threat analysis of software systems a systematic literature review

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Efficiency and Automation in Threat Analysis of Software Systems

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Threat analysis of software systems: a systematic literature review

) (doi: 10.1016/j.jss.2018.06.073 )

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Architectural threat analysis has become an important cornerstone for organizations concerned with developing secure software. Due to the large number of existing techniques it is becoming more challenging for practitioners to select an appropriate threat analysis technique. Therefore, we conducted a systematic literature review (SLR) of the existing techniques for threat analysis. In our study we compare 26 methodologies for what concerns their applicability, characteristics of the required input for analysis, characteristics of analysis procedure, characteristics of analysis outcomes and ease of adoption. We also provide insight into the obstacles for adopting the existing approaches and discuss the current state of their adoption in software engineering trends (e.g. Agile, DevOps, etc.). As a summary of our findings we have observed that: the analysis procedure is not precisely defined, there is a lack of quality assurance of analysis outcomes and tool support and validation are limited.

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A systematic literature review on software security testing using metaheuristics

• Published: 23 May 2024
• Volume 31 , article number  44 , ( 2024 )

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• Fatma Ahsan 1 &
• Faisal Anwer 1  

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The security of an application is critical for its success, as breaches cause loss for organizations and individuals. Search-based software security testing (SBSST) is the field that utilizes metaheuristics to generate test cases for the software testing for some pre-specified security test adequacy criteria This paper conducts a systematic literature review to compare metaheuristics and fitness functions used in software security testing, exploring their distinctive capabilities and impact on vulnerability detection and code coverage. The aim is to provide insights for fortifying software systems against emerging threats in the rapidly evolving technological landscape. This paper examines how search-based algorithms have been explored in the context of code coverage and software security testing. Moreover, the study highlights different metaheuristics and fitness functions for security testing and code coverage. This paper follows the standard guidelines from Kitchenham to conduct SLR and obtained 122 primary studies related to SBSST after a multi-stage selection process. The papers were from different sources journals, conference proceedings, workshops, summits, and researchers’ webpages published between 2001 and 2022. The outcomes demonstrate that the main tackled vulnerabilities using metaheuristics are XSS, SQLI, program crash, and XMLI. The findings have suggested several areas for future research directions, including detecting server-side request forgery and security testing of third-party components. Moreover, new metaheuristics must also need to be explored to detect security vulnerabilities that are still unexplored or explored significantly less. Furthermore, metaheuristics can be combined with machine learning and reinforcement learning techniques for better results. Some metaheuristics can be designed by looking at the complexity of security testing and exploiting more fitness functions related to detecting different vulnerabilities.

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Systematic literature review on software quality for AI-based software

Metaheuristics: a comprehensive overview and classification along with bibliometric analysis

Testing machine learning based systems: a systematic mapping

Abbreviations.

Firefly algorithm

Cuckoo search

Genetic algorithm

Simulated annealing

Grammatical evolution

Genetic programming

Test object

Hill climbing

Memetic algorithm

Harmony search

Evolutionary programming

• Evolutionary algorithm

Bat algorithm

Randomized algorithm

Evolutionary strategies

Differential evolution

Greedy search

Local Search

Null pointer exception

Cross site scripting

Standard genetic algorithm

Co-evolutionary algorithm

Hybrid genetic algorithm

Particle swarm optimization

Artificial bee colony optimization

Many independent objective

Hill climbing algorithm

Denial of service

Domain object model

Ant colony optimization

Improved genetic algorithm

Hill climbing using Korel’s AVM

K medoids algorithm

Hybrid evolutionary algorithm

Real-coded genetic algorithm

Whole test suite

Gene expression programming

Weighted genetic algorithm

Artificial bee colony algorithm

Memetic genetic algorithm

Structured query language injection

Extensible markup language injection

Multi-objective genetic algorithm

Dynamic principal component analysis

Multi-objective simulated annealing

Search-based software testing

Search-based software engineering

Common vulnerability scoring system

Co-operative co-evolutionary algorithm

Search-based software security testing

Multi-objective evolutionary search adaptive random testing

Fixed-sized candidate-set adaptive random testing

Collaborative co-evolutionary contract-driven algorithm

Multi-objective evolutionary algorithm based on decomposition

Multi-objective co-operative co-evolutionary algorithm

Evolutionary adaptive random testing algorithm

Dynamic multi-objective sorting algorithm

Non-dominated sorting genetic algorithm

Vector evaluated genetic algorithm

Niched pareto genetic algorithm

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Clinical evaluation of platelet-rich plasma therapy for osteonecrosis of the femoral head: A systematic review and meta-analysis

Roles Conceptualization, Data curation, Investigation, Methodology, Supervision, Writing – original draft

Affiliations Changchun University of Chinese Medicine, Changchun, China, Hospital Affiliated to Changchun University of Traditional Chinese Medicine, Changchun, China

Roles Data curation, Investigation, Methodology, Software, Writing – original draft

Roles Data curation, Investigation, Methodology, Visualization, Writing – review & editing

Roles Conceptualization, Data curation, Methodology, Writing – review & editing

* E-mail: [email protected]

• Guimei Guo, 
• Wensi Ouyang, 
• Guochen Wang, 
• Wenhai Zhao, 
• Changwei Zhao

• Published: May 24, 2024
• https://doi.org/10.1371/journal.pone.0304096
• Peer Review
• Reader Comments

This meta-analysis aims to assess the efficacy and safety of platelet-rich plasma (PRP) for osteonecrosis of the femoral head (ONFH).

We comprehensively searched randomized controlled trials in PubMed, Web of Science, EMBASE, the Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, China Science and Technology Journal Database, WanFang, and Chinese BioMedical Literature Database from inception until October 25, 2024. The literature on the clinical efficacy of autologous PRP for ONFH was collated. According to the inclusion and exclusion criteria, the literature was screened, quality evaluated and the data was extracted. Meta-analysis was carried out with the software Review Manager 5.4.1 software and Stata 17.0 software. In addition, potential publication bias was detected by the funnel plot test and Egger’s test. The GRADE system was used to evaluate the quality of evidence for outcome indicators.

