How I Treat In Brief
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 /µ L . AlloHCT was recommended and an appropriately matched donor was identified ( not homozygous for CCR5Δ32 ).
Fast Facts
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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 .
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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 .
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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 .
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Careful planning for the peritransplant management of cART can reduce risk of significant drug interactions and development of cART-resistant HIV .
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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 .
“ Investigators are developing scalable , gene-modified cellular therapies of HIV / AIDS , and ... safe and effective conditioning regimens for this approach ...”
— JOSEPH C . ALVARNAS , MD ; JOHN A . ZAIA , MD ; and STEPHEN J . FORMAN , MD
Commentary on patient selection : As with AHCT , patients need to have treatable HIV infection and adequate end-organ function to be eligible for allo- HCT . 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-versushost 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 posttransplant . CD4-positive T-cell count was 726 cells /µ L . 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 , HIVinfected 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 genemodified 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 /µ L . 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 .
Future Considerations
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 , genemodified cellular therapies of HIV / AIDS , and clinical trials to establish safe and effective conditioning regimens for this approach are underway . ●
56 ASH Clinical News May 2018