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Supplemental Material for Two strategies for partner notification and partner HIV self-testing reveal no evident predictors of male partner HIV testing in antenatal settings: A secondary analysis by Andrew Kumwenda, Ann Marie Kathryn Weideman, Lauren Aiko Graybill, Matthew Kevin Dinwiddie, Kellie Freeborn, Mildred M Lusaka, Rose Lungu, Wilbroad Mutale, Nora E Rosenberg, Margaret Kasaro, Katie R. Mollan and Benjamin H Chi in International Journal of STD & AIDS.

In an analysis of randomized trials, use of efavirenz for treatment of human immunodeficiency virus (HIV) infection was associated with increased suicidal thoughts/behaviors. However, analyses of observational data have found no evidence of increased risk. To assess whether population differences might explain this divergence, we transported the effect of efavirenz use from these trials to a specific target population. Using inverse odds weights and multiple imputation, we transported the effect of efavirenz on suicidal thoughts/behaviors in these randomized trials (participants were enrolled in 2001-2007) to a trials-eligible cohort of US adults initiating antiretroviral therapy while receiving HIV clinical care at medical centers between 1999 and 2015. Overall, 8,291 cohort participants and 3,949 trial participants were eligible. Prescription of antidepressants (19% vs. 13%) and injection drug history (16% vs. 10%) were more frequent in the cohort than in the trial participants. Compared with the effect in trials, the estimated hazard ratio for efavirenz on suicidal thoughts/behaviors was attenuated in our target population (trials:hazard ratio (HR) =2.3 (95% confidence interval (CI): 1.2, 4.4); transported: HR=1.8 (95% CI: 0.9, 4.4)), whereas the incidence rate difference was similar (trials: HR=5.1 (95% CI: 1.6, 8.7); transported: HR=5.4 (95% CI: -0.4, 11.4)). In our target population, there was greater than 20% attenuation of the hazard ratio estimate as compared with the trials-only estimate. Transporting results from trials to a target population is informative for addressing external validity.

Few prospective studies of SARS-CoV-2 transmission within households have been reported from the United States, where COVID-19 cases are the highest in the world and the pandemic has had disproportionate impact on communities of color.This is a prospective observational study. Between April-October 2020, the UNC CO-HOST study enrolled 102 COVID-positive persons and 213 of their household members across the Piedmont region of North Carolina, including 45% who identified as Hispanic/Latinx or non-white. Households were enrolled a median of 6 days from onset of symptoms in the index case. Secondary cases within the household were detected either by PCR of a nasopharyngeal (NP) swab on study day 1 and weekly nasal swabs (days 7, 14, 21) thereafter, or based on seroconversion by day 28. After excluding household contacts exposed at the same time as the index case, the secondary attack rate (SAR) among susceptible household contacts was 60% (106/176, 95% CI 53%-67%). The majority of secondary cases were already infected at study enrollment (73/106), while 33 were observed during study follow-up. Despite the potential for continuous exposure and sequential transmission over time, 93% (84/90, 95% CI 86%-97%) of PCR-positive secondary cases were detected within 14 days of symptom onset in the index case, while 83% were detected within 10 days. Index cases with high NP viral load (10^6 viral copies/ul) at enrollment were more likely to transmit virus to household contacts during the study (OR 4.9, 95% CI 1.3-18 p=0.02). Furthermore, NP viral load was correlated within families (ICC=0.44, 95% CI 0.26-0.60), meaning persons in the same household were more likely to have similar viral loads, suggesting an inoculum effect. High household living density was associated with a higher risk of secondary household transmission (OR 5.8, 95% CI 1.3-55) for households with3 persons occupying6 rooms (SAR=91%, 95% CI 71-98%). Index cases who self-identified as Hispanic/Latinx or non-white were more likely to experience a high living density and transmit virus to a household member, translating into an SAR in minority households of 70%, versus 52% in white households (p=0.05).SARS-CoV-2 transmits early and often among household members. Risk for spread and subsequent disease is elevated in high-inoculum households with limited living space. Very high infection rates due to household crowding likely contribute to the increased incidence of SARS-CoV-2 infection and morbidity observed among racial and ethnic minorities in the US. Quarantine for 14 days from symptom onset of the first case in the household is appropriate to prevent onward transmission from the household. Ultimately, primary prevention through equitable distribution of effective vaccines is of paramount importance.

Background: Crowdsourcing may be an effective strategy to develop test promotion materials. We conducted an online randomized controlled trial (RCT) to evaluate a crowdsourced intervention to promote hepatitis B virus (HBV) and hepatitis C virus (HCV) testing among men who have sex with men (MSM) in China. Methods: MSM never previously tested for hepatitis were recruited through social media. Eligible men were randomized to receive an online crowdsourced intervention or no testing promotion materials. Outcomes including self-reported and confirmed HBV and HCV test uptake were assessed after four weeks. Odds ratios (OR) with 95% confidence intervals (95% CI) of men achieving primary and secondary outcomes between the intervention and control arms were calculated. Findings: 556 eligible men were enrolled. Overall, 17•4% (97/556) of men self-reported HBV and HCV testing and 7•9% (44/556) confirmed HBV and HCV test uptake. The intervention was seen by 72•1% and 29•0% of men in the intervention and control arms, respectively. In intention-to-treat analysis, confirmed HBV and HCV test uptake was similar between the two arms, both when using a missing=failure approach (OR 0•98, 95% CI 0•53–1•82) or multiple imputation (OR 1•46, 95% CI 0•72–2•95). Interpretation: This RCT extends the literature by developing and evaluating an intervention to spur hepatitis testing in a middle-income country with a high burden of hepatitis. Overall test uptake among MSM in China was similar to previous interventions promoting hepatitis testing in high-income countries. We found frequent intervention sharing, complicating interpretation of the results, and the role of crowdsourcing to promote hepatitis testing remains unclear.

Accurate power calculations are essential in small studies containing expensive experimental units or high-stakes exposures. Herein, exact power of the Wilcoxon Mann-Whitney rank-sum test of a continuous variable is formulated using a Monte Carlo approach and defining P(X < Y) = p as a measure of effect size, where X and Y denote random observations from two distributions hypothesized to be equal under the null. Effect size p fosters productive communications because researchers understand p = 0.5 is analogous to a fair coin toss, and p near 0 or 1 represents a large effect. This approach is feasible even without background data. Simulations were conducted comparing the exact power approach to existing approaches by Rosner & Glynn (2009), Shieh et al. (2006), Noether (1987), and O'Brien-Castelloe (2006). Approximations by Noether and O'Brien-Castelloe are shown to be inaccurate for small sample sizes. The Rosner & Glynn and Shieh et al. approaches performed well in many small sample scenarios, though both are restricted to location-shift alternatives and neither approach is theoretically justified for small samples. The exact method is recommended and available in the R package wmwpow. KEYWORDS: Mann-Whitney test, Monte Carlo simulation, non-parametric, power analysis, Wilcoxon rank-sum test

BACKGROUND: Crowdsourcing, the process of shifting individual tasks to a large group, may be useful for health communication, making it more people-centered. We aimed to evaluate whether a crowdsourced video is noninferior to a social marketing video in promoting condom use. METHODS: Men who have sex with men (≥16 years old, had condomless sex within 3 months) were recruited and randomly assigned to watch 1 of the 2 videos in 2015. The crowdsourced video was developed through an open contest, and the social marketing video was designed by using social marketing principles. Participants completed a baseline survey and follow-up surveys at 3 weeks and 3 months postintervention. The outcome was compared with a noninferiority margin of +10%. RESULTS: Among the 1173 participants, 907 (77%) and 791 (67%) completed the 3-week and 3-month follow-ups. At 3 weeks, condomless sex was reported by 146 (33.6%) of 434 participants and 153 (32.3%) 473 participants in the crowdsourced and social marketing arms, respectively. The crowdsourced intervention achieved noninferiority (estimated difference, +1.3%; 95% confidence interval, -4.8% to 7.4%). At 3 months, 196 (52.1%) of 376 individuals and 206 (49.6%) of 415 individuals reported condomless sex in the crowdsourced and social-marketing arms (estimated difference: +2.5%, 95% confidence interval, -4.5 to 9.5%). The 2 arms also had similar human immunodeficiency virus testing rates and other condom-related secondary outcomes. CONCLUSIONS: Our study demonstrates that crowdsourced message is noninferior to a social marketing intervention in promoting condom use among Chinese men who have sex with men. Crowdsourcing contests could have a wider reach than other approaches and create more people-centered intervention tools for human immunodeficiency virus control.

Human immunodeficiency virus self-testing (HIVST) holds great promise for reaching high-risk key populations who do not access facility-based services. We sought to characterize unsupervised HIVST implementation among men who have sex with men in China.We conducted a nationwide online survey in China. Eligible men were at least 16 years, had anal sex with a man, and had recent condomless sex. We assessed benefits (first-time testing, increased testing frequency, confirmatory testing) and potential harms (coercion, violence, suicidality) of HIVST. Among men who have sex with men who reported ever testing for human immunodeficiency virus (HIV), we identified correlates of HIVST as first-time HIV test being a self-test using multivariable logistic regression.Among 1610 men who met the eligibility criteria and started the survey, 1189 (74%) completed it. Three hundred forty-one (29%) of 1189 reported ever self-testing for HIV. Human immunodeficiency virus prevalence was 7% (24/341) among self-testers and 5% (15/306) among non-self-testers. Two hundred (59%) of 341 men who self-tested reported HIVST as a first-time HIV test. Thirty-one (9%) men experienced coercion with HIVST. Thirty-one (78%) of 40 men with positive HIV self-tests sought confirmation. Multivariable analysis revealed that HIVST as first-time HIV test was associated with younger age (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.92-0.99), not being "out" (OR, 2.28; 95% CI, 1.60-3.28), not using the internet to meet sex partners (OR, 0.39; 95% CI, 0.22-0.69), and group sex (OR, 1.74; 95% CI, 1.02-2.9).Human immunodeficiency virus self-testing reached high-risk individuals that had never received facility-based testing. Further implementation research is needed to better understand HIVST outside of research programs.

BACKGROUND: Many men who have sex with men (MSM) in China are "in the closet." The low rate of disclosure may impact sexual behaviours, testing for HIV and other sexually transmitted infections (STIs), and diseases transmission. This study examines factors associated with overall sexual orientation disclosure and disclosure to healthcare professionals. METHODS: A nationwide cross-sectional online survey was conducted from September 2014 to October 2014 in China. Participants completed questions covering socio-demographic information, sexual behaviours, HIV/STI testing history, and self-reported HIV status. We defined healthcare professional disclosure as disclosing to a doctor or other medical provider. RESULTS: A total of 1819 men started the survey and 1424 (78.3%) completed it. Among the 1424 participants, 62.2% (886/1424) reported overall disclosure, and 16.3% (232/1424) disclosed to healthcare professionals. In multivariate analyses, the odds of sexual orientation disclosure were 56% higher among MSM who used smartphone-based, sex-seeking applications [adjusted odds ratio (aOR) = 1.56, 95% CI: 1.25-2.95], but were lower among MSM reporting sex while drunk or recreational drug use. The odds of disclosure to a healthcare professional were greater among MSM who had ever tested for HIV or STIs (aOR = 3.36, 95% CI: 2.50-4.51 for HIV, and aOR = 4.92, 95% CI: 3.47-6.96 for STIs, respectively) or self-reported as living with HIV (aOR = 1.59, 95% CI: 0.93-2.72). CONCLUSION: Over 80% of MSM had not disclosed their sexual orientation to health professionals. This low level of disclosure likely represents a major obstacle to serving the unique needs of MSM in clinical settings. Further research and interventions to facilitate MSM sexual orientation disclosure, especially to health professionals, are urgently needed.

