Cross-species prediction of human survival probabilities for accelerated anthrax vaccine absorbed (AVA) regimens and the potential for vaccine and antibiotic dose sparing.

Anthrax vaccine adsorbed (AVA, BioThrax) was recently approved by the Food and Drug Administration (FDA) for a post-exposure prophylaxis (PEP) indication in adults 18-65years of age. The schedule is three doses administered subcutaneous (SC) at 2-week intervals (0, 2, and 4weeks), in conjunction with a 60-day course of antimicrobials. The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) developed an animal model to support assessment of a shortened antimicrobial PEP duration following Bacillus anthracis exposure. A nonhuman primate (NHP) study was completed to evaluate the efficacy of a two dose anthrax vaccine absorbed (AVA) schedule (0, 2weeks) aerosol challenged with high levels of B. anthracis spores at week4- the time point at which humans would receive the third vaccination of the approved PEP schedule. Here we use logistic regression models to combine the survival data from the NHP study along with serum anthrax lethal toxin neutralizing activity (TNA) and anti-PA IgG measured by enzyme linked immunosorbent assay (ELISA) data to perform a cross-species analysis to estimate survival probabilities in vaccinated human populations at this time interval (week4 of the PEP schedule). The bridging analysis demonstrated that high levels of NHP protection also yield high predicted probability of human survival just 2weeks after the second dose of vaccine with the full or half antigen dose regimen. The absolute difference in probability of human survival between the full and half antigen dose was estimated to be at most approximately 20%, indicating that more investigation of the half-antigen dose for vaccine dose sparing strategies may be warranted.

Evaluation of early immune response-survival relationship in cynomolgus macaques after Anthrax Vaccine Adsorbed vaccination and Bacillus anthracis spore challenge.

Anthrax Vaccine Adsorbed (AVA, BioThrax) is approved by the US Food and Drug Administration for post-exposure prophylaxis (PEP) of anthrax in adults. The PEP schedule is 3 subcutaneous (SC) doses (0, 14 and 28 days), in conjunction with a 60 day course of antimicrobials. The objectives of this study were to understand the onset of protection from AVA PEP vaccination and to assess the potential for shortening the duration of antimicrobial treatment (http://www.phe.gov/Preparedness/mcm/phemce/Documents/2014-phemce-sip.pdf). We determined the efficacy against inhalation anthrax in nonhuman primates (NHP) of the first two doses of the PEP schedule by infectious challenge at the time scheduled for receipt of the third PEP dose (Day 28). Forty-eight cynomolgus macaques were randomized to five groups and vaccinated with serial dilutions of AVA on Days 0 and 14. NHP were exposed to Bacillus anthracis Ames spores on Day 28 (target dose 200 LD50 equivalents). Anti-protective antigen (PA) IgG and toxin neutralizing antibody (TNA) responses to vaccination and in post-challenge survivors were determined. Post-challenge blood and selected tissue samples were assessed for B. anthracis at necropsy or end of study (Day 56). Pre-challenge humoral immune responses correlated with survival, which ranged from 24 to 100% survival depending on vaccination group. Surviving, vaccinated animals had elevated anti-PA IgG and TNA levels for the duration of the study, were abacteremic, exhibited no apparent signs of infection, and had no gross or microscopic lesions. However, survivors had residual spores in lung tissues. We conclude that the first two doses of the PEP schedule provide high levels of protection by the scheduled timing of the third dose. These data may also support consideration of a shorter duration PEP antimicrobial regimen.

Experiences and challenges in data monitoring for clinical trials within an international tropical disease research network.

BACKGROUND: Models for the structure and procedures of data and safety monitoring boards (DSMBs) continue to evolve in response to issues of new and of old concern. Some authors have called for an open dialogue on these questions through publication of the experiences of DSMBs in addressing them. PURPOSE: The goal of this paper is to add to the current discussion about acceptable models for establishing, serving on, and reporting to monitoring committees, particularly those that oversee multiple studies in less developed countries. The paper seeks to do so by describing the establishment and subsequent operation of one such multi-trial DSMB over a five-year period. This DSMB was formed to monitor trials conducted by members of the International Centers for Tropical Disease Research (ICTDR) network of the National Institute of Allergy and Infectious Diseases (NIAID). METHODS: The operational model and experiences are summarized by the authors, who had immediate responsibilities for directing the DSMB's activities. RESULTS: The board played an active, traditional role in assuring that patient safety was maintained and that current standards for clinical research were met. In addition, both NIAID and the board members viewed education of investigators to be an important role for the board to play in this particular setting. This affected the threshold for identifying which trials would be monitored, and it impacted several procedures adopted by the board. LIMITATIONS: This report reflects the observations of those involved in managing the DSMB, including comments offered by the DSMB and by investigators, but not data gathered in a systematic way. CONCLUSIONS: The operational model described here has allowed the DSMB to fulfill its role in the oversight of the trials. We hope that the ideas we present may help others facing similar situations and may stimulate further critical thinking about DSMB structure and function.

