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Effective Health Interventions for Adolescents That Could Be Integrated With Human Papillomavirus Vaccination Programs

      Abstract

      Purpose

      We reviewed published data to identify health interventions for 9–15-year-old girls and boys that could to be usefully integrated with programs of human papillomavirus (HPV) vaccination in low- and middle-income countries (LMICs).

      Methods

      Relevant literature reviews, bibliographic databases, and journals were searched to identify health-related interventions, other than immunizations, that had been found to have beneficial outcomes among adolescent girls and/or boys. An intervention was excluded if there was no evidence of its effective delivery in LMICs or no demonstrated potential for its adaptation for delivery in such countries, and/or if there was, apparently, no feasible way in which it could be delivered during a course of HPV vaccinations.

      Results

      Overall, 33 different interventions were found to have had beneficial outcomes among adolescents living in LMICs. Of these, 19 were excluded because they were deemed too expensive or too difficult to deliver within the calendar of a HPV vaccination program. The remaining 14 health-related interventions, in the fields of screening (for schistosomiasis and defects in vision), health education (on mosquito-borne diseases, the benefits of exercise, accessing health care, and sexual and reproductive health), skills building (improving condom usage) and delivery of commodities (anthelminthic drugs, vitamin A supplements, soap and/or bed nets) were deemed potential candidates for delivery in conjunction with the HPV vaccine.

      Conclusions

      The potential benefits and selection of other health-related interventions that are delivered in conjunction with HPV vaccine will be influenced by a range of factors, including the ease of delivery, the epidemiology of the priority health problems affecting adolescents, the vaccine delivery schedule, and various environmental, economic, and social factors. However, there appear to be several interventions that could usefully be integrated in many, if not all, HPV vaccination programs. The ability to deliver multiple interventions along with HPV vaccine could not only offer important efficiencies but also serve as an entry point to increase adolescents' access to health care and services.

      Keywords

      Implications and Contribution
      The contact between adolescents and health services that results from HPV vaccinations could be exploited for the delivery of additional interventions, including health education, services and commodities. Fourteen health-related interventions were identified, via a detailed literature review that could feasibly be adapted and integrated with HPV vaccination programs.
      Adolescents, defined as those aged 10–19 years, comprise the fastest-growing age group in many low- and middle-income countries (LMICs), particularly in sub-Saharan Africa and Southeast Asia [
      • Blum R.W.
      Youth in sub-Saharan Africa.
      ,
      • Blum R.W.
      • Nelson-Mmari K.
      The health of young people in a global context.
      ]. Although there are already about 1.2 billion adolescents on the planet [
      • Kleinert S.
      Adolescent health: An opportunity not to be missed.
      ], the provision of information and services to satisfy their health and development needs is often overlooked or ignored [
      • Kleinert S.
      Adolescent health: An opportunity not to be missed.
      ].
      Adolescent-specific interventions need to be carefully designed to meet the challenges of pubertal changes, initiation of sexual activity, pressure to experiment with substances such as tobacco and alcohol, societal pressures related to gender norms and the emotional strain of the transition into adulthood [
      • Bearinger L.H.
      • Sieving R.E.
      • Ferguson J.
      • et al.
      Global perspectives on the sexual and reproductive health of adolescents: Patterns, prevention, and potential.
      ,
      • Patton G.C.
      • Viner R.
      Pubertal transitions in health.
      ,
      • Toumbourou J.W.
      • Stockwell T.
      • Neighbors C.
      • et al.
      Interventions to reduce harm associated with adolescent substance use.
      ,
      • Tylee A.
      • Haller D.M.
      • Graham T.
      • et al.
      Youth-friendly primary-care services: How are we doing and what more needs to be done?.
      ]. Although the health of adolescents, who represent future parents, educators, workers, and leaders, is critical to present and future public health, this age group typically has insufficient contact with health services.
      Vaccination against human papillomavirus (HPV), which is currently targeted at 9–13-year-old girls, provides opportunities for the health sector to make additional contact with adolescents. Every contact an adolescent has with a member of a vaccine delivery team, including the health educators, teachers, and others associated with the vaccine delivery, is a potential opportunity for the provision of additional targeted health interventions. Because the HPV vaccine trials were designed to measure efficacy against cervical intraepithelial neoplasia lesions by preventing the acquisition of HPV and therefore protecting against cervical cancer, the primary population to be targeted by HPV vaccination programs was girls and young women. Although the current World Health Organization (WHO) recommendation on HPV vaccination currently only targets girls within a limited age range, and the majority of countries follow these recommendations, boys may feature in future vaccine delivery strategies as more and more data become available on the effectiveness of HPV vaccination to prevent HPV-related cancers in males, such as cancer of the penis or anus. In any event, boys should be considered for epidemiological, human rights, and cost-effectiveness reasons when planning any additional services and commodities that might be provided when girls are vaccinated.
      The choice of intervention that might be integrated with vaccine delivery should be governed by considerations of cost, delivery method, timing, personnel and training requirements, sustainability, need, and the probable and perceived benefits and disadvantages of the intervention, including any potential effects on HPV vaccine uptake. Possibilities include health education, screening, services, and the delivery of health-related commodities. In 2006, the WHO promoted the integration of HPV vaccine delivery with other health interventions targeted at adolescents, to maximize the benefits of the contact needed for vaccine delivery [
      • World Health Organization
      Preparing for the introduction of HPV vaccines. Policy and programme guidance for countries.
      ]. In order to define a menu of potential interventions, we conducted a literature review to identify specific health-related interventions with proven benefit for girls and/or boys aged 9–15 years. We then excluded interventions that did not appear appropriate for delivery during a course of HPV vaccination in LMICs [

      World Bank. How we classify countries. Available at: http://data.worldbank.org/about/country-classifications.

