Cancer screening in people living with HIV

Abstract Background Cancer is the leading cause of mortality in people living with HIV (PWH) and is expected to account for a growing fraction of deaths as PWH age. Methods In this literature review, we have compiled the most recent developments in cancer screening and screening performance in PWH, which are currently primarily implemented in well‐resourced settings. This includes an assessment of the associated benefits, harms, and cost‐effectiveness. The article also addresses unmet needs and potential strategies for tailored screening in the HIV population. Findings Incidence and mortality due to screenable cancer are higher in PWH than in the general population, and diagnosis is frequently made at younger ages and/or at more advanced stages, the latter amenable to improved screening. Adequate evidence on the benefits of screening is lacking for most cancers in the HIV population, in whom standard practice may be suboptimal. While cancer surveillance has helped reduce mortality in the general population, and interest in risk‐based strategies is growing, implementation of screening programs in the HIV care settings remains low. Interpretation Given the devastating consequences of a late diagnosis, enhancing early detection of cancer is essential for improving patient outcomes. There is an urgent need to extend the investigation in cancer screening performance to PWH, evaluating whether personalized measures according to individual risk could result in higher efficiency and improve patient outcomes.

Findings: Incidence and mortality due to screenable cancer are higher in PWH than in the general population, and diagnosis is frequently made at younger ages and/or at more advanced stages, the latter amenable to improved screening.
Adequate evidence on the benefits of screening is lacking for most cancers in the HIV population, in whom standard practice may be suboptimal.While cancer surveillance has helped reduce mortality in the general population, and interest in risk-based strategies is growing, implementation of screening programs in the HIV care settings remains low.
Interpretation: Given the devastating consequences of a late diagnosis, enhancing early detection of cancer is essential for improving patient outcomes.There is an urgent need to extend the investigation in cancer screening performance to PWH, evaluating whether personalized measures according to individual risk could result in higher efficiency and improve patient outcomes.

K E Y W O R D S
non-AIDS cancer, screening, screening performance, surveillance The so-called non-AIDS-defining cancers (NADC), currently the dominant malignancies, 3 are now the leading cause of death among PWH. 4 The incidence and prevalence of numerous malignancies are much higher in PWH than in the general population.][7][8] Although cancer is a major factor contributing to decreased survival in PWH, and cancer surveillance has been shown to reduce mortality, 9,10 available data on cancer screening in this population are scarce and mostly limited to small observational studies.HIV society guidelines recommend cancer screening with the same methods used in the general population. 11Unfortunately, for some cancers with the highest excess incidence and/or mortality in PWH (e.g., lung cancer and hepatocellular carcinoma), standard screening may show suboptimal performance. 8,12Given the devastating consequences of late diagnosis, enhancing early detection is paramount to improving patient outcomes.
This review discusses the recent developments in cancer screening, predominantly implemented in well-resourced settings, with a focus on the HIV population; the benefits, harms, cost-effectiveness, and adherence to screening; and the unmet needs and potential strategies for tailored surveillance in PWH.

CANCER
Lung tumors are the NADCs with the highest incidence and mortality. 13In a meta-analysis of 38 studies, the overall standardized incidence ratio (SIR) for lung cancer in PWH versus the general population was 2.5 (95% confidence interval [CI] 1.9-3.52). 5In PWH, lung cancer occurs earlier in life, and younger age groups have shown the largest SIRs, although the highest absolute excess risk is observed in people aged over 60 years. 6Mortality associated with lung cancer is up to four times higher in PWH 5 (Table 1).

| Screening tests
To date, only low-dose computed tomography (LDCT) has been shown to reduce lung cancer mortality in two large randomized controlled trials (RCTs) in the general population. 9In PWH, available evidence with LDCT screening comes from a few small, uncontrolled observational studies, [14][15][16] with heterogeneous inclusion criteria and short follow-up.
Table 2 shows lung cancer screening methods and the level of evidence supporting them.

