Craig J. Hoesley

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

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<.0001) and a significant increase in non-AIDS-defining malignancies (non-ADMs; rate ratio, 10.87; P<.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.

Prevalence of Inducible Clindamycin Resistance among Community- and Hospital-Associated Staphylococcus aureus Isolates

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) infections have become common among both hospitalized and nonhospitalized patients. Optimal outpatient therapy for MRSA infections has yet to be determined, but this matter is complicated by the possibility of inducible macrolide-lincosamide-streptogramin B resistance (MLSBi). We studied the prevalence of MLSBi in community- and hospital-associated S. aureus isolates and the prevalence of community-associated MRSA (CA-MRSA) and identified clinical predictors of CA-MRSA and MLSBi. Among 402 S. aureus isolates, the overall prevalence of MLSBi was 52%, with 50% of MRSA and 60% of methicillin-susceptible S. aureus isolates exhibiting MLSBi. CA-MRSA represented 14% of all isolates and had a lower prevalence of MLSBi than hospital-associated MRSA (33% versus 55%). The presence of skin or soft-tissue infection was predictive for CA-MRSA, and the presence of a comorbidity was predictive for MLSBi. Due to the low prevalence of MLSBi among CA-MRSA isolates, clindamycin remains a useful option for outpatient therapy.

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.

Safety and acceptability of cellulose sulfate as a vaginal microbicide in HIV-infected women.

Objectives:Few studies of topical microbicides have assessed their safety in HIV-infected women. We conducted this study to evaluate the safety and acceptability of 6% cellulose sulfate (CS) gel as a vaginal microbicide in sexually abstinent and active HIV-infected women. Methods:Fifty-nine HIV-infected women were enrolled in a randomized double-blind placebo-controlled study comparing 6% CS to placebo gel used for 14 days. Sexually abstinent women applied gel once or twice daily and sexually active women used gel once daily. Results:CS gel was safe with no reported severe or life-threatening adverse events (AE). Thirty-nine (66%) of the participants experienced urogenital AE judged as probably or possibly related to gel. The majority (51%) of these participants reported only mild events. Fewer women (62%) who used CS experienced urogenital AE than those assigned to placebo gel (70%) (P = 0.59). Eleven (19%) women experienced intermenstrual bleeding judged to be probably or possibly related to gel use (four in the CS and seven in the placebo gel group). There was no increase in AE by frequency of gel use or sexual activity with the exception of abdominal/pelvic pain which was noted more frequently with twice daily use among sexually abstinent women. Women and men found the gel highly acceptable. Conclusions:This Phase I study demonstrated that CS vaginal gel was safe, well tolerated and acceptable by HIV-infected women and their male partners. Thus, further development of CS is warranted as a potential method to prevent HIV transmission and acquisition.

Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: a Double-Blind Randomized Trial

Background:Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery. Methods:MTN-013/IPM 026, a multisite, double-blind, randomized, placebo-controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics. Results:There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single-drug rings. DPV concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels. Conclusions:In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed.

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

ABSTRACT 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.

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

ABSTRACT 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.

Emergence of USA300 MRSA in a tertiary medical centre: implications for epidemiological studies

Community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA) has become a major pathogen, particularly in outbreaks of skin and soft-tissue infection (SSTI). A preliminary study conducted at our institution in 2004 revealed that up to 45% of inpatient and 70% of outpatient MRSA isolates tested were the USA300 genotype. In this report, we used pulsed-field gel electrophoresis (PFGE) in a retrospective analysis to determine the time when CA-MRSA USA300 moved from the community to the inpatient population. During the five-year period 2000 to 2004, unique MRSA isolates (N=253) were selected from inpatients in surgical and medical intensive care units, the general hospital population and outpatients. The most common PFGE types found in all populations from 2000 to 2003 were USA100, USA200 and USA600. USA300 was absent from all inpatients from 2000 to 2003 and only sporadic numbers found in the outpatient group. However, in 2004 the USA300 strain emerged in both outpatient and hospitalised patients. There was no difference in the distribution of USA300 between ICUs and the general inpatient population. The emergence of CA-MRSA has resulted in a shift of the MRSA strains that are implicated in healthcare-associated infections in our institution. This has been a recent development that has implications as to the use of PFGE to determine transmission of MRSA in the inpatient setting. Further evaluation of these data in the context of the epidemiology of these infections is needed to determine if more discriminatory approaches to typing will be required for monitoring the spread of the more virulent CA-MRSA phenotype within the inpatient population.

A Prospective Study of Genital Herpes Simplex Virus Type 2 Infection in Human Immunodeficiency Virus Type 1 (HIV-1)–Seropositive Women: Correlations with CD4 Cell Count and Plasma HIV-1 RNA Level

A cohort of 217 human immunodeficiency virus type 1 (HIV-1)-seropositive women was observed prospectively from 1996 through 2000 to determine the frequency of genital herpes simplex virus type 2 (HSV-2) disease (symptomatic and asymptomatic) and to correlate those findings with HIV-1-related immunosuppression (absolute CD4 cell counts and plasma HIV-1 RNA levels). Participants underwent twice-yearly pelvic examinations, including cultures of cervicovaginal specimens and swab specimens from genital lesions, if lesions were present. Of the participants, 72 (33%) had genital HSV-2 infection diagnosed on the basis of either history alone (23 [32%]) or positive culture results (49 [68%]). The 72 women who had genital herpes diagnosed completed 242 total visits. Of these visits, positive HSV-2 culture results were noted at 80 (33%); at 23 (29%) of the 80 visits at which there were HSV-2-positive cultures, culture results were not associated with a clinically apparent genital lesion. Positive HSV-2 culture results occurred more frequently for samples obtained from patients with higher plasma HIV-1 RNA levels (P=.019) and lower CD4 cell counts (P<.001).