      ] and interventions that did not appear feasible under the constraints of vaccine delivery in schools, health facilities, or other community settings.

      Materials and Methods

      Study design

      The review focused on identifying effective interventions that would be appropriate for delivery, with HPV vaccine, to the expected beneficiary populations: boys and girls aged 9–15 years who resided in LMICs. For each intervention identified through the literature review, contraindications, delivery method, timing, and the requirements and capacity of the health system were considered. Emphasis was placed on identifying those interventions that could be delivered ‘simultaneously’ with any of the standard three doses of HPV vaccine (Package Opportunities 1, 2, and 3 in Figure 1), during the period of education and preparation before the first shot (Package Opportunity A in Figure 1) or in the periods between the three doses of vaccine (Package Opportunities B and C in Figure 1).
      Figure thumbnail gr1
      Figure 1A timeline for a standard course of vaccinations against human papillomavirus (HPV), showing the timing in months when vaccine shots are given and other health-related commodities could be delivered (points 0, 1, and 2) and the periods before each shot (A, B, and C), when other health-related interventions, such as sexual health education and skill building on health topics could occur. The second and third shots of HPV vaccine are usually given 1–2 and 6 months after the first shot, respectively.
      We identified relevant interventions in two phases: Phases 1 and 2. In Phase 1, the focus was on searching the published literature—primarily systematic reviews—for interventions of four main types (screening, service provision, information provision, and/or commodity delivery) that showed efficacy for boys and/or girls aged 9–15 years. Immunizations were not considered. To ensure the widest possible inclusion of health-related interventions, the “where?” and “how?” of the intervention delivery were not considered as exclusion criteria at this stage. The strategy for Phase 1 consisted of searching five different databases and journals, including PubMed, the Cochrane Library, the Annual Review of Public Health, the Annual Review of Nutrition, and the Food and Nutrition Bulletin, for seven keywords: “effective,” “efficacious,” “efficacy,” “intervention,” “child,” “adolescent,” and “school.” All of the searched literature had been published in English between January 1, 1990 and July 15, 2010. The authors also reviewed references cited in the relevant publications that were identified in the search and, if appropriate, included them in the results of Phase 1. The entire list of health-related interventions identified in Phase 1 is available from the authors.
      In Phase 2, the literature search was repeated with a broader set of keywords that were derived from the results of Phase 1 or were suggested by a panel of experts in adolescent heath (Table 1). The aims of this second phase were to identify any relevant types of intervention that had been missed in Phase 1 and to help narrow down the resultant list of interventions to those that could be integrated, feasibly and rationally, into programs of HPV vaccine delivery in LMICs.
      Table 1The keywords and phrases used in the Phase 2 search for health-related interventions that might usefully be integrated with programs of human papillomavirus vaccination
      Words and phrases
      Bibliographic databases were searched not only for the listed words and phrases but also for related words. For example, they were searched for “helminth,” “helminthic,” “anthelminthic,” and “anthelmintic,” as well as for “helminths.”
      “rape,” “sexual violence,” “sexual abuse,” “violence,” “abuse,” “transactional sex,” “HIV,” “HIV/AIDS,” “AIDS,” “smoking,” “contraception,” “condom,” “physical fitness,” “obesity,” “overweight,” “schistosomiasis,” “depression,” “suicide,” “mental health,” “infectious,” “disease,” “malaria,” “vaginal discharge,” “reproduction,” “reproductive health,” “sex,” “sexual health,” “micronutrients,” “nutrition,” “supplementation,” “iron,” “circumcision,” “substance abuse,” “malnutrition,” “FGM,” “vitamin A,” “helminths,” “worms,” “anemia,” “anaemia,” “Buruli ulcers,” “breastfeeding,” “asthma,” “allergies,” “vision,” “hearing,” “growth,” “disabilities,” “screenings”
      a Bibliographic databases were searched not only for the listed words and phrases but also for related words. For example, they were searched for “helminth,” “helminthic,” “anthelminthic,” and “anthelmintic,” as well as for “helminths.”
      All identified interventions were reviewed for their potential to be delivered in conjunction with the HPV vaccination program. To be considered potentially deliverable with HPV vaccinations, an intervention had to (1) benefit adolescent girls and/or adolescent boys; (2) have proven efficacy or be likely to be effective in LMICs, with the potential for adaptation for use in such countries (even if all current evidence of the intervention's efficacy and usefulness came from experiences in high-income countries); (3) have been delivered, or apparently have the potential to be delivered, in schools or community settings in LMICs; and (4) be adaptable to the delivery contexts of HPV vaccination programs.
      An intervention was excluded if it was deemed to be too expensive for routine and widespread use in LMICs, if its delivery took longer than the standard set of HPV vaccinations, if it involved extended or multicomponent treatments, if it required clinical care and/or medical diagnosis, if compliance was likely to be hampered by local beliefs and customs, or if its delivery required greater privacy than was likely to be achievable in the settings where HPV vaccinations are likely to be delivered. Because HPV is sexually transmitted, the identification of appropriate sexual and reproductive health (SRH) interventions, which could be delivered in tandem with the HPV vaccine or in between the vaccine shots, was of particular interest.

