Mathematical Models for Evaluating Effectiveness and Cost-Effectiveness of Cervical Cancer Control Policies in Populations Including Women Living With Human Immunodeficiency Virus: A Scoping Review.

OBJECTIVES Mathematical modeling is increasingly used to inform cervical cancer control policies, and model-based evaluations of such policies in women living with human immunodeficiency virus (HIV) are an emerging research area. We did a scoping review of published literature to identify research gaps and inform future work in this field. METHODS We systematically searched literature up to April 2022 and included mathematical modeling studies evaluating the effectiveness or cost-effectiveness of cervical cancer prevention strategies in populations including women living with HIV. We extracted information on prevention strategies and modeling approaches. RESULTS We screened 1504 records and included 22 studies, almost half of which focused on South Africa. We found substantial between-study heterogeneity in terms of strategies assessed and modeling approaches used. Fourteen studies evaluated cervical cancer screening strategies, 7 studies assessed human papillomavirus vaccination (with or without screening), and 1 study evaluated the impact of HIV control measures on cervical cancer incidence and mortality. Thirteen conducted cost-effectiveness analyses. Markov cohort state-transition models were used most commonly (n = 12). Most studies (n = 17) modeled the effect of HIV by creating HIV-related health states. Thirteen studies performed model calibration, but 11 did not report the calibration methods used. Only 1 study stated that model code was available upon request. CONCLUSIONS Few model-based evaluations of cervical cancer control strategies have specifically considered women living with HIV. Improvements in model transparency, by sharing information and making model code publicly available, could facilitate the utility of these evaluations for other high disease-burden countries, where they are needed for assisting policy makers

Gynaecologic and breast cancers in women living with HIV in South Africa: A record linkage study.

Breast and gynaecologic cancers account for approximately half of all cancers diagnosed amongst women in South Africa, many of whom also live with HIV. We aimed to determine the incidence of and risk factors for developing breast and gynaecologic cancers in women living with HIV (WLHIV) in South Africa. This is a longitudinal analysis of the South African HIV Cancer Match study including women aged ≥15 years with two or more HIV-related laboratory tests. We used Cox proportional hazard models to determine the association of Human Papilloma Virus (HPV)-related and hormone-related gynaecologic cancer with patient- and municipal-level characteristics. From 3 447 908 women and 10.5 million years of follow-up, we identified 11 384 incident and 7612 prevalent gynaecologic and breast cancers. The overall crude incidence rate was 108/1 00 000 person-years (pyears) (95% confidence interval [CI]: 106-110), with the highest incidence observed for cervical cancer (70/1 00 000 pyears; 95% CI: 68.5-71.7). Low CD4 cell counts and high HIV RNA viral loads increased the risk of cervical and other HPV-related cancers. Age was associated with both HPV-related and hormone-related cancers. Women accessing health facilities in high socioeconomic position (SEP) municipalities were more likely to be diagnosed with HPV-related cancers and breast cancer than women accessing care in low SEP municipalities. It is important to improve the immunologic status of WLHIV as part of cancer prevention strategies in WLHIV. Cancer prevention and early detection programmes should be tailored to the needs of women ageing with HIV. In addition, SEP disparities in cancer diagnostic services have to be addressed

Cervical cancer in women living in South Africa: a record linkage study of the National Health Laboratory Service and the National Cancer Registry.

