Accepted Manuscript Contraceptive options for women living with HIV Sharon Phillips, M.D., M.P.H. Petrus Steyn, M.D., MMed (O&G), FCOG (SA), MPhil. Marleen Temmerman, M.D., PhD.
PII:
S1521-6934(14)00085-6
DOI:
10.1016/j.bpobgyn.2014.04.013
Reference:
YBEOG 1352
To appear in:
Best Practice & Research Clinical Obstetrics & Gynaecology
Received Date: 21 March 2014 Revised Date:
11 April 2014
Accepted Date: 22 April 2014
Please cite this article as: Phillips S, Steyn P, Temmerman M, Contraceptive options for women living with HIV, Best Practice & Research Clinical Obstetrics & Gynaecology (2014), doi: 10.1016/ j.bpobgyn.2014.04.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Contraceptive options for women living with HIV
Sharon Phillips, M.D., M.P.H. Medical Officer, Reproductive Health and Research
(includes the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme – HRP), Avenue Appia 20- 1211 Geneva –Switzerland, [email protected], Tel: +41 22 791 33
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80 Fax: +41 22 791
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Petrus Steyn, M.D., MMed (O&G), FCOG (SA), MPhil. Scientist, Reproductive Health and Research (includes the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme – HRP), Avenue Appia 20- 1211 Geneva –Switzerland, [email protected], Tel: +41 22 791 33 80 Fax: +41 22 791 2971
Marleen Temmerman, M.D., PhD. Director, Reproductive Health and Research
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(includes the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme – HRP), Avenue Appia 20- 1211 Geneva –Switzerland, [email protected], Tel: +41 22 791
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33 80 Fax: +41 22 791 5853
Disclaimer: The views expressed in this article are solely those of the authors and do
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not necessarily represent the opinions of the World Health Organization.
Corresponding author
Marleen Temmerman, Director, Reproductive Health and Research (includes the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme – HRP), Avenue Appia
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20- 1211 Geneva –Switzerland, [email protected], Tel: +41 22 791 33 80
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Fax: +41 22 791 5853
Abstract
Women living with HIV are often of reproductive age, and many desire effective
contraceptive options to delay or prevent pregnancy. We review the safety of various
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hormonal and non-hormonal contraceptive methods for women living with HIV.
Additionally, we discuss drug interactions between contraceptive methods and anti-
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retrovirals and the safety of methods with respect to onward transmission to HIVnegative partners for women in sero-discordant partnerships. In general, most methods are safe for most women living with HIV. An understanding of the reproductive goals of each individual patient, as well as her medical condition and medication, should be taken into account when counselling women on their contraceptive options. Further research is needed to understand drug interactions between contraceptives and anti-
Key words:
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retrovirals better and how to fulfill the contraceptive needs of HIV-positive women .
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Contraceptives, family planning, HIV, AIDS
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INTRODUCTION
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Globally, an estimated 35.3 million people were living with HIV in 2012. This number continues to increase as life-saving anti-retroviral (ARV) treatment becomes more
available. In 2012 there were an estimated 2.3 million new HIV infections globally, a 33% decline from a high of 3.4 million in 2001. More than half of people worldwide living with
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HIV are women; in sub-Saharan Africa, this figure is closer to 60% [1].
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Most of these women are in their childbearing years. Although some women will wish to become pregnant, and require full information and support for this decision, many will want to avoid pregnancy. Voluntary contraception is a proven, cost-effective strategy for reducing HIV infection among children [2], and is an essential component of providing optimal care and support to HIV positive women. Despite this, women living with HIV have a high unmet need for contraceptive services [3] and often face
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inequalities in care due to discrimination and the limited evidence base upon which providers may determine their decision-making [4]. In low-income countries and in countries with a high prevalence of HIV, access to safe and effective contraception is of critical importance to maintain women's health, to reduce maternal and infant deaths,
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and to uphold women's rights.
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When counselling women living with HIV about options for fertility regulation, clinicians should provide full information, not only about the safety of the methods with respect to their HIV status, but also about the relative efficacy of various methods, both with perfect use and typical use [5]. While long-acting reversible methods, such as implants or IUDs, are ideal for some women due to their high efficacy, lack of susceptibility to user error, and their potential for covert use [6], some women will prefer to use shorteracting methods over which they have more control or that confer non-contraceptive benefits. Regardless of the method chosen, informed choice is critical to ensure that women's rights are upheld [7]. 3
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HORMONAL CONTRACEPTION Hormonal contraceptives, including combined oral contraceptives pills (COCs), contraceptive patches and rings, progestin-only pills (POPs), and progestin-only
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injectables (POIs) are all highly effective and are recommended by the World Health Organization without restriction as contraceptive options for women who are HIVpositive (Tables 1 and 2) [8]. All of these options also have significant noncontraceptive benefits.
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Combined oral contraceptives, contraceptive patches, and contraceptive rings (Combined hormonal contraceptives, CHCs)
CHCs can be used to treat pre-menstrual disorders, dysfunctional menstrual bleeding, some benign breast disorders, and acne, and are protective against several kinds of cancer [9]. Although CHCs are safe for most women, women with severely elevated blood pressure (≥160/90), with vascular disease, or with migraines with aura, in addition
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to certain other medical conditions, should not use CHCs [10]. Additionally, women who weigh over 80 kg are more likely to become pregnant while using the contraceptive patch [11].
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Progestin-only pills
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For some women with medical conditions, progestin-only pills represent an important alternative if they wish to use oral contraceptive preparations. Progestin-only pills have the benefit of being safe for women with medical conditions, such as a history of venous thrombosis, multiple cardiac risk factors, or for women who are less than six months post-partum and breastfeeding [10]. There is some concern that they may be less effective with typical use than combined oral contraceptives; however evidence thus far is insufficient to determine if this is in fact the case [12].
Progestin-only injectables and implants 4
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As contraceptive pills require daily administration at the same time of day to maintain their high efficacy, some women may prefer longer-acting or long-acting methods. Widely available options include progestin-only injectables and implants. These
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methods have the advantage of lasting months (in the case of injectables) or years (as in the case of implants), and are not dependant on remembering to take a daily pill.
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All of these hormonal methods are safe for HIV-positive women (See Table 2). A recent
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systematic review identified 10 observational studies and one randomized clinical trial that assessed disease progression or death among women living with HIV using hormonal contraceptive methods, compared with non-users of hormonal contraceptives [13]. None of the observational studies identified for the systematic review found an association between the use of any hormonal contraceptive method and HIV disease progression or mortality. An additional recently published cohort study similarly failed to
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find a negative association between the use of either progestin-only injectable contraceptives or oral contraceptive pills and HIV disease progression or non-traumatic mortality [14].
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On the contrary, the randomized clinical trial that compared HIV-positive women allocated to either the copper IUD or to their choice of hormonal contraceptive method
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(either depot medroxyprogesterone acetate (DMPA) or oral contraceptive pills) did find that women using either oral contraceptive pills or DMPA were significantly more likely to reach a composite endpoint indicative of disease progression (either death or eligibility for ART) [15]. It is unclear why this RCT found results different from the multiple observational studies on the topic, although there was a significant amount of discontinuation of allocated method, loss to follow-up, and contraceptive switching that may have impacted the trial.
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Despite this outlier, the preponderance of evidence indicates that progestin-only injectables and combined oral contraceptives are safe for women living with HIV, and the WHO's expert committee determined in 2012 that all hormonal contraceptives may be used without restriction for women living with HIV [8]. It should be noted that no
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information is available on the safety of newer forms of hormonal contraceptive methods, such as the contraceptive patch, ring, or contraceptive implants, but that these methods are assumed to have properties similar enough to other combined hormonal
extrapolated from studies of other methods [16].
