Antiretroviral Safety in Pregnancy: Focus on Dolutegravir, Integrase Inhibitors, and Neural Tube Defects

The reduction in morbidity and mortality with combina­tion antiretroviral therapy (cART) in the past 2 decades has positively changed the outlook for pregnancy and extended life expectancy in mothers with HIV. Women being treated effectively with cART during pregnancy has reduced vertical transmission to 1% or less in the United States and Europe and close to zero when virologically suppressed prior to conception and throughout the pregnancy.^1-3 Women with HIV have the same reproductive desires as women without HIV infection.⁴ Therefore, in order to lower the risk of unplanned pregnancies and mother-to-child-transmission (MTCT), it is important to routinely discuss reproductive plans with women of childbearing potential.⁵

Among women with HIV who are pregnant or planning to conceive, important considerations include the thera­peutic efficacy of the individual antiretrovirals (ARVs) in pregnancy, teratogenicity, and potential for poor tolera­bility.⁵ Information that patients can use to make deci­sions about the safe use of medications in pregnancy is based on results from preliminary animal studies, preg­nancy registries, clinical trials, and reported experience. The Antiretroviral Pregnancy Registry (APR) represents a prospective, observational study of pregnancy outcomes related to ARV exposure in utero.⁶ Pregnancy cases are evaluated with the intention of identifying teratogenicity signals with exposure. In order to ascertain the risk of birth defects with a given ARV medication, the APR requires use of the individual therapy in at least 200 preg­nancies.⁶ Studies have generally found similar rates of birth defects from ARV exposure during the first and later trimesters, indicating that early ARV use is not associ­ated with an increased risk of birth defects.⁷ ARV medica­tion safety in pregnancy based on current information is provided in more detail in Table 1.⁸

In a prospective cohort study in Quebec, Canada, preg­nant women with HIV who received care between 1998 and 2015 and were exposed to antiretroviral therapy (ART) during their first trimester did not have an increased risk of major congenital malformations compared with women who were untreated.⁹ The results of a US prospective cohort study from 2007 to 2012 evaluating outcomes in first trimester ARV exposure of children noted no associa­tion between congenital anomalies and specific ARV medi­cations, drug classes, or combination therapies.¹⁰

Many studies that evaluate the association between birth defects and ARV exposure do not evaluate the use of folate during the first trimester.¹¹ The risk of neural tube defects (NTDs) is reduced with maternal folic acid supple­mentation of at least 400 mcg/d during periconception.¹² Therefore, it is recommended that women contemplating pregnancy begin folate supplementation, as the greatest fetal risk is during the first 28 days post conception.⁵

DOLUTEGRAVIR AND INTEGRASE STRAND TRANSFER INHIBITORS IN PREGNANCY

Dolutegravir (DTG) was approved in 2013. The results of animal studies in clinical development indicated no teratogenicity in pregnancy.⁸ However, in May 2018, the World Health Organization (WHO) released a statement highlighting a potential safety signal with DTG noted in a preliminary unplanned analysis of an ongoing obser­vational pregnancy surveillance study in Botswana.¹³ The study aim was to compare the prevalence of NTDs in chil­dren following exposure to DTG with other ARV regimens at conception.

Of 426 women taking DTG at conception, there were 4 cases of NTDs.¹⁴ This birth defect rate (0.94%) was much higher than that observed with exposure to other ARVs (14 of 11,300 exposures; 0.12%) at conception when evaluating data from 88,755 births.^13,14 There were no cases of NTDs in women who started DTG during pregnancy (n = 2812). Data on pregnancy outcomes through March 2019 have recently been further analyzed.¹⁵ Updated data now indicate 5 cases (5/1683; 0.30%) of NTDs among children exposed to DTG from conception and 1 NTD case (1/3,840; 0.03%) when DTG was started in pregnancy. Comparatively, 15 NTD cases (15/14,792; 0.10%) were observed in chil­dren born to women receiving non-DTG regimens during conception, 3 cases (3/7959; 0.04%) with exposure to efavirenz from conception, and 70 cases (70/89,372; 0.08%) in pregnancies of HIV-uninfected women (no ART).

