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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Antepartum Care

Monitoring of the Woman and Fetus During Pregnancy

(Last updated: August 6, 2015; last reviewed: August 6, 2015)

Panel's Recommendations

Panel's Recommendations

  • Plasma HIV RNA levels should be monitored at the initial visit (AI); 2 to 4 weeks after initiating (or changing) antiretroviral drug regimens (BI); monthly until RNA levels are undetectable (BIII); and then at least every 3 months during pregnancy (BIII). HIV RNA levels also should be assessed at approximately 34 to 36 weeks’ gestation to inform decisions about mode of delivery (see Transmission and Mode of Delivery) and to inform decisions about optimal treatment of the newborn (see Infant ARV Prophylaxis) (AIII).
  • CD4 T lymphocyte (CD4) cell count should be monitored at the initial antenatal visit (AI) and at least every 3 months during pregnancy (BIII). Monitoring of CD4 cell count can be performed every 6 months in patients on combination antiretroviral therapy (cART) with consistently suppressed viral load who have CD4 counts well above the threshold for opportunistic infection risk) (CIII).
  • Genotypic antiretroviral drug-resistance testing should be performed at baseline in all HIV-infected pregnant women with HIV RNA levels >1,000 copies/mL (AI). In individuals with HIV RNA levels >500 but <1,000 copies/mL, testing may be unsuccessful but should still be considered (BII). Tests should be performed whether the women are antiretroviral-naive or currently on therapy (AIII)
  • HIV drug-resistance studies should be performed before modifying antiretroviral regimens for those entering pregnancy with detectable HIV RNA levels that are above the threshold for resistance testing (i.e., >500 to 1,000 copies/mL) while receiving antiretroviral drugs. They should also be performed on women who have suboptimal viral suppression after starting ARV drugs during pregnancy (AII).  
  • Monitoring for complications of antiretroviral drugs during pregnancy should be based on what is known about the adverse effects of the drugs a woman is receiving (AIII).
  • HIV-infected women taking cART during pregnancy should undergo standard glucose screening at 24 to 28 weeks’ gestation (AIII). Some experts would perform earlier glucose screening in women receiving ongoing protease inhibitor-based regimens initiated before pregnancy, similar to recommendations for women with risk factors for glucose intolerance (BIII). For further information on protease inhibitors see Combination Antiretroviral Drug Regimens and Pregnancy Outcome.
  • Early ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide timing of the procedure (see Transmission and Mode of Delivery) (AII).
  • In women on effective cART, no perinatal transmissions have been reported after amniocentesis, but a small risk of transmission cannot be ruled out. Amniocentesis should be performed on HIV-infected women only after initiation of an effective cART regimen and, ideally, when HIV RNA levels are undetectable (BIII). In women with detectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should be considered (BIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion

More frequent viral load monitoring is recommended in pregnant than non-pregnant individuals because of the importance of rapid and persistent viral suppression in preventing perinatal HIV transmission. In individuals who are adherent to their antiretroviral (ARV) regimen and do not harbor resistance mutations to the prescribed drugs, viral suppression is generally achieved in 12 to 24 weeks—although it may take longer in some patients and may be dependent on starting viral load. Most patients with adequate viral response at 24 weeks of treatment have had at least a 1 log viral load decrease within 1 to 4 weeks after starting therapy.1,2 Viral load should be monitored in HIV-infected pregnant women at the initial visit, 2 to 4 weeks after initiating or changing ARV regimens, monthly until undetectable, and at least every 3 months thereafter. If adherence is a concern, more frequent monitoring is recommended because of the potential increased risk of perinatal HIV infection associated with detectable HIV viremia during pregnancy. 

Viral load also should be assessed at approximately 34 to 36 weeks’ gestation to inform decisions about mode of delivery and about optimal treatment of the newborns (see Transmission and Mode of Delivery).

