HIV Status Disclosure among Older African American Men Who Have Sex with Men and Women

Thesis (Ph.D.)--University of Washington, 2016-06

1H-1,3-Diazepines, 5H-1,3-diazepines, 1,3-diazepinones, and 2,4-diazabicyclo[3.2.0]heptenes

Tetrazolo[1,5-a] pyridines/ 2-azidopyridines 1 undergo photochemical nitrogen elimination and ring expansion to 1,3-diazacyclohepta-1,2,4,6-tetraenes 3, which react with alcohols to afford 2-alkoxy-1H-1,3-diazepines 4 (5), with secondary amines to 2-dialkylamino-5H-1,3-diazepines 16, sometimes via isolable 2-dialkylamino-1H-1,3-diazepines 15, and with water to 1,3-diazepin-2-ones 19. The latter are also obtained by elimination of isobutene or propene from 2-tert-butoxy- or 2-isopropoxy-1H-1,3-diazepines 4 or 5. 1,3-Diazepin-2-one 22B and 1,3-diazepin-4-one 24 were obtained from hydrolysis of the corresponding 4-chlorodiazepines. Diazepinones 19 undergo photochemical ring closure to diazabicycloheptenones 25 in high yields. The 2-alkoxy-1H-1,3-diazepines 4 and 5 interconvert by rapid proton exchange between positions N1 and N3. The free energies of activation for the proton exchange were measured by the Forsen - Hoffman method as DeltaGdouble dagger(298) = 16.2 +/- 0.6 kcal mol(-1) as an average for 4a - c in CD2Cl2, acetone-d(6), and methanol-d(4), and 14.1 +/- 0.6 kcal mol(-1) for 4c in acetone/D2O. The structures of 2-methoxy-5,6-bis( trifluoromethyl)-1H-1,3-diazepine 4k, 1,2-dihydro-4-diethylamino-5H-1,3-diazepin-2-one 22bB, and diazabicycloheptanone 26 were determined by X-ray crystallography. The former represents the first reported X-ray crystal structure of any monocyclic N-unsubstituted 1H-azepine.

Increased health care utilization and increased antiretroviral use in HIV-infected individuals with mental health disorders

Objectives The aims of the study were to describe the prevalence and associations of mental health disorder (MHD) among a cohort of HIV-infected patients attending the Victorian HIV/AIDS Service between 1984 and 2000, and to examine whether antiretroviral therapy use or mortality was influenced by MHD (defined as a record of service provision by psychiatric services on the Victorian Psychiatric Case Register). It was hypothesized that HIV-positive individuals with MHD would have poorer treatment outcomes, reduced responses to highly active antiretroviral therapy (HAART) and increased mortality compared with those without MHD. Methods This is a retrospective cohort of 2981 individuals (73% of the Victorian population diagnosed with HIV infection) captured on an HIV database which was electronically matched with the public Victorian Psychiatric Case Register (VPCR) (accounting for 95% of public system psychiatry service provision). The prevalence, dates and recorded specifics of mental health disorders at the time of the electronic match on 1 June 2000 are described. The association with recorded MHD, gender, age, AIDS illness, HIV exposure category, duration and type of antiviral therapy, treatment era (prior to 1986, post-1987 and pre-HAART, and post-HAART) on hospitalization and mortality at 1 September 2001 was assessed. Results Five hundred and twenty-five individuals (17.6% of the Victorian HIV-positive population) were recorded with MHD, most frequently coded as attributable to substance dependence/abuse or affective disorder. MHD was diagnosed prior to HIV in 33% and, of those diagnosed after HIV, 93.8% were recorded more than 1 year after the HIV diagnosis. Schizophrenia was recorded in 6% of the population with MHD. Hospitalizations for both psychiatric and nonpsychiatric illness were more frequent in those with MHD (relative risk 5.4; 95% confidence interval 3.7, 8.2). The total number of antiretrovirals used (median 6.4 agents vs 5.5 agents) was greater in those with MHD. When adjusted for antiretroviral treatment era, HIV exposure category, CD4 cell count and antiretroviral therapy, survival was not affected by MHD. Conclusions MHD is frequent in this population with HIV infection and is associated with increased healthcare utilization but not with reduced survival.

