Randomized controlled phase IIa clinical trial of safety, pharmacokinetics and pharmacodynamics of tenofovir and tenofovir plus levonorgestrel releasing intravaginal rings used by women in Kenya

IntroductionGlobally, many young women face the overlapping burden of HIV infection and unintended pregnancy. Protection against both may benefit from safe and effective multipurpose prevention technologies.MethodsHealthy women ages 18–34 years, not pregnant, seronegative for HIV and hepatitis B surface antigen, not using hormonal contraception, and at low risk for HIV were randomized 2:2:1 to continuous use of a tenofovir/levonorgestrel (TFV/LNG), TFV, or placebo intravaginal ring (IVR). In addition to assessing genital and systemic safety, we determined TFV concentrations in plasma and cervicovaginal fluid (CVF) and LNG levels in serum using tandem liquid chromatography-mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through ex vivo CVF activity against both human immunodeficiency virus (HIV)-1 and herpes simplex virus (HSV)-2, and LNG PD using cervical mucus quality markers and serum progesterone for ovulation inhibition.ResultsAmong 312 women screened, 27 were randomized to use one of the following IVRs: TFV/LNG (n = 11); TFV-only (n = 11); or placebo (n = 5). Most screening failures were due to vaginal infections. The median days of IVR use was 68 [interquartile range (IQR), 36–90]. Adverse events (AEs) were distributed similarly among the three arms. There were two non-product related AEs graded >2. No visible genital lesions were observed. Steady state geometric mean amount (ssGMA) of vaginal TFV was comparable in the TFV/LNG and TFV IVR groups, 43,988 ng/swab (95% CI, 31,232, 61,954) and 30337 ng/swab (95% CI, 18,152, 50,702), respectively. Plasma TFV steady state geometric mean concentration (ssGMC) was <10 ng/ml for both TFV IVRs. In vitro, CVF anti-HIV-1 activity showed increased HIV inhibition over baseline following TFV-eluting IVR use, from a median of 7.1% to 84.4% in TFV/LNG, 15.0% to 89.5% in TFV-only, and −27.1% to −20.1% in placebo participants. Similarly, anti-HSV-2 activity in CVF increased >50 fold after use of TFV-containing IVRs. LNG serum ssGMC was 241 pg/ml (95% CI 185, 314) with rapid rise after TFV/LNG IVR insertion and decline 24-hours post-removal (586 pg/ml [95% CI 473, 726] and 87 pg/ml [95% CI 64, 119], respectively).ConclusionTFV/LNG and TFV-only IVRs were safe and well tolerated among Kenyan women. Pharmacokinetics and markers of protection against HIV-1, HSV-2, and unintended pregnancy suggest the potential for clinical efficacy of the multipurpose TFV/LNG IVR.Clinical Trial RegistrationNCT03762382 [https://clinicaltrials.gov/ct2/show/NCT03762382

Sexual and reproductive health and human rights of women living with HIV

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138378/1/jia20834-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138378/2/jia20834.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138378/3/jia20834-sup-0002.pd

Pre-exposure prophylaxis for HIV-negative persons with partners living with HIV: uptake, use, and effectiveness in an open-label demonstration project in East Africa [version 2; referees: 2 approved]

Background: Pre-exposure prophylaxis (PrEP) can provide high protection against HIV infection and is a recommended intervention for HIV-negative persons with substantial HIV risk.  Demonstration projects conducted in diverse settings worldwide illustrate practical examples of how PrEP can be delivered. This manuscript presents estimates of effectiveness and patterns of PrEP use within a two-year demonstration project of PrEP for HIV-negative members of heterosexual HIV serodiscordant couples in East Africa. Methods: The PrEP delivery model integrated PrEP into HIV treatment services, prioritizing PrEP use for HIV-negative partners within serodiscordant couples before and during the first 6 months after the partner living with HIV initiated antiretroviral therapy (ART).  We measured PrEP uptake through pharmacy records and adherence to PrEP through medication event monitoring system (MEMS) bottle caps and quantification of tenofovir in plasma among a random sample of participants. We estimated HIV infections prevented using a counterfactual cohort simulated from the placebo arm of a previous PrEP clinical trial. Results: We enrolled 1,010 HIV serodiscordant couples that were naïve to ART and PrEP.  Ninety-seven percent of HIV-negative partners initiated PrEP. Objective measures suggest high adherence: 71% of HIV-negative participants took ≥80% of expected doses, as recorded via MEMS, and 81% of plasma samples had tenofovir detected.  Four incident HIV infections were observed (incidence rate=0.24 per 100 person-years), a 95% reduction (95% CI 86-98%, p<0.0001) in HIV incidence, relative to estimated HIV incidence for the population in the absence of PrEP integrated into HIV treatment services.   Conclusions: PrEP uptake and adherence were high and incident HIV was rare in this PrEP demonstration project for African HIV-negative individuals whose partners were known to be living with HIV.  Delivery of PrEP to HIV-negative partners within HIV serodiscordant couples was feasible and should be prioritized for wide-scale implementation

