Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Antepartum Care

Antiretroviral Drug Resistance and Resistance Testing in Pregnancy

Indications for Antiretroviral Drug-Resistance Testing in Pregnant Persons with HIV

Identification of baseline resistance mutations allows for the selection of more effective and durable antiretroviral (ARV) regimens. Drug-resistance testing should be performed for people with virologic failure and HIV RNA levels >200 copies/mL. For people with confirmed HIV RNA levels >200 copies/mL but <500 copies/mL, drug-resistance testing may be unsuccessful but should still be considered. Perform resistance testing before—

• Initiating antiretroviral therapy (ART) in ARV-naive pregnant patients who have not been previously tested for ARV resistance,
• Initiating ART in ARV-experienced pregnant patients (including those who have received pre-exposure prophylaxis [PrEP]), or
• Modifying ARV regimens for those who are newly pregnant and receiving ARV drugs or who have suboptimal virologic response to ARV drugs that were initiated during pregnancy.

It is also important to obtain a comprehensive history of ARV drug use, including ARVs used for HIV PrEP. In most settings, the results of resistance testing guide the selection of the initial ARV regimen. However, ART should be initiated in ARV-naive pregnant persons or ARV-experienced individuals who are not presently on ART without waiting for the results of resistance testing because earlier viral suppression is associated with lower risk of perinatal transmission. The regimen can be modified, if required, when test results return.

Integrase strand transfer inhibitors (INSTIs) are used increasingly in ART regimens for pregnant people,¹ and the INSTI cabotegravir (Apretude) has been approved for PrEP. Resistance to INSTIs is generally uncommon among ARV-naive individuals in the United States.² In studies of INSTI resistance in North Carolina, resistance was detected in 2.4% (95% confidence interval [CI], 1.5% to 3.6%) of ART-naive persons and 9.6% (95% CI, 8.3% to 11.0%) of ART-experienced persons with HIV³ and in 2.9% of ART-naive participants from an HIV clinic in Santa Clara County, California.⁴ The prevalence of INSTI resistance increased slightly from 0.0% in 2004 to 1.4% (P = 0.04) in 2013 in Washington, D.C.⁵ During 2014 to 2018, among 50,747 persons, Centers for Disease Control and Prevention surveillance within 3 months of HIV diagnosis identified 0.8% with INSTI resistance. A systematic review of 103 studies identified “surveillance” drug-resistance mutations in 0.5% of INSTI-naive individuals.^6,7 A polymorphism or a substitution associated with INSTI resistance was found in 1.4% of INSTI-naive persons in 16 clinical trials.⁸

The development of INSTI resistance is infrequent among people who receive INSTI-based ART (only 1.5% to 3.8% of people develop resistance).^9-11 A modeling study found that testing for INSTI resistance at ART initiation was not cost effective and did not improve clinical outcomes.¹² Genotype testing for INSTI resistance also is not considered cost effective in the United States when initiating ART.¹³ Routine INSTI-resistance testing generally is not indicated in pregnant persons. However, such testing can be considered when a patient received prior treatment or PrEP that included an INSTI or when a patient has had a sexual partner on INSTI therapy who was not virologically suppressed or with unknown viral load.

HIV drug-resistance genotype testing detects mutations that confer resistance to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors, and INSTIs. Phenotypic resistance testing is reserved generally for cases of complex NRTI-resistance patterns in patients with limited treatment options and is recommended for treatment-experienced persons on failing regimens with suspected multidrug resistance (see Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines). At some institutions, testing for INSTI resistance may have to be ordered separately.

There are currently no commercially available resistance tests for the CD4 T lymphocyte post-attachment inhibitor ibalizumab, gp120 attachment inhibitor fostemsavir, or capsid inhibitor lenacapavir.

Incidence and Significance of Antiretroviral Drug Resistance in Pregnancy

The development of ARV drug resistance is one of the major factors leading to therapeutic failure in individuals with HIV. In addition, pre-existing resistance to a drug in an ARV regimen may diminish the regimen’s efficacy in preventing perinatal transmission. Maternal drug resistance can be transmitted to the fetus, which can limit treatment options for the infant. Resistance to ARV drugs appears to be more common in women who acquired HIV perinatally than in other women with HIV.¹⁴ The complexities of managing pregnant people with perinatally acquired HIV warrant consultation with an expert in HIV.¹⁵ See Prenatal Care, Antiretroviral Therapy, and HIV Management in People with Perinatal-Acquired HIV Infection for more information.

Several factors that are unique to pregnancy may increase the risk of developing resistance. Problems—such as nausea and vomiting—in early pregnancy may compromise adherence, increasing the risk of developing resistance in those receiving ARV drugs. Pharmacokinetic changes during pregnancy (e.g., increased plasma volume and renal clearance) may lead to subtherapeutic drug levels, increasing the risk that resistance will develop.

