Feature

Recommended treatment options scarce for pregnant women with HIV

During a panel this year at CROI, Monica Gandhi, MD, MPH, professor of medicine and medical director of the Ward 86 HIV clinic at the University of California, San Francisco, showed a slide listing the many available ART options for adults with HIV. Then she removed the drugs that are not specifically recommended for pregnant women.

Few options remained.

“We have not done a good job in HIV medicine in figuring out which drugs are safe or not in pregnant women,” Gandhi told Infectious Disease News. “In general, we also have not done the best job in enrolling adequate numbers of women in clinical trials of HIV medications.”

According to Gandhi, in general, many pharmaceutical companies studying new drugs have registered more men, particularly men who have sex with men, in HIV clinical trials than women, even though “this representation is not reflective of the HIV epidemic worldwide,” where HIV infects men and women roughly equally.

Monica Gandhi, MD, MPH
Monica Gandhi

“In terms of pregnant women, this is a problem across all medical fields, in that we think it is more ethical to not enroll women who are pregnant or of childbearing age,” Gandhi said. “I think we are starting to shift our ideas away from justifying inclusion of women of childbearing age in trials and toward justifying exclusion instead, a shift that is being led by the field of HIV.”

At CROI, Gandhi noted that HHS and WHO do not currently recommend the use of dolutegravir during the first trimester of pregnancy and in nonpregnant women trying to conceive, but that dolutegravir is a preferred agent after the first trimester for both maternal health and as an intervention to reduce perinatal HIV transmission.

Sharon Nachman, MD
Sharon Nachman

The FDA issued a safety alert last May warning about the potential risk for neural tube birth defects when dol-utegravir is taken early in pregnancy, based on data from an observational study being conducted in Botswana.

“These data launched a new focus on the issue of enrolling women in clinical trials,” Gandhi said.

More recently, a study published this past April in the Annals of Internal Medicine reported that although dolutegravir use was linked to a higher risk for neural tube defects among newborns, it prevented many more deaths and HIV transmissions among women than efavirenz. Caitlin M. Dugdale, MD, and colleagues wrote that the results of their study, which used a computer model to project clinical outcomes of ART policies for women with HIV of childbearing age in South Africa, “argue against a blanket policy of favoring efavirenz over dolutegravir in women of childbearing potential. Rather, this study supports an open, context-specific discussion about the tradeoffs between the risks for harm and the benefits of these treatment options.”

“Essentially, every person in the world should be treated for HIV,” Gandhi said. “The best thing to do for pregnant women with HIV is to treat them both for their own health, and to prevent transmission from mothers to babies.”

Off-label use

Gandhi noted that many practitioners use medications off label for treating pregnant women with HIV. These drugs are considered safe, but many are not part of the HHS guidelines for treating pregnant women because there are insufficient data on their use. She said there is no indication from animal studies that physicians or patients should be worried about the drugs.

“Some drugs are not recommended because we simply do not have data on them,” Gandhi said. “People are using medications that are not on that narrow list [of recommended drugs for pregnant women] and that is completely fine, because that is a decision a provider makes in conjunction with their patients about what works and what doesn’t work for that patient. For instance, some women really need a single-pill combination, and that is the most important thing for them. The decision on what to use should be made based on a discussion between patients and provider.”

Sharon Nachman, MD, professor of pediatrics, chief of the division of pediatric infectious diseases and director of the office of clinical trials at Stony Brook University School of Medicine, noted that for an HIV drug to be specifically licensed for pregnant women, it must be studied in a large enough group in a phase 3 study compared with the best available therapy for HIV-infected pregnant women. She said many pharmaceutical companies have not done this.

“Companies prefer to say, ‘Our drug is licensed in adults, and if you feel it is indicated in pregnancy, go ahead and use it,’” Nachman said.

Zidovudine is the only drug specifically licensed to treat pregnant women with HIV, Nachman said. The licensure approval was based on findings from a study by Edward M. Connor, MD, and colleagues published in 1994 in The New England Journal of Medicine.

IMPAACT studies

According to Nachman, although pharmaceutical companies have not requested specific indications for pregnant women with HIV, the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network has conducted many studies in this population.

