Correspondence
Oral Ganciclovir as Prophylaxis against Cytomegalovirus
N Engl J Med 1996; 335:1395-1397October 31, 1996
- Article
To the Editor:
Spector et al. (June 6 issue)1 conclude that oral ganciclovir “promises to be a useful drug for prophylaxis against CMV [cytomegalovirus] disease in persons with AIDS [the acquired immunodeficiency syndrome].” The results of their study do not support this statement. The drug's side effects, high cost, and limited efficacy all argue against such a conclusion.
The incidence of granulocytopenia requiring treatment was 15 percentage points higher in the treatment group than in the placebo group. More patients had this complication than were prevented from having CMV, and the granulocytopenia was long-lasting. Granulocyte colony-stimulating factor (G-CSF) was required for an additional 31 days per person-year in the ganciclovir group (47 vs. 16 days per person-year). Thus, the average patient would have white-cell counts below 500 per cubic millimeter for a month as a result of treatment. The rate of anemia requiring treatment was also 8 percentage points higher in the ganciclovir group.
A year's supply of oral ganciclovir costs $18,252 (the wholesale price in Philadelphia). Additional expenses include the costs of G-CSF and erythropoietin. The cost of 31 days of G-CSF treatment at the pharmacy of the Hospital of the University of Pennsylvania is $8,181. Treated patients also required nine more days of erythropoietin treatment per person-year than did those given placebo, at a cost of $498. These costs total $26,932 per treated patient per year and do not include the costs of additional care by a physician or hospitalizations due to granulocytopenia and anemia.
The authors report rates of protocol-defined CMV disease of 26 percent in the placebo group and 14 percent in the ganciclovir group. Thus, of 100 patients treated, 88 receive no benefit (74 will not have CMV disease in any case, and 14 will get it despite treatment). To prevent one bad outcome, 8.3 patients must be treated. With each patient's treatment costing $26,932, the cost of preventing one case of CMV disease is more than $223,000.
Thus, Spector et al. are recommending that we offer our patients with advanced human immunodeficiency virus (HIV) infection a treatment that requires them to take an additional 12 pills per day, will provide no benefit in seven of eight cases, will result in prolonged low white-cell counts in one of seven cases, will prevent a disease in one of eight cases that is treatable with intravenous ganciclovir, and costs over $2,000 per month. No reasonable patient would agree to such treatment.
The authors suggest that “emerging techniques” might identify those at highest risk. This would improve the cost–benefit analysis. For now, the study demonstrates that oral ganciclovir has no place in routine prophylaxis against CMV for patients with advanced HIV disease.
1 ReferencesDavid Nicklin, M.D.
University of Pennsylvania, Philadelphia, PA 191041
Spector SA ,McKinley GF ,Lalezari JP , et al. Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. N Engl J Med 1996;334:1491-1497
Full Text | Web of Science | Medline
To the Editor:
Spector et al. reported the results of a well-designed clinical trial investigating the usefulness of oral ganciclovir as prophylaxis against CMV disease in persons with AIDS. CMV disease caused by ganciclovir-resistant strains has been documented in persons with AIDS. The risk of resistance appears to be related to the duration of ganciclovir treatment. Drew et al. reported that 5 of 13 culture-positive patients treated with ganciclovir for more than three months for CMV retinitis excreted resistant virus.1
It would be of great value to know what proportion of patients with breakthrough CMV disease who were receiving ganciclovir prophylaxis in the current trial had CMV isolates resistant to ganciclovir. In addition, the percentage of patients with urinary isolates resistant to ganciclovir and the duration of prophylaxis before the emergence of resistance would be of substantial interest. It is somewhat surprising that the data on resistance were not reported, since the reports of studies of both the antimicrobial agents approved for prophylaxis against Mycobacterium avium complex in the same patient population — rifabutin and clarithromycin — included such data.2,3
3 ReferencesCraig A. Wood, M.D.
Allegheny University of the Health Sciences, Philadelphia, PA 191021
Drew WL ,Miner RC ,Busch DF , et al. Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis 1991;163:716-719
CrossRef | Web of Science | Medline2
Nightingale SD ,Cameron DW ,Gordin FM , et al. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. N Engl J Med 1993;329:828-833
Full Text | Web of Science | Medline3
Pierce M ,Crampton S ,Henry D , et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome. N Engl J Med 1996;335:384-391
Full Text | Web of Science | Medline
To the Editor:
In the study by Spector et al. of primary prophylaxis against CMV disease in patients with AIDS, ganciclovir reduced the risk of CMV disease by 50 percent. However, CMV disease could be avoided in only 12 of 100 patients treated; hence, the efficacy is 12 percent and not 50 percent. Moreover, Spector et al. did not analyze whether primary prophylaxis reduced the risk of permanent loss of vision. If preventive oral ganciclovir does not improve survival and does not reduce the risk of blindness, why not wait for the appearance of CMV disease? Since induction therapy is usually successful 1 and the recommended dose of oral ganciclovir for secondary prophylaxis equals the dose used in this study for primary prophylaxis,2 this approach could reduce costs and side effects. It would also improve the quality of life for patients without CMV disease, who need not take an additional 12 pills every day. Finally, if primary prophylaxis induces resistance to ganciclovir, treatment of CMV disease could be more difficult.
