Prevention of Vulvar and Vaginal cancer

Gardasil Approval Expanded to Prevention of HPV-Related Vulvar, Vaginal Cancer

News Author: Laurie Barclay,
CME Author: Yael Waknine

September 18, 2008 — The US Food and Drug Administration (FDA) announced yesterday that approval for the vaccine Gardasil (HPV quadrivalent [types 6, 11, 16, and 18] recombinant vaccine) has been expanded to include the indication of preventing vaginal and vulvar cancer caused by human papillomavirus (HPV) types 16 and 18 in girls and women aged 9 to 26 years.
"There is now strong evidence showing that this vaccine can help prevent vulvar and vaginal cancers due to the same viruses for which it also helps protect against cervical cancer," Jesse L. Goodman, MD, MPH, director of the FDA's Center for Biologics Evaluation and Research, said in a news release. "While vulvar and vaginal cancers are rare, the opportunity to help prevent them is potentially an important additional benefit from immunization against HPV."
In 2006, the original FDA approval for Gardasil was for the prevention of cervical cancer caused by HPV types 16 and 18, which cause 70% of cervical cancers and which are implicated in unknown percentages of vulvar and vaginal cancers. The original approval, which was for girls and women aged 9 to 26 years, was also for the indications of preventing precancerous genital lesions caused by HPV types 6, 11, 16, and 18 and genital warts caused by HPV types 6 and 11.
In the United States, HPV is the most prevalent sexually transmitted disease, with an annual incidence of 6.2 million new infections, according to the US Centers for Disease Control and Prevention.
Merck & Co Inc, the manufacturer of Gardasil, followed up on more than 15,000 participants from the original cervical cancer prevention studies for 2 more years to determine the effects of Gardasil on the risk for vulvar and vaginal cancer compared with control participants who had not received Gardasil.
This follow-up showed that Gardasil was highly effective in preventing HPV-related precancerous vulvar and vaginal lesions in women who tested negative for HPV types 16 or 18 at study enrollment. None of the participants in the Gardasil group developed HPV type 16- or 18-related precancerous lesions compared with control group findings of 10 precancerous vulvar lesions and 9 precancerous vaginal lesions related to HPV types 16 or 18.
Women previously infected with HPV types 16 or 18 before immunization had no evidence of benefit. To optimize the preventive effects of Gardasil, the investigators therefore recommend vaccination before potential exposure to HPV types 16 or 18.
Caveats from the FDA represented in the label are that presently available information is insufficient to support use in women older than age 26 years and that Gardasil does not protect against diseases caused by other HPV types. Because Gardasil does not protect against preexisting HPV infections and because no vaccine is 100% effective, all women should continue to be monitored with Papanicolaou tests, even after vaccination.
Most adverse events of Gardasil reported since FDA approval in 2006 have not been serious. The most frequently reported adverse events have included syncope, injection site pain, headache, nausea, and fever. Observation is recommended after vaccination in case of syncope or severe allergic reactions.
A short- and long-term safety surveillance study is underway of 44,000 individuals in a managed care organization who received Gardasil for all its approved uses.
Source :Gardasil Prescribing Information

Study Highlights
The FDA has approved an expanded indication for a quadrivalent recombinant vaccine, allowing its use for the prophylaxis of vaginal and vulvar cancer caused by HPV types 16 and 18 in girls and women aged 9 to 26 years.
The HPV vaccine is administered as an intramuscular injection at 0, 2, and 6 months.
Previously, the FDA approved use of the vaccine for the prevention of cervical cancer caused by HPV types 16 and 18; precancerous genital lesions caused by HPV types 6, 11, 16, and 18; and genital warts caused by HPV types 6 and 11.
The current approval was based on data from 3 placebo-controlled, randomized studies that followed up on 18,714 participants for a mean of 3 years; approximately 50% had been vaccinated.
Results showed that the vaccine was 100% effective for preventing precancerous high-grade vulval intraepithelial neoplasia and vaginal intraepithelial neoplasia caused by HPV types 16 and 18 in girls and women who tested negative for infection up to 1 month after the last dose.
In the intent-to-treat population, which included all participants, the vaccine was 71% effective against vulvar intraepithelial neoplasia or vaginal intraepithelial neoplasia associated with HPV 16 or 18.
Results also showed the vaccine to be 49% effective against all vulvar intraepithelial neoplasia or vaginal intraepithelial neoplasia irrespective of whether HPV DNA was detected in the lesion.
No evidence of vaccination benefit was observed in girls and women previously infected with the HPV subtypes contained in the vaccine.
There is insufficient evidence to support use of the vaccine in women older than 26 years.
Adverse events most commonly include syncope, pain at the injection site, headache, nausea, and fever. Because of the potential for allergic reactions and syncope, a 15-minute postvaccination observation period is recommended.