In HIV-infected pregnant women, CD4 T lymphocyte (CD4) cell count should be monitored at the initial visit and at least every 3 months during pregnancy. CD4 cell counts can be performed every 6 months in patients who are clinically stable with consistently suppressed viral load who have CD4 counts well above threshold for opportunistic infection risk).1,3,4

Whenever feasible, ARV drug-resistance testing should be performed before initiation of ARV drugs if HIV RNA levels are above the threshold for resistance testing, but therapy should not be delayed once the blood is drawn and results are pending. If the results demonstrate resistance, then the regimen can subsequently be adjusted. Testing also should be performed on women taking an ARV regimen who have suboptimal viral suppression or who have persistent viral rebound to detectable levels after prior viral suppression on an ARV regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy). Drug-resistance testing in the setting of virologic failure should be performed while patients are receiving ARV drugs or within 4 weeks after discontinuation of drugs. Even if more than 4 weeks have elapsed since the ARVs were discontinued, resistance testing can still provide useful information to guide therapy, though it may not detect previously selected resistance mutations. Genotypic testing is preferable to phenotypic testing because it costs less, has a faster turnaround time, and is more sensitive for detection of mixtures of wild-type and resistant virus.

Monitoring for potential complications of ARV drugs during pregnancy should be based on what is known about the adverse effects of the drugs a woman is receiving. For example, routine hematologic monitoring is recommended for women receiving zidovudine-containing regimens and routine renal monitoring should be recommended for women on tenofovir. Liver function should be monitored in all women receiving ARV drugs. Hepatic dysfunction has been observed in pregnant women on protease inhibitors (PI), and hepatic steatosis and lactic acidosis in pregnancy have been related to nucleoside reverse transcriptase inhibitor use.

Women with CD4 cell counts >250 cells/mm3 were thought to be at risk of developing symptomatic, rash-associated hepatotoxicity within the first 18 weeks after initiation of nevirapine therapy. However, recent data either do not demonstrate the same association between nevirapine toxicity and CD4 cell counts among pregnant women,5 or demonstrate only a weak association.6 Additional data from a 2010 study suggest that abnormal liver transaminase levels at baseline may be more predictive of risk of nevirapine toxicity than CD4 cell count.7 Transaminase levels should be monitored more frequently and carefully in pregnant women initiating therapy with nevirapine, and they should also be watched for clinical symptoms of potential hepatotoxicity. The drug can be used cautiously with careful monitoring in women with mildly abnormal liver function tests at the time of ARV drug initiation. 

Pregnancy increases the risk of hyperglycemia. PI drugs have been associated with increased risk of hyperglycemia, new-onset diabetes mellitus, exacerbation of existing diabetes mellitus, and diabetic ketoacidosis.8-11 However, the majority of studies in HIV-infected pregnant women have not shown an increased risk of glucose intolerance with PI-based regimens during pregnancy. A prospective study including detailed evaluations for glucose intolerance and insulin resistance among HIV-infected pregnant women did not find differences between women on PI-containing and non-PI-containing regimens.12 In both groups, the rate of impaired glucose tolerance was high (38%); but, this may be related to high body mass index and race/ethnicity among trial subjects. HIV-infected women receiving cART during pregnancy should receive the standard glucose screening at 24 to 28 weeks’ gestation that is recommended for all pregnant women. Some experts would perform earlier glucose screening in women receiving ongoing PI-based cART initiated before pregnancy, similar to recommendations for women with risk factors for glucose intolerance.  

Accurate estimation of date of delivery is critical to planning elective cesarean deliveries at 38 weeks' gestation to prevent perinatal transmission in HIV-infected women with elevated HIV RNA viral loads. Therefore, first-trimester ultrasound is recommended to confirm gestational age and to provide the most accurate estimation of gestational age at delivery (see Transmission and Mode of Delivery).13-15 In patients who are not seen until later in gestation, second-trimester ultrasound can be used for both anatomical survey and determination of gestational age.