Prevalence of drug-resistance mutations and non-subtype B strains among HIV-infected infants from New York State

Summary: Prevalence studies indicate that transmission of drug-resistant HIV has been rising in the adult population, but data from the perinatally infected pediatric population are limited. In this retrospective study, we sequenced the pol region of HIV from perinatally infected infants diagnosed in New York State in 2001-2002. Analyses of drug resistance, subtype diversity, and perinatal antiretroviral exposure were conducted, and the results were compared with those from a previous study of HIV-infected infants identified in 1998-1999. Eight of 42 infants (19.1%) had provirus carrying at least 1 drug-resistance mutation, an increase of 58% over the 1998-1999 results. Mutations conferring resistance to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors were detected in 7.1%, 11.9%, and 2.4% of specimens, respectively. Consistent with previous results, perinatal antiretroviral exposure was not associated with drug resistance (P = 0.70). Phylogenetic analysis indicated that 16.7% of infants were infected with a non-subtype B strain of HIV. It seems that drug-resistant and non-subtype B strains of HIV are becoming increasingly common in the perinatally infected population. Our results highlight the value of resistance testing for all HIV-infected infants upon diagnosis and the need to consider subtype diversity in diagnostic and treatment strategies.

Legal Responses to HIV and AIDs - by James Chalmers

Book review: The Division of Wrongs: A Historical Comparative Study, by eric descheemaeker. Oxford: Oxford University Press, 2009.

Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc

Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.

Nucleoside and oligonucleotide approaches towards potential HIV chemotherapies

The use of oligonucleotides directed against the mRNA of HIV promises site-specific inhibition of viral replication. In this work, the effect of aralkyl substituents on oligonucleotide duplex stability was studied using model oligonucleotide sequences in an attempt to improve targeting of oligonucleotides to viral mRNA. Arakyl-substituted oligonucleotides were made by solid phase synthesis using either the appropriate aralkyl-substituted phosphoramidite or by post-synthetic substitution of a pentafluorophenoxy substituent by N-methylphenethylamine. The presence of phenethyl or benzoyl substituents invariably resulted in thermodynamic destabilisation of all duplexes studied. The methods which were developed for the synthesis of nucleoside intermediates for oligonucleotide applications were also used to prepare a series of nucleoside analogues derived from uridine, 2'-deoxyuridine and AZT. Crystal structures of six compounds were successfully determined. Anti-HIV activity was observed for most compounds in the series although none were without cytotoxicity. The most active compound of the series was the ribose nucleoside; 1-β-D-erythro-pentofuranosyl-4-pentafluorophenoxy-pyrimidine-2(1H)-one 95, derived directly from uridine. The same series of compounds also displayed very modest anti-cancer activity. To enable synthesis of prooligonucleotides and analogues for possible antisense applications, the properties of a new Silyl-Linked Controlled Pore Glass solid support were investigated. Synthesis of the sequences d(Tp)7T, d(Tps)7T and the base-sensitive d(Tp)3(CBzp)2(Tp)2T was achieved using the silyl-linked solid support in a fluoride-induced cleavage/deprotection strategy.

Correlates of voluntary HIV testing and counseling among middle aged and older Latinas

This study identifies and describes HIV Voluntary Counseling and Testing (VCT) of middle aged and older Latinas. The rate of new cases of HIV in people age 45 and older is rapidly increasing, with a 40.6% increase in the numbers of older Latinas infected with HIV between 1998 and 2002. Despite this increase, there is paucity of research on this population. This research seeks to address the gap through a secondary data analysis of Latina women. The aim of this study is twofold: (1) Develop and empirically test a multivariate model of VCT utilization for middle aged and older Latinas; (2) To test how the three individual components of the Andersen Behavioral Model impact VCT for middle aged and older Latinas. The study is organized around the three major domains of the Andersen Behavioral Model of service use that include: (a) predisposing factors; (b) enabling characteristics and (c) need. Logistic regression using structural equation modeling techniques were used to test multivariate relationships of variables on VCT for a sample of 135 middle age and older Latinas residing in Miami-Dade County, Florida. Over 60% of participants had been tested for HIV. Provider endorsement was found to he the strongest predictor of VCT (odds ration [OR] 6.38), followed by having a clinic as a regular source of healthcare (OR=3.88). Significant negative associations with VCT included self rated health status (OR=.592); Age (OR=.927); Spanish proficiency (OR=.927); number of sexual partners (OR=.613) and consumption of alcohol during sexual activity (.549). As this line of inquiry provides a critical glimpse into the VCT of older Latinas, recommendations for enhanced service provision and research will he offered.

