- Email: [email protected]
Hepatoxicity with antiretroviral treatment of pregnant women
Their conclusion can be interpreted as a practice standard, which puts physicians at increased medicolegal risk. This nonevidence-based opinion increases anxiety, liability, and expense without proven benefit. James L. Lindsey, MD Miche`le Hugin, MD Santa Clara Valley Health and Hospital System Valley Medical Center 751 S. Bascom Avenue San Jose, CA 95128
drugs represents a potential interaction. Until the official product labeling and patient package insert are revised to reflect a clear lack of potential drug interaction for this combination, controversy about what constitutes appropriate advice for such patients will remain. We have suggested a precautionary approach. Roy D. Altman, MD Nancy H. Nielsen, MD Melvyn L. Sterling, MD Barry D. Dickinson, PhD for the Council on Scientific Affairs
REFERENCE
REFERENCES
1. Dickinson B, Altman RD, Nielsen NH, Sterling ML. Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol 2001;98:853– 60.
1. Dickinson B, Altman RD, Nielsen NH, Sterling ML. Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol 2001;98:853– 60. 2. Demulen (ethynodiol diacetate and ethinyl estradiol). Package insert. Chicago, IL: G.D. Searle & Co., 1998. 3. Tri-Levlen (levonorgestrel/ethinyl estradiol) tablets. Package insert. Wayne, NJ: Berlex Laboratories, 1998. 4. Ortho-Novum (norethindrone/ethinyl estradiol) tablets. Package insert. Raritan, NJ: ORTHO-McNeil Pharmaceutical, Inc., 1998.
In Reply: We appreciate the comments and viewpoint of Drs. Lindsey and Hugin regarding this issue. Similar concerns were raised during debate on this report1 by a minority of physician members of the American Medical Association’s House of Delegates. However, our report does not establish a new practice standard. This standard already exists in the product labeling for combination oral contraceptive (OC) products, which asserts that “‘reduced efficacy’ . . . is possibly (associated) with ampicillin and tetracyclines.”2– 4 Additionally, the brief summary patient package insert notes that “certain drugs may interact with birth control pills to make them less effective in preventing pregnancy. Such drugs include rifampin . . . and possibly certain antibiotics [unspecified]. . . . You may need to use additional contraception when you take drugs that can make oral contraceptives less effective.”2– 4 The evidence on a possible interaction between antibiotics and OCs resulting in OC failure in otherwise compliant users is based on case reports and surveys. Under these circumstances, causality cannot be established, except by rechallenge. This experiment, of course, will not be forthcoming. Nevertheless, controlled pharmacokinetic data indicate that some women exhibit large decreases in plasma concentrations of ethinyl estradiol (or other OC components) with concomitant antibiotic therapy and appear to ovulate.1 This evidence, although not synonymous with pregnancy, suggests that a population of vulnerable women exists. Unless predictive pharmacogenetic profiling of individual patients for specific medications is available, this combination of
842
Letters to the Editor
Hepatoxicity With Antiretroviral Treatment of Pregnant Women To the Editor: Hill et al1 report two HIV-positive pregnant women who developed hepatotoxicity (fatal in one) attributed to combination antiretroviral therapy. Although, there is no evidence that hepatotoxicity is more common in pregnant women than other adult females as of yet, these cases and three fatalities with combinations which include both stavudine and didanosine (http://www.fda. gov/medwatch/safety/2001/zerit&videx_letter.htm) emphasize the need for caution in prescribing and monitoring antiretroviral therapy in pregnancy. US2 and UK3 guidelines recommend effective combination therapy for pregnant women with advanced HIV infection. However, we note that according to UK guidelines,3 and the optional in the US guidelines,2 neither woman in this report would have received combination therapy. Both had low pretreatment viremia (1477 and 3990 HIV RNA copies per mL plasma), indicative of a lower-than-average risk of HIV transmission. With pretreatment CD4 lymphocyte counts of 492 and 828 cells per L neither was at significant risk of opportunistic infection. In the absence of both robust maternal and
OBSTETRICS & GYNECOLOGY
infant safety data and evidence that triple therapy significantly reduces mother-to-child transmission compared with zidovudine monotherapy plus prelabor elective cesarian delivery, the UK guidelines3 recommend the latter for asymptomatic women with CD4 lymphocyte counts greater than 200 –350 cells per L and viral loads of less than 10,000 –20,000 HIV RNA copies per mL plasma. We endorse the concerns of Hill et al1 relating to the monitoring of antiretroviral therapy in pregnancy. Our practice is to review all pregnant women 2 weeks after initiating therapy, then every 4 weeks, with visits every 2 weeks during the third trimester. In addition to routine complete blood counts, liver and renal function tests, blood lactate levels are considered prudent, especially when more than one nucleoside analogue is prescribed. Graham P. Taylor Eva Jungmann
Danielle Mercey Danielle Mercey and Graham Taylor were members of the writing committee of the British HIV Association Guidelines.3
REFERENCES 1. Hill JB, Sheffield JS, Zeeman GG, Wendel GD. Hepatotoxicity with antiretroviral treatment of pregnant women. Obstet Gynecol 2001;98:909 –11. 2. Centers for Disease Control and Prevention. US Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;RR-2: 1–30. 3. Lyall E, Blott M, de Ruiter A, et al. Guidelines for the management of HIV infection in pregnant women and the prevention of mother-to-child transmission. HIV Medicine 2001;2:314 –34.
