A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention.

BACKGROUND: On-demand topical products could be an important tool for HIV prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG; 16 mg/20 mg) insert administered rectally. METHODS: MTN-039 was a Phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid (RF), and rectal tissue (RT) were collected over 72 hours (hr) following rectal administration of one and two TAF/EVG inserts for each participant. ClinicalTrials.gov Identifier: NCT04047420. RESULTS: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. RT EVG peaked at 2-hr (median 2 inserts= 9 ng/mg) but declined to BLQ in the majority of samples at 24-hr, whereas TFV-DP remained high >2,000 fmol/million cells for 72-hr with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each timepoint for both 1 and 2 inserts (p<0.065 and p<0.039, respectively). DISCUSSION: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours.

A Mixed-Methods Study Examining Adherence to and Acceptability of Intravaginal Rings for HIV Prevention: Behavioral Results of MTN-027.

Intravaginal rings (IVR) containing antiretroviral drugs are a promising method for HIV prevention. We triangulated quantitative and qualitative assessments to evaluate the acceptability of four IVRs used continuously for 28 days as part of a Phase I trial (N = 48 HIV-negative women; ages 18-45). Adherence was high throughout the trial, yet 30% of participants reported involuntary IVR expulsions followed by re-insertion. Most participants (93.6%) felt comfortable with the IVR being inside their body. Participants reported liking the IVR more (36.2%) or the same amount (55.3%) since starting the study. When given the option of choosing between the IVR and/or a male condom for HIV-prevention, most reported preferring the IVR (n = 29, 63.0%), and over a quarter of the sample reported liking them equally (n = 12, 26.1%). We observed no differences in IVR acceptability across the study arms. High adherence and acceptability underscores the promise of an IVR as a female-controlled, sustained mechanism for HIV prevention.

Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc (MK-4176)/MK-2048A Intravaginal Rings.

BACKGROUND: Vaginal rings (VR) containing antiretroviral (ARV) drugs can be utilized for prevention of human immunodeficiency virus (HIV) with potential for improved adherence compared to daily pills. Combination ARV VRs could improve efficacy. METHODS: MTN-027, a single-blind, randomized, placebo-controlled trial in 48 women, evaluated VRs containing MK-2048 (30 mg) and vicriviroc (VCV, 182 mg), alone or in combination, and placebo used continuously for 28 days. Safety was assessed by recording adverse events. Drug concentrations were quantified in plasma, vaginal fluid, cervical tissue, and rectal fluid. Cervical tissue was utilized for ex vivo HIV inhibition analysis. RESULTS: There was no difference in related genitourinary adverse events between treatment arms compared to placebo. VCV and MK-2048 released from single or combination VRs both achieved peak concentrations in vaginal fluids, which were substantially higher compared to plasma (200× for VCV, 30× for MK-2048) and rectal fluid. In an ex vivo challenge assay, the antiviral activity of VCV and/or MK-2048 was not correlated with tissue-associated drug concentrations. Most women (77%) were fully adherent to 28 days of continuous VR use and found the VR acceptable. CONCLUSIONS: VCV and/or MK-2048 containing VRs were safe and acceptable. Both VCV and MK-2048 were quantifiable in all matrixes tested with peak compartmental drug concentrations similar for single and combination drug VRs. Tissue-associated VCV and/or MK-2048 did not correlate with inhibition of HIV infection. These data highlight the need to assess adequacy of drug dosing in the VR and measuring genital tissue drug concentrations to develop more precise concentration-response relationships.

Phase 2a Safety, Pharmacokinetics, and Acceptability of Dapivirine Vaginal Rings in US Postmenopausal Women.