Although data are still somewhat limited, the risk of HIV transmission does not appear to be increased with amniocentesis or other invasive diagnostic procedures in women receiving effective cART resulting in viral suppression. This is in contrast to the era before effective cART, during which invasive procedures such as amniocentesis and chorionic villus sampling (CVS) were associated with a 2- to 4-fold increased risk of perinatal transmission of HIV.16-19 Although no transmissions have occurred among 159 cases reported to date of amniocentesis or other invasive diagnostic procedures among women on effective cART, a small increase in risk of transmission cannot be ruled out.20-23 HIV-infected women who have indications for invasive testing in pregnancy (e.g., abnormal ultrasound or aneuploidy screening) should be counseled about the potential risk of transmission of HIV along with other risks of the procedure and allowed to make an informed decision about testing. Some experts consider CVS and cordocentesis too risky to offer to HIV-infected women, and they recommend limiting invasive procedures to amniocentesis. At a minimum, HIV-infected pregnant women should receive effective cART before undergoing any invasive prenatal testing and, ideally, have an undetectable HIV RNA level at the time of the procedure. Consideration can also be given to noninvasive testing using cell-free fetal DNA to reduce the need for amniocentesis.24 In women with detectable HIV RNA levels for whom amniocentesis is deemed necessary, consultation with an expert should be considered.

