HIV chronicity as a predictor of hippocampal memory deficits in daily cannabis users living with HIV.

Background: Antiretroviral medications have increased the lifespan of persons living with HIV (PLWH) thereby unmasking memory decline that may be attributed to chronological age, HIV symptomatology, HIV disease chronicity, and/or substance use (especially cannabis use which is common among PLWH). To date, few studies have attempted to disentangle these effects. In a sample of daily cannabis-using PLWH, we investigated whether hippocampal memory function, assessed via an object-location associative learning task, was associated with age, HIV chronicity and symptom severity, or substance use. Methods: 48 PLWH (12.9 ± 9.6 years since HIV diagnosis), who were 44 years old on average (range: 24-64 years; 58 % male) and reported daily cannabis use (recent use confirmed by urinalysis) completed the study. We assessed each participant's demographics, substance use, medical history, current HIV symptoms, and hippocampal memory function via a well-validated object-location associative learning task. Results: Multiple regression analyses found that living more years since HIV+ diagnosis predicted significantly worse associative learning total score (r=-0.40) and learning rate (r=-0.34) whereas chronological age, cannabis-use characteristics, and recent HIV symptom severity were not significantly related to hippocampal memory function. Conclusions: In daily cannabis-using PLWH, HIV chronicity was related to worse hippocampal memory function independent from cannabis use, age, and HIV symptomatology. Object-location associative learning performance could serve as an 'early-warning' metric of cognitive decline among PLWH. Future research should examine longitudinal changes in associative learning proficiency and evaluate interventions to prevent hippocampal memory decline among PLWH. ClinicalTrials.gov: NCT01536899.

Cannabis and complementary/alternative self-treatment approaches for symptom management among African American persons living with HIV.

Persons living with HIV (PLWH) experience symptoms from disease progression and side effects of antiretroviral treatment. This study examines in African American PLWH (N = 259) commonly-endorsed symptoms, types and self-rated efficacy of therapies for symptom alleviation. Analyses were stratified by gender (n = 178 males, n = 81 females) and cannabis use typology: non-users (n = 90), mostly recreational use (n = 46), mixed recreational/therapeutic use (n = 51), or mostly therapeutic use (n = 72). Females reported greater severity for pain, fatigue, depression, weight change and tingling in extremities, but there were no gender differences for ratings of poor sleep, anxiety, poor appetite, or headache. Both marijuana (used therapeutically by females more than males) and medication(s) were among the 3 top methods for managing pain, poor sleep, anxiety, and headache. Marijuana was most often used for poor appetite, and medications for depression. Perceived efficacy of self-treatment approaches was moderately good. Among African American PLWH, symptom severity was higher for females and for therapeutic users of cannabis. Marijuana and medicine were often used to self-treat symptoms, but many participants did nothing. These results highlight the need for careful evaluation and management of symptoms in this underserved population.

Demand curve analysis of marijuana use among persons living with HIV.

BACKGROUND: Despite medicalization and legalization of marijuana use, factors influencing demand for marijuana among persons living with HIV (PLWH) are incompletely understood. This knowledge gap undermines effective clinical management and policies. This study used demand curve simulation methods to address these issues. METHODS: Marijuana-using PLWH (N = 119) completed experimental tasks to simulate amount of marijuana purchasing/use across different costs (money or time), and likelihood of reselling marijuana or marijuana therapeutic-use registration card in relation to profits. Additional simulations assessed purchasing of marijuana relative to other drug and non-drug goods. RESULTS: Simulated marijuana use decreased as money and time costs increased. Consumption was greater for participants with more severe Cannabis Use Disorder (CUD) and anxiety, intermediate pain levels, and past 90-day opioid use. Whereas few participants chose to sell their registration card, marijuana resale (diversion) steeply increased with profit. Likelihood of seeking marijuana therapeutic-use certification decreased in relation to registration card money cost, having to visit more physicians to get a signature, and delay to receiving the card, and increased with duration of certification. Participants who reported recent opioid use were more likely to seek certification. Consumption of several commodities assessed was independent of marijuana. CONCLUSIONS: Simulated marijuana use was related to participants' clinical profile (CUD, anxiety and pain symptoms, recent opioid use), and unrelated to purchasing other goods. Likelihood of seeking marijuana therapeutic-use registration was affected by several types of costs and recent opioid use. Participants were unlikely to divert registration cards. We discuss clinical and policy implications of these findings.

Primary care provider cultural competence and racial disparities in HIV care and outcomes.

BACKGROUND: Health professional organizations have advocated for increasing the "cultural competence" (CC) of healthcare providers, to reduce racial and ethnic disparities in patient care. It is unclear whether provider CC is associated with more equitable care. OBJECTIVE: To evaluate whether provider CC is associated with quality of care and outcomes for patients with HIV/AIDS. DESIGN AND PARTICIPANTS: Survey of 45 providers and 437 patients at four urban HIV clinics in the U.S. MAIN MEASURES: Providers' self-rated CC was measured using a novel, 20-item instrument. Outcome measures included patients' receipt of antiretroviral (ARV) therapy, self-efficacy in managing medication regimens, complete 3-day ARV adherence, and viral suppression. KEY RESULTS: Providers' mean age was 44 years; 56 % were women, and 64 % were white. Patients' mean age was 45; 67 % were men, and 77 % were nonwhite. Minority patients whose providers scored in the middle or highest third on self-rated CC were more likely than those with providers in the lowest third to be on ARVs, have high self-efficacy, and report complete ARV adherence. Racial disparities were observed in receipt of ARVs (adjusted OR, 95 % CI for white vs. nonwhite: 6.21, 1.50-25.7), self-efficacy (3.77, 1.24-11.4), and viral suppression (13.0, 3.43-49.0) among patients of low CC providers, but not among patients of moderate and high CC providers (receipt of ARVs: 0.71, 0.32-1.61; self-efficacy: 1.14, 0.59-2.22; viral suppression: 1.20, 0.60-2.42). CONCLUSIONS: Provider CC was associated with the quality and equity of HIV care. These findings suggest that enhancing provider CC may reduce racial disparities in healthcare quality and outcomes.

Patient activation and improved outcomes in HIV-infected patients.

BACKGROUND: The Patient Activation Measure (PAM) assesses several important concepts in chronic care management, including self-efficacy for positive health behaviors. In HIV-infected populations, better self-efficacy for medication management is associated with improved adherence to antiretroviral medications (ARVs), which is critically important for controlling symptoms and slowing disease progression. OBJECTIVE: To determine 1) characteristics associated with patient activation and 2) associations between patient activation and outcomes in HIV-infected patients. DESIGN: Cross-sectional survey. PARTICIPANTS: 433 patients receiving care in four HIV clinics. METHODS: An interviewer conducted face-to-face interviews with patients following their HIV clinic visit. Survey data were supplemented with medical record abstraction to obtain most recent CD4 counts, HIV viral load and antiretroviral medications. MAIN MEASURES: Patient activation was measured using the 13-item PAM (possible range 0-100). Outcomes included CD4 cell count > 200 cells/mL(3), HIV-1 RNA < 400 copies/mL (viral suppression), and patient-reported adherence. KEY RESULTS: Overall, patient activation was high (mean PAM = 72.3 [SD 16.5, range 34.7-100]). Activation was lower among those without vs. with a high school degree (68.0 vs. 74.0, p < .001), and greater depression (77.6 lowest, 70.2 middle, 68.1 highest tertile, p < .001). There was no association between patient activation and age, race, gender, problematic alcohol use, illicit drug use, or social status. In multivariable models, every 5-point increase in PAM was associated with greater odds of CD4 count > 200 cells/mL(3) (aOR 1.10 [95 % CI 1.01, 1.21]), adherence (aOR 1.18 [95 % CI 1.09, 1.29]) and viral suppression (aOR 1.08 [95 % CI 1.00, 1.17]). The association between PAM and viral suppression was mediated through adherence. CONCLUSIONS: Higher patient activation was associated with more favorable HIV outcomes. Interventions to improve patient activation should be developed and tested for their ability to improve HIV outcomes.

Race, Relationships and Trust in Providers among Black Patients with HIV/AIDS.

A trustful patient-provider relationship is a strong predictor of positive outcomes, including treatment adherence and viral suppression, among patients with HIV/AIDS. Understanding factors that inform this relationship is especially relevant for Black patients, who bear a disproportionate burden of HIV morbidity and mortality, and may face challenges associated with seeing providers of a racial/ethnic background that is different from their own. Using data collected through the Enhancing Communication and HIV Outcomes (ECHO) study, we build upon extant research by examining patient and provider characteristics that may influence Black patients' trust in their provider. ECHO data were collected from four ambulatory care sites in Baltimore, Detroit, New York and Portland, Oregon (N=435). Regression analysis results indicate that trust in health care institutions and cultural similarity between patient and provider are strongly associated with patients' trust in their provider. Lower perceived social status, being currently employed, and having an older provider were also related to greater patient-provide trust. These findings can inform interventions to improve trust and reduce disparities in HIV care and outcomes that stem from mistrust among Black patients.

HIV providers' perceptions of and attitudes toward female versus male patients.

As a first step in understanding the role that health care providers may play in observed gender disparities in HIV care in the United States, we sought to examine whether HIV providers' perceptions of and attitudes toward female and male patients differ. We used data from the Enhancing Communication to Improve HIV Outcomes (ECHO) study, a multisite, cross-sectional study focused on the role of the patient-provider relationship in disparities in HIV care conducted from October 2006 to June 2007. Using separate scales, we assessed HIV providers' perceptions about their patients (e.g., intelligence, compliance, responsibility) as well as providers' attitudes toward their patients (e.g., like, respect, frustrate). We used multivariable linear regression with generalized estimating equations to compare provider scores for female and male patients. Our sample comprised 37 HIV providers and 317 patients. Compared with male patients, HIV-infected females were less likely to be highly educated or employed, and more likely to report nonadherence to antiretroviral medications and depressive symptoms. In unadjusted and adjusted analyses, there was a significant difference in providers' perceptions of female and male patients, with providers having more negative perceptions of female patients. However, there was no significant difference in HIV providers' attitudes toward female and male patients in unadjusted or adjusted analyses. Further study is needed to elucidate the role of providers' perceptions and attitudes about female and male patients in observed gender disparities in HIV care.

The role of cultural distance between patient and provider in explaining racial/ethnic disparities in HIV care.

OBJECTIVE: We sought to evaluate whether cultural distance between patients and providers was associated with quality of care for people living with HIV/AIDS, and whether cultural distance helped explain racial/ethnic disparities in HIV care. METHODS: We surveyed 437 patients and 45 providers at 4 HIV clinics in the U.S. We examined the association of patients' perceived cultural distance from their providers with patient ratings of healthcare quality, trust in provider, receipt of antiretroviral therapy, medication adherence, and viral suppression. We also examined whether racial/ethnic disparities in these aspects of HIV care were mediated by cultural distance. RESULTS: Greater cultural distance was associated with lower patient ratings of healthcare quality and less trust in providers. Compared to white patients, nonwhites had significantly lower levels of trust, adherence, and viral suppression. Adjusting for patient-provider cultural distance did not significantly affect any of these disparities (p-values for mediation >.10). CONCLUSION: Patient-provider cultural distance was negatively associated with perceived quality of care and trust but did not explain racial/ethnic disparities in HIV care. PRACTICE IMPLICATIONS: Bridging cultural differences may improve patient-provider relationships but may have limited impact in reducing racial/ethnic disparities, unless coupled with efforts to address other sources of unequal care.

Substance use and the quality of patient-provider communication in HIV clinics.

The objective of this study was to estimate the influence of substance use on the quality of patient-provider communication during HIV clinic encounters. Patients were surveyed about unhealthy alcohol and illicit drug use and rated provider communication quality. Audio-recorded encounters were coded for specific communication behaviors. Patients with vs. without unhealthy alcohol use rated the quality of their provider's communication lower; illicit drug user ratings were comparable to non-users. Visit length was shorter, with fewer activating/engaging and psychosocial counseling statements for those with vs. without unhealthy alcohol use. Providers and patients exhibited favorable communication behaviors in encounters with illicit drug users vs. non-users, demonstrating greater evidence of patient-provider engagement. The quality of patient-provider communication was worse for HIV-infected patients with unhealthy alcohol use but similar or better for illicit drug users compared with non-users. Interventions should be developed that encourage providers to actively engage patients with unhealthy alcohol use.

A self-learning fuzzy discrete event system for HIV/AIDS treatment regimen selection.

The U.S. Department of Health and Human Services Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) treatment guidelines are modified several times per year to reflect the rapid evolution of the field (e.g., emergence of new antiretroviral drugs). As such, a treatment-decision support system that is capable of self-learning is highly desirable. Based on the fuzzy discrete event system (FDES) theory that we recently created, we have developed a self-learning HIV/AIDS regimen selection system for the initial round of combination antiretroviral therapy, one of the most complex therapies in medicine. The system consisted of a treatment objectives classifier, fuzzy finite state machine models for treatment regimens, and a genetic-algorithm-based optimizer. Supervised learning was achieved through automatically adjusting the parameters of the models by the optimizer. We focused on the four historically popular regimens with 32 associated treatment objectives involving the four most important clinical variables (potency, adherence, adverse effects, and future drug options). The learning targets for the objectives were produced by two expert AIDS physicians on the project, and their averaged overall agreement rate was 70.6%. The system's learning ability and new regimen suitability prediction capability were tested under various conditions of clinical importance. The prediction accuracy was found between 84.4% and 100%. Finally, we retrospectively evaluated the system using 23 patients treated by 11 experienced nonexpert faculty physicians and 12 patients treated by the two experts at our AIDS Clinical Center in 2001. The overall exact agreement between the 13 physicians' selections and the system's choices was 82.9% with the agreement for the two experts being both 100%. For the seven mismatched cases, the system actually chose more appropriate regimens in four cases and equivalent regimens in another two cases. It made a mistake in one case. These (preliminary) results show that 1) the System outperformed the nonexpert physicians and 2) it performed as well as the expert physicians did. This learning and prediction approach, as well as our original FDESs theory, is general purpose and can be applied to other medical or nonmedical problems.

A fuzzy discrete event system approach to determining optimal HIV/AIDS treatment regimens.

Treatment decision-making is complex and involves many factors. A systematic decision-making and optimization technology capable of handling variations and uncertainties of patient characteristics and physician's subjectivity is currently unavailable. We recently developed a novel general-purpose fuzzy discrete event systems theory for optimal decision-making. We now apply it to develop an innovative system for medical treatment, specifically for the first round of highly active antiretroviral therapy of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients involving three historically widely used regimens. The objective is to develop such a system whose regimen choice for any given patient will exactly match expert AIDS physician's selection to produce the (anticipated) optimal treatment outcome. Our regimen selection system consists of a treatment objectives classifier, fuzzy finite state machine models for treatment regimens, and a genetic-algorithm-based optimizer. The optimizer enables the system to either emulate an individual doctor's decision-making or generate a regimen that simultaneously satisfies diverse treatment preferences of multiple physicians to the maximum extent. We used the optimizer to automatically learn the values of 26 parameters of the models. The learning was based on the consensus of AIDS specialists A and B on this project, whose exact agreement was only 35%. The performance of the resulting models was first assessed. We then carried out a retrospective study of the entire system using all the qualifying patients treated in our institution's AIDS Clinical Center in 2001. A total of 35 patients were treated by 13 specialists using the regimens (four and eight patients were treated by specialists A and B, respectively). We compared the actually prescribed regimens with those selected by the system using the same available information. The overall exact agreement was 82.9% (29 out of 35), with the exact agreement with specialists A and B both at 100%. The exact agreement for the remaining 11 physicians not involved in the system training was 73.9% (17 out of 23), an impressive result given the fact that expert opinion can be quite divergent for treatment decisions of such complexity. Our specialists also carefully examined the six mismatched cases and deemed that the system actually chose a more appropriate regimen for four of them. In the other two cases, either would be reasonable choices. Our approach has the capabilities of generalizing, learning, and representing knowledge even in the face of weak consensus, and being readily upgradeable to new medical knowledge. These are practically important features to medical applications in general, and HIV/AIDS treatment in particular, as national HIV/AIDS treatment guidelines are modified several times per year.

Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers.

Cystic fibrosis (CF) is a recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. The risk of idiopathic chronic pancreatitis (ICP) is increased in individuals who have CFTR genotypes containing a CF-causing mutation plus a second pathogenic allele. It is unknown whether the risk of ICP is increased in CF carriers who have one CF-causing mutation plus one normal allele. In this study, 52 sporadic cases of ICP were ascertained through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen mutations were excluded. DNA was comprehensively tested for CFTR mutations using a robotically enhanced, multiplexed, and highly redundant form of single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing. Fifteen subjects had a total of 18 pathogenic CFTR alleles. Eight subjects had common CF-causing mutations. This group included seven CF carriers in whom the second CFTR allele was normal (4.3 times the expected frequency, P=0.0002). Three subjects had compound heterozygotes genotypes containing two pathogenic alleles (31 times the expected frequency, P<0.0001). A variant allele of uncertain significance (p.R75Q) was detected in eight of the 52 ICP subjects and at a similar frequency (13/96) in random donors. ICP differs from other established CFTR-related conditions in that ICP risk is increased in CF carriers who have one documented normal CFTR allele. Having two CFTR mutations imparts a higher relative risk, while having only one mutation imparts a higher attributable risk.

HIV-inducing factor in cervicovaginal secretions is associated with bacterial vaginosis in HIV-1-infected women.

