A SWOT Analysis of the Updated National HIV/AIDS Strategy for the U.S., 2015-2020.

In July 2015, President Barack Obama released an updated National HIV/AIDS Strategy (NHAS) for the United States to guide HIV efforts through the year 2020. A federal action plan to accompany the updated NHAS will be released in December 2015. In this editorial, we offer a strengths, weaknesses, opportunities and threats analysis with the aim of increasing discussion of ways to truly fulfill the promise of the updated NHAS and to address barriers that may thwart it from achieving its full potential.

Restrictions for Medicaid Reimbursement of Sofosbuvir for the Treatment of Hepatitis C Virus Infection in the United States.

The aim of this study was to systematically evaluate state Medicaid policies for the treatment of hepatitis C virus (HCV) infection with sofosbuvir in the United States. Medicaid reimbursement criteria for sofosbuvir were evaluated in all 50 states and the District of Columbia. The authors searched state Medicaid Web sites between 23 June and 7 December 2014 and extracted data in duplicate. Any differences were resolved by consensus. Data were extracted on whether sofosbuvir was covered and the criteria for coverage based on the following categories: liver disease stage, HIV co-infection, prescriber type, and drug or alcohol use. Of the 42 states with known Medicaid reimbursement criteria for sofosbuvir, 74% limit sofosbuvir access to persons with advanced fibrosis (Meta-Analysis of Histologic Data in Viral Hepatitis [METAVIR] fibrosis stage F3) or cirrhosis (F4). One quarter of states require persons co-infected with HCV and HIV to be receiving antiretroviral therapy or to have suppressed HIV RNA levels. Two thirds of states have restrictions based on prescriber type, and 88% include drug or alcohol use in their sofosbuvir eligibility criteria, with 50% requiring a period of abstinence and 64% requiring urine drug screening. Heterogeneity is present in Medicaid reimbursement criteria for sofosbuvir with respect to liver disease staging, HIV co-infection, prescriber type, and drug or alcohol use across the United States. Restrictions do not seem to conform with recommendations from professional organizations, such as the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases. Current restrictions seem to violate federal Medicaid law, which requires states to cover drugs consistent with their U.S. Food and Drug Administration labels.

Enhancement of Achilles tendon repair mediated by matrix metalloproteinase inhibition via systemic administration of doxycycline.

Collagenases or matrix metalloproteinases (MMPs) have been shown to play an important role in the matrix degradation cascade associated with Achilles tendon rupture and disease. The goal of this study was to examine the effects of daily administration of doxycycline (Doxy) through oral gavage on MMP activity and on the repair quality of Achilles tendons in vivo. Our findings indicate that Achilles tendon transection resulted in increasing MMP-8 activity from 2 to 6 weeks post-injury, with peak increases in activity occurring at 4 weeks post-injury. Doxy adiministration at clinically relevant serum concentrations was found to significantly inhibit MMP activity after continuous treatment for 4 weeks, but not for continuous administration for shorter durations (96 h or 2 weeks). Extended doxy administration was also associated with improved collagen fibril organization, and enhanced biomechanical properties (stiffness, ultimate tensile strength, maximum load to failure, and elastic toughness). Our findings indicate that a temporal delay exists between Achilles tendon transection and associated increases in MMP-8 activity in situ. Our findings suggest that inhibition of MMP-8 at its peak activity levels ameliorates fibrosis development and improves biomechanical properties of the Achilles tendon.

The road forward: the scientific basis for tetracycline treatment of arthritic disorders.

The potential role of a collagenase inhibitor for treatment of arthritis was recognized almost immediately after the discovery of vertebrate collagenase. Yet despite vast efforts from the pharmaceutical industry, no such drug has been approved for such use by a regulatory agency. Although two semisynthetic antimicrobial tetracyclines, viz. minocycline and doxycycline, have been shown to have modest clinical benefits in over a dozen trials in rheumatoid arthritis, neither drug is in widespread use. The almost universal use of methotrexate and the rapid development of potent biologic agents have eclipsed the potential usage of TETs for RA. Ironically, it is in osteoarthritis, where there has only been one clinical trial which essentially failed, that the best potential exists for use of an MMP-inhibiting TET.

Synoviocytes are more sensitive than cartilage to the effects of minocycline and doxycycline on IL-1alpha and MMP-13-induced catabolic gene responses.