Alterations in the Expression of the Apurinic/Apyrimidinic Endonuclease-1/redox Factor-1 (APE/Ref-1) in Human Melanoma and Identification of the Therapeutic Potential of Resveratrol as an APE/Ref-1 Inhibitor

Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) is a multifunctional protein involved in DNA base excision repair and redox regulation of many transcription factors. In different melanoma cell lines, we found that both nucleus and cytoplasm exhibited higher levels of Ref-1 compared with normal melanocytes. Similar increases of Ref-1 expression, detected by immunohistofluorescence, were also evident in nevi and malignant melanoma biopsies compared with normal skin, which were predominantly localized in the nucleus. Using recombinant adenovirus Adref-1, encoding full-length Ref-1, we transiently overexpressed APE/Ref-1 in human melanocytes, which protected these cells from UVB-induced apoptosis and increased foci formation in culture. Ref-1 overexpression also protected melanoma cells from cisplatin- or H2O2-induced apoptosis, whereas increased apoptosis was observed with Ref-1 antisense construct infection. These observations suggested that intracellular Ref-1 levels played an important role in sensitization of melanoma cells to apoptosis. Electrophoretic mobility shift assay results showed that in both cultured primary and metastatic melanomas DNA-binding activities of activator protein-1 and nuclear factor-κB were significantly diminished or shifted when anti-APE/Ref-1 antibody was added to deplete APE/Ref-1 from the binding complexes. Induced nuclear factor-κB transcriptional activities were also evident after Ref-1 overexpression. Furthermore, using three-dimensional molecular structure modeling and virtual screening, we found that resveratrol, a natural compound found in fruits and vegetables, docks into a druggable pocket of Ref-1 protein. In vitro studies revealed that resveratrol inhibited, in a dose-dependent manner, Ref-1-activated activator protein-1 DNA-binding activities as well as Ref-1 endonuclease activities and rendered melanoma cells more sensitive to dacarbazine treatment

Assessment of genetics knowledge and skills in medical students: Insight for a clinical neurogenetics curriculum

The pace of discovery in biochemistry and genetics and its effect on clinical medicine places new curricular challenges in medical school education. We sought to evaluate students\u27 understanding of neurogenetics and its clinical applications to design a pilot curriculum into the clinical neurology clerkship. We utilized a needs assessment and a written examination to evaluate the genetics knowledge of 81 third- and fourth-year medical students. The needs assessment surveyed students\u27 self-perceptions of their own understanding of basic and clinically related genetic principles and clinical skills, as well as the most effective educational methods. Medical students reported more competence with basic science learned during the preclinical years than clinical concepts, and they demonstrated relatively low knowledge levels in clinical neurogenetics concepts on the examination, with an average of 29% correct on questions pertaining to genetic counseling compared with 82% correct with regard to inheritance patterns. Common, cross-specialty clinical skills were attained (e.g. internet search, family histories), while at least half of students reported minimal understanding or awareness of key genetics websites (e.g. OMIM) and indications for support group recommendations and genetics referrals. Teaching these more specific genetics skills and concepts needs to be emphasized in the clinical curriculum. © 2011 by The International Union of Biochemistry and Molecular Biology

Review of different techniques to study the interaction between coke and pitch in anode manufacturing

The quality of carbon anodes, consumed in electrolysis during the primary aluminum production, has an important impact on the electrolytic cell performance. Coke and pitch are the raw materials used in anode manufacturing. The raw material properties and the process parameters during production determine the anode quality. A plant receives these materials from different sources, and the variability in their properties is usually a major concern during anode production. The interaction between coke and pitch influences strongly the anode properties. Study of coke and pitch individually as well as the interactions between them using different techniques (spectroscopic, optical, etc.) such as XRD, FTIR, XPS, and SEM help identify their compatibility. Each technique gives information on different aspects of the raw materials. In this article, the use of a number of these techniques for studying coke, pitch, and their interactions will be discussed. Results will be presented for a number of cases

Couple ART and PrEP use over time.

<p>This graph illustrates the overall distribution of ART use by HIV-1-infected partners and PrEP use by HIV-1-uninfected partners within the study partnerships, over follow-up. The proportion of couples using only PrEP for HIV-1 prevention declined over time, as HIV-1-infected participants initiated ART, as defined by the PrEP as a bridge to ART approach of the project. Through month 6, there was the greatest overlap between ART and PrEP; thereafter, couples with HIV-1 infected partners that initiated ART at or soon after enrollment begin to discontinue PrEP. The primary reason for couples using neither ART nor PrEP was missed visits, which were considered as not exposed to PrEP (since PrEP was distributed only at the study sites during the study period) nor to ART (which was assumed to have not been initiated until first reported).</p

HIV-1 incidence, expected versus observed.

<p>Expected HIV-1 incidence was estimated from a counterfactual model, bootstrapping data from a comparable at-risk population of HIV-1-serodiscordant couples. The graphic presents results for the entire study population. The table details the overall population estimates as well as analyses stratified by gender of the HIV-1-uninfected partner and baseline plasma HIV-1 RNA concentrations of the HIV-1-infected partner.</p