ABSTRACT
OBJECTIVES: Many elderly persons have drug benefits with coverage gaps, such as in Medicare Part D. Because beneficiaries who have such gaps must pay all drug costs, an accurate knowledge of gap thresholds and communication with providers about exceeding caps is important for elderly persons to manage out-of-pocket drug costs. DESIGN: Cross-sectional survey. SETTING: Health plan. PARTICIPANTS: One thousand three hundred eight health plan members aged 65 and older. The study was a 2002 cross-sectional survey of elderly persons with capped drug benefits in a managed care plan in one state. Participants were sampled so that half reached coverage caps and half did not. METHODS: Participants reported cap levels, communication with providers about exceeding caps, and decreased medication use due to cost. RESULTS: Of the 1,308 participants (65.4%response rate), 68.6%did not know their correct cap level. Rates were similar in those who exceeded caps (66.2%), reported difficulty paying for medications (63.9%), or decreased medication use (66%). For participants who exceeded caps, 59.1% did not know beforehand that they were close to exceeding caps and 50.2% did not tell providers afterward. In multivariate analyses accounting for demographics and health, the oldest participants (> or =85 vs 65-74) were at greater risk for not knowing cap levels (odds ratio (OR)=2.0, 95% confidence interval (CI)=1.2-3.4) and not telling providers about exceeding caps (OR=2.2, 95% CI=1.1-4.5). CONCLUSIONS: Elderly patients often did not know correct cap levels and did not tell providers about exceeding caps. Providers, plans, and policymakers should actively assess and improve Medicare beneficiaries' knowledge of Part D coverage gaps.
Subject(s)
Communication , Drug Costs , Health Knowledge, Attitudes, Practice , Managed Care Programs/economics , Medicare Part D , Physician-Patient Relations , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Male , Multivariate Analysis , United StatesABSTRACT
A dengue virus vaccine candidate, rDEN4Delta30, has been previously reported to be safe and immunogenic in humans, but a subset of vaccinees developed asymptomatic rash, elevation of liver enzymes and/or mild neutropenia. In the current study, mutations that had previously been shown to reduce replication of DEN4 virus in suckling mice and/or in SCID mice engrafted with human liver cells (SCID-HuH-7 mice) were introduced into rDEN4Delta30 in an attempt to further attenuate this virus. Three of the five resulting modified rDEN4Delta30 viruses showed decreased replication in SCID-HuH-7 mice relative to rDEN4Delta30. Moreover, in rhesus monkeys, two of the modified rDEN4Delta30 viruses showed a decrease in replication relative to rDEN4Delta30 while generating levels of neutralizing antibody similar to rDEN4Delta30 virus. All of the modified rDEN4Delta30 viruses completely protected immunized rhesus monkeys from challenge with wild-type DEN4 virus. Based on their attenuation for both human liver cells and rhesus monkeys, two of the modified rDEN4Delta30 vaccine candidates are currently being prepared for use in clinical trials. The application of these attenuating mutations to flavivirus vaccine development is discussed.
Subject(s)
3' Untranslated Regions/genetics , 3' Untranslated Regions/immunology , Dengue Virus/genetics , Dengue Virus/immunology , Dengue/immunology , Dengue/prevention & control , Point Mutation/genetics , Point Mutation/immunology , Viral Vaccines/genetics , Viral Vaccines/immunology , Virus Replication/physiology , Amino Acid Substitution , Animals , Chlorocebus aethiops , DNA, Complementary/genetics , DNA, Complementary/immunology , Dengue Virus/growth & development , Hepatocytes/virology , Macaca mulatta , Mice , Mice, SCID , Phenotype , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology , Vero CellsABSTRACT
An acceptable live-attenuated dengue virus vaccine candidate should have low potential for transmission by mosquitoes. We have identified and characterized a mutation in dengue virus type 4 (DEN4) that decreases the ability of the virus to infect mosquitoes. A panel of 1248 mutagenized virus clones generated previously by chemical mutagenesis was screened for decreased replication in mosquito C6/36 cells but efficient replication in simian Vero cells. One virus met these criteria and contained a single coding mutation: a C-to-U mutation at nucleotide 7129 resulting in a Pro-to-Leu change in amino acid 101 of the nonstructural 4B gene (NS4B P101L). This mutation results in decreased replication in C6/36 cells relative to wild-type DEN4, decreased infectivity for mosquitoes, enhanced replication in Vero and human HuH-7 cells, and enhanced replication in SCID mice implanted with HuH-7 cells (SCID-HuH-7 mice). A recombinant DEN4 virus (rDEN4) bearing this mutation exhibited the same set of phenotypes. Addition of the NS4B P101L mutation to rDEN4 bearing a 30 nucleotide deletion (Delta30) decreased the ability of the double-mutant virus to infect mosquitoes but increased its ability to replicate in SCID-HuH-7 mice. Although the NS4B P101L mutation decreases infectivity of DEN4 for mosquitoes, its ability to enhance replication in SCID-HuH-7 mice suggests that it might not be advantageous to include this specific mutation in an rDEN4 vaccine. The opposing effects of the NS4B P101L mutation in mosquito and vertebrate systems suggest that the NS4B protein is involved in maintaining the balance between efficient replication in the mosquito vector and the human host.
