Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries.

Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double-blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58-related persistent infection with 90.4%-100% efficacy across included countries. At month 7, ≥97.9% of participants seroconverted for each HPV type. Injection-site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722.

Correlation of susceptibility of Cryptococcus neoformans to amphotericin B with clinical outcome.

Testing of Cryptococcus neoformans for susceptibility to antifungal drugs by standard microtiter methods has not been shown to correlate with clinical outcomes. This report describes a modified quantitative broth macrodilution susceptibility method showing a correlation with both the patient's quantitative biological response in the cerebrospinal fluid (CSF) and the survival of 85 patients treated with amphotericin B (AMB). The Spearman rank correlation between the quantitative in vitro measure of susceptibility and the quantitative measure of the number of organisms in the patient's CSF was 0.37 (P < 0.01; 95% confidence interval [95% CI], 0.20, 0.60) for the first susceptibility test replicate and 0.46 (P < 0.001; 95% CI, 0.21, 0.62) for the second susceptibility test replicate. The median in vitro estimated response (defined as the fungal burden after AMB treatment) at 1.5 mg/liter AMB for patients alive at day 14 was 5 CFU (95% CI, 3, 8), compared to 57 CFU (95% CI, 4, 832) for those who died before day 14. These exploratory results suggest that patients whose isolates show a quantitative in vitro susceptibility response below 10 CFU/ml were more likely to survive beyond day 14.

End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24-45 years of age.

BACKGROUND: Previous analyses from a randomised trial in women aged 24-45 years have shown the quadrivalent human papillomavirus (qHPV) vaccine to be efficacious in the prevention of infection, cervical intraepithelial neoplasia (CIN), and external genital lesions (EGLs) related to HPV 6/11/16/18. In this report, we present end-of-study efficacy, safety, and immunogenicity data with a median follow-up time of 4.0 years. METHODS: We enrolled 3819 24-45-year-old women with no history of cervical disease or genital warts in the past 5 years. Women received quadrivalent vaccine or placebo at day 1, and at months 2 and 6. Ascertainment of CIN/EGL was accomplished through Pap testing, genital inspection, and cervicovaginal sampling (every 6 months). The main analysis was conducted in a per-protocol efficacy population (that received three doses, was naive to the relevant HPV types at day 1, and remained free of infection through month 7). Efficacy was also estimated in other naive and non-naive populations. RESULTS: Vaccine efficacy against the combined incidence of persistent infection, CIN/EGL related to HPV6/11/16/18 in the per-protocol population was 88.7% (95% CI: 78.1, 94.8). Efficacy for women who were seropositive and DNA negative for the relevant vaccine HPV type at the time of enrolment who received at least 1 dose was 66.9% (95% CI: 4.3, 90.6). At month 48, 91.5, 92.0, 97.4, and 47.9% of vaccinated women were seropositive to HPV 6/11/16/18, respectively. No serious vaccine-related adverse experiences were reported. CONCLUSIONS: The qHPV vaccine demonstrated high efficacy, immunogenicity, and acceptable safety in women aged 24-45 years, regardless of previous exposure to HPV vaccine type.

Effects of cigarette smoking on quinine pharmacokinetics in malaria.

OBJECTIVE: Quinine is an important antimalarial drug that is metabolised mainly by the hepatic mixed-function microsomal enzyme cytochrome P(450). Cigarette smoking in healthy volunteers has been reported to enhance quinine clearance. The present study evaluated the effects of smoking on quinine pharmacokinetics in patients with uncomplicated falciparum malaria treated with a 7-day course of oral quinine. Of 22 studied male patients, 10 were regular smokers and 12 were non-smokers. METHODS: All patients were treated with a 7-day oral regimen of quinine sulfate (10 mg salt/kg three times a day). Serial venous blood samples were taken for quinine levels before and during treatment at 12 h and 24 h and then daily until day 7. Plasma quinine and 3-hydroxyquinine concentrations were assayed using high-performance liquid chromatography. Quinine pharmacokinetics were evaluated using non-compartmental modelling. RESULTS: All patients recovered, and there were no significant differences in clinical responses or cure rates between the two studied groups ( P> or =0.32). The median (range) fever clearance time was 51 h (4-152 h) and mean (SD) parasite clearance time was 74+/-28 h. The overall median times to maximum concentrations of quinine and its main metabolite 3-hydroxyquinine were 1.5 days and 4.0 days, respectively. The maximum concentrations of quinine were approximately tenfold higher than 3-hydroxyquinine. There were no significant differences in any pharmacokinetic variables for the parent compound or metabolite between the two groups. The median area under the plasma drug concentration-time curve to day 7 (AUC(0-7)) of quinine in non-smokers was 67.0 micro g/ml/day and in smokers was 51.3 micro g/ml/day, and AUC(0-7) values of 3-hydroxyquinine were 6.2 micro g/ml/day and 4.8 micro g/ml/day, respectively. CONCLUSION: These results indicated that cigarette smoking has no significant effects on quinine pharmacokinetics or the therapeutic response in patients with falciparum malaria.

A prospective study of AIDS-associated cryptococcal meningitis in Thailand treated with high-dose amphotericin B.

OBJECTIVE: To assess kinetic of cryptococci in the cerebrospinal fluid (CSF) and outcome of AIDS-associated cyptococcal meningitis after high-dose amphotericin B. PATIENTS AND METHODS: A prospective study involving Thai adults (n=106) with cryptococcal meningitis associated with AIDS was conducted to determine the kinetic of cryptococci in CSF and prognostic factors affecting survival after high-dose amphotericin B (0.7 mg/kg/day) followed by oral azole treatment. Cerebrospinal fluids were collected for cryptococcal count and culture at weekly intervals for at least 2 weeks or until CSF cultures were negative for cryptococci. All patients were followed monthly for 1 year or until death in order to detect relapse or occurrence of any other opportunistic infection. RESULTS: A total of 106 AIDS patients with cryptococcal meningitis were enrolled. The geometric mean (range) total and viable cryptococcal counts in CSF on admission were 430,000 (1000 to 3.4 x 10(7)) and 31,000 (10 to 1.4 x 10(7)) per ml, respectively. Both total and viable cryptococcal counts declined monoexponentially with an elimination half life of 4 days. The cumulative CSF yeast clearance rates were 38% and 56% at 2 and 4 weeks, respectively. Early death was associated significantly with previous history of weight loss [relative risk (RR)=2.2; 95% CI, 1.2-3.9], Glasgow Coma Score <13 (RR=2.33; 95% CI, 1.55-3.50), and hypoalbuminaemia (P<0.001). Later mortality was associated delayed CSF yeast clearance (RR=3.6; 95% CI, 1.9--6.4) and relapse (RR=3.9; 95% CI, 1.4-10.8). CONCLUSION: High-dose amphotericin B was not as effective as previously thought. Cumulative mortality at 2 weeks, 4 weeks and 1 year were 16%, 24% and 76%, respectively.

AIDSVAX (MN) in Bangkok injecting drug users: a report on safety and immunogenicity, including macrophage-tropic virus neutralization.

A randomized, double-blind, placebo-controlled phase I/II study of AIDSVAX (MN) was conducted among injecting drug users in Bangkok, Thailand. Four doses of vaccine (300 microg of MN-rgp120 in alum) or placebo (alum) were given at study entry and at 1, 6, and 12 months. The objectives of the study were to evaluate (1) the feasibility of conducting vaccine trials in this population; (2) the safety of this candidate AIDS vaccine; and (3) the immunogenicity of this vaccine. Thirty-three volunteers (22 vaccine and 11 placebo recipients) were recruited. None were lost to follow-up during the 18-month study. Mild reactogenicity was noted, which was similar in both vaccine and placebo recipients. The vaccine induced anti-HIV-1 antibody in all vaccine recipients. Maximal titers of binding antibodies of MN-rgp120 and the V3 domain of MN-rgp120 were induced after the third (6 month) dose while maximal neutralizing antibodies followed the fourth (12 month) dose. The vaccine-induced antibodies from several volunteers were capable of neutralizing macrophage-tropic, subtype B viruses (301660 and JRCSF) detected in a PBMC-based assay. Binding and neutralizing antibodies declined about 10-fold in the 6 months after the last boost. Two vaccinees became infected during the trial, both with subtype E viruses. A phase III efficacy trial, using a bivalent gp120 vaccine containing antigens from a subtype B virus (MN) and a subtype E virus (A244), was initiated in March 1999 in injecting drug users in Bangkok.