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Questions Remain About Second Patient Who Demonstrates HIV Cure

Maggie L. Shaw
A second individual may have been cured of HIV following an allogeneic stem-cell transplant for stage 4b refractory Hodgkin lymphoma with Δ32-mutated cells, which are resistant to the virus. These cells did not express the CCR5 chemokine receptor, 1 of 2 methods of entry for HIV into a host cell. 
Known as the “London patient,” a second individual may have been cured of their HIV following an allogeneic stem-cell transplant for stage 4b refractory Hodgkin lymphoma with Δ32-mutated cells, which are resistant to the virus. These cells did not express the CCR5 chemokine receptor (CCR5Δ32/Δ32), 1 of 2 methods of entry for HIV into a host cell.1 His viral loads were last measured on March 4, 2020.2

The results published online today in Lancet HIV of the male patient who has been able to forgo antiretroviral treatment (ART) for 30 months—he stopped taking the anti-HIV drugs in September 2017—are a follow-up to results on this patient presented in March 2019 at the Conference on Retroviruses and Opportunistic Infections in Seattle, Washington.3 At that time, the patient had been off ART for 18 months and was deemed to be in remission from his HIV.2

“I’m not sure what this tells us,” stated Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, at that time. “It was done with Timothy Ray Brown, and now here’s another case — ok, so now what? Now where do we go with it?”

The patient is participant 36 in IciStem, a group of European scientists studying stem cell transplants as HIV treatment. Thirty-seven other HIV-positive individuals have received bone-marrow transplants as part of the program; of these, 6 transplants did not contain the mutation.3 With a goal to replace the immune system of the patient with HIV with healthy donor cells that are resistant to the virus, full body irradiation and chemotherapy are also administered to “target any residual HIV virus.”4

He is also the only other such patient to have reportedly been cured of HIV—the first being the “Berlin patient,” Timothy Ray Brown, who underwent stem cell transplant for relapsed acute myeloid leukemia1—and the transplant was meant to cure his cancer.5 Compared with Brown, who underwent 2 transplants with CCR5Δ32/Δ32-mutated cells, the London patient only had 1 transplant, with less-intense immunosuppression treatments.

By 28 months post ART, the patient’s CD4 count was close to his pretransplant level, at 430 cells per μL (23.5% of total T cells), and he had a CD4:CD8 ratio of 0.86 (normal range 1.5-2.5). Between 18 and 28 months, there was no clinically significant CMV reactivation. And at 30 months post ART, blood, cerebrospinal fluid, semen, and intestinal and lymphoid tissue samples do not show HIV-1 replication, although positive results continue for antibodies to the HIV-1 envelope protein2; however, a commentary on the present research notes that these HIV DNA were broken, meaning they can’t replicate. In addition, 99% of his peripheral T cells continue to demonstrate donor chimerism and mathematic modeling from the study that 90% or higher reduction in susceptible cells means a negligible chance of future rebound.2

“It is important to note that this curative treatment is high risk, and only used as a last resort for patients with HIV who also have life-threatening haematological malignancies. Therefore, this is not a treatment that would be offered widely to patients with HIV who are on successful antiretroviral treatment,” stated Ravindra Kumar Gupta, PhD, University of Cambridge, lead study author.

Questions remain, however, including the following6:
  • How soon can one know if someone has been cured of HIV?
  • Could the frequency of testing be reduced, one day even stopped?
  • What does a cure mean?
 

Collectively, the study authors note, “Being only the second reported patient to undergo this experimental treatment successfully, the London patient will need continued, but much less frequent, monitoring for re-emergence of the virus.”

They also note the importance of further research to refine assays that define a cure, as well as proof of gene editing efficiency and robust safety data.

References

1. Allers K, Hütter G, Hormann J, et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood. 2011;117(10):2791-2799. doi: 10.1182/blood-2010-09-309591.

2. Gupta RK, Peppa D, Hill AL, et al. Evidence for HIV-1 cure after CCR5/l32/ll32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report [published online March 10, 2020]. Lancet HIV. doi: 10.1016/S2352-3018(20)30069-2.

3. Mandavilli A. H.I.V. is reported cured in a second patient, a milestone in the global AIDS epidemic. The New York Times. March 4, 2019. nytimes.com/2019/03/04/health/aids-cure-london-patient.html. Accessed March 9, 2020.

4. The Lancet. Study suggests a second patient has been cured of HIV [press release]. London, UK: EurekAlert; March 10, 2020. eurekalert.org/pub_releases/2020-03/tl-tlh030920.php. Accessed March 10, 2020.

5. The ‘London patient,’ cured of H.I.V., reveals his identity. The New York Times. March 9, 2020. nytimes.com/2020/03/09/health/hiv-aids-london-patient-castillejo.html?utm_campaign. Accessed March 9, 2020.

6. Zerbato JM, Lewin SR. A cure for HIV: how would we know [published online March 10, 2020]? Lancet HIV. doi: 10.1016/S2352-3018(20)30075-8.

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