BACKGROUND: Postmenopausal women have unique sociobiological human immunodeficiency virus (HIV) risks. We evaluated the safety, pharmacokinetics, and acceptability of a microbicide dapivirine (DPV) vaginal ring (VR) versus placebo in postmenopausal women. METHODS: We enrolled 96 HIV-negative postmenopausal US women in a phase 2a double-blind, randomized (3:1) trial of monthly VRs containing 25 mg DPV or placebo used continuously for 12 weeks. We assessed safety by adverse events (AEs). DPV concentrations were quantified in plasma and vaginal fluid. Steady-state concentrations were analyzed at 4, 8, and 12 weeks using repeated measures ANOVA. We assessed acceptability by self-report. RESULTS: We found no differences in the proportion of women with related grade 2 or higher reproductive system AEs (DPV: 6/72 (8%), placebo: 3/24 (13%), P = .68) or grade 3 or higher AEs (DPV: 4/72 (6%), placebo: 0/24 (0%), P = .57). In the DPV arm, 2/72 (3%) declined to resume product use due to AEs. Median DPV concentrations in plasma (262.0 pg/mL at week 12) and vaginal fluid (40.6 ng/mg at week 12) were constant over 12 weeks and exceeded the in vitro 50% effective concentration by 5000-fold in vaginal fluid by week 4. VR acceptability was high; 84/93 (90%) "very much liked or liked" the VR. CONCLUSIONS: DPV VRs were safe, well tolerated, and acceptable in postmenopausal women. Plasma concentrations were comparable to published data on DPV use in reproductive-age women (median plasma concentration: 264 pg/mL). Given the reassuring safety and pharmacokinetic data, the DPV VR is promising for preexposure prophylaxis in postmenopausal women. CLINICAL TRIALS REGISTRATION: NCT02010593.

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 lavage fluid samples (CVLs) collected 4 or 24 h after the last gel application inhibited HIV-1 and human papillomavirus (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-herpes simplex virus 2 (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-1BaL infection and HIV-1BaL-HSV-2 coinfection explant models were utilized. Coinfection with HSV-2 enhanced tissue HIV-1BaL infection. In vitro exposure to PC-1005 protected cervical mucosa against HIV-1BaL (up to a 1:300 dilution) in single-challenge and cochallenge models. CG gel (PC-525) provided some barrier effect against HIV-1BaL at the 1:100 dilution in a single-challenge model but not in the cochallenge 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 cochallenge models) and HSV-2 infections in explants in a dose-dependent manner (P < 0.05). Stronger inhibition of HIV-1 infection by CVLs collected 4 h after the last gel administration was observed 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.

Adherence and Acceptability of a Multidrug Vaginal Ring for HIV Prevention in a Phase I Study in the United States.

We evaluated the adherence and acceptability of a vaginal ring containing dapivirine, maraviroc, or both drugs for 28 days during a Phase I placebo-controlled trial in 48 HIV-negative sexually abstinent U.S. women aged 18-40. Adherence was assessed weekly by clinical interview and computer-assisted self-interviewing; acceptability assessment occurred at the last product-use visit. Study retention was 98 % (47/48); 94 % (45/48) reported being fully adherent with ring use during the 28-day period. Two participants experienced the ring partially coming out. Analysis was blinded and behavioral data were combined across study groups. Most women reported being very comfortable having the ring in their vagina; 44 % preferred continuous use, whereas 51 % had no preference compared to episodic use. Although a range of minor ring concerns were expressed, few were actually experienced. High adherence to and acceptability of this vaginal ring in this Phase I trial contributes to its promise as a sustained mechanism for multidrug vaginal microbicide delivery.

Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings.

BACKGROUND: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy. METHODS: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported. RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12). CONCLUSIONS: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.

Ending Racial Bias in American Medicine: A Call for Help from the AMA, NMA, AAMC, and the Rest of Us.

Bias based on skin color, religion, immigrant status, gender, and ethnicity are deeply rooted in American culture and have existed within the infrastructure of American medicine from the beginning. Now, medical educators are struggling to find curriculum and experiences that effectively address explicit and implicit bias among our increasingly diverse group of students, house staff, and practitioners. The leadership, experience, and lessons learned needed to scrub present medical school curricula of racial bias, to develop an antiracist curriculum, and to test its effectiveness already lies with the American Medical Association (AMA), the Association of American Medical Colleges (AAMC), and the National Medical Association (NMA). We call on these organizations to jointly convene a consortium of medical educators, social scientists, curricular specialists, and others to chart a way forward to assist medical schools and professional organizations in developing evaluable curricular materials and experiences to eliminate bias in health care.

Anal-rectal cytology: correlation with human papillomavirus status and biopsy diagnoses in a population of HIV-positive patients.

