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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

Preconception Counseling and Care for HIV-Infected Women of Childbearing Age

Overview

(Last updated:March 28, 2014; last reviewed:March 28, 2014)

Panel's Recommendation

Panel’s Recommendations

  • Discuss childbearing intentions with all women of childbearing age on an ongoing basis throughout the course of their care (AIII).
  • Include information about effective and appropriate contraceptive methods to reduce the likelihood of unintended pregnancy (AI).
  • During preconception counseling, include information on safer sexual practices and elimination of alcohol, illicit drugs, and smoking, which are important for the health of all women as well as for fetal/infant health, should pregnancy occur (AII).
  • All HIV-infected women contemplating pregnancy should be on a maximally suppressive antiretroviral regimen (AII). 
  • When selecting or evaluating combination antiretroviral therapy (cART) for HIV-infected women of childbearing age, consider a regimen’s effectiveness, a woman’s hepatitis B virus disease status, teratogenic potential of the drugs in the cART regimen, should pregnancy occur, and possible adverse outcomes for the mother and fetus (AII).
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

The Centers for Disease Control and Prevention (CDC), the American College of Obstetricians and Gynecologists, and other national organizations recommend offering all women of childbearing age comprehensive family planning and the opportunity to receive preconception counseling and care as a component of routine primary medical care. The purpose of preconception care is to improve the health of each woman before conception by identifying risk factors for adverse maternal or fetal outcome, providing education and counseling targeted to patients’ individual needs, and treating or stabilizing medical conditions to optimize maternal and fetal outcomes.1 Preconception care is not something that occurs in a single clinical visit but, rather, a process of ongoing care and interventions integrated into primary care to address the needs of women during the different stages of reproductive life. Because more than half of all pregnancies in the United States are unintended2-6 it is important that comprehensive family planning and preconception care be integrated into routine health visits. Providers should initiate and document a nonjudgmental conversation with all women of reproductive age concerning their reproductive desires because women may be reluctant to bring this up themselves.7-9 HIV care providers who routinely care for women of reproductive age play an important role in promoting preconception health and informed reproductive decisions.

The fundamental principles of preconception counseling and care are outlined in the CDC Preconception Care Work Group’s Recommendations to Improve Preconception Health and Health Care. In addition to the general components of preconception counseling and care that are appropriate for all women of reproductive age, HIV-infected women have specific needs that should be addressed.10-12 Because many HIV-infected women are aware of their HIV status before becoming pregnant, issues that impact pregnancy can be addressed before conception during their routine medical care for HIV disease. In addition to the principles outlined by the CDC Preconception Care Work Group,13 the following components of preconception counseling and care are specifically recommended for HIV-infected women. Health care providers should:

  • Discuss reproductive options; actively assess women’s pregnancy intentions on an ongoing basis throughout the course of care; and, when appropriate, make referrals to experts in HIV and women’s health, including experts in reproductive endocrinology and infertility when necessary.14,15
  • Counsel on safe sexual practices that prevent HIV transmission to sexual partners, protect women from acquiring sexually transmitted diseases, and reduce the potential to acquire more virulent or resistant strains of HIV.
  • Counsel on eliminating alcohol, illicit drug use, and cigarette smoking.
  • Counsel women contemplating pregnancy to take a daily multivitamin that contains 400 ug of folic acid to help prevent certain birth defects.
  • Educate and counsel women about risk factors for perinatal transmission of HIV, strategies to reduce those risks, potential effects of HIV or of antiretroviral (ARV) drugs given during pregnancy on pregnancy course and outcomes, and the recommendation that HIV-infected women in the United States not breastfeed because of the risk of transmission of HIV to their infant and the availability of safe and sustainable infant feeding alternatives.
  • When prescribing combination antiretroviral therapy (cART) to women of childbearing age, consider the regimen’s effectiveness, an individual’s hepatitis B disease status, the drugs’ potential for teratogenicity, should pregnancy occur, and possible adverse outcomes for mother and fetus.16-18
  • Use the preconception period in women who are contemplating pregnancy to adjust cART to exclude efavirenz or other drugs with teratogenic potential.
  • Make a primary treatment goal for women who are on cART and who are planning a pregnancy to attain a stable, maximally suppressed maternal viral load prior to conception to decrease the risk of perinatal transmission and of HIV transmission to an uninfected partner.
  • Evaluate and appropriately manage therapy-associated side effects such as hyperglycemia, anemia, and hepatotoxicity that may adversely impact maternal-fetal health outcomes.
  • Evaluate the need for appropriate prophylaxis or treatment for opportunistic infections, including safety, tolerability, and potential toxicity of specific agents when used in pregnancy.
  • Administer medical immunizations for influenza, pneumococcal or hepatitis A and B vaccines, and other vaccines as indicated (see http://www.cdc.gov/vaccines/acip/committee/guidance/rec-vac-preg.html). 
  • Encourage sexual partners to receive counseling and HIV testing and, if infected, to seek appropriate HIV care.
  • Offer all women who do not desire pregnancy effective and appropriate contraceptive methods to reduce the likelihood of unintended pregnancy. HIV-infected women can use all available contraceptive methods, including hormonal contraception (e.g., pill, patch, ring, injection, implant) and intrauterine devices (IUDs).19 Providers should be aware of potential interactions between ARV drugs and hormonal contraceptives that could lower contraceptive efficacy (see Table 3 below).
  • Offer emergency contraception as appropriate, including emergency contraceptive pills and the copper IUD. Concerns about drug interactions between ARVs and emergency contraceptive pills containing estrogen and a progestin, or containing levonorgestrel only, may be similar to concerns when those formulations are used for regular contraception.20 There are no data on potential interactions between ARVs and ulipristal acetate, a progesterone receptor modulator; however, ulipristal acetate is predominantly metabolized by CYP3A4, so interactions can be expected.