Fourteen studies involving 909 patients were included in this study. Compared with non-PRP, PRP exhibited significant improvements in the Harris hip score (HHS) at 3 months (MD = 3.58, 95% Cl: 1.59 to 5.58, P = 0.0004), 6 months (MD = 6.19, 95% Cl: 3.96 to 8.41, P < 0.00001), 12 months (MD = 4.73, 95% Cl: 3.24 to 6.22, P < 0.00001), ≥ 24 months (MD = 6.83, 95% Cl: 2.09 to 11.59, P = 0.0003), and the last follow-up (MD = 6.57, 95% Cl: 4.81 to 8.33, P < 0.00001). The PRP also showed improvement in HHS compared to baseline than the non-PRP at 3 months (MD = 3.60, 95% Cl: 1.26 to 5.94, P = 0.003), 6 months (MD = 6.17, 95% Cl: 3.74 to 8.61, P < 0.00001), 12 months (MD = 5.35, 95% Cl: 3.44 to 7.25, P < 0.00001), ≥ 24 months (MD = 8.19, 95% Cl: 3.76 to 12.62, P = 0.0003), and the last follow-up (MD = 6.94, 95% Cl: 5.09 to 8.78, P < 0.00001). The change in visual analog scale (VAS) score 3 months post intervention (MD = -0.33, 95% Cl: -0.52 to -0.13, P = 0.001), 6 months (MD = -0.69, 95% Cl: -0.90 to -0.48, P < 0.00001), 12 months (MD = -0.75, 95% Cl: -1.05 to -0.46, P < 0.00001), ≥ 24 months (MD = -1.05, 95% Cl: -1.20 to -0.89, P < 0.00001), and the last follow-up (MD = -0.75, 95% Cl: -0.97 to -0.54, P < 0.00001). The PRP also showed a decrease in VAS score compared to baseline than the non-PRP at 3 months (MD = -0.29, 95% Cl: -0.41 to -0.17, P = 0.003), 6 months (MD = -0.63, 95% Cl: -0.96 to -0.30, P = 0.0002), 12 months (MD = -0.78, 95% Cl: -1.22 to -0.33, P = 0.0006), ≥ 24 months (MD = -1.11, 95% Cl: -1.27 to -0.96, P < 0.00001), and the last follow-up (MD = -0.74, 95% Cl: -1.05 to -0.43, P < 0.00001). Additionally, it was found that the PRP group had the advantages in the following aspects: collapse rate of the femoral head (RR = 0.33, 95% Cl: 0.17 to 0.62, P = 0.0006), rate of conversion to total hip arthroplasty (RR = 0.37, 95% Cl: 0.18 to 0.74, P = 0.005), and overall complications (RR = 0.33, 95% Cl: 0.13 to 0.83, P = 0.02). The GRADE evidence evaluation showed overall complication as very low quality and other indicators as low quality.

There is limited evidence showing benefit of PRP therapy for treatment of ONFH patients, and most of this evidence is of low quality. Caution should therefore be exercised in interpreting these results. It is recommended that future research involve a greater number of high-quality studies to validate the aforementioned conclusions.

Systematic review registration

https://www.crd.york.ac.uk/prospero/ #recordDetails, CRD42023463031 .

Citation: Guo G, Ouyang W, Wang G, Zhao W, Zhao C (2024) Clinical evaluation of platelet-rich plasma therapy for osteonecrosis of the femoral head: A systematic review and meta-analysis. PLoS ONE 19(5): e0304096. https://doi.org/10.1371/journal.pone.0304096

Editor: Sameh Attia, Justus Liebig University Giessen, GERMANY

Received: December 14, 2023; Accepted: May 6, 2024; Published: May 24, 2024

Copyright: © 2024 Guo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: CI, confidence interval; GRADE, Grades of Recommendation Assessment Development; HHS, Harris hip score; MD, mean difference; MCID, minimally clinical important difference; ONFH, osteonecrosis of the femoral head; PRP, platelet-rich plasma; RCTs, randomized controlled trials; RR, risk ratio; VAS, Visual analog scale

Introduction

Osteonecrosis of the femoral head (ONFH) is a common refractory disease in orthopedics, characterized by decreased local blood flow and osteoclastic death, which leads to progressive collapse and deformation of the femoral head [ 1 – 3 ]. ONFH patients with hip pain, and intermittent claudication as the main clinical symptoms, if not timely symptomatic treatment, patients gradually develop joint mobility disorders, and in serious cases, affecting normal life and work [ 4 , 5 ]. The treatment of patients with early to early- and mid-stage ONFH is currently focused on delaying femoral head collapse and protecting hip joint function to improve patient’s quality of life. According to the latest guidelines and expert consensus, the currently available standard treatment strategies mainly involve non-weight-bearing therapies, medications, physical therapy, surgical treatments, and other methods, which have some clinical efficacy but still have limitations. Therefore, there is an urgent need to propose new therapeutic options on how to improve the clinical treatment of ONFH [ 6 – 8 ].

It is well known that platelet-rich plasma (PRP) is a platelet concentrate obtained from autologous blood by high-speed centrifugation, which can effectively avoid autoimmune rejection while playing a therapeutic role [ 9 , 10 ]. PRP contains various types of growth factors, inhibitors of inflammatory factors, and a rich fibrin network. Many of the ingredients synergistically participate in cell proliferation, growth, and differentiation, thereby regulating tissue repair, healing, and regeneration [ 11 – 13 ]. The number of primary studies in this area has increased substantially over the years [ 14 – 17 ]. However, it is inconclusive whether PRP has a therapeutic effect on ONFH. Therefore, this study intends to evaluate the efficacy and safety of PRP in the treatment of ONFH using an evidence-based medicine approach, with a view to providing more therapeutic bases for clinical practitioners.

Methods and materials

Protocol register.

This systematic review and meta-analysis was structured in adherence to the guidelines of the Cochrane Handbook for Systematic Reviews and was reported as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The protocol was registered in PROSPERO (CRD42023463031) [ 18 , 19 ].

Search strategy

Two review authors (G.M.G. and W.S.O.Y.) comprehensively searched four English electronic databases (PubMed, Web of Science, EMBASE, and the Cochrane Central Register of Controlled Trials) and four Chinese electronic databases (Chinese National Knowledge Infrastructure, China Science and Technology Journal Database, WanFang, and Chinese BioMedical Literature Database) from the inception date to October 1, 2023. Search strategies include the keywords below: “platelet-rich plasma”, “platelet-rich”, “platelet rich plasma”, “osteonecrosis of the femoral head”, “femur head necrosis”, “ONFH”, and “FHN”. Search approaches included a combination of thematic and free words and were adapted to suit the characteristics of each database. Additionally, the reference lists of included articles were reviewed to obtain as much of the potential research as possible. English search strategy as follows: ((platelet-rich plasma [Title/Abstract]) OR (platelet-rich [Title/Abstract]) OR (platelet rich plasma [Title/Abstract]) AND (“osteonecrosis of the femoral head” [Mesh]) OR ((femur head necrosis [Title/Abstract])) OR (ONFH [Title/Abstract])) OR (FHN [Title/Abstract]). A detailed description of the search strategy used is provided in S1 Table .

Eligibility criteria

• Research type: Only published randomized controlled trial studies exploring the clinical outcomes of PRP therapy for ONFH in both Chinese or English languages were considered.
• Population: Patients who met the diagnostic criteria for ONFH. Patients were not limited to age, gender, ethnicity, and geographical location. Staging references were the Association Research Circulation Osseous stage and the Ficat stage [ 7 , 20 ].
• Interventions: The control group received core decompression combined with bone grafting treatment. The treatment group received core decompression combined with bone grafting treatment combined with PRP. PRP treatments are not restricted.
• Type of outcome measures: Included studies were required to include one of the following outcomes: The primary outcome was the Harris hip score (HHS) (patients were evaluated primarily in terms of pain, function, deformity, and hip range of motion, with a total score of 100. with <70 = poor result, 70–79 = fair result, 80–89 = good result, and >90 = excellent result) [ 6 ], Visual analog scale (VAS) score (from 0 to 10, with 0 = no pain and 10 the worst imaginable pain), collapse rate of the femoral head, rate of conversion to total hip arthroplasty, and overall complication.

