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Hormonal Contraception and HIV AcquisitionStudy finds no overall association. |
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Imagine Caroline, a 23-year-old, married woman from Zimbabwe who — like more than a third of women in that country using contraception — takes an oral contraceptive pill each day. By preventing pregnancy at a time in her life when she is not ready to start a family, this highly effective contraceptive provides her with not only peace of mind but also the opportunity to pursue an education and to anticipate the benefits that an education affords. Yet, she worries. Zimbabwe is a place where HIV infection is a clear danger: nearly a quarter of adult Zimbabweans are infected. And Caroline, like so many women in settings where HIV prevalence is high, has heard rumors that use of hormonal contraception may increase her risk of becoming infected with HIV if she is ever exposed to the virus. A thoughtful young woman, she weighs the possible risks and known benefits of continuing to use oral contraception. The idea of acquiring deadly HIV is chilling, and she cannot dismiss it. But she does not want to become pregnant, so she turns to her family planning provider for advice. "What should I do?" she asks. With some degree of certainty, the provider can now tell her that she does not need to abandon hormonal contraception. This advice is based on new data from the largest prospective study ever conducted on the association between hormonal contraceptive use and HIV acquisition among typical family planning users. The research, funded by the U.S. National Institute of Child Health and Human Development, was conducted by FHI and collaborating institutions* among some 6,100 family planning clients in Uganda, Zimbabwe, and Thailand. The four-year study, published in the January 2, 2007 issue of the journal AIDS, found no overall association between the use of either combined oral contraceptive (COC) pills or depot-medroxyprogesterone acetate (DMPA) and HIV acquisition.1 This finding — generated by a study with unique methodological strengths when compared with previous studies on the topic (see Why This Study Is Unique) — is reassuring for women in need of highly effective contraception in settings of high HIV risk. Neither the World Health Organization (WHO) nor the International Planned Parenthood Federation, which have reviewed the study results, plans at this time to change its guidelines for hormonal contraceptive use by such women. In June of 2005, the WHO Family Planning Guideline Steering Group issued a statement that "the study results are reassuring and that the new evidence does not modify the current guidance for contraceptive use," which states that women at risk of HIV infection or those who are HIV-infected may safely use hormonal contraception.2 The study also examined whether sexually transmitted infections (STIs) modified the relationship between hormonal contraceptive use and HIV acquisition. Among STIs included in the analyses were vaginal infections (trichomoniasis, bacterial vaginosis, and candidiasis), cervical infections (chlamydia and gonorrhea), and infection with herpes simplex virus-2 (HSV-2). The African data showed that only one STI modified the relationship between hormonal contraceptive use and HIV: Among the approximately half of African study participants testing negative for HSV-2 at enrollment, those who used either COCs or DMPA had a statistically significant increased rate of HIV acquisition compared with non-users. This finding was unexpected and has no clear biological mechanism. Thus, as is often the case with unexpected study findings, further research must evaluate this potential association. Of note, the study found that participants who were infected with HSV at the beginning of the study had higher rates of HIV infection than did those women who were HSV-negative at the start. This is consistent with data from many other published studies showing that HSV infection increases the risk of HIV acquisition. Meanwhile, Dr. Charles Morrison, a senior epidemiologist at FHI and principal investigator for the study, urges a conservative approach. "Our findings should reinforce efforts to counsel all women at risk of HIV infection to use condoms consistently and correctly to prevent HIV acquisition" in addition to their primary contraceptive method, he says. This advice is true for women using any form of contraception, since no contraceptive method besides condoms provides protection against HIV infection. — Kim Best * Institutions collaborating in this study were Makerere University, Kampala, Uganda; Case Western Reserve University, Cleveland, OH, USA; University of Zimbabwe, Harare, Zimbabwe; University of California at San Francisco, San Francisco, CA, USA; Chiang Mai University, Chiang Mai, Thailand; Johns Hopkins University, Baltimore, MD, USA; Family Health International, Durham, NC, USA; and Fred Hutchinson Cancer Research Center, Seattle, WA, USA. References
Why This Study Is Unique A possible relationship between hormonal contraceptive use and HIV acquisition has been investigated in approximately 30 studies. However, understanding of this possible relationship has remained poor. Study results have been inconsistent, in part because nearly all these studies have been designed to investigate other research questions and have had important methodological shortcomings. Only 12 prospective studies — the design of which reduces some sources of bias to results — have examined hormonal contraceptive use and HIV infection. Only six of those studies have considered a possible relationship between the use of the injectable hormonal contraceptive depot-medroxy-progesterone acetate (DMPA) and HIV infection. The present study,1 funded by the U.S. National Institute of Child Health and Human Development and conducted by FHI researchers and collaborating institutions, is unique and standard-setting in that it is:
For these reasons, this study greatly clarifies what effect hormonal contraceptive use has on HIV acquisition and serves as the strongest study to date exploring this issue. However, unlike a randomized controlled trial, a prospective, observational study cannot provide evidence to establish a direct cause-effect relationship between hormonal contraceptive use and HIV acquisition. While a randomized controlled trial is unlikely to be conducted in the near future, international reproductive health experts will continue to evaluate any additional evidence emerging from other studies. — Kim Best Reference
Questions and Answers Study of Hormonal Contraceptive Use and HIV Acquisition How widely is hormonal contraception used? Worldwide, about 84 million women currently married or in union use combined oral contraceptives (COCs) and about 24 million such women use the injectable depot-medroxyprogesterone acetate (DMPA). Many other women not currently married or in union also use these contraceptive methods.1 What are COCs? Most oral contraceptives contain both pro-gestin and estrogen and thus are called combined oral contraceptives. The COCs used in this study were low dose (30 micrograms estrogen, 150 micrograms levonorgestrel) monophasic pills. What is DMPA? DMPA, known commercially as Depo Provera, is a synthetic form of the natural hormone progesterone. The most widely used injectable contraceptive, it is among the most effective methods of contraception, with typical one-year pregnancy rates of 0.4 percent or lower. DMPA is injected intramuscularly at a dose of 150 milligrams every three months. This decreases the risk of missed doses, such as missing a daily oral contraceptive pill. Were the pills and injectables used in this study the same as those used in the United States? The COCs used in this study (Lo-Femenal and Microgynon) are what many women in the United States and other developed countries most commonly use. Similarly, the DMPA used in this study is the same as that used in the United States and in many countries throughout the world. Are other injectables safe to use? The World Health Organization's (WHO's) Medical Eligibility Criteria for Contraceptive Use currently recommends that women at risk of HIV infection may use all injectables with no restrictions.2 Another progestin-only injectable contraceptive is norethisterone enanthate (NET-EN), known commercially as Noristerat or Norigest. It differs from DMPA in that it contains a different progestin and is administered every two months at a dose of 200 milligrams. Two combined pro-gestin-estrogen injectable contraceptives, known commercially as Cyclofem and Mesigyna, are administered monthly. Determining whether the differences in dose or types of hormones in these injectables might result in different effects on HIV acquisition would require further research. (Of note, a recently completed secondary analysis of data collected as part of another study found that use of COCs, NET-EN, or DMPA by South African women from the general population was not associated with increased risk of HIV infection.3) Could hormonal contraceptives with different dosages of progestins and estrogens than those used by participants in this study pose different risks of HIV acquisition? Formulations similar to those used in this study are likely to have similar effects. However, more research is needed to investigate this possibility. Why were Uganda, Zimbabwe, and Thailand selected for this study? The use of hormonal contraception had to be tested among the populations most likely to benefit from the study results, such as those in sub-Saharan Africa, where more than 80 percent of all HIV infections worldwide among women occur. Also, the study needed to be conducted where the incidence of heterosexual HIV transmission and exposure to the virus was high enough to determine whether hormonal contraceptive use had any impact on HIV acquisition. (Although Thailand's HIV incidence rate turned out to be too low to produce useful results, HIV incidence rates in both African countries were high enough for this study to produce results. Of the 217 HIV infections that occurred during follow-up, 214 were in the two African countries.) In addition, all three countries in this study had a variety of contraceptive methods from which women could choose, allowing researchers to study large numbers of both injectable contraceptive users and oral contraceptive users. In all three settings, both U.S. and in-country investigators were interested in conducting this research and had the expertise and infrastructure to do so. Finally, these sites were part of an international network of sites participating in HIV prevention studies. Why was the study conducted primarily among family planning clients? The study was conducted primarily among family planning clients because they are more likely than other women to use hormonal contraception and because it is important to know whether that use increases their risk of HIV acquisition. Also, family planning clients are at relatively low risk of HIV infection. In contrast, many previous analyses of hormonal contraceptive use and HIV acquisition came from studies conducted among women at high risk for HIV infection: commercial sex workers or women seeking medical care for sexually transmitted infections (STIs). What was done to safeguard the rights of women participating in the study? The study was designed according to the most rigorous international ethical standards. It was reviewed and approved by the U.S. National Institutes of Health (NIH) and by 12 institutional review and human protection boards in the United States and participating countries.
In addition, highly sensitive tests were used to detect STIs at each study visit. Participants were contacted and treated free of charge for any detected STI, thus reducing the risk of HIV acquisition. How were the women who became infected with HIV during the study cared for? All HIV-infected women were encouraged to continue to return for study follow-up visits and were provided their contraceptive methods of choice. Such women were counseled to use condoms consistently, told about the implications of becoming pregnant while HIV-infected, and advised that they should bring their partners for HIV testing and counseling. All participants who became infected with HIV during the study were extensively counseled and given referrals to medical services and to research studies that provided HIV care and treatment. They were also referred to local support groups that offer HIV-related psychological and social services. In addition, women in Uganda and Zimbabwe (where almost all of the HIV infections occurred) who became HIV-infected during the study were offered the opportunity to enroll in a follow-on study of HIV-infected women. Women in that study received counseling about condom use, reduction in transmission risk, and health maintenance; their choice of contraceptive method and free condoms; diagnosis and treatment for STIs; access to a support group for HIV-infected women and to HIV support counseling; referrals for other HIV support services; referral to an HIV-experienced health care provider (as needed); antiretroviral drug therapy and prophylaxis for pneumonia or tuberculosis, if medically indicated; treatment for malaria and other common infections; Pap smears; daily multivitamins and iron; and referral for treatment to prevent mother-to-child transmission of HIV. What further analyses can we expect? Various ancillary studies and secondary analyses will be conducted, ultimately helping international normative bodies set evidence-based standards for the provision of hormonal contraception in countries with high HIV prevalence. Ancillary studies and secondary analyses will look at whether hormonal contraceptive use is associated with:
They will also evaluate the subsequent impact of these STIs on HIV acquisition. Whether hormonal contraceptive use is associated with human papillomavirus will also be examined. In addition, ancillary studies among women who become HIV-infected will examine hormonal contraceptive use and its relationship with:
Finally, the study's findings related to HIV risk among HSV-negative hormonal contraceptive users will be further analyzed. — Kim Best References
Research Implications for Users and Providers Extensive research over decades has shown that combined oral contraceptives (COCs) and the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) are extremely safe and pose few serious side effects. Recent research suggests that use of COCs1 and DMPA2 may increase risk of acquiring chlamydial infection. Otherwise, the body of existing research indicates that hormonal contraceptive use does not appear to increase the overall risk of acquiring other sexually transmitted infections (STIs), including HIV and gonorrhea. However, hormonal contraceptives do not protect against any STIs, including HIV. This means that family planning providers should counsel users of hormonal contraceptives — as well as other methods — to use condoms consistently and correctly with each sexual act if they are not in a mutually monogamous relationship with an uninfected partner. Providers often assume that men and women in married or steady relationships will not use condoms. But an FHI study conducted among 49 Ugandan women — recruited from the recently published study of hormonal contraceptive use and HIV3 — and their partners found that stable couples in settings with high fertility and high HIV prevalence may be more likely than commonly thought to use condoms.4 Meanwhile, the use of HIV voluntary counseling and testing (VCT) services should be encouraged so more individuals can learn their HIV status. This, in turn, can assist women who do not wish to become pregnant in making contraceptive choices that best meet their needs. For example, some women who learn that they are HIV-positive may strongly wish to prevent pregnancy and thus decide to use a highly effective contraceptive method. VCT programs need to ensure that they provide either contraceptive counseling or referrals for such counseling. This table suggests actions for hormonal contraceptive users and family planning and VCT providers, based on a couple's HIV status. References
Clients Can Quickly Learn HIV Status Am I infected with HIV? Is my partner infected with HIV? Most men and women throughout the world do not know the answers to these questions. But, particularly in settings of high HIV prevalence, a sexually active individual who is not in a mutually monogamous relationship with an uninfected partner needs to know. Men and women who learn that they are HIV-infected can seek care and treatment and take steps to avoid infecting their partners. Women who learn they are infected can take steps to avoid infecting any children they might conceive. Even men and women who learn that they are not infected can benefit. If at continuing risk of HIV infection, they can adopt preventive behaviors such as abstaining from sex, being faithful to one sexual partner, and using condoms consistently and correctly. Testing for HIV infection has been encouraged for many years. Since the mid-1980s, most people seeking testing have had enzyme-linked