Introduction

Worldwide, about half a million cases of cervical cancer are estimated. In developed countries, screening intervention strategies have decreased the mortality rate. In Peru, cervical cancer is the second cause of cancer in women, a serious public health issue¹. In developing countries, cases have not decreased despite the strategies implemented. For many years, the intervention tool has been conventional cytology. Currently, it is known that cytology sensitivity is about 50% in research scenarios, and about 22.1% in real scenarios².

In Latin America, nearly 69 000 new cases of cervical cancer and approximately 29 000 deaths associated with this disease are reported annually³. Cancer rates associated with HPV have varied over time based on each region. Decreasing cases of cervical cancer were found in developed countries, but the incidence of cancer of the anus, oropharynx, and vulva of the squamous type has increased. HPV 16 and 18 are estimated to be responsible for more than 90% of oropharynx, cervix and anal canal cancer cases⁴. In 2015, HPV-associated oropharynx cancer was the most frequent in the United States, above cervical cancer⁵.

Intervention strategies for cervical cancer are based on:

a) Primary prevention with vaccines

b) Secondary prevention with diagnosis and treatment of premalignant lesions and early clinical cancer stages.

HPV vaccine was introduced in 2006. In order to monitor the impact of HPV vaccination, three levels of evaluation have been used over time. The first evaluation is at short term, in months, measuring the HPV infection prevalence and the presence of genital warts. In the intermediate term, in years, reduction in the incidence of cervix, vulva, vagina, and anus premalignant lesions. Finally, in the long term, in decades, with incidence of cervical, vulva, vaginal and anal cancer⁶.

Methodology

Search of PUBMED database was performed using the following key words: HPV vaccine, cervarix, gardasil, nonavalent HPV vaccine, cervical cancer. Available data from the Ministry of Health (MINSA) was accessed through the OGTI (General Office of Information Technology).

Human papilloma virus

The human papilloma virus (HPV) is a double stranded DNA with more than 120 different genotypes⁷. It is the cause of the most frequent sexually transmitted infection. HPV types are categorized as low risk (types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81) and high risk (types 16, 18, 31, 33, 35, 45, 51, 52, 56 and 58). Those high risk or oncogenic are related to persistent HPV infection and able to generate premalignant lesions and cervical cancer; the low risk or non-oncogenic could develop genital warts, condylomata acuminata, papillomas, and laryngeal papillomatosis^7,8.

Three vaccines have historically been developed to prevent HPV-associated diseases.

Dosage and schedules

The vaccine started with three application dos-es, 0-1-6 and 0-2-6 months for each vaccine; but studies have shown changes over time.

Vaccination in Peru

In Peru, on January 28, 2011, the HPV vaccine was incorporated as part of the national vaccination scheme, according to Technical Health Standard N° 080-MINSA / DGSP V.02 "Technical Health Standard that establishes the National Vaccination Scheme", approved with Ministerial Resolution No. 510-2013 / MINSA¹⁹. By using the bivalent recombinant vaccine at 0.5 mL intramuscular dose, 3-dose schedule 0-2-6 months, the recommendation was for 10-year-old girls and, as captive population strategy, for girls not older than 15 years at schools, and on demand in health facilities.

On April 22, 2015, the Ministry of Health (MINSA) approved the Health Directive No. 064-MINSA / DGSP V.01 for the administration of the Vaccine against the Human Papilloma Virus (HPV) ²⁰, with a recombinant quadrivalent vaccine to cloudy white suspension, in 0.5 mL single dose vial, intramuscular. The vaccination strategy was recommended in a 3-dose schedule, 0-2-6 months. It was administered to 5th graders (girls aged 10 to 13), as well as on a house-to-house basis and or vaccination facilities.

Girls who had not completed the three dos-es of vaccines had to complete the vaccination schedule in order to close the gap for years 2011, 2012, 2013 and 2014, considering the vaccination schedule established in NTS N° 080- MINSA / DGSP V.03. This directive recommended the vaccination scheme for girls in the 5^th grade of public and private elementary schools. In exceptional cases, for those girls (10 to 13 years old), who were not vaccinated, it was recommended to attend a health facility to request such a vaccine²¹.

