From Reuters Health Information
David Douglas
August 6, 2010 — Siblings and offspring of patients with vesicoureteral reflux (VUR), and infants with prenatal hydronephrosis, also have high prevalences of VUR – but it's not clear how much they'll gain from having the condition diagnosed, the American Urological Association says.
On July 21st in the Journal of Urology, the Association issued updated guidelines to help physicians decide who to screen, and when.
But due to a lack of randomized clinical trials, the Association's update panel found it difficult to make evidence-based recommendations. When necessary, the panel members based the guidelines on current practice, risk assessment, meta-analysis results and consensus.
Led by Dr. Steven J. Skoog of the Oregon Health & Sciences University in Portland, the panel issued seven "summary guidelines," with two labeled "recommendations" (the first two, below) and the others labeled "options."
•In siblings of children with VUR, a voiding cystourethrogram (VCUG) or radionuclide cystogram is recommended if ultrasound shows renal corticoid abnormalities or renal size asymmetry, or if the sibling has a history of urinary tract infections (UTI).
•VCUG is recommended for infants with high-grade hydronephrosis (Society for Fetal Urology grades 3-4), hydroureter or abnormal bladder, or UTI.
•Given the unclear benefit of finding and treating VUR, siblings of children with VUR can be observed without screening, as long as any acute UTI is promptly followed by evaluation for VUR.
•Older siblings who are toilet trained may be screened, although the value of detecting VUR is unclear.
•Siblings of children with VUR can have renal ultrasound studies to identify significant renal scarring and to focus attention on the presence and potential further risk of VUR.
•Screening offspring of patients with VUR can be considered as similar to screening of siblings.
•Children with prenatal hydronephrosis (SFU grades 1-2) can be observed without screening as long as any UTI is promptly treated, given the unproven value of identifying and treating VUR. VCUG in these patients is optional.
In developing these guidelines, the panel analyzed pooled data from 22 sibling screening studies involving more than 3200 children, as well as 43 studies of more than 6500 infants with prenatal hydronephrosis.
Overall in the meta-analysis, the prevalence of VUR was 27.4% in siblings and 35.7% in offspring. The prevalence decreased as the age of the screened cohort increased, and the annual resolution rate of 4% "can aid in assessing the need for screening based on patient age," the authors note.
Infants with prenatal hydronephrosis had a 16.2% prevalence of VUR.
Overall, the panel concludes that despite absence of clear-cut benefit, "identification of VUR may increase the awareness of parents and health providers to the potentially increased risk of pyelonephritis and renal scarring."
J Urol. 2010;184:1145-1151.
Reuters Health Information 2010. © 2010 Reuters Ltd.
Wednesday, August 11, 2010
Intranasal Medication Delivery for Children Reviewed
From Medscape Medical News
Laurie Barclay, MD
August 9, 2010 — The most frequent pediatric indications for intranasal medication delivery are pain control, anxiolysis, and seizure control, according to a review published online August 9 in Pediatrics. Other potential indications for intranasal medication delivery not reviewed in this article include the treatment of epistaxis, pretreatment before nasogastric tube insertion, and administration of naloxone for reversal of narcotic overdose.
"Intranasal delivery offers unique advantages that may allow more efficient use of resources, more rapid patient care, and higher patient and provider satisfaction," write Timothy R. Wolfe, MD, from University of Utah School of Medicine in Salt Lake City, and Darren A. Braude, MD, from the University of New Mexico School of Medicine in Albuquerque. "The highly vascularized nasal mucosa and the olfactory tissue in direct contact with the central nervous system allow nasally administered drugs to be rapidly transported into the bloodstream and brain, with onsets of action approaching that of intravenous therapy. First-pass drug metabolism via the liver is also avoided, resulting in high bioavailability of many medications."
Except for orally and intranasally administered medications, most formulations require a needle injection, which may be painful, anxiety-provoking, and time-consuming for staff, who must be trained in proper injection technique and who are exposed to the risks for needle stick injury. In comparison, intranasal delivery of medication is relatively painless, inexpensive, and easy to administer with minimal training.
Specific uses of intranasally delivered medications include the following:
•For pain control, fentanyl 1.5 to 2.0 μg/kg. This may be titrated every 15 minutes as needed. Patients should be monitored for respiratory depression. It may be appropriate to administer oral medications concurrently so that they take effect as the intranasal fentanyl effect wears off.
•For anxiolysis, midazolam 0.4 to 0.5 mg/kg. The concentrated form (5 mg/mL) should be used, because other concentrations may be ineffective when administered intranasally. The patient and family should be advised that a burning sensation may last for 30 seconds.
•For seizures, midazolam 0.2 mg/kg. As for anxiolysis, the concentrated form (5 mg/mL) should be used for intranasal delivery.
Intranasal opiates may be especially useful for minor fractures, large abrasions, burns, wound-dressing changes, extremity fractures, and other acutely painful conditions in children. For treatment of acute pain, intranasal opiates have been shown to be as effective as intravenous morphine and faster than intramuscular morphine.
Procedures in which light procedural sedation and anxiolysis may be achieved with intranasal medications include laceration repair, magnetic resonance imaging and computed tomography scans, burn-dressing changes, dental extractions, endoscopies, and central venous port access. Although intranasal midazolam is the most commonly studied drug in these settings, other options may include intranasal fentanyl, ketamine, sufentanil, dexmedetomidine, and combinations of these drugs.
Intranasal midazolam is effective for prolonged seizures because it easily and rapidly crosses the nasal mucosa and the blood-brain barrier, with similar efficacy to intravenous diazepam but faster onset because of the lack of need to start an intravenous line. Intranasal midazolam and lorazepam are also safe for treating seizures outside of the hospital setting, and intranasal midazolam may be a useful option for treating status epilepticus when intravenous access is not immediately available.
Specific considerations for administering intranasally delivered medications include the following:
•Deliver immediately to allow absorption while the airway is being supported.
•The nostril should be inspected for significant amounts of blood or mucous discharge that could limit absorption of a nasal medication. When these are present, alternative delivery options should be considered, or it may be appropriate to suction the nasal passage before medication delivery.
•Deliver half of the medication dose up each nostril, which doubles the available mucosal surface area (vs a single nostril) for drug absorption and increases the rate and amount of absorption.
•The most concentrated form available of the medication should be used, because dilute forms are less effective for intranasal delivery.
•The ideal volume for intranasal medication delivery is 0.2 to 0.3 mL of medication per nostril, and volume per nostril should not exceed 0.5 to 1.0 mL. Two separate doses may be used when a higher volume is needed, with a few minutes between doses to allow the first dose to absorb.
Adverse effects of nasal medications seldom occur. The most common adverse effect is transient nasal burning and irritation with midazolam. Except with high doses of intranasal sufentanil for induction during surgery, oversedation has not been reported for intranasal medications, including fentanyl or midazolam.
"Intranasal medication delivery is an effective method of delivering analgesia, anxiolysis, and anticonvulsants to pediatric patients," the review authors conclude. "In the properly selected patient, nasal administration can reduce time to medication delivery and onset, reduce medical staff resource use, eliminate needle-stick exposure risk, and eliminate pain from the injection, thereby leading to improved patient and parent satisfaction. Pediatricians, pediatric emergency physicians, and emergency medical services medical directors should consider adopting this delivery method for medications and indications that are appropriate to their practice setting."
