Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well established treatment option for hematologic malignancies such as Hodgkin and non-Hodgkin lymphomas, acute and chronic leukemias, and other hematologic conditions in HIV-negative patients. Unfortunately, allo-HSCT is often not considered in HIV-positive patients because of multiple challenges, such as prior opportunistic infections and malignancies, concomitant infections, complex drug interactions between antiretroviral therapy (ART) and medications used in transplantation as well as the effects of HIV on T cells, the bone marrow environment, and cytokine milieu. These factors may affect engraftment, lead to an increase in conditioning regimen-related toxicity, graft-versus-host disease (GVHD), and infection risk, thus leading to increased transplant-related mortality . The so-called Berlin patient, who was cured of HIV with an allo-HSCT from a donor with genetic resistance to HIV administered for treatment of acute myeloid leukemia (AML), renewed interest in the procedure . Unfortunately, the odds of finding an human leukocyte antigen-matched suitable donor homozygous for CCR5-Δ32 deletion are low .
Recent advances in HIV management, particularly the ability to suppress viral replication during the set-up for allo-HSCT utilizing new agents with a low side-effect profile, few if any drug interactions and good oral tolerability offer the possibility of protecting the newly transplanted immune system from the effects of the virus . Participation of infectious disease consultants with experience in the management of HIV as well as infections in allo-HSCT has been proposed to optimize outcomes . Additionally, newer approaches to allo-HSCT, including the use of less toxic nonmyeloablative (reduced intensity) conditioning regimens to decrease the risk of transplant-related morbidity and mortality while preserving the graft-versus-tumor effect, as well as improved supportive care, including prophylaxis against infections and GVHD , prompted us to look at our experience over the last 5 years. During this time, our institution developed a coordinated approach for the management of these patients, with the participation of experienced infectious diseases physicians, starting before transplant and including the optimization of ART and prophylaxis regimens, the treatment or suppression of prior or concomitant infections, and follow-up during the peri- and post-transplant periods, maintaining control of HIV replication. Here, we present our experience.
The retrospective study was approved by the Institutional Review Board of MD Anderson Cancer Center. Five patients with HIV infection underwent allo-HSCT from 1 January 2010 until 31 January 2015. We retrospectively reviewed their medical records. Endpoints included duration, interruption, and adverse effects of ART, post-allo-HSCT CD4+ cell count and maintenance of an undetectable viral load, engraftment, defined as the first of 3 consecutive post-allo-HSCT days on which the absolute neutrophil count exceeded 500/μl; occurrence of acute and chronic GVHD, episodes of cytomegalovirus (CMV) reactivation, defined as CMV antigenemia at least five cells/million white blood cells (WBC) or less than five cells/million WBC if the patient received therapy or developed end-organ disease, and other infection episodes. Transplant-related mortality was defined as death from any cause without malignancy relapse in the first 100 days after allo-HSCT and overall survival was measured from date of allo-HSCT to the date of last visit or death. Endpoint follow-up was stopped upon diagnosis of disease relapse or death.
The characteristics of our five patients are summarized in Table 1. They were all men; the median age was 55 years. Two patients had AML, one each had Burkitt lymphoma, large granular lymphocytic leukemia, and myelodysplastic syndrome (MDS). Two patients had secondary malignancies, patient 1 had AML after therapy for Burkitt lymphoma, and patient 5 had therapy-related MDS after chemotherapy for anal squamous cell carcinoma. Three patients were in remission at the time of allo-HSCT.
HIV disease and antiretroviral therapy
Patients were diagnosed with HIV infection and received ART for a median of 5 years prior to allo-HSCT. Patient 1 received tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) for 5 years before allo-HSCT and continued until 169 days post-allo-HSCT, when EFV was changed to raltegravir (RAL) because of a drug interaction. Patient 2 received TDF/FTC-RAL as his first ART starting 1 month before allo-HSCT and the remaining patients were switched to TDF/FTC-RAL a median of 2.5 months before transplantation. Patient 3 had hepatitis that resolved after lopinavir/ritonavir (LPV/r) was replaced with RAL prior to allo-HSCT. Except for patient 3, all others had an undetectable pretransplant HIV viral load. The median pretransplant CD4+ cell count was 208 cells/μl (range: 33–1661 cells/μl). Four patients had history of pretransplant infections or comorbidities related to HIV infection.
Two patients received grafts from matched related and three from matched unrelated donors. All five received standard GVHD and infection prophylaxis as detailed in Table 2. In addition, two patients received weekly azithromycin prophylaxis.
All patients engrafted a median of 17 days post-allo-HSCT (range: 13–19 days) and there was no transplant-related mortality. Patients 1 and 4 relapsed after 3 months and patient 5 relapsed 9 months post-transplant. Their overall survival was 6, 7, and 13 months and transplant, respectively. All three died of relapse of their leukemia/MDS. Patients 2 and 3 were alive and in remission 55 and 42 months after transplant, respectively. Two patients had acute GVHD grades 1 and 2, and one had chronic GVHD of the skin, oral mucosa, and liver (Table 1).
Patients 1, 2, and 5 had neutropenic fever treated successfully with empiric antibiotics, their blood cultures were negative. One or two episodes of CMV reactivation, without end-organ disease, occurred in four patients and were controlled with ganciclovir or foscarnet. Only two other post-transplant infections were diagnosed in the first 100 days post-allo-HSCT: rectal herpes in patient 1 and acute cholecystitis in patient 2, both resolved.