Introduction In countries with high HIV prevalence, it is important to understand the cervical cancer (CC) patterns by HIV status to ensure targeted prevention measures. We aimed to determine the factors associated with CC compared to non-infection related cancer in women living in South Africa. Methods This was a cross-sectional study of women aged 15 years and older diagnosed with CC and non-infection related cancer in the South African public health sector from 2004 to 2014. The National Cancer Registry provided data on cancer, whilst HIV status was determined from routinely collected HIV related data from the National Health Laboratory Service. We explored the association of HIV infection, age, ethnicity and calendar period with CC compared to non-infection related cancer. Results From 2004 to 2014, 49,599 women were diagnosed with CC, whilst 78,687 women had non-infection related cancer. About 40% (n = 20,063) of those with CC and 28% (n = 5,667) of those with non-infection related cancer had a known HIV status. The median age at CC diagnosis was 44 years (interquartile range (IQR): 37-52) and 54 years (IQR: 46-64) for HIV positive and negative women, respectively, and for non-infection related cancer, 45 years (IQR: 47-55) and 56 years (IQR: 47-66) for HIV negative and positive women, respectively. Diagnosis of CC was associated with HIV positivity, Black ethnicity, earlier calendar period (2004-2006) and the ages 30-49 years. In comparison with Black women, the odds of CC were 44% less in Coloured women, 50% less in Asian women and 51% less in White women. Conclusions HIV positive women presented a decade earlier with CC compared to HIV negative women. A large proportion of women with CC were unaware of their HIV status with a disproportionate burden of CC in Black women. We recommend women attending CC screening facilities to be offered HIV testing so that recommendations for their follow-up visits are given according to their HIV status

Cancer treatment and survival among cervical cancer patients living with or without HIV in South Africa.

Objective To compare cancer treatment and all-cause mortality between HIV-positive and HIV-negative cervical cancer patients in South Africa. Methods We assessed cancer treatment and all-cause mortality in HIV-positive and HIV-negative cervical cancer patients who received cancer treatment within 180 days of diagnosis using reimbursement claims data from a private medical insurance scheme in South Africa between 01/2011 and 07/2020. We assessed treatment provision using logistic regression and factors associated with all-cause mortality using Cox regression. We assigned missing values for histology and ethnicity using multiple imputation. Results Of 483 included women, 136 (28 %) were HIV-positive at cancer diagnosis (median age: 45.7 years), and 347 (72 %) were HIV-negative (median age: 54.1 years). Among 285 patients with available ICD-O-3 morphology claims codes, the proportion with cervical adenocarcinoma was substantially lower in HIV-positive (4 %) than in HIV-negative patients (26 %). Most HIV-positive patients (67 %) were on antiretroviral therapy at cancer diagnosis. HIV-positive patients were more likely to receive radiotherapy (adjusted odds ratio [aOR] 1.90, 95 % confidence interval [CI] 1.05-3.45) or chemotherapy (aOR 2.02, 95 %CI 0.92-4.43) and less likely to undergo surgery (aOR 0.53, 95 %CI 0.31-0.90) than HIV-negative patients. HIV-positive patients were at a higher risk of death from all causes than HIV-negative patients (adjusted hazard ratio 1.52, 95 %CI 1.06-2.19). Other factors associated with higher all-cause mortality included age > 60 years and metastases at diagnosis. Conclusions HIV-positive cervical cancer patients in South Africa had higher all-cause mortality than HIV-negative patients which could be explained by differences in tumour progression, clinical care, and HIV-specific mortality

Utility of p16INK4a expression for the interpretation of uterine cervical biopsies in Kenya

Introduction: histologic interpretation of hematoxylin and eosin-stained cervical biopsies is subject to substantial discordance among pathologists. Immunohistochemical staining for p16INK4a can reduce inter-observer disagreement. We did a cross-sectional study to evaluate the utility of p16INK4a staining in the assessment of cervical biopsies in Nairobi, Kenya. Methods: hematoxylin and eosin-stained sections from 91 colposcopic biopsies diagnosed as negative for dysplasia or as cervical intraepithelial neoplasia (CIN) grade 1-3 from 2011-2013 in Nairobi, Kenya, were reviewed and immunostained for p16INK4a. Agreement in interpretation of cervical biopsies was compared between primary and consensus review results. Results: on primary evaluation, 16 cases were negative for squamous dysplasia; 23 were CIN 1; 37 CIN 2; and 15 CIN 3. On consensus review, 32 cases were negative for dysplasia; 19 were CIN 1; 16 CIN 2 and 24 CIN 3. Agreement was moderate between primary and consensus histology review results for the diagnosis of low-grade versus high-grade squamous intraepithelial lesions (Kappa = 0.568). None of the cases negative for dysplasia were positive for p16INK4a expression, but in primary and consensus review results, 17% and 5% cases of CIN 1; 49% and 69% of CIN 2, and 80% and 96% of CIN 3 were p16INK4a positive, respectively. Conclusion: there was significant variability in the interpretation of cervical biopsies on hematoxylin and eosin between primary and consensus review assessments. 75% of CIN 1 cases that were upgraded to CIN 2 during consensus review expressed p16INK4a. These findings demonstrate the role of p16INK4a in increasing diagnostic accuracy and as a marker of high-grade CIN 2/3

