Table 3. Drug Interactions Between Antiretroviral Agents and Hormonal Contraceptives

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Note: All recommendations in this table are based on consensus expert opinion. More details can be found in CDC’s U.S. Medical Eligibility Criteria for Contraceptive Use, 2016.

ARV Drug Effect on Contraceptive Drug Levels and Contraceptive’s Effects on ART and HIV Clinical Studies Dosing Recommendation/ Clinical Comment for COC/P/R Dosing Recommendation/ Clinical Comment for POPs Dosing Recommendation/ Clinical Comment for DMPAa Dosing Recommendation/ Clinical Comment for Etonogestrel Implants Justification/ Evidence for Recommendation
NNRTIs
EFV COC:
  • No effect on EE concentrations
  • ↓ active metabolites of norgestimate; LNG AUC ↓ 83% and norelgestromin AUC ↓ 64%29
  • Etonogestrel (in COC) C24h ↓ 61%35
DMPA:
  • No effect on DMPA levels26,28 
Etonogestrel Implant:
  • ↓ 49% in Etonorgestrel concentration 45
  • Etonogestrel AUC ↓ 63% to 82%49,53
  • ↑ pregnancy incidence rate among women using LNG or ENG implants, more among ENG users.51
LNG Implant:
  • ↓ 61% LNG concentration 45
  • LNG AUC ↓ 47%40
  • LNG (emergency contraception) AUC ↓ 58%24 
  • ↑ pregnancy incidence rate among women using LNG or ENG implants, more among ENG users.51
Changes in ARV Levels and/or Effects on HIV
COC:
  • No effect on EFV concentrations29
  • EFV C12h ↓ 22%; was under therapeutic threshold in three of 16 subjects35
DMPA:
  • No effect on HIV disease progression26,54,55
  • No effect on EFV concentrations26
LNG Implant:
  • No effect on HIV disease progression40
Vaginally Administered Etonogestrel/EE:
  • Etonogestrel ↓ 79%
  • EE ↓ 59%56
COC:
  • No difference in pregnancy rates50
  • Pregnancy rate was 13% higher in women using COCs and EFV than in women using COCs alone48,57
  • Progesterone >3 ng/mL (a surrogate for ovulation) in three of 16 women58
  • No ovulations29
DMPA:
  • No increase in pregnancy rates26,48,50,55
  • Low progesterone26,28,55
Etonogestrel Implant:
  • Pregnancy rate higher with EFV compared with no ART, but still lower with implants than with other hormonal methods of contraception48
  • Presumptive ovulation in 5%53
LN Implant:
  • 12% pregnancy rate36
  • 15% pregnancy rate40
  • Pregnancy rate higher with EFV compared with no ART, but still lower with implants than with other hormonal methods of contraception48
  • No increase in pregnancy rate50
Consider an alternative method (or a reliable method of barrier contraception) in addition to this method. Consider an alternative method (or a reliable method of barrier contraception) in addition to this method. No additional contraceptive protection is needed. Consider an alternative method (or a reliable method of barrier contraception) in addition to this method. For COCs, some studies suggest higher pregnancy rate and ovulation rate and decreased progestin levels. EFV may decrease, but clinical significance unclear.

For DMPA, evidence does not show effects on pregnancy rate, ovulation, or DMPA levels. Also, no effect on HIV disease progression or EFV levels.

For implants, some studies suggest higher pregnancy rate and decreased hormone levels.

For vaginally administered etonogestrel/EE, PK evaluation showed that etonogestrel levels were 79% lower and EE levels were 59% lower in participants on EFV than in controls after 21 days.56
ETR EE AUC ↑ 22%59

No significant effect on NE59
COC:
  • No ovulations59
No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. For COCs, one study found no ovulations and no significant change in progestin levels.

No data on POPs.
NVP

EE AUC ↓ 29%;60 no change in EE AUC61

NE AUC ↓ 18%60

Etonogestrel (in COC) C24h ↓ 22%35

DMPA:

  • No significant change26
LNG Implant:
  • LNG AUC ↑ 35%40
  • ↑ pregnancy incidence rate among women using LNG or ENG implants, more among ENG users.51
Changes in ARV Levels and/or Effects on HIV
COC:
  • No significant effect on NVP levels58,60,62
DMPA:
  • No effect on HIV disease progression26,54,55,63
LN Implant:
  • No effect on HIV disease progression40,64
COC:
  • No increase in pregnancy rate48,50,57,65,66
  • No ovulations58,61,66
DMPA:
  • No increase in pregnancy rate48,50,55,65
  • No ovulations26
Etonogestrel Implant:
  • No increase in pregnancy rate48
LNG Implant:
  • No increase in pregnancy rate36,40,48,50,64
No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additiofnal contraceptive protection is needed. No additional contraceptive protection is needed For COCs, evidence does not show effects on pregnancy rate or ovulations. Evidence demonstrated small decrease in progestin levels. No effect on NVP levels.

For DMPA, evidence does not show effects on pregnancy rate, ovulation, or DMPA levels. No effect on HIV disease progression.

For implants, evidence does not show effects on pregnancy rate or HIV disease progression.
RPV EE AUC ↑ 14%34​​​​​​​

No significant change on NE34

Changes in ARV Levels and/or Effects on HIV
COC:

No change in RPV levels compared to historical controls34​​​​​​​

COC:
  • No change in progesterone34
No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. For COCs, evidence does not show effects on ovulation or progestin levels. No change in RPV levels.