| Screening recommendations and performance in PWH
In 2013, the US Preventive Services Task Force (USPSTF) first recommended annual LDCT for individuals at highrisk of lung cancer, with criteria updated in 2021. 9In Europe, few countries have committed to implementing LDCT screening, although implementation programs are currently underway in several countries. 17As of 2021, the European AIDS Clinical Society (EACS) guidelines endorse screening with LDCT where local screening programs are available, based on 2021-USPSTF criteria (Table 3). 11n a simulation model developed in the US cohort of veterans living with HIV, and with a CD4 + count ≥500 cells/μL and 100% ART adherence, the estimated potential reduction in cancer mortality was 18.9% with the 2013-USPSTF criteria, similar to that of the general population. 18However, a retrospective analysis of the incident lung cancers diagnosed in the ANRS-CO4 French Database HIV cohort showed that only 31% would have been detected using the 2013-USPSTF criteria.Lowering the age and smoking thresholds would have increased sensitivity. 19In a similar study conducted in the MACS/WIHS cohorts, the 2021-USPSTF criteria outperformed 2013-USPSTF criteria in detecting lung cancer but still showed suboptimal sensitivity, particularly among women. 12The inclusion of HIVassociated factors did not improve accuracy, but lowering the age threshold and decreasing the pack-year history criterion increased sensitivity in both cohorts, particularly in women, suggesting sex differences in lung cancer risk that warrant further exploration in future prediction models.
Table 3 describes the harms and cost of the screening strategy recommended in the general population and in PWH.

| Implications for management
Besides being the most frequent NADC, lung cancer is also projected to be the most common cancer type by 2030, when the proportion of PWH older than 65 years is expected to double. 20The benefits and cost-effectiveness of LDCT might be even higher in PWH given the greater incidence of lung cancer.Contrary to initial hypotheses, the frequency of false-positive results is not higher in PWH. 14,16Additionally, different measures have been adopted to reduce false-positives rates, like volume-based nodule-management, or the Lung-RADS American College of Radiology's classification system. 9,21However, the 2021-USPSTF criteria should SMR 3.95 5,70 Younger age at presentation 6 In retrospective analysis of the incident lung cancers, low sensitivity, worse in women 12,14 Very low implementation rates  Gleason grade may be greater 64 In a small case-control study conducted in the EuroSIDA cohort, the cutoff used in the general population showed low sensitivity in PWH 68 Lower screening rates in PWH 64 High  9,11 Reduced lung cancer mortality in general population in 2 RCTs.May detect early-stage lung cancer, according to observational studies in PWH 14,18 FP results a leading to unnecessary tests and invasive procedures, overdiagnosis, incidental findings, radiation-induced cancer, and increases in distress.In PWH, no higher FP rates and similar or lower risk of radiation-induced cancers than in the general population 14,18,70 In .No specific data in HIV -Biennial screening at 50-69 years or 50-74 years, the most efficient. 59,60Screening improved QALYs and was cost-effective for women 40-64 years, with an incremental cost-effectiveness ratio of USD 50,223/QALY versus no screening 94 -MRI in its current form would not be cost-effective 95 .
-No data in WWH Prostate PSA every 1-2 years if shared decisionmaking/>50 years with a life expectancy >10 years 11,67 Meta-analysis from RCT: modest effect to reduce prostate cancer mortality (IRR 0.96, 0.85 to 1.08; low certainty) but did not have a benefit on overall mortality and was associated with biopsy and cancer treatment-related complications. 65o specific data in HIV -FP results leading to additional diagnostic procedures or prostate biopsy, overdiagnosis and overtreatment. 67otential treatment complications include incontinence and erectile dysfunction 67 .No specific data in HIV Uncertain cost-effectiveness in a systematic review of decision-analytical models based on the heterogeneity to reflect cancer progression, the inconsistent use of or using the Lung-RADS American College of Radiology's classification system.
b Efficiency frontier refers to the relative efficiency of the new intervention with the incremental cost-effectiveness ratios (ICERs) of non-dominated comparators. c The USPSTF recommendations (2021) extend the age range for screening to encompass adults aged 45-49, with a grade B recommendation.
be adapted to PWH.Approaches such as lowering the thresholds for age and smoking exposure or using biomarkers to stratify risk warrant further investigation with RCTs, including differential criteria by sex.A small single-LDCT study that reduced the age threshold to 45 years found a high prevalence of lung cancer in PWH. 15 Another relevant aspect to tackle is the low rates of lung cancer screening referrals in PWH. 22Compared to the general population, PWH may face more frequent and distinct barriers to lung cancer screening, both at the provider and patient levels.One such obstacle is the higher burden of comorbidities, particularly in the aging PWH, which may add complexity to the implementation of the screening procedures.However, there are also factors that promote screening within this population, which may offset these barriers.These factors include more common healthcare engagement, enduring and close patient-physician relationships, greater patient familiarity with evidence-based practices and willingness to undergo preventive interventions in the context of their long-term survival awareness. 23

