Prevention of HIV transmission (including female-to-male sexual HIV transmission) and prevention of unintended pregnancy (including unintended pregnancies to women living with HIV) are both important concerns for public health and for sexual and reproductive rights. Enabling HIV-positive women who wish to avoid pregnancy to use contraception is also a key strategy in reducing vertical HIV transmission. Hormonal contraceptives are among the most highly effective, reversible methods of pregnancy prevention. The World Health Organization has emphasized the need to understand if various methods of hormonal contraception affect HIV acquisition in HIV-negative women, HIV progression in HIV-positive women, transmission of HIV from an HIV-positive woman to an HIV-negative male sexual partner, and whether various hormonal contraceptive methods may interact with antiretroviral therapy (ART) .
Previous systematic reviews concluded that hormonal contraception is well tolerated by women living with HIV, but that some theoretical concerns remain . Our objective was to update previous reviews on the association between hormonal contraception use and risk of HIV transmission from HIV-positive women to HIV-negative male sexual partners. In this review, we do not address HIV acquisition, progression, or drug interactions, which have been addressed elsewhere [2–5]. An earlier version of this systematic review was prepared for a WHO technical consultation in January/February 2012, during which evidence regarding the safety of hormonal contraception for women living with HIV was considered.
Several biological mechanisms could theoretically increase risk of HIV transmission from HIV-positive hormonal contraception users, but it is unclear which, if any, are relevant . Higher genital HIV viral shedding has been associated with increased HIV transmission to men  and such shedding could be increased by direct effects of hormonal contraception on the genital tract or on local virus replication, or by indirect effects of hormonal contraception on cervical inflammation or susceptibility to sexually transmitted infections (STIs) . Oral contraceptive pills (OCPs) have been associated with cervical ectopy [9,10], which has been associated with higher genital viral load in some studies [11,12] but not others [13–15]. During pregnancy, when levels of sex steroid hormones are increased, higher levels of genital HIV shedding [11,12,16–19] and higher rates of HIV transmission to men have been reported . A causal relationship between hormonal contraception and various STIs remains unclear , but if hormonal contraception does increase STI risk, this could in turn increase genital inflammation , which has been associated with increased genital HIV shedding . STIs such as chlamydia and gonorrhea have been associated with increased viral shedding in some studies , and herpes simplex virus-2 has been directly associated with increased HIV transmission . Plasma viral load is a predictor of likelihood of HIV transmission [25,26], and any effect of hormonal contraception on plasma viral load could also affect infectiousness.
We searched PubMed and Embase for articles in any language ever published (or in press and brought to our attention) in a peer-reviewed journal through December 15, 2011 (search strategy available on request). We also searched reference lists of identified articles. We considered studies that compared HIV-positive women using hormonal contraception [injectables, OCPs, implants, the contraceptive patch, the contraceptive ring, or levonorgestrel intrauterine device (IUD)] against HIV-positive women not using these methods. We included randomized controlled trials (RCTs) or cohort studies with ‘direct evidence,’ in which incident HIV infection rates in male sexual partners was an outcome variable. We also included RCTs, cohort studies, or cross-sectional studies with ‘indirect evidence,’ which assessed proxy measures for infectivity in women, such as genital HIV shedding or plasma viral load, as an outcome variable.
We used Early Review Organizing Software during article selection . One author conducted the literature search and identified studies for full-text review; all authors determined study inclusion and independently abstracted study information. When necessary, we attempted to contact study authors for clarifications. We did not perform meta-analysis because of limited direct evidence and heterogeneity in the design and results of studies with indirect evidence .
Assessment of direct evidence
By design, studies that provide direct evidence on hormonal contraception use and female-to-male HIV transmission are conducted among serodiscordant couples. We considered multiple methodologic factors that could affect study quality and results, including:
Consideration of important confounders
The potential for confounding is inherent in observational studies. Women who use hormonal contraception may differ in important ways from nonusers, and such differences could also be related to risk of HIV transmission. For example, hormonal contraception users may have higher coital frequency or less consistent condom use than nonusers of hormonal contraception [29–32], and may also differ in age, marital status, pregnancy status, or other factors.
