AbstractBackground

More men than women develop and die of tuberculosis (TB). Fewer data exist on sex differences in latent TB infection (LTBI). We assessed for potential sex differences in LTBI acquisition among close TB contacts.

Methods

Regional Prospective Observational Research for TB (RePORT)-Brazil is an observational multi-center cohort of persons with culture-confirmed pulmonary TB and their close contacts. Participants were enrolled from five sites in Brazil from June 2015 - June 2019. Close contacts were followed for 24 months post-enrollment, with LTBI defined as a positive interferon-γ release assay (IGRA; QuantiFERON 3rd or 4th generation) at baseline or six months. We performed univariate, bivariate, and multivariable logistic regression and propensity-score weighted models to assess for odds ratios (OR) and 95% confidence intervals (CI) for LTBI acquisition by birth sex among close contacts.

Results

504 of 1,093 (46%) female close contacts were IGRA positive compared to 295 of 745 (40%) men. The unadjusted OR for IGRA positivity among women vs. men was 1.31 (95% CI: 1.08-1.58). Bivariate adjustments yielded ORs in women vs. men ranging from 1.19 to 1.33 (p-value range: <0.01-0.07). Multivariable regression and weighted models yielded similar ORs in women vs. men of 1.14 (95% CI: 0.92-1.41) and 1.15 (95% CI: 0.94-1.40), respectively.

Conclusions

The point estimate for LTBI among close TB contacts in Brazil was higher in women, though less pronounced in multivariable models. If the sex difference in LTBI is confirmed in additional settings, studies of possible underlying differences in socio-behavioral factors or TB pathogenesis are warranted.

Keywords

Introduction

It is well known that there are sex differences in active tuberculosis (TB), with men more likely to contract and die of the disease (World Health Organization, 2021). This is particularly true within low- and middle-income countries (Horton et al., 2016). While disproportionate active TB prevalence may be due in part to underreporting in female populations (Saunders et al., 2019), this is unlikely on its own to explain such trends, which have been seen in multiple settings (Neyrolles et al., 2009; Rhines, 2013). Instead, behavioral and physiologic differences have been posited as probable drivers (Nhamoyebonde et al., 2014; Dodd, 2016; Horton et al., 2020).

There are fewer data on sex differences in latent TB infection (LTBI) testing, treatment, and outcomes. While some studies have found no significant sex differences (Ting et al., 2014; Teklu et al., 2018; Ncayiyana et al., 2016), others appear to show higher rates of LTBI in men (Reichler et al., 2020; Sabri et al., 2019; He et al., 2015; de Souza et al., 2014; Chen et al., 2015). Further analyses found that men were more likely to be offered (Fiske et al., 2014) and complete LTBI treatment (Hirsch-Moverman et al., 2015), and have less antitubercular medication toxicity (Pettit et al., 2013). Of note, several of these studies were in specific populations such as healthcare workers, and only the Tuberculosis Epidemiologic Studies Consortium Task Order 2 Team evaluated large numbers of close contacts with active TB disease (Reichler et al., 2020; Fiske et al., 2014).

Several known factors may interact with sex in increasing risk for LTBI. Lower socioeconomic status groups appear to have higher prevalence of LTBI (Lule et al., 2020). Heavy alcohol use is associated with LTBI risk (Puryear et al., 2020) and incomplete treatment (Hirsch-Moverman et al., 2010), while active and passive smoking alters host immunity (Bai et al., 2018) and leads to higher infection rates (Lindsay et al., 2014; Patra et al., 2015). Comorbidities such as diabetes (Lee et al., 2017) and renal disease on dialysis (Shu et al., 2015) play a role, with diabetes in particular contributing to an ineffective or exaggerated immune response (Magee et al., 2020). Even after accounting for these separate factors, sex differences may still impact LTBI, LTBI conversion, and LTBI treatment success.

