Primary prevention.

Prophylactic HPV vaccination has been regarded as the most effective long-term strategy for preventing HPV infection, cervical cancer and other cancers associated with HPV [5]. The first HPV vaccine was licensed in 2006 [7]. HPV vaccines are designed to prevent over 95% of HPV infections caused by the common high-risk HPV types 16 and 18 as well as some cross protection against other less common HPV types that can cause cervical cancer [1]. The WHO recommends the following schedule: a one or two-dose schedule for girls aged 9–14 years, a one or two-dose schedule for girls and women aged 15–20 years and two doses with a 6-month interval for women older than 21 years [6]. A minimum of 2 doses and when feasible 3-doses remain necessary for those known to be immunocompromised and/or HIV-infected [6]. The high prevalence of HPV infections in HIV positive females emphasizes how important it is to vaccinate this population. Furthermore, HPV vaccines are most effective if administered prior to HPV-exposure [7].

Educational interventions play a crucial role in creating awareness and imparting knowledge on the importance of cervical cancer prevention strategies and risks. In providing the necessary information females are empowered to make informed decisions about their health, seek HPV vaccination services and timely screening, as well as adopt proactive measures and ultimately reduce their risk of developing cervical cancer.

Secondary prevention.

To prevent cervical cancer females can undergo various cervical screening tests to detect precancerous cells and thereafter receive timely and appropriate treatment to reduce the risk of progression to invasive cervical cancer. The conventional approach for screening involves cytology screening (conventional or liquid based), commonly known as Papanicoloau (Pap) test or Pap smear [8]. Advances in screening strategies include visual inspection with acetic acid (VIA) and more recently molecular tests such as high-risk HPV DNA testing [8].

In resource-limited settings, the predominant approach for treatment of cervical abnormalities is tissue ablation techniques such as cryotherapy or thermal ablation [9]. For women who are not eligible for ablation or in high income countries the main approach for treatment involves the excision of histologically confirmed cervical abnormalities [9].

The WHO recommends two approaches to screening and treatment namely, the “screen-and-treat” and the “screen, triage and treat” approach [6]. In the “screen-and-treat” approach treatment is administered to females solely based on a positive primary screening test (which means there is no secondary screening test and no histopathological diagnosis) [6]. In the “screen, triage and treat” approach the treatment decision is based on a positive result from the initial screening test, followed by a positive outcome in a subsequent test (referred to as a “triage” test), with or without histologically confirmed diagnosis [6]. For females in the general population, the WHO recommends HPV DNA detection as the screening method in a “screen-and-treat” or “screen, triage and treat” approach starting at the age of 30 years with regular screening every five to ten years [6]. For females living with HIV, it is recommended that HPV DNA detection be used in a “screen, triage and treat” approach starting at the age of 25 years with regular screening every three to five years [6].

Despite the development and implementation of cervical cancer prevention strategies this disease continues to be a public health concern. As a result of this, in 2020 the WHO introduced a “global strategy” to accelerate the elimination of cervical cancer [6]. This strategy proposes the following targets: 90% of adolescent girls globally should be vaccinated against HPV; 70% of women should undergo HPV screening and 90% of women diagnosed with cervical cancer should receive suitable follow-up treatment [6]. The aim of this global strategy is to reduce the incidence of cervical cancer to below a threshold of 4 cases per 100 000 women-years in every country [10]. Meeting these objectives set out by the WHO requires reconsideration of existing strategies to accelerate the adoption of HPV vaccination, cervical cancer screening and timely treatment of precancerous lesions, whilst optimizing rational resource allocation and use. The WHO advocates for the integration of these prevention strategies in other healthcare services to further enhance its effectiveness [11].

There has been a growing interest in integrating cervical cancer prevention strategies into HIV care programs [12]. For AGYW living with HIV, such integration can potentially improve access to HPV vaccination, and timely initiation of cervical cancer screening, resulting in early detection and treatment. Additionally, it may offer opportunities for the efficient utilisation of established healthcare resources and strengthen the health system’s capacity to address both HIV and cervical cancer. Integrated healthcare approaches aim to leverage existing HIV care infrastructure to provide cervical cancer preventative services, which can encompass the full complement of prevention strategies. The integration not only streamlines healthcare delivery but also capitalizes on the regular contact that AGYW living with HIV have with healthcare providers. Supporting evidence highlighting the feasibility and outcomes of such integration programs has been published. For instance, Mwanahamuntu et al., [13] conducted a study on the integration of cervical cancer prevention services into HIV care services in Zambia and reported that over the course of 2.5 years more than 20 000 women had undergone cervical cancer screening following integration. Furthermore, studies conducted in Kenya, Mozambique and Botswana have reported cervical cancer screening within HIV care services to be feasible, acceptable, and effective [14–16].

