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More Information on Ethics and Clinical Trials

More information on valacyclovir (Valtrex)

Trials of Prophylaxis to Prevent Recurrent Herpes Should Not Utilize a Placebo Arm

Valacyclovir (VALTREX) Prophylaxis to Prevent Recurrent Herpes at Delivery: A Randomized Clinical Trial

December 1, 2006

Read the press release.

Caughey AB, Urato AC, Lurie P. Valacyclovir Prophylaxis to Prevent Recurrent Herpes at Delivery: A Randomized Clinical Trial. Obstet Gynecol 2006;108:1550.

To the Editor: We were not surprised to read that valacyclovir administered to pregnant women with a history of genital herpes simplex virus (HSV) led to fewer recurrent lesions than placebo.[1] After all, valacyclovir is a prodrug of acyclovir, which has been demonstrated repeatedly to reduce recurrent lesions in pregnant women. [2], [3] We were surprised that 168 women were randomly assigned to placebo instead of acyclovir.  According to the Declaration of Helsinki, any “new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.”[4]

The study began recruiting in 1998; in 1999, the American Collegeof Obstetricians and Gynecologists (ACOG) concluded that “For women at or beyond 36 weeks of gestation with a first episode of HSV occurring during the current pregnancy, antiviral therapy should be considered.”[5]  Nonetheless, 62 women with first episode HSV were enrolled in the study.   In 2003, the same authors published a meta-analysis that reviewed five studies that included mostly recurrent HSV patients.  Their review concluded that acyclovir reduces recurrent lesions and decreases cesarean rates.[6] If the authors understood that acyclovir reduced recurrent lesions, why did they continue to assign such patients to placebo until November 2004? 

We understand that a pharmaceutical company might prefer to compare its product to placebo rather than to a known effective therapy, but we are at a loss as to why researchers would place their patients at higher risk.   What were the patients told as the new evidence accumulated?

Finally, we question why Obstetrics & Gynecology would publish such a study without at least an editorial when the Declaration of Helsinki implores journals that “Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.”[4]

Aaron B. Caughey, M.D. Ph.D.
University of California, San Francisco
Department of Obstetrics, Gynecology, and Reproductive Sciences
San Francisco, California

Adam C. Urato, M.D. 
University of South Florida
Department of Obstetrics and Gynecology
Tampa, Florida

Peter Lurie, M.D., M.P.H.
Public Citizen’s Health Research Group
Washington, DC


[1] Sheffield JS, Hill JB, Hollier LM, Laibl VR, Roberts SW, Sanchez PJ, et al. Valacyclovir prophylaxis to prevent recurrent herpes at delivery: a randomized clinical trial [published erratum appears in Obstet Gynecol 2006;108:695]. Obstet Gynecol 2006;108:141-7.

[2] Scott LL, Sanchez PJ, Jackson GL, Zeray F, Wendel GD Jr. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes.
Obstet Gynecol 1996;87:69-73.

[3] Brocklehurst P, Kinghorn G, Carney O, Helsen K, Ross E, Ellis E, et al. A randomised placebo controlled trial of suppressive acyclovir in late pregnancy in women with recurrent genital herpes infection. Br J Obstet Gynaecol 1998;105:275-80.

[4] World Medical Association. World Medical Association declaration of Helsinki: ethical principles for medical research involving human subjects. 2004. Now available at: Retrieved October 11, 2006.

[5] American College of Obstetricians and Gynecologists. Management of Herpes in Pregnancy. ACOG Practice Bulletin. Washington (DC): ACOG; 1999.

[6] Sheffield JS, Hollier LM, Hill JB, Stuart GS, Wendel GD. Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review. Obstet Gynecol 2003;102:1396-403.


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