Abstract
Background
Feminizing hormone therapy (FHT) is essential to many trans women. Concern about negative drug interactions between FHT and ART can be an ART adherence barrier among trans women with HIV.
Objectives
In this single-centre, parallel group, cross-sectional pilot study, we measured serum oestradiol concentrations in trans women with HIV taking FHT and unboosted integrase strand transfer inhibitor (INSTI)-based ART versus trans women without HIV taking FHT.
Methods
We included trans women with and without HIV, aged ≥18 years, taking ≥2 mg/day of oral oestradiol for at least 3 months plus an anti-androgen. Trans women with HIV were on suppressive ART ≥3 months. Serum oestradiol concentrations were measured prior to medication dosing and 2, 4, 6 and 8 h post-dose. Median oestradiol concentrations were compared between groups using Wilcoxon rank-sum tests.
Results
Participants (n = 8 with HIV, n = 7 without) had a median age of 32 (IQR: 28, 39) years. Among participants, the median oral oestradiol dose was 4 mg (range 2–6 mg). Participants had been taking FHT for a median of 4 years (IQR: 2, 8). Six trans women with HIV were taking bictegravir/emtricitabine/tenofovir alafenamide and two were taking dolutegravir/abacavir/lamivudine. All oestradiol concentrations were not significantly different between groups. Eleven (73%) participants had target oestradiol concentrations in the range 200–735 pmol/L at C4h (75% among women with HIV, 71% among those without HIV).
Conclusions
Oestradiol concentrations were not statistically different in trans women with HIV compared with those without HIV, suggesting a low probability of clinically relevant drug–drug interactions between FHT and unboosted INSTI-based ART.
Introduction
Transgender (trans) women are individuals who are assigned male at birth and have gender identities as women and/or as feminine. According to recent census data from Canada, the USA and some European countries, the estimated prevalence of trans people ranges from 0.3% to 3%, with nearly half identifying as trans women.1–3 This proportion could be extrapolated to an estimated 12 to 120 million trans women worldwide. Gender-affirming medical care, such as feminizing hormone therapy (FHT) and gender-affirming surgeries (e.g. breast augmentation), can support the development of physical characteristics that affirm one’s gender. This care is often critical to trans women. The use of hormones is particularly common, with 49% of 27 715 respondents to the US Trans Survey reporting currently taking hormone therapy, and 95% of trans women and trans men reporting a desire to take hormone therapy.4 With respect to FHT specifically, there are typically two components: a form of oestrogen and an androgen blocker (anti-androgen), with the occasional use of oral progestogens.
The literature has also shown that trans women are at higher risk of, and disproportionately affected by, HIV. A meta-analysis identified an HIV prevalence of 14.1% among trans women across US studies5 whereas the US national HIV prevalence is approximately 0.4%.6 An older study reported an HIV prevalence of 19.1% and a 49-fold increased odds of HIV acquisition among trans women compared with the general population.7 Although a recent Canadian study showed high levels of engagement across the HIV care continuum for trans women with HIV in care,8 analyses of US cohort and surveillance datasets showed that trans women with HIV were less likely to be engaged in care, taking ART and virologically suppressed.9,10 In the Canadian study, of the 79 trans women taking ART, 72.2% were taking a three-drug regimen with two NRTIs and an integrase strand transfer inhibitor (INSTI).8
Concerns regarding drug–drug interactions (DDIs) between ART drugs and FHT, most particularly oestrogen, may negatively impact acceptability of ART.11,12 Some trans women with HIV would rather take FHT and not ART, if they perceive having to make a choice. Further, some healthcare providers may withhold FHT if trans women with HIV are taking ART. Trans women with HIV who believe ART may have negative effects on their FHT drug levels are three times more likely to take higher than prescribed doses of hormones.13 Therefore, these concerns can lead trans women to choose either to not take ART at all, or to take ART and buy their FHT from illegitimate sources and be medically unsupervised. The ideal scenario is a shared decision-making medical care model where both the healthcare provider and the trans woman understand the science behind DDIs between ART and FHT, allowing both important therapies to be prescribed and monitored to meet the needs of the trans woman with medically safe dosing and sustained viral suppression.