Pearls for Practice
The FDA has approved an expanded indication for HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine, allowing its use for the prevention of grades 2 and 3 vulvar and vaginal intraepithelial neoplasia caused by HPV types 16 and 18 in girls and women aged 9 to 26 years. Clinical data showed 100% efficacy in women who were infection naive at baseline. Intent-to-treat efficacy was 71%.

No evidence of benefit was observed in girls previously infected with the HPV subtypes contained in the vaccine, and there is insufficient evidence to support its use in women older than 26 years. Because of the potential for allergic reactions and syncope, patients should be observed for 15 minutes after vaccination.

Thermerosal No link with Autism

California Data Do Not Support a Link Between Thimerosal in Vaccines and

Continuing Increases in Autism Reported to California's Developmental Services System: Mercury in Retrograde

Schechter R, Grether JK
Arch Gen Psychiatry. 2008;65:19-24

Summary

This study was a retrospective review of autism spectrum disorder (ASD) cases referred to the California Department of Developmental Services (DDS) from 1995 through 2007. Children enter the DDS system at 3 years old; therefore, this referral represents the prevalence of a diagnosis of ASD in this population at the age of 3 years.

The authors plotted the prevalence of ASD referrals against critical time points in US vaccine history relative to the use of thimerosal. Critical dates relative to thimerosal are:

1991: The addition of vaccines to the recommended schedule produces an increase in the total mercury exposure (via thimerosal) in vaccines; 1999: A recommendation to remove thimerosal from vaccines was made; 2001: Thimerosal is no longer present in vaccines except in trace quantities; 2002: The overall expiration time period of vaccines with anything more than trace amounts of thimerosal is reached.

The authors' hypothesis was that if thimerosal were a contributor to ASD then children born and vaccinated after 2002 should have decreased rates of ASD diagnosis, and this would be reflected in decreased numbers of referrals (ie, decreased prevalence) to California DDS.

The authors did not find a dip in referral rates; their data did not reflect a change in ASD prevalence. In fact, the prevalence of ASD was increasing before 1991 and continued on roughly the same slope throughout the 1990s and 2000s, regardless of age group evaluated.

Only one year's cohort of children was born after thimerosal was largely eliminated from vaccines and were not at risk for receiving old vaccine -- the children born in 2003. These children also had a higher prevalence of ASD than children born in previous years, and the slope was increasing along a very similar trajectory to prior years. The increase over the time period 1993 through 2003 was from 0.3 cases per 1000 births to 1.3 cases per 1000 births.

The authors conclude that the California DDS data do not support a link between thimerosal in childhood vaccines and development of ASD.

Viewpoint

This study was published in January 2008 but only recently came to my attention. The findings here mirror those of a Danish study that demonstrated ongoing increases in ASD diagnosis despite removal of thimerosal from vaccines,^[1] as well as Canadian data demonstrating no decrease in ASD diagnosis for children vaccinated with non-thimerosal-containing vaccines.^[2] The figure from the Canadian study is particularly interesting and is worth viewing separately.

Obese and Overweight Teens at Higher Risk for Chronic Diseases

News Author: Laurie Barclay, MD
CME Author: Penny Murata, MD

June 2, 2008 — Teens who were obese and overweight had a higher risk for chronic diseases such as type 2 diabetes, cardiovascular disease, and fatty liver disease, according to the results of an Australian cross-sectional study reported in the June issue of the Archives of Pediatrics & Adolescent Medicine.

"Several studies have shown that obese children and adolescents have an increased prevalence of metabolic risk factors for cardiovascular disease, type 2 diabetes, and, more recently, fatty liver disease," write Elizabeth Denney-Wilson, PhD, MPH, BN, from the University of Sydney in Sydney, Australia, and colleagues. "Although morbidity could be expected to increase in parallel with the prevalence of obesity, little is known about chronic disease risk factors in the general adolescent population. Most studies of comorbidities either have been conducted in clinic-based groups of severely obese adolescents or have not studied the full range of metabolic complications."

The goal of this study was to evaluate the association between measures of adiposity (body mass index [BMI] and waist circumference) and risk factors for heart disease, type 2 diabetes, and fatty liver disease as well as the clustering of risk factors in middle adolescence.