Despite the potential benefits of integrating cervical cancer prevention and HIV care, there is still a limited understanding of its effectiveness in the real-world setting. As such, it is important to systematically assess the effectiveness of integrating such programs across various contexts.

This systematic review seeks to comprehensively assess existing evidence, by employing a mixed methods approach, to provide a holistic understanding of the outcomes and implications of integrating cervical cancer prevention strategies into HIV care programs. This review will delve into the uptake of HPV vaccination, initiation of cervical cancer screening, treatment of precancerous lesions, and educational interventions aimed at enhancing personal urgency and positive behavioural change. In addition, we will describe the knowledge, awareness, and willingness of AGYW living with HIV with regards to utilising and adhering to these strategies following integration into existing HIV care programs. Given the increasing global burden of cervical cancer, the continued burden of HIV, and the increased risk of HPV infections in AGYW living with HIV, this review will hold significant relevance and agency for public health initiatives aimed at improving the health and well-being of AGYW living with HIV as well as reducing the incidence and mortality rates of cervical cancer.

Population.

Focusing this review on AGYW (9–25 years) living with HIV is pertinent, given the distinct factors that heighten their lifetime vulnerability to cervical cancer and position them to gain significant benefits from integrated prevention strategies (Table 1). AGYW living with HIV are at a significantly higher risk of persistent HPV infection, leading to a more rapid progression to cervical precancer and potentially invasive cervical cancer [3]. This elevated risk necessitates early and sustained cervical cancer prevention efforts tailored specifically for this population to prevent early complications and premature death. Improving the uptake of these services in this age group would promote early prevention of cervical cancer with HPV vaccination and early detection or screening services thus ensuring significant long-term reduction in the incidence and mortality associated with cervical cancer.

Intervention.

HPV vaccination is the most effective strategy for preventing cervical cancer with an efficacy rate of 95% [1,5]. Furthermore, HPV vaccines are most effective if administered prior to HPV-exposure and therefore primarily targeted at adolescent girls (9–14 years of age), prior to sexual debut [7]. Prioritising the uptake of HPV vaccination among AGYW living with HIV would contribute significantly towards reducing the global burden of cervical cancer globally. At present the WHO recommends initiating cervical cancer screening among females living with HIV at the age of 25 years as part of secondary prevention strategies [6]. Given that AGYW are a high-risk population [3], screening among this population would promote early detection and treatment of pre-cancerous lesions, thus reducing the likelihood of developing invasive cervical cancer later in life. Lastly, adolescence and young adulthood are generally regarded as the critical period for developing lifelong health behaviours. Increasing the uptake of educational interventions about HPV infection and cervical cancer among AGYW living with HIV could present an opportunity to increase knowledge and promote early adoption of cervical cancer prevention strategies among this population.

Comparator.

The evidence base on cervical cancer prevention among AGYW and adult women within the general population is substantial and as such, this population will not be the focus of this review [19]. Given our specific interest in integrated services for AGYW living with HIV, we will explore utilisation of cervical cancer prevention services when integrated into HIV care pathways compared to no integration (Table 1).

Outcomes.

The co-occurrence of cervical cancer and HIV represents a significant public health challenge and requires more effort to be placed on improving delivery and uptake of current cervical cancer prevention and control measures. Cervical cancer prevention strategies should encompass multidisciplinary approaches that include HPV vaccination, screening, treatment of precancerous lesions, and educational interventions (Table 1). Utilising existing HIV care programmes as a means of integrating cervical cancer prevention strategies into routine HIV care provides an effective way for improving cervical cancer prevention for the most at-risk population and should be prioritised. As mentioned, existing literature primarily focuses on isolated aspects of either HIV care or cervical cancer prevention, or some but not all cervical cancer preventative strategies, thus leaving a fragmented understanding of the holistic benefits of integrating services for these public health concerns. Previous studies have considered integration of these programs [12], although, more focus is placed on cervical cancer screening as a prevention strategy as opposed to a comprehensive approach that also includes vaccination, education, and treatment of precancerous lesions. Moreover, the search end dates of previous reviews are outdated - being more than six years old - and do not consider recent recommendations and advancements in the field [12]. This review aims to provide a comprehensive assessment of the effectiveness of, and knowledge, awareness, and willingness among AGYW living with HIV to utilise, integrated cervical cancer prevention strategies. The holistic approach intended for this review could provide further insights into the global stance on integration strategies. In doing this, gaps in terms of which strategies are underutilised, and less or more effective can be highlighted. Highlighting these gaps would be crucial in informing policy decisions on which prevention strategies require further development and planning. Limiting this review to just one strategy risks missing these crucial insights.

