Cynthia Kwok

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis:

In a meta-analysis of individual participant data, Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa.

Hormonal Contraception and HIV Acquisition: Reanalysis using Marginal Structural Modeling

Hormonal contraceptives are used widely worldwide; their effect on HIV acquisition remains unresolved. We reanalyzed data from the Hormonal Contraception and HIV Study using marginal structural modeling to reduce selection bias due to time-dependent confounding. Replicating our original analysis closely, we found that depo-medroxyprogesterone acetate (DMPA) but not combined oral contraceptive (COC) was associated with increased HIV acquisition. Also, young (18–24 years) but not older women who used DMPA and COCs were at increased HIV risk.

Hormonal contraceptive use, cervical ectopy, and the acquisition of cervical infections

Background and Objectives: Several previous studies have suggested that hormonal contraception could be associated with increased risk of cervical infections. However, few high-quality prospective studies have examined this relationship. Goal: The goal of this study was to measure the effect of oral contraceptives (OC) and depot-medroxyprogesterone acetate (DMPA) on the acquisition of cervical chlamydial and gonococcal infections. Study: Women attending 2 reproductive health centers in Baltimore, MD, were enrolled into a prospective cohort study. Participants were 15 to 45 years and were initiating OCs or DMPA or not using hormonal contraception. Interviews, physical examinations, and testing for incident cervical infections were conducted at 3, 6, and 12 months. Results: The analysis included 819 women. Most were single (77%) and nulliparous (75%); 43% were black. Median age was 22 years. During the study, 45 women acquired a chlamydial or gonococcal infection (6.2 per 100 women-years). DMPA use (hazard ratio [HR], 3.6; 95% confidence interval [CI], 1.6–8.5), but not OC use (HR, 1.5; 95% CI, 0.6–3.5), was significantly associated with increased acquisition of cervical infections after adjusting for other risk factors. Cervical ectopy was not an important mediator of cervical infection risk. Conclusions: DMPA use, but not OC use, appeared to be significantly associated with increased acquisition of cervical chlamydial and gonococcal infections.

Is the intrauterine device appropriate contraception for HIV-1-infected women?

Objective To assess whether the risk of complications is higher in HIV‐1‐infected women compared with non‐infected women in the two years following insertion of the intrauterine contraceptive device.

Disentangling contributions of reproductive tract infections to HIV acquisition in African women.

Objective: To estimate the effects of reproductive tract infections (RTIs) on HIV acquisition among Zimbabwean and Ugandan women. Methods: A multicenter prospective observational cohort study enrolled 4439 HIV-uninfected women aged 18 to 35 attending family planning clinics in Zimbabwe and Uganda. Participants were interviewed, and tested for HIV and RTIs every 3 months for 15 to 24 months. They received HIV risk reduction counseling, male condoms, and treatment for curable RTIs. Results: Despite HIV risk reduction counseling and regular screening and treatment for RTIs, the HIV incidence did not decline during the study. Positive HSV-2 serostatus at baseline (hazard ratio [HR] = 3.69, 95% confidence interval = 2.45–5.55), incident HSV-2 (HR = 5.35, 3.06–9.36), incident Neisseria gonorrhoeae (HR = 5.46, 3.41–8.75), and altered vaginal flora during the study (bacterial vaginosis [BV]: HR = 2.12, 1.50–3.01; and intermediate flora: HR = 2.02, 1.39–2.95) were independently associated with HIV acquisition after controlling for demographic and behavioral covariates and other RTIs (Treponema pallidum, Chlamydia trachomatis, Trichomonas vaginalis, and vaginal yeasts). For N. gonorrhoeae, C. trachomatis, T. vaginalis, and vaginal yeasts, the risk of HIV acquisition increased when the infection was identified at the visit before the HIV-detection visit or with the duration of infection. Population attributable risk percent (PAR%) calculations show that HSV-2 contributes most to acquisition of new HIV infections (50.4% for baseline HSV-2 and 7.9% for incident HSV-2), followed by altered vaginal flora (17.2% for bacterial vaginosis and 11.8% for intermediate flora). Conclusions: A substantial proportion of new HIV infections in Zimbabwean and Ugandan women are attributable to RTIs, particularly HSV-2 and altered vaginal flora.

