Abstract and Commentary
Maraviroc and graft-versus-host disease
By Dean L. Winslow, MD, FACP, FIDSA, Chairman, Department of Medicine, Santa Clara Valley, Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Winslow is a consultant for Siemens Diagnostic.
Synopsis: Maraviroc (MVC) inhibited CCR5 internalization and lymphocyte chemotaxis in vitro. 35 hematopoietic stem cell transplant (HSCT) recipients were treated with MVC starting 2 days prior to transplantation until day 30. In these patients grade II-IV acute graft- versus- host disease (GVHD) incidence was 14.7% at day 100 and 23.6% at day 180. Acute liver or gut GVHD was not observed before day 100 and remained uncommon through day 180.
Source: Reshef R, et al. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. New Eng Jrl Med 2012;367:135-145.
The CCR5 antagonist maraviroc (MVC) was tested in vitro to determine its effect on lymphocyte function and chemotaxis. 38 high-risk patients who underwent reduced intensity allogeneic HSCT were treated in a phase I/II pilot study using MVC twice daily (in addition to standard GVHD prophylaxis).
MVC inhibited CCR5 internalization and lymphocyte chemotaxis in vitro without impairing T-cell function or formation of hematopoietic-cell colonies. In 35 evaluable patients given MVC the cumulative incidence of grade II-IV acute GVHD was low at 14.7% by day 100 and 23.6% by day 180 and remained uncommon before day 180. The incidence of grade III-IV GVHD by day 180 was only 5.9%. The 1-year death rate (that was not preceded by disease relapse) was 11.7% without excessive rates of relapse or infection. MVC was well tolerated. Serum from patients receiving MVC demonstrated prevention of CCR5 internalization by CCL5 and blocked T-cell chemotaxis in vitro.
Commentary
MVC is an interesting orally bioavailable small molecule inhibitor of the chemokine receptor CCR5 (whose natural ligands are MIP-1a, MIP-1b, and RANTES). The agent was specifically designed as an antiretroviral agent and has shown both in vitro activity and clinical utility in treating HIV-infected patients infected with strains of HIV which use the CCR5 coreceptor. It is not effective in patients infected with CXCR4-tropic strains of HIV. In contrast to other effective antiretroviral agents, MVC actually binds to the cellular receptor rather than a viral target to produce its antiretroviral effect. MVC is not widely used as a component of HAART in the United States. This is likely due to the fact that other effective antiretroviral agents including second generation NNRTI's (etravirine), HIV protease inhibitors (darunavir), and integrase inhibitors (raltegravir) are now available as salvage therapy. While very well tolerated, MVC use is complicated by the fact that it must be dosed twice daily and it is only effective in patients infected with CCR5-tropic virus. The in vitro phenotype assay to determine HIV coreceptor usage costs $2,000 per assay and it often takes several weeks for the result to be available. In addition, while CCR5 coreceptor usage by HIV is common in early stage infection, CXCR4 coreceptor usage is more common in patients with more advanced HIV disease, further limiting use of MVC in treating HIV infection.
Despite initial concerns that blocking an important chemokine receptor would have serious adverse effects on the immune system, this has not been shown to be the case — probably due to the fact that there is much redundancy in this aspect of the human immune system. The only exception appears to be that individuals who are either homozygous or heterozygous for the CCR5 32 base pair deletion are susceptible to more severe infection with certain flaviviruses such as Yellow Fever and West Nile Virus.
One of the more problematic aspects of allogeneic HSCT is the need to "walk the knife edge" between engraftment (which repopulates the immune system and exhibits graft-versus-tumor effects) and GVHD. Visceral (especially GI) GVHD is a particularly severe complication and is a major cause of morbidity and mortality in HSCT recipients. This study shows that MVC (given for even a relatively short time — 30 days) appears to significantly inhibit lymphocyte trafficking and may be an effective new strategy to prevent visceral GVHD. Obviously larger studies (including randomized controlled trials) are needed to further validate this approach and to determine optimal duration of dosing.
The CCR5 antagonist maraviroc (MVC) was tested in vitro to determine its effect on lymphocyte function and chemotaxis.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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