We sought to fill a current gap in knowledge by evaluating for a potential sex difference in interferon-γ release assay (IGRA) positivity among close TB contacts in Brazil. To our knowledge, no prior studies have directly assessed for a sex difference in IGRA conversion after prolonged TB exposure. Brazil is a highly diverse upper-middle income country with large gaps in income equality and decreasing, yet still substantial TB burden. Our well-characterized multi-center cohort closely represents the TB patient population in Brazil and is well positioned to address this question (Arriaga et al., 2021). Based on preliminary data within our cohort (Souza et al., 2021; Arriaga et al., 2021), we hypothesized that female close contacts would have higher rates of IGRA positivity than men, even after adjusting for potentially confounding factors.

Methods

Study population and follow-up

Regional Prospective Observational Research for TB in Brazil (RePORT-Brazil) is a prospective observational cohort study of culture-confirmed pulmonary TB cases and their close contacts (Arriaga et al., 2021). There were five sites across three high TB-burden regions in Brazil: three in the southeast (Rio de Janeiro – Rio de Janeiro), one in the northeast (Salvador – Bahia), and one in the north (Manaus – Amazonas). Study participants were enrolled from June 2015 through June 2019 and followed for two years, with follow-up completed in June 2021. Close contacts were defined as spending at least four hours per week in proximity to an index case within the six months preceding active TB diagnosis (Loredo et al., 2014). Close contacts were excluded if they had no available IGRA result at baseline or six months and index case without culture-confirmed pulmonary disease. Index cases were not included if ≤18 years of age, pregnant, breastfeeding, already on anti-TB therapy for >7 days.

Close contacts were encouraged by phone or text to present at study enrollment sites. Baseline evaluation included questionnaires, in-person physical examination, blood work, and chest imaging. At six months, close contacts returned for clinical assessment and repeat blood work and chest imaging. Subsequent evaluations occurred at six-month intervals by phone throughout the two-year follow-up period.

Exposure, outcome, and potential confounders

Close contacts were characterized by biologic sex assigned at birth (male or female) to define the exposure of interest. No information was available on participant self-reported gender. IGRA testing was performed with QuantiFERON 3rd or 4th generation assay, at baseline evaluation and again at six months if negative or indeterminate at baseline, to define the outcome of interest. IGRA positivity was defined as a positive result at baseline or six months; IGRA indeterminate results were considered IGRA negative. For the purposes of this study, index case data were limited to sex, X-ray characteristics, and degree of smear positivity (scanty, 1+, 2+, and 3+). Later in the study, groups of close contacts were also asked whether they slept in the same room or bed as an index case or had at least five hours of indoor exposure per day. Potential confounders of the exposure-outcome relationship were as follows: close contact baseline age in years, self-identified race, region of enrollment, education level, household income, body mass index (BMI), number of household members, and index case sex, smear positivity, and X-ray cavitary disease.

Data and statistical analysis

We used chi-square and Wilcoxon Rank Sum tests to identify unadjusted differences between male and female close contacts for categorical and continuous variables, respectively. After multiply imputing variables with >10% missingness over 10 iterations, we performed unadjusted, bivariate-adjusted, and multivariable logistic regression modeling to obtain odds ratios (OR) and 95% confidence intervals (CI) for IGRA positivity by sex. Variance inflation factors were utilized within multivariable models to determine possible collinearity of included covariates. We assessed the outcome association for sex adjusting for single confounders in bivariate analyses, while we adjusted for all confounders simultaneously in the multivariable analysis. We performed propensity-score-matched models utilizing all available confounders, with exposure weights constructed and assigned according to the methods of Li and Greene (Li et al., 2013). We conducted sensitivity analyses accounting for possible false-positive IGRA conversion utilizing known specificities of QuantiFERON 3rd and 4th generation tests (Takasaki et al., 2018). Finally, we assessed for a potential sex difference in quantitative assay measurements (nil, mitogen, TB1 antigen, and TB2 antigen) using unadjusted linear regression models stratified by IGRA positivity and clustered by participant. All analyses were conducted in R version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/).

Ethical conduct of research and role of funders

The study was approved by the Institutional Review Boards at all enrollment sites and at Vanderbilt (CAAE: 25102412.3.1001.5262); all participants provided written informed consent prior to inclusion. Funding was obtained through the Brazilian Ministry of Health, Department of Science and Technology (DECIT) as well as the United States National Institutes of Health (NIH). Funders played no role in cleaning data, conducting analyses, or interpreting results.