      Results

      Overall, 14 interventions, in the categories of screening (n = 2), information provision/skill building (n = 7), or commodity delivery (n = 5), were determined to have the potential to be used in conjunction with HPV vaccination programs in LMICs. Screening and commodity delivery could be implemented on the same days as vaccine shots whereas information provision and skill building may be better implemented in the periods between shots (Figure 1). The selected interventions have been categorized, according to the existence of WHO guidelines, as per 31 December 2012 (Table 2).
      Table 2The effective interventions that could be integrated with HPV vaccine delivery, as identified in Phase 2 of the literature review
      CategoryInterventionProgrammatic opportunity
      The potential timing of the intervention in relation to the delivery of the three doses of HPV vaccine (Figure 1).
      Supported by WHO guidelines specifically for 9–13-year-oldsCommodity delivery/treatment
       Treatment of schistosomiasis0, 1, and/or 2
       Treatment of soil-transmitted helminths0, 1, and/or 2
       Distribution of insecticide-treated bed nets0, 1, and/or 2
      Information provision/skills building
       Promotion of physical activity/exerciseA, B, and/or C
       Education on mosquito-borne diseases and their preventionA, B, and/or C
      Supported by WHO guidelines, but 9–13-year-olds not currently a target age groupCommodity delivery/treatment
       Iron tablets and/or folic acidA, B, and/or C
      Information provision/skills building
       Condom demonstration and promotionC, if appropriate
       Voucher deliveryA, B, and/or C
      No current WHO guidelines on this interventionScreening
       Vision screening0, 1, and/or 2
      Commodity delivery/treatment
       Vitamin A supplementation0, 1, and/or 2
       Soap provision and hand-washing promotionA, B, and/or C
      Information provision/skills building
       Single-session multicomponent education on sexual and reproductive healthC
       Production and distribution of newsletters on sexual and reproductive healthA, B, and/or C
       Education on menstrual hygieneA, B, and/or C
      Guidelines indicate that intervention is ineffectiveScreening
       Schistosomiasis screening0, 1, and/or 2
      Information provision/skills building
       Brief education to discourage tobacco useA, B, and/or C
      a The potential timing of the intervention in relation to the delivery of the three doses of HPV vaccine (Figure 1).

      Screening

      Screening for schistosomiasis and/or defects in vision could be easily carried out with a minimum of training and under the time constraints typically seen in HPV vaccination programs.

      Schistosomiasis screening

      School-based questionnaires have been used to screen schoolchildren in LMICs for Schistosoma infection, as an effective method of determining the prevalence of such infection at the levels of both the individual and the community [
      • Ansell J.
      • Guyatt H.
      • Hall A.
      • et al.
      The reliability of self-reported blood in urine and schistosomiasis as indicators of Schistosoma haematobium infection in school children: A study in Muheza district, Tanzania.
      ,
      • Guyatt H.
      • Brooker S.
      • Lwambo N.J.
      • et al.
      The performance of school-based questionnaires of reported blood in urine in diagnosing Schistosoma haematobium infection: Patterns by age and sex.
      ,
      • Lengeler C.
      • Kilima P.
      • Mshinda H.
      • et al.
      Rapid, low-cost, two-step method to screen for urinary schistosomiasis at the district level: The Kilosa experience.
      ,
      • Lengeler C.
      • Makwala J.
      • Ngimbi D.
      • et al.
      Simple school questionnaires can map both Schistosoma mansoni and Schistosoma haematobium in the Democratic Republic of Congo.
      ,
      • Lengeler C.
      • Utzinger J.
      • Tanner M.
      Screening for schistosomiasis with questionnaires.
      ,
      • Magnussen P.
      • Ndawi B.
      • Sheshe A.K.
      • et al.
      The impact of a school health programme on the prevalence and morbidity of urinary schistosomiasis in Mwera division, Pangani district, Tanzania.
      ]. Such screening, which has been found effective in identifying both urinary schistosomiasis (caused by S. haematobium) and intestinal schistosomiasis (caused by S. mansoni), is appropriate for all ages and both sexes and can be administered with minimal training and in a very short time. The integration of schistosomiasis screening with programs of HPV vaccination would only be appropriate in areas where human schistosomiasis is endemic and treatment is available for those adolescents found to have schistosome infection. In areas where human schistosomiasis is common, the treatment of individuals found infected by screening may also be less cost-effective than mass treatment without screening.

      Vision screening

      Simple “E” cards have been found effective for determining vision function in children and adolescents, in a variety of LMICs and school settings, and such cards can be administered by teachers after minimal training [
      • Keeffe J.E.
      • Lovie-Kitchin J.E.
      • Maclean H.
      • et al.
      A simplified screening test for identifying people with low vision in developing countries.
      ,
      • Limburg H.
      • Kansara H.T.
      • d'Souza S.
      Results of school eye screening of 5.4 million children in India—a five-year follow-up study.
      ,
      • Powell C.
      • Wedner S.
      • Richardson S.
      Screening for correctable visual acuity deficits in school-age children and adolescents.
      ]. Such screening is relatively inexpensive and has been shown to be cost-effective [
      • Limburg H.
      • Vaidyanathan K.
      • Dalal H.P.
      Cost-effective screening of schoolchildren for refractive errors.
      ].
      The early identification and treatment of defective vision (a common cause of learning difficulties) could be delivered, alongside HPV vaccine delivery, in all settings that have the capacity and facilities to provide vision care and treatment for adolescents.