Social factors influencing antiretroviral therapy (ART) adherence among Black men living with HIV who use illicit drugs

In the United States 1.2 million persons are HIV infected. Among men, HIV rates in Blacks are seven times higher than Whites. More Black men progress to AIDS because of treatment failure and adherence problems. Antiretroviral therapy (ART), the only treatment effective for long term HIV suppression, requires near perfect adherence. Illicit drug use and homelessness pose further challenges. Suboptimal ART adherence leads to HIV mutations that can render entire classes of medication ineffective and transmission of mutated HIV to others in the community. The purpose of this study was to investigate ART adherence behaviors of Black men living with HIV who use illicit drugs. A sample of 160 Black men living with HIV who use illicit drugs was recruited using flyers and snowball sampling. These men completed study questionnaires that included: demographics, the K-10, PSOM and Social Capital Integrated Questionnaire, among others. One-way ANOVAs, multiple regression, and path analysis were used to address the study's research questions. Most of the Black men in this sample were high school graduates and single, with high rates of being marginally housed and homeless. Unemployment and disability were common, and personal and household income was low. The men reported high numbers of sexual partners both over the past year and during their lifetimes, suggesting continued engagement in high risk behaviors. The majority of the men attributed their HIV to heterosexual sex, with sexual commoditization being common. About half of the 105 men currently taking ART reported the current regimen was their first. Patient-provider relationship was positively associated with tolerability of ART. ART adherence was greater with less psychological distress, lower frequency of current illicit drug use, and greater tolerability of ART. Partner status negatively influenced ART adherence. This study of Black men's ART adherence behaviors has implications for public health. It identified social context factors that influence ART adherence among the men and provides evidence to refine existing, or develop new, ART adherence interventions.

Cognitive performance and the thymus among HIV-infected subjects receiving HAART

Objective: To evaluate the impact of alcohol use, which is widespread in human immunodeficiency virus (HIV)+ individuals, on highly active antiretroviral therapy (HAART)-associated immune and cognitive improvements and the relationship between those two responses. Methods: In a case-control longitudinal study, thymic volume, cognition, and immune responses were evaluated at baseline and after 6 months therapy in HIV+ and HIV- controls. Cognitive performance was evaluated using the HIV Dementia Score (HDS) and the California Verbal Learning Test (CVLT). Results: Prior to HAART, thymic volume varied considerably from 2.7 to 29.3 cm3 (11 ± 7.2 cm3). Thymic volume at baseline showed a significantly inverse correlation with the patient’s number of years of drinking (r2 = 0.207; p < 0.01), as well as HDS and the CVLT scores in both HIV-infected (r2 = 0.37, p = 0.03) and noninfected (r2 = 0.8, p = 0.01). HIV-infected individuals with a small thymic volume scored in the demented range, as compared with those with a larger thymus (7 ± 2.7 vs. 12 ± 2.3, p = 0.005). After HAART, light/moderate drinkers exhibited thymus size twice that of heavy drinkers (14.8 ± 10.4 vs. 6.9 ± 3.3 cm3). Conclusions: HAART-associated increases of thymus volume appear to be negatively affected by alcohol consumption and significantly related to their cognitive status. This result could have important clinical implications.

Progress towards Elimination of HIV Mother-to-Child Transmission in the Dominican Republic from 1999 to 2011

In 1999, prevention of mother-to-child transmission (pMTCT) using antiretrovirals was introduced in the Dominican Republic (DR). Highly active antiretroviral therapy (HAART) was introduced for immunosuppressed persons in 2004 and for pMTCT in 2008. To assess progress towards MTCT elimination, data from requisitions for HIV nucleic acid amplification tests for diagnosis of HIV infection in perinatally exposed infants born in the DR from 1999 to 2011 were analyzed. The MTCT rate was 142/1,274 (11.1%) in 1999–2008 and 12/302 (4.0%) in 2009–2011 (), with a rate of 154/1,576 (9.8%) for both periods combined. This decline was associated with significant increases in the proportions of women who received prenatal HAART (from 12.3% to 67.9%) and infants who received exclusive formula feeding (from 76.3% to 86.1%) and declines in proportions of women who received no prenatal antiretrovirals (from 31.9% to 12.2%) or received only single-dose nevirapine (from 39.5% to 19.5%). In 2007, over 95% of DR pregnant women received prenatal care, HIV testing, and professionally attended delivery. However, only 58% of women in underserved sugarcane plantation communities (2007) and 76% in HIV sentinel surveillance hospitals (2003–2005) received their HIV test results. HIV-MTCT elimination is feasible but persistent lack of access to critical pMTCT measures must be addressed.

