Tacrolimus: A Step Closer to Control of Graft Rejection

Tacrolimus: A Step Closer to Control of
Graft Rejection

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Jul- Aug 98	Rank Last Period May- Jun 98
1	S.M. Hammer, et al., "A controlled trial with two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less," New Engl. J. Med., 337(11):725-33, 11 September 1997. [15 U.S. and U.K. institutions] *XV174	30	†
2	F.M. Sacks, et al., "The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels," New Engl. J. Med., 335(14):1001-9, 3 October 1996. [8 U.S. and Canadian institutions] *VL459	28	†
3	J.D. Pirsch, et al., "A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation," Transplantation, 63(7):977-83, 15 April 1997. [5 U.S. institutions] *WU375 22 +	22	†
4	J.A. Staessen, et al., "Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension," The Lancet, 350(9080):757-64, 13 September 1997. [14 institutions worldwide] *XW282	19	†
5	J.W. Mellors, et al., "Plasma viral load and CD4⁺ lymphocytes as prognostic markers of HIV-1 infection," Ann. Int. Med., 126(12):946-54, 15 June 1997. [7 U.S. institutions] *XE549	17	†
6	J.A. Roth, et al., *"Retrovirus-mediated wild-type p53* gene transfer to tumors of patients with lung cancer,"** Nature Med., 2(9):985-91, September 1996. [U. Texas, M.D. Anderson Cancer Ctr, Houston] *VF497	16	†
7	J.P. Struewing, et al., *"The risk of cancer associated with specific mutations of BRCA1* and BRCA2 among Ashkenazi Jews,"** New Engl. J. Med., 336(20):1401-8, 15 May 1997. [NIH: NCI and NHGRI, Bethesda, MD; Westat, Inc., Silver Spring, MD] *WY577	16	†
8	D.H. Kedes, et al., "The seroepidemiology of human herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus): Distribution of infection in KS risk groups and evidence for sexual transmission," Nature Med., 2(8):918-24, August 1996. [Howard Hughes Med. Inst, U. Calif., San Francisco; U. So. Calif., Los Angeles; San Francisco Dept. Public Health, CA] *UZ804	15	†
9	S.M. Hammer, et al., "A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter," New Engl. J. Med., 335(15):1081-90, 10 October 1996. [11 U.S. institutions] *VN399	15	†
10	D.A. Katzenstein, et al., "The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter," New Engl. J. Med., 335(15):1091-8, 10 October 1996. [7 U.S. institutions] *VN399	15	†

SOURCE: ISI's Hot Papers Database. the full legend.

In approximately 30 years, organ transplantation has become almost too successful. A shortage of organs has prompted renewed debate about whether people should register their unwillingness to be a donor, all others being presumed to consent. On the research front the same scarcity has in part led to experiments with organs from pigs (genetically modified or not) for donor material or as temporary support for patients in organ failure. Both proposals are controversial, and the latter has been complicated lately by concerns about the risk of transfer of porcine endogenous retroviruses.

The difficulty in finding perfect tissue matches means that immediate post-transplant anti-rejection therapy and continued maintenance immunosuppression are the lot of patients. Transplant surgeons used to have at their disposal anti-lymphocyte (or thymocyte) globulin and the OKT3 antibody and corticosteroids and azathioprine. Then came cyclosporine. Now there are the newer monoclonal antibodies basiliximab and daclizumab plus tacrolimus, sirolimus (rapamycin), and mycophenolate mofetil. Further compounds, such as FTY720, an extract from the fungus Isaria sinclairii, are in development.

FK506 or tacrolimus (the pronunciation demands a short "o" and "i") has attracted much attention lately, with 1,000 citations on the PubMed website in the past two years. The benchmark for comparison is cyclosporine, and this was the comparison that the FK506 Kidney Transplant Study Group set out to achieve in their 12-month randomized trial (paper #3). In separate trials coordinated in the United States and Europe, this agent has been systematically studied or experimented with in the context of other organs—liver, heart, lung, bone marrow, pancreas, and small intestine, a recent example being the United States FK506 Study Group’s study in hepatic transplantation published on August 27, 1998 (Transplantation, 66:493-9, 1998).

Toxicity is an important measure in trials such as this one in renal patients (paper #3); the efficacy endpoints are survival of patient and of graft (the latter reflecting cases where the graft has been irreversibly rejected or removed for other reasons but the patient survives by returning to dialysis or having a repeat transplant) and the frequency of rejection. Neither patient survival nor graft survival were significantly different between the tacrolimus and the cyclosporine groups, but acute rejection demanding immediate treatment (e.g., with anti-lymphocyte globulin) was significantly more common in the cyclosporine group (46.4% versus 30.7%). Diabetes as a post-transplant complication was five times as common with tacrolimus (19.9% versus 4.0%), and there was also more neurotoxicity with this drug. On the other hand, patients on the newer agent seemed to be spared the serum lipid abnormalities with which cyclosporine is associated.

A "safe and effective alternative to cyclosporine" in renal transplantation was the cautious verdict on tacrolimus at the time of publication (April, 1997). Scrutiny of published evidence over the past few months does not suggest that a definitive answer to a head-to-head comparison of tacrolimus (FK506, Prograf) and cyclosporine in its modern formulation (Neoral) is yet available.

Mr David W. Sharp, M.A. (Cambridge),
is a Deputy Editor of The Lancet, London, U.K.