Paul M. Coplan

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.

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

ObjectivesTo 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. MethodsProspective, observational study of 160 HZ outpatients age ≥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. ResultsHZ 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. DiscussionAcute 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.

Postmarketing evaluation of the safety and effectiveness of varicella vaccine.

BACKGROUNDnThe Oka strain of live attenuated varicella virus was licensed for use in healthy children in the United States in March, 1995. We report a postmarketing evaluation of the short term safety of this vaccine within Kaiser Permanente.nnnMETHODSnAfter licensure varicella vaccination was introduced into the preventive care program of the Northern California Kaiser Permanente Medical Care Program. Potential adverse events after vaccination with varicella vaccine were identified from automated clinical databases of hospitalizations, emergency room visits and clinic visits. Deaths were identified from automated clinical databases at Kaiser as well as from the State death records for California. To evaluate safety, rates of diagnosis-specific events in the risk periods were compared with the rates of such diagnosis-specific events in two self control and one historical control period.nnnRESULTSnDuring the study period of April 1, 1995, to December 31, 1996, a total of 89753 adults and children received varicella vaccine. A total of 3200 relative risks were calculated, and of these 5 hospital diagnostic categories, 9 emergency visit diagnostic categories and 30 outpatient diagnostic categories demonstrated at least 1 relative risk with a P value of <0.05 in 1 or more age groups and in comparisons with 1 control period or more. The p value for these tests was not adjusted for multiple comparisons. Of these categories 14 demonstrated an increased risk either in more than 1 age group or against more than 1 comparison group. These categories included elective procedures, febrile seizure, febrile illness, well child, acute gastroenteritis, varicella, congenital anomaly, rule out sepsis, trauma, viral syndrome, apnea, back pain, congenital valvular heart disease and vision evaluation for glasses. Of these the outcomes of elective procedure, congenital anomaly, congenital valvular heart disease, well child and vision evaluation for glasses were judged not to have a biologically plausible association with vaccination. A second diagnostic grouping included febrile illness, viral illness, febrile seizure and rule out sepsis. In an analysis of these events which adjusted for the concomitant administration of M-M-R(II) vaccine, none of the associations was statistically associated with receipt of varicella vaccine. The diagnostic category of rule out sepsis still had a relative risk of 1.95 with P = 0.02. None of the children in the rule out sepsis category had positive bacteriologic cultures from any other normally sterile site. Because of the large number of gastroenteritis cases, we reviewed a random sample of 100 exposed and 100 unexposed cases. From this review no consistent time association or clustering of any of these events was seen in the exposed follow-up time interval. Only gastroenteritis and negative evaluations for sepsis were thought to be possibly associated with receipt of varicella vaccine. Although there was a statistically significant increased risk over the entire 30 day-period, there was no clustering of these events within the 30-day window.nnnCONCLUSIONnIn this study population of 89753 children and adults, the varicella vaccine (Oka strain, Merck) appeared to have a favorable safety profile. In addition rates of varicella-like rash and of breakthrough cases were both low and consistent with the rates observed in prelicensure studies.

Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women.

Objectives:To assess the local and systemic safety of dapivirine vaginal gel vs. placebo gel as well as the systemic absorption of dapivirine in healthy, HIV-negative women. Methods:Two prospective, randomized, double-blind, placebo-controlled phase I/II studies were conducted at five research centers, four in Africa and one in Belgium. A total of 119 women used dapivirine gel (concentrations of 0.001, 0.002, 0.005, or 0.02%), and 28 used placebo gel twice daily for 42 days. The primary endpoints were colposcopic findings, adverse events, Division of AIDS grade 3 or grade 4 laboratory values, and plasma levels of dapivirine. Results:Safety data were similar for the dapivirine and placebo gels. None of the adverse events with incidence more than 5% occurred with greater frequency in the dapivirine than placebo groups. Similar percentages of placebo and dapivirine gel users had adverse events that were considered by the investigator to be related to study gel. A total of five serious adverse events occurred in the two studies, and none was assessed as related to study gel. Mean plasma concentrations of dapivirine were approximately dose proportional, and, within each dose group, mean concentrations were similar on days 7, 28, and 42. The maximum observed mean concentration was 474 pg/ml in the 0.02% gel group on day 28. Two weeks after the final application of study gel, mean concentrations decreased to 5 pg/ml or less. Conclusion:Twice daily administration of dapivirine vaginal gel for 42 days was safe and well tolerated with low systemic absorption in healthy, HIV-negative women suggesting that continued development is warranted.