Nachman serves as the principal investigator for the NIH-funded network, which has studied virtually all licensed drugs when used in pregnancy. She said prescribers treating pregnant women with HIV can enroll them in a clinical trial to determine the correct dosage to use, and that IMPAACT has already enrolled more than 1,000 such participants.

“The IMPAACT study showed quite nicely that some drugs prescribed for adults have appropriate dosing for pregnant women, while other drugs as prescribed in adults should not be used in pregnancy. The reasons for this vary, including blood volume and drug metabolism [being] different during pregnancy,” Nachman said. “What you thought was the right dose in an adult turned out to be too low in a pregnant woman, and therefore, should not be used.”

Nachman said there are specific medications that should not be used during pregnancy, including any fixed-dose combination that includes cobicistat. In nonpregnant adults with HIV, cobicistat helps ART regimens achieve a therapeutic level. However, its use during pregnancy does not “super charge” the other medications, Nachman said.

“Any regimen that has cobicistat in it should not be recommended during pregnancy,” she said.

She said raltegravir and dolutegravir, both integrase strand transfer inhibitors (INSTIs), are medications that do not need dosage adjustments during pregnancy. A recent study by Martina L. Badell, MD, and colleagues that was published in Open Forum Infectious Diseases found that the use of another INSTI, elvitegravir, during pregnancy was associated with high, sustained levels of viral suppression and a low rate of perinatal transmission.

Nachman said elvitegravir, as a standalone pill used with two other antiretrovirals, is effective treatment in pregnant women; however, it is not recommended during pregnancy as a fixed-dose combination with cobicistat. She said there are no pharmacokinetic data available for pregnant women regarding the use of a fourth INSTI, bictegravir, which is approved for adults with HIV.

Nachman underscored the risk in treating pregnant women with HIV medications that are approved for adults: Research has not shown the correct dosing. If it is too low, there may be vertical transmission of HIV. If it is too high, the drug could be toxic for the mother and potentially the child.

“You kind of want to get into the right space — not too low, not too high. But, if you do not study it, you do not know,” Nachman said. – by Bruce Thiel

Disclosures: Gandhi and Nachman report no relevant financial disclosures.

During a panel this year at CROI, Monica Gandhi, MD, MPH, professor of medicine and medical director of the Ward 86 HIV clinic at the University of California, San Francisco, showed a slide listing the many available ART options for adults with HIV. Then she removed the drugs that are not specifically recommended for pregnant women.

Few options remained.

“We have not done a good job in HIV medicine in figuring out which drugs are safe or not in pregnant women,” Gandhi told Infectious Disease News. “In general, we also have not done the best job in enrolling adequate numbers of women in clinical trials of HIV medications.”

According to Gandhi, in general, many pharmaceutical companies studying new drugs have registered more men, particularly men who have sex with men, in HIV clinical trials than women, even though “this representation is not reflective of the HIV epidemic worldwide,” where HIV infects men and women roughly equally.

Monica Gandhi, MD, MPH
Monica Gandhi

“In terms of pregnant women, this is a problem across all medical fields, in that we think it is more ethical to not enroll women who are pregnant or of childbearing age,” Gandhi said. “I think we are starting to shift our ideas away from justifying inclusion of women of childbearing age in trials and toward justifying exclusion instead, a shift that is being led by the field of HIV.”

At CROI, Gandhi noted that HHS and WHO do not currently recommend the use of dolutegravir during the first trimester of pregnancy and in nonpregnant women trying to conceive, but that dolutegravir is a preferred agent after the first trimester for both maternal health and as an intervention to reduce perinatal HIV transmission.

Sharon Nachman, MD
Sharon Nachman

The FDA issued a safety alert last May warning about the potential risk for neural tube birth defects when dol-utegravir is taken early in pregnancy, based on data from an observational study being conducted in Botswana.

“These data launched a new focus on the issue of enrolling women in clinical trials,” Gandhi said.

More recently, a study published this past April in the Annals of Internal Medicine reported that although dolutegravir use was linked to a higher risk for neural tube defects among newborns, it prevented many more deaths and HIV transmissions among women than efavirenz. Caitlin M. Dugdale, MD, and colleagues wrote that the results of their study, which used a computer model to project clinical outcomes of ART policies for women with HIV of childbearing age in South Africa, “argue against a blanket policy of favoring efavirenz over dolutegravir in women of childbearing potential. Rather, this study supports an open, context-specific discussion about the tradeoffs between the risks for harm and the benefits of these treatment options.”

