If researchers finally do develop an effective HIV vaccine, what then? There's a vaccine already on the market with the potential to considerably reduce HIV transmission and disease. This is the anti-HPV vaccine, the Merck-produced Gardasil (another, Cervarix, by GSK, is on the way). Gardasil's experience is a harbinger of what's in store for an HIV vaccine.

HPV, or human papillomavirus, causes anogenital warts and asymptomatic infections. Chronic infection with some of the asymptomatic strains may lead to cervical or anal cancer. These malignancies spread to surrounding organs, causing intense suffering and death. Despite highly effective surgical treatments, there are still a substantial number of deaths from anal and cervical cancer even in rich countries -- about 5,000 deaths annually in the US alone.

Human Papillomavirus

Source: CDC/FA Murphy

HPV disease screening and treatment cost the US alone an estimated $6 billion per year. Kevin Ault of Emory University is one of the foremost HPV vaccine researchers. He told HHSWatch, "Seven percent of all cervical Pap smears are abnormal, but few turn out to be cancer. We scare everybody to death to find those few cases. The vaccine will reduce the number of these false Pap smears and the amount of inappropriate treatment." Treatment of precancerous cervical abnormalities requires carefully distinguishing high-risk from low-risk growths (American Society for Colposcopy and Cervical Pathology Consensus Guidelines, October 2007). The intervention involves excising the affected area, usually with an electric loop. These procedures compromise the cervix, doubling the risk of premature labor.

Gardasil is composed of noninfectious hollow HPV shells. Much new data on its protective ability have become available in the last few months. At the same time, the vaccine has become wracked with controversy over its safety, efficacy, high cost, muscular marketing, and efforts to make it mandatory for preteen girls.

The controversy recalls the one in the 1990s over the hepatitis B vaccine. That relatively costly vaccine protects against a virus with a number of parallels to HPV, including the potential for sexual transmission. In 1991, the CDC embarked on a policy of universal childhood hepatitis B vaccination after repeated failure of vaccination drives in high-risk groups such as hospital workers and gay men. States then adopted mandatory vaccination of schoolchildren. Although many American adults remain unvaccinated, there has been an 80% decrease in new hepatitis B cases since the 1980s (CDC. Disease Burden from Hepatitis A, B, and C in the United States and MMWR, January 2 2004).

HPV Promotes HIV Transmission and Disease

HPV is the most common STD. Most people clear the infection after six to 12 months, but they can be reinfected by another of the three dozen sexually transmitted strains. There is accumulating evidence that HPV-associated anal warts make people more susceptible to HIV. At the biannual meeting of the International Society for STD Research (ISSTDR) last July, the HIM cohort in Sydney, Australia reported its findings from annual examinations of 1,427 gay men (Feng et al. ISSTDR July 2007, abstract O-001). Nearly 20% of the men reported ever having had anal warts, with a yearly incidence of 2%. After adjustment for unprotected sex, anal warts in the past year were associated with a 3.4-fold increase in risk of acquiring HIV. This was greater than the risk from herpes in this study and comparable to the genital herpes-associated HIV risk reported elsewhere (see HHS Watch, September 2007).

HPV is an HIV prevention issue, and it is also an HIV disease prevention issue. HPV is more prevalent in populations with high HIV rates. The Women's Interagency Health Study found that women considered at high risk for HIV had anal and cervical HPV prevalences of 43% and 24%, respectively (Palefsky et al. Journal of Infectious Diseases, February 1, 2001). For HIV-positive women in the same cohort, the figures were still higher, 79% and 53%. (Note that in both cases, the anal HPV rate was even higher than the cervical one.) The San Francisco Men's Health Study detected anal HPV in 61% of HIV-negative gay men and in 93% of HIV-positive gay men (Palefsky et al. Journal of Infectious Diseases, February 1998).

Advanced Precancerous Cervical Cells

Source: International Association of Chinese Pathologists

People with HIV do not clear HPV nearly as often as their HIV-negative counterparts do, and HPV-associated abnormal cell growth is two to three times more frequent (Palefsky. Topics in HIV Medicine, August-September 2007). The immune restoration accompanying antiretroviral therapy unfortunately does not decrease the frequency of HPV-related malignancy. A study published last August found that anal warts, not usually associated with cancer, frequently contain malignant cells in HIV-positive men (McCloskey et al. International Journal of STD & AIDS, August 2007). Finally, some studies indicate that the presence of HPV-triggered genital growths is associated with increased HIV in genital secretions (Spinillo et al. Obstetrics and Gynecology, February 2006). In this way, HPV could render coinfected individuals more likely to transmit HIV.

