Pai Lien Chen

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.

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.

Hormonal contraceptive use and HIV disease progression among women in Uganda and Zimbabwe

Background:HIV-infected women need highly effective contraception to reduce unintended pregnancies and mother-to-child HIV transmission. Previous studies report conflicting results regarding the effect of hormonal contraception on HIV disease progression. Methods:HIV-infected women in Uganda and Zimbabwe were recruited immediately after seroconversion; CD4 testing and clinical examinations were conducted quarterly. The study end point was time to AIDS (two successive CD4 200 cells/mm3 or less or World Health Organization advanced Stage 3 or Stage 4 disease). We used marginal structural Cox survival models to estimate the effect of cumulative exposure to depot-medroxyprogesterone acetate and oral contraceptives on time to AIDS. Results:Three hundred three HIV-infected women contributed 1408 person-years. One hundred eleven women (37%) developed AIDS. Cumulative probability of AIDS was 50% at 7 years and did not vary by country. AIDS incidence was 6.6, 9.3, and 8.8 per 100 person-years for depot-medroxyprogesterone acetate, oral contraceptive, and nonhormonal users. Neither depot-medroxyprogesterone acetate (adjusted hazard ratio, 0.90; 95% confidence interval, 0.76-1.08) nor oral contraceptives ( adjusted hazard ratio, 1.07; 95% confidence interval, 0.89-1.29) were associated with HIV disease progression. Alternative exposure definitions of hormonal contraception use during the year before AIDS or at the time of HIV infection produced similar results. Sexually transmitted infection symptoms were associated with faster progression, whereas young age at HIV infection (18-24 years) was associated with slower progression. Adding baseline CD4 level and set point viral load to models did not change the hormonal contraception results, but Subtype D infection became associated with disease progression. Conclusion:Hormonal contraceptive use was not associated with more rapid HIV disease progression, but older age, sexually transmitted infection symptoms, and Subtype D infection were.

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.

Determinants of prevalent HIV infection and late HIV diagnosis among young women with two or more sexual partners in Beira, Mozambique.

Background The prevalence and determinants of HIV and late diagnosis of HIV in young women in Beira, Mozambique, were estimated in preparation for HIV prevention trials. Methods An HIV prevalence survey was conducted between December 2009 and October 2012 among 1,018 women aged 18–35 with two or more sexual partners in the last month. Participants were recruited in places thought by recruitment officers to be frequented by women at higher-risk, such as kiosks, markets, night schools, and bars. Women attended the research center and underwent a face-to-face interview, HIV counseling and testing, pregnancy testing, and blood sample collection. Results HIV prevalence was 32.6% (95% confidence interval (CI) 29.7%–35.5%). Factors associated with being HIV infected in the multivariable analysis were older age (p<0.001), lower educational level (p<0.001), self-reported genital symptoms in the last 3 months (adjusted odds ratio (aOR) = 1.4; CI 1.1–2.0), more than one lifetime HIV test (aOR = 0.4; CI 0.3–0.6), and not knowing whether the primary partner has ever been tested for HIV (aOR = 1.7; CI 1.1–2.5). About a third (32.3%) of participants who tested HIV-positive had a CD4 lymphocyte count of <350 cells/µl at diagnosis. Factors associated with late diagnosis in multivariable analyses were: not knowing whether the primary partner has ever been tested for HIV (aOR = 2.2; CI 1.1–4.2) and having had a gynecological pathology in the last year (aOR = 3.7; CI 1.2–12.0). Conclusions HIV prevalence and late diagnosis of HIV infection were high in our study population of young women with sexual risk behavior in Beira, Mozambique. HIV prevention programs should be strengthened, health care providers should be sensitized, and regular HIV testing should be encouraged to enroll people living with HIV into care and treatment programs sooner.

HIV incidence in a cohort of women at higher risk in Beira, Mozambique: prospective study 2009-2012

Background HIV is prevalent in Sofala Province, Mozambique. To inform future prevention research, we undertook a study in the provincial capital (Beira) to measure HIV incidence in women at higher risk of HIV and assess the feasibility of recruiting and retaining them as research participants. Methods Women age 18–35 were recruited from schools and places where women typically meet potential sexual partners. Eligibility criteria included HIV-seronegative status and self-report of at least 2 sexual partners in the last month. History of injection drug use was an exclusion criterion, but pregnancy was not. Participants were scheduled for monthly follow-up for 12 months, when they underwent face-to-face interviews, HIV counseling and testing, and pregnancy testing. Results 387 women were eligible and contributed follow-up data. Most were from 18–24 years old (median 21). Around one-third of participants (33.8%) reported at least one new sexual partner in the last month. Most women (65.5%) reported not using a modern method of contraception at baseline. Twenty-two women seroconverted for a prospective HIV incidence of 6.5 per 100 woman-years (WY; 95% confidence interval (CI): 4.1–9.9). Factors associated with HIV seroconversion in the multivariable analysis were: number of vaginal sex acts without using condoms with partners besides primary partner in the last 7 days (hazard ratio (HR) 1.7; 95% CI: 1.2–2.5) and using a form of contraception at baseline other than hormonal or condoms (vs. no method; HR 25.3; 95% CI: 2.5–253.5). The overall retention rate was 80.0% for the entire follow-up period. Conclusions We found a high HIV incidence in a cohort of young women reporting risky sexual behavior in Beira, Mozambique. HIV prevention programs should be strengthened. Regular HIV testing and condom use should be encouraged, particularly among younger women with multiple sexual partners.

