Physiologic Insulin Resensitization as a Treatment Modality for Insulin Resistance Pathophysiology.

Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.

Medication costs associated with early initiation of antiretroviral therapy.

The START Study randomly assigned 4685 persons with CD4+ counts >500 to either immediate treatment (2326 persons) or a group (2359) that had treatment delayed until the CD4+ count was <350 or clinical judgment dictated treatment. The average time in the study was three years. The immediate group (IG) had 42 serious clinical events and the delayed group (DG) had 96. Policy considerations for adopting these results should consider the cost of medications for early treatment, which is the purpose of this article. Cost of early treatment was estimated by assuming the delayed treatment group had been treated for the three-year average course of the study. However, 48% of the DG received ART before the study's end, so that portion of the group's time on ART was reduced to 1.5 years. Average wholesale prices in the United States of the five recommended ART regimens were discounted by 50% to reflect actual pricing. An average medication cost for the five regimens of $20,000 per person year was used. The three-year cost was $107,580,000 for the 52% who would have been treated for three years and for the 48% treated for an average of 1.5 years. The cost per clinical event avoided was $1,992,222. Formulae are provided that will allow the reader to adjust these results to reflect local prices and volumes. Additional factors to be considered should include the cost savings from avoiding serious clinical events, reduction in transmission of HIV for those being treated early in the infection and the issues associated with long-term adherence for those receiving ART at >500 CD4 counts.

Physicians' and nurses' thoughts and concerns about introducing neonatal male circumcision in Thailand: a qualitative study.

BACKGROUND: Neonatal male circumcision (NMC) is an alternative approach to adult male circumcision for HIV prevention. Recent studies found that NMC was rarely performed in Thailand and that most Thai health professionals did not recognize that NMC could reduce the risk of HIV infection and would not want NMC services in their hospitals. This study explored the thoughts and concerns of Thai government health staff regarding the introduction of NMC in government health facilities as a public health measure. METHODS: In-depth interviews with physicians, nurses and physician administrators from four different levels of government hospitals in four provinces representing 4 regions of Thailand were conducted after provision of education regarding the benefits and risks of NMC. Interviews were audio recorded and analyzed using Atlas.ti software to develop themes. RESULTS: Six themes emerged from the data of 42 respondents: understanding of the benefits of NMC; risks of NMC; need for a pilot project; need for staff training and hospital readiness; need for parental/family education; and need for public awareness educational campaign. Major concerns included possible medical complications of NMC, infringement of child rights, and lack of understanding from staff and parents. The respondents emphasized the need for a clear policy, proper training of staff, financial and equipment support, and piloting NMC rollout before this measure could be fully implemented. CONCLUSIONS: Thai health professionals who took part in this study expressed several concerns if NMC had to be performed in their health care facilities. There is significant preparation that needs to be done before NMC can be introduced in the country.

Thai health care provider knowledge of neonatal male circumcision in reducing transmission of HIV and other STIs.

BACKGROUND: Male circumcision (MC) reduces the risk of female-to-male transmission of HIV and other sexually transmitted infections (STIs). MC has not been practiced as a disease prevention measure in Thailand probably because of low recognition of its benefits among stakeholders. Neonatal male circumcision (NMC) is simpler, safer and cheaper than adult MC. This study aimed to assess Thai health care provider knowledge of benefits implementing NMC in Thailand. METHODS: Multi-stage sampling identified 16 government hospitals to represent various hospital sizes and regions of the country. Researchers administered a fixed choice questionnaire, developed by the research team based on a previous study, to physician administrators, practicing physicians, and nurses whose jobs involved NMC clinical procedures or oversight. The participants reviewed printed educational materials on the benefits of NMC during questionnaire completion. Data were analyzed using descriptive statistics, chi square tests, odds ratios, and logistic regression. RESULTS: One hundred thirty-three individuals participated in this quantitative study. Only 38% of the participants agreed that NMC reduced the risk of sexual transmission of HIV while 65% indicated that they knew that NMC prevented STIs. Most participants recognized the benefits of NMC on hygiene (96%) as well as cancer prevention (74%). Major concerns raised were potential trauma to the child, child rights and safety of NMC. After reviewing written information about the benefits of NMC, 59% of the participants agreed that NMC should be offered in their hospital. Physicians and nurses who had previous experience with circumcising patients of all ages were more reluctant to have NMC performed in their hospital. CONCLUSIONS: A clear policy advocating NMC, thorough preparation of health facilities, and staff training are needed before NMC could be used in Thailand as prevention strategy for HIV and other STIs.