INSTRUCTIONS FOR LETTERS TO THE EDITOR Letters posing a question or challenge to an article appearing in Obstetrics & Gynecology within the last 8 weeks will be considered for publication. Letters that raise new or controversial issues of interest to readers of this journal will also be considered. Please note the following: *Your letter must be typewritten and double spaced. *Letters are limited to a maximum of 400 words, including signatures and references. *A word count must be provided. *You must submit a signed author agreement form with your letter. *You must disclose any financial association and potential conflicts of interest. *Please include your full address, telephone number, fax number, and e-mail address. *You may send your letter by standard mail, fax, or e-mail, but the author agreement form must be submitted by mail and contain original signatures. Our address: Letters to the Editor, Obstetrics & Gynecology, 409 12th Street, SW, Washington, DC 20024 Our fax number: 202-479-0830 Our e-mail address: [email protected] The editor reserves the right to shorten letters, delete irrelevant or objectionable comments, and make changes to comply with journal style. To facilitate rapid publication, proofs are not provided.
CORRECTION In the letters to the editor section of the March issue (OBSTET GYNECOL 2002;99:514 –5), a letter written by Garite et al contained an incorrect affiliation for Richard Porreco, MD. Dr. Porreco is affiliated with Presbyterian/St. Lukes Medical Center in Denver, Colorado, not the University of Colorado as printed.
VOL. 99, NO. 5, PART 1, MAY 2002
Letters to the Editor
843
drugs represents a potential interaction. Until the official product labeling and patient package insert are revised to reflect a clear lack of potential drug interaction for this combination, controversy about what constitutes appropriate advice for such patients will remain. We have suggested a precautionary approach. Roy D. Altman, MD Nancy H. Nielsen, MD Melvyn L. Sterling, MD Barry D. Dickinson, PhD for the Council on Scientific Affairs
REFERENCE
REFERENCES
1. Dickinson B, Altman RD, Nielsen NH, Sterling ML. Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol 2001;98:853– 60.
1. Dickinson B, Altman RD, Nielsen NH, Sterling ML. Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol 2001;98:853– 60. 2. Demulen (ethynodiol diacetate and ethinyl estradiol). Package insert. Chicago, IL: G.D. Searle & Co., 1998. 3. Tri-Levlen (levonorgestrel/ethinyl estradiol) tablets. Package insert. Wayne, NJ: Berlex Laboratories, 1998. 4. Ortho-Novum (norethindrone/ethinyl estradiol) tablets. Package insert. Raritan, NJ: ORTHO-McNeil Pharmaceutical, Inc., 1998.
