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

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.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.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.ClinicalTrials.govNCT00223080

Blood stage antimalarial efficacy of primaquine in Plasmodium vivax malaria.

The blood stage antimalarial efficacy of primaquine (0.25 mg of base/kg of body weight/day over 14 days) and chloroquine (25 mg of base/kg over 3 days) were compared in 85 adult Thai men with acute Plasmodium vivax malaria. Most (75%) had at least one malaria episode previously. Parasite clearance times after primaquine alone (n = 30) were slower than after chloroquine (n = 30) or combined chloroquine-primaquine (n = 25), but all patients had a satisfactory initial therapeutic response. P. vivax malaria recurred in 10 (17%) of 60 patients followed for &gt; or = 2 months and Plasmodium falciparum malaria developed in another 5 (8%) without reexposure to infection. Recurrences occurred &lt; or = 5 weeks after primaquine treatment (n = 4), suggesting recrudescence, whereas recurrences after chloroquine treatment (n = 6) occurred &gt; or = 5 weeks later, suggesting relapse. Vivax malaria responds well initially to either primaquine or chloroquine. The blood stage antimalarial activity of primaquine may mask chloroquine resistance in combined regimens

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether > 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether &gt; 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential

Quinine in severe falciparum malaria: evidence of declining efficacy in Thailand.

Between 1981 and 1992, 196 Thai adults with severe falciparum malaria were treated with a quinine loading dose regimen. Nineteen patients died (10%) and 6 developed late hypoglycaemia. There was no serious cardiovascular or nervous system toxicity. Although there was no evidence of high grade resistance, and no change in the mortality rate, in recent years an increasing proportion of patients had a delayed clinical and parasitological response to treatment. Since 1988, 78% (29/37) of patients with cerebral malaria were unconscious for &gt; 72 h compared with 41% (11/27) between 1981 and 1987 (P = 0.002). In the past 2 years parasite clearance times have exceeded 96 h in 33% (26/78) of patients compared with 14% (15/102) previously (P = 0.006). Quinine remains an effective treatment for severe multi-drug resistant falciparum malaria in this area, but there is now evidence of a decline in the immediate therapeutic response, and its efficacy will need close monitoring as resistance increases further

Antimalarial activity and interactions between quinine, dihydroquinine and 3-hydroxyquinine against Plasmodium falciparum in vitro.

The antimalarial activities of quinine, dihydroquinine (a natural impurity found in commercial pharmaceutical formulations of quinine) and 3-hydroxyquinine (the principal metabolite of quinine in humans) were tested both individually and in pairs against 5 strains of Plasmodium falciparum isolated from patients in Thailand. The median inhibitory concentrations (IC50) were similar for quinine (168 nmol/L, range 68-366), and dihydroquinine (129 nmol/L, range 54-324), and both were significantly lower than that of 3-hydroxyquinine (1160 nmol/L, range 378-3154) (P = 0.027). When these drugs were tested in combination, there was no evidence of synergy or antagonism, as determined by fractionary inhibitory indices and isobolograms. Quinine and its impurity, dihydroquinine, have equivalent antimalarial activities which are approximately 10 times greater than that of the metabolite 3-hydroxyquinine. These 2 compounds, which are not usually measured in specific drug assays, contribute to antimalarial activity after quinine administration