The objective of this study was to determine the primary articular tissue target of doxycycline and minocycline. Synoviocytes-cartilage cocultures (n = 4) were treated with MMP-13 (25 ng/mL medium) or IL-1 (1.0 ng/mL medium) for 24 h. Doxycycline (4.3, 0.43, 0.043 microM) or minocycline (10, 1.0 or 0.1 microM) were then added and cultures were continued for 96 h. Cartilage and media were analyzed for GAG content. Quantitative PCR was used to measure cartilage MMP-3, MMP-13, aggrecan, COL2A1, ADAMTS-4, and ADAMTS-5 expression, and synoviocyte MMP-3, MMP-13, ADAMTS-4, and ADMATS-5 expression. Total and active MMP-3, MMP-13, and ADAMTS 4/5 enzymes were measured in culture medium. All concentrations of doxycycline and minocycline diminished GAG accumulation in the media. All concentrations of minocycline, but only the highest concentration of doxycycline decreased MMP-3 and MMP-13 expression in synoviocytes but not cartilage, and basal ADAMTS-5 mRNA levels in both synoviocytes and cartilage. Only minocycline decreased active MMP-13 protein in synoviocytes. In summary, the protective effects of tetracycline compounds are more pronounced in synoviocytes than cartilage, and following minocycline compared to doxycycline. Studies to determine the molecular mechanism of action of the tetracyclines in synoviocytes might lead to the design of targeted therapeutics for the treatment of OA or RA.

Reducing long-term remedial costs by transport modeling optimization.

The Department of Defense (DoD) Environmental Security Technology Certification Program and the Environmental Protection Agency sponsored a project to evaluate the benefits and utility of contaminant transport simulation-optimization algorithms against traditional (trial and error) modeling approaches. Three pump-and-treat facilities operated by the DoD were selected for inclusion in the project. Three optimization formulations were developed for each facility and solved independently by three modeling teams (two using simulation-optimization algorithms and one applying trial-and-error methods). The results clearly indicate that simulation-optimization methods are able to search a wider range of well locations and flow rates and identify better solutions than current trial-and-error approaches. The solutions found were 5% to 50% better than those obtained using trial-and-error (measured using optimal objective function values), with an average improvement of approximately 20%. This translated into potential savings ranging from 600,000 dollars to 10,000,000 dollars for the three sites. In nearly all cases, the cost savings easily outweighed the costs of the optimization. To reduce computational requirements, in some cases the simulation-optimization groups applied multiple mathematical algorithms, solved a series of modified subproblems, and/or fit "meta-models" such as neural networks or regression models to replace time-consuming simulation models in the optimization algorithm. The optimal solutions did not account for the uncertainties inherent in the modeling process. This project illustrates that transport simulation-optimization techniques are practical for real problems. However, applying the techniques in an efficient manner requires expertise and should involve iterative modification to the formulations based on interim results.

Experimental arthritis in rats induces biomarkers of periodontitis which are ameliorated by gene therapy with tissue inhibitor of matrix metalloproteinases.

BACKGROUND: Periodontal disease (PD) and rheumatoid arthritis (RA) share many common pathophysiologic features, but a clinical relationship between the two conditions remains controversial, in part because of the confounding effects of anti-inflammatory drug therapy universally used in the latter disease. To further explore this issue, inflammatory arthritis was induced in rats to determine the effect on gingival biomarkers of inflammation and tissue destruction and to investigate the effect of a therapeutic intervention devoid of conventional anti-inflammatory properties. METHODS: Adjuvant arthritis (AA) was induced in Lewis male rats by injecting mycobacterium cell wall in complete Freund's adjuvant using standard techniques. One group of animals was treated by induction of systemic tissue inhibitor of matrix metalloproteinases (TIMP-4). At 3 weeks, arthritis severity was recorded and both paw and gingival tissues were collected for matrix metalloproteinase activity (MMP) and cytokine analysis. In addition, the maxillary jaws were removed for assessment of periodontal bone loss. RESULTS: The development of arthritis was associated with elevated joint tissue MMPs, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta levels compared to control rats. In the gingival tissue of the untreated arthritic rats, gelatinase, collagenase, TNF-alpha, and IL-1beta were also elevated compared to control rats. Periodontal bone loss and tooth mobility were also increased significantly (P <0.05) in untreated arthritic rats. All parameters improved after TIMP-4 gene therapy. CONCLUSIONS: To our knowledge, this is the first study to report an association between experimental systemic arthritis in rats and elevated gingival tissue MMPs, cytokine levels, and periodontal disease. Reversal of these changes with TIMP-4 gene therapy strengthens the pathophysiologic correlation between systemic and local disease.