Effect of an Empowerment Intervention on Antiretroviral Drug Adherence in Thai Youth.

A pilot study was conducted to determine effects of an empowerment intervention on antiretroviral therapy (ART) adherence among Thai youth living with HIV/AIDS. It compared two groups of 23 young persons (15-24 years) who receive ART from AIDS clinics at two community hospitals. One hospital's patients served as the experimental group, and the other as a control group. The experimental groups attended five sessions that empowered them to take control of their own health. The control group received the standard of care. The data were analyzed using descriptive statistics and Chi-square statistics. Before the empowerment, no one from the experimental group or the control group had ART adherence ≥ 95%. After the intervention, the 82.6% of the experimental group had ≥ 95% adherence compared to the control group, which had 21.7% adherence (p < .0001). The empowerment intervention resulted in a significant increase in ART adherence among Thai youth.

Capability of Thailand to implement newborn male circumcision: a nation-wide survey.

This study was designed to gain baseline information on the capability of the hospitals of Thailand to provide newborn male circumcision (NC) and on the opinions of health-care personnel towards NC. Two questionnaires were sent to every hospital in Thailand that might have obstetrical services. One questionnaire requested information about the degree to which NC was provided by the hospital. The second questionnaire targeted health-care providers' opinions about NC. The response rate was 55.1% (747/1355). Of the 562 hospitals that had deliveries in 2010, 8.2% (46) provided at least one NC. Thirty-eight percent (35/92) of private hospitals and 2.3% (11/470) of government hospitals provided the service. The primary reason for performing NC was parental request (82.6%). Some providers (31.3%) said that NC was easy to perform and 39.1% thought NC was safe. Most respondents (91.8%) stated that physicians should perform the procedure instead of nurses, and choices about undergoing NC should be left to parents (55.0%). NC was rarely performed in government hospitals, and its staffs seemed to not recognize the health benefits of NC. A massive education program for health-care providers would be necessary before implementing a national program for NC. More information on the opinions of health authorities, health-care personnel and parents as well as cost-effectiveness studies are needed before a proper policy can be implemented.

ATTITUDES AND BEHAVIOR AMONG RURAL THAI ADOLESCENTS REGARDING SEXUAL INTERCOURSE.

Early initiation of sexual intercourse has been associated with negative consequences, such as higher rates of unwanted pregnancy and HIV infection. This study examined the attitudes and behavior of rural Thai adolescent students aged 16 to 20 years from northern Thailand regarding sexual intercourse. Differences between participants who previously had sexual intercourse and those who had not were explored. Those who had not previously had sexual intercourse were asked about the reasons why they had not had sex, their future plans for having sex and their dating experiences. More than 70% of participants stated they had not previously had sexual intercourse but one third of this group reported engaging in other sexual behavior. There were significant differences by gender, religion, ethnicity, and household income between those who had previously had sex and those who had not. Among those who had not previously had sexual intercourse, concern for their parents' feelings was the most common reason for delaying intercourse. About two-thirds of this group had plans not to have sexual intercourse until after marriage; nearly half of them reported currently having a boyfriend/girlfriend. Interventions aimed at delaying sexual intercourse should involve adolescents in their design and include their attitudes for delaying intercourse. Because of many gender differences seen in our study, interventions should be designed differently for males and females in rural northern Thailand.

Effects of Internet-based instruction on HIV-prevention knowledge and practices among men who have sex with men.

HIV infection is increasing among men who have sex with men. In this study, the effects of Internet-based instruction on HIV-prevention knowledge were evaluated. The sample consisted of 162 men-who-have-sex-with-men volunteers in Thailand. The research instruments included a demographic data questionnaire, a knowledge test, and an HIV preventive practice questionnaire. The participants completed these instruments upon entry to the study and four months later. After entry to the study, the participants were given access to a previously-developed Internet-based instruction on HIV risk behaviors. Data were analyzed using descriptive statistics and paired t-test. After accessing the Internet-based instruction, the average score of HIV-prevention knowledge among the sample increased significantly, from 11.17 to 15.09 (maximum score of 20 points). The average score of practicing HIV prevention among the sample increased significantly, from 62.94 to 76.51 (maximum score of 99 points). This study demonstrated that Internet-based instruction was effective in improving HIV-prevention knowledge and practices among men who have sex with men. This suggests that Internet-based instruction could be developed for use in other countries and evaluated in a similar way.

Measurement issues in using pharmacy records to calculate adherence to antiretroviral drugs.

