The cost-effectiveness and value of information of three influenza vaccination dosing strategies for individuals with human immunodeficiency virus

Background

Influenza vaccine immunogenicity is diminished in patients living with HIV/AIDS. We evaluated the cost-effectiveness and expected value of perfect information (EVPI) of three alternative influenza vaccine dosing strategies intended to increase immunogenicity in those patients.

Methods

A randomized, multi-centered, controlled, vaccine trial was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies with seasonal, inactivated trivalent, non-adjuvanted intramuscular vaccine were used in HIV infected adults: two standard doses over 28 days (Strategy A), two double doses over 28 days (Strategy B) and a single standard dose of influenza vaccine (Strategy C), administered prior to the 2008 influenza season. The comparator in our analysis was practice in the previous year, in which 82.8% of HIV/AIDS received standard-dose vaccination (Strategy D). A Markov cohort model was developed to estimate the monthly probability of Influenza-like Illness (ILI) over one influenza season. Costs and quality-adjusted life years, extrapolated to the lifetime of the hypothetical study cohorts, were estimated in calculating incremental cost-effectiveness ratios (ICER) and EVPI in conducting further research.

Results

298 patients with median CD4 of 470 cells/µl and 76% with viral load suppression were randomized. Strategy C was the most cost-effective strategy for the overall trial population and for suppressed and unsuppressed individuals. Mean ICERs for Strategy A for unsuppressed patients could also be considered cost-effective. The level of uncertainty regarding the decision to implement strategy A versus C for unsuppressed individuals was high. The maximum acceptable cost of reducing decision uncertainty in implementing strategy A for individuals with unsuppressed pVL was $418,000 - below the cost of conducting a larger-scale trial.

Conclusion

Our results do not support a policy to implement increased antigen dose or booster dosing strategies with seasonal, inactivated trivalent, non-adjuvanted intramuscular vaccine for individuals with HIV in Canada.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00764998","term_id":"NCT00764998"}}NCT00764998.     

Manipulating the regulatory genes for teicoplanin production in <Emphasis Type="Italic">Actinoplanes teichomyceticus</Emphasis>

Actinoplanes teichomyceticus produces the lipoglycopeptide antibiotic teicoplanin, which is considered a last line of defense against multidrug resistant Gram-positive cocci. Different strategies have been employed to generate industrial producers of teicoplanin, however they do not include manipulations of teicoplanin biosynthetic genes due to a poorly developed genetic “toolkit” for this strain. Through this work, we extend the choice of vectors that can be conjugally transferred and maintained in A. teichomyceticus. Antibiotic producing properties and stability of the transconjugants have been examined. As an illustration of the utility of pSG5-based vector pKC1139, we improved teicoplanin production by the wild type strain via manipulations of two regulatory genes from the teicoplanin biosynthetic cluster, tcp28 and tcp29.     

The Brigham and Women's Hospital face transplant program: a look back

With five face transplants now successfully completed in the United States, the authors look back at their experience with the first face transplant performed in their program. They discuss the process of establishing a face transplant program, the clinical case, and the lessons learned.     

Disparities in the Burden of HIV/AIDS in Canada

Background

We aimed to characterize changes in patterns of new HIV diagnoses, HIV-related mortality, and HAART use in Canada from 1995 to 2008.

Methods

Data on new HIV diagnoses were obtained from Health Canada, HIV-related mortality statistics were obtained from Statistics Canada, and information on the number of people on HAART was obtained from the single antiretroviral distribution site in British Columbia (BC), and the Intercontinental Marketing Services Health for Ontario and Quebec. Trends of new HIV-positive tests were assessed using Spearman rank correlations and the association between the number of individuals on HAART and new HIV diagnoses were estimated using generalized estimating equations (GEE).

Results

A total of 34,502 new HIV diagnoses were observed. Rates of death in BC are higher than those in Ontario and Quebec with the rate being 2.03 versus 1.06 and 1.21 per 100,000 population, respectively. The number of HIV infected individuals on HAART increased from 5,091 in 1996 to 20,481 in 2008 in the three provinces (4 fold increase). BC was the only province with a statistically significant decrease (trend test p<0.0001) in the rate of new HIV diagnoses from 18.05 to 7.94 new diagnoses per 100,000 population. Our analysis showed that for each 10% increment in HAART coverage the rate of new HIV diagnoses decreased by 8% (95% CI: 2.4%, 13.3%)

Interpretation

Except for British Columbia, the number of new HIV diagnoses per year has remained relatively stable across Canada over the study period. The decline in the rate of new HIV diagnoses per year may be in part attributed to the greater expansion of HAART coverage in this province.     

The infective polymerization of conformationally unstable antithrombin mutants may play a role in the clinical severity of antithrombin deficiency

Mutations affecting mobile domains of antithrombin induce conformational instability resulting in protein polymerization that associates with a severe clinical phenotype, probably by an unknown gain of function. By homology with other conformational diseases, we speculated that these variants might infect wild-type (WT) monomers reducing the anticoagulant capacity. Infective polymerization of WT polymers and different P1 mutants (p.R425del, p.R425C and p.R425H) were evaluated by using native gels and radiolabeled WT monomers and functional assays. Human embryonic kidney cells expressing the Epstein-Barr nuclear antigen 1 (HEK-EBNA) cells expressing inducible (p.R425del) or two novel constitutive (p.F271S and p.M370T) conformational variants were used to evaluate intracellular and secreted antithrombin under mild stress (pH 6.5 and 39°C for 5 h). We demonstrated the conformational sensitivity of antithrombin London (p.R425del) to form polymers under mild heating. Under these conditions purified antithrombin London recruited WT monomers into growing polymers, reducing the anticoagulant activity. This process was also observed in the plasma of patients with p.R425del, p.R425C and p.R425H mutations. Under moderate stress, coexpression of WT and conformational variants in HEK-EBNA cells increased the intracellular retention of antithrombin and the formation of disulfide-linked polymers, which correlated with impaired secretion and reduction of anticoagulant activity in the medium. Therefore, mutations inducing conformational instability in antithrombin allow its polymerization with the subsequent loss of function, which under stress could sequestrate WT monomers, resulting in a new prothrombotic gain of function, particularly relevant for intracellular antithrombin. The in vitro results suggest a temporal and severe plasma antithrombin deficiency that may contribute to the development of the thrombotic event and to the clinical severity of these mutations.     

Coordination of export and glycosylation of landomycins in Streptomyces cyanogenus S136

In Streptomyces cyanogenus S136 gene cluster for biosynthesis of polyglycosylated angucycline landomycin A (LaA), a divergently oriented gene pair for a TetR-family regulator ( lanK ) and an efflux protein ( lanJ ) is located, whose functions remained obscure. Overexpression and disruption studies showed that lanK and lanJ genes control LaA resistance. Also, a constitutive lanK overexpression led to predominant accumulation of LaA precursors bearing shorter glycoside chains. These data as well as the results of in vitro and in vivo assays of LanK activity are consistent with the idea that LanK represses lanJ and some downstream genes involved in conversion of landomycin D (a disaccharide LaA precursor) into LaA. LaA and some of its precursors accumulate in the producing cell and relieve repression by LanK, thus amplifying the biosynthesis and export of landomycins with long glycoside chains. Therefore, the main biological role of LanK appears to be the inhibition of premature extrusion of early LaA precursors from the cells, which in turn creates the optimal conditions for accumulation of LaA as the major landomycin in S. cyanogenus S136.