immunosorbent assay (ELISA) tests. But ELISA tests require a blood sample drawn from a vein, skilled technicians, and a laboratory with reliable water and electricity. Forty to 90 blood specimens must be tested at once for ELISA to be cost-effective. Another disadvantage of ELISA is that the processing of test results takes several days or weeks, requiring clients to return to the testing facility to learn their HIV status. Not surprisingly, up to a third of clients having ELISA tests do not return to receive their results due to disincentives such as travel costs and time.1 Fortunately, some of these obstacles have been reduced with the development and growing availability since 1990 of a variety of new, instrument-free "rapid tests" that allow clients to learn their HIV status immediately and receive counseling about HIV prevention, care, and treatment. The World Health Organization (WHO), which has called for a major expansion of HIV testing and counseling, has embraced the idea of using rapid HIV tests in many settings.2 The tests can be particularly useful in reaching clients most likely to benefit from knowledge of their HIV status, such as pregnant women and those living in settings of high HIV prevalence. Advantages of the rapid tests are numerous. Rapid tests use saliva, urine, or finger-prick blood samples to screen for HIV antibodies; sometimes, clients receive results in less than 20 minutes. Like the ELISA tests, rapid tests can screen for HIV-1, HIV-2, and other HIV subtypes. The tests do not require any specialized instruments, and test results can be read visually and interpreted by minimally trained personnel. The rapid tests' accuracy is comparable to the accuracy of the ELISA tests. (Sensitivity and specificity can be greater than 99 percent.3) The rapid tests are also comparable in price to the ELISA tests (U.S. $0.40 to U.S. $2 per test through WHO's bulk procurement scheme). Most rapid test kits have a long shelf life (12 months), can be stored at room temperatures of up to +20°C to +30°C (equivalent to 68°F to 86°F), and do not require water or electricity. The two most commonly cited disadvantages of the rapid tests are that clients are sometimes reluctant to accept the accuracy of their results and that counselors and clients have less time to prepare for the delivery of results, especially if they are positive. In general, these tests are well suited for use in HIV voluntary testing and counseling (VCT) centers and resource-constrained facilities, particularly rural areas where the volume of testing is too low to use ELISA tests efficiently. Several programs in Africa, Europe, and the United States are using rapid tests in mobile testing centers to allow people to learn their HIV status quickly and easily. Like the ELISA tests, the rapid tests provide only initial screening for HIV antibodies and positive results must then be confirmed with another test. WHO has developed testing algorithms of two or three sequential tests (including the initial test) that can reliably confirm HIV test results. HIV rapid tests can take somewhat longer than ELISA tests to detect HIV antibodies (in rare cases, up to three months after infection has occurred). Therefore, persons who have a negative rapid test result but were recently exposed to HIV are counseled to be tested again at least three months after possible infection. Several dozen brands of rapid test kits are now available on the market worldwide, and many countries are quickly adopting their use. When selecting the kit that best fits their needs, governments and ministries of health are urged to evaluate each kit carefully in terms of cost, availability, and prevalence of particular HIV strains in specific settings. Evaluations of many of the rapid tests kits are available at the WHO Web site. — Chris Parker References
Research Implications for Policy-makers In light of recent research showing no overall association between hormonal contraceptive use and HIV acquisition among women at relatively low risk of HIV infection, no changes should be made in the provision or use of combined oral contraceptives (COCs) or depot-medroxyprogesterone acetate (DMPA). The World Health Organization's Medical Eligibility Criteria for Contraceptive Use currently states that even women at risk of HIV infection may use hormonal contraception with no restrictions.1 However, no form of contraception other than condoms has been shown to protect women from sexually transmitted infections, including HIV. This means that any sexually active woman not desiring pregnancy and not in a mutually monogamous relationship with an HIV-uninfected partner should consider how best to obtain dual protection against both pregnancy and HIV infection. Dual protection can be achieved by using male latex condoms or female condoms alone or in combination with other contraceptive methods. Notably, recent research implications for hormonal contraceptive use include the need to carefully balance HIV risks with pregnancy-related risks. These pregnancy-related risks are high in countries where childbirth is unsafe or abortion is illegal, resulting in high maternal and infant mortality and morbidity. It may be helpful for policy-makers in specific settings to identify the type of HIV epidemic (i.e., low level, concentrated, or generalized) and then determine pregnancy-related risks faced by women of reproductive age. The following table shows the policy implications of balancing relative HIV and pregnancy-related risks. Reference
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