Results

The source population included 1,917 close contacts and 1,181 index cases, of which there were 1,840 close contacts of 601 culture-confirmed pulmonary TB index cases. Two further close contacts were excluded because IGRA results were not available at baseline or month six. Of the 1,838 remaining close contacts, 1,093 (59%) were female and 745 (41%) were male. Female close contacts were a median of 36 years old (interquartile range [IQR]: 20, 50), as compared with males at 26 (IQR: 13, 42). Both female and male contacts had similar percentages in self-reported race categories: 19% vs. 20% White, 21% vs. 20% Black, and 59% vs. 59% Pardo/Mixed, respectively. Very few close contacts identified as Asian, Indigenous, or unknown (1%). Female close contacts were more often living in Rio de Janeiro (38% vs. 34%) or Salvador (19% vs. 13%) and residing within a poor community (favela, 25% vs. 20%) than males. Female close contacts had similar exposure to index case cavitary disease (53% vs. 50%; p=0.40) and high smear positivity (3+: 29% vs. 28%; p=0.24) compared to males. Furthermore, female close contacts described similar household exposure – sleeping in the same room (35% vs. 31%; p=0.22) and sleeping in the same bed (19% vs. 17%; p=0.58) – but more daily five-hour indoor exposure (87% vs. 78%; p<0.001) compared to males. There were 46 participants living with HIV, including 22 females (2%) and 24 males (3%); 13 participants living with HIV were IGRA positive (28%). Two participants had end-stage renal disease, eight were on chemotherapy, and 20 received immunosuppressive medications.

A total of 799 close contacts had a positive IGRA result, including 504 (46%) females and 295 (40%) males (Table 1). 433 (40%) female and 246 (33%) male close contacts were IGRA positive at baseline, with 71 (6%) female and 49 (7%) male close contacts IGRA positive at six months. IGRA positive close contacts were older (median age 36 years [IQR: 18, 50]) in comparison to IGRA negative close contacts (median age 29 years [IQR: 15, 44]). Black race (53%), Rio de Janeiro region (55%), Salvador region (52%), community settings (favela, 63%), and exposure to cavitary disease (54%) or high smear positivity (2+: 54%; 3+: 53%) resulted in high IGRA positivity. There were two pregnant female participants at the time of enrollment, one of whom had a positive IGRA result at baseline. See Supplemental Tables 1 and 2 for detailed close contact demographics and exposure characteristics.

Table 1The association of female sex with IGRA positivity, accounting for various demographic, contextual, and clinical characteristics, among close contacts of an index pulmonary TB source case

IGRA positivity was defined as a single positive QuantiFERON 3rd or 4th generation result at baseline or six months from enrollment. IGRA indeterminate results were considered IGRA negative.

Abbreviations: BMI = body mass index; CI = confidence interval; IGRA = interferon-γ release assay; IQR = interquartile range; N = number; OR = odds ratio; TB = tuberculosis.

The unadjusted odds of IGRA positivity were significantly higher for females compared to males (OR=1.31; CI: 1.08-1.58). Sensitivity analyses accounting for possible false positive IGRA results yielded the same unadjusted OR of 1.31 (CI: 1.09-1.59). Bivariate ORs for IGRA positivity, adjusted for single potential confounding factors, resulted in sex-specific effect estimates ranging from 1.19-1.33. Of these, only the bivariate OR adjusting for age had a CI including the null (OR=1.19; CI: 0.98-1.45) (Table 1).

After performing multiple imputation for household income, education level, and index case smear positivity, multivariable logistic regression yielded a sex-specific OR of 1.14 (CI: 0.92-1.41). Propensity-score-matched weighted regression within and across multiply imputed datasets found similar ORs of 1.15 (CI: 0.94-1.40) and 1.15 (CI: 0.94-1.40), respectively. The multivariable adjusted OR and propensity-score-matched ORs had CIs that included the null, though they all yielded effect estimates that remained in the same direction as the unadjusted and bivariate-adjusted models.

For IGRA negative participants, Wilcoxon Rank Sums revealed slight differences in IGRA quantitative assay measurements between male and female sex (Table 2). This was not seen, however, for IGRA positive participants. Univariate linear regression modeling demonstrated no differences in quantitative assay measurements by birth sex when stratified by IGRA positivity.

Table 2Close contact IGRA quantitative assay measurements, by sex and participant IGRA positivity

IGRA positivity was defined as a single positive QuantiFERON 3rd or 4th generation result at baseline or six months from enrollment. IGRA indeterminate results were considered IGRA negative. Among 1,039 IGRA negative participants, there were 1,894 IGRA results: 1,853 negative and 41 indeterminate. Among 799 IGRA positive participants, there were 925 IGRA results: 114 negative, 7 indeterminate, and 804 positive. Quantitative assay measurements were clustered by participant to account for repeat testing. Wilcoxon Rank Sums and univariate linear regression models were performed to assess for a possible sex difference in quantitative assay measurements for IGRA negative and positive groups.

Abbreviations: IGRA = interferon-γ release assay; IQR = interquartile range; QFT = QuantiFERON; N = number; SE = standard error; TB1 = tuberculosis antigen tube 1 (CD4 response); TB2 = tuberculosis antigen tube 2 (CD4 and CD8 response).

Discussion

For all analyses, the odds of LTBI acquisition (i.e., IGRA positivity) among female close contacts was higher than among males. Bivariate adjustments had limited effect on the sex-specific effect size, and of these, only adjustment for age resulted in a confidence interval containing the null. Unweighted and weighted multivariable regression modeling resulted in more attenuated ORs, again with confidence intervals containing the null. These findings suggest a small possible difference in sex-specific IGRA positivity within our close contact population.

If replicated in other settings, a sex difference in LTBI would be informative from a health equity standpoint. TB disease stigma persists in Brazil, with higher stigmatization paradoxically among those with knowledge of LTBI (Rebeiro et al., 2020). Identification and dismantling of structural barriers that reinforce stigma can decrease active TB disease burden – in part, this can be achieved through early recognition, education, and treatment of LTBI. While there have been advances in sex and gender health equity in Brazil, there remains a divide in wages and labor force participation, which can result in downstream healthcare access disparities (Chant, 2007). Knowledge of LTBI risk in female close contacts can provide clinicians with the impetus for broader outreach and education within vulnerable populations.

Excess unadjusted LTBI acquisition was at least partially attributable to age, region, and income. Age is known to correlate with IGRA positivity and may indirectly represent duration of exposure (Zelner et al., 2014). Our female cohort had a median age 10 years older than the male cohort, with proportionately more female close contacts aged 25 and older (Figure 2). Still, female close contacts at all age groups were found to have slightly higher IGRA positivity rates compared to males. Region and household income are likely correlated with other factors that contribute to LTBI and active TB disease, such as unstable housing, lower health awareness, overcrowding, and air pollution. We measured residence in rural, suburban, and community settings, but did not include this in the multivariable model given its collinearity with other confounders. Instead, we utilized number of household members as this was thought to be a better proxy for overcrowding.

Figure 1Forest plot for unadjusted, adjusted, and propensity score weighted sex-specific IGRA positivity odds ratios among close contacts of an index pulmonary TB source case. IGRA positivity was defined as a single positive QuantiFERON 3rd or 4th generation result at baseline or six months from enrollment. IGRA indeterminate results were considered IGRA negative. Abbreviations: IGRA = interferon-γ release assay; OR = odds ratio; CI = confidence interval; TB = tuberculosis; BMI = body mass index. *For bivariate-adjusted OR, IGRA positivity was adjusted for sex and the following factor. Multiple imputation was performed for household income, education level, and index case smear positivity prior to bivariate regression modeling. ᶧFor multivariable adjusted OR, IGRA positivity was adjusted for sex, age, region, race, household income, education level, BMI, household members, index case sex, index case cavitary disease, and index case smear positivity. Multiple imputation was performed for household income, education level, and index case smear positivity prior to bivariate regression modeling. ᶴMultiple imputation was performed for all missing variables prior to propensity score weighting with univariate regression modeling.