BACKGROUND: Researchers often use pharmacy records to calculate adherence to antiretrovirals. Variability in the findings may be due to inconsistent methods of calculating adherence. OBJECTIVE: Determine the impact on adherence rates of 6 different calculations that include accounting for whether filled antiretroviral prescriptions were picked up and whether the patient had medications at the start of the observation period. METHODS: Fifty-six patients of a public care system, who had ordered, but failed to pick up, antiretroviral prescriptions from the clinic pharmacy at least once from September thru December, were identified using an electronic pharmacy database. Their adherence during the 4 months was calculated using refilled doses and picked up doses as a percent of prescribed doses. The effect on the calculation of adherence of medications in the patients' possession from August was examined. RESULTS: When medications in the patients' possession from August were considered in calculating adherence, the rate was 54% based on the prescription refill date and 33.4% based on the prescription pick-up date. If medications in the patients' possession at the beginning of the observation period were ignored, adherence based on refill was 48.9% and 28.1% based on pick-up. If the start date for calculating adherence was the date of the first refill or pick-up during the first month of the observation period, adherence rates were 56.2% and 41%, respectively. CONCLUSIONS: This study demonstrated that 6 different methods of calculating adherence from pharmacy records yielded adherence rates of 28.1% to 56.2%. Studies using pharmacy records should specify how adherence is calculated.

The role of trust in delayed HIV diagnosis in a diverse, urban population.

Delayed diagnosis of HIV infection is a common problem. We hypothesized that persons with less trust in physicians and in the healthcare system would be diagnosed with lower CD4 cell counts than persons with more trust because they would delay seeking healthcare. From January 2006 to October 2007, 171 newly diagnosed HIV-infected persons, not yet in HIV primary care, were recruited from HIV testing sites in Houston, Texas, that primarily serve the under- and un-insured. The participants completed instruments measuring trust in physicians and trust in the healthcare system. Initial CD4 cell counts were obtained from medical record review. Mean trust scores for participants with CD4 cell counts ≥200 cells/mm(3) were compared with scores from participants with CD4 cell counts <200 cells/mm(3). We found that 51% of the cohort was diagnosed with a CD4 cell count <200 cells/mm(3). Neither trust in physicians nor trust in the healthcare system was an independent predictor of delayed diagnosis of HIV infection. In multivariate analysis, men who have sex with men and injection drug users were more likely to have early HIV diagnosis. Race/ethnicity was the only variable statistically significantly predictive of trust in physicians and in the healthcare system. Hispanics had the highest trust scores, followed by Blacks and Whites. Low trust is likely not a barrier to timely diagnosis of HIV infection.

Using cost as a consideration for antiretroviral regimen selection: an example using average wholesale prices.

Funding for the AIDS Drug Assistance Program (ADAP) has lagged behind the number of persons needing antiretroviral therapy, leading to waiting lists and reduction of needed treatments and services. This paper demonstrates a method of providing more treatment for the same amount of money by selecting clinically equivalent, but lower-cost drug regimens. Average wholesale prices (AWPs) were used to calculate the annual costs of preferred, alternative, and acceptable regimens. The cost of each regimen was divided into $1,000,000 to determine how many patients could be treated per $1,000,000 that an ADAP had to spend. AWPs for preferred regimens ranged from $25,318 to 35,645 per year. For alternative regimens, the range of annual AWPs was $22,002-$32,335. The range for the acceptable regimens was $19,031-$31,543. The range of person treated per $1,000,000 per year was from 28 to 52. Funding shortages will lead ADAPs to resort to waiting lists or other means of denying appropriate care unless alternative approaches to treatment are sought. Cost conscious selection of regimens where there is no harm to individual patients is one alternative approach. Medical conditions that allow exceptions to lower-cost-based regimens must be developed with the assistance of clinicians.

Reversal of diabetic retinopathy in two patients following the use of physiologic insulin Resensitization.

We followed two patients with diabetic retinopathy over the course of their treatment with physiologic Insulin resensitization. Both patients showed improvement of their diabetic retinopathy, after treatment.

HIV positive but not in care: a follow-up study from Thailand.

Twenty-two persons in Northern Thailand who knew of their HIV positivity but were not in care were identified. They had significant medical, economic, behavioral, and family problems. A nurse researcher carried out a 6-month intervention with them to (1) assess whether they would remain in contact with the researcher for 6 months and (2) assess whether they would make positive changes in their lives. All 22 participants remained in contact for 6 months. A 5-step intervention process resulted in substantial improvements in their lives. Eleven patients entered care. Five needed immediate antiretroviral therapy (ART) and improved their CD4 counts. Six others established primary care relationships for non-HIV care. Twelve obtained legal, full-, or part-time employment. Eight disclosed to family members. Nine participants and/or family members entered counseling. Twelve persons publicly disclosed themselves. Twelve reported reducing or stopping substance abuse. Of 4 sex workers, 2 ceased engaging in that work.