To fill these critical gaps in knowledge that impede the health of trans women living with HIV, the objective for this study was to compare serum oestradiol concentrations between two cohorts of trans women. The first group included trans women with HIV taking an unboosted INSTI-based ART regimen and FHT, including oral oestradiol at a dose equal to or greater than 2 mg/day as well as a form of anti-androgen therapy. The second group consisted of trans women without HIV taking comparable FHT regimens. This study was a pilot study aimed to optimize study procedures for a future larger study (registered on clinicaltrials.gov as NCT05663892).
Materials and methods
Ethics
All study procedures were conducted in accordance with the Declaration of Helsinki14 and were approved by Veritas Independent Review Board Inc. (#2022-2848-9788-1), Women’s College Hospital’s Research Ethics Board (REB# 2022-0013-E) and Unity Health’s Research Ethics Board (REB 22-034).
Study design and participants
We conducted a single-centre, parallel group, cross-sectional pilot study of trans women with and without HIV. The inclusion criteria included: trans women who were 18 years or older living with or without HIV and who were taking at least 2 mg of oral 17-β-oestradiol plus a form of anti-androgen therapy [either pharmaceutical (e.g. spironolactone, cyproterone, finasteride, leuprolide, bicalutamide, dutasteride) and/or surgical (orchidectomy) and/or medical (hypogonadism)], with no medication changes for at least 1 month prior to inclusion. Trans women with HIV were to be on a combination ART regimen for at least 3 months with a suppressed viral load (<40 copies/mL). We excluded participants who were taking non-prescription hormonal or natural health products in addition to FHT, taking their oestradiol sublingually or crushing it, taking HIV pre-exposure prophylaxis (PrEP), living with a severe underlying disease (including an estimated creatine clearance <30 mL/min and/or liver enzymes >5 times the upper limit of normal), and taking medications known to interact with feminizing hormones. The aim was to recruit eight trans women with HIV and eight without HIV; recruitment of the participants occurred through five sites, including four family medicine practices that specialize in trans health and HIV: (i) the Maple Leaf Medical Clinic, (ii) the Church Wellesley Clinic, (iii) the Sherbourne Health Centre, (iv) St Michael’s Hospital Academic Family Health Team, and (v) one endocrinologist’s practice with expertise in trans health at Michael Garron Hospital. All study visits and procedures were run out of a single site, Maple Leaf Research. The sample size was chosen as an appropriate one for a pilot study.15
Study management of FHT and ART
For homogeneity of oestrogen supplementation, only trans women taking oral oestradiol were enrolled and they were required to be taking ≥2 mg/day. Oral oestradiol was chosen as the oestrogen formulation of choice because it is the only one covered by the regional drug benefit plan. If study participants were taking their oral oestradiol at night, they were asked to move it to the morning for at least 1 month prior to the study visit. If they were taking >2 mg/day, they were asked to divide the dose to twice a day with 2 mg in the morning and the rest at night (e.g. 3 mg of oestradiol would be divided into 2 mg qAM and 1 mg qPM). There are no known side effects related to this change in dosing, and the American Endocrinology Society recommends dividing the dose of oral oestradiol to twice a day when over 2 mg/day.16 Participants who were crushing or taking their oestradiol sublingually were asked to refrain from doing so for 1 month prior to the study visit. Likewise, for those on ART, if they were taking their ART at night, they were asked to take it in the morning for 1 month prior to the study visit.
Study procedures
Candidates were screened as per eligibility criteria, and written informed consent was obtained from those interested in participating. Participants then completed a sociodemographic and clinical questionnaire. The study visit was booked to occur within 1 month, and participants were asked to refrain from taking their morning FHT and ART medications on the day of their clinic visit. They were contacted the day prior to the study visit to confirm FHT and ART medication adherence. At the study visit, the participants were given breakfast (350–500 kcal) and had blood collected prior to oral oestradiol and ART dosing for the oestradiol C0h. After the blood was drawn at T0h, participants were asked to take their FHT and ART 30 min after starting their breakfast. Subsequently, blood was drawn 2, 4, 6 and 8 h post-dosing to measure serum oestradiol concentrations at times as per prior similar studies.17 All oestradiol concentrations were carried out at LifeLabs® using chemiluminescent micro-particle immunoassay.