Dr. Wolfe is affiliated with Wolfe Tory Medical, Inc, the maker of the MAD nasal drug delivery device. Dr. Braude has disclosed no relevant financial relationships.
Pediatrics. Published online August 9, 2010.
Laurie Barclay, MD
August 9, 2010 — The most frequent pediatric indications for intranasal medication delivery are pain control, anxiolysis, and seizure control, according to a review published online August 9 in Pediatrics. Other potential indications for intranasal medication delivery not reviewed in this article include the treatment of epistaxis, pretreatment before nasogastric tube insertion, and administration of naloxone for reversal of narcotic overdose.
"Intranasal delivery offers unique advantages that may allow more efficient use of resources, more rapid patient care, and higher patient and provider satisfaction," write Timothy R. Wolfe, MD, from University of Utah School of Medicine in Salt Lake City, and Darren A. Braude, MD, from the University of New Mexico School of Medicine in Albuquerque. "The highly vascularized nasal mucosa and the olfactory tissue in direct contact with the central nervous system allow nasally administered drugs to be rapidly transported into the bloodstream and brain, with onsets of action approaching that of intravenous therapy. First-pass drug metabolism via the liver is also avoided, resulting in high bioavailability of many medications."
Except for orally and intranasally administered medications, most formulations require a needle injection, which may be painful, anxiety-provoking, and time-consuming for staff, who must be trained in proper injection technique and who are exposed to the risks for needle stick injury. In comparison, intranasal delivery of medication is relatively painless, inexpensive, and easy to administer with minimal training.
Specific uses of intranasally delivered medications include the following:
•For pain control, fentanyl 1.5 to 2.0 μg/kg. This may be titrated every 15 minutes as needed. Patients should be monitored for respiratory depression. It may be appropriate to administer oral medications concurrently so that they take effect as the intranasal fentanyl effect wears off.
•For anxiolysis, midazolam 0.4 to 0.5 mg/kg. The concentrated form (5 mg/mL) should be used, because other concentrations may be ineffective when administered intranasally. The patient and family should be advised that a burning sensation may last for 30 seconds.
•For seizures, midazolam 0.2 mg/kg. As for anxiolysis, the concentrated form (5 mg/mL) should be used for intranasal delivery.
Intranasal opiates may be especially useful for minor fractures, large abrasions, burns, wound-dressing changes, extremity fractures, and other acutely painful conditions in children. For treatment of acute pain, intranasal opiates have been shown to be as effective as intravenous morphine and faster than intramuscular morphine.
Procedures in which light procedural sedation and anxiolysis may be achieved with intranasal medications include laceration repair, magnetic resonance imaging and computed tomography scans, burn-dressing changes, dental extractions, endoscopies, and central venous port access. Although intranasal midazolam is the most commonly studied drug in these settings, other options may include intranasal fentanyl, ketamine, sufentanil, dexmedetomidine, and combinations of these drugs.
Intranasal midazolam is effective for prolonged seizures because it easily and rapidly crosses the nasal mucosa and the blood-brain barrier, with similar efficacy to intravenous diazepam but faster onset because of the lack of need to start an intravenous line. Intranasal midazolam and lorazepam are also safe for treating seizures outside of the hospital setting, and intranasal midazolam may be a useful option for treating status epilepticus when intravenous access is not immediately available.
Specific considerations for administering intranasally delivered medications include the following:
•Deliver immediately to allow absorption while the airway is being supported.
•The nostril should be inspected for significant amounts of blood or mucous discharge that could limit absorption of a nasal medication. When these are present, alternative delivery options should be considered, or it may be appropriate to suction the nasal passage before medication delivery.
•Deliver half of the medication dose up each nostril, which doubles the available mucosal surface area (vs a single nostril) for drug absorption and increases the rate and amount of absorption.
•The most concentrated form available of the medication should be used, because dilute forms are less effective for intranasal delivery.
•The ideal volume for intranasal medication delivery is 0.2 to 0.3 mL of medication per nostril, and volume per nostril should not exceed 0.5 to 1.0 mL. Two separate doses may be used when a higher volume is needed, with a few minutes between doses to allow the first dose to absorb.
Adverse effects of nasal medications seldom occur. The most common adverse effect is transient nasal burning and irritation with midazolam. Except with high doses of intranasal sufentanil for induction during surgery, oversedation has not been reported for intranasal medications, including fentanyl or midazolam.
"Intranasal medication delivery is an effective method of delivering analgesia, anxiolysis, and anticonvulsants to pediatric patients," the review authors conclude. "In the properly selected patient, nasal administration can reduce time to medication delivery and onset, reduce medical staff resource use, eliminate needle-stick exposure risk, and eliminate pain from the injection, thereby leading to improved patient and parent satisfaction. Pediatricians, pediatric emergency physicians, and emergency medical services medical directors should consider adopting this delivery method for medications and indications that are appropriate to their practice setting."
Dr. Wolfe is affiliated with Wolfe Tory Medical, Inc, the maker of the MAD nasal drug delivery device. Dr. Braude has disclosed no relevant financial relationships.
Pediatrics. Published online August 9, 2010.
Iron-Deficiency Anemia Linked to Memory Deficits in Children
From Medscape Medical News
Laurie Barclay, MD
August 6, 2010 — Iron-deficiency anemia (IDA) is linked to memory deficits in children, according to the results of a study reported online July 26 in Pediatrics.
"IDA in infancy is associated with cognitive deficits, which may persist later in life," write R. Colin Carter, MD, from Children's Hospital Boston and Harvard Medical School in Boston, Massachusetts, and colleagues. "Socioemotional deficits are also consistently observed in infants with IDA, but it is not known whether these deficits affect cognitive function."
The goal of the study was to determine effects of IDA on specific functions involved in infant cognition, as well as the effect of socioemotional deficits related to IDA in modulating these effects. During routine 9-month visits to an inner-city clinic, infants were recruited into the study. Criteria for IDA were hemoglobin levels of less than 110 g/L with abnormal values for at least 2 of the following iron deficiency indicators: mean corpuscular volume, red cell distribution width, zinc protoporphyrin-heme ratio, transferrin saturation, and ferritin.
Cognitive testing at 9 and 12 months included the Fagan Test of Infant Intelligence; A-not-B task; Emotionality, Activity, and Sociability Temperament Survey; and Behavior Rating Scale. The investigators adjusted the analyses for age, sociodemographic variables, and other potential confounders.
Study participants were 28 infants with IDA, 28 with nonanemic iron deficiency, and 21 with iron sufficiency. At 9 months, infants with IDA were least likely to demonstrate object permanence, iron sufficiency most likely, and nonanemic iron deficiency intermediate, suggesting a linear effect.
Compared with infants without IDA, those with IDA and those with hemoglobin level of 105 g/L or less had worse recognition memory on the Fagan Test of Infant Intelligence, but these effects were partially mediated by the Behavior Rating Scale orientation/engagement measure. Infants with poorer scores on the socioemotional measures had stronger effects of IDA on these outcomes.
"These data indicate poorer object permanence and short-term memory encoding and/or retrieval in infants with IDA at 9 months," the study authors write. "These cognitive effects were attributable, in part, to IDA-related deficits in socioemotional function. Children with poor socioemotional performance seem to be more vulnerable to the effects of IDA on cognitive function."
Limitations of this study include small sample size, inability to supervise iron administration, and inability to determine response to iron for infants who did not come for a subsequent blood test. In addition, the degree of IDA in this sample was relatively mild and duration probably quite short, limiting generalizability to more severe cases.
"Our findings provide evidence of specific deficits in cognitive processing (attention and memory) with IDA during an important period of infant development before the usual age for IDA screening in the primary care setting," the study authors conclude. "Deficits in these processes, which have demonstrated predictive validity for later cognitive function, have implications for intellectual function in childhood. Furthermore, these early cognitive deficits seem to be mediated, in part, by the effects of IDA on the infant's ability to engage affectively with the environment, and socioemotional deficits seem to increase the infant's vulnerability to the cognitive effects of early IDA."
Pediatrics. Published online July 26, 2010.
Laurie Barclay, MD
August 6, 2010 — Iron-deficiency anemia (IDA) is linked to memory deficits in children, according to the results of a study reported online July 26 in Pediatrics.
"IDA in infancy is associated with cognitive deficits, which may persist later in life," write R. Colin Carter, MD, from Children's Hospital Boston and Harvard Medical School in Boston, Massachusetts, and colleagues. "Socioemotional deficits are also consistently observed in infants with IDA, but it is not known whether these deficits affect cognitive function."
The goal of the study was to determine effects of IDA on specific functions involved in infant cognition, as well as the effect of socioemotional deficits related to IDA in modulating these effects. During routine 9-month visits to an inner-city clinic, infants were recruited into the study. Criteria for IDA were hemoglobin levels of less than 110 g/L with abnormal values for at least 2 of the following iron deficiency indicators: mean corpuscular volume, red cell distribution width, zinc protoporphyrin-heme ratio, transferrin saturation, and ferritin.
Cognitive testing at 9 and 12 months included the Fagan Test of Infant Intelligence; A-not-B task; Emotionality, Activity, and Sociability Temperament Survey; and Behavior Rating Scale. The investigators adjusted the analyses for age, sociodemographic variables, and other potential confounders.
Study participants were 28 infants with IDA, 28 with nonanemic iron deficiency, and 21 with iron sufficiency. At 9 months, infants with IDA were least likely to demonstrate object permanence, iron sufficiency most likely, and nonanemic iron deficiency intermediate, suggesting a linear effect.
Compared with infants without IDA, those with IDA and those with hemoglobin level of 105 g/L or less had worse recognition memory on the Fagan Test of Infant Intelligence, but these effects were partially mediated by the Behavior Rating Scale orientation/engagement measure. Infants with poorer scores on the socioemotional measures had stronger effects of IDA on these outcomes.
"These data indicate poorer object permanence and short-term memory encoding and/or retrieval in infants with IDA at 9 months," the study authors write. "These cognitive effects were attributable, in part, to IDA-related deficits in socioemotional function. Children with poor socioemotional performance seem to be more vulnerable to the effects of IDA on cognitive function."
Limitations of this study include small sample size, inability to supervise iron administration, and inability to determine response to iron for infants who did not come for a subsequent blood test. In addition, the degree of IDA in this sample was relatively mild and duration probably quite short, limiting generalizability to more severe cases.
"Our findings provide evidence of specific deficits in cognitive processing (attention and memory) with IDA during an important period of infant development before the usual age for IDA screening in the primary care setting," the study authors conclude. "Deficits in these processes, which have demonstrated predictive validity for later cognitive function, have implications for intellectual function in childhood. Furthermore, these early cognitive deficits seem to be mediated, in part, by the effects of IDA on the infant's ability to engage affectively with the environment, and socioemotional deficits seem to increase the infant's vulnerability to the cognitive effects of early IDA."
Pediatrics. Published online July 26, 2010.
Early Cholesterol Predicts Later Coronary Calcium
From Heartwire
Reed Miller
August 3, 2010 (San Francisco, California) — A new prospective cohort study suggests younger people will pay for high cholesterol in the present with coronary calcium in the future, according to results of a study published in the August 3, 2010 issue of the Annals of Internal Medicine [1].
In the latest study from the ongoing Coronary Artery Risk Development in Young Adults (CARDIA) trial, Dr Mark Pletcher (University of California, San Francisco) and colleagues measured low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and coronary calcium in 3258 subjects age 18 to 20 in 1985 and 1986. They estimated time-averaged cumulative exposures to lipids between age 20 and 35 with repeated serum lipid measurements over 20 years and then related these data to coronary calcium scores acquired with computed tomography at years 15 and 20.
Nonoptimal levels of LDL cholesterol (>100 mg/dL), HDL cholesterol (<60 mg/dL), or triglycerides >150 mg/dL were found in 87% of young adults in the study. Coronary calcium prevalence 20 years later was 8% in participants who maintained optimal LDL levels <70 mg/dL and 44% in participants with LDL-cholesterol levels of >160 mg/dL (p<0.001). The same association was found in all races and genders.
The odds of finding coronary calcium increased as LDL increased. For example, compared with people with LDL levels less than 70 mg/dL, the odds ratio for coronary calcium later in life for patients with 70 to 99 mg/dL in their early adulthood was 1.5. For people with LDL of 100 to 129 mg/dL, the odds ratio was 2.4, and for people with LDL of 160 mg/dL or greater, the odds ratio was 5.6.
The results show that nonoptimal LDL-cholesterol levels during young adulthood are linked to coronary calcification down the road and that accounting for later-life lipid exposure does not explain the association of young adult LDL-cholesterol levels with later calcification. After the authors adjusted their analysis for "the potentially obscuring influences" of subjects' medication and clinically abnormal levels of other lipids, they observed an inverse association with HDL-cholesterol levels but no association with triglyceride levels.
Pletcher et al acknowledge that coronary calcium is a "subclinical end point," because the cohort is still too young to have enough MIs or deaths to study the connection between early lipid levels and those clinical outcomes. However, they point out that coronary calcium has been shown to be a strong independent predictor of coronary heart disease events and that the absence of coronary calcium is a strongly protective factor.
The authors recall previous studies that have found associations between lipid levels and atherosclerosis in children and young adults, demonstrated by autopsy, carotid intima–media thickness, and coronary calcium. But this CARDIA analysis is the first with adequate sample size, repeated measurements of the three major lipids, and sufficient follow-up to isolate the link between lipid levels during young adulthood with atherosclerosis during middle age while controlling for confounders, they claim.
"Our results suggest that atherosclerotic changes begin during young adulthood as a result of commonly observed nonoptimal lipid levels, that these changes persist into middle age, and that maintaining optimal levels of lipids--particularly LDL cholesterol--throughout young adulthood could provide substantial benefits in terms of lifetime coronary heart disease prevention," Pletcher et al conclude. "These findings reinforce the importance of a heart-healthy diet, exercise, and maintenance of normal weight beginning in young adulthood."
"What we show here is that it matters what your cholesterol level is during young adulthood, and you should be thinking about it and trying to optimize it during young adulthood so that you have less built-up atherosclerosis later in life, and that will stand you in good stead for reducing your heart-attack risk later in life," Pletcher told heartwire. "We're not directly testing the hypothesis that modifying cholesterol with diet and exercise during young adulthood makes a difference later in life. But there's so much evidence that cholesterol really is a cause of heart disease that we think that it's reasonable that the same thing is going on here--that it's a treatable cause of disease that can be avoided."
He cautioned that the study does not address whether medication to lower cholesterol early in life will be beneficial, but Pletcher says these data support the AHA recommendation to begin cholesterol tests as early as 20. "I'm a general believer in the tenet that if you want to have an effect on some parameter, you have to measure it and watch it. It provides motivation."
References
Reed Miller
August 3, 2010 (San Francisco, California) — A new prospective cohort study suggests younger people will pay for high cholesterol in the present with coronary calcium in the future, according to results of a study published in the August 3, 2010 issue of the Annals of Internal Medicine [1].
In the latest study from the ongoing Coronary Artery Risk Development in Young Adults (CARDIA) trial, Dr Mark Pletcher (University of California, San Francisco) and colleagues measured low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and coronary calcium in 3258 subjects age 18 to 20 in 1985 and 1986. They estimated time-averaged cumulative exposures to lipids between age 20 and 35 with repeated serum lipid measurements over 20 years and then related these data to coronary calcium scores acquired with computed tomography at years 15 and 20.
Nonoptimal levels of LDL cholesterol (>100 mg/dL), HDL cholesterol (<60 mg/dL), or triglycerides >150 mg/dL were found in 87% of young adults in the study. Coronary calcium prevalence 20 years later was 8% in participants who maintained optimal LDL levels <70 mg/dL and 44% in participants with LDL-cholesterol levels of >160 mg/dL (p<0.001). The same association was found in all races and genders.
The odds of finding coronary calcium increased as LDL increased. For example, compared with people with LDL levels less than 70 mg/dL, the odds ratio for coronary calcium later in life for patients with 70 to 99 mg/dL in their early adulthood was 1.5. For people with LDL of 100 to 129 mg/dL, the odds ratio was 2.4, and for people with LDL of 160 mg/dL or greater, the odds ratio was 5.6.
The results show that nonoptimal LDL-cholesterol levels during young adulthood are linked to coronary calcification down the road and that accounting for later-life lipid exposure does not explain the association of young adult LDL-cholesterol levels with later calcification. After the authors adjusted their analysis for "the potentially obscuring influences" of subjects' medication and clinically abnormal levels of other lipids, they observed an inverse association with HDL-cholesterol levels but no association with triglyceride levels.
Pletcher et al acknowledge that coronary calcium is a "subclinical end point," because the cohort is still too young to have enough MIs or deaths to study the connection between early lipid levels and those clinical outcomes. However, they point out that coronary calcium has been shown to be a strong independent predictor of coronary heart disease events and that the absence of coronary calcium is a strongly protective factor.
The authors recall previous studies that have found associations between lipid levels and atherosclerosis in children and young adults, demonstrated by autopsy, carotid intima–media thickness, and coronary calcium. But this CARDIA analysis is the first with adequate sample size, repeated measurements of the three major lipids, and sufficient follow-up to isolate the link between lipid levels during young adulthood with atherosclerosis during middle age while controlling for confounders, they claim.
"Our results suggest that atherosclerotic changes begin during young adulthood as a result of commonly observed nonoptimal lipid levels, that these changes persist into middle age, and that maintaining optimal levels of lipids--particularly LDL cholesterol--throughout young adulthood could provide substantial benefits in terms of lifetime coronary heart disease prevention," Pletcher et al conclude. "These findings reinforce the importance of a heart-healthy diet, exercise, and maintenance of normal weight beginning in young adulthood."
"What we show here is that it matters what your cholesterol level is during young adulthood, and you should be thinking about it and trying to optimize it during young adulthood so that you have less built-up atherosclerosis later in life, and that will stand you in good stead for reducing your heart-attack risk later in life," Pletcher told heartwire. "We're not directly testing the hypothesis that modifying cholesterol with diet and exercise during young adulthood makes a difference later in life. But there's so much evidence that cholesterol really is a cause of heart disease that we think that it's reasonable that the same thing is going on here--that it's a treatable cause of disease that can be avoided."
He cautioned that the study does not address whether medication to lower cholesterol early in life will be beneficial, but Pletcher says these data support the AHA recommendation to begin cholesterol tests as early as 20. "I'm a general believer in the tenet that if you want to have an effect on some parameter, you have to measure it and watch it. It provides motivation."
References
Physicians Avoid Recommending HPV Vaccine in Girls Aged 11 to 12 Years
From Medscape Medical News
Fran Lowry
August 4, 2010 — The majority of pediatricians and family physicians in the United States are offering the human papillomavirus (HPV) vaccine to their older adolescent patients, but fewer are recommending the vaccine to their younger patients (those aged 11 to 12 years) — the age group that is particularly targeted for vaccination by national guidelines — according to a survey reported online August 2 and in the September print issue of Pediatrics.
"A HPV vaccine was licensed in 2006," write Matthew F. Daley, MD, from the University of Colorado School of Medicine and the Kaiser Permanente Institute for Health Research, Denver, and colleagues. "In surveys before vaccine licensure, physicians generally viewed HPV vaccines positively, but some expressed reservations about vaccinating young adolescents. Little is known about current HPV vaccination practices of US physicians."
The aims of this study were to assess HPV-related attitudes and vaccination practices, perceived barriers to vaccination, and factors associated with whether physicians strongly recommended HPV vaccine to 11- to 12-year-old female patients in a sample of US pediatricians and family physicians.
From January to March 2008, the researchers administered a survey through the Internet or by mail to a national network of 429 pediatricians and 419 family physicians recruited from the American Academy of Pediatrics and the American Academy of Family Physicians. Eighty-one percent of pediatricians and 79% of family physicians responded to the survey.
Virtually all pediatricians (98%) and 88% of family physicians reported administering HPV vaccine to female patients in their offices (P < .001). Female family physicians were more likely to give the vaccine than male family physicians (95% vs 83%; P = .001).
The survey also showed regional variation in vaccine administration among family physicians. In the South, 79% reported administering HPV vaccine in their offices, compared with 89% in the Northeast, 95% in the Midwest, and 92% in the West (P = .005). Comparisons of HPV vaccine administration rates by sex and region were not done for pediatricians because only 6 pediatricians reported they did not offer the vaccine.
Fewer respondents strongly recommended HPV vaccination for 11-to 12-year old girls than for older female patients. Among pediatricians, 57% said they recommended the vaccine for that age group, but 90% recommended the vaccine for their 13- to 15-year old patients (P < .001).
Among family physicians, 50% said they recommended the vaccine for 11- to 12-year-old girls, and 86% recommended the vaccine for their 13- 15-year-old patients (P < .001).
The survey also found that vaccine costs and insurance coverage were the main financial barriers to strongly recommending HPV vaccination. Another barrier was reluctance to discuss sexuality with 11- to 12-year-olds (risk ratio [RR], 1.27; 95% confidence interval, 1.07 - 1.51).
Parental concern about HPV vaccination was also a barrier, with 39% of pediatricians and 43% of family physicians reporting that parents of their adolescent patients worried that vaccination against a sexually transmitted infection may encourage earlier or riskier sexual behavior. The survey also found that 22% of pediatricians and 23% of family physicians reported that parents of their 11- to 12-year-old patients were upset that they were offering the vaccine to that age group. Eighteen percent of pediatricians and 29% of family physicians reported that at least one fourth of parents of 11- to 12-year-old patients refused HPV vaccine (P < .01). Common reasons for parent refusals were that the vaccine was too new, the child was too young, and lack of health insurance for HPV vaccination.
"These survey data indicate that there may be substantial challenges to timely initiation and completion of the 3-dose HPV vaccine series," the study authors write.
The possibility that attitudes of network physicians in the survey might differ from those of physicians outside of the network is one limitation of the study. Another is that only family physicians and pediatricians were surveyed. Finally, the study assessed physician-reported behavior but did not observe actual vaccination practices. "It is not known how physicians convey a 'strong vaccination recommendation' to patients and parents, and this may differ among physicians and between pediatricians and family physicians," the authors note.
Because physicians are more likely to recommend the HPV vaccine strongly at older ages, and because parents are more likely to refuse or defer vaccination at younger ages, vaccination may not occur at the age recommended by national guidelines. "It is also likely that proactive, innovative strategies will be needed to achieve high levels of 3-dose HPV vaccination coverage in the United States," the authors write in their conclusion.
"HPV vaccination is our best chance at preventing cervical cancer, so it's reassuring [that] doctors are using it. However, vaccination should ideally begin at 11 years of age, so that young women complete the 3-dose series and are protected," Dr. Daley added in a statement.
Pediatrics. Published online August 2, 2010.
Fran Lowry
August 4, 2010 — The majority of pediatricians and family physicians in the United States are offering the human papillomavirus (HPV) vaccine to their older adolescent patients, but fewer are recommending the vaccine to their younger patients (those aged 11 to 12 years) — the age group that is particularly targeted for vaccination by national guidelines — according to a survey reported online August 2 and in the September print issue of Pediatrics.
"A HPV vaccine was licensed in 2006," write Matthew F. Daley, MD, from the University of Colorado School of Medicine and the Kaiser Permanente Institute for Health Research, Denver, and colleagues. "In surveys before vaccine licensure, physicians generally viewed HPV vaccines positively, but some expressed reservations about vaccinating young adolescents. Little is known about current HPV vaccination practices of US physicians."
The aims of this study were to assess HPV-related attitudes and vaccination practices, perceived barriers to vaccination, and factors associated with whether physicians strongly recommended HPV vaccine to 11- to 12-year-old female patients in a sample of US pediatricians and family physicians.
From January to March 2008, the researchers administered a survey through the Internet or by mail to a national network of 429 pediatricians and 419 family physicians recruited from the American Academy of Pediatrics and the American Academy of Family Physicians. Eighty-one percent of pediatricians and 79% of family physicians responded to the survey.
Virtually all pediatricians (98%) and 88% of family physicians reported administering HPV vaccine to female patients in their offices (P < .001). Female family physicians were more likely to give the vaccine than male family physicians (95% vs 83%; P = .001).
The survey also showed regional variation in vaccine administration among family physicians. In the South, 79% reported administering HPV vaccine in their offices, compared with 89% in the Northeast, 95% in the Midwest, and 92% in the West (P = .005). Comparisons of HPV vaccine administration rates by sex and region were not done for pediatricians because only 6 pediatricians reported they did not offer the vaccine.
Fewer respondents strongly recommended HPV vaccination for 11-to 12-year old girls than for older female patients. Among pediatricians, 57% said they recommended the vaccine for that age group, but 90% recommended the vaccine for their 13- to 15-year old patients (P < .001).
Among family physicians, 50% said they recommended the vaccine for 11- to 12-year-old girls, and 86% recommended the vaccine for their 13- 15-year-old patients (P < .001).
The survey also found that vaccine costs and insurance coverage were the main financial barriers to strongly recommending HPV vaccination. Another barrier was reluctance to discuss sexuality with 11- to 12-year-olds (risk ratio [RR], 1.27; 95% confidence interval, 1.07 - 1.51).
Parental concern about HPV vaccination was also a barrier, with 39% of pediatricians and 43% of family physicians reporting that parents of their adolescent patients worried that vaccination against a sexually transmitted infection may encourage earlier or riskier sexual behavior. The survey also found that 22% of pediatricians and 23% of family physicians reported that parents of their 11- to 12-year-old patients were upset that they were offering the vaccine to that age group. Eighteen percent of pediatricians and 29% of family physicians reported that at least one fourth of parents of 11- to 12-year-old patients refused HPV vaccine (P < .01). Common reasons for parent refusals were that the vaccine was too new, the child was too young, and lack of health insurance for HPV vaccination.
"These survey data indicate that there may be substantial challenges to timely initiation and completion of the 3-dose HPV vaccine series," the study authors write.
The possibility that attitudes of network physicians in the survey might differ from those of physicians outside of the network is one limitation of the study. Another is that only family physicians and pediatricians were surveyed. Finally, the study assessed physician-reported behavior but did not observe actual vaccination practices. "It is not known how physicians convey a 'strong vaccination recommendation' to patients and parents, and this may differ among physicians and between pediatricians and family physicians," the authors note.
Because physicians are more likely to recommend the HPV vaccine strongly at older ages, and because parents are more likely to refuse or defer vaccination at younger ages, vaccination may not occur at the age recommended by national guidelines. "It is also likely that proactive, innovative strategies will be needed to achieve high levels of 3-dose HPV vaccination coverage in the United States," the authors write in their conclusion.
"HPV vaccination is our best chance at preventing cervical cancer, so it's reassuring [that] doctors are using it. However, vaccination should ideally begin at 11 years of age, so that young women complete the 3-dose series and are protected," Dr. Daley added in a statement.
Pediatrics. Published online August 2, 2010.
Tuesday, August 10, 2010
Sucralose-Sweetened vs Rice-Based Oral Rehydration Solutions May Be More Palatable
From Medscape Medical News
Laurie Barclay, MD
August 6, 2010 — Sucralose-sweetened oral rehydration solutions may be more palatable than rice-based solutions, according to the results of a prospective, blinded, randomized 3-period, 3-treatment crossover trial reported in the August issue of the Archives of Pediatrics & Adolescent Medicine.
"Acute gastroenteritis accounted for more than 20 million episodes of diarrhea and 1.5 million outpatient visits annually in the United States by children younger than 5 years," write Stephen B. Freedman, MDCM, MSc, FRCPC, from The Hospital for Sick Children, University of Toronto in Ontario, Canada, and colleagues. "Therapy with oral rehydration solutions (ORSs) has reduced the mortality rates in underdeveloped countries, but its effect has been less dramatic in developed regions. Although this may be due to misperceptions regarding the need for extra time and effort to perform oral rehydration therapy, one possible explanation is that ORSs may not be appealing to children owing to their poor palatability."
The goal of this study was to compare the palatability of 3 oral rehydration solutions. The 2 solutions were sucralose sweetened (Pedialyte; Abbott Laboratories, Abbott Park, Illinois; and Pediatric Electrolyte; PendoPharm, Mont-Royal, Quebec, Canada), and 1 solution was rice based (Enfalyte; Mead Johnson Nutritionals, Evansville, Indiana).
At the emergency department of a tertiary care pediatric hospital, the investigators evaluated 66 children aged 5 to 10 years who presented with problems other than in the gastrointestinal tract. During a 15-minute period, the children were permitted to consume as much of each solution as they desired. Each child's taste rating on a 100-mm visual analog scale, where 0 mm was the worst taste and 100 mm was the best taste, was the main study endpoint. Volume consumed, willingness to drink each liquid again, and the most preferred liquid were secondary endpoints.
All participants completed all 3 study periods, with a carryover effect observed for taste scores (P = .03). These scores were significantly different with and without adjustment for the carryover effect (P < .001). Unadjusted taste scores were 65 mm for Pedialyte, 58 mm for Pediatric Electrolyte, and 23 mm for Enfalyte. Although differences in mean volume consumed were not significant (P = .44), the percentage of participants who said they would drink each beverage in the future was significantly different for Enfalyte vs Pediatric Electrolyte (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.11 - 0.46) and for Enfalyte vs Pedialyte (OR, 0.38; 95% CI, 0.25 - 0.57).
The best-tasting solution was identified as Pedialyte by 35 (53%) of 66 children, Pediatric Electrolyte by 26 (39%) of 66 children, and Enfalyte by 5 (8%) of 66 children (P < .001).
The OR of choosing Pedialyte vs Enfalyte was 12.3 (95% CI, 4.9 - 31.0) and vs Pediatric Electrolyte, 0.78 (95% CI, 0.44 - 1.4). Pediatric Electrolyte was preferred to Enfalyte (OR, 15.9; 95% CI, 6.0 - 41.7). No adverse effects were reported.
"Sucralose-sweetened oral rehydration solutions (Pedialyte and Pediatric Electrolyte) were significantly more palatable than was a comparable rice-based solution (Enfalyte)," the study authors write. "...Whether taste has a role in improving clinical outcomes remains unknown. Given the similar content of the solutions evaluated and that the sucralose solutions are less expensive, perhaps they should be recommended as initial therapy."
Limitations of this study include evaluation only of school-aged children without gastrointestinal tract complaints.
In an accompanying commentary, Peter Cummings, MD, MPH, from the University of Washington in Seattle, discusses the role of carryover bias as it affects this study.
"Despite the evidence of carryover bias reported by Freedman et al, their data still support their main findings," Dr. Cummings writes. "I doubt that carryover bias alone can explain the large taste score differences in their study; 2 sucralose solutions had tolerable flavor, while a rice-based solution tasted like dirt. But carryover bias could make it hard to interpret smaller taste score differences. Future studies of taste, and possibly other subjective outcomes, might be better conducted as parallel-group randomized studies."
The Paediatric Consultants Partnership's Grant for Creative Professional Activity supported this study. PendoPharm, a division of Pharmascience Inc, provided the Pediatric Electrolyte used in this study. The Hospital for Sick Children's Division of Nutrition Services provided the Enfalyte used in this study. The study authors and Dr. Cummings have disclosed no relevant financial relationships.
Arch Pediatr Adolesc Med. 2010;164:696-702, 703-705. Abstract
Laurie Barclay, MD
August 6, 2010 — Sucralose-sweetened oral rehydration solutions may be more palatable than rice-based solutions, according to the results of a prospective, blinded, randomized 3-period, 3-treatment crossover trial reported in the August issue of the Archives of Pediatrics & Adolescent Medicine.
"Acute gastroenteritis accounted for more than 20 million episodes of diarrhea and 1.5 million outpatient visits annually in the United States by children younger than 5 years," write Stephen B. Freedman, MDCM, MSc, FRCPC, from The Hospital for Sick Children, University of Toronto in Ontario, Canada, and colleagues. "Therapy with oral rehydration solutions (ORSs) has reduced the mortality rates in underdeveloped countries, but its effect has been less dramatic in developed regions. Although this may be due to misperceptions regarding the need for extra time and effort to perform oral rehydration therapy, one possible explanation is that ORSs may not be appealing to children owing to their poor palatability."
The goal of this study was to compare the palatability of 3 oral rehydration solutions. The 2 solutions were sucralose sweetened (Pedialyte; Abbott Laboratories, Abbott Park, Illinois; and Pediatric Electrolyte; PendoPharm, Mont-Royal, Quebec, Canada), and 1 solution was rice based (Enfalyte; Mead Johnson Nutritionals, Evansville, Indiana).
At the emergency department of a tertiary care pediatric hospital, the investigators evaluated 66 children aged 5 to 10 years who presented with problems other than in the gastrointestinal tract. During a 15-minute period, the children were permitted to consume as much of each solution as they desired. Each child's taste rating on a 100-mm visual analog scale, where 0 mm was the worst taste and 100 mm was the best taste, was the main study endpoint. Volume consumed, willingness to drink each liquid again, and the most preferred liquid were secondary endpoints.
All participants completed all 3 study periods, with a carryover effect observed for taste scores (P = .03). These scores were significantly different with and without adjustment for the carryover effect (P < .001). Unadjusted taste scores were 65 mm for Pedialyte, 58 mm for Pediatric Electrolyte, and 23 mm for Enfalyte. Although differences in mean volume consumed were not significant (P = .44), the percentage of participants who said they would drink each beverage in the future was significantly different for Enfalyte vs Pediatric Electrolyte (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.11 - 0.46) and for Enfalyte vs Pedialyte (OR, 0.38; 95% CI, 0.25 - 0.57).
The best-tasting solution was identified as Pedialyte by 35 (53%) of 66 children, Pediatric Electrolyte by 26 (39%) of 66 children, and Enfalyte by 5 (8%) of 66 children (P < .001).
The OR of choosing Pedialyte vs Enfalyte was 12.3 (95% CI, 4.9 - 31.0) and vs Pediatric Electrolyte, 0.78 (95% CI, 0.44 - 1.4). Pediatric Electrolyte was preferred to Enfalyte (OR, 15.9; 95% CI, 6.0 - 41.7). No adverse effects were reported.
"Sucralose-sweetened oral rehydration solutions (Pedialyte and Pediatric Electrolyte) were significantly more palatable than was a comparable rice-based solution (Enfalyte)," the study authors write. "...Whether taste has a role in improving clinical outcomes remains unknown. Given the similar content of the solutions evaluated and that the sucralose solutions are less expensive, perhaps they should be recommended as initial therapy."
Limitations of this study include evaluation only of school-aged children without gastrointestinal tract complaints.
In an accompanying commentary, Peter Cummings, MD, MPH, from the University of Washington in Seattle, discusses the role of carryover bias as it affects this study.
"Despite the evidence of carryover bias reported by Freedman et al, their data still support their main findings," Dr. Cummings writes. "I doubt that carryover bias alone can explain the large taste score differences in their study; 2 sucralose solutions had tolerable flavor, while a rice-based solution tasted like dirt. But carryover bias could make it hard to interpret smaller taste score differences. Future studies of taste, and possibly other subjective outcomes, might be better conducted as parallel-group randomized studies."
The Paediatric Consultants Partnership's Grant for Creative Professional Activity supported this study. PendoPharm, a division of Pharmascience Inc, provided the Pediatric Electrolyte used in this study. The Hospital for Sick Children's Division of Nutrition Services provided the Enfalyte used in this study. The study authors and Dr. Cummings have disclosed no relevant financial relationships.
Arch Pediatr Adolesc Med. 2010;164:696-702, 703-705. Abstract
Monday, August 9, 2010
Human Papillomavirus Vaccine May Offer Prolonged Protection Against Genital Warts and Low-Grade Precancerous Growths
From MedscapeCME Clinical Briefs
News Author: Laurie Barclay, MD
CME Author: Charles P. Vega, MD
July 29, 2010 — Human papillomavirus (HPV) quadrivalent vaccine offers prolonged protection against anogenital warts and low-grade cervical, vulvar, and vaginal neoplasias, according to the results of 2 randomized controlled trials reported in the July 21 issue of the BMJ.