Data on drug interactions between ARV agents and hormonal contraceptives primarily come from drug labels and limited studies,21-28 and the clinical implications have not been well studied. The magnitude of changes in contraceptive drug levels that may reduce contraceptive efficacy or increase contraceptive-associated adverse effects is unknown. No studies have addressed differences in pregnancy rates in women using hormonal contraception and ARVs compared to those not using ARVs. Hormonal contraceptives can be used with cART in women without other contraindications. Additional or alternative methods of contraception may be recommended when drug interactions are known. For women using ritonavir-boosted protease inhibitors who are on combination hormonal contraceptives (e.g., pills, patches, rings) or progestin-only pills, use of an alternative or additional method of contraception is recommended. Implants generally can be used, but providers may also consider use of an alternative method or recommend the additional use of a reliable barrier method. Depot medroxyprogesterone acetate (DMPA) can be used without restriction because of its relative higher dose and limited studies that have shown no significant interaction between DMPA and ARVs.22,24 
 
Because no high-quality, definitive, evidence-based studies exist on pregnancy rates among women on different hormonal contraceptives and ARVs, the dosing recommendations in Table 3 are based on consensus expert opinion. Whenever possible, we based our recommendations on available data regarding pharmacokinetic (PK) interactions between ARVs and combined hormonal methods, DMPA and etonogestrel implants. The lowest decrease in PK for which we recommended use of an alternative method was 14% decrease in norethindrone (with ritonavir-boosted darunavir) and 19% decrease in ethinyl estradiol (ritonavir-boosted atazanavir). For women using atazanavir without ritonavir boosting (ethinyl estradiol increase 48%, norethindrone increase 110%), we recommend use of oral contraceptives containing ≤30 ug ethinyl estradiol. The panel did not recommend any ethinyl estradiol dose change for etravirine (ethinyl estradiol increase 22%), rilpivirine (ethinyl estradiol increase 14%), or indinavir (ethinyl estradiol increase 25%, norethindrone increase 26%).

Click here to view this table as an image

All recommendations in the following table are based on consensus expert opinion.

Table 3. Drug Interactions Between Antiretroviral Agents and Hormonal Contraceptives (CIII).
ARV Drug
Effect on Contraceptive Drug Levels Dosing Recommendation/
Clinical Comment for Combined Hormonal Methods and Progestin-Only Pills
Dosing Recommendation/
Clinical Comment for DMPAa
Dosing Recommendation/
Clinical Comment for Etonogestrel Implants 
NNRTIs
EFV Oral Ethinyl Estradiol/Norgestimate:
  • No effect on ethinyl estradiol concentrations
  • ↓ active metabolites of norgestimate (levonorgestrel AUC ↓ 83%; norelgestromin AUC ↓ 64%)
Implant:
  • ↓ etonogestrel
Levonorgestrel (Emergency contraception) AUC ↓ 58%
Use alternative or additional contraceptive method.
No additional contraceptive protection is needed.
Use alternative or additional contraceptive method.
ETR Ethinyl estradiol AUC ↑ 22%