Post-transplant monitoring of HIV infection
We performed a total of 27 post-transplant HIV PCR quantitative viral load measurements, a median of 3 per patient (range: 2–11), all were undetectable except one, patient 3 had 138 copies/ml, and the following viral load was undetectable. We had 31 CD4+ cell count values, a median of 5 per patient (range: 2–11). Patients 2 and 3, who achieved complete remission, had the longest follow-ups and highest post-allo-HSCT CD4+ cell counts, which peaked 20 and 29 months post-allo-HSCT, respectively.
Adverse effects of antiretroviral therapy
Patient 3 developed acute kidney injury, presenting 218 days after transplant with nausea, vomiting, and hyperkalemia. He was dehydrated and his creatinine was 7.3 mg/dl. He responded to supportive measures. TDF/FTC and RAL were held for 7 days, and then replaced with abacavir/lamivudine, RAL was restarted. His HIV viral load remained undetectable and his creatinine was 0.9 mg/dl on last follow-up.
Antiretroviral therapy interruptions and substitutions
There were no other documented interruptions, and only one additional substitution: patient 1 had EFV replaced for RAL 169 days post-allo-HSCT, to avoid a drug interaction with voriconazole. All patients continued on ART until their last follow-up, except patient 5, who discontinued ART when he was transferred to hospice.
Five HIV-infected patients underwent allo-HSCT for different hematologic malignancies and received different myeloablative and nonmyeloablative conditioning chemotherapy regimens in a single institution after 2010. The conditioning regimens were those used in HIV-negative patients with a similar indication for transplantation and the rates of relapse, GVHD, and other complications were within expectations for similar HIV-negative patients [7,8]. The practice of scheduled ART interruption during the peritransplant period [1,9], when mucositis makes oral intake difficult and drug interactions with the conditioning regimen may increase drug toxicity, was not necessary because of the use of well tolerated, low pill burden regimens with little or no drug interactions. Standard anti-infectious and GVHD prophylaxis regimens were used. Before transplant, they had well controlled HIV infection, a good performance status and protease inhibitor-free ART regimens.
Compared with patients reported previously, our patients were older, with a mean age of 55 years compared with 37, 34, and 42 years in previous reports [1,6,10]. All patients engrafted within the expected time and were alive at 100 days after transplant. This is in contrast with very high transplant-related mortality at day 100 in previous reports, affecting 10 of 23 (43%) patients reported to the Center for International Blood and Bone Marrow Transplant Research between 1987 and 2003 , and attributed mainly to treatment-related toxicities and infection. In a more recent review of published cases reported in the literature between 2000 and 2009 totaling 17 patients, transplant-related mortality decreased to 24%, and total nonrelapse mortality was 29% . However, a review of published reports is susceptible to publication bias.
Only one of our patients had ART-related toxicity, his acute kidney injury was probably multifactorial, as the patient was acutely dehydrated and receiving tacrolimus, TDF, and trimethoprim/sulfamethoxazole. He improved with supportive care and TDF was replaced with abacavir. TDF is reported to cause acute tubular necrosis and Fanconi syndrome in HIV-infected patients with complete or partial improvement in renal function in most cases after discontinuation . A new formulation, TDF alafenamide, is reported to have reduced nephrotoxicity when compared with TDF, and is now available and recommended as part of optimal initial ART regimens . It may be a better alternative for allo-HSCT patients, already at high risk of nephrotoxicity.
Peritransplant treatment interruptions may cause rebound viremia and an acute febrile illness similar to primary HIV, along with infection of donor T cells. There is also the risk of developing ART resistance, thus, they should be avoided if possible . Our patients were able to continue on their ART without programmed or documented interruptions, which led to excellent viral control after transplant, all achieving undetectable viral loads in the first 90 days post-allo-HSCT and subsequently. They had good recovery of their CD4+ cell counts, which continued to rise, in the two long-term survivors, for up to 3 years. Johnston et al. reported that only six of 15 HIV-positive autologous and allo-HSCT patients missed a median of three doses of ART and three patients that were not fully suppressed pre-HSCT had detectable HIV RNA post-HSCT, all subsequently controlled.
The most common post-transplant infection was CMV reactivation in four patients, similar to what is seen in HIV-negative patients . The primary cause of death was malignancy relapse in three patients, with two alive and in remission after prolonged follow-up. Chemotherapy-related toxicities and infection were the most frequent causes of death post-allo-HSCT in patients receiving ART in a previous review of reported cases  and a single-institution case series , whereas relapse-related mortality was uncommon, presumably because of the short survival. A more recent case series reported seven deaths of malignancy relapse and one of GVHD out of eight HIV-positive allo-HSCT recipients .
Our case series demonstrates that advances in the management of HIV infection allowed us to treat our patients’ hematologic malignancies as we would in HIV-negative patients with other comorbidities, such as diabetes or heart disease: by providing state of the art multidisciplinary management and supportive therapy through the peritransplant period.
V.E.M. designed the collection form, reviewed data, prepared tables, and wrote most of the manuscript. P.A.D. designed the collection form, reviewed charts, had limited participation in writing the manuscript, and reviewed and approved the article. U.R.P. contributed to the study design, obtained IRB approval, accessed the transplant registry to find the cases, and reviewed and approved the article.
Partial support was given by NIH/NCI under award number P30CA016672.
Conflicts of interest
There are no conflicts of interest.
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