A mixed methods systematic review is an ideal research design for this study as it allows for an overall examination of both quantitative and qualitative data. The quantitative evidence will provide insights into the types of integration strategies adopted and their effectiveness, whilst the qualitative evidence can shed light on the knowledge, awareness, and willingness of AGYW living with HIV to utilise cervical cancer prevention strategies following integration. Findings from this review will have the potential to inform reforms to current policy and practice, thereby contributing to improving health outcomes for AGYW living with HIV.

Inclusion criteria.

1. All primary research studies (including those with quantitative, qualitative, and mixed methods research designs) reporting findings on the effectiveness, knowledge, awareness, and willingness related to integrating cervical cancer prevention strategies (vaccination, education, screening, treatment of precancerous lesions, and educational interventions) into existing HIV care services will be considered. This includes all observational studies (cross-sectional and cohort), interventional studies (single-arm intervention studies, randomised control trials, cluster randomised control trials, cross-over trials, and non-randomised control trials) and qualitative studies (interviews, surveys, focus groups, ethnography, phenomenology, grounded theory studies and qualitative process evaluations).
2. The target population for this review are AGYW living with HIV, aged between 9 and 25 years of age. Therefore, only studies that include females within this age group living with HIV will be included.
3. Initially, we will not place any time limitations on our search strategy to ensure that we comprehensively scope the evidence base for relevant literature. We do anticipate that any literature relating to HPV vaccination in our target population will be published from 2006 onward in line with when the vaccine was first made available.
4. This systematic review has global significance that aims to address universal challenges affecting cervical cancer research on a global scale and therefore there will be no geographical limits placed on the search strategy.
5. We will not enforce any limitations on the language of publication. Instead, we will facilitate the translation of any potentially relevant publications into English to ensure their inclusion in the selection process and facilitate data extraction.

Exclusion criteria.

1. Studies that exclusively focus on AGYW living without HIV or that do not clearly specify the age and HIV status of the study participants will be excluded as this review focuses primarily on AGYW living with HIV.
2. Studies that include females younger the 9 or older than 25 years of age as this does not align with the target population for this review.
3. Studies that evaluate the integration of cervical cancer prevention strategies into programs other than HIV care services will not be considered.
4. This review will exclude all other review studies, modelling studies, evidence synthesis studies, case studies, case series, case reports and conference proceedings.

Quantitative studies.

To assess randomised controlled trials (RCTs) included in this review we plan to utilise the Cochrane risk of bias tool (ROB-2) [27]. This tool evaluates selection, performance, detection, attrition, reporting and additional sources of bias allowing us to categorize each of the included studies as having low, moderate, or high risk of bias. A summary of the assessment of each study with the overall judgement will be recorded and tabulated.

Non-randomised controlled trials (non RCTs) will be critically appraised using the Newcastle-Ottawa Scale (NOS) [28]. The NOS uses a star system for each included non RCT, which entails scoring stars based on a specific criterion. The overall quality of each study will be interpreted based on the total number of stars awarded. A comprehensive summary of all the assessments conducted, along with an overall judgement, will be recorded and tabulated.

Qualitative studies.

The Critical Appraisal Skills Programme (CASP) quality assessment tool for qualitative studies will be applied to determine the rigour of qualitative methods used in included studies. The CASP tool will be used to examine the quality of a study in relation to 10 questions about research aims, appropriateness of methodology and design, recruitment strategy, data collection, researcher reflexivity, consideration of ethical issues, data analysis, statement of findings and the value of the research [29].

Mixed methods studies.

The Mixed Methods Appraisal Tool (MMAT) will be applied to assess the risk of bias for mixed methods studies [30]. The following criteria will be used to assess the risk of bias:

1. Is there an adequate rationale for using a mixed methods design to address the research question?
2. Are the different components of the study effectively integrated to answer the research question?
3. Are the outputs of the integration of qualitative and quantitative components adequately addressed?
4. Are divergences and inconsistencies between quantitative and qualitative results adequately addressed?
5. Do the different components of the study adhere to the quality criteria of each tradition of the methods involved?

Quantitative studies.

The findings from the included quantitative studies will be narratively summarised and graphically illustrated [31]. Study results will be expressed as either numeric results or measures of association, with their associated variation and confidence intervals. The magnitude of heterogeneity between the included studies will then be assessed quantitatively using the I² statistic [32]. I² values will be interpreted as follows: 0–40% might not be important; 30–60% may represent moderate heterogeneity; 50–90% may represent substantial heterogeneity and 75–100% represents considerable heterogeneity [32]. The significance of heterogeneity will be determined by the p-value as outlined in the Cochrane Handbook [32]. For studies with moderate to significant heterogeneity, a random effects model will be used to obtain a pooled estimate of the outcome. If heterogeneity is between 0–40% a random effects model will also be used. In this instance, the random effects model will account for our lack of knowledge about why real, or apparent, intervention effects differ by considering the differences as if they were random [32].