      Information provision and skill building

      Improving awareness and prevention of mosquito-borne diseases

      Provision of the relevant health education to adolescents can increase knowledge of the human pathogens that are transmitted by mosquitoes, increase the use of bed nets, and reduce the number of vector breeding habitats [
      • Ayi I.
      • Nonaka D.
      • Adjovu J.K.
      • et al.
      School-based participatory health education for malaria control in Ghana: Engaging children as health messengers.
      ,
      • LaBeaud A.D.
      • Glinka A.
      • Kippes C.
      • et al.
      School-based health promotion for mosquito-borne disease prevention in children.
      ,
      • Madeira N.G.
      • Macharelli C.A.
      • Pedras J.F.
      • et al.
      Education in primary school as a strategy to control dengue.
      ,
      • Winch P.J.
      • Leontsini E.
      • Rigau-Pérez J.G.
      • et al.
      Community-based dengue prevention programs in Puerto Rico: Impact on knowledge, behavior, and residential mosquito infestation.
      ]. Such education can be successfully delivered in school settings with minimal training, and appears equally effective for girls and boys. Following their education on mosquito-borne diseases, schoolchildren may become “agents of change,” passing on their knowledge to their families and other community members.

      Promotion of physical activity/exercise

      Many interventions to reduce obesity and/or increase the physical activity of adolescents have been tested [
      • Dietz W.H.
      • Gortmaker S.L.
      Preventing obesity in children and adolescents.
      ,
      • Flynn M.A.
      • McNeil D.A.
      • Maloff B.
      • et al.
      Reducing obesity and related chronic disease risk in children and youth: A synthesis of evidence with ‘best practice’ recommendations.
      ,
      • Summerbell C.D.
      • Waters E.
      • Edmunds L.D.
      • et al.
      Interventions for preventing obesity in children.
      ,
      • Whitlock E.P.
      • Williams S.B.
      • Gold R.
      • et al.
      Screening and interventions for childhood overweight: A summary of evidence for the US Preventive Services Task Force.
      ,
      • van Sluijs E.M.
      • McMinn A.M.
      • Griffin S.J.
      Effectiveness of interventions to promote physical activity in children and adolescents: Systematic review of controlled trials.
      ]. However, most of these interventions have been explored in developed countries and most have been multicomponent programs lasting several months or longer. Most have also been delivered in schools or clinics and many have been family-based, often with a community component. One study showed that a brief, clinic-based counseling session was effective in increasing physical activity among adolescents [
      • Ortega-Sanchez R.
      • Jimenez-Mena C.
      • Cordoba-Garcia R.
      • et al.
      The effect of office-based physician's advice on adolescent exercise behavior.
      ]. Similar sessions could probably be developed for integrated delivery, with HPV vaccinations, in school and/or community settings in LMICs. Such an intervention would only be recommended in areas where adolescents show low levels of activity and/or increasing weight or body mass index.

      Improving health seeking behavior through vouchers

      Adolescents in LMICs may be inhibited from accessing heath care by their (or their caregivers') perception of the probable costs of such care. It has therefore been suggested that the distribution of vouchers to cover the costs of, at least, an initial consultation could improve the use of local health services by adolescents. After such vouchers were delivered throughout a community in Nicaragua, there was an increase in the utilization of medical services, especially among females aged 12–20 years [
      • Meuwissen L.E.
      • Gorter A.C.
      • Knottnerus A.J.
      Impact of accessible sexual and reproductive health care on poor and underserved adolescents in Managua, Nicaragua: A quasi-experimental intervention study.
      ]. A similar intervention should be feasible, in school and/or community settings, in any country with a relatively accessible, working, and willing health system. No training would be needed and it should be possible to integrate voucher delivery with HPV vaccine delivery.

      Newsletter delivery

      In a single study set in schools in North America, newsletters were found to be an effective means of delivering information on reproductive health [
      • Sanderson C.A.
      The effectiveness of a sexuality education newsletter in influencing teenagers' knowledge and attitudes about sexual involvement and drug use.
      ]. When used among Ugandan adolescents, as part of a mass media approach to the provision of information on sexual health, regular newsletters also had a positive impact [

      Adamchak SE, Kiragu K, Watson C, et al. The Straight Talk Campaign in Uganda: Impact of Mass Media Initiatives. Summary Report. Kampala, Uganda: Straight Talk Foundation.

      ]. With minimal training, newsletters could be used to provide a relatively large amount of information on SRH to adolescents in school or community settings, within the time constraints of HPV vaccine delivery. The engagement of adolescents in the development of the newsletters could improve the relevance, comprehension, and retention of the information included in the newsletters. The content of the newsletter could be reinforced by other interventions for improving SRH, delivered between the vaccine shots.