HEPATOCELLULAR CARCINOMA
Hepatocellular carcinoma (HCC) is a common cancer with an increasing incidence rate (IR) in PWH 24,25 and the second most common cause of NADC-related death. 13HIV infection confers a higher risk of developing HCC and lower survival than the general population. 5Non-alcoholic fatty liver disease (NAFLD), currently the fastest growing cause of HCC in Western countries, shows a higher prevalence in PWH. 26 Since 2018, nonviral liver disease has surpassed hepatitis C virus (HCV) as the leading indication for liver transplant in PWH in the United States, and non-alcoholic steatohepatitis (NASH) accounted for nearly half of nonviral causes. 26

| Screening tests
Ultrasound is the primary test for HCC screening.
Observational studies have reported that ultrasounds are beneficial for early diagnosis and mortality reduction in people with viral cirrhosis. 27Sensitivity is particularly low in cirrhotic patients with obesity and NASH, 28 two conditions expected to increase in the near future.Magnetic resonance imaging (MRI), but not computed tomography (CT), has shown higher HCC detection rates than ultrasound. 29Blood biomarkers and algorithms including biomarkers plus clinical data have shown suboptimal results, but more recent genetic testing has demonstrated improved accuracy to predict HCC. 30 Performance data on HCC screening methods are limited in PWH. 8 Most surveillance studies have been conducted in individuals with viral hepatitis, but the benefits and strategies of screening in patients with NAFLD-related cirrhosis have yet to be elucidated.
Table 2 shows the screening methods for HCC detection.

| Screening recommendations and performance in PWH
Professional society guidelines recommend screening for HCC in high-risk individuals, with consensus for cirrhosis of any etiology and higher variability for other risk groups 31 (Table 3).The screening modality of choice is semi-annual ultrasound.No agreement exists regarding the addition of alpha fetoprotein, 31 though this combination has been estimated to be more cost-effective than ultrasound alone in people with compensated cirrhosis. 30creening recommendations in PWH are in line with those of the general population. 11There is a paucity of data on the accuracy of ultrasound for diagnosing HCC in PWH.An observational study demonstrated lower performance in detecting early-stage HCC compared to HIV-negative individuals, with a rate of screening failure of 57% vs 29%, respectively, and lower survival rates. 8Compliance with hepatocellular carcinoma screening is low in PWH. 32able 3 summarizes the harms and cost of the recommended screening strategy for HCC.

| Implications for management
The poor performance observed with ultrasound will presumably be aggravated by the growing prevalence of NAFLD in PWH.Both awareness campaigns on the need for surveillance and research on alternative screening strategies are imperative.Shorter intervals between ultrasounds and/or screening in non-cirrhotic advanced fibrosis remain to be explored in PWH.Using a Markov model, MRI was costeffective in a subgroup of HIV-negative patients with compensated cirrhosis and annual HCC risk over 3%, identified via a scoring system. 33Similarly, HIV-adapted screening testing, preceded by risk stratification to select the most suitable candidates, would contribute to increasing the efficiency of the process.New algorithms including clinical variables and blood biomarkers, particularly the promising genetic biomarkers, could be candidates to stratify HCC risk.

CANCER
Of all the NADCs, invasive anal cancer is the malignancy with the highest excess incidence and mortality. 5,34Anal cancer represents the third NADC with the highest mortality after lung and liver cancer, 13 and the first NADC in years of life lost in PWH in the United States 35 (Table 1).

