CD4+ cell count falling below 200 cells/μl or initiating antiretroviral therapy
A total of 148 women either had their CD4+ cell count falling below 200 cells/μl, initiated ART during follow-up, or both. The rates of women meeting these criteria in the IUD arm were 11.2/100 woman-years of follow-up, compared with 17.5/100 woman-years in the DMPA group and 14.3/100 woman-years in the OCP group. In crude analysis using the IUD as the referent group, the hazard ratios for DMPA and OCP groups were 1.81 (95% CI 1.26–2.60) and 1.54 (95% CI 0.98–2.42), respectively. A Kaplan–Meier analysis indicates a difference between the three contraception arms in the time to either of the two outcomes (log-rank test P = 0.01; Fig. 1b). After treating contraception as a time-varying exposure and adjusting for initial CD4+ cell count, the hazard ratios for DMPA and OCP groups for this outcome were 1.56 (95% CI 1.08–2.26) and 1.69 (95% CI 1.09–2.64), respectively. Controlling for baseline BMI, education, and breast-feeding did not significantly change the results (data not shown).
Composite outcome of death, CD4+ cell count falling below 200 cells/μl, or initiating antiretroviral therapy
One hundred and seventy-five of 595 women met the criteria of the composite outcome. In the IUD group, the rate was 13.1/100 woman-years; in the DMPA group, it was 20.9/100 woman-years, and in the OCP group, it was 16.9/100 woman-years. Compared with the IUD or nonhormonal group, the crude hazard ratios from the intent-to-treat Cox analysis for the composite outcome in DMPA and OCP groups were 1.81(95% CI 1.30–2.53) and 1.52 (95% CI 1.00–2.32). The Kaplan–Meier analysis indicates a difference between the three contraceptive groups in the time to any of the three outcomes (log-rank test P = 0.005; Fig. 1c). After treating the contraception exposure as a time-varying exposure, the hazard ratios for DMPA and OCP groups were 1.62 (95% CI 1.16–2.28) and 1.67 (95% CI 1.10–2.51), respectively. Controlling for baseline BMI, education, and breast-feeding did not significantly change the results (data not shown).
The contraceptive trial that formed the basis for this report was designed to evaluate the efficacy and safety of the IUD in HIV-infected women. Our study found, unexpectedly, that women initiating hormonal contraception had more rapid progression of their HIV disease. In this secondary report, we examined the hormonal contraceptive groups separately with HIV disease progression as an endpoint and found that compared with the IUD, both OCPs and DMPA were associated with accelerated HIV disease progression.
Animal models suggest that hormones such as progesterone may promote simian immunodeficiency disease [7,10], as does at least one study on humans. Lavreys et al.  showed that newly HIV-infected Kenyan sex workers using DMPA at the time of HIV acquisition had higher viral load set points than those without the exposure (high viral load set points have been shown to be predictive of HIV disease progression). In addition, the Kenyan study found that multiple viral genotypes were more commonly detected in women who acquired HIV while using hormonal contraception (either OCPs or DMPA), and women with multiple viral genotypes had higher viral loads over 4–24 months, lower CD4+ cell counts, and faster CD4+ cell count declines over time .
Other studies [12,13] have not observed an association between hormonal contraception exposure and HIV disease progression. Richardson et al.  analyzed data on 193 women, some of whom were using hormonal contraception (both DMPA and OCPs) and others who were not. Hormonal contraception was not associated with appreciable changes in CD4+ cell count or viral load, either after short-term (<5 months) or long-term follow-up (up to 24 months) .
A large body of literature suggests that estrogen and progesterone have a broad array of effects on immune function. Estrogen and progesterone receptors are found on many immune cells, including T lymphocytes, B lymphocytes, monocytes, and neutrophils [14,15]. Potential effects on the immune system include the following: modulation of cellular activation levels (measured through CD38, CD25, CD69), which can impact both the number of lymphocytes infected with HIV and the rate of clearance of the infected cells ; disruption of the cytokine balance between T helper 1 (TH1) and T helper 2 (TH2) cells, which diminishes the clearance of HIV-infected cells ; and increased cellular senescence (measured through CD57, ki67, indoleamine 2,3-dioxygenase) [18–20].
On the basis of the basic science literature, we expected to find in our current study that DMPA would hasten HIV disease progression more than OCPs; however, this is not what we observed. In the crude analysis, there was a suggestion that DMPA might be worse than OCPs, but in the time-varying analysis, which accounts for switching among methods, as well as adherence to methods, this association all but disappeared. It is important to note, however, that a relationship between hormonal contraception and disease progression was not an a priori hypothesis of our trial.
Among this study's limitations is our inability to assess the specific contribution of progesterone and estrogen to the outcomes. No women received estrogen monotherapy (this is not a contraceptive method), and of those who received OCPs, there was exposure to combination estrogen–progesterone, progesterone-only, or both formulations. All breastfeeding women who chose OCPs were, as per Ministry of Health protocol, prescribed progesterone-only pills until their babies were 6 months old. Thereafter, they were switched to combination formulations. Unfortunately, we do not have data available distinguishing the various OCP formulations.
Another limitation of this analysis is the large proportion of women who switched contraceptive methods, withdrew from the study, or were lost to follow-up (n = 281, 47.2% in total). We addressed the switching within our proportional hazards regression by treating contraceptive method as a time-varying exposure. Although women who were lost to follow-up appeared to have a similar prognosis based on the change in their CD4 cell count prior to leaving the study, we cannot rule out informative censoring. Furthermore, women who became pregnant were censored in this study. This is another possible source of bias based on differential censoring among the contraceptive methods. Finally, although the initial method allocation was randomized (IUD vs. hormonal contraception), women were allowed to choose their type of hormonal contraception. This is a potential source of confounding for which we may not have controlled completely.