Estimation of pertussis vaccine efficacy in the presence of covariates in three randomized trials.

We estimated efficacy of pertussis vaccines in three randomized controlled trials with adjustment for several baseline covariates: presence of one or more other children in the household, sex of the study child, and geographical area. Adjusted and unadjusted efficacy estimates differed only trivially. We also assessed the association of efficacy with time since vaccination and background pertussis incidence. The acellular vaccines, except for the two-component vaccine in the Stockholm trial, appeared to maintain their efficacy during two years of follow-up. In contrast, efficacy of a whole-cell vaccine decreased significantly in both the Stockholm and Italian trials. The relationship between efficacy and background incidence was not consistent across studies and vaccines.

Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection.

BACKGROUND: For many people infected with the hepatitis C virus (HCV), the route of exposure, risk of transmission, and severity of associated liver disease are unknown. We studied these variables in people who donated blood voluntarily. METHODS: Blood donors who tested positive for HCV antibodies on enzyme immunoassay were classified according to whether the results of a confirmatory second-generation recombinant immunoblot assay (RIBA) for HCV were positive, negative, or indeterminate. The evaluations also included an assessment of risk factors, a physical examination, serial determinations of alanine aminotransferase levels and HCV serologic assays, a polymerase-chain-reaction assay for HCV RNA, testing of sexual contacts and family members, and liver biopsies in some participants who were HCV-positive by RIBA. RESULTS: A total of 481 donors were studied, among whom 248 were positive for HCV by RIBA, 102 had indeterminate results, and 131 were HCV-negative. In a logistic-regression analysis, significant risk factors for HCV infection among the HCV-positive participants were a history of blood transfusion in 66 (27 percent; P < 0.001 for the comparison with RIBA-negative donors), intranasal cocaine use in 169 (68 percent, P < 0.001), intravenous drug use in 103 (42 percent, P = 0.001), sexual promiscuity in 132 (53 percent, P = 0.002), and ear piercing among men (P < 0.05). Nine of 85 sexual partners of HCV-positive donors were anti-HCV-positive; 8 had used intravenous drugs or received transfusions. HCV RNA was found in 213 HCV-positive donors (86 percent), 3 who had indeterminate results by RIBA (2 of these 3 tested positive with a more specific, third-generation RIBA), and none who were HCV-negative. Of the HCV-positive donors, 69 percent had biochemical evidence of chronic liver disease; among 77 donors positive for HCV by RIBA who underwent liver biopsy, 5 had severe chronic hepatitis or cirrhosis, 66 had mild-to-moderate chronic hepatitis, and 6 had no evidence of hepatitis. CONCLUSIONS: Among volunteer blood donors, prior blood transfusion, intranasal cocaine use, intravenous drug use, sexual promiscuity, and ear piercing in men are risk factors for HCV infection. The high frequency of intravenous drug use was unexpected, because these donors had denied such use when questioned directly at the time of their blood donations.

Depressive symptoms as predictors of medical outcomes in HIV infection. Multicenter AIDS Cohort Study.

OBJECTIVE: To ascertain whether depressive symptoms as determined by the Center for Epidemiologic Studies-Depression scale (CES-D) predict accelerated mortality and worse medical outcomes in patients infected with human immunodeficiency virus (HIV). DESIGN: Eight-year cohort study with semiannual follow-up. SETTING: Community volunteers. PARTICIPANTS: A total of 1809 HIV-seropositive homosexual men without the acquired immunodeficiency syndrome (AIDS) who entered the Multicenter AIDS Cohort Study in 1984 or 1985. Eight-year follow-up data were available on 75% of eligible participants. OUTCOME MEASURES: Times to AIDS, death, and prophylactic treatment, and slopes describing the decline in CD4 count for each individual participant. RESULTS: Using a conventional definition of depression (CES-D > or = 16 at the first study visit), 21.3% of participants were classified as depressed. Depressed participants had lower CD4 counts and reported more AIDS-related symptoms. There were no significant differences between depressed and nondepressed participants on any of the outcome measures (P > .05 in all cases). In contrast, men reporting AIDS-related symptoms had shorter times to AIDS and to death even after adjusting for CD4 counts (P < .01). The analyses were repeated, with similar results, using different definitions of depression based on the CES-D. CONCLUSIONS: We find no evidence that depressive symptoms independently prognosticate worse outcomes in HIV infection. Because of associations of depression with symptom reports, CD4 counts, and indicators of socioeconomic status, future studies of the relationship between depression and HIV outcome should consider these variables as confounders.