An Effective Vaccine, With Caveats

There is no doubt that the HPV vaccine is highly effective in protecting women against the associated abnormal cervical growths (Ault et al. Lancet, June 2, 2007) and warts (Ault. ISSTDR July 2007, abstract O-109). Modeling of the rate of antibody decay indicates that the protection afforded by the vaccine probably lasts for decades if not for life (Fraser et al. Vaccine, May 22, 2007).

There are four major caveats to these findings: First, they do not yet apply to men or to anal disease -- those trials are still ongoing. Secondly, you have to receive all three doses of the vaccine according to schedule. Thirdly, the vaccine mainly protects against the HPV strains for which it contains representative envelope proteins. The two carcinogenic strains in the vaccine are responsible for 70% of cervical malignancy. (Gardasil, but not Cervarix, also protects against two HPV strains responsible for 90% of anogenital warts.) Finally, the vaccine is not protective against HPV strains you contracted before being immunized.

Among 20,000 women in Merck-sponsored trials, the vaccine was 99% protective against precancerous and cancerous cervical lesions for the three years of observation (Ault et al. Lancet, June 2, 2007). That's if all the above conditions were met. The vaccine provided little, if any, benefit to people who entered the trial already infected with one of the vaccine's HPV strains.

One new study reported that there is 40% cross-protection against carcinogenic strains not contained in the vaccine (Brown et al. ICAAC September 2007, abstract G-1720b). Again, you have to be vaccinated before exposure. The large Merck trials detected no protection against cervical conditions arising from nonvaccine HPV strains. That is at least partly because many trial participants had previously contracted those strains. For the general public, HPV testing and Pap smears will continue to be useful, if less critical, in reducing the overall cervical cancer rate.

These issues are magnified in poorer nations, where regular Pap smears and HPV testing are uncommon. Cervical cancer in poor countries is three to ten times more frequent than in the US. A mathematical model, taking into account both difficulties in vaccinating all women and the lack of protection against all HPV strains, forecast that providing the vaccine alone to girls aged 9 to 12 in poor countries would decrease cervical cancer by 40% (Sherris, ISSTDR July 2007, Monday morning plenary presentation -- no abstract). In comparison, three lifetime cancer screenings (at ages 35, 40 and 45) would reduce cervical cancer by less than 30%. Combining the two would yield still better protection -- a 60% decline in new cervical cancer.

Safety: Everybody Has an Agenda

In 2007, with the push toward mandatory HPV vaccination of schoolchildren in 26 state legislatures, the vaccine came under considerable attack by a tacit alliance of anti-vaccine activists and right-wing groups. In October, the conservative legal gadfly Judicial Watch issued a scathing criticism of the vaccine's safety (Judicial Watch, October 4, 2007). The group examined the raw records in the CDC/FDA Vaccine Adverse Event Reporting System (VAERS).

Judicial Watch President Tom Fitton summed up his organization's conclusions by saying, "In light of this information, it is disturbing that state and local governments might mandate in any way this vaccine for young girls. These adverse reaction reports suggest the vaccine not only causes serious side effects, but might even be fatal."

HHSWatch examined the VAERS data on December 15. On that day, VAERS contained 799 serious event records for Gardasil, including 11 deaths. The problem with the VAERS records is that they are very rough and preliminary. Anybody, including the general public, can provide VAERS reports. Frequently they describe an event that one person heard about from somebody else. The only criterion for including the report is that the reporter believes there is a link to the vaccine.

Judicial Watch does not seem to have read the VAERS records very closely. Its web site presents ten copies of VAERS records describing Gardasil-related deaths. Of these, two are duplicates, four are based on hearsay (one notes, "the patient may not have expired"), two involved serious viral infections, and one had evidence of a prior unrecorded heart condition. In this last case, the patient's collapse and death occurred two weeks after vaccination. It is difficult to ascribe any of these cases to the vaccine without further investigation.

It is even hard to say how many deaths really occurred. As of last June, the CDC reported that it could confirm only four deaths occurring after vaccination (Iskander. Advisory Committee on Immunization Practices, June 28, 2007). Its investigation did not attribute any of these to Gardasil.