Exclusion criteria

• Literature with overlapping data or duplicate publications.
• Literature reviews, case reports, animal experiments, basic experimental studies, letters, and review articles.
• Patients received other treatment during the period of PRP treatment.
• Primary or relevant outcome indicators are unavailable.

Data extraction

Two independent review authors (G.C.W. and W.H.Z.) screened the literature for inclusion criteria and exclusion criteria. Any discordance was resolved through in-depth discussions and, if necessary, in collaboration with a third reviewer (C.W.Z.) to reach a unanimous decision. Two independent review authors (W.S.O.Y. and G.M.G.) employed a systematic data extraction template to mine essential study features. The extracted data elements included first authors, publication year, mean age, number of participants and hips, stage of necrosis, type of mechanical support, PRP preparation techniques, PRP application schemes, follow-up time, and outcome indicators. Key outcomes were extracted separately by two other review authors (G.C.W. and C.W.Z.) for data synthesis. A collaborative consensus approach was adopted in data extraction discrepancies between reviewers, involving all reviewers.

Assessment of the risk of bias

The methodological quality of each included literature was separately assessed by two review authors (G.M.G. and W.S.O.Y.) by using the Cochrane Risk of Bias tool. If the two researchers disagree, it can be resolved by consulting a third reviewer author (C.W.Z.). The quality evaluation includes the following seven aspects: random sequence generation, allocation concealment, blinding of study participants and outcome assessors, completeness of outcome data, selective reporting bias, and other biases [ 21 ].

The Grades of Recommendation Assessment Development and Evaluation

We used the principles of the Grades of Recommendation Assessment Development and Evaluation (GRADE) system to assess the quality of the body of evidence associated with outcomes [ 22 ]. Developed to grade the overall certainty of a body of evidence, this approach incorporates five main domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias [ 23 ]. Two review authors (G.M.G. and W.S.O.Y.) separately assessed each domain for each selected outcome. If the two researchers disagree, it can be resolved by consulting a third reviewer author (C.W.Z.). We documented all decisions regarding up- or down-grading the certainty of evidence to ensure transparency.

Statistical analysis

Statistical analysis was conducted using Review Manager 5.4.1 software and Stata 17.0 software. We used the Risk Ratio (RR) for comparisons of binary data and Mean Difference (MD) for comparisons of continuous data. Both measures were accompanied by a 95% Confidence Interval (CI) to encapsulate the effect magnitude when juxtaposing intervention groups and control groups. In each analysis, heterogeneity was tested by the χ 2 test and the I 2 value was calculated for quantification. When I 2 was less than 50%, it indicated that no significant homogeneity among the included studies, and the fixed-effects model can be used for statistical analysis. When I 2 was greater than 50%, it indicated that the homogeneity among the included studies was obvious, and the random-effects model was used for statistical analysis. To assess the stability of the outcomes, a sensitivity analysis was carried out by excluding the studies one by one at a time. Publication bias was visually assessed by the funnel plot test and Egger’s test. We compared pre-to-post-treatment score changes to the minimally clinical important difference (MCID) thresholds determined by previous studies. For HHS, we defined a difference of 10 points to represent the MCID [ 24 ]. For VAS score, we defined a difference of 0.9 points to represent the MCID. All selected MCID threshold values were calculated by prior studies via an anchor-based approach [ 25 ].

Search selection process

During our database search, 448 potentially relevant articles on the treatment of PRP for ONFH were preliminarily retrieved, and 352 duplicate studies were removed by using EndNote software. Then, 61 articles were excluded due to the titles and abstracts that were without high relevance to this study. Two review authors (G.M.G. and W.S.O.Y.) respectively read the full manuscript of 35 publications and excluded 21 of them. Ultimately, 14 published articles [ 24 , 26 – 38 ] that met the inclusion criteria were identified for inclusion in this meta-analysis ( Fig 1 ). PRISMA checklist is shown in the S2 Table .

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https://doi.org/10.1371/journal.pone.0304096.g001

Characteristics of the included researchs

A total of 909 adult participants with ONFH were included in the 14 eligible studies [ 24 , 26 – 38 ]. There were 454 participants in the control group and 455 participants in the treatment group. The detailed characteristics of all the research included are presented in Tables 1 and 2 . All studies had clear inclusion and exclusion criteria and there were no significant differences in baseline information between the control groups and treatment groups. The 6 studies [ 24 , 27 , 31 , 32 , 35 , 37 ] were supported by the government or a professional organization. The 8 studies [ 26 , 28 – 30 , 33 , 34 , 36 , 38 ] did not report the funding. The 9 studies [ 24 , 26 – 29 , 31 , 32 , 34 , 36 ] followed the Association Research Circulation Osseous classification, and 5 studies [ 30 , 33 , 35 , 37 , 38 ] followed the Ficat classification. All of the studies described mechanical structural enhancements, 5 of which used β-tricalcium phosphate bioceramic bone [ 26 , 31 , 32 , 34 , 35 ], 1 of which used porous tantalum rod [ 27 ], and 7 of which used autologous bone graft [ 24 , 29 , 30 , 33 , 36 – 38 ]. All the studies describe the PRP preparation technique, but the details vary ( Table 3 ).

https://doi.org/10.1371/journal.pone.0304096.t001

https://doi.org/10.1371/journal.pone.0304096.t002

https://doi.org/10.1371/journal.pone.0304096.t003

Assessment of risk of bias

Among the 14 RCTs, 9 studies [ 26 , 28 – 33 , 35 , 38 ] appropriately described the randomization methods such as random number tables and computerized random methods were rated low risk. Four studies [ 24 , 27 , 34 , 37 ] only indicated the use of randomization and did not specify the randomization method, so they were rated as unclear risk. One study [ 36 ] did not report randomization methods such as the admission order grouping method was rated high risk. Two studies [ 30 , 35 ] referred to the use of double-blind methods that were judged at low risk of bias. Three studies [ 24 , 26 , 38 ] conducted blind methods on participants or personnel who were judged at unclear risk of bias. The remaining studies [ 27 – 29 , 31 – 34 , 36 , 37 ] were judged at high risk of bias. All studies were at low risk for incomplete outcome data. For selective reporting, only two [ 27 , 37 ] studies reported overall complications and were judged to be low risk. In terms of other biases, All studies were rated as unclear risk ( Fig 2 ).

https://doi.org/10.1371/journal.pone.0304096.g002

Meta-analysis results

Harris hip score (hhs)..

