Hormonal contraceptive method use is associated with decreased maternal-child mortality, reduced unintended pregnancy, and improved reproductive autonomy for women.1 Hormonal methods are also a mainstay of Prong II (prevention of unintended pregnancy) of the WHO's 4-pronged prevention of mother-to-child transmission (PMTCT) strategy.2 However, conflicting evidence exists as to whether hormonal method use increases HIV disease progression in infected women.3 A systematic review by Phillips et al4 found that 10 of 11 observational studies showed no increased risk for HIV disease progression for hormonal versus nonhormonal method users. However, a randomized controlled trial (RCT) in which Zambian women were randomized to receive either the copper intrauterine device (IUD) or hormonal contraception [depot medroxyprogesterone acetate (DMPA) injectables or oral contraceptive pills (OCPs)] found in an intention-to-treat analysis that OCP use and DMPA use were associated with (1) CD4 <200 cells per cubic millimeter or antiretroviral treatment (ART) initiation and (2) death or CD4 <200 cells per cubic millimeter or ART initiation compared with women using the copper IUD.5 Although an RCT, this study suffered from high rates of method stopping and switching.3 Current WHO Medical Eligibility Criteria recommendations, developed after reviewing this literature, place no restriction on use of hormonal contraceptive methods by women based on HIV status.3
The alternative to contraception is often pregnancy, and the relationship between pregnancy and associated hormonal changes and HIV disease progression has been studied for over 2 decades6,7 also with mixed findings. A recent systematic review and meta-analysis7 synthesized findings from several observational studies. Of 4 studies meeting inclusion criteria,8–11 pregnancy was marginally though not significantly associated with low CD4 among ART-naive women; the only study from an Africa cohort (Uganda) also did not find an association between pregnancy and time to CD4 <200 cells per cubic millimeter.10 Conversely, in 5 studies meeting inclusion criteria,12–15 pregnancy was significantly associated with HIV-related death; the only study from an African cohort (Rwanda) did not find an association with time-to-HIV–related death.12 Three other recent observational studies (with the primary objective of assessing the relationship between hormonal contraception and HIV disease progression) also reported measures of effect for time-varying pregnancy with conflicting findings. A study of 2269 chronically HIV-infected women from 7 East and Southern African countries found that pregnancy was significantly associated with first occurrence of CD4 <200 cells per cubic millimeter, ART initiation, or nontraumatic death.16 Conversely, another study among 303 recently HIV-infected women from Uganda and Zimbabwe found no significant association between pregnancy and time-to-clinical AIDS, death, or ART initiation.17 Finally, a study among 625 Ugandan women also found no significant association between pregnancy and time to AIDS or death.18
Finally, as pregnancy is often followed by breastfeeding, which is also associated with hormonal changes, researchers have undertaken studies of the relationship between breastfeeding and HIV disease progression again with mixed findings. An RCT in Kenya showed that mortality among women randomized to breastfeeding increased 3-fold,19 whereas studies in Tanzania, Zambia, South Africa, Zimbabwe, and Malawi have not observed associations between breastfeeding and death or decreased CD4 count.20–24
With a growing population of HIV-infected women in sub-Saharan Africa, evaluating factors that may predict disease progression is imperative to improve health outcomes. In this study, we identify factors associated with HIV disease progression in HIV-positive women in Zambia and specifically evaluate the impact of contraceptive use, pregnancy, and breastfeeding on disease progression.
Approvals by the Office for Human Research Protections–registered Institutional Review Boards at Emory University and in Zambia were obtained. All participating couples provided written informed consent.
Study recruitment, eligibility, follow-up, and data collection methods used by the Rwanda Zambia HIV Research Group (RZHRG) have been reported previously.25–28 Briefly, we recruited cohabiting couples in Lusaka, Zambia, through community promotions29–31 to receive couples' voluntary HIV counseling and testing services.32 HIV discordant couples were enrolled in 3-monthly longitudinal follow-up between 1994 and 2012. This analysis considers only couples in which the woman was HIV positive at enrollment; women were censored if the couple separated, their male partner seroconverted, or if either partner was lost to follow-up. HIV testing using rapid serologic tests was conducted at baseline (and 3-monthly visits for negative partners).33 The primary objective of this cohort study was to determine predictors of heterosexual HIV-1 transmission, and censoring criteria were selected based on that primary objective.
