- Email: [email protected]
Gardasil: from bench, to bedside, to blunder
Comment
7
8 9
Rawson R, McCann M, Huber A, et al. Contingency management and relapse prevention as stimulant abuse treatment interventions. In: Higgins ST, Silverman K, eds. Motivating behavior change among illicit-drug abusers: research on contingency management interventions. Washington, DC: American Psychological Association, 1999. Des Jarlais D, Arasteh K, McKnight C, Ringer M, Friedman SR. Syringe exchange, injecting and intranasal drug use. Addiction 2010; 105: 155–58. Kahneman D, Tversky A, eds. Choices, values and frames. New York: Cambridge University Press, 2000.
10
Lau R, Lev J. Contributions of behavioural decision theory to research in political science. Appl Psychol 1998: 47: 29–44. Hammett TM, Norton GD, Kling R, et al. Community attitudes toward HIV prevention for injection drug users: findings from a cross-border project in southern China and northern Vietnam. J Urban Health 2005; 82 (suppl 3): iv34–42. Semaan S, Des Jarlais D, Malinowska-Sempruch K, et al. Human rights and HIV prevention among drug users. In: Beracochea E, Weinstein C, Evans D, eds. Right based approaches to public health. New York: Springer (in press).
11
12
Gardasil: from bench, to bedside, to blunder
www.thelancet.com Vol 375 March 20, 2010
A 60 RI
MA
NH
2008 HPV vaccine coverage (%)
AZ
VT
50 WA WI
CT
SD
WY MN 30
MD
OR
CO
NE
FL OK
NC MI
ND
DE NJ
IA VA
ME HI AK
40
NY NM
PA CA
MO KS OH
ID
LA AL
NV
WV TX TN
IL KY
IN
AR 20
SC GA MS
10 1·0
1·5
2·0 2·5 3·0 Cervical cancer mortality per 100 000 women (2001–05)
3·5
4·0
B 60 RI AZ NY
50 NM 2008 HPV vaccine coverage (%)
The 2006 approval of Merck’s human papillomavirus (HPV) vaccine (Gardasil) by the US Food and Drug Administration (FDA) exemplified the potential of bench-to-bedside research. This vaccine against the virus that causes cervical cancer received immediate recommendation by the Advisory Committee on Immunization Practices at the US Centers for Disease Control and Prevention (CDC)1 for routine use in girls aged 11 and 12 years, along with catch-up vaccination for girls and women aged 13–26 years. The vaccine was incorporated into the CDC’s Vaccines for Children Program at the same time. Some public health professionals speculated that the vaccine’s rapid FDA approval and lightning-fast inclusion in CDC programmes would be followed by a colossal failure in the delivery system.2 Specifically, although the vaccine’s greatest potential clearly lies in the benefits it could confer on girls who face a high risk of cervical cancer, public health experts anticipated that the vaccine would mostly go to girls at low risk of the disease. The groups of girls more and less likely to benefit from HPV vaccination can be readily distinguished in the USA. Those who are poor and have restricted access to regular Pap testing (and the follow-up assessments and treatments that it triggers) are at high risk of invasive cervical cancer. Those who are more affluent and have access to regular Pap testing are at low risk of the disease because the test, when properly done, is highly effective.3 Cervical cancer burden differs greatly between these two groups. In the fairly poor state of Mississippi (median annual household income US$36 674), the ageadjusted cervical cancer mortality rate is 3·6 per 100 000. In Rhode Island, which is a wealthy state (median $55 980), the cervical cancer mortality rate is 50% lower (1·8 per 100 000). Were the vaccine to mostly go to girls in states such as Rhode Island rather than those in Mississippi, such a pattern would not only fail to match
SD ME
40
MA
WI PA IA
DEWACA
CT NJ
VA AK
LA
OK WV AL
30
NC TN
KY
NH
VT
FL WY OR
MI TX MO KS NE NV OH ND ID IL IN
HI
MD
CO MN
AR 20
SC
GA
MS 10 30 000
40 000
50 000 60 000 Median household income (US$ 2005–06)
70 000
80 000
Figure 1: Correlations between Gardasil coverage rates in girls aged 13–17 years and cervical cancer mortality rates (A) and median income levels (B) in US states Data are from references 5, 6, and 7. Ordinary least squares regression lines are shown for each correlation. No data are available for Montana or Utah. HPV= human papillomavirus.