At secondary schools in Sydney, 496 grade 10 students were categorized as overweight or obese by the International Obesity Task Force cutoff points and the UK waist circumference cutoff points. Mean age was 15.4 ± 0.4 years; 58.4% were boys. Blood samples were tested for high-density lipoprotein (HDL) and low-density lipoprotein (HDL) cholesterol, triglycerides, insulin, glucose, alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), and high-sensitivity C-reactive protein (CRP) levels. Published guidelines were used to categorize these results as normal or abnormal. Logistic regression helped define associations between overweight and obesity and risk factors, and clustering of risk factors within individuals was also examined.

In adolescent boys, factors significantly associated with overweight and obesity were insulin levels (P <.001), ALT (P <.001), GGT (P = .005), HDL cholesterol levels (P < .001), high-sensitivity CRP levels (P <.001), and blood pressure (P <.001). Factors significantly associated with overweight and obesity in adolescent girls were insulin, HDL cholesterol (P <.001) and high-sensitivity CRP levels (P < .001).

Compared with adolescents who were not overweight, obese adolescent boys and girls were significantly more likely to have 2 or more risk factors (boys: 73.5% vs 7.6%; girls: 44.4% vs 5.4%; P < .001 for both).

"Overweight and obese adolescents, especially boys, are at substantial risk for chronic conditions," the study authors write. "Waist circumference is not a better predictor of metabolic risk factors than is . . . BMI."

Limitations of this study include lack of data on family history of cardiovascular disease and lack of reporting of the consumption of alcohol and other drugs.

"The propensity of adiposity, behaviors, and risk factors to track from adolescence through adulthood would suggest that health care systems can expect a greater burden of disease from obesity-related conditions when today's young people achieve adulthood," the study authors conclude.

Pearls for Practice

• In adolescent boys, overweight and obesity are linked with abnormal values of insulin, ALT, GGT, HDL cholesterol, high sensitivity CRP, and blood pressure. In adolescent girls, overweight and obesity are linked with abnormal values of insulin, HDL cholesterol, and high sensitivity CRP.
• Obese adolescents, especially boys, are more likely to have at least 2 risk factors for heart disease, type 2 diabetes, and fatty liver disease than nonobese adolescents.

The New South Wales Department of Health supported this study. The study authors have disclosed no relevant financial relationships.

Arch Pediatr Adolesc Med. 2008;162:566-573.

Sucrose before Vaccination can Reduce pain

How to Stop the Hurt -- Sucrose Prior to Infant Vaccinations:
A Best Evidence Review Medscape CME/CE Posted 06/16/2008

Charles P. Vega, MD

Vaccination is the most common procedure performed in infancy, although parents might have significant concerns regarding the pain associated with routine vaccinations. Moreover, painful experiences very early in life can promote somatization later in life. Oral sucrose has been demonstrated to reduce pain reactions among neonates, and the current study examines this simple intervention prior to administration of routine vaccination at 2 and 4 months of age.

Participants received either a 24% disaccharide solution at a dose of 0.6 mL/kg, or matching placebo. Infants were not swaddled, cuddled, or restrained during vaccination or the ensuing data collection period.

Sucrose has previously been demonstrated to improve outcomes among neonates undergoing painful procedures. In an analysis of 21 randomized controlled trials involving 1616 infants, sucrose at a wide range of doses (0.012 mg to 0.12 mg) improved the rate of crying at 30 and 60 seconds after heel lance.^[8] However, sucrose was not effective in reducing heart rate at 1 and 3 minutes after heel lance.

Some practices employ other analgesic measures to reduce the pain of pediatric vaccinations. The application of the lidocaine-prilocaine patch prior to the first measles-mumps-rubella vaccine among children at least 12 months of age resulted in a significant reduction in Behavior Pain Scale scores vs placebo treatment.^[9] Moreover, rates of irritability after vaccination were 16% in the lidocaine-prilocaine group vs 31% in the placebo group, and the antibody responses in the 2 groups to the vaccine components were similar.

Parents may also pretreat their children with oral analgesic medications prior to appointments for vaccination, and a study of acetaminophen delivered prior to administration of the diphtheria-pertussis-tetanus toxoids-polio vaccine largely supports this practice.^[10] Compared with placebo, acetaminophen reduced the risk for fever greater than 38 degrees Celsius from 44% to 27%. Rates of behavioral changes after vaccination were 0.9% among the acetaminophen group vs 13% with placebo. However, acetaminophen was superior to placebo for primary vaccinations at 2 to 6 months of age but not for booster vaccination at 18 months of age. At the 18-month vaccination, the overall rate of systemic and local reactions was higher in both the acetaminophen and placebo groups. Another study has demonstrated that neither acetaminophen nor ibuprofen was effective in reducing the risk for local reactions such as erythema and swelling following the fifth diphtheria-tetanus toxoids-acellular pertussis vaccination.