Exposures of Interest
Time-varying contraceptive method, pregnancy, and breastfeeding were the exposures of interest. Contraceptive methods were provided at the research site at each 3-monthly follow-up visit34,35 categorized as: condoms alone (OCPs were typically combination estrogen and progesterone; progesterone-only pills were prescribed to breastfeeding women until children were 6 months old), DMPA injectables (150 mg intramuscular dosage), copper IUD, contraceptive implant (Norplant or Jadelle levonorgestrel implant), or permanent methods (hysterectomy, tubal ligation, or vasectomy). Contraceptive methods were categorized as implant, injectable, or OCP versus nonhormonal contraception control (including condoms alone, copper IUD, or permanent methods). Time-varying pregnancy was determined by pregnancy test or visual confirmation by a nurse counselor. Time-varying breastfeeding included intervals in which women self-reported breastfeeding and all intervals that were up to 6 months postpartum without infant death.
As previously reported, baseline and time-varying demographic, family planning, behavioral, sexual history, and clinical data are collected from each couple.28 In this analysis, we considered covariates known or hypothesized to be related to disease progression, including baseline measures of women's year of study enrollment, age (continuous and categorical measures considered), monthly household income (US Dollar equivalent, adjusted for exchange rate, continuous and categorical measures considered), literacy in Nyanja (the most common local language), and stage of HIV. We used the Modified Kigali combined HIV staging system, which incorporates clinical stage with erythrocyte sedimentation rate, hematocrit, and body mass index.32,36
Primary outcomes of interest are time to (1) all-cause death among female partners (>90% of which were HIV related) or (2) ART initiation (not including short course for PMTCT) among female partners. Since ART was not readily available in Zambia before 2003 and the first ART initiation occurred in November of 2003, analysis of ART initiation is restricted to November 2003 to 2012. Date of death among women was reported by male study partners or other family members. Time of ART initiation was obtained by self-report or plasma ART levels. Since we censor at ART initiation, no ART users are included in the time-to-death analysis.
Analyses were conducted with SAS v9.4 (Cary, NC). Outcome rates were calculated as the number of outcomes per woman-year of follow-up, stratified by time-varying contraceptive method exposure, pregnancy, and breastfeeding. Event rates were compared with reference groups using univariate Cox models. Outcome rates were also calculated stratified by other demographic and clinical covariates. Associations between these covariates and the outcomes of interest were evaluated using univariate Cox models. Crude hazard ratios (HRs), 95% confidence intervals (CIs), and associated P values are presented.
Multivariate Cox models accounting for repeated observations estimated the effect of time-varying contraceptive methods and covariates on the outcomes of interest. Covariates included in the models were those that were significantly associated with the outcome of interest in univariate analyses using Bonferroni corrected P values (P = 0.006) and which changed point estimates for any exposures of interest by ±10%. Multicollinearity was assessed; if any 2 variables were collinear, the variable with the weakest association with the outcome was removed. The proportional hazard assumption was confirmed for time-independent covariates.
Sensitivity analyses explored the effects of running models using censoring during pregnancy intervals and, for time to death, we additionally ran a model including women's baseline viral load (VL), which was a significant predictor of death but only available from 1999 onward. We also built multivariate models assessing the effect of progestin-only and combined OCPs separately, and removing IUDs from the reference group. Finally, we varied the assumed duration of breastfeeding from 4-month to 1-year postpartum.
Outcome Rates Overall and by Contraceptive Methods, Unadjusted
Among 1656 M-F+ couples followed for 3359 person-years (PY), 224 women died (6.7/100 PY; 95% CI: 5.8–7.6) (Table 1). Compared with women using nonhormonal methods, women using implants (HR = 0.32, P = 0.051) and injectables (HR = 0.60, P = 0.040) experienced lower rates of death, whereas women using OCPs did not (HR = 1.19, P = 0.340). Compared with women who were not pregnant, women who were currently pregnant did not experience significantly increased rates of death (HR = 1.32, P = 0.211), whereas women who were currently breastfeeding (HR = 0.32, P < 0.001) experienced lower rates of death.