Further evaluation of the 4 NTD cases with DTG expo­sure in the original analysis revealed the women were not taking folate supplementation at conception and their past medical history did not include risk factors for NTDs, such as diabetes or epilepsy.¹⁴ When the safety of DTG-based regimens (n = 1729) and efavirenz-based regi­mens (n = 4593) started during pregnancy were compared in the Botswana surveillance study between 2016 and 2017, the prevalence rates of adverse pregnancy outcomes (eg, preterm birth, stillbirth, and small for gestational age) were similar between groups (33.2% and 35.0%, respectively).16 In this study period, 32% of women began DTG-based regi­mens after conception.

Recently, other prospective cohort studies have eval­uated the safety of DTG and other integrase strand transfer inhibitors (INSTIs) early in pregnancy in real-world settings (Table 2).^14,17-25 In these studies, the majority of the women were taking INSTIs before their first trimester. Neonatal outcomes following prenatal and first-trimester exposure to DTG were analyzed in 2 large prospective pregnancy registries: Antiretroviral Pregnancy Registry and the European Pregnancy and Pediatric Cohort Collaboration.¹⁷ No cases of NTDs were observed in over 300 pregnancies.

Data from other cohort studies in the United States, Canada, Sweden, and France reported similar results following preconception and first trimester use of DTG.^18-21 In a Canadian Perinatal HIV Surveillance Program representing 23 Canadian HIV centers, there were 3 cases of NTDs in women taking ART other than DTG, which was a similar rate (0.13%) to the Botswana data.²⁰

Surveillance studies of congenital anomalies associated with the use of elvitegravir (EVG) and raltegravir (RAL) early in pregnancy were also analyzed to determine if there were safety signals within the INSTI class.^21-25 The greatest use during conception was with RAL, but no reports of NTDs were identified in over 800 cases.^22-23 Cases reviewed for RAL use from the Merck safety database resulted in no cases of NTD with prospective data, as well; however, there were 3 cases (1 of which was during periconception) from among retrospective data.²⁴ Gilead reviewed its Global Safety Database for EVG and bictegravir (BIC)-containing regimens for pregnancy outcomes.²⁵ There were no reports of NTDs from prospective data from 155 reported pregnan­cies using EVG and 18 pregnancies using BIC, including preconception and first trimester use.

Following the release of the original Botswana surveil­lance data in 2018, HIV guidelines were updated regarding the use of DTG in women of childbearing potential and pregnancy.^26-29 However, recently the WHO released updated recommendations for the preferen­tial use of DTG in all populations, including pregnancy and women of childbearing potential, based on the body of evidence to date.³⁰ In light of the updated Botswana information, other HIV guidelines may soon revise their guidance, but at this time the following are recom­mended prior to use of DTG in women of childbearing potential: a pregnancy test, determination of their desire to become pregnant, and a discussion of the risks and benefits of conceiving on DTG therapy. DTG should be avoided in patients during the first trimester of pregnancy and in women who are of childbearing potential who desire to become pregnant or who are not consistently using effective contra­ception. In susceptible patients, RAL is the INSTI with the most early-preg­nancy data and could be used. DTG appears safe after the first trimester and may be used at that time.

In reality, prevention of MTCT in women who are highly treatment-expe­rienced with multiclass ARV resistance (such as women vertically infected) may require use of INSTIs, such as DTG and BIC.³¹ Currently, in light of the limited safety data with BIC in pregnancy and its structural similarity to DTG, the same concerns exist and treatment is not recommended.²⁵

The NTDs observed in the Botswana study may repre­sent folate deficiency, but ongoing surveillance is neces­sary to determine the association. Other prospective cohort trials have not produced evidence of an increased risk of NTDs with DTG, EVG, RAL, or BIC. Analysis of these cohort studies revealed no NTDs or clustering of congen­ital malformations associated with the use of DTG or other INSTIs in early pregnancy. Continued surveillance studies with DTG and other contemporary antiretroviral therapies, including provider reporting of pregnancy outcomes to the APR, are needed to further evaluate the safety of ART during pregnancy.