Postlicensure study of varicella vaccine effectiveness in a day-care setting.

BACKGROUNDnVaricella vaccine has been licensed for use in the United States since the spring of 1995. The acceptance of the vaccine and its effect on varicella incidence in children is important.nnnAIMnTo document the effectiveness of the varicella vaccine in children attending day care in 11 centers in North Carolina.nnnMETHODSnA dynamic cohort study design was used in 11 day-care centers in North Carolina. Multiple cross-sectional evaluations were performed and children were noted to be vaccinated or not and diseased or not. Vaccine effectiveness was estimated by comparing the varicella attack rate in the vaccinated with the varicella attack rate in the unvaccinated. Person time was used as the denominator for all calculations.nnnRESULTSnDuring the study period February 1, 1996, to September 1, 1997, 134 cases of varicella occurred in the unvaccinated and 11 cases occurred in the vaccinated children. The attack rates in the vaccinated and unvaccinated were 2.49 and 14.66, respectively, for an overall vaccine effectiveness of 83% for mild/moderate disease.nnnCONCLUSIONSnIn the day-care setting varicella vaccine demonstrated benefit in preventing and modifying wild-type varicella disease.

Cross-Reactivity of Anti–HIV-1 T Cell Immune Responses among the Major HIV-1 Clades in HIV-1–Positive Individuals from 4 Continents

BACKGROUNDnThe genetic diversity of human immunodeficiency virus type 1 (HIV-1) raises the question of whether vaccines that include a component to elicit antiviral T cell immunity based on a single viral genetic clade could provide cellular immune protection against divergent HIV-1 clades. Therefore, we quantified the cross-clade reactivity, among unvaccinated individuals, of anti-HIV-1 T cell responses to the infecting HIV-1 clade relative to other major circulating clades.nnnMETHODSnCellular immune responses to HIV-1 clades A, B, and C were compared by standardized interferon- gamma enzyme-linked immunospot assays among 250 unvaccinated individuals, infected with diverse HIV-1 clades, from Brazil, Malawi, South Africa, Thailand, and the United States. Cross-clade reactivity was evaluated by use of the ratio of responses to heterologous versus homologous (infecting) clades of HIV-1.nnnRESULTSnCellular immune responses were predominantly focused on viral Gag and Nef proteins. Cross-clade reactivity of cellular immune responses to HIV-1 clade A, B, and C proteins was substantial for Nef proteins (ratio, 0.97 [95% confidence interval, 0.89-1.05]) and lower for Gag proteins (ratio, 0.67 [95% confidence interval, 0.62-0.73]). The difference in cross-clade reactivity to Nef and Gag proteins was significant (P<.0001).nnnCONCLUSIONSnCross-clade reactivity of cellular immune responses can be substantial but varies by viral protein.

Pharmacokinetic Assessment of Dapivirine Vaginal Microbicide Gel in Healthy, HIV-Negative Women