Hormonal contraception and the risk of HIV acquisition among women in South Africa

Objectives:To evaluate the effect of hormonal contraception including combined oral contraceptives (COCs), and the injectable progestins depo-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (Net-En) on the risk of HIV acquisition among women in South Africa. Design/methods:We analyzed data from 5567 women aged 16–49 years participating in the Carraguard Phase 3 Efficacy Trial. Participants were interviewed about contraceptive use and sexual behaviors and underwent pelvic examinations and HIV testing quarterly. We used marginal structural Cox regression models to estimate the effect of hormonal contraception exposure on HIV acquisition risk among women overall and among young women (16–24 years) in particular. Results:Two hundred and seventy participants became HIV-infected (3.7 per 100 woman-years); HIV incidence was 2.8, 4.6, 3.5 and 3.4 per 100 woman-years in the COC, DMPA, Net-En and nonhormonal contraceptive groups, respectively (P = 0.09). The adjusted hazard ratios (AHRs) were 0.84 [95% confidence interval (CI) 0.51–1.39], 1.28 (95% CI 0.92–1.78) and 0.92 (95% CI 0.64–1.32) among COC, DMPA and Net-En users, respectively, compared with the nonhormonal group controlling for covariates. Age modified the effect of hormonal contraception on HIV acquisition risk; among young women, the AHRs were 1.02 (95% CI 0.46–2.28) for COCs, 1.68 (95% CI 0.96–2.94) for DMPA and 1.36 (95% CI0.78–2.35) for Net-En users. Conclusions:In this study conducted among South African women, hormonal contraception did not significantly increase the risk of HIV acquisition. However, the effect estimate does not rule out a moderate increase in HIV risk associated with DMPA use found in some other recent studies.

Plasma and Cervical Viral Loads among Ugandan and Zimbabwean Women during Acute and Early HIV-1 Infection

Objectives:High levels of HIV-1 viremia exist in peripheral blood during acute and early infection; however, data on HIV-1 viral loads in female genital secretions during this period are sparse. Design:Prospective cohort of 188 African women with primary HIV-1 infection. Methods:HIV-uninfected and infected women were followed quarterly; we tested serial plasma specimens by HIV PCR to estimate infection dates. We used the Loess procedure to estimate the magnitude and timing of viral setpoints in plasma and cervical secretions and generalized estimating equations (GEE) to identify predictors of plasma and cervical viral setpoints. Results:We estimated the mean HIV-1 plasma setpoint to be 4.20 log10 HIV-1 RNA copies/ml [95% confidence interval (CI) 4.04–4.35] at 121 days (95% CI 91–137) from infection; an analogous mean cervical viral setpoint was 1.64 log10 HIV-1 RNA copies/swab (95% CI 1.46–1.82) at 174 days (95% CI 145–194) from infection. Cervical loads were significantly higher (0.7–1.1 log10 copies/swab) during acute infection than subsequently. Subtype D infection, pregnancy, breastfeeding, and older age at the time of infection were associated with higher plasma viral setpoint. Subtype C infection, nonviral sexually transmitted infections, having a partner spending nights away from home, recent unprotected sex, and shorter time since infection were associated with higher cervical HIV-1 loads. Hormonal contraception was not associated with either the HIV-1 plasma setpoint or cervical loads during early infection. Conclusion:Cervical HIV-1 viral loads were highest during acute infection and then declined up to 6 months following infection, when a ‘setpoint’ was attained. The prognostic value of a cervical ‘setpoint’ on future transmission risk remains unclear.

Cervical inflammation and immunity associated with hormonal contraception, pregnancy, and HIV-1 seroconversion.

Objective:Hormonal contraception (HC), younger age, and pregnancy have been associated with increased HIV risk in some studies. We sought to elucidate the biological mechanisms for these associations. Design:Case–control selection of specimens from a large, prospective, clinical study. Methods:We enrolled and followed 4531 HIV-negative women from Uganda and Zimbabwe using either the injectable depo-medroxyprogesterone acetate (DMPA), combined oral contraception, or no HC (NH). Innate immunity mediators were measured in cervical samples collected from women at their visit before HIV seroconversion (n = 199) and matched visits from women remaining HIV uninfected (n = 633). Generalized linear models were applied after Box–Cox power transformation. Results:Higher RANTES and lower secretory leukocyte protease inhibitor (SLPI) levels were associated with HIV seroconversion. DMPA users had higher RANTES and lower BD-2 levels. Most inflammation-promoting and/or inflammation-inducible mediators were higher [interleukin (IL)-1&bgr;, IL-6, IL-8, MIP-3&agr;, vascular endothelial growth factor, and SLPI], and the protective BD-2 and IL-1RA:IL-1&bgr; ratio were lower among combined oral contraception users. Pregnant women showed a similar cervical immunity status (higher IL-1&bgr;, IL-6, IL-8, vascular endothelial growth factor, SLPI, and IL-1RA; lower IL-1RA:IL-1&bgr;). Age <25 years was associated with lower SLPI, IL-8, MIP-3&agr; but higher IL-1RA:IL-1&bgr;. Zimbabwean women (with higher HIV seroconversion rates) had overall higher pro-inflammatory and lower anti-inflammatory protein levels than Ugandan women. Conclusions:HC use, pregnancy, and young age alter cervical immunity in different ways known to increase risk of HIV, for example, through increased levels of pro-inflammatory cytokines or decreased levels of SLPI. Higher levels of RANTES may be one factor underlying a possible association between DMPA use and risk of HIV acquisition.