We considered how studies assessed potential confounders, and whether they used multivariate analysis to attempt to adjust for confounding. Factors, which vary over time may result in time-dependent confounding. In such cases, marginal structural models (MSM) fit with inverse probability weights may be preferred [33–35], but these models are complex and require multiple assumptions. As with traditional statistical approaches, causal inference relies on the assumption that all confounders have been adequately measured and controlled for, or addressed with study design.
Statistical adjustment is not always sufficient to eliminate confounding. For example, information on self-reported condom use is often inaccurate [36–38], and using inadequately measured information for statistical adjustment (or failing to adjust for important covariates) can leave residual confounding. Comparing hormonal contraception users to women who use condoms as a primary contraceptive method may be problematic if consistency of condom use differs between these groups (as has been suggested in previous studies [39–42]), but is not adequately controlled. However, reasons for condom use may be unclear, and the correlation between reason for condom use and patterns of consistency of use may vary. Conducting sensitivity analyses restricted to women who report never using condoms during the study period may help to assess the robustness of results. Correlating self-reported consistent condom use with reductions in HIV or pregnancy rates, or providing information on concordance of dyad partner reports of condom use may help to increase confidence in accuracy of self-reported condom use information, and enhance confidence in successful adjustment for condom use.
Low loss to follow-up
We defined low loss to follow-up as less than 20% at 12 months.
Frequency and accuracy in measurement of exposure, outcome, and key variables
If both hormonal contraception use and HIV status are not measured repeatedly, frequently, and with respect to the same intervals of time, it is difficult to determine if hormonal contraception was used at the time of HIV transmission, or whether exposure misclassification occurred. Although nondifferential exposure misclassification could bias results towards the null, direction of the effect of differential exposure misclassification from contraceptive discontinuation, initiation, and switching on estimates is unclear, and could be more problematic for OCP versus injectable estimates, given the shorter duration of effect. Use of time-varying information, preferably in conjunction with short intersurvey intervals, can reduce misclassification. Longer intersurvey intervals increase the possibility of recall bias, make it more difficult to establish temporality, and may not accurately capture contraceptive-switching or other time-varying behaviors. We considered an intersurvey interval of less than 6 months a methodologic advantage. Most contraceptive information is collected via self-report, but validation using clinic contraceptive records can increase accuracy. Studies should collect information on type of hormonal contraception method (and dosage, if applicable), present estimates separately for different hormonal contraception methods, exclude other hormonal contraception methods from the comparison group, and use time-varying information.
Purpose of data collection
Studies specifically intended to assess the relationship between hormonal contraception use and HIV transmission may theoretically collect more comprehensive information on key variables. For secondary data analyses, the effects of study inclusion and exclusion criteria, as well as the quality of information available on key factors, should be considered. Studies should ideally specify analysis plans in advance to discourage selective reporting of statistically significant results from posthoc analyses.
Study power and precision
Studies may have limited statistical power to detect an effect if the sample size is small, the number of HIV-infected hormonal contraception users is low, or few men contract HIV. In attempting to draw causal inference, particularly in observational data, caution is justified if confidence intervals (CI) are wide and P values are marginal, particularly if point estimates are small .
Genetically linked transmissions
Confirming that HIV seroconversion in the male partner was genetically linked to sexual exposure from a female partner for whom hormonal contraception use status was known reduces the potential for exposure misclassification from transmission originating from a female partner in whom hormonal contraception use status is unknown.
Supplementary information on potential biological mechanisms
In studies that directly assessed hormonal contraception use and female-to-male HIV transmissions, supplementary information on hormonal contraception use and genital viral shedding is a methodologic advantage.
Assessment of indirect evidence
Studies with only indirect evidence (i.e., studies assessing the association between hormonal contraception use and plasma or genital viral load in women) did not undergo quality assessment for several reasons. First, genital viral shedding is a proxy measure for infectivity. The two metrics for assessing genital HIV viral shedding are whether virus is detected in the genital tract and the genital viral load in people with detectable virus. Evidence on the amount of increase in viral load necessary to increase risk of heterosexual HIV transmission is limited, although one study has suggested that each 1.0 log10 increase in cervical HIV RNA is significantly associated with a 67% increase in risk of HIV transmission after adjustment for plasma viral load . Second, preferred methodologic approaches to assessing the association between hormonal contraception use and genital HIV viral shedding remain unclear. Multiple factors might affect the amount of virus shed in the genital tract , and individual day-to-day variation may also occur. Although plasma HIV viral load and genital HIV viral load are moderately correlated [44,45], differences between viral load in these compartments may arise as a consequence of genital tract inflammation or other factors . Cross-sectional studies on shedding may provide a proxy for infectivity at a given point in time, but several studies have demonstrated greater within-woman variability over time of genital HIV viral load compared with plasma viral load, complicating interpretation of studies that do not use repeated measurements of genital HIV viral shedding [47,48].