| Screening tests
The natural history of anal cancer can be modified by early treatment of high-grade squamous intraepithelial lesion (HSIL), the necessary precursor of invasive carcinoma, to prevent progression to anal cancer. 36Unlike other types of cancer, most information about anal cancer screening derives from the HIV population.Furthermore, the only RCT demonstrating the benefits of anal cancer screening has been conducted in PWH.Diagnosis and treatment of HSIL through high-resolution anoscopy (HRA), a procedure adapted from cervical cancer screening, has been shown to prevent anal cancer in the Anal Cancer HSIL Outcomes Research (ANCHOR) study, published by Palefsky et al. 37 This phase 3 trial included 4446 PWH aged 35 years or older with biopsy-proven anal HSIL (bHSIL) who were randomized to treatment versus active monitoring without treatment of bHSILs through biannual HRA.The initial treatment was electrocautery ablation in 83.6% of participants, infrared coagulation in 4.8%, and ablation or excision under anesthesia, topical fluorouracil, and topical imiquimod in the remainder.After a median follow-up of 25.8 months, there was a significant, 57% (95% CI 6% to 80%) reduction in the rate of progression to anal cancer in the treatment group.The frequency of adverse events was low, and two-thirds of cancers were diagnosed at stage I or II.
Despite the proven benefits, HRA has currently limited availability due to the scarcity of expert capacity and infrastructure.The procedure should therefore be reserved for people at the highest risk of cancer.Accurate screening tests for selecting the individuals with the highest pre-HRA probability of bHSIL are particularly important to optimize the procedure.Although there is still no consensus, the most widely used screening test for referral to HRA is anal cytology; however, performance is suboptimal. 38Molecular tests including oncogenic strains of human papillomavirus (hrHPV) DNA, hrHPV E6/E7 mRNA, and DNA methylation have shown advantages in sensitivity or specificity but have not outperformed cytology. 38Screening algorithms combining two or more tests merit further investigation.A recommendation for anal cancer screening in high-risk PWH is currently undergoing evaluation by the USPSTF.
Available screening tests to predict bHSIL are shown in Table 2.
Although the prevalence of bHSIL is up to 47% in men who have sex with men (MSM) with HIV, 38 only a small proportion progress to cancer 39 and spontaneous regression has been described. 40Accordingly, another aspect to be considered in screening is the detection of the bHSILs with the highest probability of malignant transformation, and therefore candidates for ablative therapy.DNA methylation, anal condyloma, low CD4 counts, and CD4/CD8 rate have been linked with a higher risk of bHSIL progression and anal cancer 41,42 (Table 2).
If early treatment of HSIL through HRA is not available, digital anal rectal examination (DARE) may allow early diagnosis of invasive carcinoma.Data on the benefits of DARE for early diagnosis of anal cancer are extremely limited.The size of the tumor is an important prognostic factor, and in one phase II clinical trial, the procedure was able to detect tumors of 3 mm or more. 43The optimal time interval remains to be defined.

| Screening recommendations and performance in PWH
To date, there is no international consensus on routine anal cancer screening.Due to the preponderance of anal cancer in PWH, some HIV management guidelines recommend screening with DARE, with or without anal cytology plus HRA if abnormal, usually in MSM/transgender women and in persons with HPV-associated dysplasia, 11,36 but protocols differ between centers.

| Implications for management
The relevance of the results of the ANCHOR trial will directly impact cancer screening guidelines.Anal cancer screening with HRA should be incorporated as a routine procedure among the screenable cancers in people at risk.This implies a need for training in HRA on a large-scale, ideally to infectious disease specialists, who are the physicians with the greatest involvement in PWH care.There is also a need for standardized protocols to select patients for HRA.A crucial step to optimize the procedure is to stratify people according to their anal cancer risk in order to identify the best candidates both for screening and treatment.Algorithms combining clinical/biological risk factors with biomarkers for bHSIL prediction and for bHSIL progression might be helpful for personalized anal cancer screening, warranting further research.

CANCER
In women with HIV (WWH), the risk of developing cervical cancer is six-fold that of the general population, 44 probably due to higher rates of persistent HPV infection (Table 1).

| Screening tests
Treatment of precancerous lesions (HSIL) can prevent the development of invasive carcinoma and reduce mortality.Multiple observational studies and at least one RCT have shown that different screening strategies-even if performed only once in a lifetime-decrease mortality, reduce incidence of invasive cancer, and increase cure rates. 45The available screening strategies are based on early detection of HSIL through cervical cytology, testing for hrHPV, and co-testing with both methods.Patients with abnormal results are referred for colposcopy and directed biopsy, and subsequent local treatment of HSIL or follow-up of lesions with lower risk."Screen-and-treat" methods, which imply testing and treating a positive result at the same visit, are accepted in resource-limited regions [46][47][48] (Table 2).