Random effects models for meta-analysis will be performed using Review Manager software (RevMan 2020, V.5.4.1). If the heterogeneity detected is significantly high, a subgroup analysis will be performed to detect the possible sources [33]. A funnel plot will be used to assess for publication bias using R software (R Studio version 2023.03.0 + 386). Asymmetric distribution of the plot will indicate potential publication bias [34]. In addition, to statistically confirm whether the asymmetry is significant or not, the Begg and Egger’s test will be performed using R software, where a p-value less than 0.05 indicates asymmetry and potential publication bias (R Studio version 2023.03.0 + 386) [34].

Qualitative studies.

For the qualitative analysis thematic synthesis will be used to combine the findings of studies that describe the knowledge, awareness, and willingness of AGYW living with HIV to utilise and adhere to cervical cancer prevention strategies following integration [35]. The findings of included qualitative studies will be examined against the aims of this review, recurring patterns will be identified, and the qualitative data patterns will be interpreted by developing a coding framework. One article that closely answers the review objectives will be selected and used as a starting point to build a coding list. Two authors (KG and NB) will conduct “line-by-line” coding according to the content and meaning of the relevant findings of the article. The two authors (KG and NB) will subsequently discuss the "free" codes, with a third author (EA-D), develop an initial coding list, and independently test this list on two additional articles to determine if and how well the concepts translate from one study to another. The three authors (KG, NB and EA-D) will subsequently discuss the codes emerging from the data and agree on a preliminary coding framework. The remaining studies will then be coded line-by-line using the agreed coding framework, adding new codes as necessary. Relevant findings, reported anywhere in the primary qualitative studies, will be coded. If new codes arise during the analysis process, a discussion among the three authors will be conducted (KG, NB and EA-D) and the coding list will be amended accordingly. Two authors (KG and NB) will revisit articles already coded to determine if the new codes apply or not. This process will continue until they have extracted data from all the included articles.

Data extraction will be verified by a third author (EA-D). Review findings will then be synthesised from the data that have been given the same codes across the studies. Findings will be shared with the third author (EA-D) to review. Finally, we will re-read the included studies to check that we have extracted all data relevant to the findings.

Combining quantitative and qualitative data.

Following the synthesis of quantitative and qualitative data independently, they will be combined using the methods and suggestions provided in the Cochrane Handbook [36]. According to the Johanna Briggs guidelines on data synthesis and integration for mixed method reviews, if the research question can be addressed by quantitative and qualitative research designs, a convergent integrated approach will be followed [37]. However, if the review aims to explore various aspects or dimensions of a particular phenomenon of interest the convergent segregated approach will be followed [37].

Quantitative studies.

The quality of evidence for primary quantitative outcomes will be evaluated using the five Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria: risk of bias, consistency of effect, imprecision, indirectness, and publication bias [38]. To facilitate this process, we will utilize GRADEpro GDT software and include footnotes to elucidate any determinations made to downgrade the quality of evidence. We will use the study design of each included study as a determining factor of whether to upgrade (i.e., observational studies) or downgrade (i.e. RCTs) the quality of evidence.

An assessment of each outcome will be presented in a GRADE Evidence Profile. Two authors (KG and NB) will detail the number of studies, the number of participants, and the numerical result of the meta-analysis for each outcome. The effects of interventions on the outcomes included in the GRADE Evidence Profiles will be interpreted according to magnitude of effect and certainty of the evidence, using GRADE guidance on informative statements to combine size and certainty of an effect [38]. If meta-analysis is unsuitable or units of analysis are incomparable, results will be presented in a narrative ‘Summary of findings’ table format, with a recognition of the imprecision in evidence due to the absence of a quantitative effect measure [39]. This process will be reviewed by a third author (EA-D).

Qualitative studies.

To evaluate the confidence in synthesized qualitative findings, the Grades of Recommendation, Assessment, Development, and Evaluation- Confidence in the Evidence from Qualitative Reviews (CERQual) approach will be used [40]. This approach encompasses four key domains: methodological limitations, relevance of contributing studies to the research question, coherence of study findings, and adequacy of data supporting the study findings. For each outcome, two authors (KG and NB) will consolidate the findings from these four domains and offer rationale to elucidate any determinations made to downgrade the quality of evidence. This process will be reviewed by a third author (EA-D).