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INTRA-UTERINE CONTRACEPTION
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contraceptives and progestin-only contraceptives that evidence of their safety can be
Intrauterine contraception — both the copper-releasing intrauterine device (IUD) and the levonorgestrel-releasing intrauterine device (LNG-IUD) — is highly effective, long-acting, and reversible, and can be used by most HIV-positive women, including those with AIDS, provided they are clinically well on antiretroviral (ARV) therapy (Table 3) [10].
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There are, however, a number of theoretical concerns regarding intrauterine contraception use among women with HIV. These mainly include the question of increased risk of complications, such as acute pelvic inflammatory disease immediately
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after insertion [17].
A systematic review specifically assessed whether there was an increased risk among
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HIV-positive women using the IUD of pelvic inflammatory disease or other infections or complications due to IUD insertion or increased disease progression. The review concluded that although data on the effect of the use of intrauterine contraception on HIV disease progression and transmission are very limited, those that are available are reassuring and fail to show increased disease progression or infectious complications of IUD insertion among women living with HIV who receive the IUD [17].
In one of the two studies that were identified, 156 women living with HIV and 493 women who were HIV-negative underwent copper IUD insertion; complication rates, 6
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including pelvic infection, were similar in both groups [18]. Complication rates were no different among women with mild, moderate, or severe immunocompromise, although only 9% were severely immunocompromised. Another study randomized women living with HIV (excluding women with severe HIV-related illness) to either the copper IUD or
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their choice of hormonal contraceptive and similarly found few complications from IUD insertion [19]. Several small studies have similarly failed to find any negative effects, either in terms of insertion-related infections or increased disease progression, among
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women using the LNG IUD [20, 21].
Due to theoretical concerns about increased infection risk, and lack of evidence of
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safety of IUD insertion in women with advanced HIV-related disease, current recommendations are that positive women, who are not clinically well, generally should not initiate intrauterine contraception. If they wish to use an IUD, they may , however, initiate the method once they are clinically well on treatment. As the concern of increased infection risk is solely at the time of insertion, women who have an IUD inserted prior to becoming ill need not have it removed, regardless of the clinical stage
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of their disease [10].
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The utility and cost-effectiveness of routine prophylaxis before insertion of intrauterine contraception remains questionable. The use of either doxycycline 200 mg or
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azithromycin 500 mg orally prior to insertion was found to provide no benefit in preventing pelvic inflammatory disease acquisition, but the reduction in unscheduled visits after insertion was marginally significant [22]. Routine antibiotic prophylaxis prior to IUD insertion is not recommended by WHO guidelines [23], but some regional guidelines do recommend such prophylaxis due to high prevalence of STIs and limited availability of screening tests [24].
MALE AND FEMALE STERILISATION
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Sterilization should only be performed with the full consent of the patient. No person, including HIV-positive women, should be coerced into being sterilized. As women living with HIV may be a vulnerable group due to stigma and discrimination, special care must be taken to ensure their rights are upheld and that the sterilization procedure is
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voluntary [25]. Although upholding human rights and ensuring informed decision-
making is of concern for provision of all family planning methods [7], it is of particular importance with permanent methods.
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There are no data with regard to the effect of male or female sterilization on HIV
disease progression and transmission. A woman living with HIV, AIDS, or on ARV
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therapy can safely undergo female sterilization, although the presence of an AIDSrelated illness may require the procedure to be delayed until her health improves [10].
CONDOMS AND SPERMICIDES
Male and female condoms are the only contraceptive methods that also prevent HIV transmission from women to men. Consistent use of condoms, as defined by use of
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condoms for all acts of penetrative vaginal intercourse, results in an 80% reduction in HIV incidence [26]. Women living with HIV can also protect themselves from reproductive tract infections by using condoms. There is no evidence to suggest that condom use impacts HIV-related disease progression. Because male condoms, as
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used typically, have a 15% annual pregnancy rate and female condoms have a 21% annual pregnancy rate, condoms alone are not an ideal contraceptive method for
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women who do not wish to be pregnant, although with perfect use one-year failure rates can be as low as 5% for female condoms and 2% for male condoms [5].
Nonoxynol-9 spermicide use has been shown to have possible harmful effects through an increased risk of genital lesions and might therefore theoretically be associated with an increased risk of HIV viral transmission [27]. Women living with HIV are advised against using nonoxynol-9 or other spermicides [10].
DRUG INTERACTIONS WITH CONTRACEPTIVE METHODS 8
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As treatment guidelines have been revised to recommend earlier treatment with antiretroviral (ARV) therapy, including recommendations to treat HIV-positive partners in sero-discordant partnerships to prevent onward transmission regardless of their CD4 count [28], the need to understand how ARVs interact with contraceptive methods
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becomes increasingly urgent.
ARVs could theoretically decrease contraceptive efficacy, leading to unintended
pregnancy, or increase effective levels of the contraceptive method, leading to toxicity.
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Similarly, hormonal contraceptives could theoretically either decrease efficacy of ARVs, leading to increased likelihood of treatment failure, or increase active drug levels,
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leading to toxicity [29]. Unfortunately, although a fair amount of information is available from pharmacokinetic and pharmacodynamic studies on this topic, few studies have assessed the clinical outcomes (such as failure of viral suppression, HIV-related clinical disease progression, or unintended pregnancy) that are most important to women and clinicians when choosing ARVs and contraceptive methods. Additionally, many studies examine the interactions between just one ARV and a given contraceptive method by
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giving the medications simultaneously to healthy women [30]. Although such research can provide valuable information, real-world treatment regimens include multiple medications from different drug classes.
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Estrogen-containing combined hormonal contraceptive methods are particularly likely to interact with various ARVs; women using such methods should either use an additional
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contraceptive method or change methods if they are using efavirenz or a boosted protease inhibitor (PI). Interactions are not, however, considered problematic with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) [28]. Potential interactions exist between most non-nucleoside reverse transcriptase inhibitors (NNRTIs) and combined hormonal methods, although rilpivirine appears not to have interactions, and a recent study was reassuring for another NNRTI as it failed to show a difference in rates of ovulation or pregnancy between women living with HIV who were on low-dose COCs and using nevirapine and women on low-dose COCs who were not on any ARV treatment [31]. Similarly, progestin-only pills may interact with PIs or 9
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NNRTIs [28]. Depot medroxyprogesterone acetate (DMPA), on the other hand, maintains its contraceptive efficacy when taken with any ARVs [30]. Its effect on efficacy of ARVs remains less clear, as its use has been shown to lead to decreased AUC, Cmax and Cmin of nelfinavir, [32, 33], decreased AUC and Cmax and increased Cmin
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among women using efavirenz [32], and has not been studied in conjunction with
atazanavir [28]. In general, DMPA is considered the least likely hormonal contraceptive to have drug interactions with ARVs [30].
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As the use of levonorgestrel and etonogestrel contraceptive implants has become more common among women living with HIV, increasing concerns about decreased efficacy
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of pregnancy prevention have surfaced. Although until recently the literature was limited to case reports [30], several new studies assessing clinical outcomes have addressed this concern. One study assessed pregnancy outcomes among women using the etonogestrel implant, together with various ARV regimens, and found no pregnancies among 79 women followed over three years [34]. Another small study assessed women using first line ARVs (either stavudine or zidovudine and lamivudine +
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nevirapine) and included 48 implant users, compared with 33 women who were not using any hormonal contraceptive method. There was no significant difference between the groups in CD4 cell counts or rates of opportunistic infections, and there were no pregnancies in the implant group, compared with one in the non-hormonal group [35].