Outcomes and statistical analysis
Sociodemographic and clinical characteristics were summarized and compared between the trans women with HIV and without HIV using medians and IQRs and Wilcoxon rank sum tests for continuous variables, frequencies and proportions; Fisher exact tests were used for categorical variables. The outcomes included the medians and IQRs and geometric means (GMs) with 90% CIs of oestradiol concentrations at each time point (T0h, T2h, T4h, T6h, T8h) as well as the observed Cmax and Tmax and compared between groups using Wilcoxon rank-sum tests. The AUC for each group was calculated over the 8 h pharmacokinetic (PK) sampling period (AUC0–8h). The oestradiol AUCs were calculated using the trapezoidal rule using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). We summarized the oestradiol PK differences between trans women with HIV and trans women without HIV using GM ratios (GMRs) and associated 90% CIs. All other statistical analyses were conducted using either R version 3.6.1 or SPSS Version 27 (IBM, Armonk, NY, USA). The methods used to calculate the GMs, GMRs and associated CIs are described in a prior publication.18
For clinical interest, we assessed whether the serum oestradiol C4h reached target.17 C4h was chosen as other studies have shown T4h to be near the Tmax and for consistency.17,19 The target oestradiol concentration range was determined using the local Sherbourne’s guidelines for gender-affirming primary care with trans and non-binary patients20 and the Endocrine Society guidelines.16 In the Sherbourne’s guidelines, the target oestradiol concentrations are 200 to 500 pmol/L whereas in the Endocrine Society guidelines, the target oestradiol concentrations are 370 to 735 pmol/L. For our study, these two ranges were merged for our target clinical oestradiol concentration range of 200–735 pmol/L.
Results
Study participants
Between 21 March and 26 August 2022, 16 participants were enrolled: 8 trans women with HIV and 8 trans women without HIV. One trans woman without HIV was excluded from these analyses because she was taking <2 mg of oestradiol per day. Sociodemographic and clinical characteristics are summarized in Table 1. The participants with HIV were older than those without HIV [36 years (IQR: 32, 49) versus 30 years (IQR: 27, 42)] (P = 0.04). Although trans women with HIV had a lower median weight than trans women without HIV [67.2 kg (IQR: 63.0, 79.0) versus 97.8 kg (IQR: 85.6, 102.5)] (P = 0.03), there was no statistical difference in BMI [24.1 (IQR: 22.6, 26.5) versus 29.9 (IQR: 27.3, 36.4)] (P = 0.15). Among trans women with HIV, six were taking bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) and two were taking dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC). Among all participants (n = 15), the median oral oestradiol dose was 4 mg (IQR: 4, 4; range 2–6 mg; 3 on 2 mg, 10 on 4 mg, and 2 on 6 mg). There was no statistical difference in the dose of oral oestradiol between groups. The anti-androgen therapy (some on multiple) included spironolactone (n = 8), orchidectomy (n = 6), central hypogonadism (n = 1) and cyproterone (n = 1). Three participants (all without HIV) were taking progesterone.
Table 1.
