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Background: Male circumcision reduces the risk of human immunodeficiency virus infection in men. We assessed the effect of male circumcision on the incidence and natural history of human papillomavirus (HPV) in a randomized clinical trial in Kisumu, Kenya. Methods: Sexually active, 18- to 24-year-old men provided penile exfoliated cells for HPV DNA testing every 6 months for 2 years. HPV DNA was detected via GP5+/6+ PCR in glans/coronal sulcus and in shaft samples. HPV incidence and persistence were assessed by intent-to-treat analyses. Results: A total of 2,193 men participated (1,096 randomized to circumcision; 1,097 controls). HPV prevalence was 50% at baseline for both groups and dropped to 23.7% at 24 months in the circumcision group, and 41.0% in control group. Incident infection of any HPV type over 24 months was lower among men in the circumcision group than in the control group [HR = 0.61; 95% confidence interval (CI), 0.52–0.72]. Clearance rate of any HPV infection over 24 months was higher in the circumcision group than in the control group (HR = 1.87; 95% CI, 1.49–2.34). Lower HPV point-prevalence, lower HPV incidence, and higher HPV clearance in the circumcision group were observed in glans but not in shaft samples. Conclusion: Male circumcision reduced the risk of HPV acquisition and reinfection, and increased HPV clearance in the glans. Impact: Providing voluntary, safe, and affordable male circumcision should help reduce HPV infections in men, and consequently, HPV-associated disease in their partners.

Background We analyzed associations between immunodeficiency and cancer incidence in a nationwide cohort of people living with human immunodeficiency virus (HIV; PLWH) 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 (aHRs) over a grid of CD4 values and estimated the aHR per 100 CD4 cells/µL decrease. Results Of 3 532 266 PLWH, 15 078 developed cancer. The most common cancers were cervical cancer (4150 cases), Kaposi sarcoma (2262 cases), and non-Hodgkin lymphoma (1060 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 esophageal 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.

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.PLWH (both adults and children) who accessed HIV care in public sector facilities and had HIV diagnostic or monitoring laboratory tests from NHLS.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.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.

Background: Primary high-risk human papillomavirus (hr-HPV) testing of self-collected cervico-vaginal swabs could increase cervical cancer screening coverage, although triage strategies are needed to reduce unnecessary colposcopies. We evaluated the use of extended hr-HPV genotyping of self-collected samples for cervical cancer screening. Methods: We recruited women ages 25–65 years at two colposcopy clinics in North Carolina between November 2016 and January 2019, and obtained self-collected cervico-vaginal samples, provider-collected cervical samples, and cervical biopsies from all enrolled women. Self- and provider-collected samples were tested for 14 hr-HPV genotypes using the Onclarity Assay (Becton Dickinson). We calculated hr-HPV genotype–specific prevalence and assessed agreement between results in self- and provider-collected samples. We ranked the hr-HPV genotypes according to their positive predictive value (PPV) for the detection of cervical intraepithelial neoplasia (CIN) grade 2 or higher (CIN2+). Results: A total of 314 women participated (median age, 36 years); 85 women (27%) had CIN2+. More women tested positive for any hr-HPV on self-collected (76%) than on provider-collected samples (70%; P = 0.009) with type-specific agreement ranging from substantial to almost perfect. HPV-16 was the most common genotype in self-collected (27%) and provider-collected samples (20%), and HPV-16 prevalence was higher in self- than provider-collected samples (P < 0.001). In self- and provider-collected samples, HPV-16 had the highest PPV for CIN2+ detection. Conclusions: Overall sensitivity for CIN2+ detection was similar for both sample types, but the higher HPV-16 prevalence in self-collected samples could result in increased colposcopy referral rates. Impact: Additional molecular markers might be helpful to improve the triage of women who are hr-HPV positive on self-collected samples.

