Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States

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The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Recommendations for Use of Antiretroviral Drugs During Pregnancy

Pregnant Women Living with HIV Who Have Previously Received Antiretroviral Treatment or Prophylaxis but Are Not Currently Receiving Any Antiretroviral Medications

Last Updated: December 7, 2018; Last Reviewed: December 7, 2018

Panel's Recommendations for Pregnant Women Living with HIV Who Have Previously Received Antiretroviral Treatment or Prophylaxis but Are Not Currently Receiving Any Antiretroviral Medications
Panel's Recommendations
  • Obtain an accurate history of all prior antiretroviral (ARV) regimens used for treatment of HIV disease or prevention of transmission, including virologic efficacy, the patient’s tolerance of the medications, results of prior resistance testing, and problems with adherence (AIII).
  • Choose and initiate a combination antiretroviral therapy (ART) regimen based on results of prior resistance testing, prior ARV use, concurrent medical conditions, and current recommendations for ART in pregnancy, avoiding drugs with potential known adverse effects for the mother or fetus/infant (see Table 7) (AII).
  • If HIV RNA is above the threshold for resistance testing (i.e., >500 to 1,000 copies/mL), ARV resistance testing should be performed prior to starting an ARV drug regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy) (AIII).
  • In general, ART should be initiated prior to receiving results of current ARV resistance studies, because longer use of ART during pregnancy has been associated with reduced transmission rates to the infant compared to shorter treatment periods. ART should be modified based on the results of the resistance assay, if necessary (BIII).
  • If the ART regimen results in insufficient viral suppression, repeat resistance testing and assess other considerations, including adherence, food requirements, and drug interactions (AII).
  • Consider consulting with an HIV treatment specialist about the choice of ART regimen to initiate in women who previously received ARV drugs or to modify ART in those who are not fully suppressed (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

Pregnant women living with HIV who are currently not receiving antiretroviral therapy (ART) may have received ART in the past for their own health and/or prevention of perinatal transmission in a prior pregnancy. A small number of clinical trials and observational studies have generated information about effectiveness of combination ART in individuals who previously received ART for prevention of perinatal transmission of HIV.1-4

There has been concern that prior, time-limited use of ART during pregnancy for prevention of perinatal transmission may lead to resistance and, thus, reduced efficacy if these antiretroviral (ARV) drugs are used as a part of subsequent ART regimens. Rates of resistance appear to be low, based on standard genotyping, after time-limited use of ART consisting of zidovudine, lamivudine, and nevirapine during pregnancy.5,6 However, minority populations of virus with resistance to nevirapine or lamivudine have been detected using sensitive allele-specific polymerase chain reaction techniques, particularly in women whose virus was inadequately suppressed.6-11 Both standard and sensitive genotyping techniques appear to show a low rate of resistance to protease inhibitors (PIs) after pregnancy-limited use of PI-based ART, but these results reflect assessments in a limited number of women.8,12

Increased risk of treatment failure has not been demonstrated with re-initiation of ART following time-limited use for prevention of perinatal transmission. However, only a limited number of sufficiently large, prospective, observational studies and/or clinical trials have been done to assess the effect of pregnancy-limited ART on the outcome of subsequent treatment. In ACTG 5227, 52 women who had previously received pregnancy-limited ART and who had no evidence of resistance were started on a fixed-dose combination of efavirenz/tenofovir disoproxil fumarate/emtricitabine once daily. After 6 months of therapy, 81% of these women achieved plasma viral loads that were below the limit of detection; the virologic suppression rate was not affected by the classes of previously used ARV drugs or whether women had received similar ART during one or more previous pregnancies.1 Data from the French Perinatal Cohort was used to assess virologic suppression with PI-based ART administered to women who had received ART during a previous pregnancy for prevention of perinatal transmission. ARV-naive women and women who received ART during previous pregnancies had similar rates of undetectable viral load at delivery. The type of ART previously received did not affect the rate of undetectable viral load at delivery.13 In addition, the National Study of HIV in Pregnancy and Childhood in the United Kingdom and Ireland found no increased risk of perinatal transmission in sequential pregnancies compared with a single pregnancy when most women received ART for prevention of perinatal HIV transmission.14 However, in a comparison between 5,372 ARV-naive pregnant women and 605 women who had previously received ART (but who were not being treated immediately prior to the current pregnancy), ARV-experienced women had a small but significant increase in the risk of detectable viral load at delivery (adjusted odds ratio [aOR] 1.27; 95% CI, 1.01–1.60). This risk was confined to those ARV-experienced women who received non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy, as opposed to those who received PI-based therapy.15

