Reduction by combination prophylactic therapy with CMV hyperimmune globulin and acyclovir of the risk of primary CMV disease in renal transplant recipients

CMV-seronegative recipients of kidneys from CMV-seropositive donors (D⁺/R⁺) are at highest risk for developing clinical CMV disease. Even with routine prophylactic use of low-dose acyclovir we had a CMV disease incidence of 26% (5/19) in these patients. Published studies using either acyclovir or CMV hyperimmune globulin (HIG) alone as prophylaxis have also shown clinical disease in 20-30% of D⁺/R⁺ patients-less than controls but still significantly greater than in comparable CMV⁺ recipients (R⁺). The purpose of this study was to determine whether the risk of primary CMV disease in D⁺/R^- patients was reduced by prophylaxis with combined CMV-HIG and low- dose acyclovir as follows: CMV-HIG (Immuno) 1 ml/kg i.v. immediately prior to transplantation and at 3-week intervals for 6 months; acyclovir 600 mg/day p.o. for 3 months. A total of 361 consecutive renal transplants were studied prospectively. All D⁺/R^- pts (n=73) received CMV-HIG and acyclovir, the others (91 D⁺/R⁺, 74 D^-/R⁺, 123 D^-/R^-) received only low-dose acyclovir. The incidence of clinical CMV disease, CMV-related graft loss, graft and patient survival, and the influence of ALG and OKT-3 were analyzed and compared between groups. Of the 361 patients only 18 (5%) developed CMV disease, with 5 CMV-related graft losses. CMV disease occurred in only 10% of the D⁺/R^- patients, lower than in previously reported studies. Significantly the incidence was as low as in CMV⁺ recipients of kidneys from both CMV⁺ (6%) and CMV^- (7%) donors. Use of OKT-3 for steroid-resistant rejection increased the risk of developing CMV disease: 11/50 (22%) receiving OKT-3 developed CMV disease vs. only 7/311 (2%) who did not (P<0.001); 11/18 (61%) with CMV disease had received OKT-3. ALG induction immunosuppression did not increase the risk of CMV in patients who subsequently received OKT- 3. No patient developed CMV disease after discontinuing prophylaxis. There were no complications related to either CMV-HIG or acyclovir use. Compared with all other patients, the D⁺/R^- group had superior graft survival at 1 and 3 years (94% vs. 87% and 86% vs. 74%, P<0.05) but similar patient survival. Combined CMV-HIG and low-dose acyclovir appear to be better than either agent alone in preventing primary CMV disease in CMV^- patients who receive CMV⁺ kidneys. Low-dose oral acyclovir (600 mg/day) may be as effective in preventing CMV disease as higher-dose prophylactic regimens, at least when accompanied by CMV-HIG. Treatment of steroid-resistant rejection with OKT-3 is a major risk factor for CMV disease in D⁺/R^- and all CMV⁺ renal transplant recipients.