Concordance of 3 alternative teratogenicity assays with results from corresponding in vivo embryo-fetal development studies: Final report from the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) DruSafe working group 2.

An IQ DruSafe working group evaluated the concordance of 3 alternative teratogenicity assays (rat whole embryo culture, rWEC; zebrafish embryo culture, ZEC; and murine embryonic stem cells, mESC) with findings from rat or rabbit embryo-fetal development (EFD) studies. Data for 90 individual compounds from 9 companies were entered into a database. In vivo findings were deemed positive if malformations or embryo-fetal lethality were reported in either species. Each company used their own criteria for deciding whether the alternative assay predicted the in vivo findings. Standard concordance parameters were calculated, positive and negative predictive values (PPV and NPV) were adjusted for the aggregate portfolio prevalence of positive compounds (established by a survey of participating companies), and positive and negative likelihood ratios (LR+ and iLR-) were calculated. Of the 3 assays, only rWEC data were robustly predictive, particularly for negative predictions (NPVadj = 92%). However, both LR+ (4.92) and iLR- (4.72) were statistically significant for the rWEC assay. When analyzed separately for rats, the NPVadj and iLR-values for the rWEC assay increased to 96% and 9.75, respectively. These data suggest that a negative rWEC outcome could defer or replace a rat EFD study in certain regulatory settings.

Inter-laboratory assessment of a harmonized zebrafish developmental toxicology assay - progress report on phase I.

This report provides a progress update of a consortium effort to develop a harmonized zebrafish developmental toxicity assay. Twenty non-proprietary compounds (10 animal teratogens and 10 animal non-teratogens) were evaluated blinded in 4 laboratories. Zebrafish embryos from pond-derived and cultivated strain wild types were exposed to the test compounds for 5 days and subsequently evaluated for lethality and morphological changes. Each of the testing laboratories achieved similar overall concordance to the animal data (60-70%). Subsequent optimization procedures to improve the overall concordance focused on compound formulation and test concentration adjustments, chorion permeation and number of replicates. These optimized procedures were integrated into a revised protocol and all compounds were retested in one lab using embryos from pond-derived zebrafish and achieved 85% total concordance. To further assess assay performance, a study of additional compounds is currently in progress at two laboratories using embryos from pond-derived and cultivated-strain wild type zebrafish.

Predictive teratology: teratogenic risk-hazard identification partnered in the discovery process.

Unexpected teratogenicity is ranked as one of the most prevalent causes for toxicity-related attrition of drug candidates. Without proactive assessment, the liability tends to be identified relatively late in drug development, following significant investment in compound and engagement in pre clinical and clinical studies. When unexpected teratogenicity occurs in pre-clinical development, three principle questions arise: Can clinical trials that include women of child bearing populations be initiated? Will all compounds in this pharmacological class produce the same liability? Could this effect be related to the chemical structure resulting in undesirable off-target adverse effects? The first question is typically addressed at the time of the unexpected finding and involves considering the nature of the teratogenicity, whether or not maternal toxicity could have had a role in onset, human exposure margins and therapeutic indication. The latter two questions can be addressed proactively, earlier in the discovery process as drug target profiling and lead compound optimization is taking place. Such proactive approaches include thorough assessment of the literature for identification of potential liabilities and follow-up work that can be conducted on the level of target expression and functional characterization using molecular biology and developmental model systems. Developmental model systems can also be applied in the form of in vitro teratogenicity screens, and show potential for effective hazard identification or issue resolution on the level of characterizing teratogenic mechanism. This review discusses approaches that can be applied for proactive assessment of compounds for teratogenic liability.

Adherence to guidelines for antiretroviral therapy and for preventing opportunistic infections in HIV-infected adults and adolescents in Ryan White-funded facilities in the United States.

To determine adherence by health care providers to guidelines for antiretroviral therapy and for prevention of opportunistic infections (OIs) in adults with HIV infection in federally funded facilities in the United States, we reviewed records of HIV-infected adults (>13 years) in 11 Ryan White Title III facilities in four states for information on eight standard-of-care recommendations during November 1996 through September 1997. Eligibility required a visit to the facility within 6 months before record abstraction and a lowest CD4+ lymphocyte count <500 cells/microl. Reviews were completed for 148 patients in Maryland, 355 in New York, 370 in Georgia, and 538 in Illinois. Adherence to prevention measures by health care providers was >85% for HIV plasma RNA testing, prescription of antiretroviral therapy, Pneumocystis carinii pneumonia (PCP) prophylaxis, anti-Toxoplasma antibody testing, and obtaining Papanicolaou (Pap) smears but lower (69%-80%) for Mycobacterium avium complex (MAC) prophylaxis, tuberculin skin testing (TST), and pneumococcal vaccination. Adherence was similar by patient age, gender, racial/ethnic group, urban versus rural, and hospital versus clinic setting but was generally lower for injecting drug users (IDUs) than for patients with other HIV exposures (p < .05 by multivariate analysis for TST, anti-Toxoplasma antibody testing, Pap smear, and measurement of HIV plasma RNA). Adherence by health care providers to guidelines for preventing OIs in these federally funded facilities is generally high but could be improved for some prevention measures, for instance, MAC prophylaxis, TST, and pneumococcal vaccination, especially for IDUs.