| Screening recommendations and performance in WWH
The American Society for Colposcopy and Cervical Pathology (ASCCP) 2019 guidelines provide specific screening recommendations for high-risk groups such as WWH, and these recommendations have been adopted by other societies. 11,47,48Screening through cytology should begin within a year of first insertive sexual activity or by age 21 years (HPV testing is not recommended before age 30 years because of the high incidence of HPV in this age group).Screening should be on an annual basis for the first 3 years, and once every 3 years thereafter.After 30 years of age, cytology or cotesting should be conducted every 3 years throughout a woman's lifetime (Table 3).In resource-limited settings, WHO recommends HPV DNA detection in a screen, triage and treat approach every 3 to 5 years from age 25. 46 Table 1 shows screening performance in WWH, whose adherence to screening recommendations is lower than in uninfected women. 49

| Implications for management
WWH are a high-risk group, and guidelines recommend longer and more frequent screening than in the general population.The rate of false-positives is high, 50 highlighting the need for a more precise identification of high-risk patients who may benefit from more intensive surveillance and/or from screening methods with greater specificity and positive predictive value to avoid unnecessarily invasive procedures.

COLORECTAL CANCER
The incidence of colorectal cancer (CRC) seems to be similar in PWH and the general population 5,51 ; however, two studies have reported a higher frequency of rectal carcinoma 34 and specifically of rectal squamous cell carcinoma, 52 presumably associated with HPV and immunosuppression.PWH have been diagnosed with CRC at younger ages 53 and have shown higher CRC-associated mortality. 5

| Screening tests
Screening can prevent CRC by diagnosing and treating premalignant adenomas or sessile serrated lesions in early stages through endoscopy.Screening tests can be divided into one-step tests like colonoscopy, which is both diagnostic and therapeutic, and two-step tests consisting of a stool-based test or structural examination followed by colonoscopy if positive.Whereas genetic tests in stools and plasma hold promise (Table 2), only the guaiac-based fecal occult blood test and sigmoidoscopy have been shown to reduce the incidence and/or mortality of CRC in RCTs. 10

| Screening recommendations and performance in PWH
The American College of Gastroenterology updated 2021 guidelines recommend colonoscopy every 10 years and annual fecal immunochemical testing as the primary screening modalities for CRC screening in average-risk individuals aged 50 to 75 years. 10The EACS subscribes to these recommendations. 11The USPSTF recommendations (2021) extend the age range for screening to encompass adults aged 45 to 49, with a grade B recommendation. 54There is no evidence to date of the benefits of screening for CRC in PWH.Studies assessing the CRC screening rates in PWH compared to the general population have shown inconsistent results. 51able 3 summarizes the harms and costs of the screening methods for CRC.

| Implications for management
Despite having a similar frequency to the general population, CRC occurs at younger ages in PWH, which would support earlier initiation of screening.This would be of particular interest in MSM who have been severely immunosuppressed because of the increased risk for rectal squamous cancer.

| 20599
MASIÁ et al. 7 | SCREENING FOR BREAST CANCER Breast cancer incidence may be slightly lower in WWH compared to uninfected women. 5,55However, they are diagnosed at younger ages and at more advanced stages of disease. 56,57In North American and sub-Saharan African WWH, survival rates were lower than in uninfected women, even after adjusting for classic prognostic risk factors and, in the USA study, for specific cancer treatments. 57,58

| Screening tests
Table 2 shows the screening modalities for breast cancer surveillance. 59,60Mammography is the only method that has been shown to reduce breast cancer mortality in several randomized controlled trials, although ultrasound and MRI have demonstrated better sensitivity. 60

| Screening recommendations and performance in WWH
Most scientific society guidelines recommend a biennial mammography for all women aged 50 to 74 years, extendable to some women aged 40 to 50 years based on individual patient characteristics. 59,60EACS guidelines recommend mammography every 1-3 years in women aged 50-74 years. 11Results about the frequency of breast cancer screening in WWH have ranged from 50% to 80%, with discrepant data when compared to the general population. 61,62

| Implications for management
Both the younger age and more advanced stage at diagnosis in WWH would support earlier initiation of screening, more frequent screening, or adapted screening with more sensitive procedures like ultrasound or MRI, particularly in higher-risk subgroups.In view of the poorer prognosis of WWH, campaigns addressing the importance of breast cancer screening in WWH are desirable to raise awareness in both physicians and patients.