Two key questions remain regarding the implementation of sucrose for the prevention of pain in pediatric vaccinations. First, the weight-based dosing algorithm for sucrose in the current study certainly appeared effective, but the dosage range used in different studies has generally been quite wide. Further research should address the issue of the optimal dose of sucrose. In addition, it would be very easy to conceive that using other analgesics such as acetaminophen in addition to sucrose could be synergistic in improving pain and behavior after vaccination. Moreover, the use of antipyretic medications could also reduce the risk for postvaccination fever.

Regarding the practical utility of different methods of analgesia for routine infant vaccinations, lidocaine-prilocaine can be difficult to apply and maintain in place for the 30 minutes required for effective analgesia prior to procedures.

Oral analgesics must also be delivered well before the vaccine is administered to be effective, and they expose infants and children to the remote possibility of significant adverse events.

In contrast, sucrose appears to be a readily available and applicable means to reduce infants' pain with vaccination. It is inexpensive and safe. Sucrose can also help parents to feel actively involved in protecting their infant from pain, and this should help increase acceptance of routine vaccinations. And that outcome should taste just like sugar for clinicians.

Probiotic Relieves Diarrhea in Infants and Toddlers

By Will Boggs, MD

NEW YORK (Reuters Health) Jun 25 - The probiotic Escherichia coli Nissle 1917 is effective in treating diarrhea greater than 4 days' duration in infants and toddlers, according to a report in the June issue of The Pediatric Infectious Disease Journal.

"There is more and more evidence now for the effectiveness and safety of probiotic drugs," Dr. Jobst Henker from University Carl-Gustav-Carus, Dresden, Germany told Reuters Health. "Earlier data for probiotic foods or food supplements show an excellent safety record but sometimes lack firm data on efficacy."

Dr. Henker and colleagues note that the nonpathogenic E. coli strain Nissle 1917 (EcN) has been licensed in Europe for 90 years for treating bowel diseases. They investigated the response rate and time to response using EcN suspension or placebo in 151 infants and toddlers with diarrhea lasting more than 4 days.

More children treated with EcN than with placebo showed a response to treatment on day 7 (78.7% versus 59.2%, respectively), day 14 (93.3% versus 65.8%), and day 21 (98.7% versus 71.1%), the investigators report.

Diarrhea lasted a median 3.3 days less in children treated with EcN, the report indicates, and the number of stools decreased to three or less daily 2 days sooner in the EcN group than in the placebo group.

More children in the placebo group exhibited dehydration at the end of the study, the researchers note, and more children in the EcN group (97.0%) than in the placebo group (62.3%) improved from a "moderate" state of health to a "good" or "very good" state of health in the course of treatment.

There were no serious or severe adverse events, the investigators say, and only four events were judged to be possibly related to study medication. Parents' and investigators' ratings indicated that EcN was well tolerated by the children.

"Since there is one other successful EcN study by our group in acute children's diarrhea, we believe it is best to start probiotic therapy as early as possible," Dr. Henker said.

"We would like to address the subject of inflammatory bowel disease," Dr. Henker added. "Not only do excellent data exist for the use of EcN in ulcerative colitis remission maintenance in an adult population, but we were able to show similar results in children."

Pediatr Infect Dis J 2008;27:494-499.

Secondhand Smoke Decrease Lung function in Child

Children exposed to secondhand smoke (SHS) at home during early infancy have an increased risk for serious infections requiring hospitalization, according to the results of a prospective cohort study reported in the May 27 Online First issue of Tobacco Control.

"Second-hand smoke ... exposure is a modifiable cause of ill health," write M.K. Kwok from the University of Hong Kong in Hong Kong SAR, China, and colleagues.

Previous research by Moshammer and colleagues suggests that passive smoking has a significant deleterious effect on lung function among children. Their study, which was published in the June 1, 2006, issue of the American Journal of Respiratory and Critical Care Medicine, examined more than 20,000 children between the ages of 6 and 12 years.

They found that maternal smoking during pregnancy was associated with a reduced forced expiratory volume in 1 second as well as a lower maximal expiratory flow among children. Passive smoking during childhood also reduced lung function in children though not to the same degree as in utero exposure to smoking.