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However, a recently study based on a retrospective chart review that had a larger sample size raises concerns regarding the impact of ARVs on the efficacy of the
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levonorgestrel implant [36]. The study identified 18 women who had used ARVs containing lopinavir/ritonavir, 208 who had used ARVs containing nevirapine, and 121 who had used ARVs containing efavirenz. The only pregnancies observed in the study were among women using efavirenz; 15 of 121 women became pregnant, with a mean time of pregnancy 16 months after insertion. These findings add to concerns that efavirenz may interact with levonorgestrel.
Very limited data from studies of women using the levonorgestrel IUD concurrently with ARV use have failed to find any association between use of the LNG IUD and serum 10
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LNG levels among women using ARVs in a study of 12 women [37]. A larger study of 40 women found no pregnancies among 15 HIV-positive LNG IUD users, and similarly found no pregnancies among 25 HIV-positive women not using the LNG IUD [20]. The groups were no different in terms of HIV viral load or CD4 counts. Although low levels
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of levonorgestrel are absorbed systemically among LNG IUD users, its primary
mechanism of action appears to be through local effects on the endometrium and
cervical mucus [38, 39] and therefore it may be less likely that ARVs would interfere with its efficacy. The lower systemic levels of levonorgestrel may also be less likely to
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lead to decreased ARV effectiveness.
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As new evidence emerges on the safety of various hormonal contraceptive methods for women using ARVs, providers may wish to counsel their clients about the lack of definitive information about drug interactions for certain methods. For such women the copper IUD is a viable alternative to hormonal methods that may be acceptable, is
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highly effective, and should not interfere with ARVs. A useful website listing HIV drug interactions, which is updated regularly, is www.hiv-druginteractions.org.
TRANSMISSION FROM HIV-POSITIVE WOMEN TO HIV-NEGATIVE MEN
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Women living with HIV whose partners are HIV-negative may be concerned about the impact of their use of various contraceptive methods on their potential to transmit the
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virus to their partners. Although consistent, correct condom use and ARV use for the HIV-positive partner regardless of CD4 count are currently the best ways to prevent HIV transmission within sero-discordant couples [40], these measures may not be available or acceptable to all women or couples.
Only two prospective studies have assessed the impact of the use of hormonal contraceptives by HIV-positive women in sero-discordant partnerships by directly, prospectively measuring HIV acquisition their partners. One of these studies involved 2476 couples (out of which 93 male partners seroconverted, 59 of whom had strains 11
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genetically linked to their female partner's) and found a significantly increased risk of HIV acquisition among male partners of women using injectable contraceptives. The association was not significant for women using oral contraceptives [41]. The estimate in this study was based on relatively few seroconversions among contraceptive users,
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and the difficulty of accounting for confounding factors, particularly differential condom use between contraceptive arms, is a further limitation of this observational study [42, 43]. Another prospective study, which only assessed time intervals during which
couples reported no condom use, with the assumption that reporting of condom non-use
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is less susceptible to bias than condom use, failed to find an association between use of either injectable or oral contraceptives and female-to-male HIV transmission [44]. This
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study is however limited by its relatively small sample size (190 couples) and long intersurvey interval (12-16 months between visits).
Even less evidence is available on the risk of female-to-male HIV transmission among women using the IUD. Only one prospective study has directly assessed HIV acquisition among male partners of HIV-positive women using the IUD. This study,
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which took place in nine European countries in the era before ARVs were available failed to find an association between copper IUD use and HIV transmission among 151 male partners of HIV positive women [45]. The findings are however difficult to interpret as no adjustments were made for sexual behavior and the majority of those men who
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sero-converted were HIV positive at the time of study entry, making it difficult to be
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certain of the temporal relationship and direction of transmission within the partnership.
In the absence of definitive information from clinical studies of HIV-serodiscordant couples using hormonal contraceptive methods, an assessment of the impact of various contraceptives on proximal variables associated with HIV transmission, such as genital viral shedding and plasma viral load, may be helpful. However, a recent systematic review assessing this indirect evidence found that while some studies showed an association between use of injectable or combined oral contraceptives and increased plasma viral load or genital viral shedding, many other studies failed to find such an association [46]. Another systematic review, from 2009, identified four studies that 12
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assessed the association between use of the LNG or copper IUD and genital viral shedding [17]; none found any association between IUD use and shedding.
In the absence of definitive evidence, counselling HIV-positive women about their risk of
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transmitting HIV to their partners presents a challenge. Ideally women in serodiscordant partnerships should be offered ARVs to reduce the risk of onward
transmission to their partners, regardless of their CD4 count [40]. Such a strategy,
coupled with other preventive measures such as counselling for consistent condom use,
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can significantly decrease risk of HIV transmission within couples regardless of the
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contraceptive method chosen [47].
MULTIPURPOSE PREVENTION TECHNOLOGIES
Given the difficulties some women and couples face in consistently and correctly using condoms, alternative methods to prevent transmission of HIV and other reproductive tract infections (RTIs), while simultaneously preventing pregnancy, would be welcome and could enhance women's ability to exercise autonomy in their sexual relationships
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[48]. Such Multipurpose Prevention Technologies (MPTs) currently under development include rings, gels, microbicides, vaccines, and diaphragms. Although proof of concept of several potential MPTs has been achieved, for such products to be used on a wide scale such technologies must be accessible, affordable, and acceptable to women [49].
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Although many MPTs have been designed with the aim of simultaneously preventing HIV acquisition and pregnancy among HIV-negative women, such developments could
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also help HIV-positive women protect themselves from other RTIs, from pregnancy, and potentially minimize onward HIV transmission to partners.
SUMMARY
With the exception of male and female condoms, no contraceptive option provides protection against HIV transmission. In general women living with HIV may use any contraceptive method of their choosing, although women with advanced HIV-related disease should not initiate IUD use until they are on treatment and clinically well. Substantial uncertainty remains regarding drug interactions between some 13
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contraceptive methods and antiretrovirals. Clinicians may therefore wish to advise patients on certain antiretrovirals to use alternative contraception or also to use condoms for additional protection against pregnancy. There is concern about enhanced female-to-male transmission of HIV with the use of injectable progestogens, although
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the data are limited and thus far difficult to interpret. Male or female sterilization is an appropriate contraceptive method for women living with HIV who have completed
childbearing, but care is necessary to ensure it is undertaken without coercion and with
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full consent and understanding of the long-term implications.