References

  1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2014. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed May 11, 2015.
  2. Read PJ, Mandalia S, Khan P, et al. When should HAART be initiated in pregnancy to achieve an undetectable HIV viral load by delivery? AIDS. 2012;26(9):1095-1103. Available at http://www.ncbi.nlm.nih.gov/pubmed/22441248.
  3. Gale HB, Gitterman SR, Hoffman HJ, et al. Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with counts >=300 cells/muL and HIV-1 suppression? Clin Infect Dis. 2013;56(9):1340-1343. Available at http://www.ncbi.nlm.nih.gov/pubmed/23315315.
  4. Girard PM, Nelson M, Mohammed P, Hill A, van Delft Y, Moecklinghoff C. Can we stop CD4+ testing in patients with HIV-1 RNA suppression on antiretroviral treatment? AIDS. 2013;27(17):2759-2763. Available at http://www.ncbi.nlm.nih.gov/pubmed/23842127.
  5. Peters PJ, Polle N, Zeh C, et al. Nevirapine-Associated Hepatotoxicity and Rash among HIV-Infected Pregnant Women in Kenya. J Int Assoc Physicians AIDS Care (Chic). 2012;11(2):142-149. Available at http://www.ncbi.nlm.nih.gov/pubmed/22020069.
  6. Ford N, Calmy A, Andrieux-Meyer I, Hargreaves S, Mills EJ, Shubber Z. Adverse events associated with nevirapine use in pregnancy: a systematic review and meta-analysis. AIDS. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23299174.
  7. Peters PJ, Stringer J, McConnell MS, et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count >/=250 cells/muL among women in Zambia, Thailand and Kenya. HIV Med. 2010;11(10):650-660. Available at http://www.ncbi.nlm.nih.gov/pubmed/20659176.
  8. Food and Drug Administration. FDA Public Health Advisory: reports of diabetes and hyperglycemia in patients receiving protease inhibitors for treatment of human immunodeficiency virus (HIV). Food and Drug Administration, Public Health Service, Department of Health and Human Services. Rockville, MD. June 11, 1997. Available at http://www.fda.gov/cder/news/proteaseletter.htm. Accessed May 11, 2015.
  9.  Eastone JA, Decker CF. New-onset diabetes mellitus associated with use of protease inhibitor [letter]. Ann Intern Med. 1997;127(10):948. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9382376&dopt=Abstract.
  10. Visnegarwala F, Krause KL, Musher DM. Severe diabetes associated with protease inhibitor therapy. Ann Intern Med. 1997;127(10):947. Available at http://www.ncbi.nlm.nih.gov/pubmed/9382374.
  11. Dube MP, Sattler FR. Metabolic complications of antiretroviral therapies. AIDS Clin Care. 1998;10(6):41-44. Available at http://www.ncbi.nlm.nih.gov/pubmed/11365497.
  12. Hitti J, Andersen J, McComsey G, et al. Protease inhibitor-based antiretroviral therapy and glucose tolerance in pregnancy: AIDS Clinical Trials Group A5084. Am J Obstet Gynecol. 2007;196(4):331 e331-337. Available at http://www.ncbi.nlm.nih.gov/pubmed/17403409.
  13. Bulletins ACoP. ACOG Practice Bulletin No. 58. Ultrasonography in pregnancy. Obstet Gynecol. 2004;104(6):1449-1458. Available at http://www.ncbi.nlm.nih.gov/pubmed/15572512.
  14. Bennett KA, Crane JM, O'Shea P, Lacelle J, Hutchens D, Copel JA. First trimester ultrasound screening is effective in reducing postterm labor induction rates: a randomized controlled trial. Am J Obstet Gynecol. 2004;190(4):1077-1081. Available at http://www.ncbi.nlm.nih.gov/pubmed/15118645.
  15. American Council of Obstetricians and Gynecologists. Committee opinion: method for estimating due date. Obstet Gynecol. 2014;124(5):863-866. 
  16. Mandelbrot L, Mayaux MJ, Bongain A, et al. Obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: the French perinatal cohorts. SEROGEST French Pediatric HIV Infection Study Group. Am J Obstet Gynecol. 1996;175(3 Pt 1):661-667. Available at http://www.ncbi.nlm.nih.gov/pubmed/8828431.
  17. Tess BH, Rodrigues LC, Newell ML, Dunn DT, Lago TD. Breastfeeding, genetic, obstetric and other risk factors associated with mother-to-child transmission of HIV-1 in Sao Paulo State, Brazil. Sao Paulo Collaborative Study for Vertical Transmission of HIV-1. AIDS. 1998;12(5):513-520. Available at http://www.ncbi.nlm.nih.gov/pubmed/9543450.
  18. Shapiro DE, Sperling RS, Mandelbrot L, Britto P, Cunningham BE. Risk factors for perinatal human immunodeficiency virus transmission in patients receiving zidovudine prophylaxis. Pediatric AIDS Clinical Trials Group protocol 076 Study Group. Obstet Gynecol. 1999;94(6):897-908. Available at http://www.ncbi.nlm.nih.gov/pubmed/10576173.
  19. Maiques V, Garcia-Tejedor A, Perales A, Cordoba J, Esteban RJ. HIV detection in amniotic fluid samples. Amniocentesis can be performed in HIV pregnant women? Eur J Obstet Gynecol Reprod Biol. 2003;108(2):137-141. Available at http://www.ncbi.nlm.nih.gov/pubmed/12781400.
  20. Somigliana E, Bucceri AM, Tibaldi C, et al. Early invasive diagnostic techniques in pregnant women who are infected with the HIV: a multicenter case series. Am J Obstet Gynecol. 2005;193(2):437-442. Available at http://www.ncbi.nlm.nih.gov/pubmed/16098867.
  21. Coll O, Suy A, Hernandez S, et al. Prenatal diagnosis in human immunodeficiency virus-infected women: a new screening program for chromosomal anomalies. Am J Obstet Gynecol. 2006;194(1):192-198. Available at http://www.ncbi.nlm.nih.gov/pubmed/16389031.
  22. Ekoukou D, Khuong-Josses MA, Ghibaudo N, Mechali D, Rotten D. Amniocentesis in pregnant HIV-infected patients. Absence of mother-to-child viral transmission in a series of selected patients. Eur J Obstet Gynecol Reprod Biol. 2008;140(2):212-217. Available at http://www.ncbi.nlm.nih.gov/pubmed/18584937.
  23. Mandelbrot L, Jasseron C, Ekoukou D, et al. Amniocentesis and mother-to-child human immunodeficiency virus transmission in the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales French Perinatal Cohort. Am J Obstet Gynecol. 2009;200(2):160 e161-169. Available at http://www.ncbi.nlm.nih.gov/pubmed/18986640.
  24. American Council of Obstetricians and Gynecologists. Committee opinion: non-invasive prenatal testing for fetal aneuploidy. 2012;545:1-3. Available at http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Genetics/Noninvasive_Prenatal_Testing_for_Fetal_Aneuploidy.

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