Hester is an associate clinical professor in the Department of Pharmacy Practice at Auburn University Harrison School of Pharmacy in Auburn, Alabama, and currently provides collaborative medication therapy management for the HIV and primary care needs of her patients. Areas of clinical interest include metabolic and cardiovascular disease in the HIV population, antiretroviral therapy in pregnancy, HIV pharmacotherapy, and antiretroviral stewardship.

Caulder is an associate clinical professor in the Department of Clinical Pharmacy and Outcomes Sciences at the University of South Carolina College of Pharmacy in Columbia, South Carolina, and she maintains a clinical practice in internal medicine and infectious diseases at Prisma Health — Richland in Columbia, South Carolina. Areas of clinical interest include HIV pharmacotherapy, gram-negative and gram-positive bacterial resistance, antimicrobial dosing in obesity, and antimicrobial/ antiviral stewardship.

References:

1. Nesheim SR, Wiener J, Fitz Harris LF, Lampe MA, Weidle PJ. Estimated incidence of perinatally acquired HIV infection in the United States, 1978-2013. J Acquir Immune Defic Syndr. 2017 Dec 15;76(5):461-464. doi: 10.1097/QAI.0000000000001552.
2. Peters H, Francis K, Sconza R, et al. UK mother-to-child HIV transmission rates continue to decline: 2012-2014. Clin Infect Dis. 2017 Feb 15;64(4):527-528. doi: 10.1093/cid/ciw791.
3. Mandelbrot L, Tubiana R, Le Chenadec J, et al. No perinatal HIV-1 transmission from women with effective antiretroviral therapy starting before conception. Clin Infect Dis. 2015 Dec 1;61(11):1715-25. doi: 10.1093/cid/civ578.
4. Hoyt MJ, Storm DS, Aaron E, Anderson J. Preconception and contraceptive care for women living with HIV. Infect Dis Obstet Gynecol. 2012;2012:604183. doi: 10.1155/2012/604183.
5. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Preconception counseling and care for women of childbearing age living with HIV. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed May 29, 2019.
6. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry Interim Report for 1 January 1989 through 31 July 2018. Wilmington, NC: Registry Coordinating Center; 2018. Available from URL: www.APRegistry.com
7. Watts DH, Huang S, Culnane M, et al. Birth defects among a cohort of infants born to HIV-infected women on antiretroviral medication. J Perinat Med. 2011 Mar;39(2):163-70. doi: 10.1515/JPM.2010.139.
8. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Appendix B Safety and Toxicity of Individual Antiretroviral Agents in Pregnancy. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed June 21, 2019.
9. Berard A, Sheehy O, Zhao J, et al. Antiretroviral combination use during pregnancy and the risk of major congenital malformations. AIDS. 2017 Oct 23;31(16):2267-2277. doi: 10.1097/QAD.0000000000001610.
10. Williams PL, Crain MJ, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatr. 2015 Jan;169(1):48-55. doi: 10.1001/jamapediatrics.2014.1889.
11. Ford N, Shubber Z, Jao J, Abrams EJ, Frigati L, Mofenson L. Safety of cotrimoxazole in pregnancy: a systematic review and meta-analysis. J Acquir Immune Defic Syndr. 2014 Aug 15;66(5):512-21. doi: 10.1097/QAI.0000000000000211.
12. Cavalli P. Prevention of neural tube defects and proper folate periconceptional supplementation. J Prenat Med. 2008 Oct;2(4):40-1.
13. WHO. Statement on DTG.; 2018. http://www.who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdf?ua= 1. Accessed May 4, 2019.
14. Zash R, Makhema J, Shapiro RL. Neural-tube defects with dolutegravir treatment from the time of conception. N Engl J Med. 2018 Sep 6;379(10):979-981. doi: 10.1056/NEJMc1807653.