Temporal trends in human immunodeficiency virus type 1 seroconversion 1984-1989. A report from the Multicenter AIDS Cohort Study (MACS).

The 5-year temporal trends in human immunodeficiency virus type 1 (HIV-1) seroconversion between 1984 and 1989 among homosexual/bisexual men participating in the Multicenter AIDS Cohort Study (MACS) are reported. Of 3,262 initially seronegative men, 368 (11.3%) had seroconverted by December 31, 1989. Although the incidence of seroconversion declined precipitously during the first 3 years of follow-up (from 4.1% to 0.9% per 6 months), no evidence for a further substantial reduction was noted after mid-1987, since 6-month incidence rates ranged between 0.5% and 1.2%. The Chicago cohort experienced an increase in HIV-1 seroconversion during both semesters of 1989; 2.1% and 1.6% per 6 months, respectively, became newly infected. Other MACS centers did not report such an increase. Center-specific differences were observed by race; black men were at higher seroconversion risk than white men in Baltimore/Washington (relative risk (RR) = 3.4) and Chicago (RR = 2.4), while Hispanic men were at higher risk than white men in Chicago (RR = 3.3). Younger age (less than 35 years) was also associated with HIV-1 seroconversion (RR = 1.5). It is disturbing to report an overall annual seroconversion rate of 1.2% for the 2 years prior to December 31, 1989, as well as evidence for a sustained recent increase in Chicago during 1989. Long-term maintenance of safe-sex behaviors should be the cornerstone of acquired immunodeficiency syndrome prevention among homosexual/bisexual men.

Association of hepatitis B surface antigen and core antibody with acquisition and manifestations of human immunodeficiency virus type 1 (HIV-1) infection.

We examined the associations between seropositivity for hepatitis B virus (HBV) with the presence or development of antibodies to human immunodeficiency virus (HIV-1) and with HIV-1 induced T-helper lymphocyte deficiency or acquired immunodeficiency syndrome (AIDS). Serologic data on HBV and HIV-1, cytometric enumeration of CD4+ lymphocytes, clinical events (AIDS by Centers for Disease Control criteria) and hepatitis B vaccination histories were available on 4,498 homosexual participants in the Multicenter AIDS Cohort Study, Men were classified as to previous infection with HBV and prevalent or incident infection with HIV-1. Although there was an association between seropositivity for HBV infection and HIV-1 infection at enrollment (odds ratios anti-HBc 2.6; HBsAg 4.2), the relation between HBV seropositivity and subsequent seroconversion to HIV-1 was weaker (odds ratios 1.3 and 1.6). HIV-1 seroconversion was also associated with a history of certain other sexually transmitted diseases, but predisposing sexual practices did not account for the association between HBV and HIV-1 infection. Seropositivity for HBV infection at entry was not related to initially low or more rapid subsequent decline in T-helper lymphocyte counts and was not associated with an increased incidence of AIDS during 2.5 years of follow-up. History of vaccination against HBV did not appear to decrease susceptibility to HIV-1 infection or to subsequent progression of immunodeficiency. We conclude that prior HBV infection is unlikely to be specifically associated with acquisition of HIV-1 infection and is unrelated to more rapid progression of HIV-1-induced immunodeficiency.

Prevalence of human immunodeficiency virus type 1 p24 antigen in U.S. blood donors--an assessment of the efficacy of testing in donor screening. The HIV-Antigen Study Group.

BACKGROUND: We performed a multicenter study in 1989 to determine whether screening whole-blood donors for human immunodeficiency virus type 1 (HIV-1) p24 antigen would improve transfusion safety by identifying carriers of the virus who are seronegative for HIV-1 antibody. METHODS: More than 500,000 donations were tested at 13 U.S. blood centers with test kits from two manufacturers. Units found repeatedly reactive were retested in a central laboratory; if the results were positive, they were confirmed by a neutralization assay. A subgroup of units was also tested for HIV-1 by the polymerase chain reaction. Selected donors confirmed or not confirmed as having p24 antigen were contacted for follow-up interviews to identify risk factors and undergo retesting for HIV-1 markers. RESULTS: Positive tests for p24 antigen were confirmed by neutralization in five donors (0.001 percent of all donations tested), all of whom were also positive for HIV-1 antibody and HIV-1 by polymerase chain reaction. Three of the antigen-positive donors had other markers of infectious disease that would have resulted in the exclusion of their blood; two had risk factors for HIV-1 that should have led to self-exclusion. Of 220 blood units with repeatedly reactive p24 antigen whose presence could not be confirmed by neutralization (0.04 percent of the donations studied), none were positive for HIV-1 antibody, HIV-1 by polymerase chain reaction (120 units tested), or virus culture (76 units tested)--attesting to the specificity of confirmatory neutralization. CONCLUSIONS: The finding that no donation studied was positive for p24 antigen and negative for HIV-1 antibody suggests that screening donors for p24 antigen with tests of the current level of sensitivity would not add substantially to the safety of the U.S. blood supply.