Figure 2Histogram with number of close contacts by age and sex. There were proportionately more female close contacts from age 25 and on, as compared with males.

Behavioral factors that affect sex differences in active TB disease may play a role in LTBI. Women may be at increased risk for LTBI as they represent a growing percentage of the total work force in Brazil (Bruschini, 2007). Furthermore, women spend more time performing indoor household tasks on a weekly basis (Bruschini, 2007), which could affect exposure dynamics for domestic close contacts. Female-headed households have increased over time within Brazil, with female single-parent families often remaining within the lowest income quintile (Gukovas et al., 2016). The intersection between female sex and poverty has shown to be exceedingly complex (Chant, 2007), yet this may provide some explanation for LTBI risk, at least among female population subsets.

Physiologic mechanisms may be important in driving sex differences in LTBI among close contact populations. Macrophages are the primary targets of Mycobacterium tuberculosis upon inhalation into the lung, with multiple surface receptors to facilitate entry via phagocytosis (Glickman et al., 2001). At the same time, macrophages within females have enhanced phagocytic activity (Nhamoyebonde et al., 2014). Once within phagosome vacuoles, M. tuberculosis alters compartmental characteristics for intracellular survival. This may not result in higher rates of active TB disease in females, as hormonal exertion of various proapoptotic effects counteracts mycobacterial proliferation. However, sex differences in macrophage activation could contribute to higher initial mycobacterial uptake among female close contacts.

There were limitations to our study. We cannot provide detailed commentary on M. tuberculosis transmission dynamics. We did not assess the impact of multiple index cases or whether there were social or occupational exposures. Nor did we have information on total duration of exposure, of which 250 hours may predict risk for LTBI (Reichler et al., 2020). Nevertheless, we obtained information on exposure via chest X-ray findings and smear positivity results that could only be ascertained with parallel enrollment of index cases and close contacts, a strength of this cohort. Five hour daily indoor exposure was likely a strong proxy for total duration of exposure, as this represented high average exposure in the six months preceding index case diagnosis.

A second limitation was that IGRA testing remains a surrogate marker for LTBI, measuring disease via immune reactivity. Individuals with immunodeficiency are more likely to test falsely negative or indeterminate. Only small subsets of our population had end-stage renal disease, HIV, or use of chemotherapy or immunosuppressive medications; due to their effects on model fit, none of these variables were included in our regression analyses. False positive results were likely uncommon because all close contacts had culture-confirmed pulmonary TB exposure. This was reflected in our sensitivity analysis to account for false positive testing, which did not alter our results. Although not described in the literature, IGRA reactivity could theoretically differ between male and female individuals – mouse models have shown a more robust Th1 response with increased interferon-γ production in the presence of estradiol (Klein et al., 2016). An inverse relationship may occur following testosterone exposure, with lower levels of interferon-γ secretion in natural killer cells of female-treated mice. In our cohort, there were slightly higher quantitative assay measurements among female populations compared with males, with significant Wilcoxon Rank Sums for nil, TB1 antigen, and TB2 antigen by sex among IGRA negative participants. Even though no linear relationships were found between IGRA quantification and sex, future studies would help to tease out subtle differences.

A final limitation involved losses across the cascade of care, which we have reported previously (Souza et al., 2021). This included attrition from initial outreach to informed consent, to baseline and follow-up evaluations, and to treatment start and completion. We were unable to assess whether persons who did not participate in our study differed significantly from those who enrolled. This could have led to sampling or selection biases, although less likely as we identified for enrollment all new TB diagnoses for each site over the study period.

Our findings suggest a possible sex difference in LTBI among close contacts in Brazil. Effect estimates were consistent across multiple analyses, although adjusted and weighted regression models resulted in attenuated sex-specific associations with IGRA positivity. If these findings are confirmed in other study populations, investigation of underlying socio-behavioral and biologic mechanisms to explain apparent sex disparities would be warranted.