Background Portable devices that can be used to perform colposcopy may improve cervical cancer screening in low- and middle-income countries (LMIC) where access to colposcopy is limited. The objective of this study was to systematically review the diagnostic test accuracy (DTA) of these devices for the detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+). Methods In accordance with our protocol (Prospero CRD42018104286), we searched Embase, Medline and the Cochrane Controlled Register of Trials up to 9/2019. We included DTA studies, which investigated portable devices with moderate-to-high optical magnification (≥ 6×) for colposcopy, as described in the manual for Colposcopy and Treatment by the International Agency for Research on Cancer, with a histopathological reference standard. We used the QUADAS-2 tool to assess study quality. We examined results for sensitivity and specificity in paired forest plots, stratified by stages in the clinical pathway. We pooled estimates of test accuracy for the index test, used as an add-on to other tests, using a bivariate random-effect model. Results We screened 1737 references and assessed 239 full-text articles for eligibility. Five single-gate DTA studies, including 2693 women, met the inclusion criteria. Studies evaluated two devices (Gynocular™ and Pocket) at different stages of the screening pathway. In three studies, which used the index test in an add-on capacity in 1273 women, we found a pooled sensitivity of 0.79 (95% CI 0.55–0.92) and specificity of 0.83 (95% CI 0.59–0.94). The main sources of bias were partial verification, incorporation and classification bias. Conclusion Few studies have evaluated portable devices able to perform colposcopy, so their accuracy for the detection of CIN2+ remains uncertain. Future studies should include patient-relevant and long-term outcomes, including missed cases, overtreatment, residual and recurrent disease. To meet the challenge of eliminating cervical cancer in LMIC, methods for visual assessment of the cervix need urgent redress.

Background: We compared women's acceptability of urine and cervico-vaginal sample self-collection for high-risk (oncogenic) human papillomavirus (hrHPV) testing and assessed whether acceptability v...

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 . © the authors; licensee.

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.

Background: Privacy-preserving probabilistic record linkage (PPPRL) methods were developed and applied in high-income countries to link records within and between organizations under strict privacy protections. PPPRL has not yet been used in African settings.Methods: We used HIV-related laboratory records from National Health Laboratory Services (NHLS) in South Africa to construct a cohort of HIV-positive patients and link them to the National Cancer Registry (NCR) with PPPRL. The study was restricted to Gauteng province from 2004 to 2014. We used records with national IDs (gold standard) to determine precision, recall, and f-measure of the linkages. We included all patients with ≥ 2 HIV-related lab records measured in the cohort and assessed the number of cancers diagnosed in people living with HIV (PLWH).Results: We included 11,480,118 HIV-related laboratory records and 664,869 cancer records in the linkage. We included 1,173,908 persons in the HIV cohort; 66.6% were female and median age at first HIV-related lab test was 33.9 years (IQR 27.4-41.3). Of the patients in the cohort, 26,348 were diagnosed with at least one cancer and 8,329 of these cancers were diagnosed before or on the date of the patient’s first HIV-related record; 18,019 were diagnosed after their first HIV-related record. For all linkages, precision, recall, and f-measures were high.Conclusion: Our study showed it is feasible to use PPPRL in an African setting to link routinely collected health records from different data sources and create a longitudinal HIV cohort with cancer outcomes while strictly protecting patient privacy. This work served as the foundation to create a nationwide population-based cohort including all South African provinces which will be used to inform cancer control programs.