Immunodeficiency and Cancer in 3.5 Million People Living With Human Immunodeficiency Virus (HIV):the South African HIV Cancer Match Study

BACKGROUND We analysed associations between immunodeficiency and cancer incidence in a nationwide cohort of people living with the human immunodeficiency virus (HIV) in South Africa. METHODS We used data from the South African HIV Cancer Match study built on HIV-related laboratory measurements from the National Health Laboratory Services and cancer records from the National Cancer Registry. We evaluated associations between time-updated CD4 cell count and cancer incidence rates using Cox proportional hazards models. We reported adjusted hazard ratios (aHR) over a grid of CD4 values and estimated the aHR per 100 CD4 cells/µl decrease. RESULTS Of 3,532,266 people living with HIV (PLWH), 15,078 developed cancer. The most common cancers were cervical cancer (4,150 cases), Kaposi sarcoma (2,262 cases), and non-Hodgkin lymphoma (1,060 cases). The association between lower CD4 cell count and higher cancer incidence rates was strongest for conjunctival cancer (aHR per 100 CD4 cells/µl decrease: 1.46, 95% confidence interval [CI] 1.38-1.54), Kaposi sarcoma (aHR 1.23, 95% CI 1.20-1.26), and non-Hodgkin lymphoma (aHR 1.18, 95% CI 1.14-1.22). Among infection-unrelated cancers, lower CD4 cell counts were associated with higher incidence rates of oesophageal cancer (aHR 1.06, 95 CI 1.00-1.11), but not breast, lung, or prostate cancer. CONCLUSIONS Lower CD4 cell counts were associated with an increased risk of developing various infection-related cancers among PLWH. Reducing HIV-induced immunodeficiency may be a potent cancer prevention strategy among PLWH in sub-Saharan Africa, a region heavily burdened by cancers attributable to infections

Cervical precancer and cancer incidence among insured women with and without HIV in South Africa.

HIV infection increases the risk of developing cervical cancer; however, longitudinal studies in sub-Saharan Africa comparing cervical cancer rates between women living with HIV (WLWH) and women without HIV are scarce. To address this gap, we compared cervical precancer and cancer incidence rates between WLWH and women without HIV in South Africa using reimbursement claims data from a medical insurance scheme from January 2011 to June 2020. We used Royston-Parmar flexible parametric survival models to estimate cervical precancer and cancer incidence rates as a continuous function of age, stratified by HIV status. Our study population consisted of 518 048 women, with exclusions based on the endpoint of interest. To analyse cervical cancer incidence, we included 517 312 women, of whom 564 developed cervical cancer. WLWH had an ~3-fold higher risk of developing cervical precancer and cancer than women without HIV (adjusted hazard ratio for cervical cancer: 2.99; 95% confidence interval [CI]: 2.40-3.73). For all endpoints of interest, the estimated incidence rates were higher in WLWH than women without HIV. Cervical cancer rates among WLWH increased at early ages and peaked at 49 years (122/100 000 person-years; 95% CI: 100-147), whereas, in women without HIV, incidence rates peaked at 56 years (40/100 000 person-years; 95% CI: 36-45). Cervical precancer rates peaked in women in their 30s. Analyses of age-specific cervical cancer rates by HIV status are essential to inform the design of targeted cervical cancer prevention policies in Southern Africa and other regions with a double burden of HIV and cervical cancer

Cohort profile: the South African HIV Cancer Match (SAM) Study, a national population-based cohort.