Author Contributions

PYW, PFR, and TRS conceptualized the research question. PYW, PFR, and TRS made substantial contributions to data analysis and interpretation. AGC, MAP, BBD, ABS, MSR, MCF, MMT, VCR, ALK, MCS, BBA were responsible for data acquisition. All authors contributed to important intellectual content to subsequent revisions of the manuscript and approved of the final version to be published.

Acknowledgments

The RePORT-Brazil Consortium consists of 12 partner institutions from Brazil represented by the following members: Amanda Araújo da Costa, Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil; André Luiz Bezerra, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Anna Cristina Calçada Carvalho, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, and Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Anna Karla Silveira, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Betânia M. F. Nogueira, IBIT, Fundação José Silveira, Salvador, Brazil, Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador, Brazil, and Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Brazil; Bruna da Costa Oliveira Lima, Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil; Brenda Karoline Souza Carvalho, Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil; Bruna da Costa Oliveira Lima, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil; Bruna Pires de Loiola, Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil; Carolina Arana Schmaltz Stanis, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Eline Naiane de Freitas Medeiros, Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil; Francine Peixoto Ignácio, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Hayna Malta-Santos, Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Brazil, and Laboratório de Inflamação e Biomarcadores, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil; Jéssica Rebouças Silva, Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Brazil, and Laboratório de Inflamação e Biomarcadores, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil; João Marine Neto, SMS-RJ, Rio de Janeiro, Brazil, and Hospital Federal do Andaraí, Ministério da Saúde, Brazil; Leandro Sousa Garcia, Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil; Maria Luciana Silva-Freitas, Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil; Mayla Gabriele Miranda de Melo, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Rosa Maria Placido-Pereira, Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil; Samyra Almeida-Da-Silveira, Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil; Vanessa de Souza Nascimento, IBIT, Fundação José Silveira, Salvador, Brazil, MONSTER Initiative, Salvador, Brazil, and Bahiana School of Medicine and Public Health, Bahia Foundation for the Development of Sciences, Salvador, Brazil. Team members of clinical and laboratory platforms of RePORT-Brazil include: Aline Benjamin, Quezia Medeiros, Francine Ignacio, Adriano Gomes, Elisangela Silva, Jamile Garcia, Renta Spener-Gomer, Martinelle Godinho, Adriana Rezende, Andre Bezerra, Alice Andrade, and others. A special thanks to the following members for their administrative and logistical support: Elze Leite, FIOCRUZ, Salvador, Brazil; Eduardo Gama, FIOCRUZ, Rio de Janeiro, Brazil; Elcimar Junior, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil; Leticia Linhares, Vanderbilt University Medical Center, Nashville, USA; Hilary Vansell, Vanderbilt University Medical Center, Nashville, USA.

Conflict of Interest

We declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

PYW: No conflict

AGC: No conflict

MAP: No conflict

BBD: No conflict

ABS: No conflict

MSR: No conflict

MCF: No conflict

MMT: No conflict

VCR: The author has served as a consultant for ONU-OMS for the HIV response in Myanmar and received payment from GlaxoSmithKline, Qiagen, and Virology Education for educational events

ALK: No conflict

MCS: No conflict

BBA: No conflict

TRS: No conflict

PFR: The author has served as a consultant for Gilead (2020) and Johnson & Johnson (2021)

Funding

This work was supported by the Departamento de Ciência e Tecnologia–Secretaria de Ciência e Tecnologia–Ministério da Saúde, Brazil (25029.000507/2013-07) and the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (U01 AI069923, R01 AI147765, R01 AI20790, K01 AI131895).

Ethical Approval Statement

The study was approved by the Institutional Review Boards at all enrollment sites and at Vanderbilt (CAAE: 25102412.3.1001.5262); all participants provided written informed consent prior to inclusion. Funding was obtained through the Brazilian Ministry of Health, Department of Science and Technology (DECIT) as well as the United States National Institutes of Health (NIH). Funders played no role in cleaning data, conducting analyses, or interpreting results.

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Appendix. Supplementary materialsArticle InfoPublication History

Accepted: July 9, 2022

Received: June 3, 2022

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DOI: https://doi.org/10.1016/j.ijid.2022.07.031

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