Managing Antiretroviral Resistance During Pregnancy

The most effective way to prevent the development of ARV drug resistance in pregnancy is to follow recommendations for resistance testing and viral load monitoring and to support adherence to an effective ARV regimen that achieves maximal viral suppression (see Monitoring During Pregnancy). Management of pregnant people who have received ART or ARV prophylaxis previously, including resistance testing, is discussed in Pregnant People with HIV Who Have Previously Received Antiretroviral Medication But Are Not Currently on Antiretroviral Medications. Inadequate adherence and viral resistance should be considered when there is a suboptimal virologic response or viral rebound to an ARV regimen (see Pregnant People Who Have Not Achieved Viral Suppression on Antiretroviral Therapy). Because studies have shown that adherence to ART may worsen during the postpartum period,^16-19 arrangements should be made during pregnancy for appropriate postpartum follow-up and adherence support to prevent loss of virologic control and the development of resistance (see Postpartum Follow-Up of People with HIV).

The optimal prophylactic regimen for newborns of persons with drug-resistant HIV is unknown. Therefore, ARV prophylaxis for infants born to persons with known or suspected drug-resistant HIV should be determined with the help of a pediatric HIV specialist, preferably before delivery (see Antiretroviral Management of Newborns with Perinatal HIV Exposure or HIV Infection). No evidence exists that neonatal prophylaxis regimens that have been customized to address maternal drug resistance are more effective than standard neonatal prophylaxis regimens.

Zidovudine Resistance During Pregnancy

Those who have documented zidovudine (ZDV) resistance and who did not receive ZDV as part of their antepartum regimen should still receive intravenous (IV) ZDV during labor when indicated. IV ZDV is indicated for patients with HIV RNA >1,000 copies/mL or unknown HIV viral load near delivery (see Intrapartum Care for People with HIV). A patient’s ARV regimen should be continued orally during labor to the extent possible. The rationale for including ZDV intrapartum when a patient is known to have HIV with ZDV resistance is based on several factors. First, only wild-type virus appears to be transmitted to infants by mothers who have mixed populations of wild-type virus and virus with low-level ZDV resistance²⁰; drug-resistance mutations may diminish viral fitness and possibly decrease transmissibility.²¹ Second, the efficacy of ZDV prophylaxis appears to be based not only on a reduction in maternal HIV viral load, but also on the on its role as both PrEP and post-exposure prophylaxis in the infant.^22-24 ZDV crosses the placenta readily and has a high cord-to–maternal blood ratio. In addition, ZDV is metabolized to the active triphosphate within the placenta,²⁵ which may provide additional protection against transmission. Third, ZDV penetrates the central nervous system better than other recommended nucleoside analogues; this may help eliminate a potential reservoir for transmitted HIV in the infant.²⁶ ZDV’s unique characteristics and its proven record in reducing perinatal transmission support the recommendation to administer intrapartum IV ZDV when indicated, even in the presence of known ZDV resistance. 