Why Thailand should consider promoting neonatal circumcision?

Male circumcision (MC) has been proven to reduce the risk of HIV transmission. The WHO and UNAIDS jointly recommend the international community consider MC as an HIV prevention measure. MC reduces the risk of acquiring other sexually transmitted infections (STIs) among men, urinary tract infections among children and penile cancer. Lowering the prevalence of STIs in men may reduce the incidence of STIs among women. High levels of adult MC are difficult to achieve in cultures where it has not been customary. Adult MC is associated with a high prevalence of post-operative complications. Neonatal male circumcision (NC) is simpler, safer, and cheaper. Higher coverage with MC can be achieved through NC. Thailand is a good country to promoting NC for the following reasons: most HIV infections are contracted through heterosexual transmission, there is a low MC rate, most newborn deliveries occur in hospitals, there is a relatively strong health care infrastructure and Thailand has well developed HIV care services. Issues of concern regarding promoting NC include length of time before seeing benefits, cost effectiveness of the intervention, the burden to the health care delivery system and concerns about children's rights. NC is an efficacious HIV prevention strategy that should be considered by those involved in HIV/AIDS prevention planning in Thailand. Further studies are needed to determine whether NC should be promoted in Thailand.

Cancer Patient Acceptance of HIV Screening at a Large Tertiary Cancer Center.

The U.S. Centers for Disease Control and Prevention (CDC), the U.S. Preventive Services Task Force (USPSTF) and the National Comprehensive Cancer Network (NCCN) recommend offering HIV testing for patients presenting for cancer care. Not recognizing and treating HIV infection adversely impacts both cancer treatment and HIV outcomes. Acceptance rates of oncology patients for HIV screening are not known. Our tertiary cancer center inserted language requesting permission to screen for HIV infection into the consent forms for initial presentation for cancer care. Willingness to undergo testing was examined in 29,549 consecutive new patients. These were analyzed by gender and age. Overall, 80.9% of patients agreed to HIV screening. Incorporation of language requesting permission for HIV screening into the consent form provided at presentation for cancer care, relieves clinicians from adding this task.

Synthesis and SAR of acyclic HCV NS3 protease inhibitors with novel P4-benzoxaborole moieties.

We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series.

Has Diarrhea Ceased to be a Concern in Persons Living With HIV? Results From a Cross-sectional Study.

ABSTRACT: Diarrhea has been associated with HIV throughout the epidemic. Few recent studies have addressed diarrhea in persons living with HIV (PLWH) despite evolving knowledge and ever-changing practice standards. The fact that patient care has become more complex, with comorbid conditions requiring additional attention without additional time allotment, potentiates the risk of common symptoms being overlooked. Patients (n = 190) 18 years and older, living with HIV, completed a questionnaire collecting information specific to attitudes, definitions, and beliefs regarding diarrhea. Of the 190 participants, only 5.3% said that they had diarrhea, but 11.1% described their bowel movements as being in the group associated with diarrhea. Approximately, 93.7% of the participants defined diarrhea as either soft or watery; 34.2% defined frequency as more than three times per day, but 64.2% said that it would have to be more than three times per day to mention it to a provider. PLWH continue to experience diarrhea warranting assessment and discussions between the PLWH and the provider.

Readiness: the state of the science (or the lack thereof).

HIV treatment guidelines state that patients' readiness should be assessed before initiating highly active antiretroviral therapy (HAART) to assure adherence. None of the guidelines provide a way to measure readiness. Therefore, this article sought to review the literature on readiness to determine if there was a viable predictor of adherence. Twenty-seven articles were reviewed. Nine described studies that examined the relationship between a measure of readiness and HAART adherence. No readiness measure demonstrated clinical utility as a predictor of adherence. Study flaws included small sample sizes (only one study >100 patients), short follow-up periods (all ≤1 year and six were ≤5 months, four ≤1 month), measures of readiness that related poorly to adherence, and inconsistent adherence measures (eight different measures were used by the researchers). Neither the guidelines nor the literature will help clinicians judge who should initiate HAART and who should delay treatment.

Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates.

A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.

Synthesis and evaluation of novel alpha-amino cyclic boronates as inhibitors of HCV NS3 protease.

We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described.