HIV disease progression by hormonal contraceptive method: secondary analysis of a randomized trial
Stringer, Elizabeth Ma,b; Levy, Jensc; Sinkala, Mosesd; Chi, Benjamin Ha,b; Matongo, Inutua; Chintu, Namwingaa; Stringer, Jeffrey SAa,b
aCentre for Infectious Disease Research in Zambia, Lusaka, Zambia
bDepartment of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama, USA
cCenters for Disease Control and Prevention, Bangkok, Thailand
dCatholic Medical Mission Board, Lusaka, Zambia.
Received 6 January, 2009
Revised 7 April, 2009
Accepted 9 April, 2009
Correspondence to Dr Elizabeth M. Stringer, MD, MSc, Centre for Infectious Disease Research in Zambia, Plot 5977, Benakale Road, Northmead, Lusaka, Zambia. Tel: +260 1 293 361; fax: +260 1 293 783; e-mail: firstname.lastname@example.org
Background: HIV-infected women need access to safe contraception. We hypothesized that women using depomedroxyprogesterone acetate (DMPA) contraception would have faster HIV disease progression than women using oral contraceptive pills (OCPs) and nonhormonal methods.
Methods: In a previously reported trial, we randomized 599 HIV-infected women to the intrauterine device (IUD) or hormonal contraception. Women randomized to hormonal contraception chose between OCPs and DMPA. This analysis investigates the relationship between exposure to hormonal contraception and HIV disease progression [defined as death, becoming eligible for antiretroviral therapy (ART), or both].
Results: Of the 595 women not on ART at the time of randomization, 302 were allocated to hormonal contraception, of whom 190 (63%) initiated DMPA and 112 (37%) initiated OCPs. Women starting IUD, OCPs, or DMPA were similar at baseline. Compared with women using the IUD, the adjusted hazard of death was not significantly increased among women using OCPs [1.24; 95% confidence interval (CI) 0.42–3.63] or DMPA (1.83; 95% CI 0.82–4.08). However, women using OCPs (adjusted hazard ratio (AHR) 1.69; 95% CI 1.09–2.64) or DMPA (AHR 1.56; 95% CI 1.08–2.26) trended toward an increased likelihood of becoming eligible for ART. Women exposed to OCPs (AHR 1.67; 95% CI 1.10–2.51) and DMPA (AHR 1.62; 95% CI 1.16–2.28) also had an increased hazard of meeting our composite disease progression outcome (death or becoming ART eligible) than women using the IUD.
Conclusion: In this secondary analysis, exposure to OCPs or DMPA was associated with HIV disease progression among women not yet on ART. This finding, if confirmed elsewhere, would have global implications and requires urgent further investigation.
Worldwide, 15.4 million women are infected with HIV . The majority is of childbearing age and not in immediate need of antiretroviral therapy (ART). Provision of safe and effective contraception prevents maternal mortality, reduces unsafe abortions, and allows control of childbearing [2,3]. The WHO also promotes effective contraception as a major component of preventing perinatal HIV infection . Two of the most common methods of modern contraception in sub-Saharan Africa are oral contraceptive pills (OCPs) and injectable progestins, such as depomedroxyprogesterone acetate (DMPA). Use of DMPA appears to be rising in many countries owing to its discreteness and its convenient 3-month dosing schedule .
We recently reported a randomized trial  that examined the contraceptive efficacy and safety of the intrauterine device (IUD) among HIV-infected women in Lusaka, Zambia. This trial found the IUD to be safe and effective, but subsequent analysis indicated that women allocated to the hormonal contraception control arm had faster progression of their HIV disease (on the basis of death and decline in CD4+ cell count). This finding corroborated by other research on both macaques  and humans  suggests a link between progesterone exposure and both HIV acquisition and faster disease progression. We therefore hypothesized that progesterone might be primarily responsible for the trial's observation and sought to examine the question in greater detail.
We have described details of this randomized trial and its methods previously . Briefly, postpartum HIV-infected women desiring contraception were randomized to either the copper-T IUD or hormonal contraception. Women allocated to the hormonal arm were allowed to choose between DMPA and OCPs. If breastfeeding, women choosing OCPs were placed on progesterone-only pills until their baby was 6 months old (according to Zambian national guidelines). Contraceptives were dispensed every 3 months. Study visits occurred at enrollment, 1 month after enrollment, and then every 6 months until the last randomized woman had been followed for 24 months. At each study visit, women were asked whether they were still using their randomized method of contraception, and if not, which method they were currently using (if any). Patient report was our only measure of adherence; we did not perform pill counts. Patients who missed scheduled study visits were followed up at home by community volunteers. Although study assignment was not masked, these volunteers were not informed of the patients' contraceptive methods in an effort to avoid differential follow-up by the study arm.
CD4+ cell counts were obtained every 12 months until August 2003, when ART became available in the public sector through the Mother-To-Child Transmission Plus Initiative . Thereafter, we obtained CD4+ cell counts every 6 months. Women were allowed to switch from their originally allocated contraceptive method and remain in the study.
