Trends in AIDS-defining and non-AIDS-defining malignancies among HIV-infected patients: 1989-2002

In a comparison of rates of acquired immunodeficiency syndrome (AIDS)-defining malignancies (ADMs) for 1989-1996 versus 1997-2002, we found a decrease in ADMs (rate ratio, 0.31; P\u3c.0001) and a significant increase in non-AIDS-defining malignancies (non-ADMs; rate ratio, 10.87; P\u3c.0002). The mean CD4 cell count was lower among patients with ADMs than among those with non-ADMs. A longer duration of survival during highly active antiretroviral therapy might explain the increasing incidence of non-ADMs

MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background: Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. Objective: MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. Methods and Findings: We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Conclusions: Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. Trial Registration: ClinicalTrials.gov NCT00592124

A Phase 1 Randomized, Double Blind, Placebo Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel (MTN-007)

Objective: Rectal microbicides are needed to reduce the risk of HIV acquisition associated with unprotected receptive anal intercourse. The MTN-007 study was designed to assess the safety (general and mucosal), adherence, and acceptability of a new reduced glycerin formulation of tenofovir 1% gel. Methods: Participants were randomized 1:1:1:1 to receive the reduced glycerin formulation of tenofovir 1% gel, a hydroxyethyl cellulose placebo gel, a 2% nonoxynol-9 gel, or no treatment. Each gel was administered as a single dose followed by 7 daily doses. Mucosal safety evaluation included histology, fecal calprotectin, epithelial sloughing, cytokine expression (mRNA and protein), microarrays, flow cytometry of mucosal T cell phenotype, and rectal microflora. Acceptability and adherence were determined by computer-administered questionnaires and interactive telephone response, respectively. Results: Sixty-five participants (45 men and 20 women) were recruited into the study. There were no significant differences between the numbers of ≥ Grade 2 adverse events across the arms of the study. Likelihood of future product use (acceptability) was 87% (reduced glycerin formulation of tenofovir 1% gel), 93% (hydroxyethyl cellulose placebo gel), and 63% (nonoxynol-9 gel). Fecal calprotectin, rectal microflora, and epithelial sloughing did not differ by treatment arms during the study. Suggestive evidence of differences was seen in histology, mucosal gene expression, protein expression, and T cell phenotype. These changes were mostly confined to comparisons between the nonoxynol-9 gel and other study arms. Conclusions: The reduced glycerin formulation of tenofovir 1% gel was safe and well tolerated rectally and should be advanced to Phase 2 development. Trial Registration: ClinicalTrials.gov NCT01232803

Nosocomial Spread of Enterococcus faecium Resistant to Vancomycin and Linezolid in a Tertiary Care Medical Center

In May 2004 our institution encountered its first clinical isolate of linezolid-resistant, vancomycin-resistant Enterococcus faecium (LRVRE). Between October 2004 and July 2005, 40 patients from whom LRVRE organisms were recovered in clinical specimens were characterized. Epidemiologic investigation and pulsed-field gel electrophoresis patterns indicated a clonal outbreak related to nosocomial spread

USA300 Genotype Community-Associated Methicillin-Resistant Staphylococcus aureus as a Cause of Surgical Site Infections▿

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains are increasingly recovered from nosocomial settings. We conducted a retrospective study of surgical site infections (SSI) during 2004 and 2005 to determine the prevalence of CA-MRSA; 57% of MRSA strains tested belonged to the USA300 genotype. CA-MRSA has become a prominent cause of SSI at our institution

First-in-human safety and pharmacokinetics (PK) of a MIV-150/zinc acetate/carrageenan gel (PC-1005)