      Condom demonstrations

      Several studies have indicated the importance of condom demonstration in the context of sexual health education for adolescents [
      • Bankole A.
      • Ahmed F.H.
      • Neema S.
      • et al.
      Knowledge of correct condom use and consistency of use among adolescents in four countries in sub-Saharan Africa.
      ]. Condom demonstrations can improve condom use and enable participants to become more comfortable in handling condoms [
      • Elkins D.B.
      • Dole L.R.
      • Maticka-Tyndale E.
      • et al.
      Relaying the message of safer sex: Condom races for community-based skills training.
      ,
      • Hayden J.
      The condom race.
      ,
      • Lindemann D.F.
      • Brigham T.A.
      • Harbke C.R.
      • et al.
      Toward errorless condom use: A comparison of two courses to improve condom use skills.
      ,
      • Paul-Ebhohimhen V.A.
      • Poobalan A.
      • van Teijlingen E.R.
      A systematic review of school-based sexual health interventions to prevent STI/HIV in sub-Saharan Africa.
      ]. They may increase community acceptance of condom use and stimulate condom-related discussions among community members [
      • Elkins D.B.
      • Dole L.R.
      • Maticka-Tyndale E.
      • et al.
      Relaying the message of safer sex: Condom races for community-based skills training.
      ]. They have been reported to be especially empowering for women participants [
      • Elkins D.B.
      • Dole L.R.
      • Maticka-Tyndale E.
      • et al.
      Relaying the message of safer sex: Condom races for community-based skills training.
      ]. Programmatic literature and the results of at least one retrospective cross-sectional study [
      • Bankole A.
      • Ahmed F.H.
      • Neema S.
      • et al.
      Knowledge of correct condom use and consistency of use among adolescents in four countries in sub-Saharan Africa.
      ] illustrate the feasibility and potential impact of condom demonstrations in schools.

      Single-session multicomponent education on sexual and reproductive health

      Due to the complexity of the issues involved, most education of adolescents on SRH has been delivered by following long-term, multicomponent strategies, involving trained professionals and encompassing a wide variety of both materials and methods. There is, however, evidence to show that, in LMICs, single-day, peer-led education on SRH can improve participants' knowledge, attitudes, and risk perception regarding specific SRH issues [
      • Paul-Ebhohimhen V.A.
      • Poobalan A.
      • van Teijlingen E.R.
      A systematic review of school-based sexual health interventions to prevent STI/HIV in sub-Saharan Africa.
      ,
      • Speizer I.S.
      • Magnani R.J.
      • Colvin C.E.
      The effectiveness of adolescent reproductive health interventions in developing countries: A review of the evidence.
      ,
      • Gallant M.
      • Maticka-Tyndale E.
      School-based HIV prevention programmes for African youth.
      ,
      • Agha S.
      An evaluation of the effectiveness of a peer sexual health intervention among secondary-school students in Zambia.
      ,
      • Agha S.
      • Van Rossem R.
      Impact of a school-based peer sexual health intervention on normative beliefs, risk perceptions, and sexual behavior of Zambian adolescents.
      ,
      • Hull T.H.
      • Hasmi E.
      • Widyantoro N.
      “Peer” educator initiatives for adolescent reproductive health projects in Indonesia.
      ,
      • Johnson B.T.
      • Carey M.P.
      • Marsh K.L.
      • et al.
      Interventions to reduce sexual risk for the human immunodeficiency virus in adolescents, 1985–2000: A research synthesis.
      ,
      • Kirby D.
      • Short L.
      • Collins J.
      • et al.
      School-based programs to reduce sexual risk behaviors: A review of effectiveness.
      ,
      • Kirby D.B.
      • Laris B.A.
      • Rolleri L.A.
      Sex and HIV education programs: Their impact on sexual behaviors of young people throughout the world.
      ,
      • Mbizvo M.T.
      • Kasule J.
      • Gupta V.
      • et al.
      Effects of a randomized health education intervention on aspects of reproductive health knowledge and reported behaviour among adolescents in Zimbabwe.
      ,
      • Robin L.
      • Dittus P.
      • Whitaker D.
      • et al.
      Behavioral interventions to reduce incidence of HIV, STD, and pregnancy among adolescents: A decade in review.
      ]. Most of the relevant studies involved school-based delivery. With some adaptation, based upon the stated need, the age of the audience, delivery capacity, and local knowledge and customs, it may be possible to deliver effective SRH education on the same days as HPV vaccine shots.

      Improving menstrual hygiene

      In a study in rural India, three 90-minute school-based sessions designed to increase knowledge of menstruation and menstrual hygiene among adolescent girls led to increased awareness of these issues, increased use of commercially available sanitary pads, and decreased reuse of homemade cloth pads [
      • Dongre A.R.
      • Deshmukh P.R.
      • Garg B.S.
      The effect of community-based health education intervention on management of menstrual hygiene among rural Indian adolescent girls.
      ]. To be integrated in HPV vaccination programs, such sessions would have to be adapted to certain time constraints but could easily be delivered in school settings.

