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Esteban Gonzalez Burchard and colleagues explore how making medical research more diverse would aid not only social justice but scientific quality and clinical effectiveness, too.Esteban Gonzalez Burchard and colleagues explore how making medical research more diverse would aid not only social justice but scientific quality and clinical effectiveness, too.

Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60-93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. ClinicalTrials.gov NCT00903084.

Abstract Rationale Microbiome studies typically focus on bacteria, but fungal species are common in many body sites and can have profound effects on the host. Wide gaps exist in the understanding of the fungal microbiome (mycobiome) and its relationship to lung disease. Objectives To characterize the mycobiome at different respiratory tract levels in persons with and without HIV infection and in HIV-infected individuals with chronic obstructive pulmonary disease (COPD). Methods Oral washes (OW), induced sputa (IS), and bronchoalveolar lavages (BAL) were collected from 56 participants. We performed 18S and internal transcribed spacer sequencing and used the neutral model to identify fungal species that are likely residents of the lung. We used ubiquity–ubiquity plots, random forest, logistic regression, and metastats to compare fungal communities by HIV status and presence of COPD. Measurements and Main Results Mycobiomes of OW, IS, and BAL shared common organisms, but each also had distinct members. Candida was dominant in OW and IS, but BAL had 39 fungal species that were disproportionately more abundant than in the OW. Fungal communities in BAL differed significantly by HIV status and by COPD, with Pneumocystis jirovecii significantly overrepresented in both groups. Other fungal species were also identified as differing in HIV and COPD. Conclusions This study systematically examined the respiratory tract mycobiome in a relatively large group. By identifying Pneumocystis and other fungal species as overrepresented in the lung in HIV and in COPD, it is the first to determine alterations in fungal communities associated with lung dysfunction and/or HIV, highlighting the clinical relevance of these findings. Clinical trial registered with www.clinicaltrials.gov (NCT00870857).

The importance of reviewing and studying sex-based differences in pharmacologic parameters is demonstrated by the increasing data on gender variation in drug efficacy and toxicity profiles. Sex-based differences in the four major factors that contribute to interindividual pharmacokinetic variability—bioavailability, distribution, metabolism, and elimination—are theorized to stem from variations between men and women in factors such as body weight, plasma volume, gastric emptying time, plasma protein levels, cytochrome P450 activity, drug transporter function, and excretion activity. Sex-determined variations in pharmacodynamics have traditionally been more difficult to study, but a number of recent studies have explored these differences. This review examines the biologic basis of differences in pharmacokinetics and pharmacodynamics between the sexes and summarizes studies that have addressed these differences. As an example, sex-based variation in the efficacy and toxicity of antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients is explored more thoroughly to illustrate some of the factors underlying sex-based differences in drug therapy.

Understanding early events of HIV transmission within mucosal tissues is vital for developing effective prevention strategies. Here, we report that primary stromal fibroblasts isolated from endometrium, cervix, foreskin, male urethra, and intestines significantly increase HIV infection of CD4+ T cells-by up to 37-fold for R5-tropic HIV and 100-fold for X4-tropic HIV-without themselves becoming infected. Fibroblasts were more efficient than dendritic cells at trans-infection and mediate this response in the absence of the DC-SIGN and Siglec-1 receptors. In comparison, mucosal epithelial cells secrete antivirals and inhibit HIV infection. These data suggest that breaches in the epithelium allow external or luminal HIV to escape an antiviral environment to access the infection-favorable environment of the stromal fibroblasts, and suggest that resident fibroblasts have a central, but previously unrecognized, role in HIV acquisition at mucosal sites. Inhibiting fibroblast-mediated enhancement of HIV infection should be considered as a novel prevention strategy.

It is critical to assess adherence to pre-exposure prophylaxis (PrEP) in clinical trials. The relationship between pharmacokinetic measures of PrEP adherence and other adherence measures used in PrEP trials requires further characterization. Plasma, peripheral blood mononuclear cells (PBMCs), and hair samples were collected from 88 HIV-uninfected men who have sex with men in a placebo-controlled randomized PrEP trial; announced pill counts, medication electronic monitoring (MEMS), and self-report using visual analog scale (VAS) were also collected. Tenofovir (TFV or TFV-DP) in plasma, hair, and PBMCs were quantified. Proportions with drug detection, Spearman correlation coefficients, and univariate and multivariable regression models were used. Drug detection in plasma, PBMC, and hair samples was highly concordant with treatment arm assignment. TFV or TFV-DP levels were detected in most active-arm participants: 44/47 (94%) in plasma, 46/47 (98%) in hair, and 44/47 (94%) in PBMCs and in only 1/41 placebo arm participant. Correlation coefficients were r = 0.59 for plasma and PBMC, r = 0.34 for PBMC and hair and r = 0.36 for plasma and hair. MEMS and announced pill-counts were moderately correlated (r = 0.52) but less so with pharmacologic measures (range of r = 0.12 to 0.38). Self-reported adherence by visual analog scale demonstrated essentially no correlation with drug levels (r = 0.06 for hair, PBMC or plasma) and was a poor indicator of exposure to study product. Indices of drug exposure are important indicators in assessing adherence to PrEP; accounting for variability between measures may improve interpretation and use of adherence measures in future PrEP studies. Clinical trial registration Clinical Trials.gov NCT00131677

