International epidemiology of human pre-existing adenovirus (Ad) type-5, type-6, type-26 and type-36 neutralizing antibodies: correlates of high Ad5 titers and implications for potential HIV vaccine trials.

Replication-defective adenoviruses have been utilized as candidate HIV vaccine vectors. Few studies have described the international epidemiology of pre-existing immunity to adenoviruses. We enrolled 1904 participants in a cross-sectional serological survey at seven sites in Africa, Brazil, and Thailand to assess neutralizing antibodies (NA) for adenovirus types Ad5, Ad6, Ad26 and Ad36. Clinical trial samples were used to assess NA titers from the US and Europe. The proportions of participants that were negative were 14.8% (Ad5), 31.5% (Ad6); 41.2% (Ad26) and 53.6% (Ad36). Adenovirus NA titers varied by geographic location and were higher in non-US and non-European settings, especially Thailand. In multivariate logistic regression analysis, geographic setting (non-US and non-European settings) was statistically significantly associated with having higher Ad5 titers; participants from Thailand had the highest odds of having high Ad5 titers (adjusted OR=3.53, 95% CI: 2.24, 5.57). Regardless of location, titers of Ad5NA were the highest and Ad36 NA were the lowest. Coincident Ad5/6 titers were lower than either Ad5 or Ad6 titers alone. Understanding pre-existing immunity to candidate vaccine vectors may contribute to the evaluation of vaccines in international populations.

Effectiveness of a bivalent Haemophilus influenzae type B-hepatitis B vaccine in preventing hepatitis B virus infection among children born to hepatitis B e antigen-positive carrier mothers.

BACKGROUND: This observational study evaluated a modified immunoprophylactic regimen (hepatitis B immune globulin [HBIG]) and a dose of thimerosal-free monovalent hepatitis B (HB) vaccine shortly after birth followed by doses of thimerosal-free bivalent Haemophilus influenzae type b (Hib)-HB vaccine at 2 and 4 months of age, and a booster at 12 months of age) in infants at high risk of hepatitis B virus (HBV) infection (mothers HBeAg+). METHODS: Children >or=6 months of age vaccinated in routine clinical practice were tested twice (>or=6 months apart) for HBV antigens surface antigen (HBsAg) and "e" antigen, and for antibody to HBsAg. Partial nucleotide sequence analysis was performed on HBV DNA isolated from infants identified with a breakthrough chronic HBV infection. A fully sequential statistical design was used to maximize patient safety and study efficiency. RESULTS: Four of 60 children developed chronic HBV infection despite vaccination, but at no point did the cumulative number of cases reach the boundary of statistical significance. Overall, the analysis adjusted for sequential testing yielded an estimated breakthrough rate of 6.7% (90% CI: 2.3%-14.6%). In a subset of uninfected children tested for antibody to HBsAg 1 to 4 months after the second dose of Hib-HB vaccine, 90% (9/10) had >or=10 milli-International Units per milliliter (mIU/mL). The third dose of Hib-HB vaccine induced a secondary increase in the level of antibody; 94.7% (18/19) of a second group developed >or=100 mIU/mL, with a geometric mean concentration of 771 mIU/mL (95% CI: 351.4-1692.1 mIU/mL). CONCLUSION: The tested regimen is comparably effective to historical experience with a standard one employing HBIG plus monovalent thimerosal-containing HB vaccine given at 0, 1, and 6 months of age.

Lack of association between age at varicella vaccination and risk of breakthrough varicella, within the Northern California Kaiser Permanente Medical Care Program.