OBJECTIVES: We describe the cytological distribution of disease, correlate cytological diagnoses with human papillomavirus (HPV) DNA status and surgical biopsy diagnoses, determine if CD4 counts correlate with lesion severity, and compare anal-rectal data of HIV-infected patients (primarily men) with cervical data. MATERIALS AND METHODS: A retrospective search of the computerized database identified 118 HIV-positive patients who had anal-rectal cytology. Cytology results were compared with available follow-up data including repeat anal-rectal cytology tests, surgical biopsy, CD4 counts, and HPV DNA polymerase chain reaction-based genotyping. RESULTS: Cytological diagnoses included 3% unsatisfactory for diagnosis, 41% negative for intraepithelial lesion or malignancy (NILM), 23% atypical squamous cells of undermined significance (ASC-US), 31% low-grade squamous intraepithelial lesion (LSIL), and 2% high-grade squamous intraepithelial lesion (HSIL) (ASC-US/squamous intraepithelial lesion, 0.7:1). Two anal intraepithelial neoplasia (AIN) II, 10 AIN III, and 1 invasive squamous cell carcinoma were histologically detected (11%). The majority of AIN II was preceded by LSIL, 54%; ASC-US, 15%; and HSIL, 8%. The false-negative fraction was 23%. Sensitivity, specificity, negative predictive value, and positive predictive value were 92%, 8%, 33%, and 67%, respectively. Of those HPV tested concurrent with the first cytology specimen, 48% NILM, 78% ASC-US, and 100% LSIL were HPV positive. Mean CD4 counts (per microliter) were lower in patients with HSIL (243 [SD, 65]) compared with LSIL (400 [SD, 261]) and NILM (428 [SD, 232]). CONCLUSIONS: Anal-rectal cytology is a useful screening test. A high percentage of AIN II lesions were detected in this at-risk population, and the majority was detected following cytological abnormality.

Novel methodology for antiretroviral quantitation in the female genital tract.

PURPOSE: Challenges exist regarding antiretroviral quantitation in the female genital tract. Endocervical wicking using sterile tear flow test strips is an alternative to conventional methods due to the consistent sample volume obtained. METHODS: A novel method for measuring antiretrovirals in cervicovaginal secretions using Sno-strip wicking was developed and tested by spiking Sno-strips with known concentrations of tenofovir, nevirapine, atazanavir, lopinavir, and ritonavir in blank cervicovaginal lavage fluid. Drug concentrations were determined by high-performance liquid chromatography with ultraviolet or mass spectrometry detection. RESULTS: Mean extraction recoveries were 91% for tenofovir, 89% for nevirapine, 63% for atazanavir, 60% for lopinavir, and 61% for ritonavir relative to controls. Freezing spiked samples for 24 hours at -80 degrees C had no effect on recovery. CONCLUSIONS: Results suggest that the antiretrovirals tested can be efficiently extracted from Sno-strips, although a greater percentage of tenofovir and nevirapine was recovered. Storage of Sno-strip samples up to 24 hours before analysis showed no difference in the percentage of drug recovered compared with immediate analysis. Quantitating antiretroviral penetration into the female genital tract may assist in determining optimal therapeutic antiretroviral regimens to both decrease the risk of HIV transmission and prevent development of HIV drug resistance.

Dissemination of community-associated methicillin-resistant Staphylococcus aureus in a tertiary care hospital.

BACKGROUND: The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) was investigated at a tertiary care hospital, and relationship was made between the clinical and genetic definitions of community- and healthcare-associated MRSA. METHODS: Nonduplicate isolates of S. aureus were collected during 2004. Isolates were classified clinically as community-associated (CA) or healthcare-associated (HA). Molecular typing studies were performed on the isolates. RESULTS: Four hundred and two S. aureus isolates were collected, of which 281 (70%) were MRSA. By clinical definition, 58 (21%) were classified as CA-MRSA and 215 (77%) as HA-MRSA. Among CA-MRSA, 36 (62%) harbored a SCCmec type IV gene. None of the SCCmec type IV CA-MRSA expressed inducible clindamycin resistance (MLSBi). Among 57 HA-MRSA isolates, 31 (54.4%) harbored a SCCmec type IV gene; MLSBi present in 5 (16%). Type IV SCCmec MRSA were most often associated with skin and soft tissue infections (RR 3.34 95% CI 1.43, 7.8). USA300 was the most common genotype among both CA- and HA-MRSA. CONCLUSIONS: Community-associated MRSA is a prominent pathogen with its most common genotype, USA300, representing a significant proportion of CA- and HA-MRSA infections in our institution. Clinical definitions of CA- and HA- status do not correlate well with the genetic definitions, particularly for HA-MRSA.

Improvement of gram-negative susceptibility to fluoroquinolones after implementation of a pre-authorization policy for fluoroquinolone use: A decade-long experience.