ART is now recommended worldwide for women living with HIV during pregnancy and throughout their lives.16 Data have been reported regarding the benefits of ART for women with higher CD4 T lymphocyte (CD4) cell counts (>350 cells/mm3) and the potential harm of stopping ARV after pregnancy in such women. Data from the HAART Standard version of the PROMISE study showed that women with CD4 cell counts ≥400 cells/mm3 who were randomized to continue ART postpartum had half the rate of WHO Stage 2 and 3 events as those who discontinued ART.17 Further, poor adherence was a common problem for women during the postpartum period in this study. Among women randomized to continue ART, 189 of 827 women (23%) had virologic failure. Of the 156 women with virologic failure who had resistance testing, 12% had resistance to their current ART (which was more common in women experiencing failure on NNRTI-based regimens), but 66% did not have resistance to their current regimen, suggesting nonadherence.17 When counselling women about the benefits of taking ART during pregnancy and continuing for life, health care providers should emphasize the health benefits of maintaining ART and the importance of adherence during the postpartum period (see Postpartum Follow-Up of Women Living with HIV Infection).

Women may choose to discontinue ART for a variety of reasons, and the length of time off treatment prior to pregnancy may vary. Choice of ART in pregnant women who have been previously treated should be made based on treatment history and all prior drug resistance test results, even when the results of drug resistance testing performed during the current pregnancy are not yet available. Interpretation of resistance testing can be complex because it is most accurate when performed while an individual is still taking ART or within 4 weeks of treatment discontinuation. In the absence of selective drug pressure, resistant virus may revert to wild-type and, although detection of drug resistance mutations is informative for choosing a regimen, a negative finding does not rule out the presence of archived resistant virus that could re-emerge once ART is restarted. Therefore, when selecting a new ART regimen, all information, including regimens received, viral response, laboratory testing (including HLA-B*5701 results), any tolerance or adherence problems, food requirements, concomitant medications, prior medical conditions, and the results of resistance testing should be taken into consideration. In general, ART should be initiated prior to receiving the results of ARV drug-resistance studies, especially because longer duration of ART has been associated with reduced transmission rates compared to shorter treatment periods.18,19 ART should be modified, when necessary, based on subsequent resistance assay results. Careful monitoring of virologic response is essential.

A woman may restart a previous ARV regimen that successfully suppressed her viral load, if the regimen was well tolerated, there is no evidence of resistance to that regimen, and (preferably) the regimen is currently recommended as first-line or an alternative regimen for initial ART in pregnancy (see Table 6: What to Start). Drugs that are not recommended for initial use because of toxicity (stavudine, didanosine, treatment-dose ritonavir) should not be used; drugs that are not recommended for initial use because of concerns about viral breakthrough during pregnancy should also be avoided. Even experienced health care providers may have difficulty with the selection of appropriate ART for women who have advanced HIV disease, a history of extensive prior ART, or previous significant toxicity or nonadherence. In addition to obtaining genotypic resistance testing, it is strongly recommended that specialists in the treatment of HIV be consulted early in the pregnancy about the choice of a suitable ART regimen for such women.

If ART produces an insufficient viral response (e.g., <1 log drop over 2–4 weeks),20 repeat resistance testing and assess medication adherence, food requirements, and potential drug interactions (including, if available, relevant pharmacokinetic studies) to inform potential regimen changes. Consultation with an HIV treatment specialist is recommended (see Lack of Viral Suppression).