Partner notification and the control of human immunodeficiency virus infection. Two years of experience in San Francisco.

To evaluate partner notification of opposite-sex sexual partners of AIDS patients as a means of limiting sexual and vertical transmission of human immunodeficiency virus (HIV), the authors examined the first 27 months of their experience with partner notification. Overall, of 145 AIDS patients eligible to participate, 51 (35%) were interviewed and identified 135 opposite-sex sexual partners. Of the 135 partners, 59 (44%) were interviewed and 34 (25%) were tested, resulting in the diagnosis of 7 (5%) HIV-infected partners. Refusal rates for index patients and partners were low (9% and 12%, respectively). Costs for the program were $454 per partner interviewed and $2,203 per seropositive partners identified. The authors conclude that although partner notification is more expensive than more widely targeted AIDS prevention and education efforts, its ability to target case finding, education, and counseling to women at highest risk of infection makes it potentially cost-effective for prevention of vertically transmitted HIV infection.

Seroprevalence rates of human immunodeficiency virus infection at sentinel hospitals in the United States. The Sentinel Hospital Surveillance Group.

BACKGROUND AND METHODS: To evaluate the epidemiology of infection with human immunodeficiency virus type 1 (HIV-1) in selected urban communities in the United States, we instituted active surveillance at sentinel hospitals by anonymous testing of samples of blood specimens for HIV-1 antibody. To reflect better the rates of HIV-1 seroprevalence in the communities served by the sentinel hospitals, we excluded specimens from all patients with diagnoses that are often associated with HIV infection. RESULTS: From January 1988 to June 1989, 89,547 specimens were tested at 26 hospitals in 21 cities. The overall rate of HIV-1 seroprevalence was 1.3 percent, but it ranged from 0.1 to 7.8 percent according to hospital (median, 0.7 percent). The age distribution of persons seropositive for HIV-1 was similar across hospitals and closely paralleled that of persons with the acquired immunodeficiency syndrome (AIDS). In areas of low seroprevalence, HIV-1 infections were highly concentrated among men. However, the male-to-female ratio (median, 7.0) decreased steadily with an increasing overall rate of seroprevalence (P less than 0.001); at the five hospitals with the highest rates of seroprevalence, the median male-to-female ratio was only 2.9. The median black-to-white ratio of HIV-1 seroprevalence was 1.8, but at hospitals with low rates of seroprevalence the rates in blacks and whites were nearly equal. At two hospitals in the communities with the highest prevalence of AIDS, 1.1 to 3.8 percent of adolescents 15 to 19 years old and 18 to 22 percent of all men 25 to 44 years old were seropositive for HIV-1. CONCLUSIONS: In these sentinel, urban populations there is tremendous variation in the rate of HIV-1 infection (over 70-fold). The very high seroprevalence at some sentinel hospitals indicates the need for routine screening for HIV-1 infection among some groups of patients, regardless of clinical presentation.

Methods of surveillance for HIV infection at U.S. sentinel hospitals.

The U.S. sentinel hospital surveillance system for human immunodeficiency virus (HIV) infection includes approximately 40 short-stay hospitals located in 31 metropolitan areas in the United States and Puerto Rico. Several hospitals began testing in late 1986, and additional sentinel hospitals have since been recruited. At each sentinel hospital, anonymous, unlinked testing for antibody to HIV is conducted monthly on 300 blood specimens, selected systematically and stratified by age of the patient. Specimens are excluded from patients whose reason for hospital visit on that occasion was for a medical condition associated with HIV infection or with risk factors for HIV infection, in order to limit the expected overrepresentation of HIV-infected persons among hospital patients compared with the general catchment population of the hospital. The incidence of acquired immunodeficiency syndrome (AIDS) in metropolitan areas with sentinel hospitals has been approximately twice the incidence of AIDS in the entire United States. However, while absolute levels of HIV seroprevalence should therefore be interpreted with caution, trends in the age-, sex-, and race-specific HIV seroprevalence at sentinel hospitals likely reflect trends in the communities served by the hospitals. Although concentrated in areas disproportionately affected by AIDS, sentinel hospitals will contribute seroprevalence data over time that reflect the impact of HIV infection across all age and behavioral risk groups. Sentinel hospitals will also constitute a key surveillance system to help integrate the age group-specific and risk group-specific findings from other activities in the CDC family of seroprevalence surveys.

The economic impact of the first 10,000 cases of acquired immunodeficiency syndrome in the United States.

Acquired immunodeficiency syndrome (AIDS) is a serious, fatal disease affecting a relatively young population and has a great economic impact. Expenditures for hospitalization and economic losses from disability and premature death were estimated for the first 10,000 patients with AIDS reported in the United States. Extrapolation of data from surveys done in New York City, Philadelphia, and San Francisco suggests that these 10,000 patients with AIDS will require an estimated 1.6 million days in the hospital, resulting in over $1.4 billion in expenditures. Losses incurred for the 8,387 years of work that will be lost from disability and from the premature death of the 10,000 patients will be over $4.8 billion. The total economic burden of the AIDS epidemic will continue to rise as the number of diagnosed cases increases. These estimates reinforce the need for effective disease prevention strategies to reduce the number of cases.