We still think that it is necessary to define which patients with low CD4+ lymphocyte counts have a higher risk of CMV disease before routine ganciclovir prophylaxis can be recommended.
2 ReferencesFederico Pulido, M.D.
Hospital 12 de Octubre, 28041 Madrid, SpainDaniel Carnevali, M.D.
Clínica Moncloa, 28008 Madrid, SpainRafael Rubio, M.D.
Hospital 12 de Octubre, 28041 Madrid, Spain1
Collaborative DHPG treatment study Group
Full Text | Web of Science | Medline2
Drew WL ,Ives D ,Lalezari JP , et al. Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. N Engl J Med 1995;333:615-620
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: In our study the most important side effects associated with ganciclovir were neutropenia and anemia. As compared with the placebo group, the ganciclovir group received 31 more days of granulocyte colony-stimulating factor and 9 more days of erythropoietin per person-year; however, there was no increase in the incidence of serious bacterial infections or other adverse events. Thus, the adverse events associated with oral ganciclovir in this setting are moderate and readily controlled with the use of hematopoietic stimulating factors.
We agree that taking 12 additional capsules per day is difficult for many persons with AIDS. Both a 500-mg ganciclovir capsule and a ganciclovir prodrug are being developed. The cost of ganciclovir prophylaxis is an important concern that was not addressed in our article.
Oral ganciclovir prophylaxis did not adversely affect the subsequent response to induction doses of intravenous ganciclovir. Moreover, persons receiving oral ganciclovir prophylaxis in whom CMV retinitis developed were less likely to have zone 1 involvement than those receiving placebo.1 In addition, as a planned part of this study, Drew et al.2 examined CMV isolates cultured from persons receiving ganciclovir prophylaxis for 4 to 19 months (mean, 8.3) and found an overall prevalence of resistance in ganciclovir-treated persons of less than 1 percent.
We agree that there is a need for improved methods of identifying the persons with AIDS who are at highest risk for CMV disease. As part of this study, we are examining the usefulness of qualitative and quantitative analysis of plasma DNA with the polymerase chain reaction as such a marker.3 We believe that targeted intervention should improve the cost effectiveness of oral ganciclovir prophylaxis.
Finally, we believe that some of the correspondents have underestimated the psychological and visual implications of CMV retinitis. A recent study has demonstrated that two thirds of patients with AIDS and CMV retinitis have a significant decline in vision within 12 months of the onset of retinitis, despite treatment.4 Moreover, as suggested in our article, it is likely that the incidence of CMV disease is underestimated in persons with AIDS and that prophylaxis may have benefit with respect to these other underdiagnosed conditions. The incidence of investigator-reported CMV disease was 47 percent in the placebo group at 18 months. In addition, both our study and one conducted by the Terry Beirn Community Programs for Clinical Research on AIDS demonstrated a similar, though not statistically significant, trend toward improved survival among persons receiving ganciclovir prophylaxis.5 Thus, we continue to believe that oral ganciclovir “promises to be a useful drug for prophylaxis against CMV disease in persons with AIDS.”
5 ReferencesStephen A. Spector, M.D.
University of California, San Diego, La Jolla, CA 92093-0672Mary Jean Stempien, M.D.
Roche Pharmaceuticals, Palo Alto, CA 943031
Wolitz R, Friedberg D, Spector SA, Wong R, Stempien MJ. Presentation and treatment outcome of CMV retinitis after oral ganciclovir prophylaxis. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28–February 1, 1996. Washington, D.C.: Infectious Diseases Society of America, 1996:54.
2
Drew WL, Miner RC, Crager M, Stempien MJ. Prevalence of ganciclovir-resistant cytomegalovirus during oral ganciclovir prophylaxis. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28–February 1, 1996. Washington, D.C.: Infectious Diseases Society of America, 1996:164.
3
Spector SA, Pilcher M, Lamy P, Hsia K, Wong R, Stempien MJ. PCR of plasma for cytomegalovirus DNA identifies HIV-infected persons most likely to benefit from oral ganciclovir prophylaxis. In: Program and abstracts of the 11th International Conference on AIDS, Vancouver, B.C., Canada, July 7–12, 1996. Vol. 2. Vancouver, B.C., Canada: Transcontinental Printing, 1996:226.
4
Holbrook JT, Davis M, Gilpin AK, Hubbard L, Martin B. Association of cytomegalovirus (CMV) retinitis characteristics with disease progression and vision loss. In: Program and abstracts of the 11th International Conference on AIDS, Vancouver, B.C., Canada, July 7–12, 1996. Vol. 1. Vancouver, B.C., Canada: Transcontinental Printing, 1996:297.
5
Brosgart C, Craig C, Hillman D, et al. Final results from a randomized placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of CMV retinal and gastrointestinal mucosal disease. In: Program and abstracts of the 11th International Conference on AIDS, Vancouver, B.C., Canada, July 7–12, 1996. Vol. 2. Vancouver, B.C., Canada: Transcontinental Printing, 1996:225.