Practice points
Most contraceptive methods are appropriate for most women living with HIV,
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although intra-uterine contraceptives should not be inserted in women with severe disease •
Only barrier methods prevent onward HIV transmission to partners
•
Drug interactions are possible with some hormonal methods and anti-retrovirals, but evidence is limited
Women living with HIV may constitute a vulnerable population; care should be
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taken to ensure full information is shared and women have the choice to use or not use contraceptive methods
•
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Research agenda
Further information is needed on the effect all contraceptive methods have on
•
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female-to-male HIV transmission Studies that report on clinical outcomes of pregnancy, treatment failure, or HIV disease progression among women concomitantly using ARVs and hormonal contraceptive methods
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Multi-purpose prevention technologies that give women and couples more
choices to prevent pregnancy, onward transmission of HIV, and reproductive tract infections
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18. Sinei SK, Morrison CS, Sekadde-Kigondu C, Allen M, Kokonya D. Complications of use of intrauterine devices among HIV-1-infected women. Lancet. 1998;351(9111):1238-41. 19. Stringer EM, Kaseba C, Levy J, Sinkala M, Goldenberg RL, Chi BH, et al. A randomized trial of the intrauterine contraceptive device vs hormonal contraception in women who are infected with the human immunodeficiency virus. Am J Obstet Gynecol. 2007;197(2):144.e1-8. 20. Heikinheimo O, Lehtovirta P, Aho I, Ristola M, Paavonen J. The levonorgestrel-releasing intrauterine system in human immunodeficiency virus-infected women: a 5-year follow-up study. Am J Obstet Gynecol. 2011;204(2):126.e1-4. 21. Lehtovirta P, Paavonen J, Heikinheimo O. Experience with the levonorgestrel-releasing intrauterine system among HIV-infected women. Contraception. 2007;75(1):37-9. 22. Grimes DA, Schulz KF. Antibiotic prophylaxis for intrauterine contraceptive device insertion. Cochrane Database Sys Rev. 2001(2):Cd001327. 23. World Health Organization. Selected Practice Recommendations for Contraceptive Use: A WHO Family Planning Cornerstone. 4th ed. Geneva, Switzerland: World Health Organization; 2004. [Available at: http://www.who.int/reproductivehealth/publications/family_planning/9241562846index/en/; accessed April 10, 2014] 24. Department of Health Republic of South Africa. National Contraception Clinical Guidelines. Pretoria, South Africa: Department of Health, 2012. [Available at: http://www.gov.za/documents/download.php?f=183520; accessed April 10, 2014] 25. The International Community of Women Living with HIV/AIDS. The Forced and Coerced Sterilization of HIV Positive Women in Namibia. London, United Kingdom: ICW, 2009. [Available at: http://www.icw.org/files/The%20forced%20and%20coerced%20sterilization%20of%20HIV%20positive% 20women%20in%20Namibia%2009.pdf; accessed April 10, 2014] 26. Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission. The Cochrane database of systematic reviews. 2002(1):Cd003255. 27. Wilkinson D, Ramjee G, Tholandi M, Rutherford G. Nonoxynol-9 for preventing vaginal acquisition of HIV infection by women from men. Cochrane Database Sys Rev. 2002(4):Cd003936. 28. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach. Geneva, Switzerland: World Health Organization, 2013. [Available at: http://www.who.int/hiv/pub/guidelines/arv2013/en/; accessed April 10, 2014] 29. Thurman AR, Anderson S, Doncel GF. Effects of Hormonal Contraception on Antiretroviral Drug Metabolism, Pharmacokinetics and Pharmacodynamics. Am J Reprod Immunol. 2014. [Epub ahead of print] doi: 10.1111/aji.12210. 30. Robinson JA, Jamshidi R, Burke AE. Contraception for the HIV-positive woman: a review of interactions between hormonal contraception and antiretroviral therapy. Infectious diseases in obstetrics and gynecology. Vol. 2012, Article ID 890160, 15 pages, 2012. doi:10.1155/2012/890160 31. Nanda K, Delany-Moretlwe S, Dube K, Lendvay A, Kwok C, Molife L, et al. Nevirapine-based antiretroviral therapy does not reduce oral contraceptive effectiveness. AIDS. 2013;27 Suppl 1:S17-25. 32. Cohn SE, Park JG, Watts DH, Stek A, Hitti J, Clax PA, et al. Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Clin Pharmacol Ther. 2007;81(2):222-7. 33. Watts DH, Park JG, Cohn SE, Yu S, Hitti J, Stek A, et al. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception. 2008;77(2):84-90.
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34. Kreitchmann R, Innocente AP, Preussler GM. Safety and efficacy of contraceptive implants for HIV-infected women in Porto Alegre, Brazil. Int J Gynaecol Obstet. 2012;117(1):81-2. 35. Hubacher D, Liku J, Kiarie J, Rakwar J, Muiruri P, Omwenga J, et al. Effect of concurrent use of anti-retroviral therapy and levonorgestrel sub-dermal implant for contraception on CD4 counts: a prospective cohort study in Kenya. J Int AIDS Soc. 2013;16:18448. 36. Perry SH, Swamy P, Preidis GA, Mwanyumba A, Motsa N, Sarero HN. Implementing the Jadelle implant for women living with HIV in a resource-limited setting in sub-Saharan Africa: concerns for drug interactions leading to unintended pregnancies. AIDS. 2014;28(5):791-793. 37. Heikinheimo O, Lehtovirta P, Suni J, Paavonen J. The levonorgestrel-releasing intrauterine system (LNG-IUS) in HIV-infected women--effects on bleeding patterns, ovarian function and genital shedding of HIV. Hum Reprod. 2006;21(11):2857-61. 38. Natavio MF, Taylor D, Lewis RA, Blumenthal P, Felix JC, Melamed A, et al. Temporal changes in cervical mucus after insertion of the levonorgestrel-releasing intrauterine system. Contraception. 2013;87(4):426-31. 39. Ortiz ME, Croxatto HB. Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action. Contraception. 2007;75(6 Suppl):S16-30. 40. World Health Organization. Guidance on couples HIV testing and counselling - including antiretroviral therapy for treatment and prevention in serodiscordant couples: Recommendations for a public health approach. Geneva, Switzerland: World Health Organization, 2012. [Available at: http://www.who.int/hiv/pub/guidelines/9789241501972/en/; accessed April 10, 2014] 41. Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12(1):19-26. 42. Polis CB, Westreich D, Balkus JE, Heffron R. Assessing the effect of hormonal contraception on HIV acquisition in observational data: challenges and recommended analytic approaches. AIDS. 2013;27 Suppl 1:S35-43. 43. Wawer MJ, Gray RH. Challenges in assessing associations between hormonal contraceptive use and the risks of HIV-1 acquisition and transmission. Future Microbio. 2012;7(3):315-8. 44. Lutalo T, Musoke R, Kong X, Makumbi F, Serwadda D, Nalugoda F, et al. Effects of hormonal contraceptive use on HIV acquisition and transmission among HIV-discordant couples. AIDS. 2013;27 Suppl 1:S27-34. 45. European Study Group on Heterosexual Transmission of HIV. Comparison of female to male and male to female transmission of HIV in 563 stable couples. BMJ (Clinical research ed). 1992;304(6830):809-13. 46. Polis CB, Phillips SJ, Curtis KM. Hormonal contraceptive use and female-to-male HIV transmission: a systematic review of the epidemiologic evidence. AIDS. 2013;27(4):493-505. 47. Baggaley RF, White RG, Hollingsworth TD, Boily MC. Heterosexual HIV-1 infectiousness and antiretroviral use: systematic review of prospective studies of discordant couples. Epidemiology. 2013;24(1):110-21. 48. Lusti-Narasimhan M, Merialdi M, Holt B. Multipurpose prevention technologies: maximising positive synergies. BJOG. 2014;121(3):251. 49. Thurman AR, Clark MR, Doncel GF. Multipurpose prevention technologies: biomedical tools to prevent HIV-1, HSV-2, and unintended pregnancies. Infect Dis Obstet Gynecol. 2011;2011:1-10.