No data on POPs.
DOR No clinically significant interaction with EE and LNG67​​​​​​​ N/A No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No clinical data.
RTV-Boosted PIs
ATV/r EE AUC ↓ 19%68​​​​​​​

Norgestimate AUC ↑ 85%68​​​​​​​

POP:
  • NE AUC ↑ 50%69​​​​​​​
Vaginally Administered Etonogestrel/EE:
  • Etonogestrel ↑ 71%
  • EE ↓ 38%56
N/A No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. For COCs, increase in progestin levels seen in only one study.

For POPs, increase in progestin levels seen in only one study.

RTV inhibits CYP3A4, which may increase contraceptive hormone levels.
DRV/r EE AUC ↓ 44%70 

NE AUC ↓ 14%70
N/A Can consider an alternative method (or a reliable method of barrier contraception) in addition to this method. 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. For COCs, small decrease in progestin levels.

No data on POPs.
LPV/r EE AUC ↓ 55%25

NE AUC ↓ 17%

Patch:
  • EE AUC ↓ 45%25
  • Norelgestromin AUC ↑ 83%25
DMPA:
  • DMPA AUC ↑ 46%38
Etonogestrel Implant:
  • Etonogestrel AUC ↑ 52%53​​​​​​​
Changes in ARV Levels and/or Effects on HIV
Patch:
  • LPV/r ↓ 19%25
DMPA:
  • No effect on HIV disease progression38​​​​​​​
  • No change in LPV/r levels38
COC:
  • Increased pregnancy rate, but CIs overlap48
Patch:
  • No ovulations25
DMPA:
  • No pregnancies and no ovulations38
  • Increased pregnancy rate, but CIs overlap48
Etonogestrel Implant:
  • No increase in pregnancy rate48
LNG Implant:
  • No increase in pregnancy rate36,48
No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. For COCs, nonsignificant increase in pregnancy rate. Small decrease in progestin level.

For patch, no ovulations and progestin levels increased.

For DMPA, evidence shows no effect on pregnancy rate or ovulations. Progestin levels increased.

For implants, evidence shows no effect on pregnancy rate. Progestin levels increased.
COBI-Boosted PIs
ATV/c

Drospirenone AUC ↑ 2.3-fold

No change in LNG concentration

25% decrease in EE C2442

N/A Contraindicated with drospirenone-containing hormonal contraceptives due to potential for hyperkalemia.

Consider alternative or additional contraceptive method.
No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No data on POPs.
DRV/c Drospirenone AUC ↑ 1.6-fold

EE AUC ↓ 30%43
N/A Clinical monitoring is recommended when DRV/c is used in combination with drospirenone-containing COCs as a result of the potential for hyperkalemia.

Consider alternative or additional contraceptive method.
No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No data on POPs.
PIs without RTV
ATV COC:
  • EE AUC ↑ 48%71
  • NE AUC ↑ 110%71
N/A Prescribe oral contraceptive that contains no more than 30 mcg of EE or recommend alternative contraceptive method. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. For COCs, increased concentrations of estrogen and progestin, but the only data available are from the product label.

No data on POPs.
CCR5 Antagonist
MVC COC:
  • No significant effect on EE or LN72
N/A No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. For COCs, no change in EE or progestin. No clinical data.

No data on POPs.
INSTIs
BIC/FTC/TAF No significant drug interactions with EE or norgestimate. N/A No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No clinical data.
DTG COC:
  • No significant effect on norgestimate or EE
  • No change in DTG AUC39
N/A No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. For COCs, no change in EE or progestin. No clinical data.

No data on POPs.
EVG/c COC:
  • Norgestimate AUC ↑ 126%
  • EE AUC ↓ 25%73,74​​​​​​​
N/A No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. When administered as the four-drug regimen EVG/c/FTC/TDF, increases in progestin and a small decrease in EE were observed. No clinical data.

No data on POPs.
RAL COC:
  • No change in EE
  • Norgestimate AUC ↑ 14% 75
N/A No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. No additional contraceptive protection is needed. For COCs, no change in EE and a small increase in progestin. No clinical data.

No data on POPs.
a Because the hormonal levels achieved with DMPA are substantially higher than the levels that are required for contraception, any small reduction in hormonal level attributed to ARV drugs is unlikely to reduce contraceptive effectiveness.

Key to Symbols:
↑ = increase
↓ = decrease

Key: APV = amprenavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; AUC = area under the curve; BIC = bictegravir; C12h = concentration at 12 hours post-dose; C24h = concentration at 24 hours post-dose; CD4 = CD4 T lymphocyte; CDC = Centers for Disease Control and Prevention; CHC = combination hormonal contraceptives; CI = confidence interval; Cmin = minimum plasma concentration; COBI = cobicistat; COC/P/R = combined oral contraceptives/patch/ring; CYP = cytochrome P450; DMPA = depot medroxyprogesterone acetate; DOR= doravirine; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EE = ethinyl estradiol; EFV = efavirenz; ENG = etonogestrel; ETR = etravirine; EVG/c = elvitegravir/cobicistat; FPV = fosamprenavir; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LNG = levonorgestrel; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NE = norethindrone; NFV = nelfinavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = nevirapine; P = progestin; PI = protease inhibitor; PI/r = protease inhibitor/ritonavir; PK = pharmacokinetic; POP = progesterone-only oral contraceptive pills; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SQV/r = saquinavir/ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TPV = tipranavir; TPV/r = tipranavir/ritonavir​​​​​​​

Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Tables 21a, 21b, and 21d.