PURPOSE The South African HIV Cancer Match (SAM) Study is a national cohort of people living with HIV (PLWH). It was created using probabilistic record linkages of routine laboratory records of PLWH retrieved by National Health Laboratory Services (NHLS) and cancer data from the National Cancer Registry. The SAM Study aims to assess the spectrum and risk of cancer in PLWH in the context of the evolving South African HIV epidemic. The SAM Study's overarching goal is to inform cancer prevention and control programmes in PLWH in the era of antiretroviral treatment in South Africa. PARTICIPANTS PLWH (both adults and children) who accessed HIV care in public sector facilities and had HIV diagnostic or monitoring laboratory tests from NHLS. FINDINGS TO DATE The SAM cohort currently includes 5 248 648 PLWH for the period 2004 to 2014; 69% of these are women. The median age at cohort entry was 33.0 years (IQR: 26.2-40.9). The overall cancer incidence in males and females was 235.9 (95% CI: 231.5 to 240.5) and 183.7 (181.2-186.2) per 100 000 person-years, respectively.Using data from the SAM Study, we examined national cancer incidence in PLWH and the association of different cancers with immunodeficiency. Cancers with the highest incidence rates were Kaposi sarcoma, cervix, breast, non-Hodgkin's lymphoma and eye cancer. FUTURE PLANS The SAM Study is a unique, evolving resource for research and surveillance of malignancies in PLWH. The SAM Study will be regularly updated. We plan to enrich the SAM Study through record linkages with other laboratory data within the NHLS (eg, tuberculosis, diabetes and lipid profile data), mortality data and socioeconomic data to facilitate comprehensive epidemiological research of comorbidities among PLWH

HHV-8 seroprevalence: a global view

BACKGROUND: Human herpes virus 8 (HHV-8) is the underlying infectious cause of Kaposi sarcoma (KS) and other proliferative diseases; that is, primary effusion lymphoma and multicentric Castleman disease. In regions with high HHV-8 seroprevalence in the general population, KS accounts for a major burden of disease. Outside these endemic regions, HHV-8 prevalence is high in men who have sex with men (MSM) and in migrants from endemic regions. We aim to conduct a systematic literature review and meta-analysis in order 1) to define the global distribution of HHV-8 seroprevalence (primary objective) and 2) to identify risk factors for HHV-8 infection, with a focus on HIV status (secondary objective).METHODS/DESIGN:We will include observational studies reporting data on seroprevalence of HHV-8 in children and/or adults from any region in the world. Case reports and case series as well as any studies with fewer than 50 participants will be excluded. We will search MEDLINE, EMBASE, and relevant conference proceedings without language restriction. Two reviewers will independently screen the identified studies and extract data on study characteristics and quality, study population, risk factors, and reported outcomes, using a standardized form. For the primary objective we will pool the data using a fully bayesian approach for meta-analysis, with random effects at the study level. For the secondary objective (association of HIV and HHV-8) we aim to pool odds ratios for the association of HIV and HHV-8 using a fully bayesian approach for meta-analysis, with random effects at the study level. Sub-group analyses and meta-regression analyses will be used to explore sources of heterogeneity, including factors such as geographical region, calendar years of recruitment, age, gender, ethnicity, socioeconomic status, different risk groups for sexually and parenterally transmitted infections (MSM, sex workers, hemophiliacs, intravenous drug users), comorbidities such as organ transplantation and malaria, test(s) used to measure HHV-8 infection, study design, and study quality.DISCUSSION:Using the proposed systematic review and meta-analysis, we aim to better define the global seroprevalence of HHV-8 and its associated risk factors. This will improve the current understanding of HHV-8 epidemiology, and could suggest measures to prevent HHV-8 infection and to reduce its associated cancer burden

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

Objective: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. Methods: HICs were identified in COHERE on the basis of \ue2\u89\ua55 consecutive viral loads (VL) \ue2\u89\ua4500 copies/mL over \ue2\u89\ua51 year whilst ART-naive, with the last VL \ue2\u89\ua4500 copies/mL measured \ue2\u89\ua55 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. Results: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Discussion: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs