Epidemiology and Social: Editorial Comment
Hormonal contraception and incident HIV-1 infection: new insight and continuing challenges
Bulterys, Marca,c; Smith, Dawnb,d; Chao, Annc; Jaffe, Harolde
From the aGlobal AIDS Program and
bDivision of HIV/AIDS Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA
cCDC-Zambia, Lusaka, Zambia
dCDC-Botswana (BOTUSA), Gaborone, Botswana
eDepartment of Public Health, University of Oxford, UK.
Received 25 September, 2006
Accepted 3 October, 2006
Dr M. Bulterys, CDC Global AIDS Program Zambia, American Embassy, Independence Avenue, PO Box 31617, Lusaka, Zambia. E-mail: email@example.com
Understanding whether hormonal contraception increases the risk of incident HIV-1 infection among women is a critical public health issue. Hormonal contraception, a novelty just four decades ago, has become the norm in many countries because of its high efficacy and ease of use. Over 120 million women worldwide use hormonal contraception, and its use, especially depo-medroxyprogesterone acetate (DMPA), is increasing rapidly in many resource-limited settings [1–3]. Effective contraception has a key role to play in reducing maternal and infant mortality (by spacing pregnancies) and in allowing women a measure of control over when and how often they become pregnant. At the same time, the HIV/AIDS epidemic has reached crisis proportions in a number of sub-Saharan countries and calls for a rapid expansion of both prevention and treatment in resource-limited settings, particularly among women of childbearing age [4–6]. Despite the magnitude of the HIV/AIDS epidemic, the level of condom use among married or cohabiting couples in countries classified by UNAIDS as experiencing a generalized HIV epidemic remains very low . Most women who do use contraception rely on oral contraceptives (OC) or injectable DMPA.
A number of epidemiological studies have been conducted among women of childbearing age to examine hormonal contraception as a potential risk factor for acquiring HIV-1 infection [8–10]. Investigators have proposed several possible mechanisms for how hormonal contraception may affect HIV-1 acquisition, including physiological effects on the integrity of the vaginal epithelium (i.e., unopposed progesterone leads to increased susceptibility to vaginal SIV infection in macaque monkeys ), changes in the genital microflora , an increased likelihood of cervical ectopy , an effect on the cell-surface levels of CCR5, which is key to HIV-1 entry , and upregulation of HIV-1 gene expression . Detailed virological studies among commercial sex workers in Kenya suggested that hormone use predisposes them to the acquisition of a diverse HIV-1 virus population, which leads to higher levels of viral replication and more rapid HIV disease progression [16–18]. It is possible that these biological effects are more pronounced in young women and adolescent girls, who have been shown to be at disproportionately high risk of acquiring HIV-1 infection in sub-Saharan Africa .
To date, at least 13 published prospective studies worldwide [20–32] have reported on the association between risk of HIV-1 infection and hormonal contraception; nine of these were conducted in high-prevalence settings in sub-Saharan Africa [20–28]. Multivariate-adjusted relative risks of incident HIV-1 infection varied substantially among study populations both for OC use and for injectable hormones. Completeness of follow-up was highly variable and poor in some studies; statistical control for potentially strong confounders such as sexually transmitted diseases, number of sexual partners, and other sexual risk behavior was often suboptimal . Self-reported use of hormonal contraception and sexual behavior, even in the methodologically strongest studies, could have suffered from non-differential or differential exposure misclassification, leading to biased risk estimates and residual confounding. However, rather than dismissing the variation observed among studies, we should examine if such variation may be reflecting real differences in at-risk populations such as sex workers and adolescent girls.
In this issue of AIDS, Morrison and colleagues  describe the findings of a prospective study (> 4500 HIV-uninfected women in Uganda and Zimbabwe, aged 18–35 years) specifically designed to assess the relationship between hormonal contraception and incident HIV-1 infection. No overall association was found between use of hormonal contraception and the risk of HIV-1 acquisition, nor among the subset of participants with cervical or vaginal infections. These findings provide reassurance for women needing effective contraception in settings of high HIV-1 prevalence. However, the authors also report that among the smaller subgroup of women who were seronegative for herpes simplex virus type 2 (HSV-2) at enrollment, users of OC (adjusted hazard ratio, 2.9; 95% confidence interval, 1.4–5.8) or DMPA (adjusted hazard ratio, 4.0; 95% confidence interval, 2.0–8.0) were at increased risk of incident HIV-1 infection compared with non-users.
These findings concerning HSV-2-negative participants were unexpected and have not yet been reported by other investigators. Perhaps an important uncontrolled confounder could be responsible for the observed association between hormonal contraception and HIV infection among HSV-2-negative women in this study. Differential condom use might also confound the association with HIV incidence. HSV-2 infection has been shown to be a particularly strong risk factor for acquisition [34–37] and genital shedding [38,39] of HIV-1. Is it possible, as the authors also suggest, that HIV-1 acquisition attributable to hormonal contraception in the HSV-2-positive group (> 50% of all participants in the current study) was masked by HIV-1 seroconversion associated with HSV-2? Or, is this simply a chance finding?
A marginally higher risk for HIV-1 acquisition associated with hormonal contraception was observed among women in Uganda compared with Zimbabwe, where overall HIV-1 incidence was much higher than in Uganda . It remains possible that the ability to detect an association between hormonal contraception and risk of HIV-1 acquisition differs by the prevalence of exposure to hormonal contraception, sexual risk behaviors, other sexually transmitted diseases, and by age at exposure. Further studies in populations with different risk, using frequent monitoring and even more precise measures of contraceptive exposure and confounding variables, may help to clarify these findings. Unfortunately, no randomized clinical trial can be conducted owing to ethical and adherence issues resulting from randomly assigning women to contraceptive methods with substantially differing efficacy.
Most importantly, the study by Morrison et al.  demonstrated no overall association between use of hormonal contraception and risk of HIV acquisition among a large study population of African women with moderately high risk of HIV infection. While contraception has traditionally been the domain of family planning clinics, the findings of Morrison et al.  highlight the opportunity to integrate family planning and HIV/STD prevention, care, and treatment services, including prevention of mother-to-child HIV transmission [40–42]. Sexual activity leads to transmission of both sperm and microorganisms . Any fertility regulation counseling must be coupled with condom promotion and counseling about HIV and prevention and treatment of sexually transmitted infections. Dual protection (condom use in addition to hormonal contraception) should be recommended.
For those women already living with HIV/AIDS in sub-Saharan Africa, there is an ethical and public health imperative to offer them free, effective, and acceptable family planning services in the context of rapidly expanding HIV care and treatment services . As many more HIV-1-infected women are now accessing antiretroviral therapy, including in resource-limited settings [5,44,45], future studies will need to evaluate any possible impact of hormonal contraception on HIV-1 infectivity and viral replication among women using antiretroviral therapy. In addition, more complete data are urgently needed on the safety, efficacy, and pharmacokinetics of antiretroviral drugs when used in conjunction with hormonal contraceptives.
We acknowledge and thank the following individuals for thoughtful discussion on the issues raised in this editorial: Drs. Omotayo Bolu, Rokaya Ginwalla, Denise Jamieson, Alwyn Mwinga, Stewart Reid, Mark Shields, and Elizabeth Stringer.
Note: The findings and conclusions in this editorial commentary are those of the authors and do not necessarily represent the views of the CDC or the US Department of Health and Human Services.
1. Shah I. Contraceptive use patterns in countries with different levels of HIV epidemic. J AIDS 2005; 38(Suppl 1):S5–S6.
2. United Nations. World Contraceptive Use 2003. New York: United Nations; 2004.
3. Cates W Jr. Use of contraception by HIV-infected women. IPPF Med Bull 2001; 35:1–3.
4. De Cock KM, Marum E, Mbori-Ngacha D. A serostatus-based approach to HIV/AIDS prevention and care in Africa. Lancet 2003; 362:1847–1849.
5. Stringer JS, Zulu I, Levy J, Stringer EM, Mwango A, Chi BH, et al
. Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes. JAMA 2006; 296:782–793.
6. Bulterys M, Weidle PJ, Abrams EJ, Fowler MG. Combination antiretroviral therapy in African nursing mothers and drug exposure in their infants: new pharmacokinetic and virologic findings. J Infect Dis 2005; 192:709–712.
7. Ali MM, Cleleand JG, Shah IH. Condom use within marriage: a neglected HIV intervention. Bull WHO 2004; 82:180–186.
8. Wang CC, Reilly M, Kreiss JK. Risk of HIV infection in oral contraceptive pill users: a meta-analysis. J Acquir Immune Defic Syndr 1999; 21:51–58.
9. Stephenson JM. Systematic review of hormonal contraception and risk of HIV transmission: when to resist meta-analysis. AIDS 1998; 12:545–553.
10. Howe JE, Minkoff HL, Duerr AC. Contraceptives and HIV. AIDS 1994; 8:861–867.
11. Marx PA, Spira AI, Gettie A, Dailey PJ, Veazey RS, Lackner AA, et al
. Progesterone implants enhance SIV vaginal transmission and early virus load. Nat Med 1996; 2:1084–1089.
12. Hillier SL. The vaginal microbial ecosystem and resistance to HIV. AIDS Res Hum Retroviruses 1998; 14:S17–S21.
13. Kuhn L, Denny L, Pollack AE, Wright TC. Prevalence of visible disruption of cervical epithelium and cervical ectopy in African women using Depo-Provera. Contraception 1999; 59:363–367.
14. Patterson BK, Landay A, Andersson J, Brown C, Behbahani H, Jiyamapa D, et al
. Repertoire of chemokine receptor expression in the female genital tract: implications for human immunodeficiency virus transmission. Am J Pathol 1998; 153:481–490.
15. Hunt JS, Miller L, Platt JS. Hormonal regulation of uterine macrophages. Dev Immunol 1998; 6:105–110.
16. Martin HL Jr, Nyange PM, Richardson BA, Lavreys L, Mandaliya K, Jackson DJ, et al
. Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1. J Infect Dis 1998; 178:1053–1059.
17. Lavreys L, Baeten JM, Kreiss JK, Richardson BA, Chohan BH, Hassan W, et al
. Injectable contraceptive use and genital ulcer disease during early human immunodeficiency virus type 1 (HIV-1) infection increase plasma virus load among women. J Infect Dis 2004; 189:202–211.
18. Sagar M, Lavreys L, Baeten JM, Richardson BA, Mandaliya K, Chohan BH, et al
. Infection with multiple HIV-1 variants is associated with faster disease progression. J Virol 2003; 77:12921–12926.
19. Buve A, Carael M, Hayes RJ, Auvert B, Ferry B, Robinson NJ, et al
. Multi-centre study on factors determining differences in rate of spread of HIV in sub-Saharan Africa: methods and prevalence of HIV infection. AIDS 2001; 15(Suppl. 4):S5–S14.
20. Laga M, Manoka A, Kivuvu M, Malele B, Tuliza M, Nzila N, et al
. Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: results from a cohort study. AIDS 1993; 7:95–102.
21. Plourde PJ, Pepin J, Agoki E, Ronald AR, Ombette J, Tyndall M, et al
. Human immunodeficiency virus type 1 seroconversion in women with genital ulcers. J Infect Dis 1994; 170:313–317.
22. Bulterys M, Chao A, Habimana P, Dushimimana A, Nawrocki P, Saah A. Incident HIV-1 infection in a cohort of young women in Butare, Rwanda. AIDS 1994; 8:1585–1591.
23. Sinei SK, Fortney JA, Kigondu CS, Feldblum PJ, Kuyoh M, Allen MY, et al
. Contraceptive use and HIV infection in Kenyan family planning clinic attenders. Int J STD AIDS 1996; 7:65–70.
24. Kapiga SH, Lyamuya EF, Lwihula GK, Hunter DJ. The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania. AIDS 1998; 12:75–84.
25. Martin HL Jr, Nyange PM, Richardson BA, Lavreys L, Mandaliya K, Jackson DJ, et al
. Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1. J Infect Dis 1998; 178:1053–1059.
26. McClelland RS, Wang CC, Richardson BA, Corey L, Ashley RL, Mandaliya K, et al
. A prospective study of hormonal contraceptive use and cervical shedding of herpes simplex virus in human immunodeficiency virus type 1-seropositive women. J Infect Dis 2002; 185:1822–1825.