Studies demonstrate that Tropheryma whipplei (T. whipplei) is present in the lungs of healthy individuals without acute respiratory symptoms or acute respiratory infection and is more common in the lungs of HIV-infected individuals and in smokers. The impact of T. whipplei colonization in the lung on local inflammation and pulmonary dysfunction in HIV-infected individuals is currently unknown. In this study, we performed specific polymerase chain reaction (PCR) and sequencing for T. whipplei in bronchoalveolar lavage (BAL) and induced sputum (IS) samples in 76 HIV-infected participants from three clinical sites. Pulmonary function and proinflammatory cytokine and chemokine levels in BAL were measured. Frequency of T. whipplei in either BAL or IS was 43.4%. The sensitivity and specificity of IS compared to BAL for detection of T. whipplei was 92.3% and 84.2%, respectively, and isolates of T. whipplei in the BAL and IS in the same subject shared genetic identity. Pulmonary function measures were not associated with T. whipplei colonization, and proinflammatory cytokine and chemokine levels in BAL and plasma as well as percentages of inflammatory cells in BAL and IS were not higher in colonized individuals. Overall, these results indicate that T. whipplei colonization in the lung is common, but may not be associated with decreased pulmonary function or inflammation in HIV-infected individuals.

Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women's Interagency HIV Study, who reported NVP use for >1 month from 2003-2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%-94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2-26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity.

Ambulatory function predicts morbidity and mortality and may be influenced by cardiopulmonary dysfunction. Persons living with HIV (PLWH) suffer from a high prevalence of cardiac and pulmonary comorbidities that may contribute to higher risk of ambulatory dysfunction as measured by 6-minute walk test distance (6-MWD). We investigated the effect of HIV on 6-MWD. PLWH and HIV-uninfected individuals were enrolled from 2 clinical centers and completed a 6-MWD, spirometry, diffusing capacity for carbon monoxide (DLCO) and St. George's Respiratory Questionnaire (SGRQ). Results of 6-MWD were compared between PLWH and uninfected individuals after adjusting for confounders. Multivariable linear regression analysis was used to determine predictors of 6-MWD. Mean 6-MWD in PLWH was 431 meters versus 462 in 130 HIV-uninfected individuals (p = 0.0001). Older age, lower forced expiratory volume (FEV1)% or lower forced vital capacity (FVC)%, and smoking were significant predictors of decreased 6-MWD in PLWH, but not HIV-uninfected individuals. Lower DLCO% and higher SGRQ were associated with lower 6-MWD in both groups. In a combined model, HIV status remained an independent predictor of decreased 6-MWD (Mean difference = -19.9 meters, p = 0.005). HIV infection was associated with decreased ambulatory function. Airflow limitation and impaired diffusion capacity can partially explain this effect. Subjective assessments of respiratory symptoms may identify individuals at risk for impaired physical function who may benefit from early intervention.

Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV) replication in elite controllers (EC) remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC) and viremic noncontrollers (HN) on highly active antiretroviral therapy (HAART). Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays. Measurements for IgG were performed in parallel. EC were found to have stronger p24- and V1V2-specific IgG responses than HN, but there were no IgG differences for EC and HC. In contrast, IgA in EC serum bound more frequently to gp160 and gag proteins than IgA in HC or HN. The avidity of anti-gp41 IgA was also greater in EC, and these subjects had stronger IgA responses to the gp41 heptad repeat region 1 (HR1), a reported target of anti-bacterial RNA polymerase antibodies that cross react with gp41. However, EC did not demonstrate greater IgA responses to E. coli RNA polymerase or to peptides containing the shared LRAI sequence, suggesting that most of their HR1-specific IgA antibodies were not induced by intestinal microbiota. In both EC and HAART recipients, the concentrations of HIV-specific IgG were greater than HIV-specific IgA, but their avidities were comparable, implying that they could compete for antigen. Exceptions were C1 peptides and V1V2 loops. IgG and IgA responses to these antigens were discordant, with IgG reacting to V1V2, and IgA reacting to C1, especially in EC. Interestingly, EC with IgG hypergammaglobulinemia had greater HIV-specific IgA and IgG responses than EC with normal total IgG levels. Heterogeneity in EC antibody responses may therefore be due to a more focused HIV-specific B cell response in some of these individuals. Overall, these data suggest that development of HIV-specific IgA responses and affinity maturation of anti-gp41 IgA antibodies occurs to a greater extent in EC than in subjects on HAART. Future studies will be required to determine if IgA antibodies in EC may contribute in control of viral replication.