The first ART initiation occurred in November 2003. Between November 2003 and 2012, 290 women initiated ART (14.5/100 PY; 95% CI: 12.9 to 16.2). Compared with women using nonhormonal methods, women using implants (HR = 0.45, P = 0.004) and OCPs (HR = 0.65, P = 0.044) experienced significantly lower rates of ART initiation in univariate analyses, as did women using injectables though this was not significant (HR = 0.71, P = 0.098). Compared with women who were not pregnant, women who were currently pregnant experienced non–statistically significantly increased rates of ART initiation (HR = 1.28, P = 0.217), whereas women who were currently breastfeeding (HR = 0.45, P = 0.003) experienced significantly lower rates of ART initiation.
Outcome Rates by Covariates, Unadjusted
Covariates significantly (Bonferroni P < 0.006) associated with time to death included enrolling in the study at any time before 2007 (HR between 2.12 and 3.02) versus after 2007, and having stage III (HR = 2.15) or stage IV (HR = 2.91) HIV disease versus stage I at enrollment, and increasing VL (HR = 2.43) (Table 2).
Covariates associated (Bonferroni P < 0.006) with time-to-ART initiation included enrolling in the study before 2007 (HR between 0.21 and 0.42) versus any time after 2007, increasing woman's age (HR = 1.06), being literate in Nyanja (HR = 1.43), and having stage III (HR = 1.90) or stage IV (HR = 3.09) HIV disease versus stage I at enrollment.
Multivariate Models and Sensitivity Analyses: Time-to-Death
In a multivariate model of time to death (model 1), hormonal implant [adjusted hazard ratio (aHR) = 0.30] and injectable (aHR = 0.59) were significantly protective relative to nonhormonal method use, whereas OCP use was not [aHR = 1.08, not significant (NS)] controlling for baseline HIV disease stage, time-varying pregnancy, breastfeeding, and year of study enrollment (Table 3). Pregnancy was not significantly associated with death (aHR = 1.07, NS), whereas breastfeeding significantly delayed death (aHR = 0.34) in multivariate analyses. In the model censoring for pregnancy intervals (model 2), implant use (P = 0.040), injectable use (P = 0.032), and breastfeeding (P < 0.001) reached significance for their protective effects on time to death. In both models 1 and 2, having stage III (aHR = 2.00–2.01) or stage IV (aHR = 2.66–2.95) HIV disease versus stage I at enrollment was significantly associated with time to death.
In a multivariate model additionally controlling for baseline log VL, though VL was significantly associated with time to death (aHR = 2.66; 95% CI: 1.99 to 3.53, P < 0.0001), the addition of VL did not change the point estimates for the exposures of interests by ±10% and was therefore not considered a confounder of the associations of interest. Running models among those with VL measures (collected after 1999) but without the VL covariate showed similar results (data not shown).
Multivariate Models and Sensitivity Analyses: Time-to-ART Initiation
In a multivariate model of time-to-ART initiation post-November 2003 (model 1), implant was significantly protective (aHR = 0.54), whereas OCP (aHR = 0.70, NS) and injectable (aHR = 0.85, NS) use were not significantly protective relative to nonhormonal method use controlling for woman's baseline age, literacy, HIV disease stage, time-varying pregnancy, time-varying breastfeeding, and year of study enrollment. Pregnancy was not significantly associated with ART initiation (aHR = 1.24, NS), whereas breastfeeding was significantly protective for ART initiation (aHR = 0.49) in multivariate analyses (Table 4). In the model censoring for pregnancy intervals (model 2), implant use (P = 0.048) and breastfeeding (P = 0.013) reached significance for their protective effects on time to ART initiation, whereas injectable (P = 0.393) and OCP use (P = 0.162) were non–significantly protective. In both models 1 and 2, increasing age (aHR = 1.05), being literate in Nyanja (aHR = 1.39–1.41), and having stage III (aHR = 2.13–2.15) or stage IV (aHR = 3.62–3.82) HIV disease versus stage I at enrollment were significantly associated with time to ART initiation.
