Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials.

BACKGROUND: Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans. METHODS: The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection. RESULTS: Each AMP trial is designed to have 90% power to detect PE > 0% if PE is ≥ 60%. The AMP trials are also designed to identify VRC01 properties (i.e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions. CONCLUSIONS: The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark for future vaccine evaluation and constituting a bridge to other bnAb approaches for HIV-1 prevention.

Development of a PIV-vectored RSV vaccine: preclinical evaluation of safety, toxicity, and enhanced disease and initial clinical testing in healthy adults.

MEDI-534 is a bivalent live attenuated vaccine candidate against human respiratory syncytial virus (hRSV) and human parainfluenza virus type 3 (hPIV3) that was previously shown to be immunogenic and to protect rodents and African green monkeys from wild-type (wt) hRSV challenge. We performed further preclinical evaluations to address the safety of MEDI-534 prior to human testing. MEDI-534 did not predispose rodents to enhanced RSV disease following wt-RSV challenge, and the tissue tropism of the chimeric virus was confined to the respiratory tract. Representative clinical trial material did not produce toxicity in rats. In adults, MEDI-534 was highly restricted in replication, did not boost RSV and PIV3 antibody titers, and produced no medically significant vaccine-related adverse events thereby warranting further evaluation in pediatric populations.

Survival times and complications of catheters used for outpatient parenteral antibiotic therapy in children.

Outpatient parenteral antibiotic therapy is routinely used in pediatrics, but few data are available on catheter-associated complications and survival times. Catheter-associated complications, defined as mechanical or nonmechanical, and survival times in peripherally inserted central catheters and central venous catheters used for outpatient parenteral antibiotic therapy in childhood were compared. The life test procedure was performed to determine survival time. Cox proportional hazards model was used to compare the independent effect of variables such as age and gender on catheter survival. There were 104 peripheral and 130 central venous catheters, of which 28 peripheral and 19 central catheters had mechanical complications, and 13 peripheral and 17 central catheters had nonmechanical complications. Peripheral catheters are more likely to develop mechanical complications and have a shorter survival time than central venous catheters. For outpatient parenteral antibiotic therapy longer than 6 weeks, central venous catheters appear to be a better choice.

Sertraline treatment of pathological gambling: a pilot study.

OBJECTIVE: Several open-label and double-blind studies have suggested that selective serotonin reuptake inhibitors may be useful in the treatment of pathological gambling. The purpose of this study was to evaluate the efficacy of sertraline in the treatment of pathological gambling. METHOD: Sixty patients meeting the DSM-IV criteria for pathological gambling were treated for 6 months in a double-blind, flexible-dose, placebo-controlled study of sertraline 50 to 150 mg/day. Data were collected from November 1998 to January 2001. The primary outcome measure assessing change in clinical status was the responder rate with respect to the Criteria for Control of Pathological Gambling Questionnaire (CCPGQ). Secondary measures included the Clinical Global Impressions scale (CGI) (Severity of Illness and Improvement subscales), and Visual Analogue Scales assessing gambling frequency, severity, amount, and improvement. Concomitant medication and psychotherapy were not allowed during the study. RESULTS: At the end of the study, 23 sertraline-treated subjects (74%) and 21 placebo-treated subjects (72%) were considered as responders on the CCPGQ (p = .9). Similar results were obtained when the CGI-Improvement scale limited to symptoms of pathological gambling was used as an outcome measure. Sertraline was well tolerated throughout the study. CONCLUSION: Sertraline was not statistically significantly superior to placebo in the overall sample. The power of the study was limited by the high placebo-response rate and the small sample size.

Outpatient parenteral antimicrobial therapy in osteoarticular infections in children.

There are few data on the use of outpatient parenteral antimicrobial therapy (OPAT) in the management of osteoarticular infections (OAIs) in childhood. The objective of this study was to determine if OPAT is safe and effective in the management of OAIs. Using their OPAT database, the authors evaluated the use of OPAT in children younger than 18 years old treated for OAIs between January 1, 1995, and December 31, 1999. One hundred eighty-four OAIs were treated in 179 patients over 5 years. OPAT involved central venous lines (CVLs) in 110 (59.8%), peripherally inserted central catheters (PICCs) in 71 (38.6%), and peripheral cannulas in 3 (1.6%). One hundred eighteen (64%) OPAT courses were completed without interruption. Rehospitalization occurred in 48 (26.1%) courses and occurred earlier with PICC. OPAT complications were catheter-related in 58 (30%) courses, not catheter-related in 60 (32%), and unknown in 10 (5.3%). The mechanical complication rate was 6.3 per 1,000 catheter-days (CVL 4.2, PICC 10.6), and the rate of infectious complications was 2.7 per 1,000 catheter-days (CVL 2.8, PICC 2.4). One hundred sixty-eight (98%) of 172 evaluable OAIs were cured. Four (2.2%) patients failed treatment: one had recurrence and three had persistent infection. The authors conclude that OPAT can be safely used to manage OAIs in children without compromising outcome. Mechanical complications are more common with PICCs.

Higher occurrence of hepatotoxicity and rash in patients treated with oxacillin, compared with those treated with nafcillin and other commonly used antimicrobials.

This study compared adverse drug reactions (ADRs) to oxacillin with those to nafcillin and other antibiotics. We reviewed the medical records of 222 children receiving outpatient parenteral antimicrobial therapy (OPAT) from February 1995 through June 1999. The diagnosis, antibiotics used, ADRs, action taken, and patient demographics were recorded. The most common ADRs were neutropenia (9.8%), rash (8.5%), and hepatotoxicity (3.8%). ADRs occurred more frequently in the oxacillin group (58.5%) than in the nafcillin group (29.3%; P=.004), the clindamycin group (12.5%; P<.001) and the "other" antibiotics group (14.4%; P<.001). Hepatotoxicity and rash occurred more frequently in the oxacillin group (22% and 31.7%, respectively) than in the nafcillin group (0% [P<.001] and 10.3% [P=.008]), the clindamycin group (1.4% [P<.001] and 8.3% [P=.001]), and the other antibiotics group (1.4% [P<.001] and 1.4% [P<.001]). On the basis of this retrospective analysis, oxacillin use in children was associated with a higher incidence of hepatotoxicity and rash, compared with the use of nafcillin and other intravenous antimicrobials.