A total of 13 studies [ 24 , 26 , 27 , 29 – 38 ] with 809 participants reported HHS between the treatment groups and control groups. Among the 13 studies, 7 studies [ 26 , 27 , 31 – 35 ] reported HHS at 3 months postoperatively, 9 studies [ 26 , 27 , 29 – 35 ] reported HHS at 6 months postoperatively, 9 studies [ 26 , 27 , 31 , 32 , 34 – 38 ] reported HHS at 12 months postoperatively, and 3 studies [ 25 , 30 , 32 ] reported HHS at ≥ 24 months postoperatively. Meta-analysis was performed on the last follow-up time points, and at different follow-up time points postoperatively (3-, 6-, 12-, and ≥ 24-month follow-ups) when those were reported by the respective studies. The meta-analysis revealed overall better treatment group versus control group function although considerable heterogeneity was evident. The results showed that HHS at 3-, 6-, 12-, ≥ 24- month, and last follow-ups postoperatively were higher in the treatment group than that in the control group (3 months, MD = 3.58, 95% Cl: 1.59 to 5.58, P = 0.0004; 6 months, MD = 6.19, 95% Cl: 3.96 to 8.41, P < 0.00001; 12 months, MD = 4.73, 95% Cl: 3.24 to 6.22, P < 0.00001; ≥ 24 months, MD = 6.83, 95% Cl: 2.09 to 11.56, P = 0.005; last follow-up, MD = 6.57, 95% Cl: 4.81 to 8.33, P < 0.00001). The difference was statistically significant but did not reach the set MCID threshold, suggesting that the difference was not clinically significant ( Fig 3 ).

https://doi.org/10.1371/journal.pone.0304096.g003

Chang from baseline HHS The results showed that treatment groups were associated with higher HHS from the baseline compared with control groups (3 months, MD = 3.60, 95% Cl: 1.26 to 5.94, P = 0.003; 6 months, MD = 6.17, 95% Cl: 3.74 to 8.61, P < 0.00001; 12 months, MD = 5.35, 95% Cl: 3.44 to 7.25, P < 0.00001; ≥ 24 months, MD = 8.19, 95% Cl: 3.76 to 12.62, P = 0.0003; last follow-up, MD = 6.94, 95% Cl: 5.09 to 8.78, P < 0.00001) ( Table 4 , S1 Fig ).

https://doi.org/10.1371/journal.pone.0304096.t004

Visual analog scale (VAS) score.

A total of 12 studies [ 24 , 26 – 29 , 31 – 36 , 38 ] with 809 participants reported VAS score between the treatment groups and control groups. Among the 12 studies, 8 studies [ 26 – 28 , 31 – 35 ] reported VAS score at 3 months postoperatively, 9 studies [ 26 – 29 , 31 – 35 ] reported VAS score at 6 months postoperatively, 9 studies [ 26 – 28 , 31 , 32 , 34 – 36 , 38 ] reported VAS score at 12 months postoperatively, and 2 studies [ 24 , 32 ] reported VAS score at ≥ 24 months postoperatively. Meta-analysis was performed on the last follow-up time points, and at different follow-up time points postoperatively (3-, 6-, 12-, and ≥ 24-month follow-ups) when those were reported by the respective studies. The meta-analysis showed better overall pain relief in the treatment group compared to the control group function although considerable heterogeneity was evident. The results showed that VAS at 3-, 6-, 12-, ≥ 24- month, and last follow-ups postoperatively were lower in the treatment group than that in the control group (3 months, MD = -0.33, 95% Cl: -0.52 to -0.13, P = 0.001; 6 months, MD = -0.69, 95% Cl: -0.90 to -0.48, P < 0.00001; 12 months, MD = -0.75, 95% Cl: -1.05 to -0.46, P < 0.00001; ≥ 24 months, MD = -1.05, 95% Cl: -1.20 to -0.89, P < 0.00001; last follow-up, MD = -0.75, 95% Cl: -0.97 to -0.54, P < 0.00001), and the differences were all statistically significant. With the exception of ≥ 24-month follow-up results (only two studies included), none of the outcomes met the set MCID threshold, suggesting that the difference was not clinically significant. The cause may occur incidentally and does not represent a true difference in treatment. Therefore, it is uncertain whether PRP treatment has clear clinical significance for pain improvement ( Fig 4 ).

https://doi.org/10.1371/journal.pone.0304096.g004

Chang from baseline VAS score The results showed that treatment groups were associated with more lowered VAS score from the baseline compared with control groups (3 months, MD = -0.29, 95% Cl: -0.41 to -0.17, P < 0.00001; 6 months, MD = -0.63, 95% Cl: -0.96 to -0.30, P = 0.0002; 12 months, MD = -0.78, 95% Cl: -1.22 to -0.33, P = 0.0006; ≥ 24 months, MD = -1.11, 95% Cl: -1.27 to -0.96, P < 0.00001; last follow-up, MD = -0.74, 95% Cl: -1.05 to -0.43, P < 0.00001) ( Table 4 , S2 Fig ).

Collapse rate of the femoral head.

A total of 7 studies [ 26 , 28 , 30 , 31 , 34 , 35 , 38 ] reported the collapse rate of the femoral head between the treatment groups and control groups. Minimal heterogeneity was found (P = 0.83, I 2 = 0%), allowing the use of a fixed effect model. The meta-analysis results show better outcomes after PRP therapy (RR = 0.33, 95% Cl: 0.17 to 0.62, P = 0.0006) ( Fig 5 ).

https://doi.org/10.1371/journal.pone.0304096.g005

Rate of conversion to total hip arthroplasty.

A total of 6 studies [ 24 , 26 , 30 , 32 , 35 , 38 ] reported a rate of conversion to total hip arthroplasty between the treatment groups and control groups. Minimal heterogeneity was found (P = 0.93, I 2 = 0%), allowing the use of a fixed effect model. The meta-analysis results show better outcomes after PRP therapy (RR = 0.37, 95% Cl: 0.18 to 0.74, P = 0.005) ( Fig 6 ).

https://doi.org/10.1371/journal.pone.0304096.g006

Overall complications.

Only two studies [ 27 , 37 ] with 180 participants reported overall complications between the groups. In Guo’s study [ 27 ], one instance of postoperative anemia in the control group and one instance of vein thrombosis in the treatment group were noted. Zhao’s study [ 37 ] documented six cases of infection, three instances of hypovolemic shock, four cases of skin redness, and one case of vein thrombosis in the control group and a single case of infection, one instance of hypovolemic shock, and two cases of skin redness in the treatment group. A fixed effect model was utilized given the low heterogeneity (P = 0.40, I 2 = 0%). It was statistically significant (RR = 0.33, 95% Cl: 0.13 to 0.83, P = 0.02) ( Fig 7 ). It is worth noting that there is a lack of strict criteria for complications and the result should be treated with caution.

https://doi.org/10.1371/journal.pone.0304096.g007

Sensitivity analysis

We conducted a sensitivity analysis by means of a one-by-one exclusion study, the results of which verified the robustness of our findings. The details of sensitivity analysis are presented in S3 and S4 Tables.

GRADE evaluation

Based on the principles of the GRADE evaluation, we evaluated the quality of the evidence provided via the HHS, VAS score, collapse rate of the femoral head, rate of conversion to total hip arthroplasty, and overall complication. Table 5 shows that, except for overall complication which was classified as very low-quality, the others were evaluated as low in quality.

https://doi.org/10.1371/journal.pone.0304096.t005

Publication bias

We performed a funnel plot test and Egger’s test on the results of ten or more studies. The results showed that no significant publication bias was found in the HHS and VAS score. The details of publication bias are presented in S3 , S4 Figs and S5 Table .

It has been a hot topic among doctors to determine the most effective surgical approach for patients with ONFH that will result in the most satisfactory outcome while minimizing the possibility of postoperative complications. Expert consensus on clinical drug prevention and treatment of osteonecrosis of the femoral head (2022), formulated by the Center for Osteonecrosis and Joint-Preserving & Reconstruction, suggests that PRP therapy can induce angiogenesis and osteogenesis, thereby accelerating bone healing and inhibiting inflammatory responses in necrotic lesions [ 39 ]. The results of the meta-analysis revealed that PRP therapy could improve the HHS and lower the VAS score, collapse rate of the femoral head, rate of conversion to total hip arthroplasty, and overall complications. Most studies did not meet the MCID threshold for HHS and VAS score, resulting in uncertain clinical relevance. This may have something to do with the fact that the results of our quantitative analysis are highly dependent on MCID values selected from prior studies. These MCID values are highly impacted by the patient population being studied, and anchor-based approaches are subject to recall bias.

Our review has produced consistent findings with one systematic review published in the English language on PRP for ONFH [ 40 ]. Compared to the previous reviews, our review provides a variety of new perspectives. First, more rigorous inclusion criteria and exclusion criteria could increase the quality of evidence. Additionally, the article included the most recent clinical studies that comprehensively assessed important outcome indicators such as HHS, VAS, and femoral head collapse rate, which made this study more convincing and credible.

The HHS has been widely used in the evaluation of clinical efficacy by comprehensively evaluating joint pain, hip function, and daily living abilities. According to a study by Yuan’s study [ 35 ], HHS at 18 months postoperatively was significantly better in the PRP group than in the non-PRP group, which is consistent with the results of this analysis. Similarly, Chai’s study [ 26 ] also indicated that the intraoperative use of PRP can reduce patient’s pain, improve joint function, and enhance the quality of life, which has some clinical application prospects. Numerous animal experiments have shown that PRP has a positive role in the process of bone repair. Wang’s study [ 41 ] found in a New Zealand rabbit model that injection of PRP after core decompression promotes the recovery of endosteal trabecular structures in the femoral head. As well, Saginova’s study showed that PRP in combination with bone allografts significantly promoted the early stages of bone defect healing [ 42 ].

The VAS score is an important indicator for assessing pain in patients. The causes of postoperative pain in patients with ONFH are complex. Intraoperative operations such as scraping of necrotic bone tissue, placement of bone substitutes, and suturing can damage the bone, joint capsule, and blood vessels, resulting in joint pain. Guo’s study [ 27 ] showed a significant decrease in VAS score for 60 participants who received PRP through intraoperative injections. Surgical trauma and other related injury stimuli can lead to a large release of inflammatory factors such as TNF-α and IL-1β, resulting in the sensitization of peripheral tissues and central nervous injury receptors, lowering the patient’s own pain threshold, so the body feels pain. Su’s study [ 43 ] showed that CRP and WBC levels were upregulated to varying degrees in both groups, but they were significantly lower in the PRP group than in the non-PRP group, demonstrating the ability of PRP to improve postoperative analgesic efficacy and downregulate inflammatory factor levels. It is worth noting that scholars have suggested that the pain-relieving effect of PRP may be related to the substance 5-HT in PRP, and a large number of studies have confirmed that 5-HT can influence the transmission of injury to peripheral tissues through receptors and reduce pain levels [ 44 , 45 ].

For the patient, delaying the collapse of the femoral head is the main principle in the treatment of ONFH. Chen’s study indicated that PRP could improve the success rate of core decompression combined with bone graft and effectively reduce the collapse rate of early- and mid-stage ONFH [ 46 ]. Similarly, animal experiments by Chen’s study demonstrated that PRP promotes the ability of bone marrow mesenchymal stem cells to proliferate and differentiate osteoblasts, and reduces the rate of bone trap vacancies [ 47 ]. Some scholar’s basic experiments also further confirmed that PRP can promote bone cell growth and bone tissue healing [ 48 , 49 ].

Meta-analysis results also showed that PRP therapy was effective in reducing the rate of total hip replacement. Zhang’s study [ 32 ] concluded that the implant’s structure facilitates the crawling of neovascularization while mechanically acting as a structural weight-bearing support. PRP therapy through the slow release of active repair factors, promotes neovascular growth crawl through and induces osteoblast proliferation and growth, and then the local presentation of new bone mineralization, accelerates the formation of new bone, and can effectively reduce the number of revision surgeries. Chen’s study [ 46 ] concluded that PRP may achieve the effect of delaying or even avoiding arthroplasty by controlling infection, inhibiting inflammatory response, and promoting tissue repair, but its long-term efficacy requires further follow-up.

The quality of the RCTs included in our review was assessed by the GRADE system. The GRADE system utilizes a highly structured approach to classify the level of evidence and clearly presents the evaluation items in an item-by-item listing so that clinicians can understand the effectiveness and feasibility of the interventions on their own, and then make clinical decisions. Of the indicators in this study, the overall complications were rated as very low quality, the HHS, VAS score, the collapse rate of the femoral head, and rate of conversion to total hip arthroplasty were rated as low quality, suggesting that there is a discrepancy between the predicted efficacy and the true efficacy of this study. The reasons may be related to the lack of blinding of the included studies, inadequate allocation concealment, large heterogeneity among some studies, and publication bias, which are important issues that need to be addressed in current systematic evaluation studies of the same type. Therefore, it is still necessary to include higher quality RCTs to improve the level of evidence in the future. In the clinical management of patients with ONFH, a comprehensive assessment of the patient’s overall condition is still needed to make clinical decisions.

Limitations and future directions

This systematic review aimed to determine the effectiveness of PRP therapy in managing ONFH. However, there are several limitations to consider: (1) Although the included literature was all RCTs, most articles did not mention randomization methods, allocation concealment, and blinding, which may affect the reliability of the conclusions. (2) There was a high degree of heterogeneity in some of the outcome indicators in the included studies, which may be related to pathogenic factors, diagnostic criteria, and degree of femoral head collapse. (3) Among the included studies, the duration of follow-up was not uniform, and some of the literature had incomplete data information, which may have contributed to some bias in this study. (4) Overall complications have been under-reported and safety needs to be further investigated. (5) The lack of standardization of PRP production and protocols for clinical application, makes the PRP products heterogeneous and qualitatively very different from each other, thus limiting the validity of an inter-studies comparison.

To better understand PRP therapy efficacy, addressing these limitations in future research is crucial. With the popularization and application of PRP technology, future research needs to be focused on PRP preparation methods, effective concentrations, intervention doses, and methods of use [ 50 , 51 ]. In the future, we can focus on patient’s coagulation indices, quality of life, and patient satisfaction, making the results of the study more reliable.

We conclude that there is insufficient evidence to regularly recommend PRP therapy for the treatment of ONFH. In future studies, higher-quality RCTs should be needed to better define PRP therapy as a treatment option for ONFH.

