Antiretroviral Medications and Hormonal Contraceptive Agents

Background

Few pharmacokinetic or clinical studies have examined interactions between antiretroviral (ARV) medications and hormonal contraceptives, but it is known that certain protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), as well as the boosted integrase inhibitor combination elvitegravir/cobicistat, do interact with hormonal contraceptives. These interactions may increase the risk of medication failure or medication adverse effects of either the ARV or the contraceptive. There are no known interactions between hormonal contraceptives and nucleoside analogues or the CCR5 antagonist.

Oral Contraceptives

All oral contraceptives currently marketed in the United States, with the exception of progestin-only pills (which contain norethindrone), contain both ethinyl estradiol and a progestin (desogestrel, drospirenone, ethynodiol diacetate, levonorgestrel, norethindrone, norethindrone acetate, norgestimate, or norgestrel). The oral contraceptives ethinyl estradiol and norethindrone may interact in complex ways with PIs and NNRTIs. The mechanism of these interactions may be multifactorial and includes the activity of these agents on cytochrome P450 enzymes. Pharmacokinetic studies have shown changes (either increases or decreases) in levels of ethinyl estradiol and norethindrone in women who are taking certain PIs, NNRTIs, or elvitegravir/cobicistat. Other studies have shown decreases in levels of amprenavir (the active agent of fosamprenavir) in women taking oral contraceptives.

The clinical significance of these drug interactions has not been evaluated thoroughly, but may cause oral contraceptive failure, ARV failure, or medication toxicity, depending on whether drug levels are lowered or raised by the interacting drug. The consequences of decreased hormone levels may include an increased risk of pregnancy, so an alternative or additional method of contraception is commonly recommended. The consequences of decreased ARV levels may include virologic failure and development of resistance mutations. The consequences of a higher level of hormones may include risk of thromboembolism, breast tenderness, headache, nausea, and acne.

The available pharmacokinetic data are summarized in Table 1. For further discussion of oral and non-oral contraceptives for HIV-infected women, see chapter Health Care of HIV-Infected Women Through the Life Cycle.

Table 1. Interactions Between Antiretroviral Agents and Oral Contraceptives
Antiretroviral AgentPharmacokinetic Changes with Oral ContraceptivesComments

Key to symbols:
✖ Use alternative/additional method or do not administer together
! Use with caution
✓ Safe to use in combination or no dosage adjustment necessary

Abbreviations: AUC = area under the time-concentration curve (drug exposure); C max = maximum concentration; C min = minimum concentration; EE = ethinyl estradiol; LN = levonorgestrel; NE = norethindrone; NG = norgestimate; OC = oral contraceptive; RTV = ritonavir; /r = low-dose ritonavir

Adapted 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.