Sensitivity Analyses (Data Not Shown)
Multivariate models assessing the effect of progestin-only and combined OCPs separately did not change our findings related to OCPs (ie, the point estimates for OCPs in multivariate models did not change in magnitude by ±10%, direction, or statistical significance). For example, in multivariate model 1 of time-to-ART initiation, the HR for combined OCPs was 0.69; 95% CI: 0.42 to 1.12 and for progestin-only OCPs was 0.78; 95% CI: 0.19 to 3.20. Excluding IUDs from the referent group leads to similar findings (ie, the point estimates for contraceptive methods in multivariate models did not change in magnitude by ±10%, direction, or statistical significance). We do not have the power to look at IUD users individually (only 1.5% of all intervals were IUD using intervals). Assuming breastfeeding of 4 months up to 1 year did not change our findings (ie, the point estimates for breastfeeding in multivariate models did not change in magnitude by ±10%, direction, or statistical significance).
In this prospective cohort of HIV-positive Zambian women in discordant couples, we found injectable hormonal contraception and hormonal implant associated with significantly lower mortality rates when adjusted for pregnancy, breastfeeding, and demographic and clinical covariates. We did not observe this association with OCP. In an analogous analysis of time-to-ART initiation, only the protective effect of the hormonal implant was statistically significant. Time-dependent measures of pregnancy were not significantly associated with either death or ART initiation, whereas breastfeeding was significantly protective for both.
The majority of published observational studies have found no increased HIV disease progression among women using hormonal methods.4 Our study shows a protective effect of hormonal implant and injectable contraception. These findings are similar to Allen et al,35 which found a borderline protective effect for time varying injectable (P = 0.09) and OCP (P = 0.08) use and time-to-HIV–related death in Rwandan women in multivariate models. Similarly, Heffron et al16 found that rates of disease progression (using a composite outcome of CD4 decline to less than 200 cells per cubic millimeter, initiation of ART, or death) were significantly lower for women using hormonal contraceptives versus nonhormonal contraceptive methods in a prospective cohort of women from 7 East and southern African countries.
We also did not find that time-varying measures of pregnancy were significantly associated with either HIV disease progression outcome, similar to findings from several meta-analyses and individual studies, which do not indicate a deleterious effect of pregnancy on HIV disease progression6,7,17,18,35,37 and in contrast to the relatively few studies that have seen this association.7,16 The finding that breastfeeding was strongly associated with a delay in both death and ART initiation was somewhat surprising given an RCT in Kenya, which showed that mortality among women randomized to breastfeeding was 3 times higher than the corresponding rate among bottle-feeding women.19 However, subsequent studies in Tanzania, Zambia, South Africa, Zimbabwe, and Malawi have not seen an association between breastfeeding and death or decreased CD4 count.20–24 We may be observing the result of the “healthy pregnant woman” bias, since women who are able to get pregnant (and then breastfeed a child who survives) are healthier.
The association between women who experience pregnancy or breastfeeding (not necessarily those who are currently pregnant or breastfeeding) is also of interest. In the time-to-ART initiation analysis, cumulative previous pregnancies and associated breastfeeding reported at enrollment were collinear with age. We retained age in the model (which was a significant risk factor); replacing age with cumulative previous pregnancy gave a nonsignificant protective effect for that variable (aHR = 0.99; 95% CI: 0.94 to 1.05, P = 0.75). Neither age nor cumulative previous pregnancies and associated breastfeeding were associated with death in univariate or multivariate analyses.
Although the findings of the START trial suggest that ART should now be offered at the time of diagnosis,38 we feel that use of ART initiation as a proxy outcome for disease progression remains relevant given that ART rationing is a current front-line reality in many locations.39,40 Despite the lowering of initiation criteria by WHO over the years, a review of 56 articles from 2002 to 2013 showed that “CD4 counts at ART presentation in sub-Saharan Africa have not increased over the past 10 years.41 However, it is possible that changes in national guidelines may lead to increased median CD4 counts at ART initiation, as it has in Rwanda42 and if economic conditions improve so that initiation on diagnosis becomes a reality, ART as a proxy outcome for disease progression may become less relevant.