PAGE BREAK

“Essentially, every person in the world should be treated for HIV,” Gandhi said. “The best thing to do for pregnant women with HIV is to treat them both for their own health, and to prevent transmission from mothers to babies.”

Off-label use

Gandhi noted that many practitioners use medications off label for treating pregnant women with HIV. These drugs are considered safe, but many are not part of the HHS guidelines for treating pregnant women because there are insufficient data on their use. She said there is no indication from animal studies that physicians or patients should be worried about the drugs.

“Some drugs are not recommended because we simply do not have data on them,” Gandhi said. “People are using medications that are not on that narrow list [of recommended drugs for pregnant women] and that is completely fine, because that is a decision a provider makes in conjunction with their patients about what works and what doesn’t work for that patient. For instance, some women really need a single-pill combination, and that is the most important thing for them. The decision on what to use should be made based on a discussion between patients and provider.”

Sharon Nachman, MD, professor of pediatrics, chief of the division of pediatric infectious diseases and director of the office of clinical trials at Stony Brook University School of Medicine, noted that for an HIV drug to be specifically licensed for pregnant women, it must be studied in a large enough group in a phase 3 study compared with the best available therapy for HIV-infected pregnant women. She said many pharmaceutical companies have not done this.

“Companies prefer to say, ‘Our drug is licensed in adults, and if you feel it is indicated in pregnancy, go ahead and use it,’” Nachman said.

Zidovudine is the only drug specifically licensed to treat pregnant women with HIV, Nachman said. The licensure approval was based on findings from a study by Edward M. Connor, MD, and colleagues published in 1994 in The New England Journal of Medicine.

IMPAACT studies

According to Nachman, although pharmaceutical companies have not requested specific indications for pregnant women with HIV, the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network has conducted many studies in this population.

Nachman serves as the principal investigator for the NIH-funded network, which has studied virtually all licensed drugs when used in pregnancy. She said prescribers treating pregnant women with HIV can enroll them in a clinical trial to determine the correct dosage to use, and that IMPAACT has already enrolled more than 1,000 such participants.

PAGE BREAK

“The IMPAACT study showed quite nicely that some drugs prescribed for adults have appropriate dosing for pregnant women, while other drugs as prescribed in adults should not be used in pregnancy. The reasons for this vary, including blood volume and drug metabolism [being] different during pregnancy,” Nachman said. “What you thought was the right dose in an adult turned out to be too low in a pregnant woman, and therefore, should not be used.”

Nachman said there are specific medications that should not be used during pregnancy, including any fixed-dose combination that includes cobicistat. In nonpregnant adults with HIV, cobicistat helps ART regimens achieve a therapeutic level. However, its use during pregnancy does not “super charge” the other medications, Nachman said.

“Any regimen that has cobicistat in it should not be recommended during pregnancy,” she said.

She said raltegravir and dolutegravir, both integrase strand transfer inhibitors (INSTIs), are medications that do not need dosage adjustments during pregnancy. A recent study by Martina L. Badell, MD, and colleagues that was published in Open Forum Infectious Diseases found that the use of another INSTI, elvitegravir, during pregnancy was associated with high, sustained levels of viral suppression and a low rate of perinatal transmission.

Nachman said elvitegravir, as a standalone pill used with two other antiretrovirals, is effective treatment in pregnant women; however, it is not recommended during pregnancy as a fixed-dose combination with cobicistat. She said there are no pharmacokinetic data available for pregnant women regarding the use of a fourth INSTI, bictegravir, which is approved for adults with HIV.

Nachman underscored the risk in treating pregnant women with HIV medications that are approved for adults: Research has not shown the correct dosing. If it is too low, there may be vertical transmission of HIV. If it is too high, the drug could be toxic for the mother and potentially the child.

“You kind of want to get into the right space — not too low, not too high. But, if you do not study it, you do not know,” Nachman said. – by Bruce Thiel

Disclosures: Gandhi and Nachman report no relevant financial disclosures.