High levels of adherence have been identified as a key factor for effective pre-exposure prophylaxis medication (PrEP). Because PrEP is a new concept in HIV prevention, there are limited data on predictors of adherence, though initial findings indicate that sexual behavior could be an influencing factor. This study examines different aspects of sexual behavior and their associations with monthly rates and patterns of adherence. We enrolled 1147 HIV-negative individuals living in long-term serodiscordant relationships at three sites in Uganda. Sexual behavior was assessed via monthly in-person interviews and adherence was measured through electronic monitoring of pill bottle openings. We used generalized estimation equations to adjust for risk factors of low adherence to PrEP medication. Fifty-three percent of participants were male, 51% were aged between 18 and 34 years, the median number of years they had lived with the HIV-positive partner was 8.5 years and 24.2% were in polygamous relationships. Participants who had sex with other partners and also had less than 100% use of condoms were more than twice as likely to have less than 80% adherence (OR=2.48, 95%CI=1.70-3.62). Per electronic monitoring, 54.7% of cohort participants had at least one 72-hour consecutive gap in adherence. Participants who had sex with other partners and were also had also reported less than 100% use of condoms had a 50% increase in odds of having a 72-hour gap in adherence (OR=1.50, 95%CI=1.19-31.91). Low overall adherence and extended gaps in adherence were more common in participants that abstained from sex and those that reported sex outside their primary partnership. Despite high monthly adherence rates, many study participants had long periods of non-adherence during which they engaged in risky sexual behavior with potential for HIV acquisition.

Background Vancomycin dosing strategies targeting trough concentrations of 15–20 mg/L are no longer supported due to lack of efficacy evidence and increased risk of nephrotoxicity. Area-under-the-curve (AUC24) nomograms have demonstrated adequate attainment of AUC24 goals ≥ 400 mg h/L with more conservative troughs (10–15 mg/L). Objective The purpose of this study is to clinically validate a vancomycin AUC24 dosing nomogram compared to conventional dosing methods with regards to therapeutic failure and rates of acute kidney injury. Setting This study was conducted at a tertiary, community, teaching hospital in the United States. Method This retrospective, cohort study compared the rates of therapeutic failures between AUC24-extrapolated dosing and conventional dosing methods. Main outcome measure Primary outcome was treatment failure, defined as all-cause mortality within 30 days, persistent positive methicillin-resistant Staphylococcus aureus blood culture, or clinical failure. Rates of acute kidney injury in non-dialysis patients was a secondary endpoint. Results There were 96 participants in the extrapolated-AUC24 cohort and 60 participants in the conventional cohort. Baseline characteristics were similar between cohorts. Failure rates were 11.5% (11/96) in the extrapolated-AUC24 group compared to 18.3% (11/60) in the conventional group (p = 0.245). Reasons for failure were 6 deaths and 5 clinical failures in the extrapolated-AUC24 cohort and 10 deaths and 1 clinical failure in the conventional group. Acute kidney injury rates were 2.7% (2/73) and 16.4% (9/55) in the extrapolated-AUC24 and conventional cohorts, respectively (p = 0.009). Conclusion Extrapolated-AUC24 dosing was associated with less nephrotoxicity without an increase in treatment failures for bloodstream infections compared to conventional dosing. Further investigation is warranted to determine the relationship between extrapolated-AUC24 dosing and clinical failures.

Treatment of enterococcal endocarditis requires up to 6 weeks of intravenous (IV) antimicrobial therapy. When susceptible, an ampicillin-based regimen is preferred. Studies evaluating ampicillin stability utilizing high-pressure liquid chromatography have indicated enhanced stability (greater than 24 hours at room temperature), supporting outpatient administration. Thus, we report the successful treatment of a 30-year-old male with tricuspid valve enterococcal endocarditis in an outpatient setting using continuous infusion ampicillin via an ambulatory infusion pump. The patient received daily gentamicin at an outpatient infusion center with the ampicillin dose to be infused over the next 24 hours. Outpatient ambulatory infusion pumps allow for delivery of ampicillin via continuous infusion or pump-programmed pulse dosing. Preparation and administration in an outpatient infusion center may be a viable option to circumvent stability and delivery issues. Furthermore, 81% (34/42) of treatment days were completed outpatient, supporting that this approach may increase access to treatment and help reduce the economic burden to health care.

