HIV infection impacts on sexual practices, reproductive health and contraceptive choice1. For a woman who knows that she is HIV infected and wishes to avoid pregnancy, access to effective contraception is essential. The choice of contraception in HIV-positive women is constrained by the need to prevent sexual transmission as well as unwanted pregnancies. The male condom, used consistently and correctly, is effective in preventing HIV transmission within HIV-discordant couples2. However, it provides less protection against pregnancy. The rate of unwanted pregnancies is 3% in perfect users, whereas it is 0.1% in OC users3. Furthermore, the correct and consistent use of condoms is seldom achieved. OC remain the most popular method of contraception in many countries. OC have the advantage of high safety, efficacy and rapid reversibility, but do not prevent HIV transmission. The recent widespread use of HAART has dramatically improved the survival and quality of life of HIV-infected individuals4,5. In the present changing treatment environment, contraception counselling should be carried out with particular sensitivity, and with specific regard to drug–drug interaction (Table 1).
Interactions between EE and antiretroviral drug regimens non-nucleoside reverse transcriptase inhibitors and protease inhibitors are metabolized through the cytochrome P450 liver enzyme complex, as are EE, the major estrogen component in OC. EE is metabolized via CYP3-mediated 2-hydroxylation and undergoes conjugation with glucuronid acid and sulphate. Induction of the P450 system by antiretroviral drugs may modify EE levels in the blood. Several interactions with oral contraceptives have been documented in the literature6. A decrease in EE concentrations has been observed with the co-administration of phenytoin, rifampicine, phenobarbitone and carbamazepine7,8. The AUC of EE increased by 37% with efavirenz and 24% with indinavir. On the contrary, the AUC of EE decreased by 42% with lopinavir/ritonavir, by 32% with ritonavir, by 19% with nevirapine and by 47% with nelfinavir9. It has been suggested that the decrease in EE concentration results from an increase in EE clearance from enzymatic induction10. For Ouellet et al.10, enzyme induction rather than altered absoption are the probable causes of the interaction.
Decrease in Ethinyl Estradiol Concentration and Contraceptive Failure
The exact mode of action of OC has not been elucidated. Progestins inhibit the luteinizing hormone peak, whereas estrogens are responsible for endometrial stability. The additional contraceptive effect of estrogens remains to be established. OC use results in a gradual decline of gonadotrophins in the first week of medication, leading to the suppression of the development of non-dominant follicles and subsequent estradiol demise11.
Low-dose OC demonstrate contraceptive efficacy comparable to that of oral contraceptives with higher doses of EE. The decrease in the estrogen content of OC increases the risk of the development of dominant follicles during the pill-free period, and may be responsible for breakthrough bleeding11. A significant decrease in the mean AUC of EE and of norethindrone was observed in two recent studies aimed at evaluating the effects of rifabutin and rifampicin on the pharmacokinetics of EE and norethindrone12,13. Nevertheless, despite these changes, subjects did not ovulate (as determined by progesterone concentration). The incidence of spotting was higher in treated than in control cycles.
Interactions Between Norethindrone and Antiretroviral Drug Regimens
Norethindrone, which is a coumpound of progestin-only contraception and of OC, is reduced by 18% with nelfinavir, whereas it is increased by 26% with indinavir9. Levonorgestrel is used as an efficient emergency contraception, and is recommended in the case of failure of condom use. An apparent interaction between warfarin and levonorgestrel used for emergency contraception has been described14. Levonorgestrel concentration may decrease in the case of treatment with ritonavir. No data are available specifically about interactions between the emergency contraception regimen and other drugs.
Because of drug interactions between hormonal contraceptives and antiretroviral treatment, the CDC recommended the use of an alternative or additional method of birth control, such as barrier methods or condoms9. In the 2002 French guidelines for the treatment of HIV-positive individuals, it was suggested that the dose of EE in OC might be adapted according to the antiretroviral treatment15. Low-dose OC should not be prescribed in the case of treatment with nelfinavir, ritonavir, lopinavir or nevirapine because of the risk of breakthrough bleeding. On the contrary, low-dose OC should be preferred in the case of treatment with efavirenz or indinavir, because of a possible increase in the cardiovascular risk, already high in patients under HAART.
Knowledge about contraception and access to family planning should be emphasized in HIV-positive women. Healthcare providers treating women with HIV should consider the reasons for using contraceptives, including the woman's choice to prevent a pregnancy that could result in the perinatal transmission of HIV. Clinicians treating HIV-positive women who are at risk of drug interactions should review the need for the possible use of alternative methods of contraception or dose adjustment. Family planning counselors should be trained to counsel HIV-positive women in the present changing treatment environment. Studies should be performed to evaluate the efficacy of OC in treated HIV-positive women.
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