Background Women infected with HIV have a risk of preterm birth (PTB) that is twice that among uninfected women, and treatment with antiretroviral therapy (ART) may further increase this risk. Progesterone supplementation reduces the risk of preterm delivery in women who have a shortened cervix in the midtrimester. We propose to study the feasibility of a trial of vaginal progesterone (VP) to prevent PTB among HIV-infected women receiving ART in pregnancy. Given low adherence among women self-administering vaginal study product in recent microbicide trials, we plan to investigate whether adequate adherence to VP can be achieved prior to launching a full-scale efficacy trial. Methods and design One hundred forty HIV-infected pregnant women in Lusaka, Zambia, will be randomly allocated to daily self-administration of either VP or matched placebo, starting between 20 and 24 gestational weeks. The primary outcome will be adherence, defined as the proportion of participants who achieve at least 80% use of study product, assessed objectively with a validated dye stain assay that confirms vaginal insertion of returned single-use applicators. Secondary outcomes will be study uptake, retention, and preliminary efficacy. We will concurrently perform semi-structured interviews with participants enrolled in the study and with women who decline enrollment to assess the acceptability of VP to prevent PTB and of enrollment to a randomized controlled trial. Discussion We hypothesize that VP could prevent PTB among women receiving ART in pregnancy. In preparation for a trial to test this hypothesis, we plan to assess whether participants will be adherent to study product and protocol. Trial registration ClinicalTrial.gov, NCT02970552 .

This secondary analysis explored changes in protein-unbound concentrations of lopinavir and amprenavir when co-administered in HIV-infected subjects. Total and unbound pharmacokinetic parameters were calculated and compared between subjects receiving each agent alone, and co-administration. When co-administered, unbound and total concentrations decrease. Co-administration significantly increased lopinavir unbound clearance, while significant changes in fraction unbound (fu) were not detected. For amprenavir, significant increases in fu and unbound clearance occurred with co-administration. This demonstrates the complex nature of drug-drug interactions between highly protein-bound, CYP-metabolized drugs, and the need to measure unbound concentrations in disease states like hepatitis C, where such agents are co-administered.

Background The worldwide increase in life expectancy has been associated with an increase in age-related morbidities. The underlying mechanisms resulting in immunosenescence are only incompletely understood. Chronic viral infections, in particular infection with human cytomegalovirus (HCMV), have been suggested as a main driver in immunosenescence. Here, we propose that rhesus macaques could serve as a relevant model to define the impact of chronic viral infections on host immunity in the aging host. We evaluated whether chronic rhesus CMV (RhCMV) infection, similar to HCMV infection in humans, would modulate normal immunological changes in the aging individual by taking advantage of the unique resource of rhesus macaques that were bred and raised to be Specific Pathogen Free (SPF-2) for distinct viruses. Results Our results demonstrate that normal age-related immunological changes in frequencies, activation, maturation, and function of peripheral blood cell lymphocytes in humans occur in a similar manner over the lifespan of rhesus macaques. The comparative analysis of age-matched SPF-2 and non-SPF macaques that were housed under identical conditions revealed distinct differences in certain immune parameters suggesting that chronic pathogen exposure modulated host immune responses. All non-SPF macaques were infected with RhCMV, suggesting that chronic RhCMV infection was a major contributor to altered immune function in non-SPF macaques, although a causative relationship was not established and outside the scope of these studies. Further, we showed that immunological differences between SPF-2 and non-SPF macaques were already apparent in adolescent macaques, potentially predisposing RhCMV-infected animals to age-related pathologies. Conclusions Our data validate rhesus macaques as a relevant animal model to study how chronic viral infections modulate host immunity and impact immunosenescence. Comparative studies in SPF-2 and non-SPF macaques could identify important mechanisms associated with inflammaging and thereby lead to new therapies promoting healthy aging in humans.