Protease Inhibitors
Atazanavir (ATV, Reyataz) (unboosted)
  • EE AUC ↑ 48%
  • NE AUC ↑ 110%
!
  • OC should contain ≤30 mcg EE. Monitor for side effects, or use alternative method.
ATV/r
  • EE AUC ↓ 19%
  • 17-deacetyl norgestimate (active metabolite of NG) AUC ↑ 85%
!
  • OC should contain ≥35 mcg EE.
  • OCs containing progestins other than norethindrone or norgestimate have not been studied.
Darunavir (DRV, Prezista) DRV/r
  • EE AUC ↓ 44%
  • NE AUC ↓ 14%
  • Use alternative or additional method of contraception.
Fosamprenavir (FPV, Lexiva)
  • EE Cmin↑ 32%
  • NE Cmin↑ 45%; AUC ↑ 18%
  • Amprenavir AUC ↓ 22%
  • Amprenavir Cmin↓ 20%
  • Data are derived from studies with amprenavir (the active metabolite of FPV).
  • Risk of ARV failure and of EE or NE adverse effects: do not coadminister fosamprenavir with OCs.
  • Use alternative method of contraception.
FPV/r
  • EE AUC ↓ 37%
  • NE AUC ↓ 34%
  • Risk of contraceptive failure and of ritonavir adverse effects.
  • Use alternative method of contraception.
Indinavir (IDV, Crixivan)
  • EE AUC ↑ 24%
  • NE AUC ↑ 26%
  • No dosage adjustment is recommended.
  • Monitor for EE or NE adverse effects.
IDV/r
  • No data
  • Risk of contraceptive failure; use alternative or additional method of contraception.
Lopinavir/r (LPV/r, Kaletra)
  • EE AUC ↓ 42%
  • NE AUC ↓ 17%
  • Risk of contraceptive failure; use alternative or additional method of contraception.
Nelfinavir (NFV, Viracept)
  • EE AUC ↓ 47%
  • NE AUC ↓ 18%
  • Risk of contraceptive failure; use alternative or additional method of contraception.
Ritonavir (RTV, Norvir)
  • EE AUC ↓ 40%
  • Risk of contraceptive failure; use alternative method of contraception.
Saquinavir (SQV, Invirase)/r
  • No data; theoretic EE ↓
  • SQV kinetics not affected by OC
  • Risk of contraceptive failure; use alternative or additional method of contraception.
Tipranavir (TPV, Aptivus)/r
  • EE AUC ↓ 48%
  • NE no significant change
  • Risk of contraceptive failure; use alternative or additional method of contraception.
Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz (EFV, Sustiva)
  • EE AUC no significant change
  • 17-deacetyl norgestimate (active metabolite of NG)AUC ↓ 64%
  • LN AUC ↓ 58-83%
  • NE: AUC ↓ predicted
  • Decrease in progestin levels: risk of contraceptive failure [including failure of emergency contraception (Plan B)]; use alternative or additional method of contraception.
Etravirine (ETR, Intelence)
  • EE AUC ↑ 22%
  • NE AUC ↓ 5%
  • No dosage adjustment is necessary.
Nevirapine (NVP, Viramune)
  • EE AUC ↓ 20%
  • NE AUC ↓ 19%
  • Risk of contraceptive failure; use alternative or additional method of contraception.
Rilpivirine (RPV, Edurant)
  • EE AUC ↑ 14%
  • NE no significant change
  • No dosage adjustment is necessary.
CCR5 Antagonist
Maraviroc (MVC, Selzentry)
  • No significant effect on EE or LN
  • No dosage adjustment is necessary.
Integrase Inhibitor
Dolutegravir (DTG, Tivicay)
  • No significant change in EE AUC or NG AUC
  • No dosage adjustment is necessary
Elvitegravir

(EVG, Stribild)

  • NE AUC ↓ 25%, Cmin↓ 44%
  • NG AUC, Cmax, Cmin ↑ >2-fold
!
  • Risk of NG adverse effects (not fully known; may include venous thrombosis); consider alternative method of contraception.
Raltegravir (RAL, Isentress)
  • No significant change in EE AUC or NG AUC
  • No dosage adjustment is necessary.

Non-Oral Hormonal Contraceptives

Hormonal contraceptives using delivery methods other than oral include the following:

  • Products containing both progestin and estrogen components: transdermal patch, vaginal ring
  • Products containing a progestin alone (medroxyprogesterone acetate, levonorgestrel, norelgestromin, or etonogestrel): subcutaneous or IM injection, intrauterine system, implantable device

There has been little research on the interactions between ARVs and most of these agents. Theoretically, interactions with ARVs would be less likely with contraceptive methods that have primarily local action and minimal systemic absorption, and for injection or transdermal delivery systems, since first-pass metabolism is avoided. However, caution is still warranted, as this assumption has not been proven.

Because the transdermal patch and vaginal ring contain ethinyl estradiol, women who take ARVs that increase or decrease serum estradiol levels (see Table 1) are advised to use an alternative (or additional) contraceptive method. Small studies of depo-medroxyprogesterone acetate (DMPA, or Depo-Provera) have shown no significant interactions between DMPA and nelfinavir, efavirenz, or nevirapine. Interactions between DMPA and other ARVs have not been studied, but DMPA's interactions with PIs and NNRTIs would be expected to be similar to those of norethindrone (see Table 1). For other non-oral hormones, pending further study, an alternative (or additional) method of contraception should be considered.

References

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly