Table 4.
Summary of pharmacokinetic studies between hormonal contraceptives and antiretroviral therapy. Hormone pharmacokinetic parameters are presented as a ratio measure or summary value. The p value represents a comparison between antiretroviral treatment groups compared to a control, if available.
| ART evaluated | Hormones evaluated | Study groups | Study design | Hormone AUC Ratio ART:Control | Hormone Cmax Ratio ART:Control | Hormone Cmin Ratio ART:Control | Clinical conclusions by study authors |
|---|---|---|---|---|---|---|---|
| Combined Oral Contraceptives (COC) | |||||||
| Atazanavir/ritonavir [56]a | Ethinyl estradiol | Atazanavir/ritonavir monotherapy, HIV-negative (n=18) | Prospective, randomized, crossover study; hormone PK evaluated mid-cycle of COC alone and in combination with atazanavir/ritonavir monotherapy. | 0.81 (0.75, 0.87) |
0.84 (0.74, 0.95) |
0.63 (0.55, 0.71) |
An oral contraceptive agent containing ≥30 mcg of ethinyl estradiol may minimize breakthrough bleeding due to the reduced ethinyl estradiol exposure when combined with atazanavir/ritonavir. Contraceptive effectiveness of COC is unlikely to decrease given the increase in progestin exposure. |
| Norgestimate | 1.85 (1.67, 2.05) |
1.68 (1.51, 1.88) |
2.02 (1.77, 2.31) |
||||
| Darunavir/ritonavir [54]b | Ethinyl estradiol | Darunavir/ritonavir monotherapy, HIV-negative (n=13) | Prospective, randomized, crossover study; hormone PK evaluated mid-cycle of COC alone and in combination with darunavir/ritonavir monotherapy. | 0.56 (0.50, 0.63) |
0.68 (0.61, 0.74) |
0.38 (0.27, 0.53) |
Darunavir/ritonavir significantly reduced ethinyl estradiol exposure, which the authors concluded were clinically relevant, while the progestin exposure was non-significantly decreased. |
| Norethindrone | 0.86 (0.75, 0.98) |
0.90 (0.83, 0.97) |
0.70 (0.51–0.97) |
||||
| Dolutegravir [42]b | Ethinyl estradiol | Dolutegravir monotherapy, HIV-negative (n=16) | Prospective, randomized, double-blind, placebo-controlled, cross-over study; hormone PK evaluated on days 10 and 21 of COC in combination with dolutegravir or placebo. | 1.03 (0.96, 1.11) |
0.99 (0.91, 1.08) |
1.02 (0.93, 1.11) |
Coadministration of dolutegravir and COC does not affect hormone PK. |
| Norgestimate | 0.98 (0.91, 1.04) |
0.89 (0.82, 0.97) |
0.93 (0.85, 1.03) |
||||
| Efavirenz [47]a | Ethinyl estradiol | Efavirenz monotherapy, HIV-negative (n=28) | Prospective, non-randomized, cross-over study; hormone PK evaluated mid-cycle of COC alone and in combination with efavirenz monotherapy; post-hoc analysis of efavirenz impact on levonorgestrel PK. | 0.90 (0.80, 1.01) |
1.06 (0.95, 1.19) |
0.92 (0.75, 1.14) |
Given the significant decrease in progestin exposure, a second form of barrier contraception is recommended when efavirenz is combined with COCs. |
| Norgestimate | 0.36 (0.33, 0.38) |
0.54 (0.48, 0.61) |
0.18 (0.15, 0.21) |
||||
| Levonorgestrel (active metabolite of norgestimate) | 0.17 (0.13, 0.21) |
0.20 (0.17, 0.23) |
0.14 (0.10, 0.20) |
||||
| Efavirenz and Nevirapine [45]c | Ethinyl estradiol | Efavirenz-based ART, HIV-positive (n=16) Nevirapine-based ART, HIV-positive (n=18) HIV-negative (n=14) |
Prospective, non-randomized, parallel group study; hormone PK evaluated on day 16 of the second cycle of COC. | … | … | EFV: 0.91 (0.74, 1.11) NVP: 0.42 (0.30, 0.57) |
Caution against the use of this COC in HIV-positive women on efavirenz-based ART due to possible contraceptive failure. Hormone PK changes in the nevirapine-based ART group did not affect the contraceptive efficacy of the COC. |
| Etonogestrel (active metabolite of desogestrel) | … | … | EFV: 0.39 (0.30, 0.51) NVP: 0.78 (0.53, 1.15) |
||||
| Elvitegravir/cobicistat [43]b | Ethinyl estradiol | Elvitegravir/cobicistat, HIV-negative, (n=13) | Prospective, non-randomized, cross-over study; hormone PK evaluated mid-cycle of COC alone and in combination with elvitegravir/cobicistat-based ART. | 0.75 (0.69, 0.81) |
0.94 (0.86, 1.04) |
0.56 (0.52, 0.61) |
Elvitegravir/cobicistat-based ART significantly reduced ethinyl estradiol exposure, while the progestin exposure was significantly increased. Contraceptive effectiveness of COC is unlikely to decrease given the increase in progestin exposure. |
| Norgestromin (active metabolite of norgestimate) | 2.26 (2.15, 2.37) |
2.08 (2.00, 2.17) |
2.67 (2.43, 2.92) |
||||
| Etravirine [50]b | Ethinyl estradiol | Etravirine monotherapy, HIV-negative (n=30) | Prospective, non-randomized, cross-over study; hormone PK evaluated on day 15 of COC alone (second cycle) and in combination with etravirine monotherapy (third cycle). | 1.22 (1.13, 1.31) |
1.33 (1.21, 1.46) |
1.09 (1.01, 1.18) |
No loss in contraceptive efficacy is expected when COC is coadministered with etravirine. |
| Norethindrone | 0.95 (0.90, 0.99) |
1.05 (0.98, 1.12) |
0.78 (0.68, 0.90) |
||||
| Lopinavir/ritonavir [55]c | Ethinyl estradiol | Lopinavir/ritonavir-based ART, HIV-positive (n=16) Historical control, HIV-negative (n=14) |
Prospective, non-randomized, intervention group compared to historical control patients; hormone PK evaluated on day16 of the second cycle of COC. | … | … | 0.68 (0.42, 1.08) |
High variability in hormone Cmin values were observed, but no clinically significant effect was observed based on measures of ovulation. |
| Etonogestrel (active metabolite of desogestrel) | … | … | 1.08 (0.73, 1.60) |
||||
| Lopinavir/ritonavir [53]d | Ethinyl estradiol (given as COC with norethindrone) | Lopinavir/ritonavir-based ART, HIV-positive (n=8) HIV-positive controls (n=24) |
Prospective, non-randomized, parallel group study; ethinyl estradiol PK evaluated after a single dose. Norethindrone PK not evaluated. | LPV/r: 344.67 (310.43, 476.52) pg•h/mL No ART: 765.38 (680.48, 890.69) pg•h/mL** |
… | LPV/r: 1.00 (1.00, 2.13) pg/mL No ART: 4.15 (3.11, 5.81) pg/mL* |
Lopinavir/ritonavir significantly decreased ethinyl estradiol exposure. |
| Nevirapine [44]d | Ethinyl estradiol | Nevirapine-based ART, HIV-positive (n=3) No ART, HIV-positive control (n=3) HIV-negative control (n=3) |
Prospective, non-randomized, parallel group study; hormone PK evaluated on day 14 of the second cycle of COC. | NVP: 1384 (1130, 1425) pg•h/mL No ART: 1457 (1371, 1610) pg•h/mL Control: 1144 (1111, 1583) pg•h/mL |
… | NVP: 57.3 (40.8, 60.7) pg/mL No ART: 82.2 (67.1, 98.2) pg/mL Control: 47.0 (39.3, 81.7) pg/mL |
Hormone concentrations were higher in women with HIV compared to uninfected women, irrespective of combined use with ART. |
| Levonorgestrel (active metabolite of norgestrel) | NVP: 147 (112, 177) ng•h/mL No ART: 114 (105, 139) ng•h/mL Control: 37.9 (36.9, 107) ng•h/mL |
… | NVP: 6.11 (3.50, 7.02) ng/mL No ART: 4.72 (4.03, 7.36) ng/mL Control: 1.41 (1.04, 4.03) ng/mL |
||||
| Raltegravir [41]a | Ethinyl estradiol | Raltegravir monotherapy, HIV-negative (n=19) | Prospective, randomized, placebo-controlled, cross-over study; hormone PK evaluated day 21 of COC and placebo and COC in combination with raltegravir monotherapy. | 0.99 (0.94, 1.04) |
1.06 (0.98, 1.14) |
… | Coadministration of raltegravir with COC does not have a clinically meaningful effect on hormone PK. |
| Norelgestromin (active metabolite of norgestimate) | 1.16 (1.09, 1.22) |
1.29 (1.23, 1.37) |
… | ||||
| Rilpivirine [51]b | Ethinyl estradiol | Rilpivirine monotherapy, HIV-negative (n=18) | Prospective, non-randomized, sequential design study; hormone PK evaluated day 15 of COC alone (second cycle) and in combination with rilpivirine monotherapy (third cycle). | 1.14 (1.10, 1.19) |
1.17 (1.06, 1.30) |
1.09 (1.03, 1.16) |
Coadministration of rilpivirine with COC does not affect hormone PK. |
| Norethindrone | 0.89 (0.84, 0.94) |
0.94 (0.83, 1.06) |
0.99 (0.90, 1.08) |
||||
| Ritonavir [52]c | Ethinyl estradiol (given as COC with ethynodiol diacetate) | Ritonavir monotherapy, HIV-negative (n=23) | Prospective, non-randomized, sequential design study; ethinyl estradiol PK evaluated after a single dose alone (day 1) and in combination with ritonavir monotherapy (day 29). | 0.60 (0.51, 0.70) |
0.68 (0.61, 0.76) |
… | High dose, steady-state ritonavir (500mg twice daily) significantly decreased ethinyl estradiol exposure. |
| Tenofovir [39]a | Ethinyl estradiol | Tenofovir monotherapy, HIV-negative (n=20) | Prospective, non-randomized, sequential design study; hormone PK evaluated on day 21 of COC alone (second cycle) and in combination with tenofovir monotherapy (third cycle) | 0.96 (0.91, 1.01) |
0.94 (0.88, 1.00) |
0.98 (0.91, 1.06) |
Coadministration of tenofovir with COC does not influence hormone exposure. |
| Norelgestromin (active metabolite of norgestimate) | 0.95 (0.91, 0.99) |
0.94 (0.87, 1.01) |
0.96 (0.92, 1.01) |
||||
| Progestin Only Oral Contraceptive Pill (POP) | |||||||
| Atazanavir/ritonavir [58]e | Norethindrone | Atazanavir/riton avir-based ART, HIV-positive (n=10) Non-interacting ART, HIV-positive controls (n=17) |
Prospective, non-randomized, parallel group study; hormone PK evaluated on day 22 of POP with either atazanavir/ritonavir-based or a non-interacting ART regimen. | ATV/r: 25.20 (17.94, 32.73) ng•h/mL Control: 16.69 (13.28, 20.55) ng•h/mL* |
ATV/r: 3.19 (2.19, 4.79) ng/mL Control: 2.09 (1.49, 3.06) ng/mL* |
ATV/r: 0.45 (0.32, 0.59) ng/mL Control: 0.27 (0.19, 0.37) ng/mL |
Progestin-only contraceptives benefit from protease inhibitor-based drug-drug interactions by achieving higher levels of progestin exposure. |
| Efavirenz [48]a | Levonorgestrel emergency contraception | Efavirenz monotherapy, HIV-negative (n=21) | Prospective, non-randomized, cross-over study; hormone PK evaluated after a single dose of emergency contraception alone and in combination with steady-state efavirenz monotherapy. | 0.42 (0.36, 0.48) |
0.55 (0.49, 0.63) |
0.31 (0.26, 0.36) |
Efavirenz significantly reduced exposure to levonorgestrel for emergency contraception. |
| Protease inhibitor-based ART (various) [57]c | Norethindrone | Protease inhibitor-based therapy (total n=16:
No or non-interacting ART, HIV-positive controls (n=17) |
Prospective, non-randomized, parallel group study; hormone PK evaluated on day 22 of POP in combination with protease inhibitor-based ART or with a non-interacting or no ART | 1.50 (1.21, 1.86) |
1.33 (0.93, 1.88) |
1.26 (1.05, 1.51) |
Progestin concentrations were higher in women receiving protease-inhibitor-based ART; this increase is not expected to result in clinically significant adverse events. |
| Transdermal combined contraceptives | |||||||
| Lopinavir/ritonavir [53]d | Ethinyl estradiol | Lopinavir/ritonavir-based ART (n=8) No or non-interacting ART, HIV-positive controls (n=24) |
Prospective, non-randomized, parallel group study; hormone PK evaluated during the third weekly patch cycle. | LPV/r: 6010.36 (5140.83, 7388.01) pg•h/mL No ART: 10911.42 (7548.36, 15667.44) pg•h/mL |
… | LPV/r: 32.10 (28.60, 39.15) pg/mL No ART: 44.40 (4.59, 67.60) pg/mL |
Lopinavir/ritonavir non-significantly decreased ethinyl estradiol exposure, while significantly increasing progestin exposure. The contraceptive efficacy of the patch is likely to be maintained. |
| Norelgestromin | LPV/r: 138.39 (106.44, 234.75) ng•h/mL No ART: 75.63 (59.20, 121.13) ng•h/mL* |
… | LPV/r: 0.63 (0.51, 0.89) ng/mL No ART: 0.27 (0.22, 0.43) ng/mL |
||||
| Injectable contraceptives | |||||||
| Efavirenz [61]a | Depot medroxyprogesterone | Efavirenz-based ART (n=15) No ART, HIV-positive controls (n=15) |