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Table 4 ARV and contraceptive drug interactions: MEC recommendations†
NNRTIs
Progestinonly pills 3
DMPA
Cu-IUD*
LNG-IUD*
1
LNG/ETG implant 2
Insertion: 2/3 Continuation: 2
Insertion: 2/3 Continuation: 2
1
1
1
1
2
1
2
Insertion: 2/3 Continuation: 2 Insertion: 2/3 Continuation: 2
2
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Ritonavirboosted PIs NRTIs
Combined oral contraceptives 3
Insertion: 2/3 Continuation: 2 Insertion: 2/3 Continuation: 2
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†Although we provide class-related recommendations in this table, some ARVs within a class may be known to not have an interaction, while others may. For the most up-to-date information on potential interactions by specific ARV, please see www.hiv-druginteractions.org.
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*Note that the MEC recommendations for IUDs reflect a concern about increased risk of pelvic infection rather than concern about interactions with ARVs. IUDs are a 2 for insertion in women who are clinically well, and a 3 for women with moderate or severe HIV-related illness. Women may continue the method regardless of the status of their HIV-related illness.
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Table 1: WHO Medical Eligibility Criteria Categories (10) Category Description 1
A condition for which there is no restriction for the use of the contraceptive
2
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method A condition where the advantages of using the method generally outweigh the theoretical or proven risks 3
A condition where the theoretical or proven risks usually outweigh the
4
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advantages of using the method
A condition which represents an unacceptable health risk if the contraceptive
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method is used
Table 2: WHO recommendations for the use of combined and progestin-only contraceptives (8) Condition
Combined oral Contraceptive
HIV-
DMPA
LNG/
patch/
only
NET-EN
ETG
ring
pill
1
1
1
1
1
1
1
1
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contraceptives
Progestin-
1
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infected 1
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AIDS
Implant
Table 3: WHO recommendations for the use of intra-uterine contraceptives for women living with HIV (10) Condition
Copper IUD
Insertion
Levonorgestrel IUD
Continuation
Insertion Continuation
HIV-infected
2
2
2
2
AIDS
3
2
3
2
1
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Clinically well
2
2
2
2
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on ARV therapy
2
PII:
S1521-6934(14)00085-6
DOI:
10.1016/j.bpobgyn.2014.04.013
Reference:
YBEOG 1352
To appear in:
Best Practice & Research Clinical Obstetrics & Gynaecology
Received Date: 21 March 2014 Revised Date:
11 April 2014
Accepted Date: 22 April 2014
Please cite this article as: Phillips S, Steyn P, Temmerman M, Contraceptive options for women living with HIV, Best Practice & Research Clinical Obstetrics & Gynaecology (2014), doi: 10.1016/ j.bpobgyn.2014.04.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Contraceptive options for women living with HIV
Sharon Phillips, M.D., M.P.H. Medical Officer, Reproductive Health and Research
(includes the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme – HRP), Avenue Appia 20- 1211 Geneva –Switzerland, [email protected], Tel: +41 22 791 33
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80 Fax: +41 22 791
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Petrus Steyn, M.D., MMed (O&G), FCOG (SA), MPhil. Scientist, Reproductive Health and Research (includes the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme – HRP), Avenue Appia 20- 1211 Geneva –Switzerland, [email protected], Tel: +41 22 791 33 80 Fax: +41 22 791 2971
Marleen Temmerman, M.D., PhD. Director, Reproductive Health and Research
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(includes the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme – HRP), Avenue Appia 20- 1211 Geneva –Switzerland, [email protected], Tel: +41 22 791
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33 80 Fax: +41 22 791 5853
Disclaimer: The views expressed in this article are solely those of the authors and do
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not necessarily represent the opinions of the World Health Organization.
Corresponding author
Marleen Temmerman, Director, Reproductive Health and Research (includes the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme – HRP), Avenue Appia
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20- 1211 Geneva –Switzerland, [email protected], Tel: +41 22 791 33 80
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Fax: +41 22 791 5853
Abstract
Women living with HIV are often of reproductive age, and many desire effective
contraceptive options to delay or prevent pregnancy. We review the safety of various
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hormonal and non-hormonal contraceptive methods for women living with HIV.
Additionally, we discuss drug interactions between contraceptive methods and anti-
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retrovirals and the safety of methods with respect to onward transmission to HIVnegative partners for women in sero-discordant partnerships. In general, most methods are safe for most women living with HIV. An understanding of the reproductive goals of each individual patient, as well as her medical condition and medication, should be taken into account when counselling women on their contraceptive options. Further research is needed to understand drug interactions between contraceptives and anti-
Key words:
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retrovirals better and how to fulfill the contraceptive needs of HIV-positive women .
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Contraceptives, family planning, HIV, AIDS
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INTRODUCTION
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Globally, an estimated 35.3 million people were living with HIV in 2012. This number continues to increase as life-saving anti-retroviral (ARV) treatment becomes more
available. In 2012 there were an estimated 2.3 million new HIV infections globally, a 33% decline from a high of 3.4 million in 2001. More than half of people worldwide living with
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HIV are women; in sub-Saharan Africa, this figure is closer to 60% [1].
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Most of these women are in their childbearing years. Although some women will wish to become pregnant, and require full information and support for this decision, many will want to avoid pregnancy. Voluntary contraception is a proven, cost-effective strategy for reducing HIV infection among children [2], and is an essential component of providing optimal care and support to HIV positive women. Despite this, women living with HIV have a high unmet need for contraceptive services [3] and often face
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inequalities in care due to discrimination and the limited evidence base upon which providers may determine their decision-making [4]. In low-income countries and in countries with a high prevalence of HIV, access to safe and effective contraception is of critical importance to maintain women's health, to reduce maternal and infant deaths,
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and to uphold women's rights.
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When counselling women living with HIV about options for fertility regulation, clinicians should provide full information, not only about the safety of the methods with respect to their HIV status, but also about the relative efficacy of various methods, both with perfect use and typical use [5]. While long-acting reversible methods, such as implants or IUDs, are ideal for some women due to their high efficacy, lack of susceptibility to user error, and their potential for covert use [6], some women will prefer to use shorteracting methods over which they have more control or that confer non-contraceptive benefits. Regardless of the method chosen, informed choice is critical to ensure that women's rights are upheld [7]. 3
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HORMONAL CONTRACEPTION Hormonal contraceptives, including combined oral contraceptives pills (COCs), contraceptive patches and rings, progestin-only pills (POPs), and progestin-only
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injectables (POIs) are all highly effective and are recommended by the World Health Organization without restriction as contraceptive options for women who are HIVpositive (Tables 1 and 2) [8]. All of these options also have significant noncontraceptive benefits.
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Insert Table 1 about here
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Combined oral contraceptives, contraceptive patches, and contraceptive rings (Combined hormonal contraceptives, CHCs)
CHCs can be used to treat pre-menstrual disorders, dysfunctional menstrual bleeding, some benign breast disorders, and acne, and are protective against several kinds of cancer [9]. Although CHCs are safe for most women, women with severely elevated blood pressure (≥160/90), with vascular disease, or with migraines with aura, in addition
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to certain other medical conditions, should not use CHCs [10]. Additionally, women who weigh over 80 kg are more likely to become pregnant while using the contraceptive patch [11].
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Progestin-only pills
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For some women with medical conditions, progestin-only pills represent an important alternative if they wish to use oral contraceptive preparations. Progestin-only pills have the benefit of being safe for women with medical conditions, such as a history of venous thrombosis, multiple cardiac risk factors, or for women who are less than six months post-partum and breastfeeding [10]. There is some concern that they may be less effective with typical use than combined oral contraceptives; however evidence thus far is insufficient to determine if this is in fact the case [12].