Immune responses in Ugandan women infected with subtypes A and D HIV using the BED capture immunoassay and an antibody avidity assay.

Introduction:Analysis of samples from Uganda using serologic HIV incidence assays reveal that individuals with subtype D infection often have weak humoral immune responses to HIV infection. It is unclear whether this reflects a poor initial response to infection or a waning antibody response later in infection. Materials and Methods:Samples (N = 2614) were obtained from 114 women aged 18–45 years in the Ugandan Genital Shedding and Disease Progression Study cohort (2001–2009; 82 subtype A, 32 subtype D; median 23 samples/women, range 3–41 samples, median follow-up of 6.6 years). Samples were analyzed using the BED capture immunoassay (cutoff, 0.8 OD-n) and the avidity assay (cutoff, 90% Avidity Index). Antibody maturation was assessed by having the BED capture enzyme immunoassay (BED-CEIA) or avidity value exceed the assay cutoff 1 or 2 years after infection. The waning antibody response was measured by having the BED-CEIA or avidity value fall >20% below the maximum value. Results:For the BED-CEIA, 8 women with subtype A infection and 3 women with subtype D infection never progressed previously the cutoff value (median, 5.9 years follow-up after infection). Six women with subtype D infection never achieved an avidity index >90%. Subtype did not impact the proportion of women whose assay values regressed by >20% of the maximal value (for BED-CEIA: 33% for A, 41% for D, P = 0.51; for avidity: 1% for A, 6% for D, P = 0.19). Discussion:The higher frequency of misclassification of individuals with long-term subtype D infection as recently infected using serologic incidence assays reflects a weak initial antibody response to HIV infection that is sustained over time.

Prevalence, incidence and determinants of herpes simplex virus type 2 infection among HIV-seronegative women at high-risk of HIV infection: a prospective study in Beira, Mozambique.

Objectives To estimate the prevalence, incidence and determinants of herpes simplex type 2 (HSV-2) infection, and associations between HSV-2 and incident HIV infection, among women at higher risk for HIV infection in Beira, Mozambique. Methods Between 2009 and 2012, 411 women aged 18–35 years at higher risk of HIV acquisition (defined as having had two or more sexual partners in the month prior to study enrollment) were enrolled and followed monthly for one year. At each study visit, they were counseled, interviewed, and tested for HSV-2 and HIV antibodies. Results The HSV-2 prevalence at baseline was 60.6% (95% CI: 55.7% –65.4%). Increasing age (aOR = 2.94, 95% CI: 1.74–4.97, P<0.001 and aOR = 3.39, 95% CI: 1.58–7.29, P = 0.002 for age groups of 21–24 and 25–35 years old respectively), lower educational level (aOR = 1.81, 95% CI: 1.09–3.02, P = 0.022), working full time (aOR = 8.56, 95% CI: 1.01–72.53, P = 0.049) and having practiced oral sex (aOR = 3.02, 95% CI: 1.16–7.89, P = 0.024) were strongly associated with prevalent HSV-2 infection. Thirty one participants seroconverted for HSV-2 (20.5%; 95% CI: 14.4% –27.9%) and 22 for HIV during the study period. The frequency of vaginal sex with a casual partner using a condom in the last 7 days was independently associated with incident HSV-2 infection (aOR = 1.91, 95% CI: 1.05–3.47, P = 0.034). Positive HSV-2 serology at baseline was not significantly associated with risk of subsequent HIV seroconversion. Conclusions Young women engaging in risky sexual behaviors in Beira had high prevalence and incidence of HSV-2 infection. Improved primary HSV-2 control strategies are urgently needed in Beira.

Infecting HIV-1 Subtype Predicts Disease Progression in Women of Sub-Saharan Africa

Introduction Long-term natural history cohorts of HIV-1 in the absence of treatment provide the best measure of virulence by different viral subtypes. Methods Newly HIV infected Ugandan and Zimbabwean women (N = 303) were recruited and monitored for clinical, social, behavioral, immunological and viral parameters for 3 to 9.5 years. Results Ugandan and Zimbabwean women infected with HIV-1 subtype C had 2.5-fold slower rates of CD4 T-cell declines and higher frequencies of long-term non-progression than those infected with subtype A or D (GEE model, P < 0.001), a difference not associated with any other clinical parameters. Relative replicative fitness and entry efficiency of HIV-1 variants directly correlated with virulence in the patients, subtype D > A > C (P < 0.001, ANOVA). Discussion HIV-1 subtype C was less virulent than either A or D in humans; the latter being the most virulent. Longer periods of asymptomatic HIV-1 subtype C could explain the continued expansion and dominance of subtype C in the global epidemic.