Supporting information

S1 table. search strategy..

https://doi.org/10.1371/journal.pone.0304096.s001

S2 Table. PRISMA checklist.

https://doi.org/10.1371/journal.pone.0304096.s002

S3 Table. Sensitivity analysis for Harris hip score.

https://doi.org/10.1371/journal.pone.0304096.s003

S4 Table. Sensitivity analysis for visual analog scale score.

https://doi.org/10.1371/journal.pone.0304096.s004

S5 Table. Publication bias evaluated by egger test.

https://doi.org/10.1371/journal.pone.0304096.s005

S1 Fig. Forest plot of the meta-analysis comparing the Harris hip score change from baseline: a the duration of follow-up 3 months b the duration of follow-up 6 months c the duration of follow-up 12 months d the duration of follow-up longer than 24 months e the last follow-up.

https://doi.org/10.1371/journal.pone.0304096.s006

S2 Fig. Forest plot of the meta-analysis comparing the visual analog scale score change from baseline: a the duration of follow-up 3 months b the duration of follow-up 6 months c the duration of follow-up 12 months d the duration of follow-up longer than 24 months e the last follow-up.

https://doi.org/10.1371/journal.pone.0304096.s007

S3 Fig. The funnel plot of Harris hip score.

https://doi.org/10.1371/journal.pone.0304096.s008

S4 Fig. The funnel plot of visual analog scale score.

https://doi.org/10.1371/journal.pone.0304096.s009

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• 19. Higgins JPT., Thomas J, Chandler J., Cumpston M., Li T., Page MJ., et al., 2022. Cochrane Handbook for Systematic Reviews of Intervention, Chichester: John Wiley & Sons, 2019.

• Systematic Review
• Open access
• Published: 23 May 2024

Prevalence of human papillomavirus in head and neck cancer patients in India: a systematic review and meta-analysis

• Prakasini Satapathy 1 , 2 ,
• Mahalaqua Nazli Khatib 3 ,
• Shilpa Gaidhane 4 ,
• Quazi Syed Zahiruddin 5 ,
• Hashem Abu Serhan 6 ,
• Rakesh Kumar Sharma 7 , 8 ,
• Divya Sharma 9 ,
• Mithhil Arora 10 ,
• Sarvesh Rustagi 11 ,
• AlKaabi NA   ORCID: orcid.org/0000-0002-7680-1141 12 , 13 ,
• Ahmed Alsayyah 14 ,
• Marwan Al-Hajeili 15 ,
• Maha F. Al-Subaie   ORCID: orcid.org/0000-0001-5486-8057 16 , 17 ,
• Mubarak Alfaresi   ORCID: orcid.org/0000-0003-2523-835X 18 , 19 ,
• Mohammed Alissa   ORCID: orcid.org/0000-0002-4045-0810 20 &
• Ali A. Rabaan   ORCID: orcid.org/0000-0002-6774-9847 17 , 21 , 22  

BMC Infectious Diseases volume  24 , Article number:  516 ( 2024 ) Cite this article

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Human papillomavirus (HPV) is increasingly recognized as a significant risk factor in the development of head and neck cancers (HNCs), with varying prevalence and impact. This study aims to systematically review and analyze the prevalence of HPV in HNCs in India, providing insights into regional variations.

A comprehensive literature search was carried out using PubMed, Embase, and Web of Science up to November 10, 2023. Inclusion criteria focused on original research reporting HPV-positive cases among HNC patients in India. We used Nested-Knowledge software, for screening, and data extraction. The modified Newcastle-Ottawa Scale was used for quality assessment of included studies. We pooled the prevalence of HPV among HNC patients and performed a random-effects model meta-analysis using R software (version 4.3).

The search yielded 33 studies, encompassing 4654 HNC patients. The pooled prevalence of HPV infection was found to be 33% (95% CI: 25.8–42.6), with notable heterogeneity (I² = 95%). Analysis of subgroups according to geographical location indicated varying prevalence rates. Specifically, the prevalence was 47% (95% CI: 32.2–62.4) in the eastern regions and 19.8% (95% CI: 10.8–33.4) in the western regions. No evidence of publication bias was detected.

The observed considerable regional disparities on the prevalence of HPV in HNC patients in India emphasizes the need for integrated HPV vaccination and screening programs in public health strategies. The findings underline the necessity for further research to explore regional variations and treatment responses in HPV-associated HNCs, considering the impact of factors such as tobacco use and the potential benefits of HPV vaccination.

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Introduction

Head and neck cancers (HNC), also known as head and neck squamous cell carcinomas (HNSCC), consist of various malignancies impacting the mucosal surfaces of the upper aerodigestive tract, in areas like the nasopharynx, oral cavity, larynx, oropharynx, hypopharynx, and paranasal sinuses [ 1 ]. Annually, HNSCC is responsible for over 650,000 new cancer cases and causes more than 350,000 deaths worldwide [ 2 , 3 , 4 ]. Traditional primary risk factors for these cancers have been alcohol and tobacco use. However, in recent years, the human papillomavirus (HPV) has been recognized as a significant emerging risk factor, particularly for oropharyngeal squamous cell carcinoma (OPSCC). This has led to the identification of a distinct subtype of HPV-related tumors, which differ from those not associated with HPV. The prevalence of HNSCC tends to vary based on the specific anatomical location and the geographic area [ 5 ].

The carcinogenic nature of HPV was definitively established in 1983 when Durst et al. successfully cloned HPV type 16 from cervical carcinoma tissue [ 6 ]. It is now widely acknowledged that high-risk HPV types are accountable for almost all cases of cervical cancer. While most HPV infections are asymptomatic and tend to resolve spontaneously, persistent HPV infection in the basal cells of the cervix can lead to the development of cervical cancer [ 6 , 7 ].

Numerous research articles indicate that epithelial cells from the oral cavity and tonsils can undergo immortalization through the influence of the full-length HPV-16 or its E6/E7 oncogenes [ 8 , 9 , 10 , 11 , 12 ]. Furthermore, studies using transgenic mice have shown that the E6/E7 genes of HPV 16 significantly heighten the risk of developing oral and oropharyngeal cancers [ 13 ]. It was found that the E7 gene, in particular, is more effective in triggering these cancers, yet there is a noticeable synergistic effect between E6 and E7 in the genesis of HNSCC [ 14 ].

In 2020, India accounted for 7% of the total cancer cases worldwide and a significant 24% of the global incidence of HPV-related cancers [ 15 ]. Additionally, it was reported that 80% of cervical cancer cases in India were attributed to HPV subtypes 16 and 18 [ 16 , 17 ]. As part of its cancer control strategy, India has started implementing opportunistic screening programs for common cancers, including those of the cervix and oral cavity, in its healthcare facilities [ 18 ]. A notable increase in HNC occurrences was observed in the population-based cancer registries (PBCRs) for cities such as Aurangabad, Delhi, Chennai, and Bhopal among men, and in Nagpur among women, in India [ 19 ]. The age-adjusted incidence rate of HNC stood at approximately 25.9 (95% CI 25.7–26.1) and 8.0 (95% CI 7.9–8.1) per 100,000 people for men and women, respectively [ 20 ]. HNC represented around 26% of all cancer diagnoses in men and 8% in women. The likelihood of being diagnosed with HNC was 1 in 33 for men and 1 in 107 for women [ 20 ].

Despite the growing body of literature on HPV’s role in HNC, there remains a lack of consensus on its prevalence and impact. This variability is partly due to differences in study designs, population demographics, and detection methods used across various research studies. A systematic review and meta-analysis of the existing studies can provide a more comprehensive understanding of HPV’s prevalence in HNC, offering insights into regional variations.

This systematic review was conducted in accordance with PRISMA guidelines [ 21 ] (Table S1 ) and has been registered in PROSPERO.

Literature search

An electronic literature search was conducted in various databases, including PubMed, Embase, and Web of Science from inception up to November 10, 2023. Keywords and MeSH terms related to HPV and HNC were used to devise the search strategy. No restrictions have been placed on the type of article, year of publication, or language in the search. Table S2 shows the detailed search strategy.

Inclusion criteria

Original research that reports the number of HPV-positive cases among HNC patients is included in this study. We are considering only studies conducted in India. Excluded from this study are case reports, case series, or studies lacking quantitative data. The same exclusion criteria apply to animal studies, commentaries, in vitro studies, and reviews. Studies from any location within India, whether conducted in a hospital or community setting, are eligible. There are no restrictions on the type of test used to detect HPV. A detailed inclusion criterion is specified in Table S3 .

Screening and study selection

Two independent reviewers performed the screening of the articles. Nested-Knowledge software was employed for this process. The screening involved a primary review of titles and abstracts, followed by a full-text reading to assess the eligibility of studies for inclusion. An independent third reviewer was consulted to resolve any discrepancies.

Data extraction and quality assessment

Data extraction was performed using the Tag function of the Nested-Knowledge software. Three reviewers carried out the data extraction process. A fourth reviewer cross-checked and validated the extracted data. The data extracted covered the author’s name, year of publication, state/location of the study, study design, age and percentage of males in the sample, total number of HNC patients in the study, number of HPV-positive samples, and the type of test employed for detecting HPV. Quality assessment was done using a modified Newcastle-Ottawa Scale (NOS) version [ 22 , 23 ].

Statistical analysis

A pooled prevalence of HPV is determined by performing a meta-analysis. A random-effects model is employed to conduct the meta-analysis. The variability in study outcomes was measured using the I 2 statistic, which quantifies heterogeneity on a scale from 0 to 100%, where higher values indicate greater heterogeneity [ 24 ]. The heterogeneity was further assessed using the 95% prediction interval. We calculated the tau-squared value using maximum likelihood estimation to gain additional insights into heterogeneity [ 25 , 26 , 27 , 28 ]. Subgroup analysis was conducted based on the location of the study. We used a funnel plot and the Egger test to detect any potential publication bias. A p-value below 0.05 was typically regarded as statistically significant. All statistical analyses were performed using R software, version 4.3 [ 23 , 29 , 30 ].

In the literature search, 4,972 articles were identified from multiple databases. Among these, 521 were duplicates. After removing duplicates, 4,451 articles were subjected to screening, of which 3,981 were excluded. The remaining 470 articles were screened by full text for eligibility, resulting in the exclusion of 440, leaving 30 for inclusion. Additionally, 3 studies were added from a citation search. Finally, 33 studies were included in the review. Figure  1 depicts the PRISMA flow chart of the selection and screening process.

PRISMA flow diagram showing the screening and selection process

Characteristics of included studies

The studies included in this review examining the prevalence of HPV in HNC cases in India are characterized by a diverse methodology and geographical spread. Table  1 summarises the characteristics of included studies. These investigations employ various study designs, including prospective, retrospective, case-control, cohort, and cross-sectional studies, providing a thorough exploration of the subject. The studies are conducted across multiple states and regions of India, representing a broad geographic distribution, and include participants across different age groups, offering insights into age-related variations in HPV prevalence. The proportion of male participants in these studies varies, suggesting potential gender differences in HPV prevalence. The primary diagnostic methods used in these studies are Polymerase Chain Reaction (PCR), genotyping, PCR and P16 Immunohistochemistry (IHC), and Chromogenic In Situ Hybridization (ISH), noted for their high sensitivity. The size of the study populations ranges from small cohorts to large groups, affecting the statistical power of the findings. Rates of HPV positivity exhibit considerable variability, underlining the complexity of understanding HPV prevalence in HNC in this context. These studies span a wide time frame, allowing for the analysis of temporal trends in HPV prevalence. New Delhi contributed 4 studies to the research on HPV prevalence in HNC [ 31 , 32 , 33 ], while Uttar Pradesh was represented by 5 studies [ 34 , 35 , 36 , 37 , 38 ]. Maharashtra was the focus of 4 studies [ 39 , 40 , 41 , 42 ]. Multiple studies were conducted in South India [ 43 , 44 ], Haryana [ 45 , 46 , 47 ], and Tamil Nadu [ 48 , 49 ]. Single studies were conducted in several other locations: Andhra Pradesh [ 50 ], Kerala [ 51 ], Kolkata [ 52 ], Mumbai [ 53 , 54 ], Karnataka [ 55 , 56 ], Chandigarh [ 57 , 58 ], and Assam [ 59 , 60 ]. Additionally, one study was a multi-regional study encompassing several states [ 42 ]. The included studies were overall of moderate to high quality in modified NOS (Table S4 ).

Meta-analysis

From 33 studies encompassing a total of 4654 patients with HNC, the pooled prevalence of HPV infection was determined to be 33% (95% CI: 25–42%). Notably, substantial heterogeneity was observed among these studies (I² = 96%). A prediction interval ranging from 6.2 to 79% was also observed. Figure  2 illustrates the forest plot depicting the pooled prevalence.

Forest plot depicting the overall HPV pooled prevalence in head and neck cancer patients

Subgroup analysis

Subgroup analysis was performed on the basis of the location of the study (Fig.  3 ). The North region is represented by 14 studies encompassing a total of 2236 patients, revealing a pooled HPV prevalence of 27% (95% CI: 17.4–40.4%), and a high degree of heterogeneity (I² = 95%). The South region, with 7 studies and 335 patients, has a pooled prevalence of 46.3% (95% CI: 15.6–80%), also accompanied by significant heterogeneity (I² = 87%). In the West Middle region, 5 studies totalling 865 patients show a pooled prevalence of 19.8% (95% CI: 10.8–33.4%) with substantial heterogeneity (I² = 88%). A single study spans multiple locations—Madhya Pradesh, Gujarat, Rajasthan, Uttar Pradesh, West Bengal, and Assam—encompassing 170 patients and reporting a higher pooled prevalence of 39% (95% CI: 32–47%). Lastly, the East region, represented by 7 studies with 1048 patients, presents a pooled prevalence of 47% (95% CI: 32.2–62.4%) with high heterogeneity (I² = 92%).

Forest plot illustrating the results of sub-group analysis-based location

Meta-regression and sensitivity analysis

Meta-regression was performed to determine the effect of sample size on the pooled prevalence of HPV in HNC cases, as depicted in Fig.  4 . However, the meta-regression analysis indicated that sample size was not significantly associated with the pooled prevalence results ( p  = 0.20). Additionally, a leave-one-out sensitivity analysis was conducted to identify individual studies that might affect the overall prevalence rate. This analysis revealed that the exclusion of no single study resulted in any significant changes to the overall pooled prevalence, as illustrated in Fig.  5 .