Influence of religious coping on the substance use and HIV risk behaviors of recent Latino immigrants

This study examines the influence of acculturative stress on substance use and HIV risk behaviors among recent Latino immigrants. The central hypothesis of the study is that specific religious coping mechanisms influence the relationship that acculturative stress has on the substance use and HIV-risk behaviors of recent Latino immigrants. Within the Latino culture religiosity is a pervasive force, guiding attitudes, behaviors, and even social interactions. When controlling for education and socioeconomic status, Latinos have been found to use religious coping mechanisms more frequently than their Non-Latino White counterparts. In addition, less acculturated Latinos use religious coping strategies more frequently than those with higher levels of acculturation. Given its prominent role in Latino culture, it appears probable that this mechanism may prove to be influential during difficult life transitions, such as those experienced during the immigration process. This study examines the moderating influence of specific religious coping mechanisms on the relationship between acculturative stress and substance use/HIV risk behaviors of recent Latino immigrants. Analyses for the present study were conducted with wave 2 data from an ongoing longitudinal study investigating associations between pre-immigration factors and health behavior trajectories of recent Latino immigrants. Structural equation and zero-inflated Poisson modeling were implemented to test the specified models and examine the nature of the relationship among the variables. Moderating effects were found for negative religious coping. Higher levels of negative religious coping strengthened an inverse relationship between acculturative stress and substance use. Results also indicated direct relationships between religious coping mechanisms and substance use. External and positive religious coping were inversely related to substance use. Negative religious coping was positively related to substance use. This study aims to contribute knowledge of how religious coping influence's the adaptation process of recent Latino immigrants. Expanding scientific understanding as to the function and effect of these coping mechanisms could lead to enhanced culturally relevant approaches in service delivery among Latino populations. Furthermore this knowledge could inform research about specific cognitions and behaviors that need to be targeted in prevention and treatment programs with this population.

Specific Increase in MDR1 Mediated Drug-Efflux in Human Brain Endothelial Cells following Co-Exposure to HIV-1 and Saquinavir

Persistence of HIV-1 reservoirs within the Central Nervous System (CNS) remains a significant challenge to the efficacy of potent anti-HIV-1 drugs. The primary human Brain Microvascular Endothelial Cells (HBMVEC) constitutes the Blood Brain Barrier (BBB) which interferes with anti-HIV drug delivery into the CNS. The ATP binding cassette (ABC) transporters expressed on HBMVEC can efflux HIV-1 protease inhibitors (HPI), enabling the persistence of HIV-1 in CNS. Constitutive low level expression of several ABC-transporters, such as MDR1 (a.k.a. P-gp) and MRPs are documented in HBMVEC. Although it is recognized that inflammatory cytokines and exposure to xenobiotic drug substrates (e.g HPI) can augment the expression of these transporters, it is not known whether concomitant exposure to virus and anti-retroviral drugs can increase drug-efflux functions in HBMVEC. Our in vitro studies showed that exposure of HBMVEC to HIV-1 significantly up-regulates both MDR1 gene expression and protein levels; however, no significant increases in either MRP-1 or MRP-2 were observed. Furthermore, calcein-AM dye-efflux assays using HBMVEC showed that, compared to virus exposure alone, the MDR1 mediated drug-efflux function was significantly induced following concomitant exposure to both HIV-1 and saquinavir (SQV). This increase in MDR1 mediated drug-efflux was further substantiated via increased intracellular retention of radiolabeled [3H-] SQV. The crucial role of MDR1 in 3H-SQV efflux from HBMVEC was further confirmed by using both a MDR1 specific blocker (PSC-833) and MDR1 specific siRNAs. Therefore, MDR1 specific drug-efflux function increases in HBMVEC following co-exposure to HIV-1 and SQV which can reduce the penetration of HPIs into the infected brain reservoirs of HIV-1. A targeted suppression of MDR1 in the BBB may thus provide a novel strategy to suppress residual viral replication in the CNS, by augmenting the therapeutic efficacy of HAART drugs.

The influence of neurocognitive impairment, alcohol and other drug (AOD) use, and psychosocial factors on antiretroviral treatment adherence, service utilization and viral load among HIV-seropositive adults