27. Kiddugavu M, Makumbi F, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F, et al
. Hormonal contraceptive use and HIV-1 infection in a population-based cohort in Rakai, Uganda. AIDS 2003; 17:233–240.
28. Lavreys L, Baeten JM, Martin HL, Overbaugh J, Mandaliya K, Ndinya-Achola J, et al
. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS 2004; 18:695–697.
29. Saracco A, Musicco M, Nicolosi A, Angarano G, Arici C, Gavazzeni G, et al
. Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men. J Acquir Immune Defic Syndr 1993; 6:497–502.
30. De Vincenzi I, for the European Study Group on Heterosexual Transmission of HIV. A longitudinal study of human immunodeficiency virus transmission by heterosexual partners. N Engl J Med 1994; 331:341–346.
31. Ungchusak K, Rehle T, Thammapornpilap P, Spiegelman D, Brinkmann U, Siraprapasiri T. Determinants of HIV infection among female commercial sex workers in North Eastern Thailand: results from a longitudinal study. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 12:500–507.
32. Kilmarx PH, Limpakarnjanarat K, Mastro TD, Saisorn S, Kaewkungwal J, Korattana S, et al
. HIV-1 seroconversion in a prospective study of female sex workers in northern Thailand: continued high incidence among brothel-based women. AIDS 1998; 12:1889–1898.
33. Morrison CS, Richardson BA, Mmiro F, Chipato T, Celentano DD, Luoto J, et al
. Hormonal contraception and the risk of HIV acquisition. AIDS 2006; 20:85–95.
34. Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis. J Infect Dis 2002; 185:45–52.
35. Weiss HA, Buve A, Robinson NJ, Van Dyck E, Kahindo M, Anagonou S, et al
. The epidemiology of HSV-2 infection and its association with HIV infection in four urban African populations. AIDS 2001; 15(Suppl. 4):S97–S108.
36. Ramjee G, Williams B, Gouws E, Van Dyck E, de Deken B, Abdool Karim S. The impact of incident and prevalent herpes simplex virus-2 infection on the incidence of HIV-1 infection among commercial sex workers in South Africa. J Acquir Immune Defic Syndr 2005; 39:333–339.
37. Todd J, Grosskurth H, Changalucha J, Obasi A, Mosha F, Balira R, et al
. Risk factors influencing HIV infection incidence in a rural African population: a nested case-control study. J Infect Dis 2006; 193:458–466.
38. Mbopi-Keou FX, Gresenguet G, Mayaud P, Weiss HA, Gopal R, Matta M, et al
. Interactions between herpes simplex virus type 2 and human immunodeficiency virus type 1 infection in African women: opportunities for intervention. J Infect Dis 2000; 182:1090–1096.
39. McClelland RS, Wang CC, Overbaugh J, Richardson BA, Corey L, Ashley RL, et al
. Association between cervical shedding of herpes simplex virus and human immunodeficiency virus type 1. AIDS 2002; 16:2425–2430.
40. Stein Z. Family planning, sexually transmitted diseases, and prevention of AIDS: divided we fail? Am J Public Health 1996; 86:783–784.
41. Duerr A, Hurst S, Kourtis AP, Rutenberg N, Jamieson DJ. Integrating family planning and prevention of mother-to-child HIV transmission in resource-limited settings. Lancet 2005; 366:261–263.
42. Cleland J, Watkins SC. The key lesson of family planning programmes for HIV/AIDS control. AIDS 2006; 20:1–3.
43. Bunnell R, Mermin J, De Cock KM. HIV prevention for a threatened continent: implementing positive prevention in Africa. JAMA 2006; 296:855–858.
44. Harries AD, Libamba E, Schouten EJ, Mwansambo A, Salaniponi FM, Mpazanje R. Expanding antiretroviral therapy in Malawi: drawing on the country's experience with tuberculosis. Br Med J 2004; 329:1163–1166.
45. Gilks CF, Crowley S, Ekpini R, Gove S, Perriens J, Souteyrand Y, et al
. The WHO public-health approach to antiretroviral treatment against HIV in resource-limited settings. Lancet 2006; 368:505–510.
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