Furthermore, consensus does not exist on the best way to measure genital HIV viral shedding in terms of method and site of collection [direct swab of vaginal or endocervical epithelium or cervicovaginal lavage (CVL)], type or amount of diluent used for CVL (e.g. saline, water), or outcome measured (e.g. proviral DNA, cell-free RNA, or cell-associated RNA). The preferred approaches to assess differences in genital HIV viral load between hormonal contraception users and nonusers are unknown, given the potential effects of different hormonal contraception methods on cervical mucus . Ideal approaches may vary according to the characteristics of the study population (e.g. ART use) , and using multiple methods (e.g. swabs and CVL) may be helpful [51,52]. In terms of outcomes measured, it is unclear whether DNA, cell-free RNA, or cell-associated RNA is more indicative of infectivity .
For studies with indirect evidence on genital HIV viral shedding, we present selected methodologic issues, including whether studies collected genital samples at one time point (cross-sectional) or multiple time points, form of virus measured (DNA, cell-free RNA, cell-associated RNA), technique (swab, CVL, or both), site of sample collection (cervical, vaginal, or cervicovaginal), number of women assessed, whether multivariate analysis was conducted, and covariates considered. We noted whether each analysis addressed potential effects related to ART use (by restriction or statistical control), the potential for blood contamination in samples (since viral load results from a contaminated sample could be indicative of plasma HIV viral load rather than genital HIV viral load), or potential for partner contamination by screening samples for spermatozoa or Y-chromosome (samples containing seminal fluid could be indicative of the viral load in the seminal fluid of an HIV-infected male partner rather than in the female who provided the sample).
We considered genital HIV viral load as a biologic mediator between plasma HIV viral load and HIV transmission and determined it to be the more proximal indirect outcome. We briefly describe studies assessing the association between hormonal contraception and plasma HIV viral load or setpoint.
Of 634 articles collected, we assessed 23 full-text articles, excluded six for the reasons detailed in Figure 1 [54–59], and identified 17 studies eligible for inclusion. Only one had direct and indirect evidence ; the others had only indirect evidence on genital HIV viral shedding (in addition to information on plasma HIV viral load for some studies) [11–13,15,16,61–64], cervical HIV viral load setpoint (and plasma viral load) , or only plasma HIV viral load or set point [65–70]. No available studies randomized women to different hormonal contraception methods and followed them to assess differences in HIV transmission to men. Thirteen studies were conducted in sub-Saharan Africa [11–13,16,17,60,61,63,66–70], three in the United States [15,62,65], and one in Italy . No studies had information about use of the contraceptive patch, contraceptive ring, or levonorgestrel IUD.
Only one included study had direct prospective evidence on the effect of HC use on HIV transmission to men (Table 1). Heffron and colleagues conducted secondary data analysis on information from 3790 serodiscordant couples in seven African countries. Among these couples, 2476 included an HIV-positive female and HIV-negative male partner (F + M−); we focus on this subset of couples at risk of female-to-male HIV transmission. Data were primarily drawn from an RCT designed to assess the effect of acyclovir on HIV transmission, and a small proportion (about 10%) of observations were drawn from a concurrent observational study focused on determining immune correlates of HIV protection. Eligible HIV-positive female participants had no history of AIDS-defining disorders and were not using ART at enrollment. Time on ART during follow-up was censored . About 11% of follow-up intervals involved self-reported sex without a condom, which was more commonly reported during intervals in which female partners reported using hormonal contraception (P = 0.009). Ninety-three incident HIV infections occurred in men (2.76 infections per 100 person-years), of which 59 (63.4%) were genetically linked to the index female partner with known hormonal contraception use status (1.75 infections per 100 person-years). Forty infections occurred in men whose partner reported not using hormonal contraception (i.e. used condoms, had a hysterectomy or tubal ligation, or used no contraception; 1.51 infections per 100 person-years) and 19 occurred to men with partners using hormonal contraception (15 used injectables and four used OCPs; 2.64 and 2.50 infections per 100 person-years, respectively).