Medscape News Author: Laurie Barclay, MD

Meningococcal Vaccine Not Routine 2-10yrs Child

MMWR Morbid Mortal Wkly Rep. 2008;57(17):462-465.

Clinical Context

The MCV4 (Menactra; Sanofi-Pasteur) was approved by the US Food and Drug Administration on October 17, 2007, for use in children aged 2 to 10 years, adding to the existing approval for use in persons aged 11 to 55 years. MCV4 licensure was based on clinical trials in which the safety and immunogenicity of MCV4 was compared with the MPSV4 and was found to be safe and noninferior to the MPSV4 for all serogroups.

From June 2007 to February 2008, the ACIP Meningococcal Vaccine Workgroup considered use of MCV4 in children aged 2 to 10 years. They reviewed data on MCV4 immunogenicity and safety in this age group, the epidemiology and burden of meningococcal disease, the cost-effectiveness of different vaccination strategies, and the programmatic implications. Based on this review, the expert opinion of workgroup members, and feedback from partner organizations, the ACIP decided at its February 2008 meeting not to routinely vaccinate children aged 2 to 10 years.

Study Highlights

• ACIP evaluated data and concluded that evidence was insufficient to determine that 1 dose of MCV4 administered at age 2 years would protect against meningococcal disease through late adolescence and college entry.
• Serum bactericidal activity among children aged 2 to 3 years who received MCV4 was lower vs children aged 4 to 10 years.
• ACIP also reviewed the burden of meningococcal disease among children aged 2 to 10 years.
• Between 1998 and 2007 in the United States, overall rates of meningococcal disease were lower in children aged 2 to 10 years vs infants younger than 2 years and adolescents aged 11 to 19 years.
• Of cases in children aged 2 to 10 years, 41% occurred among children aged 2 to 3 years.
• Among cases that occurred in children 2 to 10 years old, 59% were caused by serogroups contained in MCV4 (A, C, Y, and W-135) vs 77% of cases among those 11 to 19 years old.
• A cost-effectiveness analysis determined that vaccinating children aged 2 years was less cost effective than vaccinating children aged 11 years.
• As of February 2008, the ACIP does not recommend routine vaccination of children aged 2 to 10 years against meningococcal disease unless the child is at increased risk.
• ACIP continues to recommend vaccination for children aged 2 to 10 years who are at increased risk for meningococcal disease.
• Risk factors for meningococcal disease include travel to or residence in countries where meningococcal disease is hyperendemic or epidemic, terminal complement deficiencies, and anatomic or functional asplenia.
• Using clinical judgment on a case-by-case basis, clinicians may also decide to vaccinate children aged 2 to 10 years who are infected with HIV.
• MCV4 is preferred to MPSV4 for children aged 2 to 10 years at increased risk, for control of meningococcal disease outbreaks, and when clinicians or parents decide on meningococcal vaccination for other children aged 2 to 10 years.
• Children aged 2 to 10 years who have received MPSV4 and who are still at increased risk for meningococcal disease should be vaccinated with MCV4 3 years after receiving MPSV4.
• Children who last received MPSV4 less than 3 years before and who are still at increased risk for meningococcal disease should receive MCV4 vaccination as soon as possible.
• Recommendations for use of MCV4 in persons aged 11 to 55 years remain unchanged from earlier published guidelines.
• ACIP continues to recommend routine vaccination against meningococcal disease for all persons aged 11 to 18 years.
• ACIP recommends vaccination against meningococcal disease for persons aged 2 to 55 years who are at increased risk for meningococcal disease.
• Children at increased risk for meningococcal disease throughout their lifetime will most likely need subsequent doses of MCV4, with specific recommendations anticipated based on ongoing ACIP monitoring on duration of protection.
• A history of GBS is a precaution to MCV4 vaccination because these individuals might be at increased risk for GBS after MCV4 vaccination.

Pearls for Practice

• As of February 2008, the ACIP does not recommend routine vaccination of children aged 2 to 10 years against meningococcal disease unless the child is at increased risk because of travel to or residence in countries where meningococcal disease is hyperendemic or epidemic, terminal complement deficiencies, or anatomic or functional asplenia.
• Recommendations for use of MCV4 in persons aged 11 to 55 years remain unchanged from earlier published guidelines. ACIP continues to recommend routine vaccination against meningococcal disease for all persons aged 11 to 18 years. ACIP recommends vaccination against meningococcal disease for persons aged 2 to 55 years who are at increased risk for meningococcal disease.