Bubble plot depicting the results of meta-regression based on sample size

Sensitivity analysis of pooled prevalence

Publication bias

Publication bias was assessed using funnel plot asymmetry and Egger’s test, as shown in Figure S1 . The results of our analysis did not provide evidence of publication bias (Egger’s test, p  = 0.71).

In the best of our knowledge, this is the first meta-analysis to determine the prevalence of HPV among HNC patients in India. In our analysis, we found an overall prevalence of 33% for HPV among HNC patients. South India and the eastern part of India have shown slightly greater prevalence compared to the north and west parts of India. Meta-regression, sensitivity analysis couldn’t resolve the s0000ource of heterogeneity.

Previous systematic reviews have established evidence that infection with HPV is a distinct risk factor for developing HNCs [ 61 , 62 ]. The risk associated with tonsil carcinoma is notably high and aligns with what one would anticipate from an infectious cause. Our findings indicate that HPV’s involvement in tonsil cancer is similar to the role of Epstein-Barr virus in nasopharyngeal cancer, suggesting that this is yet another instance of a virus-induced cancer in the pharyngeal lymphoid tissue [ 62 ].

The risk associated with the progression or death, along with the likelihood of developing a secondary primary HNOSCC, increases by 1% and 1.5% respectively for each additional year of smoking. This remains true even when accounting for the HPV tumor status and other important factors. Importantly, the risk of death doubles for patients who continue smoking during radiation therapy. The detection of HPV in HNCs is highly significant for prognosis and can influence the modification of treatment plans based on the HPV status [ 63 ]. Thus, the accurate identification of HPV as a contributing factor in HNCs is of paramount importance. Typically, a biopsy or cytological analysis from the primary tumor site or enlarged lymph nodes is crucial for an initial diagnosis. PCR or RT-PCR (Reverse Transcriptase-PCR) are commonly employed methods for detecting HPV in tumor tissues, particularly for identifying E6/E7 in fresh frozen samples. However, these methods are associated with high setup costs and longer turnaround times [ 64 ].

The presence of HPV in HNCs significantly alters the disease’s prognosis and therapeutic approach. HPV-positive HNCs typically present with a better response to standard treatment modalities like radiotherapy and chemotherapy, leading to an overall better prognosis compared to HPV-negative cases [ 65 ]. This is primarily attributed to the distinct biological behavior of HPV-positive tumors, which tend to be more sensitive to radiation and cytotoxic agents. Studies has indicated that individuals diagnosed with HPV-positive oropharyngeal cancer have higher survival rates and lower risks of recurrence [ 66 ].

Given these differences, there is an emerging consensus on tailoring treatment strategies based on HPV status. For instance, the concept of treatment de-escalation for HPV-positive HNCs is gaining traction. This approach involves reducing the intensity of standard treatments to minimize long-term side effects without compromising the efficacy of cancer control [ 67 ]. Clinical trials are currently exploring various de-escalation strategies, including reduced-dose radiotherapy, omission of chemotherapy, and the use of minimally invasive surgeries [ 68 , 69 ]. However, it’s important to approach de-escalation cautiously, ensuring that patient selection is based on robust biomarkers and clinical criteria to avoid under-treatment.

The accurate determination of HPV status in HNCs is pivotal for both prognostic assessment and guiding treatment decisions. Polymerase Chain Reaction (PCR) and Reverse Transcriptase-PCR (RT-PCR) are the gold standards for detecting HPV, particularly E6/E7 mRNA, in tumor tissues [ 70 , 71 , 72 ]. These methods are highly sensitive and specific but are often hindered by high costs and longer turnaround times, posing challenges in resource-limited settings. Emerging diagnostic techniques, such as liquid biopsies and next-generation sequencing (NGS), are promising alternatives. Liquid biopsies, which detect circulating tumor DNA (ctDNA) in blood samples, offer a less invasive method for HPV detection and monitoring [ 73 , 74 , 75 ]. NGS, on the other hand, allows for the comprehensive analysis of HPV integration sites and co-mutations, providing a more detailed tumor profile [ 76 ]. These technologies not only improve the accessibility of HPV testing but also enhance our understanding of the tumor biology, which is crucial for personalized medicine.

The significant role of HPV in HNCs necessitates public health interventions, particularly in countries like India where the burden of these cancers is high. HPV vaccination, which has been successful in reducing the incidence of cervical cancer, presents a viable strategy to curb HPV-related HNCs. The expansion of HPV vaccination programs to include both girls and boys could significantly reduce the future burden of these cancers [ 77 , 78 ]. It is crucial to integrate HPV vaccination into national immunization programs and to raise public awareness about its benefits. Furthermore, the compounded risk of tobacco use in HPV-positive HNC patients highlights the urgent need for effective tobacco cessation programs. Tobacco, being a well-established risk factor for HNCs, exacerbates the risk even in the context of HPV-positive cancers. Public health campaigns targeting tobacco cessation are not only essential for preventing HNCs but also for improving outcomes in patients with existing HPV-related cancers [ 79 , 80 , 81 ].

Our study acknowledges certain limitations that should be considered. Firstly, our analysis was restricted to articles published in the English language, potentially omitting relevant research published in other languages. Additionally, the geographic coverage of our data is not comprehensive; studies from all regions of India were not available, which may affect the generalizability of our findings. While subgroup analysis was conducted, it was not sufficient to completely address the sources of heterogeneity observed in the results. We were unable to perform subgroup analysis based on site-specific cancer prevalence due to the unavailability of reported data. Future studies should include detailed data on site-specific HNC and HPV to facilitate more comprehensive analyses. This heterogeneity could stem from various factors such as differences in study design, populations, or methodologies, which our subgroup analysis could not fully disentangle. The overall sample size of the included studies was relatively small. This limitation could impact the statistical power of our findings and might lead to less precise estimates. Given these constraints, we recommend that future research should include a broader range of languages and geographic areas, especially underrepresented regions of India. More extensive studies with larger sample sizes would also be beneficial to provide more robust and generalizable results, and to further explore the sources of heterogeneity observed in this study. The absence of publication bias in our findings further strengthens the reliability of these insights.

This comprehensive study underscores the significant role of HPV in the epidemiology of HNCs in India. Through a detailed systematic review and meta-analysis, we determined that the pooled prevalence of HPV among HNC patients in India is 33%, revealing a substantial impact of this virus on such cancers. Notably, the study highlighted regional variations, with the highest prevalence in eastern India (47%) and lowest in the western regions ( ∼  20%). This variability suggests the influence of regional factors in the prevalence and impact of HPV in HNCs. Overall, our study provides valuable data for healthcare professionals and policymakers, emphasizing the need for targeted interventions and policies to address the HPV-related burden in HNC patients in India, while also considering the regional disparities in prevalence and risk factors.

Data availability

All the data used in this review has been provided in the manuscript and supplementary files.

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Satapathy, P., Khatib, M.N., Gaidhane, S. et al. Prevalence of human papillomavirus in head and neck cancer patients in India: a systematic review and meta-analysis. BMC Infect Dis 24 , 516 (2024). https://doi.org/10.1186/s12879-024-09357-2

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