Background: The mechanisms linking the human immunodeficiency virus (HIV) to cancer are not fully understood. We analysed associations between immunodeficiency and the incidence of various infection-related and infection-unrelated cancers in a large cohort of people living with HIV (PLWH).Methods: We used data from the South African HIV Cancer Match (SAM) study which is the result of probabilistic record linkage between HIV laboratory measurements provided by the National Health Laboratory Services and cancer records from the National Cancer Registry in South Africa. We classified cancers based on type and related infections. For each of these cancer groups, we calculated crude incidence rates and evaluated associations between time-updated CD4 cell count and cancer incidence rates using Cox proportional hazards models. We reported the associations using adjusted hazard ratios (aHR) over a grid of CD4 values for a reference value of 200 cells/µl, and by estimating the aHR per decrease of 100 CD4 cells/µl after assuming a linear relationship between the log hazard and CD4 cell counts. Results: We analysed 3,695,723 PLWH, of which 16,274 developed cancer, for an overall crude cancer incidence rate of 169 per 100,000 person-years (py). The most common cancers were cervical cancer (4,151 cases in women, rate of 59 per 100,000 py), Kaposi Sarcoma (2,311 cases, rate of 24 per 100,000 py), and non-Hodgkin lymphoma (1,101 cases, rate of 11 per 100,000 py). There were 6,482 PLWH diagnosed with cancer not related to infection (rate of 67 per 100,000 py). The association between low CD4 cell count and higher rates of cancer was strongest in conjunctival cancer (aHR per decrease of 100 CD4 cells/µl: 1.47, 95% confidence interval [CI] 1.39-1.55), followed by Kaposi Sarcoma (aHR 1.23, 95% CI 1.20-1.26) and non-Hodgkin lymphoma (aHR 1.16, 95% CI 1.12-1.19). Among the infection-unrelated cancers, we found low CD4 cell count to be associated with higher rates of squamous cell carcinoma of the skin (aHR 1.06, 95% CI 1.02-1.11) and cancer of the oesophagus (aHR 1.06, 95 CI 1.00-1.11). We found no association between CD4 cell count and both breast and prostate cancer incidence.Conclusions: Low time-updated 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 South Africa, a region heavily burdened by cancers attributable to infections.

Purpose: The South African HIV Cancer Match Study (SAM) is a national cohort of people living with HIV (PLWH). It was created using probabilistic record linkages of routine laboratory records of PWLH retrieved by National Health Laboratory Services (NHLS) and cancer registry data from the National Cancer Registry. SAM aims to study the spectrum and risk of cancer in PLWH in the context of the evolving South African HIV epidemic. The overarching goal of SAM is to inform cancer prevention and control programmes in children and adults living with HIV in the era of antiretroviral treatment in South Africa.Participants: The SAM study is a national cohort of PLWH (both adults and children) who accessed HIV care in public sector facilities from 2004 – 2014 and had HIV diagnostic or monitoring laboratory tests from NHLS.Findings to date: The SAM cohort includes 5 248 648 PLWH; 69% of these are women. The median age at cohort entry is 33.0 years (interquartile range 26.2 - 40.9). Using SAM, we examined national cancer trends in PLWH and the association of different cancers with immunodeficiency. While the risk of Kaposi sarcoma has declined, the risk of conjunctival cancer and HPV-related anogenital cancers (cervical, anal, vulvar, and penile cancers) continues to rise, despite the widespread availability of antiretroviral treatment. Future plans: An update of the SAM cohort to include more recent data is underway. SAM also has the potential to be enriched through record linkage with other laboratory data within the NHLS (such as tuberculosis, diabetes, and lipid profile data), mortality data and socioeconomic data allowing holistic epidemiological research of co-morbidities with HIV. The SAM cohort is a unique resource for research and surveillance of malignancies in PLWH.

The objective was to assess the diagnostic test accuracy of high-risk human papillomavirus (hrHPV) testing of self-collected urine and cervicovaginal samples for the detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+). We recruited a convenience sample of women 25 to 65 years of age who were undergoing clinically indicated colposcopy at two medical centers in North Carolina between November 2016 and January 2019. Women with normal cytology results and positive hrHPV results were also recruited. Urine samples, self-collected cervicovaginal samples, provider-collected cervical samples, and cervical biopsy samples were obtained from all enrolled women. Samples were tested for hrHPV DNA using the Onclarity assay (Becton Dickinson, Sparks, MD). Biopsy samples were histologically graded as CIN2+ or

All forms of Kaposi sarcoma (KS) are more common in men than in women. It is unknown if this is due to a higher prevalence of human herpesvirus 8 (HHV-8), the underlying cause of KS, in men compared to women. We did a systematic review and meta-analysis to examine the association between HHV-8 seropositivity and gender in the general population. Studies in selected populations like for example, blood donors, hospital patients and men who have sex with men were excluded. We searched Medline and Embase from January 1994 to February 2015. We included observational studies that recruited participants from the general population and reported HHV-8 seroprevalence for men and women or boys and girls. We used random-effects meta-analysis to pool odds ratios (OR) of the association between HHV-8 and gender. We used meta-regression to identify effect modifiers, including age, geographical region and type of HHV-8 antibody test. We included 22 studies, with 36,175 participants. Men from sub-Saharan Africa (SSA) [OR 1.21, 95% confidence interval (CI) 1.09-1.34], but not men from elsewhere (OR 0.94, 95% CI 0.83-1.06), were more likely to be HHV-8 seropositive than women (p value for interaction = 0.010). There was no difference in HHV-8 seroprevalence between boys and girls from SSA (OR 0.90, 95% CI 0.72-1.13). The type of HHV-8 assay did not affect the overall results. A higher HHV-8 seroprevalence in men than women in SSA may partially explain why men have a higher KS risk in this region.

OBJECTIVE: To compare non-Hodgkin lymphoma (NHL) incidence rates in adults who started antiretroviral therapy (ART) across the Asia-Pacific, South Africa, Europe, Latin, and North America. METHODS: We included cohort data of adults living with HIV who started ART after 1995 within the framework of the International epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE). We used flexible parametric survival models to compare regional NHL rates at 2 years after ART start and to identify risk factors for NHL. RESULTS: We included 210,898 adults with 1.1 million person-years (pys) of follow-up and 1,552 incident NHL cases (raw overall incidence rate 142/100,000 pys). After adjusting for age at ART start, first-line ART regimen, calendar period of ART start, and especially current CD4 cell count, NHL rates were similar across regions for most population groups. However, South African women remained at increased risk of developing NHL compared with their European counterparts (adjusted hazard ratio [aHR] 1.79, 95% CI 1.19–2.70). In Europe, Latin and North America, NHL risk was highest in men who have sex with men (MSM, aHR 1.30, 95% CI 1.14–1.48), followed by heterosexual men (referent), and women (aHR 0.66, 95% CI 0.57–0.78). CONCLUSIONS: The risk of developing NHL is higher in women in South Africa than in Europe and higher in MSM compared with heterosexual men and women. Reasons for these differences remain unclear. Early ART access and regular patient monitoring to avert low CD4 cell counts remain key for NHL prevention.

HIV-infection is an important risk factor for developing Kaposi sarcoma (KS), but it is unclear whether HIV-positive persons are also at increased risk of co-infection with human herpesvirus 8 (HHV-8), the infectious cause of KS. We systematically searched literature up to December 2012 and included studies reporting HHV-8 seroprevalence for HIV-positive and HIV-negative persons. We used random-effects meta-analysis to combine odds ratios (ORs) of the association between HIV and HHV-8 seropositivity and conducted random-effects meta-regression to identify sources of heterogeneity. We included 93 studies with 58,357 participants from 32 countries in sub-Saharan Africa, North and South America, Europe, Asia, and Australia. Overall, HIV-positive persons were more likely to be HHV-8 seropositive than HIV-negative persons (OR 1.99, 95% confidence interval [CI] 1.70-2.34) with considerable heterogeneity among studies (I(2) 84%). The association was strongest in men who have sex with men (MSM, OR 3.95, 95% CI 2.92-5.35), patients with hemophilia (OR 3.11, 95% CI 1.19-8.11), and children (OR 2.45, 95% CI 1.58-3.81), but weaker in heterosexuals who engage in low-risk (OR 1.42, 95% CI 1.16-1.74) or high-risk sexual behavior (OR 1.66, 95% CI 1.27-2.17), persons who inject drugs (OR 1.66, 95% CI 1.28-2.14), and pregnant women (OR 1.68, 95% CI 1.15-2.47), p value for interaction