In reference to the interchangeability of the bivalent HPV vaccine with the quadrivalent HPV vaccine, MINSA followed the recommendation from USCDC’s ACIP (the Advisory Committee on Immunization of the US Center for Disease Control and Prevention). They recommend: "in case of not knowing which vaccine was previously applied or the corresponding one was not available; any vaccine can be applied to complete the scheme to protect against genotypes 16 and 18".

On August 31, 2016, the Technical Health Standard No. 080-MINSA / DGIESP-V.04 "Technical Health Standard establishing the National Vaccination Scheme" was approved, with Ministerial Resolution No. 651-2016 / MINSA that establishes vaccination against HPV for girls of 5^th and 6^th grade of public and private elementary educational institutions as well as for girls of 9 to 13 years with 11 months 29 days of urban and rural population who for some reason are not studying. They must be registered and vaccinated in health establishments and / or vaccination brigades²². The new vaccination scheme is with two 0.5 mL doses intramuscularly (0-6 months). Girls and adolescents who have already started vaccination with the previous scheme (3 doses) will continue and complete the vaccination or gap closure scheme with the three doses of vaccines, during the years 2011, 2012, 2013, 2014, 2015 and 2016.

On August 1, 2018, the Technical Health Norm No. 141-MINSA / 2018 / DGIESP "Technical Health Norm that establishes the National Vaccination Scheme" was approved with Ministerial Resolution No. 719-2018 / MINSA. This resolution did leave without effect Ministerial Resolution No. 651-2016 / MINSA, of August 31, 2016, which described the vaccination scheme for girls and adolescent women in the 5^th grade of both public and private elementary school, and for adolescent female girls from 9 to 13 years old with 11 months 29 days that for some reason were not attending school²³.

On December 29, 2016, the Technical Guide: "Clinical Practice Guide for the prevention and management of cervical cancer" was approved, with Ministerial Resolution No. 1013-2016 / MINSA, establishing HPV vaccination as part of the primary prevention of cervical uterine cancer ²⁴.

On June 26, 2019, the Health Directive No. 085-MINSA / 2019 / DGIESP "Health Directive for the prevention of cervical cancer through the early detection and treatment of pre-malignant lesions including carcinoma in situ" was approved by Ministerial Resolution No. 576-2019 / MINSA which derogated Ministerial Resolution No. 1013-2016 / MINSA. This new Ministerial Resolution establishes, as part of the primary prevention of cervical cancer, vaccination against HPV, according to Technical Health Standard No. 141-MINSA / 2018 / DGIESP "Technical Health Standard that establishes the National Vaccination Scheme": in women living with HIV under 20 years old with a negative HPV molecular test, may receive vaccination according to the evaluation of their immunological status which depends on the treating specialist physician²⁵.

The HPV vaccination goal initially projected by the Ministry of Health for 2019 according to the nominal registry of HPV vaccination, was 269 316 girls; 234 535 (87%) and 211 339 (78%) were applied as the first and second dose respectively. However, the nominal record of the 5^th grade indicated by the Ministry of Education for June 17, 2019 was 232 318 girls, establishing a different denominator. Finally, based on the new data on the nominal standard, the Ministry of Health established a higher coverage than that described. It is also noted in the OGTI (General Information Technology Office) that vaccination was completed in older girls in the same campaign. The difference in the denominator value in this calculation allows us to understand the reported values.

Discussion

HPV is the main risk factor for the formation of pre-malignant lesions and cervical cancer. The HPV family are a group of viruses that infect the skin and mucous membranes; most of these infections are cleaned by the effect of the immune system. But some people can have persistent infection and certain types of viruses could cause abnormalities in cells. These changes are called pre-malignant lesions and they could eventual ly develop cancer of cervix, vagina, vulva, anal canal, penis, head and neck, as well as develop genital warts⁷.