Progestin-only injectables and implants 4
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As contraceptive pills require daily administration at the same time of day to maintain their high efficacy, some women may prefer longer-acting or long-acting methods. Widely available options include progestin-only injectables and implants. These
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methods have the advantage of lasting months (in the case of injectables) or years (as in the case of implants), and are not dependant on remembering to take a daily pill.
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All of these hormonal methods are safe for HIV-positive women (See Table 2). A recent
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systematic review identified 10 observational studies and one randomized clinical trial that assessed disease progression or death among women living with HIV using hormonal contraceptive methods, compared with non-users of hormonal contraceptives [13]. None of the observational studies identified for the systematic review found an association between the use of any hormonal contraceptive method and HIV disease progression or mortality. An additional recently published cohort study similarly failed to
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find a negative association between the use of either progestin-only injectable contraceptives or oral contraceptive pills and HIV disease progression or non-traumatic mortality [14].
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On the contrary, the randomized clinical trial that compared HIV-positive women allocated to either the copper IUD or to their choice of hormonal contraceptive method
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(either depot medroxyprogesterone acetate (DMPA) or oral contraceptive pills) did find that women using either oral contraceptive pills or DMPA were significantly more likely to reach a composite endpoint indicative of disease progression (either death or eligibility for ART) [15]. It is unclear why this RCT found results different from the multiple observational studies on the topic, although there was a significant amount of discontinuation of allocated method, loss to follow-up, and contraceptive switching that may have impacted the trial.
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Despite this outlier, the preponderance of evidence indicates that progestin-only injectables and combined oral contraceptives are safe for women living with HIV, and the WHO's expert committee determined in 2012 that all hormonal contraceptives may be used without restriction for women living with HIV [8]. It should be noted that no
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information is available on the safety of newer forms of hormonal contraceptive methods, such as the contraceptive patch, ring, or contraceptive implants, but that these methods are assumed to have properties similar enough to other combined hormonal
extrapolated from studies of other methods [16].
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INTRA-UTERINE CONTRACEPTION
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contraceptives and progestin-only contraceptives that evidence of their safety can be
Intrauterine contraception — both the copper-releasing intrauterine device (IUD) and the levonorgestrel-releasing intrauterine device (LNG-IUD) — is highly effective, long-acting, and reversible, and can be used by most HIV-positive women, including those with AIDS, provided they are clinically well on antiretroviral (ARV) therapy (Table 3) [10].
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There are, however, a number of theoretical concerns regarding intrauterine contraception use among women with HIV. These mainly include the question of increased risk of complications, such as acute pelvic inflammatory disease immediately
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after insertion [17].
A systematic review specifically assessed whether there was an increased risk among
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HIV-positive women using the IUD of pelvic inflammatory disease or other infections or complications due to IUD insertion or increased disease progression. The review concluded that although data on the effect of the use of intrauterine contraception on HIV disease progression and transmission are very limited, those that are available are reassuring and fail to show increased disease progression or infectious complications of IUD insertion among women living with HIV who receive the IUD [17].
In one of the two studies that were identified, 156 women living with HIV and 493 women who were HIV-negative underwent copper IUD insertion; complication rates, 6
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including pelvic infection, were similar in both groups [18]. Complication rates were no different among women with mild, moderate, or severe immunocompromise, although only 9% were severely immunocompromised. Another study randomized women living with HIV (excluding women with severe HIV-related illness) to either the copper IUD or
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their choice of hormonal contraceptive and similarly found few complications from IUD insertion [19]. Several small studies have similarly failed to find any negative effects, either in terms of insertion-related infections or increased disease progression, among
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women using the LNG IUD [20, 21].
Due to theoretical concerns about increased infection risk, and lack of evidence of
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safety of IUD insertion in women with advanced HIV-related disease, current recommendations are that positive women, who are not clinically well, generally should not initiate intrauterine contraception. If they wish to use an IUD, they may , however, initiate the method once they are clinically well on treatment. As the concern of increased infection risk is solely at the time of insertion, women who have an IUD inserted prior to becoming ill need not have it removed, regardless of the clinical stage
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of their disease [10].
Insert Table 3 about here
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The utility and cost-effectiveness of routine prophylaxis before insertion of intrauterine contraception remains questionable. The use of either doxycycline 200 mg or
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azithromycin 500 mg orally prior to insertion was found to provide no benefit in preventing pelvic inflammatory disease acquisition, but the reduction in unscheduled visits after insertion was marginally significant [22]. Routine antibiotic prophylaxis prior to IUD insertion is not recommended by WHO guidelines [23], but some regional guidelines do recommend such prophylaxis due to high prevalence of STIs and limited availability of screening tests [24].
MALE AND FEMALE STERILISATION
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Sterilization should only be performed with the full consent of the patient. No person, including HIV-positive women, should be coerced into being sterilized. As women living with HIV may be a vulnerable group due to stigma and discrimination, special care must be taken to ensure their rights are upheld and that the sterilization procedure is
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voluntary [25]. Although upholding human rights and ensuring informed decision-
making is of concern for provision of all family planning methods [7], it is of particular importance with permanent methods.
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There are no data with regard to the effect of male or female sterilization on HIV
disease progression and transmission. A woman living with HIV, AIDS, or on ARV
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therapy can safely undergo female sterilization, although the presence of an AIDSrelated illness may require the procedure to be delayed until her health improves [10].
CONDOMS AND SPERMICIDES
Male and female condoms are the only contraceptive methods that also prevent HIV transmission from women to men. Consistent use of condoms, as defined by use of
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condoms for all acts of penetrative vaginal intercourse, results in an 80% reduction in HIV incidence [26]. Women living with HIV can also protect themselves from reproductive tract infections by using condoms. There is no evidence to suggest that condom use impacts HIV-related disease progression. Because male condoms, as
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used typically, have a 15% annual pregnancy rate and female condoms have a 21% annual pregnancy rate, condoms alone are not an ideal contraceptive method for
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women who do not wish to be pregnant, although with perfect use one-year failure rates can be as low as 5% for female condoms and 2% for male condoms [5].
Nonoxynol-9 spermicide use has been shown to have possible harmful effects through an increased risk of genital lesions and might therefore theoretically be associated with an increased risk of HIV viral transmission [27]. Women living with HIV are advised against using nonoxynol-9 or other spermicides [10].
DRUG INTERACTIONS WITH CONTRACEPTIVE METHODS 8
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As treatment guidelines have been revised to recommend earlier treatment with antiretroviral (ARV) therapy, including recommendations to treat HIV-positive partners in sero-discordant partnerships to prevent onward transmission regardless of their CD4 count [28], the need to understand how ARVs interact with contraceptive methods
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becomes increasingly urgent.
ARVs could theoretically decrease contraceptive efficacy, leading to unintended
pregnancy, or increase effective levels of the contraceptive method, leading to toxicity.
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Similarly, hormonal contraceptives could theoretically either decrease efficacy of ARVs, leading to increased likelihood of treatment failure, or increase active drug levels,
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leading to toxicity [29]. Unfortunately, although a fair amount of information is available from pharmacokinetic and pharmacodynamic studies on this topic, few studies have assessed the clinical outcomes (such as failure of viral suppression, HIV-related clinical disease progression, or unintended pregnancy) that are most important to women and clinicians when choosing ARVs and contraceptive methods. Additionally, many studies examine the interactions between just one ARV and a given contraceptive method by
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giving the medications simultaneously to healthy women [30]. Although such research can provide valuable information, real-world treatment regimens include multiple medications from different drug classes.