HIV-related Kaposi sarcoma (KS) is common in sub-Saharan Africa, but optimal treatment strategies in resource-limited settings remain unclear. We did a retrospective cohort study of adults diagnosed with KS before initiating antiretroviral therapy (ART) at three ART programs in South Africa, Malawi and Zambia. We extracted data from medical charts at HIV clinics and oncological referral centers and used electronic data from the International epidemiology Databases to Evaluate AIDS Southern Africa. We used descriptive statistics to assess tumor (T) and systemic illness (S) stage and treatment of AIDS-KS patients. Kaplan-Meier analyses were used to assess survival after KS diagnosis. We analyzed data from 57 patients in total (20 from South Africa, 20 from Zambia, 17 from Malawi). Median age at KS diagnosis was 35 years and similar across sites. The percentage of patients with poor risk AIDS-KS (T1S1) was similar in South Africa (25%) and Malawi (24%) and higher in Zambia (45%). All AIDS-KS patients initiated ART at the HIV clinic. For KS care, in South Africa 18 patients (90%) were referred to an oncology department; in Malawi and Zambia most patients were managed by the HIV clinics. In Malawi and South Africa, most AIDS-KS patients received systemic chemotherapy, in Zambia one patient received chemotherapy at the HIV clinic. A year after KS diagnosis, 15 patients (75%) in South Africa, 10 patients (50%) in Zambia, and 8 patients (47%) in Malawi were still alive; another 3 patients (15%) in South Africa, 8 patients (40%) in Zambia and 4 patients (24%) in Malawi were lost to follow-up. Management of AIDS-KS patients varied considerably across sites in Malawi, South Africa and Zambia. We need more reliable survival data for AIDS-KS patients in sub-Saharan Africa before we can assess which treatments and clinical pathways should be adopted in a specific setting.

Data on invasive cervical cancer (ICC) incidence in HIV-positive women and the effect of cervical cancer screening in sub-Saharan Africa are scarce. We estimated i) ICC incidence rates in women (≥18 years) who initiated antiretroviral therapy (ART) at the Themba Lethu Clinic (TLC) in Johannesburg, South Africa, between 2004 and 2011 and ii) the effect of a Pap-based screening program. We included 10,640 women; median age at ART initiation: 35 years [interquartile range (IQR) 30-42], median CD4 count at ART initiation: 113 cells/µL (IQR 46-184). During 27,257 person-years (pys), 138 women were diagnosed with ICC; overall incidence rate: 506/100,000 pys [95% confidence interval (CI) 428-598]. The ICC incidence rate was highest (615/100,000 pys) in women who initiated ART before cervical cancer screening became available in 04/2005 and was lowest (260/100,000 pys) in women who initiated ART from 01/2009 onward when the cervical cancer screening program and access to treatment of cervical lesions was expanded [adjusted hazard ratio (aHR) 0.42, 95% CI 0.20-0.87]. Advanced HIV/AIDS stage (4 versus 1, aHR 1.95, 95% CI 1.17-3.24) and middle age at ART initiation (36-45 versus 18-25 years, aHR 2.51, 95% CI 1.07-5.88) were risk factors for ICC. The ICC incidence rate substantially decreased with the implementation of a Pap-based screening program and improved access to treatment of cervical lesions. However, the risk of developing ICC after ART initiation remained high. To inform and improve ICC prevention and care for HIV-positive women in sub-Saharan Africa, implementation and monitoring of cervical cancer screening programs are essential.

BackgroundSub-Saharan Africa is the region most heavily affected by the HIV/AIDS epidemic. HIV increases the risk of developing cancer but the ascertainment of cancers in patients attending antiretroviral therapy (ART) treatment programs might be incomplete. To estimate the under-ascertainment of cancer we compared incidence rates of AIDS-defining cancers in South African HIV cohorts with and without cancer case ascertainment through record linkage with the National Cancer Registry. MethodsWe used the data of adult (≥16 years) HIV-positive persons receiving care between 2004 and 2011 at one of four ART programs in South Africa. These programs collaborate with the International Epidemiologic Databases to Evaluate AIDS Southern Africa (www.iedea-sa.org) and collected data for AIDS-defining cancers but not for other cancers. To improve cancer ascertainment we probabilistically linked patient records (using first name, surname, age, and gender) from two HIV cohorts with the cancer records of the South African National Cancer Registry. We calculated incidence rates per 100,000 person-years after starting ART for the AIDS-defining cancers, i.e. Kaposi sarcoma (KS), invasive cervical cancer (ICC) and non-Hodgkin lymphoma (NHL). We compared incidence rates before and after inclusion of record linkage identified cancer cases using the attributable fraction of cancers identified with 95% confidence intervals (CI). ResultsA total of 49,207 adults starting ART in South Africa were included. 65% of patients were female, median age at starting ART was 35 years (interquartile range 30-41 years). We identified a total of 471 incident cancer cases. With record linkage the incidence increased from 81 to 292 for KS, from 1 to 119 for NHL and 12 to 497 for ICC per 100,000 person-years. The attributable fraction of cancers identified was 72% (95% CI 63-79%) for KS, 98% (95% CI 94-99%) for NHL and 98% (95% CI 95-99%) for ICC. ConclusionAscertainment of cancer in HIV program data in African settings is incomplete. This case study has shown that probabilistic record linkage to cancer registries is both feasible and essential for cancer ascertainment in HIV cohorts in South Africa.

Since 2010, the European Medicines Agency (EMA) has provided access to clinical study reports (CSRs). We requested CSRs for randomized controlled trials (RCTs) of erythropoiesis-stimulating agents (ESAs) in cancer patients from EMA and identified RCT publications with literature searches. We assessed CSR availability and completeness, the impact of unreported and unpublished data obtained from CSRs on the effects of ESAs on quality of life (QoL) of cancer patients, and discrepancies between data reported in the public domain and in CSRs. We used random-effects meta-analyses to evaluate the effect of ESAs on QoL measured with Functional Assessment of Cancer Therapy-Anemia (FACT-An), FACT-Fatigue (FACT-F) and FACT-Anemia Total (FACT-An Total) stratified by data source and the impact of discrepancies on QoL, mortality, adverse events, and clinical effectiveness outcomes. We identified 94 eligible RCTs; CSRs or other study documentation were available for 17 (18%) RCTs at EMA. Median report length was 1,825 pages (range 72-14,569). Of 180 outcomes of interest reported in the EMA documentation, 127 (71%) were publicly available. For 80 of those (63%) we noted discrepancies, but these had little impact on the pooled effect estimates. Of 27 QoL outcomes reported in the CSRs, 17 (63%) were unpublished. Including six unpublished comparisons (pooled mean difference [MD] 0.20; 95% confidence interval [CI] -1.93, 2.33) reduced the pooled effect of ESAs for FACT-An from MD 5.51 (95% CI 4.20, 6.82) in published data to MD 3.21 (95% CI 1.38, 5.03), which is below a clinically important difference (defined as MD ≥4). Effects were similar for FACT-F and FACT-An Total. Access to CSRs from EMA reduced reporting biases for QoL outcomes. However, EMA received documentation for a fraction of all RCTs on effects of ESAs in cancer patients. Additional efforts by other agencies and institutions are needed to make CSRs universally available for all RCTs.

BACKGROUND The risk of Kaposi sarcoma (KS) among HIV-infected persons on antiretroviral therapy (ART) is not well defined in resource-limited settings. We studied KS incidence rates and associated risk factors in children and adults on ART in Southern Africa. METHODS We included patient data of 6 ART programs in Botswana, South Africa, Zambia, and Zimbabwe. We estimated KS incidence rates in patients on ART measuring time from 30 days after ART initiation to KS diagnosis, last follow-up visit, or death. We assessed risk factors (age, sex, calendar year, WHO stage, tuberculosis, and CD4 counts) using Cox models. FINDINGS We analyzed data from 173,245 patients (61% female, 8% children aged 2 years after ART initiation]. Male sex [adjusted hazard ratio (HR): 1.34; 95% CI: 1.12 to 1.61], low current CD4 counts (≥500 versus

BACKGROUND The burden of Kaposi sarcoma (KS) in human immunodeficiency virus (HIV)-infected children and adolescents on combination antiretroviral therapy (cART) has not been compared globally. METHODS We analyzed cohort data from the International Epidemiologic Databases to Evaluate AIDS and the Collaboration of Observational HIV Epidemiological Research in Europe. We included HIV-infected children aged

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.