Effective antiretroviral (ARV)-based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected 3 efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and 3 uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters to further investigate based on their affinity for 2 ARVs central to prevention (tenofovir, maraviroc). Tissue was collected from 98 donors. mRNA and protein expression were quantified using qPCR and immunohistochemistry (IHC). Hundred percent of tissues expressed efflux transporter mRNA. IHC localized them to the epithelium and/or submucosa. Multivariable analysis adjusted for age, smoking, and co-medications revealed significant (P colorectal; vaginal ABCC2 2.9-fold > colorectal; colorectal ABCC4 2.0-fold > cervical). In contrast, uptake transporter mRNA was expressed in

Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex.

Over the past decade, services to prevent mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) have expanded rapidly, resulting in reductions in paediatric acquired immunodeficiency syndrome (AIDS) worldwide.1 However, although an emerging literature demonstrates high maternal HIV incidence during pregnancy and breastfeeding,2 efforts have not focused as much on preventing new infections among pregnant women or their partners. Although recent World Health Organization (WHO) recommendations for pre-exposure prophylaxis are encouraging,3 in sub- Saharan Africa, few – if any – structured interventions are offered to women or their partners during pregnancy and breastfeeding. Most women who access PMTCT care test HIV-negative and for most, engagement in HIV prevention typically ends with individual post-test counselling. To address this gap, we describe a framework to guide HIV prevention efforts for pregnant or breastfeeding women and their partners. This approach considers the unique characteristics of pregnancy, including healthseeking behaviours of women and engagement of male partners, to stratify couples according to HIV transmission and acquisition risk. The approach also leverages the robust infrastructure of existing PMTCT programmes and integrates it within the broader context of general HIV prevention.

Background. Crowdsourcing, the process of shifting individual tasks to a large group, may enhance human immunodeficiency virus (HIV) testing interventions. We conducted a noninferiority, randomized controlled trial to compare first-time HIV testing rates among men who have sex with men (MSM) and transgender individuals who received a crowdsourced or a health marketing HIV test promotion video.

Follow-up survey. (DOCX 42 kb)

Etravirine (ETR), an NNRTI approved for 200 mg BID dosing in conjunction with other antiretrovirals (ARVs), has pharmacokinetic properties which support once-daily dosing.

As the HIV-infected population ages, the role of cellular senescence and inflammation on co-morbid conditions and pharmacotherapy is increasingly of interest. p16INK4a expression, a marker for aging and senescence in T-cells, is associated with lower intracellular concentrations of endogenous nucleotides (EN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs). This study expands on these findings by determining whether inflammation is contributing to the association of p16INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations.

Most infant deaths occur in the first year of life. Yet, our knowledge of immune development during this period is scarce and derived from cord blood (CB) only. To more effectively combat pediatric diseases, a deeper understanding of the kinetics and the factors that regulate the maturation of immune functions in early life is needed. Increased disease susceptibility of infants is generally attributed to T helper 2-biased immune responses. The differentiation of CD4+ T cells along a specific T helper cell lineage is dependent on the pathogen type, and on costimulatory and cytokine signals provided by antigen-presenting cells. Cytokines also regulate many other aspects of the host immune response. Therefore, toward the goal of increasing our knowledge of early immune development, we defined the temporal development of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling function of CD4+ T cells using cross-sectional blood samples from healthy infants ages 0 (birth) to 14 months. We specifically focused on cytokines important in T cell differentiation (IFN-γ, IL-12, and IL-4) or in T cell survival and expansion (IL-2 and IL-7) in infant CD4+ T cells. Independent of the cytokine tested, JAK/STAT signaling in infant compared to adult CD4+ T cells was impaired at birth, but increased during the first year, with the most pronounced changes occurring in the first 6 months. The relative change in JAK/STAT signaling of infant CD4+ T cells with age was distinct for each cytokine tested. Thus, while about 60% of CB CD4+ T cells could efficiently activate STAT6 in response to IL-4, less than 5% of CB CD4+ T cells were able to activate the JAK/STAT pathway in response to IFN-γ, IL-12 or IL-2. By 4–6 months of age, the activation of the cytokine-specific STAT molecules was comparable to adults in response to IL-4 and IFN-γ, while IL-2- and IL-12-induced STAT activation remained below adult levels even at 1 year. These results suggest that common developmental and cytokine-specific factors regulate the maturation of the JAK/STAT signaling function in CD4+ T cells during the first year of life.