We defined HIV disease progression as either death or becoming eligible for ART (decline in CD4+ cell count below 200 cells/μl or commencement of ART for any reason). Our primary analysis employs this composite outcome, but we also examined each factor separately (e.g. CD4+ cell count decline). Data were analyzed using SAS version 9.1.4 (SAS Institute, Cary, North Carolina, USA). Continuous covariates were compared across the three contraceptive exposures using unpaired, two-tailed t tests to evaluate means, and the nonparametric Wilcoxon's rank-sum test was used to evaluate differences in medians. Dichotomous and categorical variables were compared using the Pearson's chi-square test statistic. We used the Kaplan–Meier method and hazard rate ratios from Cox proportional hazard modeling to compare rates of clinical disease progression among the three contraceptive exposures. Multivariate models controlled for maternal baseline CD4+ cell count. Women were censored at the time of pregnancy, death, CD4+ cell count falling below 200 cells/μl, or starting ART. Of the 599 enrolled women, four were excluded from this analysis because they were already on ART at study enrollment. Women with initial CD4+ cell counts below 200 cells/μl were excluded from the analysis of the clinical outcome of CD4+ cell count falling below 200 cells/μl (n = 538). The composite analysis included all women, as those who had a CD4+ cell count less than 200 cells/μl were still ‘eligible’ to have the death outcome.
We categorized contraceptive exposure in the primary analysis by the method a woman was dispensed at her first study visit (whether their exposure was IUD or hormonal was random, but women allocated to the hormonal arm were allowed to choose between OCPs and DMPA). We refer to this as the ‘intent-to-treat’ analysis. As women were allowed to switch among methods at any time during the trial, including from IUD to hormonal or vice versa, we also performed an ‘actual-use analysis’ in which the contraceptive method was treated as a time-varying exposure in extended Cox proportional hazards regression. In this analysis, women who used more than one type of contraception contributed person-time to more than one exposure group. The study received continuing ethical review from the relevant authorities at the University of Zambia and the University of Alabama at Birmingham. All participants provided written informed consent.
We randomized 599 HIV-infected women between 12 June 2002 and 2 October 2003. Of those remaining, 303 were randomized to hormonal contraception and 296 to the IUD. Four women entered the study on ART and were excluded from this analysis (one in the hormonal arm and three in the IUD arm). One hundred and ninety (63%) of the 302 women randomized to the hormonal arm chose DMPA, and 112 (37%) chose OCPs. Women starting OCPs, DMPA, or IUD did not differ substantially by any clinical or sociodemographic factor that we measured at baseline (Table 1).
Overall, 208 of the 595 women either died (n = 27; 5%), became pregnant (n = 21; 4%), withdrew (n = 73; 12%), or were lost to follow-up (n = 90; 15%) prior to the end of the study period of 24 months. Of these women censored before 24 months, 81 (38.9%) initiated the IUD, 80 (37.9%) initiated DMPA, and 50 (23.7%) initiated OCPs. Among the 293 in the IUD group, 63 (21.5%) were either lost to follow-up or withdrawn, compared with 60 out of 190 women (31.6%) in the DMPA group and 40 out of 112 women (35.7%) in the OCP group. Compared with the IUD arm, women in the DMPA and OCP groups had 1.47 [95% confidence interval (CI) 1.09–1.99; P = 0.01] and 1.66 (95% CI 1.19–2.31; P < 0.001) increased hazard of becoming lost to follow-up or withdrawn at 24 months, respectively. We observed no statistically significant differences in baseline CD4+ cell counts or changes in CD4+ cell counts at 12 and 18 months within each exposure category prior to being lost to follow-up (data not shown).
Women randomized to the IUD arm were much more likely to discontinue their method than women in the DMPA or OCP groups. One hundred and forty-six women switched from the IUD over 504 woman-years of follow-up (switching rate 29.0/100 woman-years; 95% CI 24.6–34.0), 43 women switched from DMPA over 334 woman-years (switching rate 12.9/100 woman-years; 95% CI 9.5–17.3), and 43 women switched from OCPs over 163 woman-years (switching rate 26.4/100 woman-years; 95% CI 19.6–35.6). Compared with the IUD arm, the hazard rate ratio for switching contraception methods for the women initiated on DMPA was 0.44 (95% CI 0.31–0.62) and on OCPs was 0.94 (95% CI 0.68–1.32). The median period of follow-up for women initiating the IUD was 27.6 months, compared with 26.2 months among women initiating DMPA and 25.7 months among women initiating OCPs. To explore whether the change in methods might be driven by disease progression, we evaluated baseline CD4+ cell counts and changes in CD4+ cell counts at 12 and 18 months (delta CD4) prior to switching within strata of initial contraceptive exposure. We found no statistical evidence to suggest an association between more rapid CD4+ cell count decline and switching from a particular contraceptive method (data not shown).
Thirty women died over 1211 woman-years of follow-up (rate 2.5/100 woman-years). The mortality rate among women who started on the IUD was 2.0/100 woman-years. Mortality rates were slightly higher in women initiating DMPA (3.2/100 woman-years) and OCPs (2.4/100 woman-years). Compared with the IUD group, the crude hazard ratios for death in DMPA and OCP groups were 1.39 (95% CI 0.63–3.06) and 1.06 (95% CI 0.38–2.97), respectively (Table 2). Kaplan–Meier analysis indicated no significant difference in death between women initiating the different methods (log-rank, P = 0.48; Fig. 1a). In an actual-use analysis that treated current contraceptive method as a time-varying exposure, the hazard ratios for DMPA and OCP groups were 1.83 (95% CI 0.82–4.08) and 1.24 (95% CI 0.42–3.63; Table 2), respectively. Controlling for baseline BMI, education, and breast-feeding did not significantly change the results (data not shown).
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).
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