15. Zash R, Holmes L, Diseko M, et al. Neural tube defects and antiretroviral treatment regimens in Botswana. N Engl J Med. 2019; Jul 22. doi: 10.1056/NEJMoa1905230. [Epub ahead of print]
16. Zash R, Jacobson DL, Diseko M, et al. Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study. Lancet Glob Health. 2018 Jul;6(7):e804-e810. doi: 10.1016/S2214-109X(18)30218-3.
17. Vannappagari V, Thorne C. Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir. J Acquir Immune Defic Syndr. 2019 Aug 1;81(4):371-378. doi: 10.1097/QAI.0000000000002035. [Epub ahead of print]
18. Grayhack C, Sheth A, Kirby O, et al. Evaluating outcomes of mother-infant pairs using dolutegravir for HIV treatment during pregnancy. AIDS. 2018 Sep 10;32(14):2017-2021. doi: 10.1097/QAD.0000000000001931.
19. Bornhede R, Soeria-Atmadja S, Westling K, Pettersson K, Naver L. Dolutegravir in pregnancy — effects on HIV-positive women and their infants. Eur J Clin Microbiol Infect Dis. 2018 Mar;37(3):495-500. doi: 10.1007/s10096-018-3195-9.
20. Money D, Lee T, Farjou G, et al. An analysis of congenital anomalies in pregnant women living with HIV in Canada: no signal for neural tube defects in women exposed to dolutegravir. [abstract P001]. J Int AIDS Soc. 2018;(suppl 8):e25187.
21. Weissmann D, De Leuw P, Gute P, et al. Use of integrase inhibitors in HIV-positive pregnant women: data from the Frankfurt HIV cohort. [abstract P002]. J Int AIDS Soc. 2018;(suppl 8):e25187.
22. Chouchana L, Beeker N, Treluyer JM. Is there a safety signal for dolutegravir and integrase inhibitors during pregnancy? J Acquir Immune Defic Syndr. 2019 Aug 1;81(4):481-486. doi: 10.1097/QAI.0000000000002065. [Epub ahead of print]
23. Rasi V, Cortina-Borja M, Peters H, Sconza R, Thorne C. Surveillance of congenital anomalies after exposure to raltegravir and elvitegravir during pregnancy in the United Kingdom and Ireland, 2008-2018. J Acquir Immune Defic Syndr. 2019 Mar 1;80(3):264-268. doi: 10.1097/QAI.0000000000001924.
24. Shamsuddin H, Raudenbush CL, Sciba BL, et al. Evaluation of neural tube defcts (NTDs) after exposure to raltegravir during pregnancy. J Acquir Immune Defic Syndr. 2019 Jul 1;81(3):247-250. doi: 10.1097/QAI.0000000000002031.
25. Farrow T, Deaton C, Nguyen N, et al. Cumulative safety review of elvitegravir and bictegravir use during pregnancy and risk of neural tube defects. [abstract P030]. J Int AIDS Soc. 2018; (suppl 8): e25187.
26. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. What to start: initial combination regimens for the antiretroviral-naïve patient. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed June 23, 2019.
27. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines. Supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization; 2018 (WHO/CDS/HIV/18.51).=
28. European AIDS Clinical Society Guidelines v9.1; October 2018.
29. Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA Panel. JAMA. 2018 Jul 24;320(4):379-396. doi: 10.1001/jama.2018.8431.
30. WHO recommends dolutegravir as preferred HIV treatment option in all populations [press release]. Mexico City, Mexico: World Health Organization; July 22, 2019. https://www.who.int/news-room/detail/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations. Accessed July 23, 2019.
31. Pinnetti C, Tintoni M, Ammassari A, et al. Successful prevention of HIV mother-to-child transmission with dolutegravir-based combination antiretroviral therapy in a vertically infected pregnant woman with multiclass highly drug-resistant HIV-1. AIDS. 2015 Nov 28;29(18):2534-7. doi: 10.1097/QAD.0000000000000888.