Investigators used both Cox proportional hazards regression and MSM, and considered multiple covariates as potential confounders. Self-reported hormonal contraception use was included as a time-varying variable, which could be updated quarterly. The final multivariate models controlled for baseline age, baseline plasma viral load of the HIV-positive partner, time-varying pregnancy, and time-varying, self-reported unprotected sex in the last month (assumed to be representative of unprotected sex within the last 3 months). In multivariate analysis, both injectables (adjHR 1.95, 95% CI 1.06–3.58; MSM adjOR 3.01, 95% CI 1.47–6.16) and OCPs (Cox adjHR 2.09, 95% CI 0.75–5.84; MSM adjOR 2.35, 95% CI 0.79–6.95) generated elevated point estimates, but only injectables were significantly associated with HIV transmission to a male partner. Sensitivity analyses, including extending the exposure window for 3 months after last hormonal contraception use and censoring observations during pregnancy, did not result in substantial differences.
In the Heffron analysis, in addition to direct evidence, HIV-1 RNA measured 6 months after study enrollment was more likely to be detected in the genital tract of women using injectables than in women not using hormonal contraception (adjOR 1.67, 95% CI 1.21–2.31). Injectable users also had a greater concentration of genital HIV-1 RNA by an average of 0.19 log10 copies/swab (P = 0.0005) . OCP use was not associated with detectability or quantity of genital HIV RNA. Hormonal contraception use and plasma HIV-1 RNA were not associated.
Nine other studies examined the influence of hormonal contraception use on genital HIV DNA or RNA shedding (expressed either as detectability or quantity) [11–13,15,16,61–64], and one study assessed various hormonal contraception methods and cervical viral load setpoint (Table 2) . Most studies assessing detectability of genital viral shedding used odds ratios (OR) as a measure of association, which may exaggerate potential associations since this outcome is typically not rare (<10%) . All but one study looked exclusively at HIV-1 . Among 11 studies assessing genital HIV viral shedding or setpoint, seven used only a cervical or vaginal swab [11,13,16,17,60,62,63], two used only CVL [12,61], and two used a combination of swab and CVL [15,64]. Six studies were cross-sectional [11,13,15,16,60,61], whereas five collected information at multiple time points [12,17,62–64]. Six studies provided information on hormonal contraception use and plasma HIV viral load or setpoint, but did not assess hormonal contraception use and genital HIV viral shedding [65–70].
Genital viral detectability, quantity, or setpoint
Six studies (four of which used cross-sectional information) assessed genital HIV viral shedding with estimates specifically comparing OCP users to women not using OCPs [11,13,16,60,63,64]. Five provided estimates for cervical shedding [11,13,16,60,63], three provided estimates for vaginal shedding [11,13,63], and one provided estimates for cervicovaginal shedding . Four measured DNA and showed inconsistent results: one suggested no difference in DNA detectability in the cervical compartment , one suggested increased DNA detectability in the cervical but not vaginal compartment , one suggested decreased DNA cervicovaginal detectability , and one showed increased DNA detectability in both the cervical and vaginal compartment, with greater increases in cervical shedding for high-dose OCPs than with low-dose OCPs . Three studies measured RNA [60,63,64]: none found increased shedding in any compartment assessed, and one suggested decreased cell-associated RNA cervicovaginal detectability .
Three studies (two of which used cross-sectional shedding information) assessed genital viral shedding with estimates specifically comparing injectable users to women not using injectables [13,60,63]. Results of the Heffron study showed increases in cervical RNA associated with injectable use . Results from the other two studies found no increase in vaginal shedding (DNA or RNA), but both reported increased cervical (DNA and RNA) shedding associated with injectable use. In one of these two studies, depot medroxyprogesterone acetate (DMPA) was associated with increased odds of cervical DNA detectability (adjOR 2.9, 95% CI 1.5–5.7) ; in the other study, DMPA was associated with a 0.28 log10 copy/swab increase in cervical shedding 3 months after ART initiation. This difference was not significant after controlling for plasma viral load, nor 6 months after ART initiation .