963
Comment
the medical intervention to the needs of the population, but it would also be cost inefficient. Analyses by Kim and Goldie4 have shown that the vaccine is not particularly cost effective when given to girls who will ultimately have regular access to the Pap test, but reasonably cost effective when given to girls who will not. In September, 2009, the CDC released the first statelevel statistics for Gardasil use in girls in the USA.5 As predicted, the vaccine is not going to those girls who stand to gain the most. Only 15·8% of girls in Mississippi have received the vaccine, compared with 54·7% of girls in Rhode Island. More generally, residence in a state with a high cervical cancer mortality rate predicted a low vaccination rate (figure A, p=0·001 for the correlation), as did residence in a state with a low median income (figure B, p<0·001 for correlation). This pattern of uneven distribution of health-care services in the USA is not unusual. People who are affluent or white often receive more beneficial services than do those who are poor and black.8 But rarely are these inequitable gaps also inefficient. In most situations both groups of patients stand to benefit to about the same degree. In this respect, what is occurring with this vaccine is notably inefficient, a fact further exacerbated by the dual sources of vaccine efficacy. The vaccine is both a medical intervention delivered to a patient for the benefit of that patient and a community-level intervention aimed at lowering the prevalence of an oncogenic virus, which benefits girls who do not receive the vaccine too.
The current maldistribution of this vaccine raises questions. Should the CDC consider setting vaccination targets for those states where the cervical cancer burden is high? Should manufacturers be encouraged to play a greater role in marketing and distribution of the vaccine to the populations who will benefit the most? Both steps might help to ensure that this shining example of bench-to-bedside research actually makes its way to the people it was designed to help. Peter B Bach Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA [email protected] I thank Joshua N Mirkin for his assistance. I declare that I have no conflicts of interest. 1
2 3
4 5
6
7
8
Advisory Committee on Immunization Practices. Record of the proceedings. June 29–30, 2006. http://www.cdc.gov/vaccines/recs/acip/ downloads/min-jun06.pdf (accessed Dec 9, 2009). Rothman SM, Rothman DJ. Marketing HPV vaccine: implications for adolescent health and medical professionalism. JAMA 2009; 302: 781–86. Akers AY, Newmann SJ, Smith JS. Factors underlying disparities in cervical cancer incidence, screening, and treatment in the United States. Curr Probl Cancer 2007; 31: 157–81. Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med 2008; 359: 821–32. Centers for Disease Control and Prevention. National, state, and local area vaccination coverage among adolescents aged 13–17 years—United States, 2008. MMWR Morb Mortal Wkly Rep 2009; 58: 997–1001. Horner MJ, Ries LAG, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2006. 2009. http://seer.cancer.gov/csr/1975_2006/results_merged/ sect_05_cervix_uteri.pdf (accessed Oct 20, 2009). US Census Bureau. Two-year-average median household income by state: 2005 to 2008. 2008. http://www.census.gov/hhes/www/income/ statemedfaminc.html (accessed Oct 20, 2009). Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care, Institute of Medicine, National Academy of Sciences. Unequal treatment: confronting racial and ethnic disparities in health care. Washington, DC: National Academies Press, 2002.
A tale of two-component generalised HIV epidemics The 5-year strategy from the US President’s Emergency Plan for AIDS Relief, released in December, 2009, proposed a laudable goal: the prevention of 12 million HIV infections.1 But success will require resolving a deep gulf dividing the prevention community. One camp sees that multiple sexual partnerships drive infection in generalised epidemics in eastern and southern Africa, dispersed through the broad population.2 The other emphasises the large number of already infected individuals, particularly the many existing discordant couples, and stresses widespread HIV testing.3 But careful examination of these complex generalised epidemics reveals a crucial role 964
for both components (figure), and provides a basis for a unifying approach. A sexual epidemic necessarily depends on multiple partnering. But in view of the HIV virus’s low infectivity in heterosexual sex, how generalised epidemics materialise is rather mystifying. Risk during the dominant multiyear latent phase is remarkably low, well below one per 1000 acts of intercourse.4 This low infectivity results from the body’s eventual effective immune response, but also probably from adaption of the rapidly mutating virus in the short term to survival in the host rather than for transmission.5 Accordingly, serial monogamy, even with unrealistically high changes www.thelancet.com Vol 375 March 20, 2010
7
8 9
Rawson R, McCann M, Huber A, et al. Contingency management and relapse prevention as stimulant abuse treatment interventions. In: Higgins ST, Silverman K, eds. Motivating behavior change among illicit-drug abusers: research on contingency management interventions. Washington, DC: American Psychological Association, 1999. Des Jarlais D, Arasteh K, McKnight C, Ringer M, Friedman SR. Syringe exchange, injecting and intranasal drug use. Addiction 2010; 105: 155–58. Kahneman D, Tversky A, eds. Choices, values and frames. New York: Cambridge University Press, 2000.