References

  1. Vogler MA, Smeaton LM, Wright RL, et al. Combination antiretroviral treatment for women previously treated only in pregnancy: week 24 results of AIDS clinical trials group protocol a5227. J Acquir Immune Defic Syndr. 2014;65(5):542-550. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24759064.
  2. Aziz N, Sokoloff A, Kornak J, et al. Time to viral load suppression in antiretroviral-naive and -experienced HIV-infected pregnant women on highly active antiretroviral therapy: implications for pregnant women presenting late in gestation. BJOG. 2013;120(12):1534-1547. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23924192.
  3. Huntington S, Thorne C, Anderson J, et al. Response to antiretroviral therapy (ART): comparing women with previous use of zidovudine monotherapy (ZDVm) in pregnancy with ART naive women. BMC Infect Dis. 2014;14:127. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24593018.
  4. Geretti AM, Fox Z, Johnson JA, et al. Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. PLoS One. 2013;8(7):e69266. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23874928.
  5. Perez H, Vignoles M, Laufer N, et al. Low rate of emergence of nevirapine and lamivudine resistance after post-partum interruption of a triple-drug regimen. Antivir Ther. 2008;13(1):135-139. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18389908.
  6. Lehman DA, Chung MH, Mabuka JM, et al. Lower risk of resistance after short-course HAART compared with zidovudine/single-dose nevirapine used for prevention of HIV-1 mother-to-child transmission. J Acquir Immune Defic Syndr. 2009;51(5):522-529. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19502990.
  7. Rowley CF, Boutwell CL, Lee EJ, et al. Ultrasensitive detection of minor drug-resistant variants for HIV after nevirapine exposure using allele-specific PCR: clinical significance. AIDS Res Hum Retroviruses. 2010;26(3):293-300. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20334564.
  8. Paredes R, Cheng I, Kuritzkes DR, Tuomala RE, Women, Infants Transmission Study Group. Postpartum antiretroviral drug resistance in HIV-1-infected women receiving pregnancy-limited antiretroviral therapy. AIDS. 2010;24(1):45-53. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19915448.
  9. Olson SC, Ngo-Giang-Huong N, Beck I, et al. Resistance detected by pyrosequencing following zidovudine monotherapy for prevention of HIV-1 mother-to-child-transmission. AIDS. 2015;29(12):1467-1471. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26244386.
  10. Palombi L, Galluzzo CM, Andreotti M, et al. Drug resistance mutations 18 months after discontinuation of nevirapine-based ART for prevention of mother-to-child transmission of HIV in Malawi. J Antimicrob Chemother. 2015;70(10):2881-2884. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26111981.
  11. Samuel R, Julian MN, Paredes R, et al. HIV-1 drug resistance by ultra-deep sequencing following short course zidovudine, single-dose nevirapine, and single-dose tenofovir with emtricitabine for prevention of mother-to-child transmission. J Acquir Immune Defic Syndr. 2016;73(4):384-389. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27327263.
  12. Gingelmaier A, Eberle J, Kost BP, et al. Protease inhibitor-based antiretroviral prophylaxis during pregnancy and the development of drug resistance. Clin Infect Dis. 2010;50(6):890-894. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20166821.
  13. Briand N, Mandelbrot L, Blanche S, et al. Previous antiretroviral therapy for prevention of mother-to-child transmission of HIV does not hamper the initial response to PI-based multitherapy during subsequent pregnancy. J Acquir Immune Defic Syndr. 2011;57(2):126-135. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21436712.
  14. French CE, Thorne C, Tariq S, Cortina-Borja M, Tookey PA. Immunologic status and virologic outcomes in repeat pregnancies to HIV-positive women not on antiretroviral therapy at conception: a case for lifelong antiretroviral therapy? AIDS. 2014;28(9):1369-1372. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24685820.
  15. French CE, Tookey PA, Cortina-Borja M, de Ruiter A, Townsend CL, Thorne C. Influence of short-course antenatal antiretroviral therapy on viral load and mother-to-child transmission in subsequent pregnancies among HIV-infected women. Antivir Ther. 2013;18(2):183-192. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23475123.
  16. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection—recommendations for a public health approach; second edition. 2016. Available at: http://www.who.int/hiv/pub/arv/arv-2016/en/.
  17. Currier JS, Britto P, Hoffman RM, et al. Randomized trial of stopping or continuing ART among postpartum women with pre-ART CD4 ≥400 cells/mm3. PLoS One. 2017;12(5):e0176009. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28489856.
  18. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26197844.
  19. Townsend CL, Byrne L, Cortina-Borja M, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000–2011. AIDS. 2014;28(7):1049-1057. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24566097.
  20. Rahangdale L, Cates J, Potter J, et al. Integrase inhibitors in late pregnancy and rapid HIV viral load reduction. Am J Obstet Gynecol. 2016;214(3):385 e381-387. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26928154.

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