The purpose of this presentation is to review published data that evaluate the effect of hormonal contraception on female genital shedding of HIV-1. Because herpes simplex virus (HSV) infection has been shown to be a significant risk factor for HIV-1 acquisition1,2 and genital shedding3,4, studies of the effect of hormonal contraception on HSV reactivation are also included.
Female genital tract shedding of HIV-1 may be an important correlate of HIV-1 infectivity. Several studies have demonstrated an association between the detection of HIV-1 RNA or proviral DNA in the genital tract and the peripartum transmission of the virus from mother to infant5–8. A similar relationship between genital HIV-1 and infectivity is likely for sexual transmission9.
One investigation studied the correlates of HIV-1 proviral DNA detection (a marker for infected cells) on cervical and vaginal swabs from 318 women in Mombasa, Kenya10. Compared with women who were not using hormonal contraceptives, women were more likely to have HIV-1 DNA detected in cervical secretions if they were using DMPA (adjusted OR 2.9, 1.5–5.7), low dose combination OC (aOR 3.8, 1.4–9.9), or higher dose combination OC (aOR 12.3, 1.5–101). The effect of hormonal contraceptive use on the cervical shedding of HSV was also evaluated in this group of women11. A total of 273 women (86%) who were seropositive for HSV-2 were included. Both DMPA (aOR 3.6, 1.5–9.0) and oral contraceptives (any dose; aOR 5.3, 1.8–15.2) were associated with increased shedding of HSV.
There were important limitations to these studies. First, the cross-sectional design makes it more difficult to determine whether there is a causal association between the exposure (hormonal contraception) and the outcome (genital HIV-1 or HSV detection). Second, only a qualitative assay for the detection of HIV-1-infected cells was used, so the magnitude of change in the quantity of genital HIV-1 could not be determined. Third, only HIV-1 DNA was measured. It is not known whether HIV-1 RNA or proviral DNA provides a better marker for infectivity. Finally, in the study of HSV shedding, a semi-quantitative assay was used, so again it was not possible to determine precisely the magnitude of the difference in viral shedding associated with hormonal contraceptive use.
Prospective observational studies of the effect of the initiation of hormonal contraception on genital HIV-1 and HSV shedding were designed in order to address the limitations of the cross-sectional studies. The primary objectives of these studies were to evaluate the relationship between the initiation of hormonal contraception and cervical shedding of HIV-1 RNA, HIV-1-infected cells, and HSV.
Between September 1996 and May 1999, women were recruited into a study to evaluate the cervical shedding of HIV-1 and HSV before and 1–2 months after initiating the use of hormonal contraception12,13. A total of 213 women who presented to a family planning clinic in Mombasa, Kenya, were included in the study. The quantity of HIV-1 RNA on cervical swabs was measured using a modification of the Gen-Probe quantitative HIV-1 assay14. HIV-1 DNA was detected by nested PCR amplification of the gag gene15. Herpes simplex virus was also detected by PCR16.
Of the 213 women initiating hormonal contraception, 153 women started a progesterone-only regimen (101 started DMPA and 52 started a progesterone-only oral contraceptive), whereas 60 women used a combination oral contraceptive (53 low dose and seven high-dose estrogen/progesterone containing oral contraceptives)13. Two-hundred and ten women (94%) were seropositive for HSV-212. Overall, the detection of HSV DNA in cervical secretions was observed in 32 women (16%) before versus 25 women (13%) after initiating hormonal contraception (P = 0.4). There was no significant difference in HSV detection before versus after initiating hormonal contraceptive use in the subgroups of women who initiated progesterone-only contraception or combination oral contraceptives. Furthermore, a quantitative evaluation of HSV shedding among the 54 women who shed HSV on at least one visit revealed that the median change in cervical HSV was small, only −313 copies/swab. There was no association between the initiation of hormonal contraceptive use and genital ulcer disease (6% before versus 5% after, P = 0.8). A paper presenting the results of HIV-1 shedding analyses in this cohort of women initiating hormonal contraception has recently been published13.
Hormonal contraception has been associated with genital HIV-1 shedding in cross-sectional studies. A recent publication showed that the initiation of hormonal contraception did not increase the genital shedding of HSV12.
Several conclusions can be drawn from the available data. First, regardless of the effect of hormonal contraceptives on genital HIV-1 shedding, the possible risk of increased HIV-1 infectivity must be considered in relation to the potential benefits of hormonal contraception for individual women infected with HIV-1. HIV-1-seropositive women who choose to use hormonal contraceptives for pregnancy prevention should be counseled to use barrier methods for the prevention of HIV-1 transmission. Finally, the results of our HSV shedding study highlight the importance of prospective studies to evaluate further the associations demonstrated in hypothesis-generating cross-sectional analyses. Further research is needed to obtain a better understanding of the short and long-term effects of hormonal contraceptives on HIV-1 infectivity and natural history. Future studies will also be required in order to evaluate the effects of hormonal contraceptive methods on infectivity among women using antiretroviral therapy.
This study was supported by the National Institutes of Health through grants AI-39996, D43-TW00007, and T22-TW00001.
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