CANCER
Studies comparing the incidence of prostate cancer in PWH versus the general population have shown discordant results, ranging from lower 63 to similar incidence rates after adjusting for prostate-specific antigen (PSA) testing in a study in which Gleason grade was significantly greater in PWH. 64Prostate cancer mortality in PWH aged 65 years or older was higher after adjusting for specific cancer treatment. 58Along with the lung, the prostate is expected to emerge as the most frequent cancer site in PWH by 2030. 20

| Screening tests
Measurement of PSA blood levels is the standard procedure for prostate cancer screening.The results of a meta-analysis concluded that PSA testing may have a modest effect in reducing prostate cancer mortality but not overall mortality, and it is associated with biopsy and cancer treatment-related complications. 65However, reported trials had methodological limitations, and there was substantial heterogeneity concerning screening intensity, screening intervals, and PSA biopsy thresholds.Digital rectal examination is no longer recommended as a screening strategy due to the lack of evidence on the benefits. 66

| Screening recommendations and performance in PWH
There are no specific recommendations for prostate cancer screening.The European Association of Urology (EAU) and the USPSTF guidelines advocate shared decision-making after discussing the potential benefits and harms of screening with the patient.PSA would then be offered to men from 50 years of age or younger men at elevated risk of prostate cancer (EAU), 66 or to those aged 55 to 69 years (USPSTF). 67The EACS guidelines endorse the EAU recommendations. 11In a small case-control study conducted in the EuroSIDA cohort, the cutoff used in the general population showed low sensitivity in PWH. 68

| Implications for management
Prostate cancer is expected to be a leading NADC in the next decade as PWH become older.High-level evidence is needed to determine the usefulness of prostate cancer screening to reduce mortality; alternative screening procedures such as ultrasound or MRI might also be explored to assess their potential advantages over PSA.
Figure 1 shows the cancer screening strategies recommended by the EACS (Figure 1A) and the proposed strategies for targeted cancer screening in PWH (Figure 1B).
Cancer is the leading cause of mortality in PWH and is expected to account for a growing fraction of deaths as PWH age.Cancer screening has been shown to decrease cancer-associated mortality in the general population and should be a priority in PWH.In this review, we have compiled the most recent developments in cancer screening and screening performance in PWH, which are currently primarily implemented in well-resourced settings.This includes an assessment of the associated benefits, harms, and cost-effectiveness.The article also addresses unmet needs and potential strategies for tailored screening in the HIV population.There is an urgent need to extend the investigation in cancer screening performance to PWH, evaluating whether personalized measures according to F I G U R E 1 Cancer screening strategies in people living with HIV.(A) Strategies recommended by the European AIDS Clinical Society.(B) Proposed strategies for tailored cancer screening. 1≥ 45 years for colorectal cancer screening according to the 2021 US Preventive Services Task Force criteria (grade B). 2 MSM/transgender women living with HIV and in persons with HPV-associated dysplasia. 3Women ≥21 years. 4Cirrhotic persons Child-Pugh A/B, and C awaiting for LT; non-cirrhotic HBV infected, all or when PAGE-B score ≥ 10. 5 MSM/ transgender women living with HIV and in HPV-associated dysplasia, genital/anal condyloma or anal intercourse. 6Women ≥18 y. 7 Cirrhotic persons Child-Pugh A/B, and C awaiting for LT; non-cirrhotic HBV infected, all or when PAGE-B score ≥ 10. 8 Men ≥50 years. 9High-risk for breast cancer: known underlying genetic mutation (such as a BRCA1 or BRCA2 gene mutation or other familial breast cancer syndrome) or a history of chest radiation at a young age. 58 10Higher-risk persons for hepatocellular carcinoma, those with at least 1% per year risk of developing HCC. 29Need to develop algorithms that combine clinical factors and novel biomarkers to identify those patients.

No Yes
Ini ate screening for lung, colorectal breast, and prostate cancer Candidate for anal 5 or cervical 6

Yes
Person living with HIV individual risk could result in higher efficiency and improve patient outcomes.Randomized intervention studies that assess earlier initiation, more frequent testing, and include the most recent advances in cancer screening are needed to generate high-level evidence on cancer surveillance tailored to PWH, and to fill existing knowledge gaps. 69Nevertheless, owing to the challenges in attaining adequate statistical power to demonstrate a reduction in mortality within in this population, alternative approaches, such as modeling studies, should also be taken into consideration for evidence generation.Meanwhile, strategies for early diagnosis of cancer should be widely implemented in HIV medical care to enhance detection of screenable cancers with the highest excess incidence and mortality.At the same time, further studies also need to be conducted to develop, tailor, and evaluate interventions created to improve screening uptake and adherence in PWH.

