Several important studies derived from simian models have influenced our current thinking about hormonal contraception and HIV disease progression. Marx et al. [14
] exposed 18 macaques to progesterone-releasing pellets and 10 macaques to no progesterone (the control macaques) before vaginally inoculating both groups with simian immunodeficiency virus (SIV). Interestingly, 14 of the 18 progesterone-treated macaques acquired SIV infection, and only 1 of the 10 control macaques became infected. In addition, 3 of 18 SIV-infected macaques in the progesterone group experienced rapid progression to AIDS, compared with none of the 10 control macaques. Finally, the progesterone-treated macaques had higher viral loads during the first 3 months of infection.
Trunova et al. [15
] performed a similar study in which macaques that were either DMPA treated or DMPA naive received varying inoculations of CXCR4–simian-HIV and CCR5–simian-HIV. The DMPA-treated group showed a significantly higher mean peak and acute viral load 1–4 weeks after infection. In addition, the DMPA-treated macaques acquired a more genetically diverse population of simian HIV and had higher concentrations of CXCR4-tropic virus soon after infection, compared with the DMPA-naive macaques (a change in co-receptor use from CCR5 to CXCR4 correlates well with disease progression in humans [16
]). The authors reported no difference in antibody production between DMPA-treated and DMPA-naive macaques; however, cellular immune response rates (using INF-γ
production as a marker) were slower among the DMPA-treated macaques than among the DMPA-naive macaques.
Abel et al. [17
] revealed that a live attenuated virus vaccine for SIV in Rhesus macaques was less effective after treatment with DMPA. DMPA-treated macaques showed a significant decrease in vaccine protection and higher acute viral loads after intravaginal challenge. Similar to the findings of Trunova et al. [15
], all of the DMPA-treated macaques lost previously demonstrated HIV-specific T cell INF-γ
responses 1 week after receiving DMPA.
Four major clinical studies involving humans addressed the issue of HIV disease progression in the context of hormonal contraception. In the aforementioned Mombasa cohort, women using DMPA at the time of HIV infection acquisition had a 2-fold higher viral load set point than did women who did not use contraception (increase in viral load, 0.33 log10
copies/mL; P =
]. Viral load set point, which is typically established ~16 weeks after acquisition of infection, is highly predictive of the rate of HIV disease progression [18
]. In a separate article involving this same cohort, Lavreys et al. [19
] revealed that women with high viral load set points were more likely to die. In addition, compared with women who were not using contraception, women using hormonal contraception (DMPA or OCPs) were >2 times more likely to have multiple viral variants detected shortly after acquisition of infection, which in turn was associated with higher viral load set points (4.84 log10
copies/mL vs. 4.64 log10
copies/mL) and lower median CD4+
T cell counts (416 cells/μ
L vs. 617 cells/μ
L; P =
.01) 4–24 months after acquisition of infection and with a faster rate of CD4+
T cell depletion over time [7
A randomized trial involving 599 postpartum HIV-infected women in Lusaka, Zambia, compared the copper intrauterine device with hormonal contraception (user choice of OCPs or DMPA) [20
]. In that trial, women randomized to receive hormonal contraception were more likely to experience HIV disease progression than were those who used the intrauterine device (however, this outcome was an unanticipated finding and not the primary purpose of the clinical trial). Disease progression was defined separately as death and/or decrease in CD4+
T cell count to <200 cells/mm3
. Women who received hormonal contraception were more likely to die or experience a decrease in CD4+
T cell count (hazard ratio, 1.5; 95% CI, 1.1–2.3) than were women randomized to use the intrauterine device. This study’s patient population differed from that of the Mombasa cohort; all women were enrolled during the post-partum period after having been identified through perinatal HIV infection prevention programs. Thus, all had established infections. Unfortunately, viral load data are not available from the Zambian trial.
Two other studies were published that did not observe a relationship between hormonal contraception and HIV disease progression. A subanalysis of the Women’s Interagency Health Study [21
], a large longitudinal cohort of HIV-infected women, compared 177 women receiving hormonal contraception with 544 women not receiving contraception. This subanalysis reported a small increase in CD4+
T cell count in HIV-infected women using hormonal contraception (mean increase over 13 months, 27.6 cells/μ
L) and no change in viral load over time. Limitations of this analysis are that contraceptive exposure was obtained through self-report at baseline, and the extremely common practice of switching contraceptive methods was not reported.
Richardson et al. [22
] conducted a prospective cohort study composed of recently postpartum women in Kenya to characterize determinates of disease progression. An analysis of hormonal contraception and disease progression included 41 women exposed to OCPs, 43 exposed to DMPA, and 109 who were not exposed to hormonal contraception. The analysis used multivariate linear mixed effects models and Loess regression to compare the effect of these exposures on CD4+
T cell count and viral load over 24 months of follow-up. The study found no statistically significant changes in viral load or CD4+
T cell count that could be attributed to contraceptive exposure.
Most of the patients in the aforementioned clinical studies were not receiving antiretroviral therapy. Presumably, women receiving antiretroviral therapy who are experiencing viral suppression would not be adversely affected by factors that might accelerate disease progression in untreated women.