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Estrogen-containing combined hormonal contraceptive methods are particularly likely to interact with various ARVs; women using such methods should either use an additional
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contraceptive method or change methods if they are using efavirenz or a boosted protease inhibitor (PI). Interactions are not, however, considered problematic with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) [28]. Potential interactions exist between most non-nucleoside reverse transcriptase inhibitors (NNRTIs) and combined hormonal methods, although rilpivirine appears not to have interactions, and a recent study was reassuring for another NNRTI as it failed to show a difference in rates of ovulation or pregnancy between women living with HIV who were on low-dose COCs and using nevirapine and women on low-dose COCs who were not on any ARV treatment [31]. Similarly, progestin-only pills may interact with PIs or 9
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NNRTIs [28]. Depot medroxyprogesterone acetate (DMPA), on the other hand, maintains its contraceptive efficacy when taken with any ARVs [30]. Its effect on efficacy of ARVs remains less clear, as its use has been shown to lead to decreased AUC, Cmax and Cmin of nelfinavir, [32, 33], decreased AUC and Cmax and increased Cmin
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among women using efavirenz [32], and has not been studied in conjunction with
atazanavir [28]. In general, DMPA is considered the least likely hormonal contraceptive to have drug interactions with ARVs [30].
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As the use of levonorgestrel and etonogestrel contraceptive implants has become more common among women living with HIV, increasing concerns about decreased efficacy
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of pregnancy prevention have surfaced. Although until recently the literature was limited to case reports [30], several new studies assessing clinical outcomes have addressed this concern. One study assessed pregnancy outcomes among women using the etonogestrel implant, together with various ARV regimens, and found no pregnancies among 79 women followed over three years [34]. Another small study assessed women using first line ARVs (either stavudine or zidovudine and lamivudine +
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nevirapine) and included 48 implant users, compared with 33 women who were not using any hormonal contraceptive method. There was no significant difference between the groups in CD4 cell counts or rates of opportunistic infections, and there were no pregnancies in the implant group, compared with one in the non-hormonal group [35].
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However, a recently study based on a retrospective chart review that had a larger sample size raises concerns regarding the impact of ARVs on the efficacy of the
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levonorgestrel implant [36]. The study identified 18 women who had used ARVs containing lopinavir/ritonavir, 208 who had used ARVs containing nevirapine, and 121 who had used ARVs containing efavirenz. The only pregnancies observed in the study were among women using efavirenz; 15 of 121 women became pregnant, with a mean time of pregnancy 16 months after insertion. These findings add to concerns that efavirenz may interact with levonorgestrel.
Very limited data from studies of women using the levonorgestrel IUD concurrently with ARV use have failed to find any association between use of the LNG IUD and serum 10
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LNG levels among women using ARVs in a study of 12 women [37]. A larger study of 40 women found no pregnancies among 15 HIV-positive LNG IUD users, and similarly found no pregnancies among 25 HIV-positive women not using the LNG IUD [20]. The groups were no different in terms of HIV viral load or CD4 counts. Although low levels
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of levonorgestrel are absorbed systemically among LNG IUD users, its primary
mechanism of action appears to be through local effects on the endometrium and
cervical mucus [38, 39] and therefore it may be less likely that ARVs would interfere with its efficacy. The lower systemic levels of levonorgestrel may also be less likely to
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lead to decreased ARV effectiveness.
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Insert Table 4 about here
As new evidence emerges on the safety of various hormonal contraceptive methods for women using ARVs, providers may wish to counsel their clients about the lack of definitive information about drug interactions for certain methods. For such women the copper IUD is a viable alternative to hormonal methods that may be acceptable, is
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highly effective, and should not interfere with ARVs. A useful website listing HIV drug interactions, which is updated regularly, is www.hiv-druginteractions.org.
TRANSMISSION FROM HIV-POSITIVE WOMEN TO HIV-NEGATIVE MEN
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Women living with HIV whose partners are HIV-negative may be concerned about the impact of their use of various contraceptive methods on their potential to transmit the
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virus to their partners. Although consistent, correct condom use and ARV use for the HIV-positive partner regardless of CD4 count are currently the best ways to prevent HIV transmission within sero-discordant couples [40], these measures may not be available or acceptable to all women or couples.
Only two prospective studies have assessed the impact of the use of hormonal contraceptives by HIV-positive women in sero-discordant partnerships by directly, prospectively measuring HIV acquisition their partners. One of these studies involved 2476 couples (out of which 93 male partners seroconverted, 59 of whom had strains 11
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genetically linked to their female partner's) and found a significantly increased risk of HIV acquisition among male partners of women using injectable contraceptives. The association was not significant for women using oral contraceptives [41]. The estimate in this study was based on relatively few seroconversions among contraceptive users,
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and the difficulty of accounting for confounding factors, particularly differential condom use between contraceptive arms, is a further limitation of this observational study [42, 43]. Another prospective study, which only assessed time intervals during which
couples reported no condom use, with the assumption that reporting of condom non-use
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is less susceptible to bias than condom use, failed to find an association between use of either injectable or oral contraceptives and female-to-male HIV transmission [44]. This
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study is however limited by its relatively small sample size (190 couples) and long intersurvey interval (12-16 months between visits).
Even less evidence is available on the risk of female-to-male HIV transmission among women using the IUD. Only one prospective study has directly assessed HIV acquisition among male partners of HIV-positive women using the IUD. This study,
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which took place in nine European countries in the era before ARVs were available failed to find an association between copper IUD use and HIV transmission among 151 male partners of HIV positive women [45]. The findings are however difficult to interpret as no adjustments were made for sexual behavior and the majority of those men who
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sero-converted were HIV positive at the time of study entry, making it difficult to be
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certain of the temporal relationship and direction of transmission within the partnership.
In the absence of definitive information from clinical studies of HIV-serodiscordant couples using hormonal contraceptive methods, an assessment of the impact of various contraceptives on proximal variables associated with HIV transmission, such as genital viral shedding and plasma viral load, may be helpful. However, a recent systematic review assessing this indirect evidence found that while some studies showed an association between use of injectable or combined oral contraceptives and increased plasma viral load or genital viral shedding, many other studies failed to find such an association [46]. Another systematic review, from 2009, identified four studies that 12
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assessed the association between use of the LNG or copper IUD and genital viral shedding [17]; none found any association between IUD use and shedding.
In the absence of definitive evidence, counselling HIV-positive women about their risk of
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transmitting HIV to their partners presents a challenge. Ideally women in serodiscordant partnerships should be offered ARVs to reduce the risk of onward
transmission to their partners, regardless of their CD4 count [40]. Such a strategy,
coupled with other preventive measures such as counselling for consistent condom use,
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can significantly decrease risk of HIV transmission within couples regardless of the
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contraceptive method chosen [47].
MULTIPURPOSE PREVENTION TECHNOLOGIES
Given the difficulties some women and couples face in consistently and correctly using condoms, alternative methods to prevent transmission of HIV and other reproductive tract infections (RTIs), while simultaneously preventing pregnancy, would be welcome and could enhance women's ability to exercise autonomy in their sexual relationships
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[48]. Such Multipurpose Prevention Technologies (MPTs) currently under development include rings, gels, microbicides, vaccines, and diaphragms. Although proof of concept of several potential MPTs has been achieved, for such products to be used on a wide scale such technologies must be accessible, affordable, and acceptable to women [49].