It was not surprising that VL and HIV staging were predictive of mortality and that HIV staging was predictive of ART initiation. The staging system combining clinical and laboratory criteria used here has been shown to reflect a range of HIV-related outcomes including death and have prognostic significance among HIV-positive women in Rwanda32 and Zambia.36 This further supports the use of the modified Kigali combined staging system (using hematocrit and erythrocyte sedimentation rate in lieu of CD4, including pulmonary tuberculosis in stage 4, and substituting low body mass index for weight loss, among other less impactful adaptations) for predicting HIV-related disease outcomes among adults in circumstances that do not allow systematic CD4 screening.
Our findings also suggest that illiteracy may be a barrier to ART initiation. Similarly, recent systematic review using data from South Africa suggests that people with low education attainment have lower access to ART.43 In our study, although staff provided ART referrals and assisted patients in accessing ART services in government clinics to the extent possible if obstacles were reported, low literacy may have impeded patient willingness or their ability to follow through on referrals and prescriptions. This hypothesized role of socioeconomic disparities in health warrants further exploration among Zambian women.
Our study has limitations, including that we began following women after they were already HIV infected and therefore cannot measure time to event since HIV infection; however, we do not expect any bias introduced by not knowing the duration of infection to be differential. Similarly, we did not follow women from the time they initiated contraception before study start, but again we do not expect this bias to be differential—and in fact, most women (77.2%) were not using any method of contraception at baseline. Deaths were reported by family members, who provided verbal autopsies, and many ART initiations were self-reported, but again we do not expect any information bias to be differential by the exposure of interest. Women who chose certain contraceptive methods may be different from those who chose others by unmeasured confounders. In addition, as we censor couples at seroconversion of the HIV-negative male partner, we may be limiting our follow-up of more vulnerable woman PY. Loss to follow-up among M-F+ couples, which we have reported in our cohorts to be associated with residence far from the clinic, younger age, and younger women's age at first intercourse, no income, fewer lifetime sex partners, no history of genital abnormalities in women, and male partners having a recent concurrent partner26 may also limit the generalizability of our findings. Finally, 3-monthly study visits included assessments of HIV disease and referrals to government clinics where ART was available, so our clients were likely to initiate ART sooner than people in the general population also limiting generalizability.
Our study has several strengths. We are able to reliably assess contraceptive method use and rates of stopping/switching by providing the methods at the research site every 3 months; this overcomes limitations with self-reported method use commonly reported in other studies. As the outcomes of interest were also assessed often, at least 3-monthly, we are able to more accurately assess when outcomes occurred. We also have relatively more power than previous studies to disaggregate the effects of implant use (73% power for the time-to-death analysis and 55% power for the ART initiation analysis for implant use) on disease progression. Finally, we measure and control for several fixed and time-varying covariates associated with disease progression.
Hormonal contraceptive implants and injectable contraception were associated with significantly lower mortality rates among HIV-infected women. Hormonal implants were also protective for ART initiation. OCPs and pregnancy were not associated with death or ART initiation, whereas breastfeeding was protective for both. These findings add to a relatively small, inconclusive literature and suggest that HIV-positive women desiring pregnancy can be counseled to do so and to breastfeed without concerns about deleterious health related to pregnancy or breastfeeding.
For HIV-positive women who wish to delay fertility, our findings support the conclusion that hormonal implants and injectables can be used without concerns about deleterious health effects and with possible health benefits. Given high rates of unintended pregnancy and associated maternal-child mortality among HIV-positive women in sub-Saharan Africa, as well as the cost-effectiveness of prevention of unintended pregnancy for PMTCT strategy,44 we recommend increasing the contraceptive method mix for all women with and at risk of HIV with a focus on long-acting reversible contraceptive (LARC) methods, both hormonal and nonhormonal, which are highly effective and may be associated with better health outcomes among HIV-positive women but remain inaccessible in much of Africa. Further study is needed of the copper IUD, a nonhormonal LARC method that is highly cost-effective in preventing unplanned pregnancy and may have health benefits for HIV-positive women. Finally, as we have shown previously that contraception uptake increases, especially LARC methods, after couples' HIV and family planning counseling with fertility intention assessment,45 we recommend that HIV and family planning services in Africa be integrated with a focus on couples.
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