      Commodity delivery

      Treatments against soil-transmitted helminths

      Anthelminthic treatment has long been used, as a school-based intervention in LMICs, to reduce the prevalence of infection with soil-transmitted helminths (STH; Ascaris lumbricoides, Ancylostoma duodenale, Necator americanus, and/or Trichuris trichiura) among schoolchildren and adolescents. Such treatment is well-tolerated (although contraindicated in their first trimester of pregnancy), can be administered in schools with minimal training, and could be administered in conjunction with the HPV vaccine. It has shown to be effective not only in reducing the worm burden but also in increasing weight status, and to lead to improvements in nutritional status, hemoglobin concentration, serum ferritin levels, physical fitness, appetite, growth, school attendance, and intellectual development while reducing levels of anemia [
      • World Health Organization
      Helminth control in school-age children: A guide for managers of control programmes.
      ].
      School-based programs for the treatment of STH have been reported to be effective in many LMICs, including Kenya, Tanzania, Uganda, and Zambia [
      • Adams E.J.
      • Stephenson L.S.
      • Latham M.C.
      • et al.
      Physical activity and growth of Kenyan school children with hookworm, Trichuris trichiura and Ascaris lumbricoides infections are improved after treatment with albendazole.
      ,
      • Bhargava A.
      • Jukes M.
      • Lambo J.
      • et al.
      Anthelmintic treatment improves the hemoglobin and serum ferritin concentrations of Tanzanian schoolchildren.
      ,
      • Kabatereine N.B.
      • Fleming F.M.
      • Nyandindi U.
      • et al.
      The control of schistosomiasis and soil-transmitted helminths in East Africa.
      ,
      • Stephenson L.S.
      • Latham M.C.
      • Adams E.J.
      • et al.
      Physical fitness, growth and appetite of Kenyan school boys with hookworm, Trichuris trichiura and Ascaris lumbricoides infections are improved four months after a single dose of albendazole.
      ,
      • Stephenson L.S.
      • Latham M.C.
      • Adams E.J.
      • et al.
      Weight gain of Kenyan school children infected with hookworm, Trichuris trichiura and Ascaris lumbricoides is improved following once- or twice-yearly treatment with albendazole.
      ,
      • Albonico M.
      • Montresor A.
      • Crompton D.W.
      • et al.
      Intervention for the control of soil-transmitted helminthiasis in the community.
      ,
      • Dickson R.
      • Awasthi S.
      • Williamson P.
      • et al.
      Effects of treatment for intestinal helminth infection on growth and cognitive performance in children: Systematic review of randomised trials.
      ,
      • Hall A.
      • Hewitt G.
      • Tuffrey V.
      • et al.
      A review and meta-analysis of the impact of intestinal worms on child growth and nutrition.
      ,
      • Lammie P.J.
      • Fenwick A.
      • Utzinger J.
      A blueprint for success: Integration of neglected tropical disease control programmes.
      ,
      • Taylor-Robinson D.C.
      • Jones A.P.
      • Garner P.
      Deworming drugs for treating soil-transmitted intestinal worms in children: Effects on growth and school performance.
      ], and have been successfully incorporated into larger school- and community-based interventions that have included the treatment of schistosomiasis and lymphatic filariasis [
      • Magnussen P.
      • Muchiri E.
      • Mungai P.
      • et al.
      A school-based approach to the control of urinary schistosomiasis and intestinal helminth infections in children in Matuga, Kenya: Impact of a two-year chemotherapy programme on prevalence and intensity of infections.
      ,
      • Savioli L.
      • Albonico M.
      • Engels D.
      • et al.
      Progress in the prevention and control of schistosomiasis and soil-transmitted helminthiasis.
      ]. The incorporation of STH treatments with other interventions, including the Integrated Management of Childhood Illness, improvements in water supplies and sanitation, vitamin A supplementation, SRH education, maternal and child health interventions, and Roll Back Malaria, also appears feasible [
      • Kobayashi J.
      • Jimba M.
      • Okabayashi H.
      • et al.
      Beyond deworming: The promotion of school-health-based interventions by Japan.
      ].

      Treatments against schistosomiasis

      Praziquantel has been used effectively, in both school- and community-based settings, in LMICs and elsewhere, to treat children and adolescents infected with adult S. mansoni, S. japonicum or S. haematobium, and the drug has been deemed safe for both pregnant and lactating females [
      • Kabatereine N.B.
      • Fleming F.M.
      • Nyandindi U.
      • et al.
      The control of schistosomiasis and soil-transmitted helminths in East Africa.
      ,
      • King C.H.
      Long-term outcomes of school-based treatment for control of urinary schistosomiasis: A review of experience in Coast province, Kenya.
      ,
      • N'Goran E.K.
      • Gnaka H.N.
      • Tanner M.
      • et al.
      Efficacy and side-effects of two praziquantel treatments against Schistosoma haematobium infection, among schoolchildren from Côte d'Ivoire.
      ,
      • Saathoff E.
      • Olsen A.
      • Magnussen P.
      • et al.
      Patterns of Schistosoma haematobium infection, impact of praziquantel treatment and re-infection after treatment in a cohort of schoolchildren from rural KwaZulu-Natal/South Africa.
      ]. Treatment with praziquantel can be combined with other interventions, including the treatment of STH and, presumably, HPV vaccination programs, to increase health benefits and lower the total costs of delivery [
      • Kabatereine N.B.
      • Fleming F.M.
      • Nyandindi U.
      • et al.
      The control of schistosomiasis and soil-transmitted helminths in East Africa.
      ,
      • Lammie P.J.
      • Fenwick A.
      • Utzinger J.
      A blueprint for success: Integration of neglected tropical disease control programmes.
      ,
      • Taylor-Robinson D.C.
      • Jones A.P.
      • Garner P.
      Deworming drugs for treating soil-transmitted intestinal worms in children: Effects on growth and school performance.
      ,
      • Magnussen P.
      • Muchiri E.
      • Mungai P.
      • et al.
      A school-based approach to the control of urinary schistosomiasis and intestinal helminth infections in children in Matuga, Kenya: Impact of a two-year chemotherapy programme on prevalence and intensity of infections.
      ,
      • Savioli L.
      • Albonico M.
      • Engels D.
      • et al.
      Progress in the prevention and control of schistosomiasis and soil-transmitted helminthiasis.
      ]. Given praziquantel's efficacy, low cost, high tolerance and easy delivery, it is generally highly recommended [
      • Fenwick A.
      • Webster J.P.
      Schistosomiasis: Challenges for control, treatment and drug resistance.
      ,
      • Southgate V.R.
      • Rollinson D.
      • Tchuem Tchuenté L.A.
      • et al.
      Towards control of schistosomiasis in sub-Saharan Africa.
      ,
      • Raso G.
      • N'Goran E.K.
      • Toty A.
      • et al.
      Efficacy and side effects of praziquantel against Schistosoma mansoni in a community of western Côte d'Ivoire.
      ]. Treatment of schistosomiasis can reduce hematuria, dysuria, nutritional deficiencies, anemia, iron deficiency, school absenteeism, lesions of the bladder, kidney failure, and growth retardation. Relatively low incidences of bladder infections and other bladder abnormalities were observed in adults who had been treated with praziquantel as children or adolescents [
      • Fenwick A.
      • Webster J.P.
      Schistosomiasis: Challenges for control, treatment and drug resistance.
      ,
      • Southgate V.R.
      • Rollinson D.
      • Tchuem Tchuenté L.A.
      • et al.
      Towards control of schistosomiasis in sub-Saharan Africa.
      ,
      • Raso G.
      • N'Goran E.K.
      • Toty A.
      • et al.
      Efficacy and side effects of praziquantel against Schistosoma mansoni in a community of western Côte d'Ivoire.
      ].

