A Vaccine to Prevent Herpes Zoster
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In Gilden's editorial1 (June 2 issue) on the study by Oxman et al.,2 the derivation of the cost-effectiveness data with regard to vaccination against varicella–zoster virus among older persons in the Shingles Prevention Study is unclear. Although benefits might accumulate over time, the long-term efficacy and side-effect profiles of the investigational vaccine are unknown. Treatment offers partial relief of symptoms but no survival advantage in an older population with a relatively short life expectancy. Over the 3.1 years of the study, the number needed to treat to prevent one case of herpes zoster appears to be 59 (i.e., $29,500 at $500 per vaccination), and the number needed to treat to prevent one case of postherpetic neuralgia appears to be 363 (i.e., $181,500 at $500 per vaccination). I cannot reconcile these numbers with the $2,000 per quality-adjusted life-year (QALY) gained or with Gilden's statement that vaccination "may even be cost-saving."1 Considering the substantial total cost (literally, billions of dollars) of vaccinating a large, elderly population, clarification of these details is important.
Kenneth M. Kessler, M.D.
University of Miami School of Medicine
Miami, FL 33101
kmichaelkessler@cs.com
References
Gilden DH. Varicella-zoster virus vaccine -- grown-ups need it, too. N Engl J Med 2005;352:2344-2346.
Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-2284.
To the Editor: In their substudy of the safety and efficacy of varicella–zoster vaccination to prevent herpes zoster and postherpetic neuralgia, Oxman and colleagues report that "during the first 42 days after vaccination, significantly more subjects in the vaccine group had serious adverse events than in the placebo group (1.9 percent vs. 1.3 percent, respectively; P=0.03)." Therefore, the expected number of serious adverse events attributable to vaccination is 116 (0.6 percent of 19,254), whereas vaccination prevented only 53 cases of postherpetic neuralgia. Thus, the number and nature of serious adverse events are clinically relevant. However, the authors provide no analysis or enumeration of the serious adverse events.
Before the findings from this trial influence public health policy, Oxman and colleagues should report the frequency and nature of these serious adverse events, as well as their post hoc analysis. Only then can we, and our patients, appropriately weigh the apparent risk of having two serious adverse events against the benefit of preventing one case of postherpetic neuralgia.
Ian Carroll, M.D.
Raymond Gaeta, M.D.
Sean Mackey, M.D., Ph.D.
Stanford University Hospital
Palo Alto, CA 94304
irc38@pain.stanford.edu
Dr. Mackey reports having received lecture fees from Merck.
The authors reply: It is important to emphasize that all 38,546 subjects in the Shingles Prevention Study were actively followed for serious adverse events during the first 42 days after vaccination, not just the 6616 subjects in the adverse events substudy, and that the occurrence of serious adverse events in the total study population was the same in the two groups: 255 in the vaccine group (1.4 percent) and 254 in the placebo group (1.4 percent). There was no excess of serious adverse events among the vaccine recipients. Furthermore, the rates of serious adverse events in the entire study population and among the subjects in the substudy were similar, indicating a similar intensity of surveillance.
As we noted, a close examination of the serious adverse events reported among vaccine recipients and placebo recipients in the adverse events substudy showed no significant differences in their distribution according to body system or type of event (e.g., hospitalization) and no clinically meaningful differences in their pathophysiology, nature, timing, intensity, or outcomes.
Although we are comfortable with our overall conclusions with regard to the investigational varicella–zoster vaccine, we note that all the study data have been provided to the Food and Drug Administration for review.
Michael N. Oxman, M.D.
Veterans Affairs San Diego Healthcare System
San Diego, CA 92037
mnoxman@ucsd.edu
Myron J. Levin, M.D.
University of Colorado Health Sciences Center
Denver, CO 80262
Gary R. Johnson, M.S.
Veterans Affairs Cooperative Studies Coordinating Center
West Haven, CT 06516
for the Shingles Prevention Study Group
The editorialist and a colleague reply: Dr. Kessler has thoughtfully questioned our analysis of the cost-effectiveness of varicella–zoster vaccine. We assumed a high estimate of $500 per dose of vaccine, which would cost $9.6 million for the 19,254 people who received the investigational vaccine in the study by Oxman et al. We then estimated gains in quality of life by using the association between the Zoster Brief Pain Inventory and the EuroQol instrument.1 The Zoster Brief Pain Inventory was used to construct the score for the burden of illness due to herpes zoster, which was the primary outcome measure. A decrease of 57 percent in this score corresponds to an increase of approximately 0.08 QALY.1 When gains in QALYs are multiplied out over the 3.1 years of the study, the result is a cost-effectiveness ratio of approximately $2,000 per QALY. Admittedly, this is a rough estimate, but it gives an overall sense that the varicella–zoster vaccine is likely to be cost-effective because of the impressive gains in quality of life, even without a mortality benefit. A formal economic analysis of the Shingles Prevention Study would certainly be welcome.
Adam Gilden Tsai, M.D.
University of Pennsylvania School of Medicine
Philadelphia, PA 19104
Donald H. Gilden, M.D.
University of Colorado Health Sciences Center
Denver, CO 80262
don.gilden@uchsc.edu
Kenneth M. Kessler, M.D.
University of Miami School of Medicine
Miami, FL 33101
kmichaelkessler@cs.com
References
Gilden DH. Varicella-zoster virus vaccine -- grown-ups need it, too. N Engl J Med 2005;352:2344-2346.
Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-2284.
To the Editor: In their substudy of the safety and efficacy of varicella–zoster vaccination to prevent herpes zoster and postherpetic neuralgia, Oxman and colleagues report that "during the first 42 days after vaccination, significantly more subjects in the vaccine group had serious adverse events than in the placebo group (1.9 percent vs. 1.3 percent, respectively; P=0.03)." Therefore, the expected number of serious adverse events attributable to vaccination is 116 (0.6 percent of 19,254), whereas vaccination prevented only 53 cases of postherpetic neuralgia. Thus, the number and nature of serious adverse events are clinically relevant. However, the authors provide no analysis or enumeration of the serious adverse events.
Before the findings from this trial influence public health policy, Oxman and colleagues should report the frequency and nature of these serious adverse events, as well as their post hoc analysis. Only then can we, and our patients, appropriately weigh the apparent risk of having two serious adverse events against the benefit of preventing one case of postherpetic neuralgia.
Ian Carroll, M.D.
Raymond Gaeta, M.D.
Sean Mackey, M.D., Ph.D.
Stanford University Hospital
Palo Alto, CA 94304
irc38@pain.stanford.edu
Dr. Mackey reports having received lecture fees from Merck.
The authors reply: It is important to emphasize that all 38,546 subjects in the Shingles Prevention Study were actively followed for serious adverse events during the first 42 days after vaccination, not just the 6616 subjects in the adverse events substudy, and that the occurrence of serious adverse events in the total study population was the same in the two groups: 255 in the vaccine group (1.4 percent) and 254 in the placebo group (1.4 percent). There was no excess of serious adverse events among the vaccine recipients. Furthermore, the rates of serious adverse events in the entire study population and among the subjects in the substudy were similar, indicating a similar intensity of surveillance.
As we noted, a close examination of the serious adverse events reported among vaccine recipients and placebo recipients in the adverse events substudy showed no significant differences in their distribution according to body system or type of event (e.g., hospitalization) and no clinically meaningful differences in their pathophysiology, nature, timing, intensity, or outcomes.
Although we are comfortable with our overall conclusions with regard to the investigational varicella–zoster vaccine, we note that all the study data have been provided to the Food and Drug Administration for review.
Michael N. Oxman, M.D.
Veterans Affairs San Diego Healthcare System
San Diego, CA 92037
mnoxman@ucsd.edu
Myron J. Levin, M.D.
University of Colorado Health Sciences Center
Denver, CO 80262
Gary R. Johnson, M.S.
Veterans Affairs Cooperative Studies Coordinating Center
West Haven, CT 06516
for the Shingles Prevention Study Group
The editorialist and a colleague reply: Dr. Kessler has thoughtfully questioned our analysis of the cost-effectiveness of varicella–zoster vaccine. We assumed a high estimate of $500 per dose of vaccine, which would cost $9.6 million for the 19,254 people who received the investigational vaccine in the study by Oxman et al. We then estimated gains in quality of life by using the association between the Zoster Brief Pain Inventory and the EuroQol instrument.1 The Zoster Brief Pain Inventory was used to construct the score for the burden of illness due to herpes zoster, which was the primary outcome measure. A decrease of 57 percent in this score corresponds to an increase of approximately 0.08 QALY.1 When gains in QALYs are multiplied out over the 3.1 years of the study, the result is a cost-effectiveness ratio of approximately $2,000 per QALY. Admittedly, this is a rough estimate, but it gives an overall sense that the varicella–zoster vaccine is likely to be cost-effective because of the impressive gains in quality of life, even without a mortality benefit. A formal economic analysis of the Shingles Prevention Study would certainly be welcome.
Adam Gilden Tsai, M.D.
University of Pennsylvania School of Medicine
Philadelphia, PA 19104
Donald H. Gilden, M.D.
University of Colorado Health Sciences Center
Denver, CO 80262
don.gilden@uchsc.edu