References

1. PHACS/SMARTT. Annual administrative report. 2017. Available at: https://phacsstudy.org/cms_uploads/Latest%20Documents/SMARTT_Annual_Administrative_Report_Apr2017_web.pdf.
2. Stekler JD, McKernan J, Milne R, et al. Lack of resistance to integrase inhibitors among antiretroviral-naive subjects with primary HIV-1 infection, 2007–2013. Antivir Ther. 2015;20(1):77-80. Available at: https://pubmed.ncbi.nlm.nih.gov/24831260.
3. Menza TW, Billock R, Samoff E, et al. Pretreatment integrase strand transfer inhibitor resistance in North Carolina from 2010–2016. AIDS. 2017;31(16):2235-2244. Available at: https://pubmed.ncbi.nlm.nih.gov/28991024.
4. Chan W, Ly W. Surveillance of transmitted HIV drug resistance among newly diagnosed, treatment-naive individuals at a county HIV clinic in Santa Clara County. Heliyon. 2019;5(9):e02411. Available at: https://pubmed.ncbi.nlm.nih.gov/31535044.
5. Aldous AM, Castel AD, Parenti DM, D. C. Cohort Executive Committee. Prevalence and trends in transmitted and acquired antiretroviral drug resistance, Washington, DC, 1999–2014. BMC Res Notes. 2017;10(1):474. Available at: https://pubmed.ncbi.nlm.nih.gov/28893321.
6. Bailey AJ, Rhee SY, Shafer RW. Integrase strand transfer inhibitor resistance in integrase strand transfer inhibitor-naive persons. AIDS Res Hum Retroviruses. 2021;37(10):736-743. Available at: https://pubmed.ncbi.nlm.nih.gov/33683148.
7. McClung RP, Oster AM, Ocfemia MCB, et al. Transmitted drug resistance among human immunodeficiency virus (HIV)-1 diagnoses in the United States, 2014–2018. Clin Infect Dis. 2022;74(6):1055-1062. Available at: https://pubmed.ncbi.nlm.nih.gov/34175948.
8. Abram ME, Ram RR, Margot NA, et al. Lack of impact of pre-existing T97A HIV-1 integrase mutation on integrase strand transfer inhibitor resistance and treatment outcome. PLoS One. 2017;12(2):e0172206. Available at: https://pubmed.ncbi.nlm.nih.gov/28212411.
9. Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382(9893):700-708. Available at: https://pubmed.ncbi.nlm.nih.gov/23830355.
10. Margot N, Cox S, Das M, et al. Rare emergence of drug resistance in HIV-1 treatment-naive patients receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide for 144 weeks. J Clin Virol. 2018;103:37-42. Available at: https://pubmed.ncbi.nlm.nih.gov/29627709.
11. Underwood R, DeAnda F, Dorey D, et al. Euro resistance wk: resistance post week 48 in ART-experienced, integrase Inhibitor-naive subjects with dolutegravir (DTG) vs. raltegravir (RAL) in SAILING (ING111762). Presented at: 13th European HIV & Hepatitis Workshop; 2015. Barcelona, Spain. Available at: https://www.natap.org/2015/HIV/061715_02.htm.
12. Koullias Y, Sax PE, Fields NF, et al. Should we be testing for baseline integrase resistance in patients newly diagnosed with human immunodeficiency virus? Clin Infect Dis. 2017;65(8):1274-1281. Available at: https://pubmed.ncbi.nlm.nih.gov/28605418.
13. Hyle EP, Scott JA, Sax PE, et al. Clinical impact and cost-effectiveness of genotype testing at human immunodeficiency virus diagnosis in the United States. Clin Infect Dis. 2020;70(7):1353-1363. Available at: https://pubmed.ncbi.nlm.nih.gov/31055599.
14. Lazenby GB, Mmeje O, Fisher BM, et al. Antiretroviral resistance and pregnancy characteristics of women with perinatal and nonperinatal HIV infection. Infect Dis Obstet Gynecol. 2016;2016:4897501. Available at: https://pubmed.ncbi.nlm.nih.gov/27413359.
15. Trahan MJ, Boucher M, Renaud C, et al. Pregnancies among the first generation of survivors of perinatal HIV infection. J Obstet Gynaecol Can. 2020;42(4):446-452. Available at: https://pubmed.ncbi.nlm.nih.gov/31882286.
16. Bardeguez AD, Lindsey JC, Shannon M, et al. Adherence to antiretrovirals among US women during and after pregnancy. J Acquir Immune Defic Syndr. 2008;48(4):408-417. Available at: https://pubmed.ncbi.nlm.nih.gov/18614923.
17. Mellins CA, Chu C, Malee K, et al. Adherence to antiretroviral treatment among pregnant and postpartum HIV-infected women. AIDS Care. 2008;20(8):958-968. Available at: https://pubmed.ncbi.nlm.nih.gov/18608073.
18. Anderson J. Women and HIV: motherhood and more. Curr Opin Infect Dis. 2012;25(1):58-65. Available at: https://pubmed.ncbi.nlm.nih.gov/22156896.
19. Nachega JB, Uthman OA, Anderson J, et al. Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries: a systematic review and meta-analysis. AIDS. 2012;26(16):2039-2052. Available at: https://pubmed.ncbi.nlm.nih.gov/22951634.
20. Colgrove RC, Pitt J, Chung PH, et al. Selective vertical transmission of HIV-1 antiretroviral resistance mutations. AIDS. 1998;12(17):2281-2288. Available at: https://pubmed.ncbi.nlm.nih.gov/9863870.
21. Sheth PM, Kovacs C, Kemal KS, et al. Persistent HIV RNA shedding in semen despite effective antiretroviral therapy. AIDS. 2009;23(15):2050-2054. Available at: https://pubmed.ncbi.nlm.nih.gov/19710596.
22. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1996;335(22):1621-1629. Available at: https://pubmed.ncbi.nlm.nih.gov/8965861.
23. Wade NA, Birkhead GS, Warren BL, et al. Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. N Engl J Med. 1998;339(20):1409-1414. Available at: https://pubmed.ncbi.nlm.nih.gov/9811915.
24. Melvin AJ, Burchett SK, Watts DH, et al. Effect of pregnancy and zidovudine therapy on viral load in HIV-1-infected women. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;14(3):232-236. Available at: https://pubmed.ncbi.nlm.nih.gov/9117455.
25. Qian M, Bui T, Ho RJ, Unadkat JD. Metabolism of 3'-azido-3'-deoxythymidine (AZT) in human placental trophoblasts and Hofbauer cells. Biochem Pharmacol. 1994;48(2):383-389. Available at: https://pubmed.ncbi.nlm.nih.gov/8053935.
26. Thomas SA. Anti-HIV drug distribution to the central nervous system. Curr Pharm Des. 2004;10(12):1313-1324. Available at: https://pubmed.ncbi.nlm.nih.gov/15134483.