Objective: To compare and contrast doravirine (DOR) with other agents in the nonnucleoside reverse transcriptase inhibitor (NNRTI) class, review safety and efficacy data from both completed and ongoing clinical trials, and outline the potential place in therapy of DOR. Data Sources: A literature search using the PubMed database (inception to June 2019) was conducted using the search terms HIV, doravirine, non-nucleoside reverse transcriptase inhibitor, NNRTI, and MK-1439. Study Selection and Data Extraction: Clinical data were limited to those published in the English language from phase 2 or 3 clinical trials. Ongoing trials were identified through ClinicalTrials.gov. Data Synthesis: DOR was approved by the US Food and Drug Administration on the strength of 2 phase 3 randomized, double-blind, noninferiority clinical trials with additional studies currently underway examining its utility in other clinical scenarios. Relevance to Patient Care and Clinical Practice: The role of NNRTIs as part of antiretroviral (ARV) therapy has diminished in recent years given the introduction of more tolerable individual ARV agents and regimens. Despite this, new agents are still needed in the therapeutic arena because treatment failure as well as intolerance can still occur with many first-line therapies. The optimal place in therapy of DOR remains to be defined. Conclusions: DOR is a new NNRTI that represents a potential treatment option for treatment-naïve patients, without many of the previously described untoward effects of the NNRTI class.

Human C-reactive protein (CRP) increases survival of and decreases bacteremia in mice infected with Streptococcus pneumoniae. Such protection of mice against pneumococcal infection is seen only when CRP is administered into mice 6 hours before to 2 hours after the injection of pneumococci, but not when CRP is given to mice at a later time. Our first aim was to define the mechanism of CRP-mediated initial protection of mice against infection. It was proposed that CRP binds to phosphocholine (PCh) moieties present in the cell wall and activates the complement system on the pneumococcal surface that kills the pathogen. We generated a CRP mutant F66A/T76Y/E81A incapable of binding to PCh. Mutant CRP did not protect mice from pneumococcal infection. Thus, the proposed hypothesis was correct; the PCh-binding property of CRP contributes to the protection of mice against pneumococcal infection. Our second aim was to investigate why CRP was not protective during the late stages of infection. Pneumococci are known to recruit an inhibitor of complement activation, factor H, from the host to their surface to escape complement attack. We considered the ability of CRP, in its nonnative form, to bind to factor H, and generated a CRP mutant E42Q/F66A/T76Y/E81A capable of binding to factor H. In vivo experiments using the quadruple CRP mutant are in progress. We anticipate that the combination of wild-type and quadruple mutant CRP should be protective during the late stages of infection; wild-type CRP would bind to PCh and activate complement while mutant CRP would cover factor H to prevent its complement-inhibitory activity. Our long-term goal is to explore the possibility of developing a CRP-based strategy to treat pneumococcal infection.

C-reactive protein (CRP) binds to Streptococcus pneumoniae through the phosphocholine groups present in the cell wall and subsequently activates the complement system to kill the pathogen. To escape the attack of complement, pneumococci recruit a complement inhibitory protein, factor H, on their surface. It has been shown that CRP protects mice against pneumococcal infection only when injected within 2 hours after administering pneumococci. We hypothesized that CRP is not protective when injected at later times because, by then, factor H is recruited by pneumococci. In the current study, we evaluated the protective effects of an engineered CRP molecule (E-CRP) which does not bind to factor H in fluid phase but binds to factor H-coated pneumococci. We found that E-CRP, unlike native CRP, protected mice regardless of the timing of administering E-CRP by drastically reducing bacteremia and increasing survival of mice. Next, we established another murine model of pneumococcal infection using the antibiotic clarithromycin. We found that the combination of E-CRP and clarithromycin was more protective against infection when compared to the protective effects of either E-CRP alone or clarithromycin alone. These findings suggest that the structure of native CRP has to be altered to display its full anti-pneumococcal activity and that CRP and antibiotic act synergistically to protect against pneumococcal infection by decreasing bacteremia. These data also have implications for infections with other bacterial species that use factor H to evade the attack of complement. Additionally, the administration of E-CRP may be therapeutically beneficial to treat infections with antibiotic-resistant bacteria.