      Vitamin A supplementation

      Among adolescents, vitamin A supplementation can reportedly improve anemia status and hemoglobin levels, reduce the risk of goiter, increase serum retinol levels, increase school attendance and reduce vitamin A deficiency [
      • Zimmermann M.B.
      • Biebinger R.
      • Rohner F.
      • et al.
      Vitamin A supplementation in children with poor vitamin A and iron status increases erythropoietin and hemoglobin concentrations without changing total body iron.
      ,
      • Mahawithanage S.T.
      • Kannangara K.K.
      • Wickremasinghe R.
      • et al.
      Impact of vitamin A supplementation on health status and absenteeism of school children in Sri Lanka.
      ,
      • Mwanri L.
      • Worsley A.
      • Ryan P.
      • et al.
      Supplemental vitamin A improves anemia and growth in anemic school children in Tanzania.
      ,
      • Zimmermann M.B.
      • Jooste P.L.
      • Mabapa N.S.
      • et al.
      Vitamin A supplementation in iodine-deficient African children decreases thyrotropin stimulation of the thyroid and reduces the goiter rate.
      ]. Such supplementation has been shown to be beneficial in a wide variety of LMICs, and has been successfully delivered, albeit on a relatively small scale, in school-based settings. Delivery of vitamin A supplements to children and adolescents on a larger scale, including as an adjunct to HPV vaccination, may prove to be more difficult, with possible problems in the management of supply and delivery, sustainability after conclusion of the HPV vaccination intervention, and local resistance to the supplementation.

      Soap and the promotion of hand washing

      In a long-running study in Chinese primary schools, the promotion of hand washing and continuous provision of soap led to a significant reduction in absenteeism [
      • Bowen A.
      • Ma H.
      • Ou J.
      • et al.
      A cluster-randomized controlled trial evaluating the effect of a handwashing-promotion program in Chinese primary schools.
      ]. If such an intervention were to be integrated with HPV vaccination programs, it would have to be adapted to ensure that the messaging was relevant to the generally older audience, and be delivered within the time constraints of the programs against HPV.

      Long-lasting insecticide-treated bed nets

      The consistent and proper use of long-lasting insecticide-treated bed nets (LLITN) has been shown to reduce the incidence and prevalence of malaria and other vector-borne illnesses. On the Thai–Burmese border, for example, a 38% reduction in Plasmodium falciparum infections and a 42% reduction in the incidence of symptomatic episodes were observed among adolescents who utilized LLITNs [
      • Luxemburger C.
      • Perea W.A.
      • Delmas G.
      • et al.
      Permethrin-impregnated bed nets for the prevention of malaria in schoolchildren on the Thai–Burmese border.
      ]. Use of LLITNs by adolescents resulted in an increase in lean body mass [
      • Friedman J.F.
      • Phillips-Howard P.A.
      • Hawley W.A.
      • et al.
      Impact of permethrin-treated bed nets on growth, nutritional status, and body composition of primary school children in western Kenya.
      ] and, among 12–13-year-old, nonpregnant girls, a reduction in the prevalence of mild anemia [
      • Leenstra T.
      • Phillips-Howard P.A.
      • Kariuki S.K.
      • et al.
      Permethrin-treated bed nets in the prevention of malaria and anemia in adolescent schoolgirls in western Kenya.
      ]. Distribution of nets through schools, in conjunction with education on malaria, may result in improved use of the nets during and following pregnancy, and may result in greater use of nets by members of the schoolchildren's families. Effective delivery of LLITNs, in combination with measles vaccination programs in Zambia and Ghana, has increased the number of individuals using such nets [
      • Grabowsky M.
      • Farrell N.
      • Hawley W.
      • et al.
      Integrating insecticide-treated bednets into a measles vaccination campaign achieves high, rapid and equitable coverage with direct and voucher-based methods.
      ,
      • Grabowsky M.
      • Nobiya T.
      • Ahun M.
      • et al.
      Distributing insecticide-treated bednets during measles vaccination: A low-cost means of achieving high and equitable coverage.
      ]. There is clearly scope to distribute LLITNs during HPV vaccination programs. There is support for the free distribution of nets, as widespread delivery without cost to the community has been shown to increase both net coverage and usage [
      • Noor A.M.
      • Amin A.A.
      • Akhwale W.S.
      • et al.
      Increasing coverage and decreasing inequity in insecticide-treated bed net use among rural Kenyan children.
      ,
      • Webster J.
      • Hill J.
      • Lines J.
      • et al.
      Delivery systems for insecticide treated and untreated mosquito nets in Africa: Categorization and outcomes achieved.
      ].

