Correspondence

Prophylactic Immune Globulin in Children with HIV Disease

N Engl J Med 1995; 332:750-752March 16, 1995

Article

To the Editor:

Two double-blind, placebo-controlled trials have demonstrated that intravenous immune globulin reduces serious and minor bacterial infections and hospitalizations in children infected with the human immunodeficiency virus (HIV) who have early or advanced disease, including those receiving zidovudine.1-3 The results of the National Institute of Child Health and Human Development (NICHHD) trial contrast with those of a subgroup analysis in AIDS Clinical Trials Group (ACTG) Protocol 051, reported by Spector et al. (Nov. 3 issue).1 According to the subgroup analysis, a significant benefit of intravenous immune globulin appeared to be confined to the 174 patients not receiving trimethoprim–sulfamethoxazole three times weekly as prophylaxis against Pneumocystis carinii pneumonia. In the smaller subgroup of 81 patients receiving trimethoprim–sulfamethoxazole, bacterial-infection rates were actually higher among those receiving intravenous immune globulin than among those receiving placebo (estimated infection rate at two years, 28 percent in the immune globulin group vs. 18 percent in the placebo group). The paradoxical increase in streptococcal infections among the patients receiving trimethoprim–sulfamethoxazole and intravenous immune globulin (eight infections, as compared with two among the patients receiving trimethoprim–sulfamethoxazole and placebo) raises a question about the comparability of the immune globulin and placebo groups among patients receiving trimethoprim–sulfamethoxazole.

These data differ from the results of the NICHHD trial,4 as well as from those of a 20-month open-label follow-up study of intravenous immune globulin.5 In the follow-up study, 43 percent of the patients originally receiving placebo were receiving trimethoprim–sulfamethoxazole prophylaxis at the start of the open-label administration of intravenous immune globulin; after treatment with intravenous immune globulin, a decrease in serious and minor bacterial infections and hospitalizations was observed in the placebo group among both patients receiving and those not receiving trimethoprim–sulfamethoxazole.

Neither the NICHHD trial nor ACTG 051 was designed to compare the effectiveness of trimethoprim–sulfamethoxazole with that of intravenous immune globulin as prophylaxis against infection; the ability to detect clinically relevant differences in small subgroup analyses is limited, and bias in subgroup selection is possible. Although a study of trimethoprim–sulfamethoxazole as prophylaxis against P. carinii pneumonia in patients with cancer indicated that daily treatment with trimethoprim–sulfamethoxazole was associated with decreased bacterial infection,6 treatment with trimethoprim–sulfamethoxazole three times a week, as recommended for prophylaxis against HIV infection in children,7 may not result in decreased infection. A recent placebo-controlled trial of daily trimethoprim–sulfamethoxazole in patients with acute leukemia showed no difference in bacteremia or overall infections between the treatment and placebo groups, although trimethoprim-resistant organisms were detected in all the patients receiving trimethoprim–sulfamethoxazole.8

Although these trials indicate that intravenous immune globulin reduces bacterial infections and decreases hospitalization among HIV-infected children, regardless of the stage of disease and whether or not they were receiving antiretroviral therapy, it appears to be premature to conclude that a benefit of intravenous immune globulin would not be observed in HIV-infected children receiving trimethoprim–sulfamethoxazole prophylaxis or that trimethoprim–sulfamethoxazole would provide prophylaxis against infection equivalent to that seen with intravenous immune globulin. The role of intravenous immune globulin as prophylaxis against infection in patients receiving concomitant trimethoprim–sulfamethoxazole has not been conclusively resolved by these trials and will require further study.

Lynne M. Mofenson, M.D.
Robert Nugent, Ph.D.
National Institutes of Health, Bethesda, MD 20892

8 References

1. 1

   Spector SA, Gelber RD, McGrath N, et al. A controlled trial of intravenous immune globulin for the prevention of serious bacterial infections in children receiving zidovudine for advanced human immunodeficiency virus infection. N Engl J Med 1994;331:1181-1187
   Full Text | Web of Science | Medline

2. 2

   The National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. N Engl J Med 1991;325:73-80
   Full Text | Web of Science | Medline

3. 3

   Mofenson LM, Moye J Jr, Bethel J, Hirschhorn R, Jordan C, Nugent R. Prophylactic intravenous immunoglobulin in HIV-infected children with CD4+ counts of 0.20×10⁹/L or more: effect on viral, opportunistic, and bacterial infections. JAMA 1992;268:483-488
   CrossRef | Web of Science | Medline

4. 4

   Mofenson LM, Bethel J, Moye J, et al. Effect of intravenous immunoglobulin, PCP prophylaxis and AZT on prevention of infections in HIV-infected children. Pediatr Res 1992;31:Suppl 2:170A-170A abstract.
   

5. 5

   Mofenson LM, Moye J Jr, Korelitz J, Bethel J, Hirschhorn R, Nugent R. Crossover of placebo patients to intravenous immunoglobulin confirms efficacy for prophylaxis of bacterial infections and reduction of hospitalizations in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1994;13:477-484
   CrossRef | Web of Science | Medline

6. 6

   Hughes WT, Kuhn S, Chaudhary S, et al. Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1977;297:1419-1426
   Full Text | Web of Science | Medline

7. 7

   Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 1991;40:(RR-2):1-13
   Medline

8. 8

   Ward TT, Thomas RG, Fye CL, et al. Trimethoprim-sulfamethoxazole prophylaxis in granulocytopenic patients with acute leukemia: evaluation of serum antibiotic levels in a randomized, double-blind, placebo-controlled Department of Veterans Affairs Cooperative Study. Clin Infect Dis 1993;17:323-332
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Mofenson and Nugent have expressed concern that in a subgroup analysis it was determined that trimethoprim–sulfamethoxazole prophylaxis appeared to obscure the apparent benefit of intravenous immune globulin. However, our multivariate analyses showed interactions indicating that the main effect of intravenous immune globulin was among children who were not also receiving trimethoprim–sulfamethoxazole prophylaxis. This was so with respect to both the use of trimethoprim–sulfamethoxazole at the time of enrollment and its introduction during follow-up (as a covariate over time). Our report emphasized that appropriate caution be used in interpreting the results of retrospective subgroup analyses. In fact, the same caution is necessary for interpreting the magnitude of the effect of intravenous immune globulin in the original NICHHD trial, which was stopped early on the basis of the significant effect of intravenous immune globulin only within a retrospectively defined subgroup of patients with CD4+ lymphocyte counts above 200 per cubic millimeter.1

The paradoxical finding of an apparent increase in Streptococcus pneumoniae and other streptococcal infections among children receiving both intravenous immune globulin and trimethoprim–sulfamethoxazole in the current study did not appear to be due to an unequal randomization resulting in a disproportionately large number of children with advanced disease in this subgroup. However, this finding may be explained in part by studies indicating that intravenous immune globulin may have a negative effect on antibiotic treatment.2-4 Thus, before recommendations can be made regarding the use of intravenous immune globulin and trimethoprim–sulfamethoxazole together, in vitro and in vivo investigations are necessary to clarify the effect of an interaction between these agents on S. pneumoniae infection.

Finally, as we stressed in our article, the results of this trial should not be interpreted to indicate that no children infected with HIV should receive intravenous immune globulin. Children with advanced HIV disease who are not receiving trimethoprim–sulfamethoxazole prophylaxis may benefit from treatment with intravenous immune globulin. However, both the NICHHD trial and the current study failed to demonstrate improved survival for children receiving intravenous immune globulin. Moreover, as recent studies have shown,5 intravenous immune globulin, like any biologic product, may have unexpected risks and should be reserved for children who are likely to receive the most benefit from it.

Stephen A. Spector, M.D.
University of California, San Diego, La Jolla, CA 92093

Richard D. Gelber, Ph.D.
Harvard School of Public Health, Boston, MA 02115

Diane W. Wara, M.D.
University of California, San Francisco, San Francisco, CA 94110

5 References

1. 1

   The National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. N Engl J Med 1991;325:73-80
   Full Text | Web of Science | Medline

2. 2

   Fisher GW. Immunoglobulin therapy for neonatal sepsis: an overview of animal and clinical studies. J Clin Immunol 1990;10:40S-46S
   CrossRef | Web of Science | Medline

3. 3

   Kim KS. High-dose intravenous immune globulin impairs antibacterial activity of antibiotics. J Allergy Clin Immunol 1989;84:579-586
   CrossRef | Web of Science | Medline

4. 4

   Weisman LE, Lorenzetti PM. High intravenous doses of human immune globulin suppress neonatal group B streptococcal immunity in rats. J Pediatr 1989;115:445-450
   CrossRef | Web of Science | Medline

5. 5

   Bjoro K, Froland SS, Yun Z, Samdal HH, Haaland T. Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin. N Engl J Med 1994;331:1607-1611
   Full Text | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Andromachi Scaradavou, Susanna Cunningham-Rundles, John L. Ho, Claudia Folman, Howard Doo, James B. Bussel. (2007) Superior effect of intravenous anti-D compared with IV gammaglobulin in the treatment of HIV-thrombocytopenia: Results of a small, randomized prospective comparison. American Journal of Hematology 82:5, 335-341
   CrossRef