Latest Efficacy Data Presented
"This study gives us the latest and most comprehensive data on the efficacy of the quadrivalent HPV vaccine in protecting against low grade precancerous lesions of the cervical, vulva and vagina, and anogenital warin young women, over a longer period of follow-up than previously reported," Karen Canfell, PhD, a cancer epidemiologist at the Cancer Epidemiology Research Unit Cancer Council in New South Wales, Sydney, Australia, told Medscape Medical News when asked for independent comment. "The results confirm that the quadrivalent vaccine is highly effective in protecting against low grade disease and anogenital warts directly related to the vaccine-included HPV types in women who have not previously been exposed to these types, and this protection is sustained for at least 4 years. However, in the case of cervical low grade lesions, the protective effect against the entire spectrum of lesions is lower, because these can be caused by a variety of high risk and low risk HPV types."
The goal of the FUTURE I/II Study, by Joakim Dillner, from Lund University and Malmö University Hospital in Malmö, Sweden, and colleagues, was to determine the prophylactic efficacy of HPV quadrivalent vaccine in preventing low-grade intraepithelial neoplasias and condyloma acuminata (anogenital warts). FUTURE I (protocol 013) and FUTURE II (protocol 015) were designed to last for 4 years; this analysis was from final study data with follow-up of 42 months.
At primary care and university or hospital-associated medical centers in 24 countries and territories worldwide, 17,622 women aged 16 to 26 years were enrolled from December 2001 through May 2003. Pregnant women and those with a history of more than 4 sexual partners in their lifetime or abnormal cervical smear test results were excluded.
"Data are pooled from 2 randomized controlled trials of quadrivalent vaccine conducted in over 17,000 women aged 16-26 years, and there was an average of about 4 years of follow-up information," Dr. Canfell said.
Per-Protocol Analysis
At day 1, month 2, and month 6, participants received 3 doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo, and the primary study endpoints were vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade 1 and condyloma. Main analysis was per protocol among susceptible participants given all 3 vaccine doses who tested negative for the relevant vaccine HPV types at day 1 and whose test results remained negative through month 7 and who had no major protocol violations. The investigators also performed intent-to-treat analyses and studied generally HPV-naive and unrestricted susceptible populations.
For lesions related to the vaccine HPV types, efficacy in the per-protocol susceptible population was 96% for cervical intraepithelial neoplasia grade 1 (95% confidence interval [CI], 91% - 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade 1 (95% CI, 74% - 100% and 95% CI, 64% - 100%, respectively), and 99% for condyloma (95% CI, 96% - 100%).
In the generally naive population, vaccine efficacy against lesions of any HPV type was 30% (95% CI, 17% - 41%), 75% (95% CI, 22% - 94%), and 48% (95% CI, 10% - 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade 1, respectively, and 83% (95% CI, 74% - 89%) for condyloma.
Study Limitations
Limitations of this study include testing of the HPV-naive population only for 4 vaccine HPV types and 10 other HPV types prevalent in cervical cancer. In addition, rate estimates of disease depend on the intensity of assessment.
"The study found that in women who were negative to the vaccine-included types at baseline, the efficacy of protection against cervical low grade lesions caused by one of the vaccine-included types was ~96%," Dr. Canfell said. "However, when the protective effect against all types was considered in women not previously exposed to any HPV types, the vaccine protected against 30% of cervical low grade cervical lesions. In the overall study population (some of whom had been previously exposed to HPV), the protective effect against all cervical low grade lesions was 20%, [and] protection against warts in the overall study population was estimated to be 62%."
Assuming the vaccine will have long-duration protection, Dr. Canfell noted that the results in this group approximate the effect that will be seen on low-grade lesions "down the track" for the preadolescent girls (usually 12 -13 years old) who are vaccinated in routine vaccination programs.
"However, the effect of the vaccine in preventing high grade lesions and cervical cancer will be much greater in this group, because a higher proportion of these are caused by the HPV types in the vaccine," she explained. "In the overall study population, the protective effect against all low grade lesions was reduced to 20%, because some women had already been exposed to HPV. This approximates the effect we will see in vaccination program 'catch-up' cohorts."
Similarly, the 61% protection against condyloma approximates that expected to be seen in catch-up cohorts. This is in line with ecologic data from Australia, which has high vaccination coverage, showing that presentations for genital warts have decreased in young women since the vaccination catch-up program was implemented. These results also suggest that approximately 70% to 80% of cervical low-grade lesions will not be prevented by the vaccine, even if very high rates of vaccination coverage are achieved.
"Therefore, dramatic reductions in the number of cervical low grade precancerous lesions in vaccinated populations are not expected, especially if catch-up vaccination coverage is relatively low," Dr. Canfell said. "However, a modest reduction in the rate of cervical low grade lesions should be observed in young women in countries with high levels of vaccination coverage. The good news is that the remaining low grade lesions will be generally less likely to progress to cervical cancer, because the vaccine will have decreased the size of the subgroup of low grade lesions related to HPV 16/18, which are the types involved in the majority of cervical cancers."
Surveillance Recommended
When asked about the need for additional research, Dr. Canfell recommended surveillance of cervical low-grade lesion rates in young women in countries that have implemented vaccination catch-up programs. However, she noted that this will only be possible in settings that have comprehensive and accurate data on screening behavior, because cervical precancerous lesions are only detected via screening. Therefore, it will be important to take into account any future changes in screening behavior. She also recommended surveillance of genital wart presentations in at least some of the countries that have implemented HPV vaccination.
"In countries with high coverage levels in catch-up programs, we expect to see a decreasing rate of genital wart presentations in both females and also in heterosexual males; the effect on males will be seen even without male vaccination, because there will be fewer HPV infections circulating in the population," Dr. Canfell said. "The best way to monitor the impact on genital warts will be by using routinely collected data in settings that allow assessments of genital wart presentations in vaccinated and unvaccinated individuals to be performed. This will allow the protective effect of vaccination to be further quantified in the context of actual vaccination programs, which will add to the evidence from the clinical trials."
Merck & Co supported this study, employs 9 of the study authors, and has various financial relationships with some of the other study authors. A complete description of other various financial relationships is available in the original article. Dr. Canfell has disclosed no relevant financial relationships.
BMJ. 2010;340:c3493. Abstract
Clinical Context
The HPV quadrivalent vaccine has proven to be effective in the prevention of high-grade cervical dysplasia as well as the prevention of genital warts, but the role of the 4 HPV types contained in the vaccine (6, 11, 16, and 18) is less well established for low-grade cervical intraepithelial dysplasia. Many women clear their initial infection with HPV, and low-grade neoplasia often regresses spontaneously. Moreover, although at least 1 of the 4 HPV types contained in the vaccine are present in 25% to 50% of low-grade cervical and vulvovaginal neoplasias, these lesions frequently contain multiple HPV types, making causality difficult to prove.
One means to do so is to perform a placebo-controlled trial of the quadrivalent HPV vaccine in the prevention of low-grade disease. The results of this study are presented in the Study Highlights section.
News Author: Laurie Barclay, MD
CME Author: Charles P. Vega, MD
July 29, 2010 — Human papillomavirus (HPV) quadrivalent vaccine offers prolonged protection against anogenital warts and low-grade cervical, vulvar, and vaginal neoplasias, according to the results of 2 randomized controlled trials reported in the July 21 issue of the BMJ.
Latest Efficacy Data Presented
"This study gives us the latest and most comprehensive data on the efficacy of the quadrivalent HPV vaccine in protecting against low grade precancerous lesions of the cervical, vulva and vagina, and anogenital warin young women, over a longer period of follow-up than previously reported," Karen Canfell, PhD, a cancer epidemiologist at the Cancer Epidemiology Research Unit Cancer Council in New South Wales, Sydney, Australia, told Medscape Medical News when asked for independent comment. "The results confirm that the quadrivalent vaccine is highly effective in protecting against low grade disease and anogenital warts directly related to the vaccine-included HPV types in women who have not previously been exposed to these types, and this protection is sustained for at least 4 years. However, in the case of cervical low grade lesions, the protective effect against the entire spectrum of lesions is lower, because these can be caused by a variety of high risk and low risk HPV types."
The goal of the FUTURE I/II Study, by Joakim Dillner, from Lund University and Malmö University Hospital in Malmö, Sweden, and colleagues, was to determine the prophylactic efficacy of HPV quadrivalent vaccine in preventing low-grade intraepithelial neoplasias and condyloma acuminata (anogenital warts). FUTURE I (protocol 013) and FUTURE II (protocol 015) were designed to last for 4 years; this analysis was from final study data with follow-up of 42 months.
At primary care and university or hospital-associated medical centers in 24 countries and territories worldwide, 17,622 women aged 16 to 26 years were enrolled from December 2001 through May 2003. Pregnant women and those with a history of more than 4 sexual partners in their lifetime or abnormal cervical smear test results were excluded.
"Data are pooled from 2 randomized controlled trials of quadrivalent vaccine conducted in over 17,000 women aged 16-26 years, and there was an average of about 4 years of follow-up information," Dr. Canfell said.
Per-Protocol Analysis
At day 1, month 2, and month 6, participants received 3 doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo, and the primary study endpoints were vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade 1 and condyloma. Main analysis was per protocol among susceptible participants given all 3 vaccine doses who tested negative for the relevant vaccine HPV types at day 1 and whose test results remained negative through month 7 and who had no major protocol violations. The investigators also performed intent-to-treat analyses and studied generally HPV-naive and unrestricted susceptible populations.
For lesions related to the vaccine HPV types, efficacy in the per-protocol susceptible population was 96% for cervical intraepithelial neoplasia grade 1 (95% confidence interval [CI], 91% - 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade 1 (95% CI, 74% - 100% and 95% CI, 64% - 100%, respectively), and 99% for condyloma (95% CI, 96% - 100%).
In the generally naive population, vaccine efficacy against lesions of any HPV type was 30% (95% CI, 17% - 41%), 75% (95% CI, 22% - 94%), and 48% (95% CI, 10% - 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade 1, respectively, and 83% (95% CI, 74% - 89%) for condyloma.
Study Limitations
Limitations of this study include testing of the HPV-naive population only for 4 vaccine HPV types and 10 other HPV types prevalent in cervical cancer. In addition, rate estimates of disease depend on the intensity of assessment.
"The study found that in women who were negative to the vaccine-included types at baseline, the efficacy of protection against cervical low grade lesions caused by one of the vaccine-included types was ~96%," Dr. Canfell said. "However, when the protective effect against all types was considered in women not previously exposed to any HPV types, the vaccine protected against 30% of cervical low grade cervical lesions. In the overall study population (some of whom had been previously exposed to HPV), the protective effect against all cervical low grade lesions was 20%, [and] protection against warts in the overall study population was estimated to be 62%."
Assuming the vaccine will have long-duration protection, Dr. Canfell noted that the results in this group approximate the effect that will be seen on low-grade lesions "down the track" for the preadolescent girls (usually 12 -13 years old) who are vaccinated in routine vaccination programs.
"However, the effect of the vaccine in preventing high grade lesions and cervical cancer will be much greater in this group, because a higher proportion of these are caused by the HPV types in the vaccine," she explained. "In the overall study population, the protective effect against all low grade lesions was reduced to 20%, because some women had already been exposed to HPV. This approximates the effect we will see in vaccination program 'catch-up' cohorts."
Similarly, the 61% protection against condyloma approximates that expected to be seen in catch-up cohorts. This is in line with ecologic data from Australia, which has high vaccination coverage, showing that presentations for genital warts have decreased in young women since the vaccination catch-up program was implemented. These results also suggest that approximately 70% to 80% of cervical low-grade lesions will not be prevented by the vaccine, even if very high rates of vaccination coverage are achieved.
"Therefore, dramatic reductions in the number of cervical low grade precancerous lesions in vaccinated populations are not expected, especially if catch-up vaccination coverage is relatively low," Dr. Canfell said. "However, a modest reduction in the rate of cervical low grade lesions should be observed in young women in countries with high levels of vaccination coverage. The good news is that the remaining low grade lesions will be generally less likely to progress to cervical cancer, because the vaccine will have decreased the size of the subgroup of low grade lesions related to HPV 16/18, which are the types involved in the majority of cervical cancers."
Surveillance Recommended
When asked about the need for additional research, Dr. Canfell recommended surveillance of cervical low-grade lesion rates in young women in countries that have implemented vaccination catch-up programs. However, she noted that this will only be possible in settings that have comprehensive and accurate data on screening behavior, because cervical precancerous lesions are only detected via screening. Therefore, it will be important to take into account any future changes in screening behavior. She also recommended surveillance of genital wart presentations in at least some of the countries that have implemented HPV vaccination.
"In countries with high coverage levels in catch-up programs, we expect to see a decreasing rate of genital wart presentations in both females and also in heterosexual males; the effect on males will be seen even without male vaccination, because there will be fewer HPV infections circulating in the population," Dr. Canfell said. "The best way to monitor the impact on genital warts will be by using routinely collected data in settings that allow assessments of genital wart presentations in vaccinated and unvaccinated individuals to be performed. This will allow the protective effect of vaccination to be further quantified in the context of actual vaccination programs, which will add to the evidence from the clinical trials."
Merck & Co supported this study, employs 9 of the study authors, and has various financial relationships with some of the other study authors. A complete description of other various financial relationships is available in the original article. Dr. Canfell has disclosed no relevant financial relationships.
BMJ. 2010;340:c3493. Abstract
Clinical Context
The HPV quadrivalent vaccine has proven to be effective in the prevention of high-grade cervical dysplasia as well as the prevention of genital warts, but the role of the 4 HPV types contained in the vaccine (6, 11, 16, and 18) is less well established for low-grade cervical intraepithelial dysplasia. Many women clear their initial infection with HPV, and low-grade neoplasia often regresses spontaneously. Moreover, although at least 1 of the 4 HPV types contained in the vaccine are present in 25% to 50% of low-grade cervical and vulvovaginal neoplasias, these lesions frequently contain multiple HPV types, making causality difficult to prove.
One means to do so is to perform a placebo-controlled trial of the quadrivalent HPV vaccine in the prevention of low-grade disease. The results of this study are presented in the Study Highlights section.
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