Only one study, which used shedding information from multiple time points, assessed genital viral shedding, with estimates specifically comparing the levonorgestrel implant (Norplant) users to women not using the implant. This study reported no change in cervical or vaginal DNA at 3 or 6 months after ART initiation .
Any hormonal contraception use
Four studies (two of which were cross-sectional) provided estimates on nonspecified hormonal contraception use, and none found a change in either cervical, vaginal, or cervicovaginal RNA shedding [12,15,61,62]. Combining estimates from various methods could mask effects if different methods result in effects in opposing directions.
Cervical viral load setpoint
In one study, which used shedding information at multiple time points, no association was found between use of either OCPs or DMPA and cervical viral load setpoint compared with nonusers .
Plasma viral load or setpoint
Nine reports on eight studies included information on plasma HIV viral load or setpoint [17,60,64–70]. One reported an association between DMPA use and higher plasma HIV viral load setpoint . Although this association was not present after controlling for viral diversity , any change in viral load setpoint could still impact infectivity. In this study, OCPs, DMPA, and implants were not associated with a greater change in viral load over time. Six studies reported no association between various hormonal contraception methods (OCPs, injectables, or implants) and plasma RNA levels at one time point, changes in plasma RNA over time, or plasma HIV viral load setpoint [17,60,64–66,68]. One study reported an interaction between time since HIV seroconversion and use of injectable contraception: among 29 recent seroconverters, injectable users experienced a decline in plasma viral load compared with women not using injectables .
Direct evidence included in this review on the potential effect of OCPs or injectable contraception on the risk of female-to-male HIV transmission is limited to one study that suggests an increased risk associated with injectables. Studies with indirect evidence are heterogeneous in design and results. No studies with direct evidence included information on implants, the contraceptive patch, the contraceptive ring, or the levonorgestrel IUD, and only two studies with indirect evidence included information on implants (one related to genital viral shedding , the other related to plasma viral load setpoint ).
In addition to providing the only direct, prospectively measured estimates on use of OCPs or injectables and HIV transmission to men, the Heffron study has several methodologic strengths, including statistical adjustment for multiple potential confounders, low loss to follow-up, clear definition of exposure to hormonal contraception, use of time-varying information in conjunction with frequent follow-up, large sample size, genetic linkage of HIV transmission, and information on the use of injectables and genital viral shedding that appears to support the main analysis. However, the total number of transmissions originating from hormonal contraception users was modest (15 to partners of women using injectables and four to partners of women using OCPs), limiting statistical power and precision. Participants provided self-reported information about unprotected sex in the past month, and these responses were assumed to be accurate and consistent over the previous 3 months. Inaccuracy in measurement of this variable could have led to residual confounding in either direction.
Information on increased genital viral shedding among injectable users from the Heffron study appears to support the finding that injectable use is associated with an increase in the risk of HIV transmission. However, this evidence has some limitations. First, the amount of increased genital HIV-1 RNA shedding among injectable users was modest (+0.19 log10 copies/swab). Another analysis of these same data reported that an increase of a full 1.0 log10 copies/swab was necessary to achieve only a 67% increase in transmission risk after adjusting for plasma viral load , raising questions about whether the observed increase associated with injectable use was sufficient to double or triple transmission risk. Second, although point estimates for OCPs and HIV transmission to men did not reach statistical significance, they were larger than those observed for injectables, yet no increase in genital viral shedding was observed with OCPs. Multiple explanations are possible, including: OCPs may not increase risk of HIV transmission, but point estimates were elevated because of lack of precision; true differences in risk of HIV transmission between injectables and OCPs may exist, but imprecision in measurement of genital viral shedding did not reflect these differences; elevated point estimates for both OCPs and injectables were related to systematic bias related to uncontrolled confounding between hormonal contraception users and nonusers, or; both methods increase risk of HIV transmission but via different biological mechanisms. It is unclear if women with elevated genital viral loads collected 6 months after study enrollment were the same women who transmitted HIV.