A more carefully recorded set of data comes from the Gardasil clinical trials, in which 10,500 people received the vaccine and a similar number received placebo. The trials noted 17 deaths, ten in the HPV vaccine recipients and seven among those receiving a placebo vaccine. No particular cause of death stood out as possibly related to Gardasil (Gardasil Prescribing Information, November 2007).

A Vaccine for the People or the Privileged?

In the end, only two states, Virginia and New Jersey, passed legislation to add the HPV vaccine to the growing list of vaccines required to attend school. The mandatory vaccination bills were either withdrawn or tabled in the other states. "We're not ready for mandatory HPV vaccination," commented Lauri Markowitz, one of the CDC's top experts on these vaccines. The issue is dead for now, but the bedrock problem of accessibility remains little examined. The nation's vaccine financing system is unraveling, and many people face unexpected hurdles when seeking HPV immunization.

The CDC currently recommends that all women 11 to 26 receive the HPV vaccine as soon as possible. That's about 30 million women, and the three-shot vaccine costs about $400. The immediate outlay in the US alone would then be $12 billion. Every year, another 2 million American girls reaching age 11 would be vaccinated, at a cost of $800 million.

These calculations leave aside the question of whether males and older women should also be immunized. Merck is already asking the FDA for approval to administer its vaccine to women as old as 45 based on trial results presented last November at the 24th International Papillomavirus Conference (Merck Press Release. November 5, 2007). The theory is that vaccinating older women provides them with catch-up protection for the HPV strain to which they have not been exposed. Data on men, who are certainly also vulnerable to HPV's genital and anal effects, will be available in 2008. Bloomberg News (October 4, 2007) has estimated that Gardasil generated $1.4 billion in sales in 2007. According to Bloomberg, sales could reach $10 billion annually if approved for boys and men.

In the United States, the CDC's Vaccines for Children (VFC) program supplies vaccines for children enrolled in Medicaid plus those without insurance covering vaccinations (uninsured or underinsured children). VFC is an entitlement program whose budget increases automatically to meet costs. That budget has expanded four-fold since 2000, in parallel with the number and cost of vaccines. VFC now spends almost $2 billion annually to supply 43% of US children's vaccine needs. Just vaccinating 10 and 11 year-old girls for HPV will increase VFC expenditures by more than 10%.

Medicaid-enrolled and uninsured children are not the major gap in this program. They receive the VFC-paid vaccines from their regular care provider, as part of state Medicaid programs. There remain underinsured children, who make up 14% of Americans aged 0 to 17. VFC will pay for their vaccines only if they go to certain "federally qualified" or rural clinics, which exist only in a limited number of locations. Another barrier is that these clinics usually charge patients a $15 administrative fee. Worse yet, VFC does not cover children whose insurance will not pay for their vaccines merely because they have not met their plans' high yearly deductible.

Federal Financing for Vaccines

Source: Grace Lee, Harvard Medical School. Advisory Committee for Immunization Practices, June 27, 2007 Click image to enlarge.

Federal "section 317" grants and a patchwork of state funding attempt to fill these holes. The National Conference of State Legislatures lists 11 states that pay for vaccines to all their youthful residents, but restrictions are steadily increasing. Most state programs require that underinsured children go to public clinics to obtain the newer vaccines, and they may not be available even there. The CDC's National Immunization Survey estimates that in 2006, only 64% of children aged 19 to 35 months had complete vaccine coverage.

Four states -- Alaska, New Hampshire, South Dakota and Washington -- are now paying for universal HPV vaccination for girls. Unless they are in Medicaid, persons over the age of 18, however, have no reimburser of last resort in these states or elsewhere.

Delays in receiving the HPV vaccine may occur even for women with adequate insurance. Their doctors may be unable or unwilling to stock adequate amounts of this expensive vaccine. The traditional means of obtaining a vaccine in the United States is from your doctor, who keeps a supply on hand in the clinic, and few patients know that vaccines are also obtainable from pharmacies by prescription. For everyone, going to the drugstore to buy a vaccine is an extra, unfamiliar step.

Barriers to obtaining the HPV vaccine are critical in the adolescent years, since most women start having sex when they are 16 to 18 years old. The same can be said for young men, especially gay ones. Merck has yet to provide any data in males, and as a result, none have insurance that covers HPV immunization. Many young adults stand to miss the protection that the vaccine offers due to all these barriers. That protection marks an important advance for teens exploring their nascent sexuality. It's a human rights question as well as a health one.