Prospective, non-randomized, parallel group study; hormone PK evaluated every 2 weeks over 12 weeks post-injection. | 1.01 (0.85, 1.20) |
1.01 (0.84, 1.22) |
0.90 (0.77, 1.06) |
Efavirenz-based ART did not influence hormone PK, suggesting contraceptive effectiveness will be maintained. |
| Efavirenz, Nelfinavir, and Nevirapine [59]a | Depot medroxyprogesterone | Efavirenz-based ART (n=17) Nelfinavir-based ART (n=21) Nevirapine-based ART (n=16) No or non-interacting ART, HIV-positive controls (n=16) |
Prospective, non-randomized, parallel group study; progesterone levels were evaluated every 2 weeks over 12 weeks post-injection. | … | … | … | Raw hormone PK parameters were not reported, but authors report no statistically significant differences between groups; all progesterone levels remained below the level indicative of ovulation. |
| Lopinavir/ritonavir [60]d | Depot medroxy-progesterone | Lopinavir/ritonavir-based ART (n=24) No or non-interacting ART, HIV-positive controls (n=14) |
Prospective, non-randomized, single-arm study compared to historical controls; hormone PK evaluated every 2 weeks over 12 weeks post-injection | LPV/r: 18.08 (16.22, 24.10) ng•wk/mL No ART: 12.38 (8.88, 13.88) ng•wk/mL** |
LPV/r: 2.88 (2.28, 4.04) ng/mL No ART: 1.74 (1.02, 2.09) ng/mL** |
LPV/r: 0.47 (0.35, 0.74) ng/mL No ART: 0.43 (0.29, 0.60) ng/mL |
Although hormone exposure increased during LPV/r-based ART, the authors concluded this is not likely clinically significant. |
| Implantable Progestin-only Contraceptives | |||||||
| Efavirenz and Lopinavir/ritonavir [62]a | Etonogestrel | Efavirenz-based ART, HIV-positive (n=14) Lopinavir/ritonavir-based ART, HIV-positive (n=15) HIV-positive controls (n=15) |
Prospective, non-randomized, parallel group study; hormone PK evaluated over 24 weeks of combined use. | EFV: 0.34 (0.28, 0.42) LPV/r: 1.5 (1.2, 1.8) |
EFV: 0.38 (0.30, 0.50) LPV/r: 1.6 (1.2, 2.1) |
EFV: 0.30 (0.25, 0.36) LPV/r: 1.3 (1.1, 1.6) |
Efavirenz significantly decreased the etonogestrel exposure, while lopinavir/ritonavir significantly increased exposure. Efavirenz may reduce the effectiveness of etonogestrel implants. |
| Efavirenz and Nevirapine [63]a | Levonorgestrel | Efavirenz-based ART (n=20) Nevirapine based ART (n=20) HIV-positive controls (n=17) |
Prospective, non-randomized, parallel group study; hormone PK evaluated over 48 weeks of combined use. | EFV: 0.53 (0.52, 0.54) NVP: 1.30 (1.25, 1.37) |
EFV: 0.43 (0.41, 0.47) NVP: 1.28 (1.19, 1.43) |
EFV: 0.43 (0.42, 0.44) NVP: 1.14 (1.14, 1.16) |
Efavirenz significantly decreased levonorgestrel, paired with observed, unintended pregnancies during the study (3 of 20; 15%). In contrast, nevirapine did not significantly impact levonorgestrel exposure. |
| Tenofovir/Emtricitabine [38] | Levonorgestrel | Tenofovir/emtricitabine (n=17) Placebo (n=12) |
Prospective, randomized, placebo-controlled study of TDF/FTC for PrEP; hormone PK evaluated over 36 weeks of combined use. | … | … | … | Average exposure was not different between groups, measured via linear mixed modeling. (TDF/FTC group estimate= − 67.3 pg/mL, 95% CI: − 194.7, 60.0) |
Abbreviations: ART, antiretroviral therapy; ATV/r, atazanavir/ritonavir; AUC, area under the concentration time curve; Cmax, maximum concentration; Cmin, minimum concentration; COC, combined oral contraceptive; EE, ethinyl estradiol; EFV, efavirenz; ENG, etonogestrel; HIV, human immunodeficiency virus; LNG, levonorgestrel; LPV/r, lopinavir/ritonavir; PK, pharmacokinetic; POP, progestin-only oral contraceptive; PrEP, pre-exposure prophylaxis
*
p<0.05
**
p<0.01
a
Data presented as Geometric Mean Ratio (90% Confidence Interval)
b
Data presented as Least Squares Mean Ratio (90% Confidence Interval)
c
Data presented as Geometric Mean Ratio (95% Confidence Interval)
d
Data presented as Median (Interquartile Range)
e
Data presented as Geometric Mean (Interquartile Range)