UNLABELLEDnTo assess the pharmacokinetics of dapivirine in plasma and dapivirine concentrations in cervicovaginal fluids (CVF) and cervicovaginal tissues following vaginal administration of dapivirine microbicide gel in healthy, HIV-negative women for 10 days. A randomized, double-blind, phase I study was conducted at a single research center in South Africa. A total of 18 women used dapivirine gel (0.001%, 0.005%, or 0.02%) once daily on Days 1 and 10 and twice daily on Days 2-9. Pharmacokinetics of dapivirine were assessed in plasma on Days 1 and 10. Dapivirine concentrations were measured in CVF on Days 1 and 10 and in cervicovaginal tissues on Day 10. Safety was evaluated through laboratory tests (hematology, clinical chemistry, and urinalysis), physical examinations, and assessment of adverse events. Plasma concentrations of dapivirine increased over time with gel dose and were greater on Day 10 (C(max) 31 to 471u2009pg/ml) than Day 1 (C(max) 23 to 80u2009pg/ml). T(max) was 10-12u2009h on Day 1, and 9u2009h on Day 10. Concentrations in CVF generally increased with dose but were highly variable among participants. Mean peak values ranged from 4.6-8.3u2009×u200910(6) pg/ml on Day 1 and from 2.3-20.7u2009×u200910(6) pg/ml on Day 10 across dose groups. Dapivirine was detectable in all tissue biopsies on Day 10 at concentrations of 1.0-356u2009×u200910(3) pg/mg.nnnCONCLUSIONSnDapivirine was widely distributed throughout the lower genital tract with low systemic absorption when administered in a vaginal gel formulation for 10 consecutive days. The gel was safe and well tolerated.

The Role of Herpes Simplex Virus Type 2 and Other Genital Infections in the Acquisition of HIV-1 among High-Risk Women in Northern Tanzania

BACKGROUNDnWe examined the role of herpes simplex virus type 2 (HSV-2) and other genital infections on human immunodeficiency virus type 1 (HIV-1) incidence in a cohort study conducted between 2002 and 2005 among female bar/hotel workers in Moshi, Tanzania.nnnMETHODSnAt baseline and every 3 months thereafter, participants were interviewed, and blood and genital samples were collected. Predictors of HIV-1 incidence were evaluated using a Cox proportional hazards regression model.nnnRESULTSnOf 845 women who were HIV-1 seronegative at baseline, 689 (81.5%) were monitored in the study for a total of 698.6 person-years at risk (PYARs). The overall HIV-1 incidence was 4.6/100 PYARs (95% confidence interval [CI], 3.0-6.2/100 PYARs), and condom use was very low. After adjustment for other risk factors, the risk of HIV-1 was increased among women with HSV-2 at baseline (hazard ratio [HR], 4.3 [95% CI, 1.5-12.4]) and in those who acquired HSV-2 during the study period (HR, 5.5 [95% CI, 1.2-25.4]). Other independent predictors of HIV-1 were baseline chlamydial infection (HR, 5.2), bacterial vaginosis (HR, 2.1), and the occurrence of genital ulcers (HR, 2.7).nnnCONCLUSIONnHSV-2 and other genital infections were the most important risk factors for HIV-1. Control of these infections could help to reduce HIV-1 incidence in this population.

Modeling the Long-Term Outcomes and Costs of HIV Antiretroviral Therapy Using HIV RNA Levels: Application to a Clinical Trial

A model was developed to gain insight into the potential clinical and economic impact of antiretroviral therapy for HIV-infected patients. Observed HIV RNA levels and CD4 cell counts are used in the model to estimate the probability that an individual progresses from asymptomatic infection to the first AIDS-defining illness and death and to estimate the total net cost of care and long-term cost-effectiveness of antiretroviral therapy. The model was applied to patients in a clinical trial (Merck protocol 035) that compared the surrogate marker response to triple therapy with indinavir (IDV; 800 mg every 8 hr) plus zidovudine (ZDV; 200 mg every 8 hr) plus lamivudine (3TC; 150 mg twice a day) to double therapy with ZDV+3TC. The model projected that for an individual without AIDS who received triple therapy the progression to AIDS and death would be delayed more than for a patient who received double therapy with ZDV+3TC if no other treatment options were offered. Because of this delay in disease progression, the total discounted cost over the initial 5-year period was projected to be

Impact of an intervention to improve treatment-seeking behavior and prevent sexually transmitted diseases among Nigerian youths.

5100 lower for patients who received triple therapy compared with double therapy if suppression with triple therapy lasts up to 3 years. If suppression with triple therapy lasts up to 5 years, costs were projected to be higher with the triple combination, but 81% of the cost is offset by lower disease costs as a result of fewer patients progressing to AIDS. Over 20 years, total discounted cost was projected to be higher for the triple-therapy regimen primarily because of a longer estimated survival time. At 20 years, the incremental cost per life-year gained by adding IDV to a ZDV+3TC regimen was estimated at