Indirect evidence provides information on outcomes that are proxy measurements for infectivity, and this evidence is limited due to a lack of clarity on ideal approaches for sample collection and processing. In addition, several indirect studies were small and may have limited statistical power. Eleven indirect studies provide evidence on hormonal contraception use and genital viral shedding or setpoint, with substantial heterogeneity of methods, outcomes, and results; six studies assessed OCPs and genital viral shedding, three assessed injectables and genital viral shedding, one assessed implants and genital viral shedding, four assessed nonspecified hormonal contraception methods and genital viral shedding, and one assessed OCPs and DMPA on cervical viral load setpoint. Evidence on the association between OCPs and genital viral shedding is inconsistent. Evidence on the association between injectables and genital viral shedding is limited, mixed, and difficult to interpret. Three studies suggest increases in cervical shedding (including one for DNA  and two for RNA [60,63], one of which was not present after control for viral load or 3 months after ART initiation ), but two studies suggested no increase in vaginal shedding (one for DNA  and one for RNA ). One study found no increase in vaginal RNA shedding with use of any hormonal contraception but comprised largely of DMPA , and another found no increase in cervical RNA viral load setpoint with DMPA . Evidence on implants and genital viral shedding is extremely limited but did not suggest an association, and evidence on other hormonal contraception methods and genital viral shedding is lacking.
Most indirect evidence indicates no association between hormonal contraception use and plasma viral load or viral load at setpoint. Plasma viral load has commonly been used as a biomarker of HIV infectivity , and genital viral load has been shown to predict HIV transmission to men . The value of assessing cervical or plasma viral load setpoints as potential indicators of infectivity is also unknown. Although data are limited, the inconsistency in data on hormonal contraception use and genital viral load versus data on hormonal contraception use and plasma viral load may indicate that any potential effect of hormonal contraception use on viral load is localized to the genital tract, but future studies should assess if other factors, such as the potential for partner contamination in genital samples, contribute to this discrepancy.
HIV infection carries burdens in addition to morbidity and mortality, and HIV prevention is a public health priority. Voluntary contraceptive use offers substantial benefits to women by enabling them to prevent unintended pregnancies, which in turn decreases abortion, reduces maternal morbidity and mortality, improves child health and survival through birth spacing, and confers several nonhealth-related benefits [72–74]. HIV-positive women often report stronger desires to limit childbearing when compared with HIV-negative women, and report high levels of unmet need for contraception . Effective contraception for women living with HIV who want to prevent pregnancy is also a critical and cost-effective intervention to reduce vertical HIV transmission [76–81]. Some studies suggest that pregnancy may increase the risk of genital HIV shedding [11,12,16–19] and female-to-male HIV transmission , but evidence is limited. Any potential effect of hormonal contraception use on female-to-male transmission must also be considered within the context of increasing access to ART, and the large reduction in risk of HIV transmission that ART use confers [82,83]. Programmatic efforts must be made to expand contraceptive method choice, as access to a wide range of highly effective contraceptive methods is limited in much of the developing world, and successful use of contraception is improved when women can obtain their method of choice.
One well conducted study raises potential concerns related to the use of injectable contraception and the risk of female-to-male HIV transmission, but given the paucity of direct evidence, mixed indirect evidence, and the potential for confounding in observational data, additional evidence is needed. Clarification on the ideal methods to assess markers of infectivity, as well as studies assessing hormonal contraception methods beyond OCPs and injectables, may also be helpful.
The authors are grateful to Mary Lyn Gaffield and Nathalie Kapp for support and guidance; Roger Chou, Mark Helfand, and Ann Duerr for expert advice; Agustin Ciapponi and Demián Glujovsky for support with EROS software; and Nellie Kamau and LaToya Armstrong for assistance with our search strategy. A subgroup of the advisory committee for the WHO Hormonal Contraception and HIV consultation, including Tsungai Chipato, Anna Glasier, Ron Gray, Ying-Ru Jacqueline Lo, and Nguyen-Toan Tran, provided valuable comments on the article. We are also grateful to authors who provided additional information on their analyses. C.B.P. conducted the literature search and identified studies for full-text review. C.B.P., S.J.P., and K.M.C. assessed included studies and wrote the manuscript.
Disclosure of financial sources: There were no external sources of support. USAID, WHO, and CDC contributed staff time to conduct this review.
Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the United States Agency for International Development, the World Health Organization, or the Centers for Disease Control and Prevention.
Conflicts of interest
C.B.P. is collaborating on a study assessing the acceptability of two types of injectable contraceptive methods among HIV-positive women in Uganda (PI: Ron Gray); one of the products for that study was donated by Pfizer. S.J.P. and K.M.C. have no conflicts of interest.
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