Recreational drug use and sexual behavior change in a cohort of homosexual men. The Multicenter AIDS Cohort Study (MACS).

The relationship between use of recreational drugs and high-risk (HIV-transmitting) homosexual behavior was examined in the Multicenter AIDS Cohort Study (MACS) population. Among the 3916 men who completed both the baseline (1984) and first 6-month follow-up evaluations and were sexually active during the 6 months prior to enrollment, self-reported use of each of 10 classes of recreational drugs in conjunction with sexual activity was analyzed for both cross-sectional and prospective relationships with pattern of sexual behavior using a four-level sexual risk behavior index. At baseline, the proportion of men in the highest risk category (unprotected anal exposures with multiple partners) increased from 36 to 85% when men not using any drugs to men using three or more drugs plus volatile nitrites were examined. In multivariate logistical analyses, volatile nitrite use was significantly associated with failure to maintain or attain lower sexual risk levels after controlling for the effects of age, educational level and numbers of high-risk partners. These results suggest that volatile nitrite use may play an important role in the association between recreational drug use and high-risk sexual behavior among homosexual/bisexual men.

A1, Cw7, B8, DR3 HLA antigen combination associated with rapid decline of T-helper lymphocytes in HIV-1 infection. A report from the Multicenter AIDS Cohort Study.

108 seropositive homosexual men were examined for associations between HLA phenotype and progression of human immunodeficiency virus type 1 (HIV-1) infection. Among men of predominantly European ethnic origin, 49 with very rapid 2-year declines in CD4+ lymphocyte counts showed significant differences in antigen frequencies from 59 men matched for ethnic background, study centre, and initial CD4+ cell count but with little or no decline in CD4+ cells. Relations of varying strength (odds ratios 6.1-10.3) were seen with several HLA antigens often linked in the A1-Cw7-B8-DR3 haplotype. The strongest relation was with the A1, Cw7, B8 combination (odds ratio 10.3). Associations between these antigen combinations and development of AIDS were weaker. The frequency of HLA A24 was also significantly higher in rapid than in slow decliners (odds ratio 4.3). These findings strengthen the suggested link between the product of a gene in the A1-Cw7-B8-DR3 haplotype and HIV-1-related disease.

HIV-related symptoms and psychological functioning in a cohort of homosexual men.

The authors administered the Center for Epidemiological Studies Depression (CES-D) Scale to 4,954 homosexual men in the Multicenter AIDS Cohort Study. HIV antibody status at enrollment was a less important predictor of psychological distress than were reported physical symptoms. Multivariate analysis showed an association between a high score on each CES-D Scale component and the number of self-reported possible AIDS- or HIV-related symptoms, perceived lymphadenopathy, and absence of "someone to talk to about serious problems." This relationship between self-reported physical symptoms and psychological distress suggests a possible etiologic relationship between perceived AIDS risk and psychological symptoms in men at risk of AIDS.

Human immunodeficiency virus and hepatitis delta virus in homosexual men. A study of four cohorts.

The prevalence of hepatitis delta virus antibodies was determined in four cohorts of homosexual or bisexual men positive for hepatitis B surface antigen who were evaluated between April 1984 and April 1985. Antibodies to hepatitis delta virus were found in 16 of 106 men in Los Angeles (15.1%; 95% confidence interval [Cl], 8.3% to 21.9%); 6 of 64 men in San Francisco (9.4%; 95% Cl, 3.5% to 19.3%); 1 of 76 men in Pittsburgh (1.3%; 95% Cl, 0.03% to 7.1%); and 0 of 52 men in Chicago (0%; 95% Cl, 0% to 5.6%). From 44.0% to 65.4% of men negative for hepatitis delta virus and all men positive for hepatitis delta virus but one (P less than 0.0001) were positive for antibodies to human immunodeficiency virus (HIV). In multivariate analysis, infection with hepatitis delta virus was associated with intravenous drug use (adjusted odds ratio [OR] = 6.7, P less than 0.01), with sexual activity as measured by number of partners (adjusted OR = 8.4, p less than 0.01), and probably with rectal trauma (adjusted OR = 3.9, P = 0.17). As with HIV infection, prevalence of hepatitis delta virus infection in homosexual men differs by location and is most likely transmitted both sexually and parenterally.