BACKGROUND: Varicella vaccine currently is recommended for children between 12 and 18 months of age. However, rates of breakthrough varicella have been reported to be higher among children vaccinated before 14 or 15 months of age and to increase with time since vaccination. METHODS: An ongoing study at the Northern California Kaiser Permanente Medical Care Program is evaluating vaccine efficacy in 7585 children vaccinated with Varivax in 1995, when they were between 12 and 23 months of age. Cases of chickenpox are identified by telephone interviews with each child's parent(s) every 6 months. Mean age at varicella onset and mean time from vaccination to onset were calculated on the basis of age, in months, at vaccination. Logistic regression was used to test for trend, and the chi2 test was used to test for differences in rates of breakthrough varicella by age. RESULTS: Over the first 8 years of the study, a total of 1161 cases of breakthrough varicella were reported, for an average rate of 21.7 cases/1000 person-years. Vaccine effectiveness was 83.6% at year 8. The rate of breakthrough varicella did not change for each additional month of age at vaccination (P = .864), and no difference in the rate of breakthrough varicella was found between children vaccinated at <15 months of age and those vaccinated at > or =15 months of age. CONCLUSIONS: Our data do not show a difference in vaccine effectiveness with age at vaccination and thus support the current recommendations for initial vaccination between 12 and 18 months of age.

The impact of acute herpes zoster pain and discomfort on functional status and quality of life in older adults.

OBJECTIVES: To describe the interference of herpes zoster (HZ) pain and discomfort with activities of daily living (ADLs) and health-related quality of life (HRQL) during the acute rash phase, and to quantify the relationship between acute HZ pain and discomfort and impaired ADLs and HRQL in older persons. METHODS: Prospective, observational study of 160 HZ outpatients age > or =60 at 4 US study sites who completed the Zoster Brief Pain Inventory (ZBPI), Zoster Impact Questionnaire (ZIQ), McGill Pain Questionnaire, EuroQol, and SF-12 questionnaires on a predetermined schedule. Patients rated interference on a 0 to 10 scale for ADL items in the ZBPI and the ZIQ. Interference scores were averaged to create summary measures for the ZBPI items (ZBPI ADLI) and ZIQ items (ZIQ ADLI). A composite pain score was used in mixed-effects models analyses of the association between pain and discomfort and ADLI and HRQL measures during the first 35 days after HZ rash onset. RESULTS: HZ pain interfered with all ADLs but interference was greatest for enjoyment of life, sleep, general activity, leisure activities, getting out of the house, and shopping. For every 1.0 point increase in pain and discomfort intensity, there was a 0.69 and 0.53 point increase in ZBPI and ZIQ interference, respectively, and a 2.81 point, 1.57 point, and 1.95 point decrease in EuroQol, SF-12 physical, and SF-12 mental scales, respectively. DISCUSSION: Acute zoster pain and discomfort has a significant negative impact on functional status and HRQL in older adults. The magnitude of interference increases with increasing pain and discomfort intensity.

The incidence of herpes zoster in a United States administrative database.

BACKGROUND: Few recent studies have reported data on the incidence of herpes zoster (HZ) in U.S. general clinical practice. OBJECTIVE: To estimate the age- and sex-specific incidence of HZ among U.S. health plan enrollees. DESIGN: Data for the years 2000 to 2001 were obtained from the Medstat MarketScan database, containing health insurance enrollment and claims data from over 4 million U.S. individuals. Incident HZ cases were identified through HZ diagnosis codes on health care claims. The burden of HZ among high-risk individuals with recent care for cancer, HIV, or transplantation was examined in sub-analyses. Overall incidence rates were age- and sex-adjusted to the 2000 U.S. population. PARTICIPANTS: MarketScan U.S. health plan enrollees of all ages. MEASUREMENTS AND MAIN RESULTS: We identified 9,152 incident cases of HZ (3.2 per 1,000 person-years) (95% confidence interval [CI], 3.1 to 3.2 per 1,000). Annual HZ rates per 1,000 person-years were higher among females (3.8) than males (2.6) (P<.0001). HZ rates rose sharply with age, and were highest among individuals over age 80 (10.9 per 1,000 person-years) (95% CI, 10.2 to 11.6). The incidence of HZ per 1,000 person-years among patients with evidence of recent care for transplantation, HIV infection, or cancer (10.3) was greater than for individuals without recent care for these conditions (3.0) (P<.0001). CONCLUSIONS: The overall incidence of HZ reported in the present study was found to be similar to rates observed in U.S. analyses conducted 10 to 20 years earlier, after age- and sex-standardizing estimates from all studies to the 2000 U.S. population. The higher rate of HZ in females compared with males contrasts with prior U.S. studies.

Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief pain inventory.

UNLABELLED: In preparation for clinical trials of a vaccine against herpes zoster (HZ), we conducted a prospective, observational study to evaluate (1) the Zoster Brief Pain Inventory (ZBPI), an HZ-specific questionnaire to quantify HZ pain and discomfort, (2) an operational definition of postherpetic neuralgia (PHN), and (3) a severity-duration measure of the burden of illness caused by HZ. HZ patients aged 60 years or older (n = 121) were enrolled within 14 days of rash onset and completed ZBPI, McGill Pain Questionnaire Present Pain Intensity (PPI), quality of life (QoL), and activities of daily living (ADL) questionnaires on a predetermined schedule. Reliability, measured by intraclass correlation coefficients within 14 days of rash onset, ranged between 0.63 and 0.78. ZBPI pain scores were strongly correlated with other pain measures, interference with ADL, and worsening QoL. The operational definition of PHN, a ZBPI pain score of 3 or greater occurring 90 or more days after rash onset, had high agreement with pain worse than mild on the PPI (kappa = 0.72). The ZBPI pain severity-duration measure had high correlations with severity-duration measures of ADL interference, worsening QoL, and other pain scales. These findings support the validity and utility of the ZBPI, the definition of PHN, and the severity-duration measure of the burden of HZ illness. PERSPECTIVE: Herpes zoster pain, as measured by the ZBPI severity-duration measure, is associated with impairment in daily living activities and quality of life. The ZBPI measure appears useful for quantifying herpes zoster pain, postherpetic neuralgia, and impairment in daily living activities for clinical trials of herpes zoster prevention.

Incidence of myocardial infarction in randomized clinical trials of protease inhibitor-based antiretroviral therapy: an analysis of four different protease inhibitors.

Protease inhibitor (PI) therapy for patients infected with the human immunodeficiency virus has been associated with lipid disorders and insulin resistance. We compared the incidence of myocardial infarction (MI) among participants receiving treatment with PIs with or without nucleoside reverse transcriptase inhibitors (nRTIs) to nRTI therapy alone in 30 phase II/III double-blind, randomized studies conducted before 1999 for the first 4 PI drugs. In most trials included in this analysis, participants could receive combination therapy with a PI plus nRTIs in open-label extensions after the blinded phase concluded. Person-years (PY) of follow-up were calculated from treatment initiation to the diagnosis of MI, or to the end of the randomized phases for nRTI-only therapy or to the conclusion of the studies for PI-containing regimens. Separate analyses were conducted for the randomized and the randomized-plus-extension phases. Among 10,986 participants, 7951 (72%) received PI drugs at some point for an average duration of 12 months. There were 10 MIs (1.31/1000 PY) in the randomized phases and 19 MIs (1.63/1000 PY) in the randomized-plus-extension phases. The overall stratified relative risk of MI for PI-containing (1.82 MI/1000 PY) versus nRTI-only (1.05 MI/1000 PY) regimens of 1.69 was not significantly increased (95% confidence interval [CI], 0.54 to 7.48). The absolute difference in MI risk was +0.77 (95% CI, -0.71 to +2.26) MIs/1000 PY. Compared with NRTI-only therapy, patients receiving PI-containing regimens for an average of 1 year did not have significantly more MIs, but the upper bound of the 95% CI indicates there may be up to 2.3 additional MIs per 1000 PY. Although studies with a longer duration of PI therapy are in progress to assess whether a later increase in MI incidence occurs, our analysis did not demonstrate a dramatic increase in MI risk during the first year of PI therapy.