10
Lau R, Lev J. Contributions of behavioural decision theory to research in political science. Appl Psychol 1998: 47: 29–44. Hammett TM, Norton GD, Kling R, et al. Community attitudes toward HIV prevention for injection drug users: findings from a cross-border project in southern China and northern Vietnam. J Urban Health 2005; 82 (suppl 3): iv34–42. Semaan S, Des Jarlais D, Malinowska-Sempruch K, et al. Human rights and HIV prevention among drug users. In: Beracochea E, Weinstein C, Evans D, eds. Right based approaches to public health. New York: Springer (in press).
11
12
Gardasil: from bench, to bedside, to blunder
www.thelancet.com Vol 375 March 20, 2010
A 60 RI
MA
NH
2008 HPV vaccine coverage (%)
AZ
VT
50 WA WI
CT
SD
WY MN 30
MD
OR
CO
NE
FL OK
NC MI
ND
DE NJ
IA VA
ME HI AK
40
NY NM
PA CA
MO KS OH
ID
LA AL
NV
WV TX TN
IL KY
IN
AR 20
SC GA MS
10 1·0
1·5
2·0 2·5 3·0 Cervical cancer mortality per 100 000 women (2001–05)
3·5
4·0
B 60 RI AZ NY
50 NM 2008 HPV vaccine coverage (%)
The 2006 approval of Merck’s human papillomavirus (HPV) vaccine (Gardasil) by the US Food and Drug Administration (FDA) exemplified the potential of bench-to-bedside research. This vaccine against the virus that causes cervical cancer received immediate recommendation by the Advisory Committee on Immunization Practices at the US Centers for Disease Control and Prevention (CDC)1 for routine use in girls aged 11 and 12 years, along with catch-up vaccination for girls and women aged 13–26 years. The vaccine was incorporated into the CDC’s Vaccines for Children Program at the same time. Some public health professionals speculated that the vaccine’s rapid FDA approval and lightning-fast inclusion in CDC programmes would be followed by a colossal failure in the delivery system.2 Specifically, although the vaccine’s greatest potential clearly lies in the benefits it could confer on girls who face a high risk of cervical cancer, public health experts anticipated that the vaccine would mostly go to girls at low risk of the disease. The groups of girls more and less likely to benefit from HPV vaccination can be readily distinguished in the USA. Those who are poor and have restricted access to regular Pap testing (and the follow-up assessments and treatments that it triggers) are at high risk of invasive cervical cancer. Those who are more affluent and have access to regular Pap testing are at low risk of the disease because the test, when properly done, is highly effective.3 Cervical cancer burden differs greatly between these two groups. In the fairly poor state of Mississippi (median annual household income US$36 674), the ageadjusted cervical cancer mortality rate is 3·6 per 100 000. In Rhode Island, which is a wealthy state (median $55 980), the cervical cancer mortality rate is 50% lower (1·8 per 100 000). Were the vaccine to mostly go to girls in states such as Rhode Island rather than those in Mississippi, such a pattern would not only fail to match
SD ME
40
MA
WI PA IA
DEWACA
CT NJ
VA AK
LA
OK WV AL
30
NC TN
KY
NH
VT
FL WY OR
MI TX MO KS NE NV OH ND ID IL IN
HI
MD
CO MN
AR 20
SC
GA
MS 10 30 000
40 000
50 000 60 000 Median household income (US$ 2005–06)
70 000
80 000
Figure 1: Correlations between Gardasil coverage rates in girls aged 13–17 years and cervical cancer mortality rates (A) and median income levels (B) in US states Data are from references 5, 6, and 7. Ordinary least squares regression lines are shown for each correlation. No data are available for Montana or Utah. HPV= human papillomavirus.