Excretion of collagen derived peptides is increased in women with stress urinary incontinence.

AIMS: The objective of this study was to demonstrate that weakened pelvic floor support of the lower genitourinary tract in women with stress urinary incontinence (SUI) is due to increased collagenolysis. When fibrillar collagen is degraded, pyridinium (PYD) crosslinks are released and excreted in the urine. Degradation of collagen also results in peptide fragments of various lengths which are excreted in the urine. Degradation of mature fibrillar collagen and collagen which has not been crosslinked can be assessed independently by measurement of both PYD and collagen-derived peptides in the urine. METHODS: Twenty-four hour urine collections were obtained from women with SUI (n = 23) and women without urinary incontinence (n = 39). Urinary PYD concentration was assayed by ELISA. The urinary concentration of helical peptide alpha1 (I) 620-633 fragments derived from collagen was assayed by competitive enzyme immunoassay. Values were normalized to creatinine. RESULTS: The mean urine PYD concentration for women with SUI (110.8 +/- 19.7 nM/mM creatinine) was not significantly different than that for women without SUI (85.2 +/- 13.7 nM/mM creatinine). The mean urine concentration of helical peptide alpha1 (I) 620-633 for women with SUI (0.80 +/- 0.13 microg/mg creatinine) was significantly (P < 0.02) higher than that for women without SUI (0.49 +/- 0.06 microg/mg creatinine). CONCLUSIONS: These data suggest that collagenolytic activity in women with SUI is elevated compared to continent controls, as measured by urinary helical peptide alpha1 (I) 620-633 excretion. The lack of difference in urinary PYD excretion between the two populations suggests that the increased collagenolytic activity in women with SUI, compared to continent controls, is restricted to uncrosslinked collagen.

Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis.

Rheumatoid arthritis (RA) and adult periodontitis share common pathogenetic mechanisms and immunologic and pathological findings. One oral pathogen strongly implicated in the pathogenesis of periodontal disease, Porphyromonas gingivalis, possesses a unique microbial enzyme, peptidylarginine deiminase (PAD), the human equivalent of which has been identified as a susceptibility factor for RA. We suggest that individuals predisposed to periodontal infection are exposed to antigens generated by PAD, with de-iminated fibrin as a likely candidate, which become systemic immunogens and lead to intraarticular inflammation. PAD engendered antigens lead to production of rheumatoid factor-containing immune complexes and provoke local inflammation, both in gingiva and synovium via Fc and C5a receptors.

Potential applications of matrix metalloproteinase inhibitors in geriatric practice.

Matrix metalloproteinases are a family of enzymes that degrade different components of extracellular matrix. They play an important role in normal physiologic processes of maintaining tissue integrity and remodeling, as in wound healing, processes of development, and regeneration. However, excessive expression of MMP has been observed in many disease states, including rheumatoid arthritis and osteoarthritis, vascular remodeling in atherosclerosis and aortic aneurysm formation, neoplastic processes, macular degeneration and many others.

Inhibition of adjuvant-induced arthritis by systemic tissue inhibitor of metalloproteinases 4 gene delivery.

OBJECTIVE: An imbalance in the matrix metalloproteinase:tissue inhibitor of metalloproteinases (MMP:TIMP) ratio in favor of MMP appears to be an important determinant of tissue damage in arthritis. We undertook this study to explore whether reversal of this imbalance in favor of TIMP would alter this process and to examine the mechanism of this alteration. METHODS: We administered human TIMP-4 by electroporation-mediated intramuscular injection of naked DNA using the rat adjuvant-induced arthritis (AIA) model. RESULTS: Intramuscular naked TIMP-4 gene administration resulted in high circulating TIMP-4 levels and completely abolished arthritis development in the rat AIA model. This inhibition was associated with significantly decreased MMP activity in the joint tissue as well as with significantly decreased serum and tissue tumor necrosis factor alpha levels and serum interleukin-1alpha levels compared with animals with arthritis. The mutation of cysteine at position 1 of TIMP-4 failed to block the development of AIA. CONCLUSION: Our data indicate that TIMP-4 is a potent antiinflammatory agent, and that its antiarthritis function may be mediated by MMPs. Arthritis-inhibiting effects of TIMP-4 may suggest a unique application of this gene therapy method for arthritis.