Joseph Chiu

Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand

BACKGROUND The development of a safe and effective vaccine against the human immunodeficiency virus type 1 (HIV-1) is critical to pandemic control. METHODS In a community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial, we evaluated four priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The vaccine and placebo injections were administered to 16,402 healthy men and women between the ages of 18 and 30 years in Rayong and Chon Buri provinces in Thailand. The volunteers, primarily at heterosexual risk for HIV infection, were monitored for the coprimary end points: HIV-1 infection and early HIV-1 viremia, at the end of the 6-month vaccination series and every 6 months thereafter for 3 years. RESULTS In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], -4.0 to 47.9; P=0.08). In the per-protocol analysis involving 12,542 subjects, the vaccine efficacy was 26.2% (95% CI, -13.3 to 51.9; P=0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 52.1; P=0.04). Vaccination did not affect the degree of viremia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. CONCLUSIONS This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.)

A Placebo-Controlled Trial of Maintenance Therapy with Fluconazole after Treatment of Cryptococcal Meningitis in the Acquired Immunodeficiency Syndrome

BACKGROUND AND METHODS In patients with the acquired immunodeficiency syndrome (AIDS), the rate of relapse after primary treatment for cryptococcal meningitis remains high. We conducted a controlled, double-blind trial to evaluate the efficacy of maintenance therapy with fluconazole. At entry into the study, all participants had sterile cultures of cerebrospinal fluid, blood, and urine after following a standardized course of therapy for culture-proved cryptococcal meningitis. The patients were randomly assigned to take either fluconazole or placebo as maintenance therapy. The dose of fluconazole was 100 mg daily in the first phase of study and 200 mg daily in the second phase. RESULTS Of 84 patients initially enrolled, 16 (19 percent) were found to have silent, persistent infection on the basis of cultures that became positive after entry into the study; 7 other patients were lost to follow-up shortly after entry. Of the remaining 61 patients, 10 of 27 assigned to placebo (37 percent) and 1 of 34 assigned to fluconazole (3 percent) had a recurrence of cryptococcal infection at any site (difference in risk, 34 percent; 95 percent confidence interval, 15 to 53). Of the 11 recurrent infections, 7 were detected in urine obtained after prostatic massage. There were four recurrent meningeal infections in the patients taking placebo, but none in those taking fluconazole (mean duration of follow-up, 164 days) (P = 0.03). In multivariate analyses, the best predictors of recurrence-free survival were fluconazole treatment (P = 0.02; relative hazard, 13.2), a lower serum cryptococcal-antigen titer (P = 0.05; relative hazard, 1.2), and more prolonged primary therapy with flucytosine (P = 0.09; relative hazard, 1.1). Survival and toxicity were similar in the two maintenance-treatment groups. CONCLUSIONS In patients with AIDS, silent persistent infection is common after clinically successful treatment for cryptococcal meningitis. Maintenance therapy with fluconazole is highly effective in preventing recurrent cryptococcal infection.

Chloramphenicol-resistant Salmonella newport traced through hamburger to dairy farms. A major persisting source of human salmonellosis in California

Animal-to-human transmission of drug-resistant salmonella and the role of antimicrobial use in food animals in the emergence of these bacteria are controversial subjects. Investigation of a 4.9-fold increase in Salmonella newport isolations from Californians in 1985 showed that 87 percent of the isolates had an unusual antimicrobial-resistance pattern (including chloramphenicol resistance) and a single, identical plasmid. Interviews of 45 patients and 89 matched controls in Los Angeles County showed that illness was associated with penicillin or tetracycline use during the month before onset (P less than 0.001) and with eating ground beef during the week before onset (P = 0.052). The epidemic strain was isolated from hamburger products eaten by cases, abattoirs where the animals from which the meat came were slaughtered, dairies that sent cows for slaughter on days when culture-positive products were processed, and ill dairy cows. Isolation of salmonella from beef carcasses in abattoirs correlated with the proportion of dead or moribund animals received for slaughter (r = 0.60, P less than 0.05). Isolation of chloramphenicol-resistant salmonella from dairy farms was associated with the use of chloramphenicol at those dairies. We conclude that food animals are a major source of antimicrobial-resistant salmonella infections in humans and that these infections are associated with antimicrobial use on farms.

Risk behaviour and time as covariates for efficacy of the HIV vaccine regimen ALVAC-HIV (vCP1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 efficacy trial RV 144.

Background The Thai phase III HIV vaccine trials modest efficacy (VE 31.2% 95% CI 1.1, 51.2) represents the first demonstration that a vaccine can protect against HIV acquisition. Baseline variables of age, gender, marital status, and risk did not modify vaccine efficacy (VE). Here we explore behavioral risk and efficacy at 6 monthly intervals following vaccination.

Persistent Cryptococcus neoformans Infection of the Prostate after Successful Treatment of Meningitis

STUDY OBJECTIVE To assess the frequency of persistent Cryptococcus neoformans infection in patients with the acquired immunodeficiency syndrome (AIDS) after receiving apparently adequate treatment for meningitis. DESIGN Blood, urine, and cerebrospinal fluid were cultured at the conclusion of primary therapy to assess the adequacy of treatment. SETTING Outpatient clinics at three medical centers. PATIENTS Patients had C. neoformans grown in culture from cerebrospinal fluid. Primary therapy consisted of either 2.0 g of amphotericin B alone; 6 weeks of combination therapy with flucytosine; or, if flucytosine was poorly tolerated, an adjusted minimum total amphotericin B dose. To meet criteria for adequate treatment of meningitis all patients had two sequential cerebrospinal fluid samples which were culture negative. MEASUREMENTS AND MAIN RESULTS Nine of forty-one patients grew C. neoformans from urine after completion of primary treatment, but none had urinary symptoms. Fungi were visualized in expressed prostatic secretions in 4 of these patients. One patient refused further treatment and developed cryptococcemia within 5 weeks. Three patients received additional amphotericin B; all had persistent funguria without systemic relapse. Six patients received fluconazole; 4 became urine culture negative, and 2 had systemic relapse. CONCLUSION The persistence of urinary C. neoformans after adequate therapy for meningitis suggests that the urinary tract (probably the prostate) is a sequestered reservoir of infection from which systemic relapse may occur.

Safety and Immunogenicity of Combinations of Recombinant Subtype E and B Human Immunodeficiency Virus Type 1 Envelope Glycoprotein 120 Vaccines in Healthy Thai Adults

Safety and immunogenicity of 2 recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein (gp) 120 vaccines derived from SF2 (subtype B) and CM235 (CRF01_AE, Thai E) were evaluated in 370 Thai adults at low risk of HIV infection. Various doses of CM235 (25, 50, or 100 microg) and SF2 (0, 25, or 50 microg) gp120 were used. Eighty volunteers received placebo. There were no serious adverse events related to vaccination. Binding antibody developed in all vaccine recipients. There was no dose response to CM235 gp120, but a dose response to gp120 SF2 was present. Neutralizing antibodies to subtype E HIV-1 NPO3 and subtype B HIV-1 SF2 developed in 84% and 82% of vaccine recipients, respectively. Lymphoproliferative responses were detected in >95% of vaccine recipients. There was no evidence of antigenic interference in HIV-specific humoral or cellular responses. The gp120 Thai E and SF2 vaccines were safe and immunogenic in combination and could be advanced into phase 3 testing.

The natural history of HIV-1 infection in young Thai men after seroconversion.

Summary:The natural history and progression of HIV-1 infection in Thailand and other developing countries in Asia and Africa have not been well defined. Nevertheless, valid data are needed to evaluate the effects of interventions, which are designed to delay progression. We evaluated the progression to AIDS and death in 235 men who seroconverted during their 2 years of service in the Royal Thai Army. The men were conscripted at age 21 and seroconverted within a 6-month window during follow-up while in the military. The seroconverters were matched with men who were seronegative when discharged. Of the HIV-positive men, 156 (66.4%) were alive, 77 (32.8%) had died, and 2 (0.8%) could not be located 5–7 years after their seroconversion and discharge from the military. The 5-year survival rate was 82.3%; the median times to clinical AIDS and a CD4+ cell count of <200/μL was 7.4 years and 6.9 years, respectively. The mortality rate was 56.3 deaths per 1000 patient-years for HIV-positive men and 6.1 deaths per 1000 patient-years for HIV-negative men. Our data suggest a more rapid progression to AIDS and death after HIV-1 infection in young men in Thailand than has been reported for similarly aged cohorts in developed countries.

Safety and Reactogenicity of Canarypox ALVAC-HIV (vCP1521) and HIV-1 gp120 AIDSVAX B/E Vaccination in an Efficacy Trial in Thailand

Background A prime-boost vaccination regimen with ALVAC-HIV (vCP1521) administered intramuscularly at 0, 4, 12, and 24 weeks and gp120 AIDSVAX B/E at 12 and 24 weeks demonstrated modest efficacy of 31.2% for prevention of HIV acquisition in HIV-uninfected adults participating in a community-based efficacy trial in Thailand. Methodology/Principal Findings Reactogenicity was recorded for 3 days following vaccination. Adverse events were monitored every 6 months for 3.5 years, during which pregnancy outcomes were recorded. Of the 16,402 volunteers, 69% of the participants reported an adverse event any time after the first dose. Only 32.9% experienced an AE within 30 days following any vaccination. Overall adverse event rates and attribution of relatedness did not differ between groups. The frequency of serious adverse events was similar in vaccine (14.3%) and placebo (14.9%) recipients (p = 0.33). None of the 160 deaths (85 in vaccine and 75 in placebo recipients, p = 0.43) was assessed as related to vaccine. The most common cause of death was trauma or traffic accident. Approximately 30% of female participants reported a pregnancy during the study. Abnormal pregnancy outcomes were experienced in 17.1% of vaccine and 14.6% (p = 0.13) of placebo recipients. When the conception occurred within 3 months (estimated) of a vaccination, the majority of these abnormal outcomes were spontaneous or elective abortions among 22.2% and 15.3% of vaccine and placebo pregnant recipients, respectively (p = 0.08). Local reactions occurred in 88.0% of vaccine and 61.0% of placebo recipients (p<0.001) and were more frequent after ALVAC-HIV than AIDSVAX B/E vaccination. Systemic reactions were more frequent in vaccine than placebo recipients (77.2% vs. 59.8%, p<0.001). Local and systemic reactions were mostly mild to moderate, resolving within 3 days. Conclusions/Significance The ALVAC-HIV and AIDSVAX B/E vaccine regimen was found to be safe, well tolerated and suitable for potential large-scale use in Thailand. Trial Registration ClinicalTrials.gov NCT00223080

Motivation, recruitment, and screening of volunteers for a phase I/II HIV preventive vaccine trial in Thailand.

Data from recruitment and screening for a phase I/II preventive HIV-1 vaccine trial in Thailand were evaluated with respect to correlates of participation at each phase. Correlates included demographic variables, motivation for interest in the trial, and factors related to communication and contact. Participants were recruited at two sites through varied methods. The majority of prescreenees reported altruistic motives for interest in the trial and blood donors emerged as a group that may have been particularly altruistic. Findings indicated site differences in attrition during recruitment and screening, but not in enrollment into the vaccine trial. Blood donation and willingness to be contacted by phone at home were significantly related to making and keeping screening appointments.

Fluconazole Treatment of Persistent Cryptococcus neoformans Prostatic Infection in AIDS

The prostate gland is a common site for persistent and recurrent Cryptococcus neoformans infection after amphotericin B therapy for cryptococcal meningitis in patients with the acquired immunodefic...