Stem cell transplants have gained interest in the HIV community mainly because of their potential for curing HIV itself. However, stem cell transplants are mainly used to treat various forms of cancer in both HIV-negative and HIV-positive people. In 2012, a total of 18,284 hematopoietic (blood cell) transplants were performed in the U.S., according to the U.S. Health Resources and Services Administration. Data on how many of these involve HIV-positive patients are not available, but Christine Durand, M.D., of Johns Hopkins School of Medicine, estimates that over time "hundreds" of HIV-positive patients have received stem cell transplants.
Durand spoke at the recent 54th Interscience Conference on Antimicrobial Agents and Chemotherapy about the unique challenges of stem cell transplantation in HIV-positive recipients. Twenty-five percent to 35% of HIV-related deaths are due to cancer, mainly Hodgkin and non-Hodgkin lymphoma, acute leukemia and multiple myeloma. However, there are concerns about the risk of bacterial and viral infections in HIV-positive cancer patients, especially during the pre-transplant conditioning stage.
Two case control studies of autologous (cells are from the patient him- or herself) stem cell transplants showed slightly lower survival rates for HIV-positive patients compared to the HIV-negative control group (61.5% versus 70% in a total cohort of 106). Sixteen percent of the 19 deaths in the HIV-infected group were related to infections during the first four months after the transplant, while none of the 14 deaths in the control group were due to infections. However, the probability of overall survival evened out between the two groups a little more than one year post-transplant.
One of the main challenges in managing stem cell transplantation in HIV-positive patients is the interaction between chemotherapy drugs and antiretrovirals, both of which may interact with the cytochrome P450 (CYP450) enzymes. Other problems include impairment of renal and liver functioning that accompanies the drugs used in implantation management, but that may be exacerbated by certain antiretrovirals, as well as the nausea and vomiting that accompany chemotherapy and may inhibit absorption of some antiretrovirals that must be taken with food.
These problems would indicate that antiretroviral therapy should be stopped while the patient is being conditioned for the transplantation. But as Durand pointed out, cancer survival rates in HIV-infected patients increased dramatically with the advent of antiretroviral therapy. An early study of chemotherapy treatment for hematologic malignancies in HIV-positive patients, which was published by the AIDS Clinical Trials Group in 1997, found survival rates of only 10%, while two analyses of allogeneic (cells are from a donor) stem cell transplants performed before and after 1996 reported that survival rates increased to above 50% after antiretroviral therapy became available that year.
A multicenter observational study of HIV viremia during the first six months after a new diagnosis of lymphoma found a 35% increase in mortality for every 1-log increase in viremia. HIV-positive cancer patients should therefore be started on or remain on antiretroviral therapy while undergoing stem cell transplant treatment, Durand believes.
The HIV medications least likely to interact with drugs used for stem cell transplant conditioning and post-transplant prophylaxis are abacavir (Ziagen), emtricitabine (FTC, Emtriva), lamivudine (3TC, Epivir), rilpivirine (Edurant), dolutegravir (Tivicay, DTG), raltegravir (Isentress), maraviroc (Selzentry, Celsentri) and enfuvirtide (T-20, Fuzeon). Pharmacoenhancers (ritonavir [Norvir] and cobicistat [Tybost]), as well as boosted protease inhibitors should be avoided because they inhibit CYP450, while most non-nucleoside reverse transcriptase inhibitors induce CYP450 and should therefore not be used, either. The dosage of calcineurin inhibitors, such as tacrolimus (Prograf), post-transplant may need to be adjusted for patients who have to remain on ritonavir-boosted antiretrovirals.
One study published in 2012 also showed that off-label use of maraviroc -- the only CCR5 inhibitor currently approved in the U.S. -- may prevent graft-versus-host disease (rejection of allogeneic stem cells) in both HIV-positive and HIV-negative patients. Only 15% of participants in that study contracted graft-versus-host disease, compared to the commonly seen 50% of transplant patients.
The case of Timothy Brown, the "Berlin patient," who appears to have been functionally cured of HIV through stem cell transplantation, raised the hope that stem cell transplants may provide a cure for HIV. In Brown's case, the donor cells used had the rare genetic CCR5Δ32 mutation, which prevents the entry of HIV into cells. Durand outlined the steps that would be required to cure HIV through stem cell transplantation in the absence of that mutation:
- HIV reservoirs in hematopoietic cells would need to be eradicated. This could be accomplished through an allogeneic effect of the stem cell transplant. In this scenario, donor T cells recognize and kill the recipient's cells. The process would be similar to the graft-versus-tumor effect, a beneficial version of graft-versus-host disease that is seen in some cancer patients who receive a stem cell transplant. In theory, this mechanism could also become a graft-versus-HIV reservoir effect.
- Donor cells would need to be protected against HIV infection. Instead of the CCR5Δ32 mutation, potent antiretroviral therapy might be used in a process similar to that used in pregnant women to prevent the transmission of HIV from mother to child.
A proof-of-concept study of two patients in Boston initially appeared to provide such an approach to a cure. However, both patients' HIV ultimately rebounded after an analytic interruption of their antiretroviral therapy regimens. Durand's conclusion, therefore: "We still have a lot to learn, but for my patients, at this stage, I am not interrupting their treatment, analytic or otherwise."