In Reply: We appreciate the comments and viewpoint of Drs. Lindsey and Hugin regarding this issue. Similar concerns were raised during debate on this report1 by a minority of physician members of the American Medical Association’s House of Delegates. However, our report does not establish a new practice standard. This standard already exists in the product labeling for combination oral contraceptive (OC) products, which asserts that “‘reduced efficacy’ . . . is possibly (associated) with ampicillin and tetracyclines.”2– 4 Additionally, the brief summary patient package insert notes that “certain drugs may interact with birth control pills to make them less effective in preventing pregnancy. Such drugs include rifampin . . . and possibly certain antibiotics [unspecified]. . . . You may need to use additional contraception when you take drugs that can make oral contraceptives less effective.”2– 4 The evidence on a possible interaction between antibiotics and OCs resulting in OC failure in otherwise compliant users is based on case reports and surveys. Under these circumstances, causality cannot be established, except by rechallenge. This experiment, of course, will not be forthcoming. Nevertheless, controlled pharmacokinetic data indicate that some women exhibit large decreases in plasma concentrations of ethinyl estradiol (or other OC components) with concomitant antibiotic therapy and appear to ovulate.1 This evidence, although not synonymous with pregnancy, suggests that a population of vulnerable women exists. Unless predictive pharmacogenetic profiling of individual patients for specific medications is available, this combination of
842
Letters to the Editor
Hepatoxicity With Antiretroviral Treatment of Pregnant Women To the Editor: Hill et al1 report two HIV-positive pregnant women who developed hepatotoxicity (fatal in one) attributed to combination antiretroviral therapy. Although, there is no evidence that hepatotoxicity is more common in pregnant women than other adult females as of yet, these cases and three fatalities with combinations which include both stavudine and didanosine (http://www.fda. gov/medwatch/safety/2001/zerit&videx_letter.htm) emphasize the need for caution in prescribing and monitoring antiretroviral therapy in pregnancy. US2 and UK3 guidelines recommend effective combination therapy for pregnant women with advanced HIV infection. However, we note that according to UK guidelines,3 and the optional in the US guidelines,2 neither woman in this report would have received combination therapy. Both had low pretreatment viremia (1477 and 3990 HIV RNA copies per mL plasma), indicative of a lower-than-average risk of HIV transmission. With pretreatment CD4 lymphocyte counts of 492 and 828 cells per L neither was at significant risk of opportunistic infection. In the absence of both robust maternal and
OBSTETRICS & GYNECOLOGY
infant safety data and evidence that triple therapy significantly reduces mother-to-child transmission compared with zidovudine monotherapy plus prelabor elective cesarian delivery, the UK guidelines3 recommend the latter for asymptomatic women with CD4 lymphocyte counts greater than 200 –350 cells per L and viral loads of less than 10,000 –20,000 HIV RNA copies per mL plasma. We endorse the concerns of Hill et al1 relating to the monitoring of antiretroviral therapy in pregnancy. Our practice is to review all pregnant women 2 weeks after initiating therapy, then every 4 weeks, with visits every 2 weeks during the third trimester. In addition to routine complete blood counts, liver and renal function tests, blood lactate levels are considered prudent, especially when more than one nucleoside analogue is prescribed. Graham P. Taylor Eva Jungmann
Danielle Mercey Danielle Mercey and Graham Taylor were members of the writing committee of the British HIV Association Guidelines.3
REFERENCES 1. Hill JB, Sheffield JS, Zeeman GG, Wendel GD. Hepatotoxicity with antiretroviral treatment of pregnant women. Obstet Gynecol 2001;98:909 –11. 2. Centers for Disease Control and Prevention. US Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;RR-2: 1–30. 3. Lyall E, Blott M, de Ruiter A, et al. Guidelines for the management of HIV infection in pregnant women and the prevention of mother-to-child transmission. HIV Medicine 2001;2:314 –34.
INSTRUCTIONS FOR LETTERS TO THE EDITOR Letters posing a question or challenge to an article appearing in Obstetrics & Gynecology within the last 8 weeks will be considered for publication. Letters that raise new or controversial issues of interest to readers of this journal will also be considered. Please note the following: *Your letter must be typewritten and double spaced. *Letters are limited to a maximum of 400 words, including signatures and references. *A word count must be provided. *You must submit a signed author agreement form with your letter. *You must disclose any financial association and potential conflicts of interest. *Please include your full address, telephone number, fax number, and e-mail address. *You may send your letter by standard mail, fax, or e-mail, but the author agreement form must be submitted by mail and contain original signatures. Our address: Letters to the Editor, Obstetrics & Gynecology, 409 12th Street, SW, Washington, DC 20024 Our fax number: 202-479-0830 Our e-mail address: [email protected] The editor reserves the right to shorten letters, delete irrelevant or objectionable comments, and make changes to comply with journal style. To facilitate rapid publication, proofs are not provided.
CORRECTION In the letters to the editor section of the March issue (OBSTET GYNECOL 2002;99:514 –5), a letter written by Garite et al contained an incorrect affiliation for Richard Porreco, MD. Dr. Porreco is affiliated with Presbyterian/St. Lukes Medical Center in Denver, Colorado, not the University of Colorado as printed.
VOL. 99, NO. 5, PART 1, MAY 2002
Letters to the Editor
843