Sociodemographic and clinical characteristics among the overall study population and differentiated by HIV status
| Overall sample (n = 15) | Trans women with HIV (n = 8) |
Trans women without HIV (n = 7) |
P value | |
|---|---|---|---|---|
| Age | 32 (28, 39) | 36 (32, 49) | 30 (27, 42) | 0.04 |
| Weight (kg) | 79.9 (67.2, 99.7) | 67.2 (63.0, 79.0) | 97.8 (85.6, 102.5) | 0.03 |
| Height (cm) | 171 (164, 180) | 169 (162, 176) | 181 (168, 186) | 0.09 |
| BMI (kg/m2) | 26.7 (23.4, 32.3) | 24.1 (22.6, 26.5) | 29.9 (27.3, 36.4) | 0.15 |
| Ethnicity | 0.06 | |||
| White | 8 (53.3) | 2 (25.0) | 6 (85.7) | |
| Black | 2 (13.3) | 2 (25.0) | 0 (0) | |
| Latina | 3 (20.0) | 3 (37.5) | 0 (0) | |
| Middle Eastern or Asian | 2 (13.3) | 1 (12.5) | 1 (14.3) | |
| Country of birth | 0.13 | |||
| Canada | 7 (46.7) | 2 (25.0) | 5 (71.4) | |
| Outside of Canada | 8(53.3) | 6 (75.0) | 2 (28.6) | |
| Employment status | 0.13 | |||
| Employed | 7 (46.7) | 2 (25.0) | 5 (71.4) | |
| Not employed | 8 (53.3) | 5 (75.0) | 2 (28.6) | |
| Oral oestradiol dosing (mg/day) | 4 (4, 4) | 4 (2.5, 4) | 4 (4, 4) | 0.68 |
| Oestradiol regimens | 1.00 | |||
| 2 mg daily | 3 (20.0) | 2 (25.0) | 1 (14.3) | |
| 2 mg qAM + 1 mg qPM | 0 (0) | 0 (0) | 0 (0) | |
| 2 mg twice daily | 10 (66.7) | 5 (62.5) | 5 (71.4) | |
| 2 mg qAM + 4 mg qPM | 2 (13.3) | 1 (12.5) | 1 (14.3) | |
| Anti-androgen therapya | N/A | |||
| Spironolactone | 9 (60.0) | 5 (62.5) | 4 (57.1) | |
| Orchidectomy | 6 (40.0) | 2 (25.0) | 4 (57.1) | |
| Central hypogonadism | 1 (6.7) | 0 (0) | 1 (12.5) | |
| Cyproterone | 1 (6.7) | 0 (0) | 1 (12.5) | |
| Progesterone | 3 (20) | 0 (0) | 3 (42.9) | 0.08 |
| Duration of FHT (years) | 4 (2, 8) | 5.5 (1.5, 16.5) | 3 (2, 4) | 0.34 |
| Duration of HIV (n = 8 participants with HIV) | N/A | 9.5 (5.0, 23.0) | N/A | N/A |
| ART regimen | ||||
| BIC/FTC/TAF | N/A | 6 (75%) | N/A | N/A |
| DTG/ABC/3TC | 2 (25%) | |||
| CD4 count (n = 6) | N/A | 582.5 (423.8, 687.5) | N/A | N/A |
All continuous variables are shown as medians (IQRs) and compared between groups using Wilcoxon rank-sum tests. All categorical variables are shown as frequencies (proportions) and compared using Fisher’s exact test. ABC, abacavir; BIC, bictegravir; DTG, dolutegravir; FHT, feminizing hormone therapy; FTC, emtricitabine; TAF, tenofovir alafenamide; 3TC, lamivudine.
Non-mutually exclusive (i.e. some on multiple forms of anti-androgen therapy; P value not computed).
Comparison of serum oestradiol concentrations
Table 2 and Figure 1 summarize the median oestradiol concentrations overall and by HIV status. Table 3 summarizes the GMs and GMRs between trans women with HIV and the trans women without HIV. No statistically significant differences were identified by HIV status. Eleven of the 17 participants (73%) had target C4h oestradiol concentrations in the range 200–735 pmol/L: 6 of the 8 (75%) of the trans women with HIV and 5 of the 7 (71%) trans women without HIV.
Table 2.
Summary of median oral oestradiol concentrations and pharmacokinetic parameters overall and by HIV status
| Median (Q1, Q3) | ||||
|---|---|---|---|---|
| Overall sample (n = 15) | Trans women with HIV (n = 8) |
Trans women without HIV (n = 7) |
P value | |
| C 0h (pmol/L) | 230 (166, 333) | 226 (102, 391) | 230 (206, 256) | 0.78 |
| C 2h (pmol/L) | 331 (215, 568) | 476 (298, 805) | 225 (215, 300) | 0.19 |
| C 4h (pmol/L) | 268 (212, 503) | 421 (216, 581) | 265 (210, 319) | 0.34 |
| C 6h (pmol/L) | 256 (168, 345) | 267 (131, 379) | 233 (199, 310) | 0.96 |
| C 8h (pmol/L) | 240 (179, 365) | 235 (141, 435) | 240 (198, 303) | 0.96 |
| C max (pmol/L) | 369 (224, 666) | 560 (343, 806) | 265 (224, 319) | 0.19 |
| T max (h) | 4 (4, 4) | 4 (4, 4) | 4 (4, 4) | 0.73 |
| AUC0–8 h (pmol × h/L) | 2447 (1629, 3857) | 2839 (2177, 5027) | 1950 (1629, 2380) | 0.34 |
All continuous variables are shown as medians (IQRs) and compared using Wilcoxon rank-sum tests. Q, quartile.