Background: The candidate microbicide, PC-1005, completely protects Depo-Provera-treated macaques from a single vaginal SHIV-RT challenge 8 h post dose, and significantly reduces HPV and HSV-2 infection in murine models. PC-1005 contains 50 μM MIV-150 (NNRTI) and 14 mM zinc acetate dihydrate in a carrageenan gel. Methods: In preparation for a Phase 1 trial, an open-label, safety run-in was conducted at the University of Alabama at Birmingham to assess the safety and pharmacokinetics (PK) of PC-1005. Healthy, sexually-abstinent, HIV and Hepatitis B/C negative, STI-free, non-pregnant women aged 19–49 on effective contraception, were eligible. Under clinical supervision, women inserted 4 ml of PC-1005 once daily for 3 days. Evaluations included physical exam, pelvic exam with colposcopy, EKG, vitals, and safety labs. Blood was drawn for PK assessment at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 h post-doses 1 and 3; and 48 h and 72 h post-dose 3. Results: From June-July 2014, 5 women (2 Black, 2 White, 1 Native American) completed the study (3 doses). Median age was 29 (range 29–38). Three women reported 4 possibly-related AEs; 3 were DAIDS Grade 1: vaginal discharge, intermenstrual bleeding, lower abdominal pressure; 1 was DAIDS Grade 2: vaginal itching. Safety labs, physical exams, vital signs, and colposcopy were all normal or not considered clinically significant by investigators. All subjects had detectable MIV-150 blood levels after dosing; no accumulation was noted. On Day 3, the median (and range) of MIV-150 PK parameters were: T_1/2 of 4.98 h (3.08–6.55); C_max of 77.4 pg/ml (55.25–166.85); T_max of 4 h (2–6); AUC_last of 774.38 pg h/ml (622.14–1188.66); AUC_inf of 803.23 pg h/ml (684.82–1252). There was no increase in zinc blood levels from baseline; median C_max of zinc was 79 μg/ml (58–94) on Day 3. Conclusions: PC-1005 was well tolerated after 3 days of dosing in 5 healthy women. MIV-150 was absorbed with low levels observed systemically; no accumulation was noted. Zinc levels were unchanged from baseline

Acceptability of PC-1005 gel administered rectally to HIV-1 seronegative adults at three different volume levels (MTN-037)

Multipurpose prevention technologies (MPT) have been increasingly researched for their dual-purpose preventative properties against HIV and other STIs. The acceptability of PC-1005, a topical MPT candidate, was explored among men and women participating in the MTN-037 Phase I trial at two U.S. sites (Pittsburgh, PA, and Birmingham, AL). We triangu-lated quantitative and qualitative assessments of the acceptability of three volumes (4 mL, 16 mL, 32 mL) of PC-1005 administered rectally (N = 12; 6 males, 6 females). Participants rated overall gel acceptability on a scale of 1–10, with a median of 7.17 (SD = 2.04) and had positive feelings about all three dose volumes, citing them to be very comfortable or comfortable (dose 1 = 91.7%; dose 2 = 91.7%; dose 3 = 83.3%). High acceptability of and comfort with all three dose volumes shows promise for PC-1005 as an MPT to prevent HIV and STIs, warranting future clinical development

In vitro exposure to PC-1005 and cervicovaginal lavage fluid from women vaginally administered PC-1005 inhibits HIV-1 and HSV-2 infection in human cervical mucosa

Our recent Phase 1 trial demonstrated that PC-1005 gel containing 50 μM MIV-150, 14 mM zinc acetate dihydrate and carrageenan (CG) applied daily vaginally for 14 days is safe and well tolerated. Importantly, cervicovaginal lavages (CVLs) collected 4h or 24h after last gel application inhibited HIV-1 and HPV in cell-based assays in a dose-dependent manner (MIV-150 for HIV-1 and CG for HPV). Herein we aimed to determine the anti-HIV and anti-HSV-2 activity of PC-1005 in human cervical explants after in vitro exposure to the gel and to CVLs from participants in the Phase 1 trial. Single HIV-1_BaL infection and HIV-1_BaL/HSV-2 co-infection explant models were utilized. Co-infection with HSV-2 enhanced tissue HIV-1_BaLinfection. In vitro exposure to PC-1005 protected cervical mucosa against HIV-1_BaL (up to 1:300 dilution) in a single challenge and co-challenge models. CG gel (PC-525) provided some barrier effect against HIV-1_BaL at the 1:100 dilution in a single challenge model, but not in the co-challenge model. Both PC-1005 and PC-525 at the 1:100 dilution inhibited HSV-2 infection, pointing to a CG-mediated protection. MIV-150 and CG in CVLs inhibited HIV (single challenge or co-challenge models) and HSV-2 infections in explants in a dose-dependent manner (p \u3c 0.05). Stronger inhibition of HIV-1 infection by CVLs collected 4h post last gel administration was observed when compared to infection detected in the presence of baseline CVLs. The anti-HIV and anti-HSV-2 activity of PC-1005 gel in vitro and CVLs in human ectocervical explants supports the further development of PC-1005 gel as a broad-spectrum on-demand microbicide