OBJECTIVE: Certain cervicovaginal lavage (CVL) fluid samples obtained from HIV-1-infected and uninfected women stimulate in vitro HIV-1 replication. This activity, HIV-inducing factor (HIF), changes when CVL fluid is heated. We sought to confirm a previous observation that HIF was associated with bacterial vaginosis (BV). METHODS: HIF was measured in unheated and heated CVL fluid obtained from HIV-1-infected women and compared with the presence of BV by Nugent scores, other genital tract conditions, and cervicovaginal HIV-1 shedding. RESULTS: Among the 295 women studied, 54% of CVL samples had HIF activity and 21% showed heat-stable HIF activity. In adjusted logistic regression, heat-stable HIF was associated with BV (odds ratio [OR]=51.7, 95% confidence interval [CI]: 5.0, 530.7) and with intermediate flora (OR=43.3, 95% CI: 3.6, 521.1); heat-labile HIF was not associated with BV. Neither heat-stable nor heat-labile HIF was associated with other cervicovaginal conditions nor, after controlling for plasma viral load, with genital tract HIV-1 shedding. CONCLUSION: We confirmed the association of HIF with BV and attribute it to the heat-stable component. Heat-stable activity is also associated, although less strongly, with intermediate vaginal flora. We propose that heat-stable HIF is a result of products of BV-associated bacteria.

Reduced CFTR function and the pathobiology of idiopathic pancreatitis.

Idiopathic chronic pancreatitis (ICP) is the leading cause of chronic pancreatitis in children and nonalcoholic adults. The risk of developing ICP is increased in individuals who have mutations of the cystic fibrosis gene (CFTR) and of a trypsin inhibitor gene (PSTI). In studies from the United States and France, the risk of ICP is increased about 40-fold by having two abnormal copies of the CFTR gene, about 14-fold by having the N34S PSTI mutation, and about 500-fold by having both. When ICP patients have two abnormal copies of the CFTR gene, there is also evidence of reduced residual CFTR protein function in extrapancreatic tissues based on clinical findings and nasal ion transport responses. Thus, pancreatitis risk is highest in individuals who have abnormalities in both the pancreatic ducts (CFTR) and acini (PSTI). These findings indicate that PSTI is a modifier gene for CFTR-related ICP and have implications for the diagnosis and pathogenesis of pancreatitis.

The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis.

This article reviews current concepts regarding the pathobiology of cystic fibrosis pancreatic disease. It summarizes recent studies on the relationship between CFTR mutations and pancreatitis, and it reviews several unresolved issues in the field.

The role of cystic fibrosis gene mutations in determining susceptibility to chronic pancreatitis.

This article reviews current concepts regarding the pathobiology of cystic fibrosis pancreatic disease. It summarizes recent studies on the relationship between CFTR mutations and pancreatitis, and it reviews several unresolved issues in the field.

Protein kinase A regulates ATP hydrolysis and dimerization by a CFTR (cystic fibrosis transmembrane conductance regulator) domain.

Gating of the CFTR Cl- channel is associated with ATP hydrolysis at the nucleotide-binding domains (NBD1, NBD2) and requires PKA (protein kinase A) phosphorylation of the R domain. The manner in which the NBD1, NBD2 and R domains of CFTR (cystic fibrosis transmembrane conductance regulator) interact to achieve a properly regulated ion channel is largely unknown. In this study we used bacterially expressed recombinant proteins to examine interactions between these soluble domains of CFTR in vitro. PKA phosphorylated a fusion protein containing NBD1 and R (NBD1-R-GST) on CFTR residues Ser-660, Ser-700, Ser-712, Ser-737, Ser-768, Ser-795 and Ser-813. Phosphorylation of these serine residues regulated ATP hydrolysis by NBD1-R-GST by increasing the apparent K(m) for ATP (from 70 to 250 microM) and the Hill coefficient (from 1 to 1.7) without changing the V(max). When fusion proteins were photolabelled with 8-azido-[alpha-32P]ATP, PKA phosphorylation increased the apparent k(d) for nucleotide binding and it caused binding to become co-operative. PKA phosphorylation also resulted in dimerization of NBD1-R-GST but not of R-GST, a related fusion protein lacking the NBD1 domain. Finally, an MBP (maltose-binding protein) fusion protein containing the NBD2 domain (NBD2-MBP) associated with and regulated the ATPase activity of PKA-phosphorylated NBD1-R-GST. Thus when the R domain in NBD1-R-GST is phosphorylated by PKA, ATP binding and hydrolysis becomes co-operative and NBD dimerization occurs. These findings suggest that during the activation of native CFTR, phosphorylation of the R domain by PKA can control the ability of the NBD1 domain to hydrolyse ATP and to interact with other NBD domains.