How to Meet the HPV Counseling And Vaccination Challenge

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still “a million dollar question,” said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics' committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did “not believe the vaccine is effective in preventing the disease” (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

“If you approach it by saying 'It's time to receive your HPV vaccine,' there's often no need to go any further, other than providing parents with the appropriate information pamphlet” from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

“If you start out, on the other hand, by saying 'It's time to discuss the possibility of your daughter receiving the HPV vaccine,' immediately that sends a very different message,” said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

“Parents have never heard this type of approach used with a vaccine before,” he said.

It is important to tailor one's approach to the fact that “there isn't as immediate a preventive effect that parents can appreciate, compared with other vaccines,” said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

“We can do better at being straightforward in addressing the issues of HPV, with both children and their parents,” he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

▸ The “why now” factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

“But when a parent [of an 11- to 12-year-old] says, 'I want to have this discussion 2 years from now,' I think it's our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response … and at an age that is prior to the risk,” said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC's Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

“Most mothers aren't ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgment that their daughter is about to become sexually active, whether or not that's true,” said Dr. Pichichero.

That's why it's important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, “studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels.”

Kaiser's Dr. Wibbelsman said he tells parents that at least “10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer.”

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that “numbers give parents something concrete to hang their hats on.” He tells many parents that “the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination,” and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

“We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children,” said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. “You have to test the waters, the comfort level of the child … but whenever possible, I lay all this out.”

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child's chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. “Without a doubt, it's a malpractice risk,” he said. Sometimes, he added, such a statement or request results in parents' changing their minds.

▸ Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

“I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine,” said Dr. Freed. “Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer.”

Others said they refer parents to the CDC's Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding “no pattern or clustering … to suggest they were caused by the HPV vaccination,” the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

▸ Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8–10 years at this point, with no “breakthrough cases” of HPV infection, sources said.

“We can tell parents that – as with any new vaccine – we can't say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer,” said Dr. Bocchini. If needed in the future, a booster dose will become available.

▸ Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and −11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. “There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer,” not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their “National Advisory Boards for periodic 1-day consulting.” Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still “a million dollar question,” said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics' committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did “not believe the vaccine is effective in preventing the disease” (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

“If you approach it by saying 'It's time to receive your HPV vaccine,' there's often no need to go any further, other than providing parents with the appropriate information pamphlet” from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

“If you start out, on the other hand, by saying 'It's time to discuss the possibility of your daughter receiving the HPV vaccine,' immediately that sends a very different message,” said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

“Parents have never heard this type of approach used with a vaccine before,” he said.

It is important to tailor one's approach to the fact that “there isn't as immediate a preventive effect that parents can appreciate, compared with other vaccines,” said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

“We can do better at being straightforward in addressing the issues of HPV, with both children and their parents,” he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

▸ The “why now” factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

“But when a parent [of an 11- to 12-year-old] says, 'I want to have this discussion 2 years from now,' I think it's our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response … and at an age that is prior to the risk,” said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC's Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

“Most mothers aren't ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgment that their daughter is about to become sexually active, whether or not that's true,” said Dr. Pichichero.

That's why it's important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, “studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels.”

Kaiser's Dr. Wibbelsman said he tells parents that at least “10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer.”

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that “numbers give parents something concrete to hang their hats on.” He tells many parents that “the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination,” and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

“We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children,” said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. “You have to test the waters, the comfort level of the child … but whenever possible, I lay all this out.”

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child's chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. “Without a doubt, it's a malpractice risk,” he said. Sometimes, he added, such a statement or request results in parents' changing their minds.

▸ Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

“I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine,” said Dr. Freed. “Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer.”

Others said they refer parents to the CDC's Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding “no pattern or clustering … to suggest they were caused by the HPV vaccination,” the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

▸ Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8–10 years at this point, with no “breakthrough cases” of HPV infection, sources said.

“We can tell parents that – as with any new vaccine – we can't say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer,” said Dr. Bocchini. If needed in the future, a booster dose will become available.

▸ Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and −11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. “There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer,” not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their “National Advisory Boards for periodic 1-day consulting.” Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still “a million dollar question,” said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics' committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did “not believe the vaccine is effective in preventing the disease” (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

“If you approach it by saying 'It's time to receive your HPV vaccine,' there's often no need to go any further, other than providing parents with the appropriate information pamphlet” from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

“If you start out, on the other hand, by saying 'It's time to discuss the possibility of your daughter receiving the HPV vaccine,' immediately that sends a very different message,” said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

“Parents have never heard this type of approach used with a vaccine before,” he said.

It is important to tailor one's approach to the fact that “there isn't as immediate a preventive effect that parents can appreciate, compared with other vaccines,” said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

“We can do better at being straightforward in addressing the issues of HPV, with both children and their parents,” he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

▸ The “why now” factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

“But when a parent [of an 11- to 12-year-old] says, 'I want to have this discussion 2 years from now,' I think it's our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response … and at an age that is prior to the risk,” said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC's Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

“Most mothers aren't ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgment that their daughter is about to become sexually active, whether or not that's true,” said Dr. Pichichero.

That's why it's important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, “studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels.”

Kaiser's Dr. Wibbelsman said he tells parents that at least “10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer.”

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that “numbers give parents something concrete to hang their hats on.” He tells many parents that “the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination,” and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

“We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children,” said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. “You have to test the waters, the comfort level of the child … but whenever possible, I lay all this out.”

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child's chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. “Without a doubt, it's a malpractice risk,” he said. Sometimes, he added, such a statement or request results in parents' changing their minds.

▸ Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

“I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine,” said Dr. Freed. “Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer.”

Others said they refer parents to the CDC's Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding “no pattern or clustering … to suggest they were caused by the HPV vaccination,” the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

▸ Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8–10 years at this point, with no “breakthrough cases” of HPV infection, sources said.

“We can tell parents that – as with any new vaccine – we can't say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer,” said Dr. Bocchini. If needed in the future, a booster dose will become available.

▸ Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and −11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. “There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer,” not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their “National Advisory Boards for periodic 1-day consulting.” Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.