Increases in Human Papillomavirus Detection During Early HIV Infection Among Women in Zimbabwe

BACKGROUND Individuals who acquire human immunodeficiency virus (HIV) may experience an immediate disruption of genital tract immunity, altering the ability to mount a local and effective immune response. This study examined the impact of early HIV infection on new detection of human papillomavirus (HPV). METHODS One hundred fifty-five Zimbabwean women with observation periods before and after HIV acquisition and 486 HIV-uninfected women were selected from a cohort study evaluating hormonal contraceptive use and risk of HIV acquisition. Study visits occurred at 3-month intervals. Cervical swab samples available from up to 6 months before, at, and up to 6 months after the visit when HIV was first detected were typed for 37 HPV genotypes or subtypes. RESULTS We observed ∼5-fold higher odds of multiple (≥2) new HPV detections only after HIV acquisition, relative to HIV-negative women after adjusting for sexual behavior and concurrent genital tract infections. We also observed ∼2.5-fold higher odds of single new HPV detections at visits before and after HIV acquisition, relative to HIV-uninfected women in multivariable models. CONCLUSIONS These findings suggest that HIV infection has an immediate impact on genital tract immunity, as evidenced by the high risk of multiple new HPV detections immediately after HIV acquisition.

The Contribution of Cervicovaginal Infections to the Immunomodulatory Effects of Hormonal Contraception

ABSTRACT Particular types of hormonal contraceptives (HCs) and genital tract infections have been independently associated with risk of HIV-1 acquisition. We examined whether immunity in women using injectable depot medroxyprogesterone acetate (DMPA), combined oral contraceptives (COC), or no HCs differs by the presence of cervicovaginal infections. Immune mediators were quantified in cervical swabs from 832 HIV-uninfected reproductive-age Ugandans and Zimbabweans. Bacterial infections and HIV were diagnosed by PCR, genital herpes serostatus by enzyme-linked immunosorbent assay (ELISA), altered microflora by Nugent score, and Trichomonas vaginalis and Candida albicans infection by wet mount. Generalized linear models utilizing Box-Cox-Power transformation examined associations between levels of mediators, infection status, and HCs. In no-HC users, T. vaginalis was associated with broadest spectrum of aberrant immunity (higher interleukin 1β [IL-1β], IL-8, macrophage inflammatory protein 3α [MIP-3α], β-defensin 2 [BD2], and IL-1 receptor antigen [IL-1RA]). In women with a normal Nugent score and no genital infection, compared to the no-HC group, COC users showed higher levels of IL-1β, IL-6, IL-8, and IL-1RA, while DMPA users showed higher levels of RANTES and lower levels of BD2, both associated with HIV seroconversion. These effects of COC were blunted in the presence of gonorrhea, chlamydia, trichomoniasis, candidiasis, and an abnormal Nugent score; however, RANTES was increased among COC users with herpes, chlamydia, and abnormal Nugent scores. The effect of DMPA was exacerbated by lower levels of IL-1RA in gonorrhea, chlamydia, or herpes, SLPI in gonorrhea, and IL-1β, MIP-3α, and IL-1RA/IL1β ratio in trichomoniasis. Thus, the effects of HC on cervical immunity depend on the genital tract microenvironment, and a weakened mucosal barrier against HIV may be a combined resultant of genital tract infections and HC use. IMPORTANCE In this article, we show that in young reproductive-age women most vulnerable to HIV, hormonal contraceptives are associated with altered cervical immunity in a manner dependent on the presence of genital tract infections. Through altered immunity, hormones may predispose women to bacterial and viral pathogens; conversely, a preexisting specific infection or disturbed vaginal microbiota may suppress the immune activation by levonorgestrel or exacerbate the suppressed immunity by DMPA, thus increasing HIV risk by their cumulative action. Clinical studies assessing the effects of contraception on HIV susceptibility and mucosal immunity may generate disparate results in populations that differ by microbiota background or prevalence of undiagnosed genital tract infections. A high prevalence of asymptomatic infections among HC users that remain undiagnosed and untreated raises even more concerns in light of their combined effects on biomarkers of HIV risk. The molecular mechanisms of the vaginal microbiomes simultaneous interactions with hormones and HIV remain to be elucidated. In this article, we show that in young reproductive-age women most vulnerable to HIV, hormonal contraceptives are associated with altered cervical immunity in a manner dependent on the presence of genital tract infections. Through altered immunity, hormones may predispose women to bacterial and viral pathogens; conversely, a preexisting specific infection or disturbed vaginal microbiota may suppress the immune activation by levonorgestrel or exacerbate the suppressed immunity by DMPA, thus increasing HIV risk by their cumulative action. Clinical studies assessing the effects of contraception on HIV susceptibility and mucosal immunity may generate disparate results in populations that differ by microbiota background or prevalence of undiagnosed genital tract infections. A high prevalence of asymptomatic infections among HC users that remain undiagnosed and untreated raises even more concerns in light of their combined effects on biomarkers of HIV risk. The molecular mechanisms of the vaginal microbiomes simultaneous interactions with hormones and HIV remain to be elucidated.