963
Comment
the medical intervention to the needs of the population, but it would also be cost inefficient. Analyses by Kim and Goldie4 have shown that the vaccine is not particularly cost effective when given to girls who will ultimately have regular access to the Pap test, but reasonably cost effective when given to girls who will not. In September, 2009, the CDC released the first statelevel statistics for Gardasil use in girls in the USA.5 As predicted, the vaccine is not going to those girls who stand to gain the most. Only 15·8% of girls in Mississippi have received the vaccine, compared with 54·7% of girls in Rhode Island. More generally, residence in a state with a high cervical cancer mortality rate predicted a low vaccination rate (figure A, p=0·001 for the correlation), as did residence in a state with a low median income (figure B, p<0·001 for correlation). This pattern of uneven distribution of health-care services in the USA is not unusual. People who are affluent or white often receive more beneficial services than do those who are poor and black.8 But rarely are these inequitable gaps also inefficient. In most situations both groups of patients stand to benefit to about the same degree. In this respect, what is occurring with this vaccine is notably inefficient, a fact further exacerbated by the dual sources of vaccine efficacy. The vaccine is both a medical intervention delivered to a patient for the benefit of that patient and a community-level intervention aimed at lowering the prevalence of an oncogenic virus, which benefits girls who do not receive the vaccine too.
The current maldistribution of this vaccine raises questions. Should the CDC consider setting vaccination targets for those states where the cervical cancer burden is high? Should manufacturers be encouraged to play a greater role in marketing and distribution of the vaccine to the populations who will benefit the most? Both steps might help to ensure that this shining example of bench-to-bedside research actually makes its way to the people it was designed to help. Peter B Bach Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA [email protected] I thank Joshua N Mirkin for his assistance. I declare that I have no conflicts of interest. 1
2 3
4 5
6
7
8
Advisory Committee on Immunization Practices. Record of the proceedings. June 29–30, 2006. http://www.cdc.gov/vaccines/recs/acip/ downloads/min-jun06.pdf (accessed Dec 9, 2009). Rothman SM, Rothman DJ. Marketing HPV vaccine: implications for adolescent health and medical professionalism. JAMA 2009; 302: 781–86. Akers AY, Newmann SJ, Smith JS. Factors underlying disparities in cervical cancer incidence, screening, and treatment in the United States. Curr Probl Cancer 2007; 31: 157–81. Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med 2008; 359: 821–32. Centers for Disease Control and Prevention. National, state, and local area vaccination coverage among adolescents aged 13–17 years—United States, 2008. MMWR Morb Mortal Wkly Rep 2009; 58: 997–1001. Horner MJ, Ries LAG, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2006. 2009. http://seer.cancer.gov/csr/1975_2006/results_merged/ sect_05_cervix_uteri.pdf (accessed Oct 20, 2009). US Census Bureau. Two-year-average median household income by state: 2005 to 2008. 2008. http://www.census.gov/hhes/www/income/ statemedfaminc.html (accessed Oct 20, 2009). Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care, Institute of Medicine, National Academy of Sciences. Unequal treatment: confronting racial and ethnic disparities in health care. Washington, DC: National Academies Press, 2002.
A tale of two-component generalised HIV epidemics The 5-year strategy from the US President’s Emergency Plan for AIDS Relief, released in December, 2009, proposed a laudable goal: the prevention of 12 million HIV infections.1 But success will require resolving a deep gulf dividing the prevention community. One camp sees that multiple sexual partnerships drive infection in generalised epidemics in eastern and southern Africa, dispersed through the broad population.2 The other emphasises the large number of already infected individuals, particularly the many existing discordant couples, and stresses widespread HIV testing.3 But careful examination of these complex generalised epidemics reveals a crucial role 964
for both components (figure), and provides a basis for a unifying approach. A sexual epidemic necessarily depends on multiple partnering. But in view of the HIV virus’s low infectivity in heterosexual sex, how generalised epidemics materialise is rather mystifying. Risk during the dominant multiyear latent phase is remarkably low, well below one per 1000 acts of intercourse.4 This low infectivity results from the body’s eventual effective immune response, but also probably from adaption of the rapidly mutating virus in the short term to survival in the host rather than for transmission.5 Accordingly, serial monogamy, even with unrealistically high changes www.thelancet.com Vol 375 March 20, 2010