Pilot study results summary. (DOCX 109 kb)

Pilot study results summary. (DOCX 109 kb)

Baseline survey. (DOCX 49 kb)

HIV may amplify immunologic, physiologic, and functional changes of aging. We determined associations of frailty phenotype, a T-cell senescence marker (p16INK4a expression), age, and demographics with exposures of the intracellular metabolites (IM) and endogenous nucleotides (EN) of tenofovir/emtricitabine (TFV/FTC), efavirenz (EFV), atazanavir (ATV), and ritonavir (RTV).

Baseline survey. (DOCX 49 kb)

Although rates of sustained virologic response (SVR) after hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) surpass 90% in trials and some more “real world” settings, some patients, such as those with substance use disorders, will be challenged to adhere to HCV care.

Background: We examined associations between suicidality and genotypes that predict plasma efavirenz exposure among AIDS Clinical Trials Group study participants in the United States. Methods: Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens; suicidality was defined as reported suicidal ideation or attempted or completed suicide. Genotypes that predict plasma efavirenz exposure were defined by CYP2B6 and CYP2A6 polymorphisms. Associations were evaluated with weighted Cox proportional hazards models stratified by race/ethnicity. Additional analyses adjusted for genetic ancestry and selected covariates. Results: Among 1833 participants, suicidality was documented in 41 in exposed analyses, and 34 in on-treatment analyses. In unadjusted analyses based on 12 genotype levels, suicidality increased per level in exposed (hazard ratio, 1.11; 95% confidence interval, .96–1.27) and on-treatment 1.16; 1.01–1.34) analyses. In the on-treatment analysis, the association was strongest among white but nearly null among black participants. Considering 3 metabolizer levels (extensive, intermediate and slow), slow metabolizers were at increased risk. Results were similar after baseline covariate-adjustment for genetic ancestry, sex, age, weight, injection drug use history, and psychiatric history or recent psychoactive medication. Conclusions: Genotypes that predict higher plasma efavirenz exposure were associated with increased risk of suicidality. Strength of association varied by race/ethnicity.

Background The World Health Organization recommends all men who have sex with men (MSM) receive Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) testing. MSM in China are a high-risk group for HBV and HCV infection, but test uptake is low. Crowdsourcing invites a large group to solve a problem and then shares the solution with the public. This nationwide online randomized controlled trial will evaluate the effectiveness of a crowdsourced intervention to increase HBV and HCV testing among MSM in China. Methods Seven hundred MSM will be recruited through social media operated by MSM organizations in China. Eligible participants will be born biologically male, age 16 years or older, report previous anal sex with another man, and reside in China. After completing a baseline online survey, participants will be randomly assigned to intervention or control arms with a 1:1 allocation ratio. The intervention will include two components: (1) a multimedia component will deliver two videos and two images promoting HBV and HCV testing developed through a crowdsourcing contest in China; (2) a participatory component will invite men to submit suggestions for how to improve crowdsourced videos and images. The control arm will not view any images or videos and will not be invited to submit suggestions. All participants will be offered reimbursement for HBV and HCV testing costs. The primary outcome is HBV and HCV test uptake confirmed through electronic submission of test report photos within four weeks of enrolment. Secondary outcomes include self-reported HBV and HCV test uptake, HBV vaccination uptake, and change in stigma toward people living with HBV after four weeks. Primary and secondary outcomes will be calculated using intention to treat and as-exposed analyses and compared using two-sided 95% confidence intervals. Discussion Few previous studies have evaluated interventions to increase HBV and HCV testing in middle-income countries with a high burden of hepatitis. Delivering a crowdsourced intervention using social media is a novel approach to increasing hepatitis testing rates. HBV and HCV test uptake will be confirmed through test report photos, avoiding the limitations of self-reported testing outcomes. Trial registration NCT03482388 (29 March 2018).

Follow-up survey. (DOCX 42 kb)