Hepatitis C is the most common chronic bloodbourne infection in the United States, with an estimated prevalence of 2.7 million. The total cost of care for this patient population was estimated to be $6.5 billion in 2013. Since 1998, the Centers for Disease Control (CDC) have recommended hepatitis C screening for specific high risk populations, but until recently there was no recommendation for age-based screening. The recent advent of new, more efficacious therapies for hepatitis C have made early identification significantly more important. Consequently, the CDC updated its recommendations in 2012 based on recent evidence to include one-time screening for all individuals born between 1945 and 1965. In 2013, the US Preventive Services Task Force (USPSTF) also incorporated this recommendation into their hepatitis C screening guidelines. In spite of this, there is some debate in the medical community regarding cohort screening for hepatitis C, and some data indicates widespread misunderstanding of current screening recommendations among primary care providers. The purpose of this project was to evaluate current knowledge and understanding of hepatitis C screening guidelines among a group of family medicine residents at East Tennessee State University, and to improve their knowledge in order to promote more appropriate screening practices in their patient population. To accomplish this, 13 question surveys were administered to residents to assess their current knowledge. Following these surveys, residents attended an education session covering current recommendations from the CDC and USPSTF. The 13 question survey was administered again in the post-intervention period. A t-test revealed that post-intervention survey scores increased significantly on 8 out of 13 questions. The intervention was successful at improving knowledge of current hepatitis C screening recommendations in the target population. Future research should be directed at broadening the intervention to include a variety of other providers, and at assessing the impact on execution of screening in the patient population, particularly regarding application to people born in the specified birth cohort.

In this thesis, we investigated T cell homeostasis and DNA damage repair machineries in HIV infection. We found that the frequencies of CD4T cells were low, which is associated with cell apoptosis in HIV patients compared to healthy subjects. Importantly, these events were closely correlated to the increase in T cell exhaustion, senescence, DNA damage, and telomere attrition. Mechanistically, while the DNA damage sensors Mer11, Rad50, and NBS1 (MRN) complexes remained intact, the ataxia-telangiectasia mutated (ATM) kinase and its downstream checkpoint kinase 2 (CHK2) were significantly inhibited during HIV infection. Additionally, telomeric repeat-binding factor 2 (TRF2) that functions to protect telomeres from unwanted DNA damage was also suppressed by HIV infection. These findings revealed an important mechanism by which telomeres undergo DNA damage that remained unrepaired due to ATM deficiency and TRF2 deprotection - a process that could promote T cell apoptosis, senescence, and cellular dysfunction in HIV infection.

No description available.

In the past thirty years, HIV/AIDS (Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome) transformed from a mysteriously lethal disease affecting limited portions of the population to a true global pandemic. Although HIV/AIDS is responsible for the deaths of approximately 30 million people worldwide, prevalence rates are now increasing significantly due to increasing survival rates. However, overall increasing incidence rates now serve as a primary concern for researchers. Avert (2011) suggests that there is a lack of behavioral interventions and prevention programs aimed at decreasing the number of newly affected individuals. This is problematic as it may create not only physical and mental stress upon patients but also a source of financial and resource stress upon service organizations. In Asia, HIV/AIDS is primarily apparent in three high-risk groups: sex workers, men who have sex with men, and intravenous drug users (Avert, 2011). Service organizations target these high-risk groups with prevention programs in order to decrease infection rates and raise general awareness of the disease. This study aims to evaluate two HIV/AIDS prevention program theories(the Sonagachi Project and the 100% Condom Use Program) and the studies that implement them. This proposed evaluation assesses the effectiveness of these HIV/AIDS prevention programs in reducing infection rates and raising awareness of the disease. Due to the widespread use and apparent effectiveness of the 100% Condom Use Program and The Sonagachi Project, this study aims to assess the interventions in lessening HIV infection rates and critique the methods outlined by both. This thesis also employs a systemic review of the literature by using the program theories of The 100% Condom Use Program and The Sonagachi Project.