OBJECTIVE: Due to concerns over increasing fluoroquinolone (FQ) resistance among gram-negative organisms, our stewardship program implemented a preauthorization use policy. The goal of this study was to assess the relationship between hospital FQ use and antibiotic resistance. DESIGN: Retrospective cohort. SETTING: Large academic medical center. METHODS: We performed a retrospective analysis of FQ susceptibility of hospital isolates for 5 common gram-negative bacteria: Acinetobacter spp., Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Primary endpoint was the change of FQ susceptibility. A Poisson regression model was used to calculate the rate of change between the preintervention period (1998-2005) and the postimplementation period (2006-2016). RESULTS: Large rates of decline of FQ susceptibility began in 1998, particularly among P. aeruginosa, Acinetobacter spp., and E. cloacae. Our FQ restriction policy improved FQ use from 173 days of therapy (DOT) per 1,000 patient days to <60 DOT per 1,000 patient days. Fluoroquinolone susceptibility increased for Acinetobacter spp. (rate ratio [RR], 1.038; 95% confidence interval [CI], 1.005-1.072), E. cloacae (RR, 1.028; 95% CI, 1.013-1.044), and P. aeruginosa (RR, 1.013; 95% CI, 1.006-1.020). No significant change in susceptibility was detected for K. pneumoniae (RR, 1.002; 95% CI, 0.996-1.008), and the susceptibility for E. coli continued to decline, although the decline was not as steep (RR, 0.981; 95% CI, 0.975-0.987). CONCLUSIONS: A stewardship-driven FQ restriction program stopped overall declining FQ susceptibility rates for all species except E. coli. For 3 species (ie, Acinetobacter spp, E. cloacae, and P. aeruginosa), susceptibility rates improved after implementation, and this improvement has been sustained over a 10-year period.

Evaluation of baseline corrected QT interval and azithromycin prescriptions in an academic medical center.

BACKGROUND: Azithromycin is used in the inpatient setting for a variety of conditions. In 2013, the US Food and Drug Administration released a warning regarding risk for corrected QT (QTc) prolongation and subsequent arrhythmias. Knowledge of inpatient prescribing patterns of QTc prolonging medications with respect to patient risk factors for adverse cardiovascular events can help recognize safe use in light of these new warnings. OBJECTIVE: To assess inpatient prescribing patterns, risk factors for QTc prolongation, and relationship between drug-drug interactions and cardiac monitoring in patients receiving azithromycin. DESIGN: Retrospective cohort study. PARTICIPANTS: One hundred inpatients ≥ 19 years of age were randomly selected from 1610 patient encounters between October 2012 and April 2013 who were administered at least 1 dose of azithromycin. MEASUREMENTS: Length of stay, reason for use, therapy duration, and concomitant medications were recorded. Telemetry charges and baseline electrocardiogram (ECG) prior to administration were assessed. RESULTS: Seventy-nine percent of azithromycin use was empiric. Sixty-five percent of patients received a baseline ECG prior to prescribing azithromycin, of which 60% had borderline or abnormal QTc prolongation. Seventy-six percent of patients were prescribed 2 or more QTc prolonging medications, of which there were more abnormal ECGs at baseline (P = 0.03) despite having telemetry ordered less than half of the time. CONCLUSIONS: In a cohort of hospitalized patients, azithromycin was prescribed despite risk factors for QTc prolongation and administration of interacting medications. Selection of azithromycin by providers appears to be independent from these risk factors, and education and vigilance to drug-drug interactions may be useful in limiting cardiac events with prescribing azithromycin.

Pharmacodynamic correlations using fresh and cryopreserved tissue following use of vaginal rings containing dapivirine and/or maraviroc in a randomized, placebo controlled trial.

BACKGROUND: The ex vivo challenge assay is a bio-indicator of drug efficacy and was utilized in this randomized, placebo controlled trial as one of the exploratory endpoints. Fresh and cryopreserved tissues were evaluated for human immunodeficiency virus (HIV) infection and pharmacokinetic (PK)/pharmacodynamic (PD) relationships. METHODS: HIV-negative women used vaginal rings containing 25 mg dapivirine (DPV)/100 mg maraviroc (MVC) (n = 12), DPV only (n = 12), MVC only (n = 12), or placebo (n = 12) for 28 days. Blood plasma, cervicovaginal fluid (CVF), and cervical biopsies were collected for drug quantification and the ex vivo challenge assay; half (fresh) were exposed immediately to HIV while the other half were cryopreserved, thawed, then exposed to HIV. HIV replication was monitored by p24 enzyme-linked immunosorbent assay from culture supernatant. Data were log-transformed and analyzed by linear least squared regression, nonlinear Emax dose-response model and Satterthwaite t test. RESULTS: HIV replication was greater in fresh compared to cryopreserved tissue (P = 0.04). DPV was detected in all compartments, while MVC was consistently detected only in CVF. Significant negative correlations between p24 and DPV levels were observed in fresh cervical tissue (P = 0.01) and CVF (P = 0.03), but not plasma. CVF MVC levels showed a significant negative correlation with p24 levels (P = 0.03); drug levels in plasma and tissue were not correlated with HIV suppression. p24 levels from cryopreserved tissue did not correlate to either drug from any compartment. CONCLUSION: Fresh tissue replicated HIV to greater levels and defined PK/PD relationships while cryopreserved tissue did not. The ex vivo challenge assay using fresh tissue could prioritize drugs being considered for HIV prevention.