Norethindrone
  • No significant effect
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
NVP Ethinyl estradiol AUC ↓ 20%

Norethindrone AUC ↓ 19%

DMPA
  • No significant change
Can consider an alternative method or a reliable method of barrier contraception in addition to this method.
No additional contraceptive protection is needed.  Can consider an alternative method or a reliable method of barrier contraception in addition to this method. 
RPV Ethinyl estradiol AUC ↑ 14%

Norethindrone
  • No significant change
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
RTV-Boosted PIs
ATV/r ↓ Ethinyl estradiol AUC ↓ 19%

↑ Norgestimate ↑ 85%
Use alternative or additional contraceptive method.
No additional contraceptive protection is needed.
Can consider an alternative method or a reliable method of barrier contraception in addition to this method. 
DRV/r Ethinyl estradiol AUC ↓ 44%

Norethindrone AUC ↓ 14%
Use alternative or additional contraceptive method.
No additional contraceptive protection is needed.
Can consider an alternative method or a reliable method of barrier contraception in addition to this method. 
FPV/r Ethinyl estradiol AUC ↓ 37%

Norethindrone AUC ↓ 34%
Use alternative or additional contraceptive method.
No additional contraceptive protection is needed.
Can consider an alternative method or a reliable method of barrier contraception in addition to this method. 
LPV/r Ethinyl estradiol AUC ↓ 42%

Norethindrone AUC ↓ 17%
Use alternative or additional contraceptive method.
No additional contraceptive protection is needed.
Can consider an alternative method or a reliable method of barrier contraception in addition to this method. 
SQV/r ↓ Ethinyl estradiol
Use alternative or additional contraceptive method.
No additional contraceptive protection is needed.
Can consider an alternative method or a reliable method of barrier contraception in addition to this method. 
TPV/r Ethinyl estradiol AUC ↓ 48%

Norethindrone:
  • No significant change
Use alternative or additional contraceptive method.
No additional contraceptive protection is needed.
Can consider an alternative method or a reliable method of barrier contraception in addition to this method. 
PIs without RTV
ATV Ethinyl estradiol AUC ↑ 48%

Norethindrone AUC ↑ 110%
No additional contraceptive protection is needed.

Oral contraceptive should contain ≤30 ug of ethinyl estradiol or use alternative method. 

Oral contraceptives containing <25 ug ethinyl estradiol or progestins other than norethindrone or norgestimate have not been studied.
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
FPV Amprenavir
  • ↑ Ethinyl estradiol
  • ↑ Norethindrone
Fosamprenavir with Ethinyl Estradiol/Norethindrone
  • ↓ Amprenavir (AUC 22%, Cmin 20%)
Use alternative contraceptive method.

Use of fosamprenavir alone with ethinyl estradiol/norethindrone may lead to loss of virologic response.
No additional contraceptive protection is needed.
Use alternative or additional contraceptive method.
IDV Ethinyl estradiol AUC ↑ 25%

Norethindrone AUC ↑ 26%
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
NFV Ethinyl estradiol AUC ↓ 47%

Norethindrone AUC ↓ 18%
Use alternative or additional contraceptive method.
No additional contraceptive protection is needed.
Use alternative or additional contraceptive method.
CCR5 Antagonist
MVC No significant effect on ethinyl estradiol or levonorgestrel
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
Integrase Inhibitor
RAL
No significant effect
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
DTG No significant effect on norgestimate or ethinyl estradiol
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
EVG/COBI Norgestimate AUC ↑ 2.26

Ethinyl estradiol AUC ↓ 0.75 
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
No additional contraceptive protection is needed.
a Because the hormonal levels achieved with DMPA are substantially higher than are required for contraception, any small reduction in hormonal level due to ARVs is unlikely to reduce contraceptive effectiveness.

Key to Acronyms: ARV = antiretroviral; ATV = atazanavir; ATV/r = ritonavir-boosted atazanavir; AUC = area under the curve; Cmin = minimum plasma concentration; COBI = cobicistat; DMPA = depot medroxyprogesterone acetate; DRV/r = ritonavir-boosted darunavir; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; FPV = fosamprenavir; FPV/r = ritonavir-boosted fosamprenavir; IDV = indinavir; LPV/r = ritonavir-boosted lopinavir; MVC = maraviroc; NFV = nelfinavir; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SQV/r = ritonavir-boosted saquinavir; TPV/r = ritonavir-boosted tipranavir

Derived from: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Tables 15a, 15b, and 15d. Last accessed March 17, 2014. 

References 

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