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Although many MPTs have been designed with the aim of simultaneously preventing HIV acquisition and pregnancy among HIV-negative women, such developments could
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also help HIV-positive women protect themselves from other RTIs, from pregnancy, and potentially minimize onward HIV transmission to partners.
SUMMARY
With the exception of male and female condoms, no contraceptive option provides protection against HIV transmission. In general women living with HIV may use any contraceptive method of their choosing, although women with advanced HIV-related disease should not initiate IUD use until they are on treatment and clinically well. Substantial uncertainty remains regarding drug interactions between some 13
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contraceptive methods and antiretrovirals. Clinicians may therefore wish to advise patients on certain antiretrovirals to use alternative contraception or also to use condoms for additional protection against pregnancy. There is concern about enhanced female-to-male transmission of HIV with the use of injectable progestogens, although
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the data are limited and thus far difficult to interpret. Male or female sterilization is an appropriate contraceptive method for women living with HIV who have completed
childbearing, but care is necessary to ensure it is undertaken without coercion and with
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full consent and understanding of the long-term implications.
Practice points
Most contraceptive methods are appropriate for most women living with HIV,
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•
although intra-uterine contraceptives should not be inserted in women with severe disease •
Only barrier methods prevent onward HIV transmission to partners
•
Drug interactions are possible with some hormonal methods and anti-retrovirals, but evidence is limited
Women living with HIV may constitute a vulnerable population; care should be
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•
taken to ensure full information is shared and women have the choice to use or not use contraceptive methods
•
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Research agenda
Further information is needed on the effect all contraceptive methods have on
•
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female-to-male HIV transmission Studies that report on clinical outcomes of pregnancy, treatment failure, or HIV disease progression among women concomitantly using ARVs and hormonal contraceptive methods
•
Multi-purpose prevention technologies that give women and couples more
choices to prevent pregnancy, onward transmission of HIV, and reproductive tract infections
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34. Kreitchmann R, Innocente AP, Preussler GM. Safety and efficacy of contraceptive implants for HIV-infected women in Porto Alegre, Brazil. Int J Gynaecol Obstet. 2012;117(1):81-2. 35. Hubacher D, Liku J, Kiarie J, Rakwar J, Muiruri P, Omwenga J, et al. Effect of concurrent use of anti-retroviral therapy and levonorgestrel sub-dermal implant for contraception on CD4 counts: a prospective cohort study in Kenya. J Int AIDS Soc. 2013;16:18448. 36. Perry SH, Swamy P, Preidis GA, Mwanyumba A, Motsa N, Sarero HN. Implementing the Jadelle implant for women living with HIV in a resource-limited setting in sub-Saharan Africa: concerns for drug interactions leading to unintended pregnancies. AIDS. 2014;28(5):791-793. 37. Heikinheimo O, Lehtovirta P, Suni J, Paavonen J. The levonorgestrel-releasing intrauterine system (LNG-IUS) in HIV-infected women--effects on bleeding patterns, ovarian function and genital shedding of HIV. Hum Reprod. 2006;21(11):2857-61. 38. Natavio MF, Taylor D, Lewis RA, Blumenthal P, Felix JC, Melamed A, et al. Temporal changes in cervical mucus after insertion of the levonorgestrel-releasing intrauterine system. Contraception. 2013;87(4):426-31. 39. Ortiz ME, Croxatto HB. Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action. Contraception. 2007;75(6 Suppl):S16-30. 40. World Health Organization. Guidance on couples HIV testing and counselling - including antiretroviral therapy for treatment and prevention in serodiscordant couples: Recommendations for a public health approach. Geneva, Switzerland: World Health Organization, 2012. [Available at: http://www.who.int/hiv/pub/guidelines/9789241501972/en/; accessed April 10, 2014] 41. Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12(1):19-26. 42. Polis CB, Westreich D, Balkus JE, Heffron R. Assessing the effect of hormonal contraception on HIV acquisition in observational data: challenges and recommended analytic approaches. AIDS. 2013;27 Suppl 1:S35-43. 43. Wawer MJ, Gray RH. Challenges in assessing associations between hormonal contraceptive use and the risks of HIV-1 acquisition and transmission. Future Microbio. 2012;7(3):315-8. 44. Lutalo T, Musoke R, Kong X, Makumbi F, Serwadda D, Nalugoda F, et al. Effects of hormonal contraceptive use on HIV acquisition and transmission among HIV-discordant couples. AIDS. 2013;27 Suppl 1:S27-34. 45. European Study Group on Heterosexual Transmission of HIV. Comparison of female to male and male to female transmission of HIV in 563 stable couples. BMJ (Clinical research ed). 1992;304(6830):809-13. 46. Polis CB, Phillips SJ, Curtis KM. Hormonal contraceptive use and female-to-male HIV transmission: a systematic review of the epidemiologic evidence. AIDS. 2013;27(4):493-505. 47. Baggaley RF, White RG, Hollingsworth TD, Boily MC. Heterosexual HIV-1 infectiousness and antiretroviral use: systematic review of prospective studies of discordant couples. Epidemiology. 2013;24(1):110-21. 48. Lusti-Narasimhan M, Merialdi M, Holt B. Multipurpose prevention technologies: maximising positive synergies. BJOG. 2014;121(3):251. 49. Thurman AR, Clark MR, Doncel GF. Multipurpose prevention technologies: biomedical tools to prevent HIV-1, HSV-2, and unintended pregnancies. Infect Dis Obstet Gynecol. 2011;2011:1-10.
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Table 4 ARV and contraceptive drug interactions: MEC recommendations†
NNRTIs
Progestinonly pills 3
DMPA
Cu-IUD*
LNG-IUD*
1
LNG/ETG implant 2
Insertion: 2/3 Continuation: 2
Insertion: 2/3 Continuation: 2
1
1
1
1
2
1
2
Insertion: 2/3 Continuation: 2 Insertion: 2/3 Continuation: 2
2
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Ritonavirboosted PIs NRTIs
Combined oral contraceptives 3
Insertion: 2/3 Continuation: 2 Insertion: 2/3 Continuation: 2
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†Although we provide class-related recommendations in this table, some ARVs within a class may be known to not have an interaction, while others may. For the most up-to-date information on potential interactions by specific ARV, please see www.hiv-druginteractions.org.
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*Note that the MEC recommendations for IUDs reflect a concern about increased risk of pelvic infection rather than concern about interactions with ARVs. IUDs are a 2 for insertion in women who are clinically well, and a 3 for women with moderate or severe HIV-related illness. Women may continue the method regardless of the status of their HIV-related illness.
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Table 1: WHO Medical Eligibility Criteria Categories (10) Category Description 1
A condition for which there is no restriction for the use of the contraceptive
2
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method A condition where the advantages of using the method generally outweigh the theoretical or proven risks 3
A condition where the theoretical or proven risks usually outweigh the
4
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advantages of using the method
A condition which represents an unacceptable health risk if the contraceptive
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method is used
Table 2: WHO recommendations for the use of combined and progestin-only contraceptives (8) Condition
Combined oral Contraceptive
HIV-
DMPA
LNG/
patch/
only
NET-EN
ETG
ring
pill
1
1
1
1
1
1
1
1
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contraceptives
Progestin-
1
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infected 1
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AIDS
Implant
Table 3: WHO recommendations for the use of intra-uterine contraceptives for women living with HIV (10) Condition
Copper IUD
Insertion
Levonorgestrel IUD
Continuation
Insertion Continuation
HIV-infected
2
2
2
2
AIDS
3
2
3
2
1
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Clinically well
2
2
2
2
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on ARV therapy
2