First-in-Human Trial of MIV-150 and Zinc Acetate Coformulated in a Carrageenan Gel: Safety, Pharmacokinetics, Acceptability, Adherence, and Pharmacodynamics.

OBJECTIVE: To evaluate the safety and pharmacokinetics of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics were also explored. DESIGN: A 3-day open-label safety run-in (n = 5) preceded a placebo-controlled, double-blind trial in healthy, HIV-negative, abstinent women randomized (4:1) to vaginally apply 4 mL of PC-1005 or placebo once daily for 14 days. METHODS: Assessments included physical examinations, safety labs, colposcopy, biopsies, cervicovaginal lavages (CVLs), and behavioral questionnaires. MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and carrageenan (CVL) concentrations were determined with LC-MS/MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability, and adherence were analyzed descriptively. Pharmacokinetic parameters were calculated using noncompartmental techniques and actual sampling times. CVL antiviral EC50 values were calculated using a dose-response inhibition analysis. RESULTS: Participants (n = 20) ranged from 19-44 years old; 52% were black or African American. Among those completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 7 recommended reducing the volume. Adverse events, which were primarily mild and/or unrelated, were comparable between groups. Low systemic MIV-150 levels were observed, without accumulation. Plasma zinc levels were unchanged from baseline. Seven of seven CVLs collected 4-hour postdose demonstrated antiviral (HIV, human papillomavirus) activity. High baseline CVL anti-herpes-simplex virus type-2 (HSV-2) activity precluded assessment of postdose activity. CONCLUSIONS: PC-1005 used vaginally for 14 days was well tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Postdose CVLs had anti-HIV and anti-human papillomavirus activity. These data warrant further development of PC-1005 for HIV and sexually transmitted infection prevention.

Integration of gross anatomy in an organ system-based medical curriculum: strategies and challenges.

The University of Alabama School of Medicine (UASOM) instituted a fully integrated, organ system-based preclinical curriculum in 2007. Gross anatomy and embryology were integrated with other basic science disciplines throughout the first two years of undergraduate medical education. Here we describe the methods of instruction and integration of gross anatomy and embryology in this curriculum as well as challenges faced along the way. Gross anatomy and embryology are taught through a combination of didactic lectures, team-based learning activities, and cadaveric dissection laboratories. Vertical integration occurs through third- and fourth-year anatomy and embryology elective courses. Radiology is integrated with anatomy instruction through self-study modules and hands-on ultrasound sessions. Our model of anatomy instruction is time efficient, clinically relevant, and effective as demonstrated by student performance on the United States Medical Licensing Examination(®) (USMLE(®) ) Step 1 examination. We recommend that medical schools considering full integration of gross anatomy and embryology (1) carefully consider the sequencing of organ system modules, (2) be willing to sacrifice anatomical detail for clinical application, (3) provide additional electives to third- and fourth-year students, and (4) integrate radiology with anatomical education.

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.

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.

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).

Comparative analysis of commercial assays for the detection and quantification of Human Immunodeficiency Virus Type 1 (HIV-1) RNA in plasma from patients infected with HIV-1 subtype C.

The commercial assays commonly used to quantify plasma human immunodeficiency virus type 1 (HIV-1) RNA in clinical settings were designed to assess HIV-1 subtype B. We compared the performance of 4 commercial assays (Amplicor versions 1.0 and 1.5 [Roche]; Quantiplex [Chiron]; and NASBA HIV-1 RNA QT [Organon Teknika]) in detecting and quantifying HIV-1 RNA in plasma from HIV-infected persons from Zambia, an area where HIV-1 subtype C is predominant. Each assay detected plasma HIV-1 RNA, but they do not all measure statistically similar quantities of plasma HIV-1 RNA.