Safe and effective contraception provides many benefits, especially to HIV-infected women. The risk of maternal mortality increases with each subsequent pregnancy, and nowhere is this more evident than in sub-Saharan Africa, where a woman's lifetime risk of dying in pregnancy can be as high as one in 22 . Our findings raise the possibility that hormonal contraception, relative to the IUD, may hasten HIV disease progression. Although previous animal studies suggest a greater effect of progesterone-only methods (e.g. DMPA), this finding was not confirmed in this secondary analysis. Women using DMPA and OCPs had similarly elevated risk for HIV disease progression when compared with those without hormonal exposure. Although concerning, we strongly feel that these results are not definitive and, as such, should not influence current prescribing practice. A randomized trial designed specifically to evaluate the potential relationship between HIV disease progression and hormonal contraception is urgently needed.
The authors would like to thank Mark Giganti and Dwight Rouse for their helpful comments on this manuscript and, as always, our hard-working study team and all our participants.
This work was supported by a grant from the Elizabeth Glaser Pediatric AIDS Foundation (PG-51161) with complementary resources from the US Agency for International Development (HRN-A-00-98-00020-00; SA-04-395). Investigators received salary or stipend support from the National Institutes of Health (D43-TW01035, K23-AI01411, K01-TW05708, K01-TW06670, D43-TW010035).
1. Joint United Nations Programme on HIV/AIDS (UNAIDS), World Health Organization. Report on the global HIV/AIDS epidemic 2007
. Geneva, Switzerland: UNAIDS; 2007.
2. Grimes DA, Benson J, Singh S, Romero M, Ganatra B, Okonofua FE, Shah IH. Unsafe abortions: the preventable pandemic. Lancet 2006; 368:1908–1919.
3. Singh S, Darroch JE, Vlassoff M, Nadeau J. Adding it up: the benefits of investing in sexual and reproductive healthcare
. New York: The Allan Guttmacher Institute; 2003.
4. UNAIDS. Report on the global HIV/AIDS epidemic: 4th global report
. Geneva, Switzerland: UNAIDS; 2004.
5. Seiber EE, Bertrand JT, Sullivan TM. Changes in contraceptive method mix in developing countries. Int Fam Plan Perspect 2007; 33:117–123.
6. Stringer EM, Kaseba C, Levy J, Sinkala M, Goldenberg RL, Chi BH, et al
. A randomized trial of the intrauterine contraceptive device (IUD) versus hormonal contraception in HIV-1-infected women. Am J Obstet Gynecol 2007; 197:144.e1–144.e8.
7. 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.
8. Baeten JM, Lavreys L, Sagar M, Kreiss JK, Richardson BA, Chohan B, et al
. Effect of contraceptive methods on natural history of HIV: studies from the Mombasa cohort. J Acquir Immune Defic Syndr 2005; 38(Suppl 1):S18–S21.
9. Rabkin M, El Sadr W. Saving mothers, saving families: the MTCT-Plus initiative – case study
. Perspectives and practice in antiretroviral treatment
. Geneva, Switzerland: WHO; 2003. p. 13.
10. Trunova N, Tsai L, Tung S, Schneider E, Harouse J, Gettie A, et al
. Progestin-based contraceptive suppresses cellular immune responses in SHIV-infected rhesus macaques. Virology 2006; 352:169–177.
11. Lavreys L, Baeten JM, Chohan V, McClelland RS, Hassan WM, Richardson BA, et al
. Higher set point plasma viral load and more-severe acute HIV type (HIV-1) illness predict mortality among high-risk HIV-1-infected African women. Clin Infect Dis 2006; 42:1333–1339.
12. Cejtin HE, Jacobson L, Springer G, Watts D, Levine A, Greenblatt R, et al
. Effect of hormonal contraceptive use on plasma HIV-1 RNA levels among HIV-infected women. AIDS 2003; 17:1702–1704.
13. Richardson BA, Otieno PA, Mbori-Ngacha D, Overbaugh J, Farquhar C, John-Stewart GC. Hormonal contraception and HIV-1 disease progression among postpartum Kenyan women. AIDS 2007; 21:749–753.
14. Danel L, Vincent C, Rousset F, Klein B, Bataille R, Flacher M, et al
. Estrogen and progesterone receptors in some human myeloma cell lines and murine hybridomas. J Steroid Biochem 1988; 30:363–367.
15. Pasanen S, Ylikomi T, Palojoki E, Syvala H, Pelto-Huikko M, Tuohimaa P. Progesterone receptor in chicken bursa of Fabricius and thymus: evidence for expression in B-lymphocytes. Mol Cell Endocrinol 1998; 141:119–128.
16. Enomoto LM, Kloberdanz KJ, Mack DG, Elizabeth D, Weinberg A. Ex vivo effect of estrogen and progesterone compared with dexamethasone on cell-mediated immunity of HIV-infected and uninfected subjects. J Acquir Immune Defic Syndr 2007; 45:137–143.
17. Maret A, Coudert JD, Garidou L, Foucras G, Gourdy P, Krust A, et al
. Estradiol enhances primary antigen-specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor alpha expression in hemaotpoietic cells. Eur J Immunol 2003; 33:512–521.
18. Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, et al
. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 2003; 101:2711–2720.
19. Appay V, Almeida JR, Sauce D, Autran B, Papagno L. Accelerated immune senescence and HIV-1 infection. Exp Gerontol 2007; 42:432–437.
20. Nilsson J, Boasso A, Velilla PA, Zhang R, Vaccari M, Franchini G, et al
. HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS. Blood 2006; 108:3808–3817.
21. WHO, UNICEF, UNFPA, The World Bank. Maternal Mortality in 2005
. Geneva, Switzerland: WHO; 2007.
Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
disease progression; family planning; HIV