Among people living with HIV (PLWH), adherence to antiretroviral therapy (ART) can be affected by problems of neurocognitive (NC) impairment, stress, alcohol and other drug (AOD) abuse, and other barriers. The aims of this research were to: (1) examine factors associated with NC impairment, (2) explore relationships between psychosocial variables with ART adherence and viral load (VL), and (3) evaluate the efficacy of an evidence-based intervention in improving ART adherence, increasing service utilization, and decreasing VL. The first study (n=370) was cross sectional and used structural equation modeling to test whether AOD use, years living with HIV, and time from HIV diagnosis to seeking care were associated with poorer NC functioning. The second study (n=246) used similar methods to test the hypothesis that stress, barriers to adherence, NC impairment, poor social support, and AOD use were related to lower VL mediated by ART adherence. The third study (n=243) evaluated an evidence-based, eight-session program to improve ART adherence, reduce VL, and increase service utilization in a randomized controlled trial. Study participants were PLWH living in South Florida, 18 to 60 years old, with a history of alcohol abuse enrolled from January 2009 through November 2012. Secondary analysis of available data showed: (1) scores on interference with executive functioning increased by 0.32 for each day of marijuana use and 1.18 for each year living with HIV, but no association was found between alcohol use and NC functioning; (2) each barrier to adherence was associated with a 10% decrease in adherence to ART and a 0.42 unit increase in VL (log10) and the relationship between barriers and VL was partially mediated by ART adherence; (3) participants in the evidence-based program were more likely than the comparison group to report an undetectable VL (OR=2.25, p<0.01) at 6 months, but not 3 months, post-intervention. Psychosocial factors affect VL, but ART adherence is essential in achieving an undetectable VL in PLWH.

Social capital, HIV risk behavior and substance use among recent Latino immigrants in South Florida

Social capital, or social cohesion or group connectedness, can influence both HIV risk behavior and substance use. Because recent immigrants undergo a change in environment, one of the consequences can be a change in social capital. There may be an association among changes in social capital, and HIV risk behavior and substance use post immigration. The dissertation focused on the interface of these three variables among recent Latino immigrants (RLIs) in South Florida. The first manuscript is a systematic review of social capital and HIV risk behavior, and served as a partial background for the second and third manuscripts. Twelve papers with a measure of social capital as an independent variable and HIV risk as the dependent variable were included in the analysis. Eleven studies measured social capital at the individual level, and one study measured social capital at the group level. HIV risk was influenced by social capital, but the type of influence was dependent on the type of social capital and on the study population. Cognitive social capital, or levels of collective action, was protective against HIV in both men and women. The role of structural social capital, or levels of civic engagement/group participation, on HIV risk was dependent on the type of structural social capital and varied by gender. Microfinance programs and functional group participation were protective for women, while dysfunctional group participation and peer-level support may have increased HIV risk among men. The second manuscript was an original study assessing changes in social capital and HIV risk behavior pre to post immigration among RLIs in South Florida (n=527). HIV risk behavior was assessed through the frequency of vaginal-penile condom use, and the number of sexual partners. It was a longitudinal study using secondary data analysis to assess changes in social capital and HIV risk behavior pre immigration to two years post immigration, and to determine if there was a relationship between the two variables. There was an 8% decrease in total social capital (p < .05). Reporting of 'Never use' of condoms in the past 90 days increased in all subcategories (p < .05). Single men had a decrease in number of sexual partners (p < .05). Lower social capital measured on the dimension of 'friend and other' was marginally associated with fewer sexual partners. The third manuscript was another original study looking at the association between social capital and substance use among RLIs in South Florida (n=527). Substance use with measured by frequency of hazardous alcoholic drinking, and illicit drug use. It was a longitudinal study of social capital and substance-use from pre to two years post immigration. Post-immigration, social capital, hazardous drinking and illicit drug use decreased (p<.001). After adjusting for time, compared to males, females were less likely to engage in hazardous drinking (OR=.31, p<.001), and less likely to engage in illicit drug use (OR=.67, p=.01). Documentation status was a moderator between social capital and illicit drug use. 'Business' and 'Agency' social capital were associated with changes in illicit drug use for documented immigrants. After adjusting for gender and marital status, on average, documented immigrants with a one-unit increase in 'business' social capital were 1.2 times more likely to engage in illicit drug use (p<.01), and documented immigrants with one-unit increase in 'agency' social capital were 38% less likely to engage in illicit drug use (p<.01). 'Friend and other' social capital was associated with a decrease in illicit drug use among undocumented immigrants. After adjusting for gender and marital status, on average, undocumented immigrants with a one-unit increase in 'friend and other' social capital were 45% less likely to engage in hazardous drinking and 44% less likely to use illicit drugs (p<.01, p<.05). Studying these three domains is relevant because HIV continues to be a public health issue, particularly in Miami-Dade County, which is ranked among other U.S. regions with high rates of HIV/AIDS prevalence. Substance use is associated with HIV risk behavior; in most studies, increased substance use is associated with increased chances of HIV risk behavior. Immigration, which is the hypothesized catalyst for the change in social capital, has an impact on the dynamic of a society. Greater immigration can be burdensome on the host country's societal resources; however immigrants are also potentially a source of additional skilled labor for the workforce. Therefore, successful adaption of immigrants can have a positive influence on receiving communities. With Florida being a major receiver of immigrants to the U.S, this dissertation attempts to address an important public health issue for South Florida and the U.S. at large.