There are two approaches to cervical cancer prevention: A primary prevention through HPV vaccine, the causative agent of the disease; and a secondary prevention through screening, detection, and treatment of pre-malignant lesions before they become invasive cancer¹⁶. In low-income countries, where cancer control is a challenge due to funding, technical resources, and limited human resources, prevention through cervical screening and early detection can provide great benefits in cancer control^20,21. In places where screening strategies have not been successful, intervention through immunization with HPV will play a significant role in controlling the disease²⁶. A special population is patients treated with CIN2 + with LLETZ (large loop excision of the transformation zone), where the quadrivalent vaccine was applied after the procedure in doses 0-2-6, finding that it could reduce the risk of recurrence by 80%.

Genital warts represent another frequent pathology that also has an impact on the morbidity of women. Genital warts are generally associated with under registration; the prevalence is 2.28% (CI 95%: 2.02 to 2.56) in Peru and apparently these are cases usually seen in medical offices²⁷.

Screening with HPV is the ideal test as primary screening. This test should be used especially in places where no response has been found with other strategies²⁸. The HPV test has high sensitivity and reproducibility compared to cytology. Additionally, the HPV test could be used in the future with self-sampling^18,24. Another benefit is that the interval between a HPV test and the next screening can be extended to 5 years²⁸. A drawback of the HPV test is the high prevalence compared to cytology. This, in turn, increases the number of patients referred to colposcopy. For this reason, a prior triage test must be found. This unknown triage test is intended to be found by the ESTAMPA study²⁹.

It can be concluded that there is scientific evidence of the efficacy of the HPV vaccine against pre-malignant lesions and genital warts; but, given the long latency time between HPV infection and invasive cancer, the real effect of the impact of vaccination on incidence of cervical cancer will show up after several years¹⁶. Australia was one of the first countries to include the vaccine as a national vaccination program in April 2007 with girls 12-13 years old and with catch-up in women younger than 26 years; in 2013 it included children 12-13 years with catch-up in children up to 15 years; the coverage achieved was 70%. Currently, if the high vaccination and screening coverage is maintained, it could be considered that cervical cancer will be a disease of the past for that country.

The vaccination strategy in Peru is for girls in the 5^th grade of elementary schools, chosen as the target population. This intervention strategy depends on each country.

Given the coronavirus pandemic, it is expected that the vaccination schedule will have to be modified. So, moving to a 2-dose strategy (0-12 months) in schools would be an option, because it would allow a single visit for the first dose in the 5^th grade of elementary and a second dose in the 6^th grade of elementary, a vaccination scheme that is managed in different countries.

With the implementation of vaccination in Latin America, a high impact is expected in the reduction of cases with cervical cancer, but the efficacy of the vaccination program is still a challenge at the regional level. The cost-effectiveness studies of the HPV vaccine in women in Peru after 10 years of implementation suggest that they are cost-effective compared to the unvaccinated group²⁸. The HPV vaccine is a very cost-effective strategy in Peru according to the WHO's recommendations. In conclusion, screening and vaccinating is more cost-effective than screening only. In a systematic review of cost-effectiveness studies on gender-independent G9 vaccine, it was confirmed the health and economic benefit of the introduction of vaccination programs be-cause the increase in the cost-effectiveness rate does not exceed the respective local economic limits in any of the studies.

We should use formative research as an introduction strategy for the HPV vaccine, which aims to understand the sociocultural environment of the health system and provide the research keys to share the HPV vaccine introduction programs. We should also use participatory community-based research, which will provide techniques to help implement cervical screening, treatment and vaccination processes^30,31. The next generation of vaccines could increase the range of protection against HPV¹⁶ and perhaps decrease the regimen to a single dose.

Finally, the HPV vaccine has been shown to be effective, safe, and well tolerated. The coverage against cervical cancer with G4 is 70% of protection; while the coverage with G9 vaccine is 90% of protection. There are challenges in the HPV vaccine intervention strategy to achieve greater coverage. It is important to emphasize that the incidence of cervical cancer has not changed in the last 10 years despite efforts in secondary prevention. Therefore, in these scenarios, the implementation of an adequate vaccination program with high coverage could decrease the incidence of the disease. We must continue to use for prevention:

The main multifactorial barriers to HPV vaccination are limited knowledge of HPV and misguided safety concerns. The implementation of the HPV vaccine in Latin American countries will need to adapt to a school-based vaccination program, followed by integrated monitoring to be able to reach the expected coverage³⁴.