Figure 1.
Median (IQR) oestradiol concentration–time for trans women with HIV (n = 8), and trans women without HIV (n = 7). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Table 3.
Geometric mean oestradiol concentrations and pharmacokinetic parameters by HIV status
| Trans women with HIV (n = 8) GM (90% CI) |
Trans women without HIV (n = 7) GM (90% CI) |
Trans women with HIV: negative GMR (90% CI) |
P value | |
|---|---|---|---|---|
| C 0h | 203.5 (108, 382) | 248 (192, 320) | 0.82 (0.42, 1.60) | 0.78 |
| C 2h | 496.5 (280, 882) | 261.5 (191, 358) | 1.90 (1.01, 3.58) | 0.19 |
| C 4h | 384.2 (261, 566) | 271(188, 390) | 1.42 (0.86, 2.33) | 0.34 |
| C 6h | 249 (157.5, 393.5) | 257 (188, 352.5) | 0.97 (0.57, 1.65) | 0.96 |
| C 8h | 254 (159, 406) | 261 (191, 358) | 0.97 (0.57, 1.67) | 0.96 |
| C max | 538 (311, 931) | 292 (216, 395) | 1.84 (1.00, 3.38) | 0.19 |
| AUC0–8 h | 2946 (1908, 4547) | 2097 (1533, 2868) | 1.40 (0.84, 2.34) | 0.34 |
All continuous variables are shown as medians (IQRs) and compared compared using Wilcoxon rank-sum tests. GM, geometric mean; GMR, geometric mean ratio.
Discussion
Our two-group parallel pilot study is one of a few studies that have compared serum oestradiol concentrations in trans women with HIV taking FHT and ART versus trans women without HIV taking FHT. The results of the study showed that median oestradiol concentrations were not significantly different between the two groups, and similar proportions of women in both groups reached the target C4h oestradiol concentrations based on the most commonly used guidelines.16 Specifically, six out of eight (75%) of the trans women with HIV and five out of seven (71%) of those without HIV had oestradiol C4h within the target of 200 to 735 pmol/L.17,19
Our results differed from the iFACT study, which evaluated DDIs between oral FHT (oral oestradiol valerate and cyproterone) and tenofovir dispoproxil fumarate (TDF)/FTC/efavirenz (EFV).17 In contrast to our results, they observed a 36% reduction in oestradiol concentrations when administered with TDF/FTC/EFV. Efavirenz has been shown to reduce oestradiol concentrations by inducing the activity of CYP3A4 and CYP2B6 enzymes and glucuronidation.21 Additionally, efavirenz is known to decrease the production of oestradiol by decreasing the activity of the enzyme aromatase. The iFACT study group also assessed DDIs between FHT and the PrEP regimen of tenofovir disoproxil fumarate/emtricitabine in 20 trans women without HIV and did not find a reduction in oestradiol concentrations, further supporting the hypothesis of efavirenz having the negative impact on oestradiol concentrations.17 Another group studied DDIs in 15 trans women without HIV taking FHT with either oral, sublingual or transdermal oestradiol with spironolactone who were given tenofovir disoproxil fumarate/emtricitabine as PrEP for 14 days. This group found a reduction in oestradiol concentrations from a baseline median of 189 (IQR: 145, 267) pg/mL to a 14 day median of 108 (IQR: 87, 158) pg/mL (P < 0.0001).22 The discrepancy between these two PrEP studies potentially relates to the differing formulations of oestradiol and requires further investigation. Most recently, the iFACT group assessed DDIs between oral oestradiol and the PrEP regimen of tenofovir alafenamide/emtricitabine in 18 trans women without HIV and found a slight reduction in oestradiol AUC0–24h with a GMR of 0.80 (IQR: 0.72, 0.90; P = 0.002) but no difference in Cmax with a GMR of 1.11 (IQR: 0.96, 1.27; P = 0.26). They deemed these changes not clinically relevant as they were in the bioequivalence range.23
Our investigation of oestradiol concentrations in trans women living with HIV utilized contemporary, INSTI-based ART regimens, which enhances the relevance and applicability of our results to current clinical practice. Although serum oestradiol concentrations were not significantly different between groups in our study at any timepoint, there was a trend for a higher Cmax of serum oestradiol for trans women with HIV compared with those without HIV (Table 3). The elevated peak is depicted in Figure 1. However, Table 3 also illustrates the wide overlapping CIs, highlighting the lack of statistically significant differences. Although our findings suggest serum oestradiol concentrations are not negatively impacted in trans women living with HIV treated with unboosted INSTI-based ART, caution must be exercised in interpreting these findings due to the limited sample size. Further, the trans women without HIV in this study did have a higher median weight than trans women with HIV, which may influence the oestradiol concentrations. Weight has been shown to negatively correlate with oestradiol concentration among trans women taking FHT in a prior study.24
We found that Tmax occurred at a median of 4 h (IQR: 4, 4) in both groups. These results differ from the iFACT study, which observed a Tmax 4 h (IQR: 2, 8) post-dosing when FHT was given alone and 2 h (IQR: 2, 6) when given with efavirenz-based ART. Again, the differences found between studies are likely due to differing ART regimens and further support the lack of DDIs between INSTI-based ART and oral oestradiol. This information is important for future studies that have the ability to only measure one timepoint of serum oestradiol concentration. Furthermore, knowing the timing of the maximal oestradiol concentrations after dosing is of clinical relevance to determine the optimum timing of blood sampling to assess dosing responses.
The other setting where oestrogen-ART DDIs have been assessed is when hormonal contraception is being taken by cis women with HIV. Most clinical studies evaluating DDIs between combined oral contraceptives and ART have been with ART regimens including efavirenz, nevirapine and protease inhibitors, and evaluated the use of exogenous ethinyl oestradiol.25 The majority of these studies demonstrate a reduction in ethinyl oestradiol concentrations when co-administered with efavirenz and some ritonavir-boosted protease inhibitors,26–28 and guidelines recommend caution when given together. There have been limited studies assessing the DDIs of oestrogen-based contraception and unboosted INSTI-based ART regimens. Song et al.29 studied 16 women given oral norgestimate/ethinyl oestradiol and dolutegravir 50 mg twice a day and found no effect on norgestimate/ethinyl oestradiol PK. Similarly, Bishop et al.30 assessed etonogestrel concentrations in 30 women taking dolutegravir-based regimens and the single-rod etonogestrel contraceptive implant and found no reduction. Investigations into the potential DDIs between bictegravir and oestrogen-based contraceptive methods have been limited, and the available data are from healthy volunteers as reported in the product monograph. However, it is speculated that these interactions are similar to those observed with dolutegravir.
Our study has several limitations that are important to consider. Our sample size was small, impacting the power of our study, because this was a pilot study for a larger one where 15 trans women in each group will be recruited. Nonetheless, the findings of this study are an important preliminary contribution. Also, variable dosing of oral oestradiol was allowed, as were various anti-androgen therapies, and some trans women were taking progesterone. Impact of the variable oestradiol dosing was mitigated by limiting dosing to those taking ≥2 mg/day and dividing the dose to twice daily if taking >2 mg/day. Furthermore, no differences were found in median dosing between the groups. Adherence with FHT and ART regimens, and exclusion of participants who crushed or took the FHT sublingually, cannot be ensured because dosing was not directly observed between screening and baseline visits. Our decision to limit the study to those taking oral oestradiol limits the generalizability of our findings for trans women taking other regimens or routes of administering oestrogen.
Conclusion
Overall, our study provides important insights into the use of FHT in trans women with HIV taking unboosted INSTI-based ART regimens and suggests that similar oestradiol concentrations can be achieved in this population compared with trans women without HIV. However, further research is needed with larger sample sizes to fully understand the impact of HIV and ART on FHT in trans women with HIV.
Acknowledgements
We acknowledge the participants of this study and the women living with HIV, healthcare advocates and community members around the globe who have inspired this work for a stigma-free world.
