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Second Patient Reported to Achieve Long-Term HIV Remission

MAR 05, 2019 | MICHAELA FLEMING
The absence of viral HIV rebound was observed for 16 months following interruption to antiretroviral therapy at 17 months after a single allogenic CCR5-d32 hematopoietic stem cell transplant using a no irradiation approach with only mild graft-versus-host disease.

According to Reuters, Ravindra Gupta, a professor and HIV biologist who co-led a team of doctors treating the man described his patient as “functionally cured” and “in remission”, but cautioned: “It’s too early to say he’s cured.”

This documentation is similar to only that of the so-called “Berlin patient.”

Details on this patient, referred to as the London patient, will be presented tomorrow, March 5, 2019 in a late breaker oral abstract session at the Conference on Retroviruses and Opportunistic Infections (CROI 2019) and published in the journal Nature.

The Berlin patient was “cured of HIV” following 2 consecutive hematopoietic stem cell transplants (HSCT) with total body irradiation. However, it is unclear which aspects of treatment contributed to this only known case of HIV cure.

The London patient has been described as an HIV-infected male diagnosed with Hodgkin’s lymphoma who underwent allogenic HSCT using a homozygous CCR5d32 donor. The nadir CD4 count was 290 cells/mm and the baseline viral load was 180,000 copies/ml.

Antiretroviral therapy comprising tenofovir disoproxil fumarate/emtricitabine/efavirenz was started in 2012 and, during episodes of ART interruption, the investigators observed viral rebound and nucleoside reverse transcriptase inhibitor resistance.

The Hodgkin’s lymphoma was resistant to first-line chemotherapy and other treatment regimens.
 
An unrelated CCR5d32 homozygous donor was identified with 1 allelic mismatch at HLA-B gene.

Therefore, conditioning with implemented Lomustine, cyclophosphamide, Ara-C, and etoposide, which was followed by 3.6 million CD34+ cells/kg. Graft-versus-host disease prophylaxis consisted of cyclosporine and methotrexate and in vivo T-cell depletion employed anti-CD52.

The patients developed mild gut graft-versus-host disease, however full donor chimerism was maintained in the blood. Additionally, antiretroviral therapy of rilpivirine, lamivudine, and dolutegravir was continues throughout.

Six months following the transplant, complete remission was observed, according to the investigators.

The investigators report the use of Geno2Pheno to predict co-receptor tropism based on single genome sequencing. Further, post-HSCT peripheral blood mononuclear cells were analyzed by droplet digital polymerase chain reaction and quantitative polymerase chain reaction. Quantitative viral outgrowth assay was employed to analyzed infectious virus levels and isolated CD4 T cells were experimentally infected with X4 and R5 HIV.

Single genome sequencing conducted using pre-transplant peripheral blood mononuclear cells identified distinct envelope clones, all with predicted R5 tropisms. The ART regimen was halted 17 months following HSCT and plasma HIV viral loads were reported to have remained undetectable (<1.4 copies/ml) at 33 months, with ART drugs not detectable in plasma by liquid chromatography-mass spectrometry.

The investigators write that at 33 months, “the total HIV DNA in CD4+ T cells showed 2 positive droplets in 1 out of 8 replicated (ddPCR HIV LTR, 10^6 cells tested) and no signal in qPCR (<0.69 HIV-gag and <0.65 HIV-LRT copies/million cells).” The team also indicates that “at 16 months post-transplant an HIV-specific Western blot was positive while p24/31 bands were absent.”

VITROS analysis revealed low quantity and quality of HIV antibody titers. And, at 3 distinct time points, post-transplant quantitative viral outgrowth assay demonstrated no reactivatable virus using a total of 23 million resting CD4+ T cells. Additionally, post-transplant CD4+ T cells did not express CCR5 and were susceptible in vitro to X4 but not R5 tropic virus.

The investigators conclude that “to our knowledge, this is the longest adult HIV remission observed since the Berlin patient.”

The study, “Sustained HIV-1 Remission Following Homozygous CCR5 Delta32 Allogenic HSCT,” will be presented on Tuesday, March 5, 2019 at CROI 2019 in Seattle, Washington.
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