4 ••
Annual LDCT for 50-80 year-old smokers of ≥20 pack-years, ac ve or quit within Semiannual utrasound ± AFP in cirrhosis C-P A/B and C awai ng transplant; non-cirrho HBV infected, all or when PAGE-

SMR compared to the general population Clinical differences with the general population Performance of recommended tests and compliance with screening in PWH Implications for management/unmet needs
Epidemiology of non-AIDS-defining cancers and screening performance in people living with HIV.
T A B L E 1 22

B L E 2 Performance characteristics of cancer screening tests. Cancer Imaging test Biomarkers Genetic tests Cytology Endoscopy
T A ; higher rates of colposcopy; high prevalence of transient HPV infection in women under 30 years old.-HPVE6/E7mRNA:effective to reduce colposcopy referrals and highly specific 85 -Methylation levels of the CADM1, MAL, and MIR124-2 genes: AUC 0.80 to predict CIN2/ PSA: modest reduction in prostate cancer mortality (IRR 0.96, 95% CI 0.85-1.08;lowcertainty) in a meta-analysis; no benefit on overall mortality; associated with biopsy and cancer treatment-related complications 65 Percent-free PSA, prostate health index or 4 K score may increase specificity and reduce the number of unnecessary biopsies 101 PCA3 (prostate cancer gene 3) may reduce repeated biopsies for high PSA levels 101 .Abbreviations: AFP, alpha fetoprotein; ALT, alanine aminotransferase; AP, alkaline phosphatase; AUC, area under the receiver-operating characteristic curve; bHSIL, high-grade intraepithelial squamous lesion in anal biopsy; cfDNA, cell-free DNA; CI, confidence interval; CIS: carcinoma in situ; circRNA, circular RNAs; CRC: colorectal cancer; CT, computed tomography; DCP: Des-gamma-carboxy prothrombin; EV, extracellular vehicles; HCC, hepatocellular cancer; HES, HCC early detection screening; hrHPV, high-risk or oncogenic human papillomavirus; IRR, incidence rate ratio; lncRNA, long noncoding RNAs; LC, lung cancer; LDCT, lowdose computed tomography; lncRNA, long noncoding RNA; miRNAs, microRNAs; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; MSM, men who have sex with men; mt-HBT, multitarget HCC blood test; NLST, National Lung Screening Trial; NPV, negative predictive value; PSA, prostate-specific antigen; RCT, randomized controlled trial; RR, relative risk; S, sensitivity; Sp, specificity.T A B L E 2 (Continued)T A B L E 3 Recommended surveillance interventions for cancer screening in people living with HIV, benefits, harms, and cost-effectiveness.Cancer Recommended

surveillance test/target population for surveillance Evidence on benefits in the general population and PWH Harms Cost-effectiveness
PWH, screening with LDCT fell in the efficiency frontier b Gleason grade, the absence of reference to clinical verification, overdiagnosis and overtreatment, or inadequate methods used to assess quality of life96 21breviations: AFP, alpha fetoprotein; ART, antiretroviral therapy; CI, confidence interval; CIN, cervical intraepithelial neoplasia; C-P, Child-Pugh score; CRC, colorectal cancer; DARE, digital ano-rectal examination; FP, false positive; gFOBT, guaiac fecal occult blood test; HCC, hepatocellular cancer; IR, incidence rate; IRR, incidence rate ratio; HSIL, high-grade squamous intraepithelial lesion; LDCT, low-dose computed tomography; MRI, magnetic resonance imaging; MSM, men who have sex with men; NAFLD, non-alcoholic fatty liver disease; QALY, quality-adjusted life years; p-y, per year; PAP, Papanicolau; PWH, people living with HIV; RCT, randomized clinical trial; RC, randomized controlled; VIA, visual inspection with ascetic acid; WWH, women with HIV.a Different measures have been implemented to reduce false-positive results, such as volume-based nodule-management,21