Contributor Information
Mona Loutfy, Women’s College Research Institute, Women's College Hospital, Toronto, Ontario, Canada; Maple Leaf Research, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Ashley Lacombe-Duncan, Women’s College Research Institute, Women's College Hospital, Toronto, Ontario, Canada; School of Social Work, University of Michigan, Ann Arbor, MI, USA.
Alice Tseng, Toronto General Hospital, Unity Health Network, Toronto, Ontario, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Yasmeen Persad, Women’s College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.
Angela Underhill, Women’s College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.
V Logan Kennedy, Women’s College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.
Ian Armstrong, Maple Leaf Medical Clinic, Toronto, Ontario, Canada.
Raymond Fung, Michael Garron Hospital, Toronto, Ontario, Canada.
Amy Bourns, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Sherbourne Health, Toronto, Ontario, Canada.
Quang Nguyen, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Sherbourne Health, Toronto, Ontario, Canada.
Sue Hranilovic, Academic Family Health, St. Michael’s Hospital, Toronto, Ontario, Canada.
Thea Weisdorf, Academic Family Health, St. Michael’s Hospital, Toronto, Ontario, Canada.
L Y L Chan, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Church-Wellesley Medical Clinic, Toronto, Ontario, Canada.
Hannah Kia, School of Social Work, University of British Columbia, Vancouver, British Columbia, Canada.
Roberta Halpenny, Maple Leaf Research, Toronto, Ontario, Canada.
Harshita Iyer, Women’s College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.
Nirubini Jeyarajah, Maple Leaf Research, Toronto, Ontario, Canada.
George Kovchazov, Maple Leaf Research, Toronto, Ontario, Canada.
Jennifer McCully, Maple Leaf Research, Toronto, Ontario, Canada.
Kimberly K Scarsi, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
Funding
This work was supported by the Canadian Institutes of Health Research (CIHR) (grant number #FDN154325).
Transparency declarations
There are no competing financial interests or conflicts of interests to disclose.
Author contributions
M.L.: conceptualization (lead), funding acquisition (lead), formal analysis (supporting), investigation (lead), methodology (lead), project administration (lead), resources (lead), supervision (lead), validation (lead), writing—original draft (lead). A.L.-D.: conceptualization (lead), data curation (lead), formal analysis (lead), investigation (lead), writing—original draft (lead), writing—review and editing (lead). A.T.: conceptualization (supporting), formal analysis (lead); writing—review and editing (supporting). Y.P.: conceptualization (lead), methodology (supporting), project administration (supporting), writing—review and editing (supporting). A.U.: project administration (lead), resources (lead), methodology (supporting), writing—review and editing (supporting). V.L.K.: project administration (supporting), resources (supporting), writing—review and editing (supporting). I.A.: conceptualization (supporting), formal analysis (supporting), resources (lead), writing—review and editing (supporting). A.B.: formal analysis (supporting), resources (lead), writing—review and editing (supporting). L.Y.L.C.: formal analysis (supporting), resources (lead), writing—review and editing (supporting). R.F.: formal analysis (supporting), resources (lead), writing—review and editing (supporting). S.H.: formal analysis (supporting), resources (lead), writing—review and editing (supporting). Q.N.: formal analysis (supporting), resources (lead), writing—review and editing (supporting). T.W.: conceptualization (supporting), formal analysis (supporting), resources (lead), writing—review and editing (supporting). H.K.: conceptualization (supporting), writing—review and editing (supporting). R.H.: data curation (lead), investigation (lead), project administration (lead), resources (lead), writing—review and editing (supporting). H.I.: project administration (supporting), writing—original draft (supporting), writing—review and editing (supporting). N.J.: data curation (supporting), investigation (supporting), project administration (supporting), software (supporting), resources (supporting), writing—review and editing (supporting). G.K.: data curation (supporting), investigation (supporting), project administration (supporting), resources (supporting), software (supporting), writing—review and editing (supporting). J.M.: analysis (supporting), software (supporting), writing—review and editing (supporting). K.K.S.: conceptualization (lead), data curation (lead), formal analysis (lead), resources (lead), writing—review and editing (supporting).
References
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