This month, Joseph C. Alvarnas, MD, John A. Zaia, MD, and Stephen J. Forman, MD, discuss the use of hematopoietic cell transplantation (HCT) to treat patients with HIV–related hematologic malignancies.
This material was repurposed from “How I Treat Patients With HIV-Related Hematological Malignancies Using Hematopoietic Cell Transplantation,” published in the November 2, 2017, edition of Blood.
- HCT may be safe and effective for selected patients with HIV infection and hematologic malignancies.
- To be considered for HCT, patients must have HIV infection that is responsive to cART.
- AHCT is the standard of care for patients with HIV-related lymphomas and treatable HIV infection who otherwise meet standard transplant criteria. Limited data support the use of alloHCT in this patient group.
- Patients with HIV-related lymphomas should be enrolled in clinical trials that offer the prospect of access to CCR5Δ32 homozygous donors. Patients also may be considered for participation in trials evaluating the activity of gene-modified hematopoietic stem cells in conferring resistance to HIV infection.
- Careful planning for the peritransplant management of cART can reduce risk of significant drug interactions and development of cART-resistant HIV.
- After undergoing HCT, patients must be closely monitored for development of opportunistic infections, such as CMV. Prevention of these infections should include prophylactic and preemptive antimicrobials.
In the U.S., more than 1.2 million people are infected with HIV. Despite effective combination antiretroviral therapy (cART), HIV remains incurable and carries substantial morbidity and mortality risks. For example, patients with HIV are at an increased risk of developing non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), acute leukemia, myelodysplastic syndromes (MDS), and other cancers.
Today, patients with HIV-related lymphomas (HRL) are treated with regimens similar to the standards of care used in the general population, with HCT playing an important role.
The use of autologous HCT (AHCT) for patients with HRL and treatable HIV infection is supported by clinical trials and is now the standard of care for patients who are otherwise eligible for transplant. The prospective Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0803/AIDS Malignancy Consortium (AMC) 071 trial demonstrated that outcomes for 40 HIV-infected patients with HRL was comparable to 151 non–HIV-infected matched patients. At a median follow-up of 24.8 months (range not provided), two-year overall survival among HIV-infected patients was 87.3 percent and progression-free survival was 79.8 percent.
Data supporting the use of allogeneic HCT (alloHCT) for HIV-infected patients are even more sparse. The largest prospective trial to date is the BMT CTN 0903/AMC 080 trial, in which 17 patients underwent alloHCT. Despite limited clinical evidence, alloHCT is a reasonable option for selected patients with treatable HIV infection who meet standard transplant criteria.
AHCT cannot eradicate HIV, but results from two small studies suggest alloHCT has an anti-HIV/graft-versus-HIV effect. The experience of the “Berlin patient” is one reason researchers are exploring alloHCT as a means of altering the natural history of HIV infection. This patient underwent alloHCT from an unrelated donor homozygous for the CCR5Δ32 mutation of the CCR5 receptor. Because the CCR5 receptor is required for HIV entry into CD4-positive T cells, homozygotes for this mutation have inherited HIV resistance. Eight years post-transplant, the “Berlin patient” remains in hematologic remission with apparent eradication of his HIV infection.
Although the success of the “Berlin patient” awaits validation, it has prompted the development of autologous transplantation strategies using hematopoietic progenitor cells (HPCs) that have been genetically modified for HIV resistance. As of early 2018, treatment of HIV-infected patients with gene-modified HCT (gmHCT) is available only in clinical trials.
Here, we describe the selection of patients for HCT and the management of HIV treatment in transplant recipients using three clinical cases.
Case #1: AHCT
A 47-year-old man infected with HIV for 15 years and treated with cART was diagnosed with diffuse large B-cell lymphoma. At diagnosis, HIV viral load was undetectable and CD4-positive T-cell count was 348 cells/µL. The patient achieved a complete remission (CR) following firstline lymphoma therapy, but NHL recurred after 18 months and he was considered for AHCT.
Commentary on patient selection: As illustrated in this patient scenario, treatment considerations for HIV-infected patients should reflect those used in the treatment of HIV-uninfected patients. However, because HIV infection affects many organs, patients should be adequately screened to ensure that there is no compromise in performance status or organ function that would increase the morbidity and mortality risk of AHCT. Prior to consideration for AHCT, patients must also have a treatable HIV infection; patients with previously untreated HIV infection should not be excluded but should be evaluated for adequacy of virologic control or potential for responsiveness.
The patient was treated with the BEAM AHCT conditioning regimen (carmustine, etoposide, cytarabine, melphalan). His cART regimen was held from initiation of BEAM until resolution of mucositis.
Commentary on conditioning and management of cART: Careful planning of HIV treatment during the peritransplant period is important because treatment interruptions and continued subtherapeutic levels of some antiretrovirals are associated with a greater risk of developing HIV resistance.
AHCT relies on dose intensity of radiation therapy and chemotherapy for its effectiveness, so we recommend a planned interruption of cART during the period of possible therapy-related mucositis/enteritis to reduce the likelihood of significant gastrointestinal toxicity. This strategy mitigates the risk of stops/starts and sub-therapeutic cART.
Immediately post-AHCT, the patient’s HIV viral load rose to 1,024 copies/mL and his CD4-positive T-cell count fell to 120 cells/µL. One year after AHCT, the patient’s HIV viral load was undetectable and his CD4-positive T-cell count was 458 cells/µL. The patient remains in CR one year post-AHCT.
