Tetravalent Rotavirus Vaccine

Pediatrics

Tetravalent Rotavirus Vaccine Todd L Wandstrat, Barbara Kaplan-Machlis, Mary E Temple, and Milap C Nahata

OBJECTIVE:

To review the clinical efficacy, safety, and pharmacoeconomic data about the use of rhesus–human reassortant rotavirus tetravalent vaccine (RRV-TV) in infants and children. DATA SOURCES: A MEDLINE search (January 1990–December 1998) was conducted to identify all publications on the RRV-TV vaccine including pharmacology, clinical trials, adverse effects, and pharmacoeconomics in infants and children. Bibliographies of articles were also used. STUDY SELECTION: All randomized and placebo-controlled clinical efficacy trials were reviewed. Additionally, pharmacoeconomic studies focusing on the potential impact on healthcare costs were chosen for review. DATA SYNTHESIS: Rotavirus-induced gastroenteritis is a significant problem in developed and developing countries. Various forms of a rotavirus vaccine have been studied worldwide. The tetravalent vaccine appears to have similar efficacy in developed and developing countries. It seems to be most effective against the most severe forms of gastroenteritis, with an 80% overall efficacy rate. This vaccine is well tolerated; the most common adverse effect is fever after the first dose. Pharmacoeconomic studies indicate that although the vaccine may be only moderately effective against less severe gastroenteritis, over $1 billion annually could potentially be saved in the US with its universal use. CONCLUSIONS: The new rotavirus vaccine is effective in preventing and reducing the incidence of rotavirus-induced gastroenteritis. The morbidity, mortality, and healthcare costs from this disease may be reduced if this vaccine is provided to children worldwide. Todd L Wandstrat PharmD, National Health Management Director, Health Care Management, Novartis Pharmaceuticals, Scott Depot, WV Barbara Kaplan-Machlis PharmD, Associate Professor, Departments of Clinical Pharmacy and Family Medicine, Schools of Pharmacy and Medicine, Robert C Byrd Health Sciences Center of West Virginia University, Charleston, WV Mary E Temple PharmD, Fellow, Pediatric Infectious Disease, College of Pharmacy, The Ohio State University, Columbus, OH Milap C Nahata PharmD, Kimberly Professor of Pharmacy and Pediatrics, Colleges of Pharmacy and Medicine, The Ohio State University and Children’s Hospital, Columbus Reprints: Milap C Nahata PharmD, College of Pharmacy, The Ohio State University, Columbus, OH 43210, FAX 614/292-1335, E-mail [email protected]

This article is approved for continuing education credit. ACPE Universal Program Number 407-000-99-018-H01

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KEY WORDS:

rhesus–human reassortant rotavirus tetravalent vaccine,

rotavirus. Ann Pharmacother 1999;33:833-9.

H

uman rotavirus gastroenteritis is most commonly caused by group A rotaviruses; serotypes 1, 2, 3, and 4 lead to about 95% of all cases.1,2 Rotavirus gastroenteritis is the most important etiology of diarrhea in infants and children worldwide.3 In developing countries, rotavirus gastroenteritis causes >800 000 deaths annually.4 In developed countries, rotavirus is the leading cause of hospitalization due to severe diarrheal disease. Rotavirus is shed in the stool and is highly contagious. It is spread by oral–fecal contamination. Handwashing may not prevent viral transmission. Ingested virus particles infect the cells in the villi of the small intestine leading to the illness. Infection usually occurs in children younger than two years, with peak prevalence at three to 15 months.5 By age three, 90% of children with the disease were infected with the virus.1 Although rotavirus follows a seasonal outbreak pattern in the US (fall in the southwest, winter to spring in the northeast), no such pattern exists in other parts of the world. The incubation period is two to four days and clinical illness is evident for four to eight days. Vomiting and copious acute diarrhea are the most common symptoms of rotavirus illness. Other complications include otitis media, fever, and upper respiratory tract infections. Until recently, no preventive therapy for rotavirus disease existed. Patients who developed severe illness experienced 10–20 episodes of diarrhea and 10–15 episodes of vomiting per day. Only supportive care, including fluid and electrolyte replacement, was available for treatment of an active rotavirus infection.6 In September 1998, the Food and Drug Administration approved an oral tetravalent rotavirus vaccine to prevent

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rotavirus infections. The vaccine is marketed as Rotashield by Wyeth-Lederle Pediatrics and Vaccines.7

Rotavirus Genetics Rotavirus is a double-stranded RNA virus that belongs to the family Reoviridae. There are four major human serotypes of rotavirus (1, 2, 3, 4). A genome containing 11 segments or glycoproteins exists within each rotavirus. These segments encode for the production of inner and outer capsid viral polypeptides. Of these 11 segments, viral protein 4 and viral protein 7 are responsible for induction of neutralizing antibodies. Antibodies provide humoral immunity to the rotavirus.3,8 Research on prevention of rotavirus has focused on the development of a vaccine that is active against one major serotype of rotavirus (serotype 1) or the four serotypes of group A rotavirus (serotypes 1, 2, 3, 4).9

Formulation of Rotavirus Vaccine Rotashield is commercially available as a tetravalent preparation.7 The vaccine contains 1 × 105 plaque forming units (PFU) of a rhesus serotype 3 rotavirus, and three rhesus–human reassortant serotypes including 1, 2, and 4. Each 2.5-mL dose contains equal quantities of each rotavirus serotype for a total of 4 × 105 PFU. The serotype 3 component has strong serologic cross-reactivity with human rotavirus serotype 3, while the reassortant provides antigens identical to rotavirus serotypes 1, 2, and 4.

Clinical Efficacy and Safety The clinical efficacy and safety of rhesus–human reassortant rotavirus tetravalent vaccine (RRV-TV) has been studied in three multicenter trials in the US, a multicenter trial in Finland, and three single-site trials in Venezuela, Peru, and Brazil.9-15 A multicenter, randomized, double-blind, placebo-controlled trial performed in the US9 compared the efficacy of monovalent (RRV-S1) vaccine with RRV-TV and placebo during two rotavirus seasons. A total of 898 healthy infants (aged 4–26 wk) were enrolled and received three doses of vaccine or placebo. Exclusion criteria included chronic illness, an immunosuppressed individual in the household, or a pregnant caretaker. Infants received three doses separated by at least two weeks, with the final dose administered by 30 weeks of age. Evaluations of efficacy were based on the incidence of rotavirus gastroenteritis that occurred two or more weeks after the child received the third dose of vaccine (Table 1). The efficacy analysis was conducted in 898 subjects meeting the inclusion criteria for the first year, and in 864 subjects followed through the end of the second season. During the first season, a significant decrease in rotavirus gastroenteritis was noted for both treatment groups as compared with controls (p < 0.001). Relative efficacy of the monovalent vaccine was similar to that of the tetravalent vaccine after the first season. In the second season, recipients of the tetravalent vaccine developed less rotavirus disease than those who received placebo (p = 0.03). The

Table 1. Clinical Efficacy and Safety Trials of the Rotavirus Vaccine Reference

Country

Bernstein et al. (1995)9

US

Rennels et al. (1996)10

US

Santosham et al. (1997)11

US

Perez-Schael et al. (1997)12 Joensuu et al. (1997)13

Group

No. of Infants

% Efficacy > Placebo a

Adverse Effects a

RRV-TV RRV-S1 placebo RRV-TV RRV-S1 placebo

305 297 296 398 404 385

57% first year ; 46% second year 73% first yeara; 26% second yeara

RRV-TV

396

RRV-S1

398

69% first year, severe; 44% second year, severe 48% first year, severe; 35% second year, severe

placebo Venezuela RRV-TV placebo Finland RRV-TV

391 1112 1095 1191

Lanata et al. (1996)14

Peru

Linhares et al. (1996)15

Brazil

placebo RRV-TV (1 dose) RRV-TV (3 doses) placebo RRV-TV placebo

1207 212 207 218 361 363

49% overall; 68% in severe 54% in any severity; 56% in severe

88% in severe 91% in severe

35% in severe 66% in severe 35% in any severity; 91% in severe

fever 14% fever 10% fever 8% fever 2.2% after first dose diarrhea 4.2% after second dose fever 0.2% after first dose; diarrhea 1.5% after second dose fever 18% after second dose; 4 deaths not due to RRV-TV

fever 12% after second dose fever 15% fever 6% fever 31% after first dose (p < 0.001); excess crying 42% (p < 0.001); unusual irritability 37% (p < 0.001) fever 41% after first dose fever 39% after first dose fever 42% after first dose fever 1.6–2.9% fever 0.4–1.2%

RRV-S1 = rhesus–human reassortant rotavirus monovalent vaccine; RRV-TV = rhesus–human reassortant rotavirus tetravalent vaccine. a p < 0.05 for efficacy of vaccine versus placebo.

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Tetravalent Rotavirus Vaccine

tetravalent vaccine efficacy remained relatively consistent. However, the efficacy of the monovalent vaccine was significantly reduced from 73% greater than placebo in the first season to 26% greater than placebo in the second season (p value not reported).9 Hypothesis for the lower efficacy rates for the monovalent vaccine is that it only provides protection from rotavirus serotype 1. A majority of the infections in the second season were nonserotype 1 rotavirus infections. Most importantly, the efficacy of both vaccines was markedly higher than that of placebo when the incidence of severe rotavirus gastroenteritis was assessed: 73% greater efficacy than placebo with the monovalent vaccine and 82% greater efficacy than placebo with the tetravalent vaccine (p > 0.05). The tetravalent vaccine reduced the number of episodes of rotavirus disease by 57%, number of days with rotavirus diarrhea by 75%, and number of episodes of rotavirus illness requiring medical visits by 78% compared with those with placebo. The tetravalent vaccine was generally well tolerated, although a significant increase in low-grade fever on days 4 and 5 after administration of the first vaccine was observed as compared with the monovalent vaccine group. Despite the fact that the relative efficacy of the tetravalent vaccine was moderate relative to placebo, the vaccine is projected to prevent more than 1 million cases of rotavirus gastroenteritis in the US annually.9 A double-blind, randomized, multicenter, placebo controlled trial10 compared the efficacy of RRV-S1 and RRVTV. The vaccines (consisting of 1 × 105 PFU) or placebo were administered to infants at two, three, and four months of age. A total of 1278 healthy infants (aged 5–25 wk) were enrolled; 1216 completed surveillance and 1187 received all three oral doses of RRV-S1, RRV-TV, or placebo. Analyses were based on the 1187 patients who received all three doses. Compared with placebo, the reduction in the incidence of rotavirus gastroenteritis in both vaccine groups was significant (p < 0.0001), but the difference between RRV-TV and RRV-S1 groups was not. Both vaccines were most effective against clinically severe rotavirus gastroenteritis. The vaccines were well tolerated and the incidence of adverse reactions such as diarrhea, fever, and vomiting during the five-day surveillance period after any dose did not differ among treatment groups. The efficacy of RRV-TV against dehydrating gastroenteritis was 100% in this trial; however, the vaccine’s full clinical and economic impact (morbidity, mortality, medical costs) were not evaluated in this study. Efficacy and safety of RRV-TV were evaluated in a twoyear randomized, placebo-controlled, double-blind study of Native American infants.11 Patients were included if they were six to 24 weeks old and had no underlying illnesses. Exclusion criteria included infants with a chronic disease or cohabitation with an immunosuppressed individual. Four Native Indian populations (total 1185 infants) were studied due to the known high risk of severe rotavirus diarrhea in such populations. Infants received orally administered RRV-TV (1 × 105 PFU), RRV-S1 (4 × 105 PFU), or placebo at two, four, and six months of age. During the www.theannals.com

first year of surveillance, overall vaccine efficacy for preventing all rotaviral gastroenteritis cases was 50% and 29% greater than placebo for RRV-TV and RRV-S1, respectively (p = 0.10). Similar to other trials,9-15 efficacy of the vaccines versus placebo was substantially higher for severe disease. No statistically significant differences among groups were noted with regard to diarrhea or vomiting during the five-day period after each of the doses. However, recipients of the second dose of RRV-TV were more likely to have a temperature >38 ˚C in comparison with placebo recipients (p = 0.02). The efficacy and safety results were consistent with those of two other multicenter trials conducted in the general US population.9,10 Due to serotype differences and year-to-year variation in serotype distribution, RRV-TV may be a better choice than RRV-S1 at the national level. Since vaccine studies in developed countries demonstrated efficacy in preventing rotavirus gastroenteritis, the impact of the vaccine was assessed in developing countries such as Venezuela.12 A randomized, double-blind, placebocontrolled study enrolled 2207 infants who received either three doses of RRV-TV (1 × 105 PFU) or placebo at two, three, and four months of age. Infants receiving vaccine had more febrile episodes during the six days after the first dose compared with those who received placebo (p < 0.001). No other differences in adverse effects were observed between vaccine and placebo groups. The vaccine was most effective against severe diarrhea caused by rotavirus. It reduced dehydration by 75%, hospital admissions by 70%, and illnesses lasting more than four days by 71% as compared with placebo. The overall efficacy of RRV-TV vaccine over placebo for protection against a first episode of rotavirus diarrhea was 48% greater than placebo. The efficacy of RRV-TV was greater in children older than one year (61%) versus infants four to 12 months of age (41%). A randomized, double-blind, placebo-controlled Finnish study was conducted to evaluate the efficacy of RRV-TV in infants with severe rotavirus gastroenteritis.13 Infants were included if they were between 50 and 130 days at the time of the first dose, in good health with no underlying illnesses, and if their family had a telephone. Infants were excluded if they cohabited with an immunosuppressed individual. The study conditions closely resembled a naturalistic environment, since study vaccine was administered at the same time as other childhood immunizations (ages 2, 3, and 5 mo). The enrollment period covered one calendar year, and the follow-up period included one or two rotavirus epidemic seasons. A total of 2398 children were enrolled and received at least one dose of RRV-TV (4 × 105 PFU) or placebo. The primary efficacy analysis was based on children who received three doses of RRV-TV or placebo. The majority of the 256 episodes of rotavirus gastroenteritis occurred in the placebo group. In the intentionto-treat analysis, vaccine efficacy was 66% greater than placebo. One hundred episodes of gastroenteritis were considered severe, eight in RRV-TV recipients and 92 in the placebo group. Thus, in the primary efficacy analysis, the vaccine was very effective in preventing severe gastroen-


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teritis. While patients receiving the vaccine were more likely to develop a fever after the first dose than those receiving placebo, no difference in fever was noted between the groups with subsequent doses. The efficacy, safety, and immunogenicity of RRV-TV was evaluated in Peru in a densely populated periurban area of low socioeconomic status where diarrheal diseases are highly endemic.14 This was a double-blind, randomized, placebo-controlled trial that compared one dose of RRV-TV, three doses of RRV-TV, or placebo. No inclusion or exclusion criteria were specified in this study. Infants received the vaccine (1 × 104 PFU) or placebo at two, three, and four months of age in conjunction with inactivated polio vaccine combined with diphtheria–tetanus toxoid–pertussis vaccine. Rotavirus-specific immunoglobulin A (IgA) responses were detected by enzyme-linked immunosorbent assay (ELISA) in 75% of the three-dose vaccine group, 59% of the one-dose vaccine group (p = 0.05), and 24% of the placebo group (p < 0.001). A neutralizing antibody response to at least one serotype was observed in 64% among the three-dose group, 48% among the one-dose group, and 12% among the placebo group. Neither of the vaccine groups demonstrated a significant level of protection against rotavirus diarrhea; however, some protection was observed against more severe rotavirus diarrhea. This study indicated greater difficulty in providing high-level protection against rotavirus diarrhea in a developing country. Although extrapolation may be difficult due to lack of specified inclusion and exclusion criteria, the tendency for greater protection against more severe rotavirus diarrhea was consistent with other study results, suggesting that the RRV-TV vaccine may be more useful for prevention of severe disease.14 A two-year, randomized, double-blind, placebo-controlled trial was conducted in Brazil which utilized a 3:1 vaccine to placebo randomization scheme.15 Three doses of rotavirus vaccine or placebo were administered to infants at one, three, and five months of age. The primary end points of this study were comparison of efficacy (diarrheal episodes), immunogenicity, and safety between the RRV-TV vaccine and placebo. Infants were excluded if they had a chronic illness or if they cohabited with an immunosuppressed person. The vaccine in this trial consisted of 4 × 104 PFU. RRV-TV prevented 57% more diarrheal illness than placebo in the first year and 12% more than placebo in the second year of the study against all cases of rotavirus diarrhea. RRV-TV provided better overall protection (p = 0.03). When considering the most common causative forms of rotavirus, serotypes 1 and 2, RRV-TV provided 25–61% greater protection than placebo over the two-year period. Rotavirus-specific IgA responses were detected by ELISA in 58% of the vaccine group and 33% of the placebo group (p = 0.005). Patients in the study tolerated the RRV-TV well. Low-grade fever was more common in the RRV-TV group after the first dose (p < 0.05). No difference in fever was noted after administration of the second and third doses of the vaccine or placebo. 836

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In summary, the RRV-TV appears to be efficacious and safe in preventing rotavirus gastroenteritis in developed and developing countries. Lower rates of protective efficacy were reported in studies where the RRV-TV product contained 4 × 104 PFU14,15 compared with those containing 1– 4 × 105 PFU.10-13 The difference in vaccine strength could account for the differences observed among studies conducted around the world. Other reasons for reduced immunogenicity in certain trials may include antibody suppressive effect from breast milk or transplacental acquisition, although no studies involving three doses of rotavirus have validated these possibilities or nonrotavirus enteric virus competition.15,16 Considerable reductions in morbidity and mortality from rotavirus diarrhea may be realized by assuming its administration along with routine immunizations.

Adverse Effects Adverse effects after rotavirus vaccine administration have included increased temperature, vomiting, and diarrhea.10-15 In one trial,10 four infants who had received vaccine required hospitalization. Two of the infants had fever, vomiting, and diarrhea beginning on days 3 and 4 after vaccination. One patient was hospitalized with fever, sterile pyuria, and urinary reflux three days after vaccination. The fourth infant developed fever, vomiting, and diarrhea seven days after vaccination. Two multicenter trials9,11 documented a higher number of patients with temperature >38.1 ˚C among infants receiving vaccine (5%) versus placebo (1%) (p = 0.01). More infants receiving vaccine than placebo were reported to have elevated temperature (>38 ˚C) (18% vs. 12%; p = 0.02) after the second dose of vaccine.11 Comparison of monovalent and tetravalent rotavirus vaccine with placebo found more infants in the tetravalent vaccine group developing a fever >38 ˚C on day 4 (p = 0.04), day 5 (p = 0.01), and overall (p = 0.01) than those receiving placebo.9 Similar results were reported in the Peruvian study of one dose of vaccine versus three doses versus placebo.14 Fever was most common within the first 24 hours in all three arms of the trial and the incidence of fever did not differ significantly between groups. This appears to be the only adverse effect that occurs more frequently in vaccinated infants than in those receiving placebo.

Economic Issues Viral gastroenteritis leads to approximately 2 million to 3.7 million visits to pediatricians per year in the US.17 In 1984, The Centers for Disease Control and Prevention (CDC) found that two-thirds of viral gastroenteritis cases were attributed to rotavirus.18 In the US, rotavirus disease is estimated to cause 3.1 million cases of diarrhea, 65 000–70 000 hospital admissions, and 75–125 deaths per year. In developing countries, as many as 870 000 children die per year from this disease.18,19 Although difficult to estimate, a yearly cost (direct and indirect) of rotavirus disease was $1.38


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Tetravalent Rotavirus Vaccine

billion (1993 dollars) when calculated from a US birth cohort of 4.1 million children.20 The outpatient cost of one disease episode of diarrhea has been estimated at $289 in the US.18 Using 1985 dollars, a CDC group estimated the annual US economic burden of rotavirus diarrhea to be over $255 million.21 This estimate included costs of physician office visits, hospitalizations, and follow-up visits. If the costs of a rotavirus vaccine program were similar to those of measles or polio ($5–20 per child), then the program would be cost-effective. A major limitation of this study was the fact that the indirect costs were not included. A cost–benefit analysis of a rotavirus vaccine program was performed assuming a cohort of 60 000 infants followed for the first three years of life.22 An 80% efficacy rate of the vaccine against severe and moderately severe rotavirus diarrhea and an 80% compliance rate was assumed. Costs of rotavirus diarrhea included outpatient physician visits and, for severe cases, a 2.5-day hospital stay. The direct benefits of a vaccine program were estimated with varying incidence rates. Both a high incidence of rotavirus diarrhea (0.3 episodes per child per 3 y with 90% of cases requiring medical attention) or low incidence of rotavirus diarrhea (0.2 episodes per child per 3 y with 90% of cases requiring medical attention) were included in the calculation. The break-even point for a vaccination for a high and low incidence of diarrhea was $36 and $27, respectively.22 Other economic analyses of rotavirus vaccination programs have considered various direct and indirect costs from the healthcare system or societal perspective.20,23,24 Data from a US multicenter trial23 were utilized to determine costs associated with rotavirus disease and vaccination. A break-even analysis from the societal perspective was used to analyze the data for 1278 subjects. Costs included the use of inpatient and outpatient facilities, physicians, prescription and nonprescription medications, caretaker travel, childcare, meals, and missed work. Three study groups were evaluated: a tetravalent vaccine, serotype monovalent vaccine, and placebo. Three doses of vaccine were given two months apart. Costs of the vaccine and administration were excluded. During the study period, the mean total costs incurred by the tetravalent, monovalent, and placebo groups were $78, $71, and $113, respectively (p = 0.001). Costs incurred due to an episode of rotavirus gastroenteritis in each of the three arms of the trial were also reported. The tetravalent group had a mean total cost of $91 ± 116 and the monovalent group, $246 ± 675. The cost savings or break-even point for the tetravalent group was $11 per dose. Assuming 3.3 million births per year and a 100% risk of acquiring rotavirus infection by age five years, estimated cost savings from immunization were $36 million to $40 million per year. A decision tree analysis using national estimates of costs was developed to compare rotavirus vaccination and no vaccination options on a US national level.20 Direct and indirect costs were used to calculate the total cost of a physician visit, hospitalization, and death. A decision tree www.theannals.com

was also created to allow for partial vaccination (1–2 doses) versus full vaccination (3 doses). In the cost–benefit analysis of a national rotavirus vaccination program, assuming a birth cohort of 4.1 million children followed until age five years, discounted cost savings to society were $466 million. For every case of rotavirus prevented, costs were decreased by $78 and $459, based on healthcare system and societal perspectives, respectively. Using a healthcare system perspective, the break-even point analysis for vaccine cost was $17–74 per dose. Another decision model was developed to include chance nodes for rotavirus vaccination, partial vaccination, or no vaccination.24 Chance nodes also were included for no diarrhea, physician visits, emergency department visits, hospitalizations, and deaths. Using a hypothetical US birth cohort of 3.9 million in 1997, the economic impact of rotavirus disease and vaccine-associated prevention was examined during the first five years of the children’s lives. Healthcare system and societal perspectives were used in the analysis. Costs used to calculate total healthcare expenditures and savings included direct costs such as outpatient visits, emergency department visits, hospitalizations, vaccine product and administration costs. Indirect costs included transportation, extra diapers, caretaker earnings lost, and productivity lost due to death of a child. The hypothetical rotavirus vaccine was administered in three doses during the first six months of life. The healthcare perspective calculation included all medical costs and the societal perspective included medical and nonmedical costs. All costs were discounted 3% and were calculated in 1996 dollars using consumer price index and nonfarm sector payroll index. Rotavirus vaccine efficacy rates were taken from three multicenter trials performed at various international centers. An administrative cost of $10 per vaccine dose was added to medical costs. Adverse effects from the vaccine were not included. The total medical costs (healthcare system perspective) of a no-vaccine and a vaccine program were $264 490 and $371 218, respectively. Based on a societal perspective, the total nonmedical and medical costs of a no-vaccine and a vaccine program were $1 000 758 and $704 758, respectively. Therefore, a nationwide rotavirus vaccine program, from the societal perspective, exhibited a cost savings of $296 000. A break-point analysis found the break-even costs per dose of vaccine were $9 and $51 for the healthcare system and societal perspectives, respectively. The authors identified hospitalization costs, vaccine efficacy, and vaccine price as the major determinants in the cost-effectiveness equation. Limitations of this investigation included assumed cost for hospitalizations, outpatient visits, and other direct medical charges.24

Dosage, Administration, and Cost Rotavirus vaccine is approved for prevention of rotavirus infections and is administered orally at a dose of 2.5 mL.7 Each dose of the vaccine costs $47. The vaccine is supplied in single-dose vials as a lyophilized preparation with one pouch for the vaccine and another for the diluent.


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The diluent contains citric acid and sodium bicarbonate, which are used to neutralize stomach acidity and to protect the acid-labile vaccine from destruction. The vaccine is stable for 24 months when stored at 2–25 ˚C before reconstitution and for 60 minutes after reconstitution at room temperature. The first dose of the vaccine can be administered as early as six weeks of age and as late as six months of age. The vaccine is administered at two, four, and six months of age with at least three weeks between each dose. According to The American Academy of Pediatrics,25 doses should be administered prior to the anticipated annual onset of rotavirus infections.

Summary Rotavirus has been recognized as a cause of human illness for >25 years. Rotavirus gastroenteritis causes significant morbidity and mortality among infants and small children worldwide and leads to enormous healthcare costs. An effective rotavirus vaccine is now available to prevent this disease. The RRV-TV vaccine is efficacious against rotavirus gastroenteritis and is well tolerated by infants and children. The vaccine’s 80% prevention efficacy against severe disease has been an impetus for its use.25 Additionally, lack of widespread oral rehydration programs to prevent morbidity reinforces the use of the vaccine. Fever is the main adverse effect and occurs in 10–20% of individuals. Theoretical economic studies have estimated a wide range of potential cost savings with the use of this vaccine. However, prospective cost–benefit and cost-effectiveness trials are needed to confirm the economic impact. When considering the worldwide need for rotavirus vaccine and the probable lack of national programs to support an immunization program in developing countries, the societal economic perspective would need to be considered. For adequate worldwide distribution of the vaccine, the economic burden of providing rotavirus vaccine will most likely be reflected in the market prices of the US and other developed countries. However, many countries in the developing world may not be able to afford three doses of the vaccine. The lack of affordability of this vaccine in developing countries may curtail eradication of rotavirus. In the current global community, where infectious disease in one country can affect the majority of the world, it is insufficient to assess the impact of immunization programs on healthcare at only the local or national level. Collaboration between countries is needed to ensure that this vaccine is available on a worldwide basis regardless of cost. ADDENDUM. The CDC has recommended26 postponing the administration of RRV-TV in children, including those who have already begun the vaccine series. This is in response to 15 cases of intussusception (a clinical syndrome that may include persistent vomiting, bloody stools, black stools, abdominal distension, and/or severe colic pain) in children who have received the vaccine. Although the incidence of intussusception in the postmarketing phase has

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not been found to be significantly different in those receiving the vaccine versus those who have not (p = 0.39), the CDC and Wyeth Lederle Vaccines have initiated a case– control study to determine if an association exists. Because more data are anticipated in the next several months and the rotavirus season is four to six months away in most parts of the US, postponement of vaccine administration is recommended until November 1999.

References 1. Marwick M. Rotavirus vaccine a boost to children. JAMA 1998;279: 489-90. 2. Foster RH, Wagstaff AJ. Tetravalent human–rhesus reassortant rotavirus vaccine. Biol Drugs 1998;9:155-78. 3. Kapikian AZ, Chanock RM. Rotaviruses. In: Fields BN, Knipe DM, Howley PM, Johnson AM, Thompson JC, Anderson TM, et al., eds. Fields virology. 3rd ed. Philadelphia: Lippincott–Raven Publishers, 1996:1657-708. 4. de Zoysa I, Feachem RG. Interventions for the control of diarrheal diseases among young children: rotavirus and cholera immunization. Bull World Health Organ 1985;63:569-83. 5. Ho MS, Glass RI, Pinsky PF, Anderson LJ. Rotavirus as a cause of diarrheal morbidity and mortality in the United States. J Infect Dis 1988;158: 1112-6. 6. Bernstein DJ, Ward RL. Rotavirus. In: Feigin RD, Cherry JD, eds. Textbook of pediatric infectious diseases. Philadelphia: WB Saunders, 1998: 1901-22. 7. Product information. Rotashield (rhesus–human reassortant rotavirus tetravalent vaccine). Philadelphia: Wyeth-Lederle Vaccines and Pediatrics, 1998. 8. Ward RL, Knowlton DR, Zito ET, Davidson BL, Rappaport R, Mack ME. Serologic correlates of immunity in a tetravalent reassortant rotavirus vaccine trial. J Infect Dis 1997;176:570-7. 9. Bernstein DI, Glass RI, Rodgers G, Davidson BL, Sack DA, for the US Rotavirus Vaccine Efficacy Group. Evaluation of rhesus rotavirus monovalent and tetravalent reassortant vaccines in US children. JAMA 1995; 273:1191-6. 10. Rennels MB, Glass RI, Dennehy PH, Bernstein DI, Pichichero ME, Zito ET, et al. for the US Rotavirus Vaccine Efficacy Group. Safety and efficacy of high-dose rhesus–human reassortant rotavirus vaccines — report of the national multicenter trial. Pediatrics 1996;97:7-13. 11. Santosham M, Moulton LH, Reid R, Croll J, Weatherholt R, Ward R, et al. Efficacy and safety of high-dose rhesus–human reassortant rotavirus vaccine in Native American populations. J Pediatr 1997;131:632-8. 12. Perez-Schael I, Guntinas MJ, Perez M, Pagone V, Rojas AM, Gonzalez R. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. N Engl J Med 1997;337:1181-7. 13. Joensuu J, Koskenniemi E, Pang XL, Verikari T. Randomized placebocontrolled trial of rhesus–human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis. Lancet 1997;350:1205-9. 14. Lanata CF, Midthun K, Black RE, Butron B, Huapaya A, Penny ME, et al. Safety, immunogenicity, and protective efficacy of one and three doses of the tetravalent rhesus rotavirus vaccine in infants in Lima, Peru. J Infect Dis 1996;174:268-75. 15. Linhares AC, Gabbay YB, Mascarenhas JDP, de Freitas RB, Oliveira CS, Bellisi N, et al. Immunogenicity, safety and efficacy of tetravalent rhesus–human, reassortant rotavirus vaccine in Belem, Brazil. Bull World Health Organ 1996;74:491-500. 16. Rennels MB, Wasserman SS, Glass RI, Keane VA, for the US Rotavirus Vaccine Efficacy Group. Comparison of immunogenicity and efficacy of rhesus rotavirus reassortant vaccines in breastfed and nonbreastfed infants. Pediatrics 1995;96:1132-6. 17. Glass RI, Lew JF, Gangarosa RE, LeBaron CW, Ho MS. Estimates of morbidity and mortality rates for diarrheal disease in American children. J Pediatr 1991;118(suppl):S27-33. 18. Avendano P, Matson D, Long J, Whitney S, Matson CC, Pickering LK. Costs associated with office visits for diarrhea in infants and toddlers. Pediatr Infect Dis J 1993;12:897-902. 19. Matson DO, Estes MK. Impact of rotavirus infection at a large pediatric hospital. J Infect Dis 1990;162:598-604.


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Tetravalent Rotavirus Vaccine 20. Smith JC, Haddix AC, Teutsch SM, Glass RI. Cost-effectiveness analysis of a rotavirus immunization program for the United States. Pediatrics 1995;96:609-15. 21. Glass RI, Ho MS, Lew J, LeBaron CW, Ing D. Cost–benefit studies of rotavirus vaccines in the United States. In: Sack DA, Freij L, eds. Prospects for public health benefits in developing countries from new vaccines against enteric infections. Stockholm, Sweden: Swedish Agency for Research Cooperation with Developing Countries Conference Report, 1990;2:102-7. 22. Vessikari T, Ruuska T. Cost–benefit estimation of rotavirus vaccination in Finland. In: Sack DA, Freij L, eds. Prospects for public health benefits in developing countries from new vaccines against enteric infections. Stockholm, Sweden: Swedish Agency for Research Cooperation with Developing Countries Conference Report, 1990;2:108-14. 23. Griffiths RI, Anderson GF, Powe NR, Oliveras E, Herbert RJ, Grant CC, et al. Economic impact of immunization against rotavirus gastroenteritis. Arch Pediatr Adolesc Med 1995;149:407-14. 24. Tucker AW, Haddix AC, Bresee JS, Holman RC, Parashar UD, Glass RI. Cost-effectiveness analysis of a rotavirus immunization program for the United States. JAMA 1998;279:1371-6. 25. American Academy of Pediatrics. Committee on Infectious Diseases. 1998–1999. Prevention of rotavirus disease: guidelines for use of rotavirus vaccine. Pediatrics 1998;102:1483-91. 26. Intussusception among recipients of rotavirus vaccine — United States, 1998–1999. MMWR Morb Mortal Wkly Rep 1999;48:577-81.

EXTRACTO OBJETIVO: Revisar la eficacia clínica, seguridad, y aspectos farmacoeconómicos del uso de la vacuna tetravalente de rotavirus (VTR) en infantes y niños. FUENTES DE INFORMACIÓN: Se realizó una búsqueda computadorizada con MEDLINE de la literatura (1990–1998) para identificar todas las publicaciones sobre VTR incluyendo la farmacología, estudios clínicos, reacciones adversas, y farmacoeconomía en infantes y niños. Se utilizó además la bibliografía de los artículos encontrados. EXTRACCIÓN DE FUENTES DE INFORMACIÓN: Se revisaron todos los estudios aleatorios y controlados con placebo que evaluaban la eficacia clínica. También se escogieron para la revisión los estudios de farmacoeconomía que enfocaban en el impacto potencial en los costos de servicios de salud. SÍNTESIS: La gastroenteritis inducida por rotavirus es un problema significativo tanto en países desarrollados como sub-desarrollados. Varias formas de vacunas contra rotavirus se han estudiado a nivel mundial. La vacuna tetravalente (Rotashield) aparenta tener eficacia similar en países desarrollados y sub-desarrollados. Aparenta ser más

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efectiva contra las formas más severa de gastroenteritis con una tasa de eficacia de un 80%. Esta vacuna es bien tolerada y el efecto adverso más común es fiebre después de la primera dosis. Los estudios farmacoeconómicos indican que aunque la vacuna podría ser sólo moderadamente efectiva contra las gastroenteritis menos severas, con su uso universal en los Estados Unidos de América se podría ahorrar anualmente sobre un millón de dolares. CONCLUSIONES: La vacuna nueva contra rotavirus es efectiva en prevenir y reducir la incidencia de gastroenteritis inducida por rotavirus. La morbilidad, mortalidad, y costos de servicios de salud asociados a esta enfermedad podrían reducirse si esta vacuna se provee a los niños mundialmente. GISELLE C RIVERA-MIRANDA RÉSUMÉ OBJECTIF:

Réviser l’efficacité clinique, l’inocuité, et les données pharmacoéconomiques concernant l’emploi du vaccin tétravalent contre le rotavirus (RRV-TV) chez les nourrissons et les enfants. REVUE DE LITTÉRATURE: Une recherche de type MEDLINE (1990–1998) a été effectuée pour cibler les publications sur le vaccin RRV-TV au sujet de la pharmacologie, des études cliniques, des effets secondaires, et des données pharmacoéconomiques chez les nourrissons et les jeunes enfants. SÉLECTION DES ÉTUDES: Toutes les études cliniques contrôlées randomisées avec placébo ont été révisées. De plus, les études pharmacoéconomiques discutant de l’impact potentiel sur les coûts de santé ont été vérifiées. RÉSUMÉ: La gastro-entérite induite par le rotavirus est un important problème de santé autant dans les pays développés que ceux en voie de développement. Plusieurs types de vaccin contre le rotavirus ont été étudiés à travers le monde. Le vaccin tétravalent (Rotashield) semble avoir la même efficacité dans les pays développés que ceux en voie de développement. Le vaccin semble surtout être efficace contre les formes les plus sévères de gastro-entérite avec un taux d’efficacité de plus de 80%. Il est bien toléré et l’effet désirable le plus fréquent après la première dose est la fièvre. Les études pharmacoéconomiques indiquent que bien que le vaccin soit seulement modérément efficace contre les formes moins sévères de gastro-entérite, on estime que plus d’un billion de dollars pourraient être économisés annuellement aux Etats-Unis avec un usage universel. CONCLUSIONS: Le nouveau vaccin contre le rotavirus prévient et diminue l’incidence de gastro-entérite induite par le rotavirus. Advenant un usage mondial, les coûts de santé en plus de la mortalité et de la morbidité seraient réduits de façon importante.


LOUISE GAGNON

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