      Discussion

      Challenges to implementation

      There are several challenges to interpreting the findings of this literature review and applying them to strategies for HPV vaccine delivery. There are, for example, environmental (e.g., school or health system), economic and social factors that may affect decisions on adding any of the 14 interventions to HPV vaccination programs. In communities, there may be objections to some interventions, in particular those relating to SRH, which may conflict with local moral, religious, or other beliefs and may therefore need to be offered with considerable care and delicacy.

      Limitations

      This review has several limitations. Firstly, the study population, of individuals aged 9–15 years, was set broader than the age group targeted for HPV vaccination in the current (2009) guidelines of the WHO. (When this review was initiated, the 9–13-year-old focus for HPV vaccination had not been set.) Secondly, this literature review did not follow the WHO's requirements for assessing evidence effectiveness prior to making recommendations because the literature review began before the adoption of the WHO procedures [
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: An emerging consensus on rating quality of evidence and strength of recommendations.
      ]. Thirdly, since the analyzed articles were published, it is possible that the interventions discussed have become less cost-effective or have been superseded, as technology and interventions have evolved. Fourthly, the inclusion criteria for the literature review did not include particular levels of efficacy, effectiveness, experience of implementation, or cost. The final shortlist of “recommended” interventions, therefore, represents greatly varying levels of evidence of beneficial outcomes, and this needs to be taken into consideration when choosing an intervention to integrate with HPV vaccinations.

      Choice of adjunct intervention

      With the possible exception of the promotion of hand washing, none of the interventions that were included in the final list is appropriate for all situations. The selection of intervention to be added to HPV vaccine delivery will depend on several factors, including the type and epidemiology of diseases in the setting, the available resources, and existing programs for improving the health of adolescents. Some of the interventions (e.g., deworming) have well-proven efficacy, have already been implemented in many countries, and have well-known costs and feasibility. Others (e.g., condom demonstration) have a more limited evidence base for efficacy, have not been implemented in many countries, may raise issues of cultural sensitivity, and may be more relevant for an older age group; some interventions may have intuitive appeal (e.g., newsletter production and delivery, vouchers) but do not have a strong evidence base and need further exploration.

      Comments on specific interventions

      Screening

      One of the basic public health premises for screening programs is that it should be possible to resolve most of the problems identified. There is little point in screening adolescents for defects in vision in a setting where the correct spectacles cannot be supplied or where adolescents will not use spectacles that they have been given [
      • Odedra N.
      • Wedner S.H.
      • Shigongo Z.S.
      • et al.
      Barriers to spectacle use in Tanzanian secondary school students.
      ].

      Information provision and skill building

      It is important to link any information provision/skill building provided at the time of HPV vaccination with ongoing health education in the targeted school or community. This is particularly important for information on adolescent SRH and comprehensive sex education; where this is taking place, information and skill building provided at the time of HPV vaccination should be seen as an opportunity to reinforce existing health education programs in the school. Similarly, although newsletters might usefully be delivered at the same time as HPV vaccine, they could and probably should be produced and distributed throughout each year.

      Commodity delivery

      There are growing concerns about the potential harm caused by vitamin A supplements among those who eat foods that have already been fortified with vitamin A and also concerns that vitamin A supplements should be contraindicated during pregnancy. Further review is needed on the use and effectiveness of such supplements. During education on menstrual hygiene, it may often be beneficial to engage the private sector in improving the local provision of commercial sanitary pads.
      Even if the vaccine is only given to girls, some of the interventions, particularly most of those involving education about health, should also be targeted to adolescent boys.

      Follow-up

      The WHO will clarify the level of evidence for each of the 14 interventions that appeared on the final list. Each of the interventions will be categorized according to the available level of evidence, with the categories ranging from “WHO guidelines available for the intervention and target age group” to “limited evidence for the intervention.” The interventions that appear to be supported by only limited evidence will be investigated further, with a new search for (and careful grading of) evidence of their benefits, disadvantages, costs and feasibility, and the appropriate interpretation of the evidence to support programmatic action and better decision-making.
      Overall, 14 types of intervention that could be reasonably considered for integration in HPV vaccination programs were identified. Although the focus of this review has been LMICs, some of the proposed interventions and the overall approach may also be of relevance in high-resource settings.
      Despite the limitations of this work, the authors considered it important to share the outcome of this exercise because many countries have started to introduce HPV vaccine and this trend will accelerate with the increasing support to low-income countries from the Global Alliance for Vaccines and Immunization. Although this review is only up to mid-2010, and more recent evidence may well be available to further develop and elaborate potential interventions, the proposed list and approach to integrate them with HPV vaccine delivery can already be used by LMICs to adapt and implement an intervention package that responds to adolescent needs and is tailored to the specific epidemiological, cultural, and health system context.

      Acknowledgments

      We would like to thank Keith Wallbanks for his crucial assistance with editing a previous version of this article.

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