HPV Vaccination Program: Bhutan Make Headway Towards Eliminating Cervical Cancer

A national program for human papillomavirus (HPV) vaccination initiated in 2010 for girls aged 12-18 years achieved roughly 90% coverage in Bhutan and led to an 88% reduction in vaccine-related, high-risk HPV throughout the country. These results lend support to the goal of the World Health Organization to eliminated cervical cancer completely, and are published in Annals of Internal Medicine.

“Cervical cancer is the most frequent cancer type among women in Bhutan, where the age standardized (world) incidence rate — 14.5 per 100,000 persons — is similar to rates reported from the rest of South Asia,” wrote Iacopo Baussano, MD, of the International Agency for Research on Cancer, Lyon Cedex, France, and fellow researchers.

Currently, there are three effective HPV vaccines available:

1. Quadrivalent vaccine: Protects against HPV6, 11, 16, and 18.
2. Bivalent vaccine: Protects against HPV16 and 18, with cross-protection against HPV31, 33, and 45.
3. Nonvalent vaccine: Protects against HPV6, 11, 16, and 18, with additional protection against HPV31, 33, 45, 52, 58.

All three vaccines are administered on a two-dose schedule, but one-dose administration may also be sufficient, according to recent studies.

Bhutan’s HPV vaccination program — mainly school-based and focused on 12-year-old girls — is comprised of a three-dose schedule of quadrivalent vaccine that targets HPV6, 11, 16, and 18. In 2016, the three-dose schedule was switched to a two-dose schedule.

To estimate the efficacy of this program, Baussano and colleagues conducted two separate cross-sectional surveys in two hospitals in Thimphu, the capital of Bhutan. The first was conducted between 2011 and 2012 and the second, in 2018.

They recruited 1,597 women, in whom they assessed HPV via cervical cell samples using GP5+/GP6+-mediated polymerase chain reaction. In all, 1,595 women completed an online questionnaire and were eligible for study inclusion.

Of the 1,258 women aged ˂27 years old, 77% reported receiving the HPV vaccine. Of these, 62% reported immunization before the age of 15 years, while 83% received more than one dose of the vaccine.

Upon analysis, Baussano and fellow researchers found that the prevalence of HPV vaccine types—including HPV6, 11, 16, and 18—decreased from 8.3% to 1.4%, while that of nonvaccine types (including ɑ-9 types, other ɑ -7 types, or non-ɑ-7/9 types) increased from 25.8% to 1.4%. Overall adjusted vaccine effectiveness (VE) against vaccine-targeted HPV types was 88% (95% CI: 80%-90%) and the indirect (herd immunity) adjusted VE was 78% (95% CI: 61%-88%).

In women younger than 27 years old targeted by the program, the overall adjusted VE was 93% (95% CI: 87%-97%), while the indirect adjusted VE was 88% (95% CI: 69%-95%). It had no impact on nonvaccine HPV types.

The prevalence of HPV decreased steadily with age. In women aged ≤19 years, prevalence was 42%, and in those aged ≥25 years, 28%. HPV prevalence was also higher in women who had been married more than once (PR: 1.5; 95% CI: 1.1-1.9), women with more lifetime sexual partners and those having partners who had extramarital sex (PR: 1.4; 95% CI: 1.1-1.9), and women who had a history of receiving cash for sex (PR: 2.2; 95% CI: 1.5-3.1).

“The total effectiveness of vaccination against vaccine-targeted HPV types, which provides vaccine efficacy estimates from real-life settings, was 95%—very similar to that reported from clinical trials,” wrote Baussano et al. “In summary, we believe this study provides the first evidence from a lower-middle-income country of the effectiveness of a high-coverage national program of HPV vaccination. Continued assessment will be necessary to monitor the sustained effect of the 2-dose HPV vaccination schedule recently introduced into Bhutan and to observe whether the effectiveness increases, as expected, in cohorts that were vaccinated at age 12 years rather than during a catch-up program. The findings reported here strengthen stakeholders’ commitment to support HPV vaccination in lower-middle-income countries and help tailor cervical cancer screening programs to the substantial decline of HPV16/18 in adequately vaccinated populations,” they concluded.

Timothy Palmer, BSc, of the University of Edinburgh, and Kate Cuschieri, MSc, PhD, of the Royal Infirmary of Edinburgh, both in Edinburgh, Scotland, weighed in on these results in an accompanying editorial.

“These results are extremely encouraging considering the global burden of cervical cancer. A recent assessment placed cervical cancer among the top 3 cancer types affecting women younger than 45 years in nearly 80% of the 185 countries surveyed. This finding has major consequences in terms of lost productivity and disruption of families. By far, low- and middle-income countries (LMICs) bear the greatest burden,” they wrote.

Palmer and Cuschieri also detailed the many developments and hurdles that mark the history of HPV vaccination, from development of the vaccine, to molecular HPV testing, to the affordability and accessibility of these vaccines in LMICs and the infrastructure required to deliver the vaccines. Finally, the choice of the appropriate vaccine and schedule for its administration are also important considerations.

“These factors are irrelevant, however, without the willingness of the population to be vaccinated. Achieving and sustaining the level of uptake needed for elimination of cervical cancer requires communicating to girls, women, and their families the effectiveness and safety of the vaccines,” they added.

“A wealth of published data and reports from countries that have well-established immunization and monitoring programs document effectiveness and safety. Robust evidence is important, but a successful communication campaign needs to appeal to the heart as well as the mind. Countries implementing HPV immunization must monitor the effectiveness of the vaccine in reducing infection and preinvasive disease, but mortality reductions will take many years to become evident. Countries must also demonstrate a political and professional commitment, using real-life stories of the benefits of immunization to show the safety and value of the immunization program. Bhutan shows that all of this is possible. Other countries should now follow suit,” concluded Palmer and Cuschieri.

Study limitations include its focus on only two hospitals in Bhutan, self-reported vaccination status, and lack of data allowing researchers to estimate study participation rates.

1. Human papillomavirus (HPV) immunization program in Bhutan achieved a high vaccination uptake (~90%) in girls and women aged 12-18 years via a school-based approach, as well as in older women using a catch-up approach.

2. Use of the quadrivalent HPV vaccine reduced vaccine-related, high-risk HPV by a full 88% in Bhutan.

E.C. Meszaros, Contributing Writer, BreakingMED™

Cat ID: 190

Topic ID: 79,190,190,31,191,138,44,192,925