in Paris voices this sentiment:
“There may be viral rebound in the future, although we hope that this situation of viral remission remains permanent.”
The uncertainty is not unwarranted, since two Boston patients and a Minnesota patient have shown researchers that even trace amounts of replication-competent HIV can cause a viral rebound. From another perspective, HIV remission in cases such as the Mississippi Baby show us that extended periods of undetectable status do not necessarily indicate curative status. That being said, HIV remission and rebound have been studied for decades, so doctors can refer to a sizeable knowledgebase to help them assess even the rarest of cases. After 12 months of undetectable HIV status during ART interruption, Dr Asier Sáez‐Cirión says:
“… the probability that it will be undetectable in the future increases significantly.”
Researchers will continue analyzing the case study as they search for answers. Perhaps all replication-competent HIV reservoirs were cleared when chemotherapy and radiation was used, perhaps the immunosuppressive therapy had a role to play, or maybe the GvH incident had an effect.
Regardless of the mechanisms at play, the Geneva Patient has expressed his gratitude and excitement over this unexpected outcome. IAS president Sharon Lewin comments,
“The likelihood of rebound is impossible to say, but all of the reservoir measurements to date could not find any intact virus.”
Researchers will continue studying the Geneva Patient, but Professor Lewin urges a realistic view of this case:
“This is great news, but case reports are case reports.”
Until more evidence is analyzed, this case study does not have any applicable lessons to the transplantation procedure for patients with both HIV infection and hematological malignancies, though it would certainly be impactful if the incidence of GvH or the use of immunosuppressants do prove to be significant.
A deliberate approach: using gene therapy to cure HIV
The Geneva Patient’s outcome was unexpected and rare, with most patients experiencing a viral rebound in the same set of circumstances. In fact, even patients who receive CCR5Δ32/Δ32 stem cells in their stem cell/bone marrow transplant are not guaranteed to be cured of HIV, as evidenced by the Essen Patient. Due to safety concerns, it is not ethical to use chemotherapy and radiation to decimate the cells HIV normally infects unless the patient has another condition (like blood cancer) that necessitates such treatment. The safety concerns of this approach, and the scalability issues related to the rarity of CCR5Δ32/Δ32 cells, have spurred research groups like Addimmune to develop a gene and cell therapy for HIV.
By creating CCR5-null cells instead of sourcing them, Addimmune’s AGT103-T can circumvent the scalability problems related to the rarity of CCR5Δ32/Δ32 cells. And since these cells can be collected from the patient with a blood draw, modified outside the body, and then returned with a simple infusion, AGT103-T does not necessitate risky bone marrow / stem cell transplant procedures. We and others are working to bring curative therapies to people living with HIV because we believe today’s technology is capable of solving the root cause of HIV infection. It’s also a solid business case since the alternative is a pill a day for life, and beyond that, it’s just the right thing to do.
If you want to observe our progress as we move from our completed Phase 1 human trial to larger, later-stage trials, we encourage you to follow our clinical progress and our company’s milestones. The best way to stay up to date is to follow us on social media or sign up for our newsletter. We cover case studies on HIV and provide new perspectives on HIV science for curious readers as well, so if you want to stay updated on events such as the Geneva Patient, you’ll enjoy our articles.
If you would like to learn more about the Geneva Patient from other news sources, here are some links:
If you’re looking for a non-news source of information, the best primary source of information is the IAS 2023 conference, where the case study was detailed.