Commentary on post-AHCT outcomes: Most studies describe spikes in viral load and reduction in CD4-positive T-cell counts following AHCT. These are rarely associated with clinical sequelae. By one year post-AHCT, most patients return to having baseline control of their HIV infection and T-cell reconstitution. Viral load assessments should be performed every two to four weeks following re-initiation of cART, until undetectable viral load is achieved. Thereafter, HIV viral loads and CD4-positive T-cell counts should be reassessed every three months.
While the patient is recovering after AHCT and cART interruption, he or she should be monitored carefully for opportunistic infections (OI). For patients with increasing cytomegalovirus (CMV) viral loads greater than 1,000 copies/mL, we recommend preemptive treatment using ganciclovir, valganciclovir, or comparably effective anti-CMV chemotherapeutic drugs. Patients should receive prophylaxis for Pneumocystis jiroveci, herpes viruses, and Mycobacterium avium complex until they achieve adequate recovery of CD4-positive T-cell counts.
Case #2: AlloHCT
A 25-year-old man with an eight-year history of HIV infection presented with MDS. Eighteen months earlier, he underwent AHCT for HL, and remained in CR from HL. Viral load was undetectable, and his CD4-positive T-cell count ranged from 500 to 700 cells/µL. AlloHCT was recommended and an appropriately matched donor was identified (not homozygous for CCR5Δ32).
Commentary on patient selection: As with AHCT, patients need to have treatable HIV infection and adequate end-organ function to be eligible for alloHCT. If patients have already undergone AHCT, their underlying hematologic malignancy must also have demonstrated adequate treatment response prior to consideration for alloHCT. Those with an active, concurrent OI are contraindicated for transplant. When counseling patients prior to alloHCT, clinicians should carefully discuss the unlikelihood of a cure for HIV infection.
The patient’s cART regimen was changed from efavirenz/emtricitabine/tenofovir to emtricitabine/tenofovir combined with raltegravir. He received the conditioning regimen fludarabine/melphalan using tacrolimus/sirolimus to prevent graft-versus-host disease (GVHD). cART was continued uninterrupted.
Commentary on cART and GVHD prophylaxis: Peritransplant management of cART is more complex for alloHCT than for AHCT because of potential interactions between cART and the conditioning chemotherapeutic agents, immunosuppressive drugs, antimicrobials, and supportive care agents commonly used with alloHCT.
In general, we recommend against the use of boosted proteasome inhibitors and non-nucleotide reverse transcriptase inhibitors in the cART regimen, in favor of nucleoside reverse transcriptase inhibitors and integrase inhibitors (without cobicistat). When feasible, our preference is to continue cART uninterrupted for patients undergoing reduced-intensity or non-myeloablative alloHCT; this approach limits the risk of gastrointestinal toxicities and of impaired drug absorption or start/stop interruptions in cART.
Standard alloHCT preparative regimens should be used, along with standard treatments for prophylaxis and management of GVHD.
At three months post-AHCT, HIV viral load was undetectable and remained so at one year post-transplant. CD4-positive T-cell count was 726 cells/µL. The patient remains in CR from both HL and MDS at seven years and five years post-alloHCT, respectively.
Commentary on outcomes: HIV viral load and CD4-positive T-cell reconstitution should be followed as described for AHCT. Post-alloHCT planned interruption of effective cART should not be performed outside of an appropriately designed clinical trial. Because alloHCT involves major therapy-related immunosuppression, HIV-infected patients need to be monitored for OI. Surveillance for CMV reactivation for the first 100 days post-alloHCT is extremely important; if viral load is >1,000 copies/mL, patients should start preemptive treatment, as with AHCT. Also, patients undergoing alloHCT should remain on appropriate OI prophylaxis until adequate CD4-positive T-cell counts are reached.
Case #3: gmHCT
A 25-year-old HIV-infected man with chemotherapy-sensitive, persistent NHL participated in a clinical trial using gmHCT: Participants’ HPCs were genetically modified to express three anti-HIV, RNA-based moieties. Before mobilization for stem cell collection, cART was suspended to avoid compromising lentiviral transduction of the gene-modified product. This patient’s cART remained on hold through the preparative regimen and period of mucositis/enteritis to avoid induction of HIV resistance. He subsequently underwent BEAM conditioning, followed by infusion of both gene-modified and unmanipulated HPCs.
Prior to AHCT, HIV viral load was less than 400 copies/mL and CD4-positive T-cell count was 577 cells/µL. After recovering from mucositis, the patient resumed his prior cART regimen and promptly achieved an undetectable HIV viral load. He remains in CR two years post-AHCT.
Commentary on the role of gmHCT: Because of the pressing scientific questions regarding the promise of this treatment approach, we strongly support participation in well-designed clinical trials evaluating the impact of gmHCT for the HIV-infected patient population.
Investigators continue to evaluate HCT-based therapies as a potential cure for HIV infection. The effectiveness of the “Berlin patient” paradigm needs validation in clinical trials using alloHCT and homozygous CCR5Δ32 donors. Also, gmHCT is under investigation as an avenue to affect the underlying HIV infection.
Investigators are developing scalable, gene-modified cellular therapies of HIV/AIDS, and clinical trials to establish safe and effective conditioning regimens for this approach are underway.