Infectious pathogens and risk of esophageal, gastric and duodenal cancers and ulcers in China: A case-cohort study.

Infection by certain pathogens is associated with cancer development. We conducted a case-cohort study of ~2500 incident cases of esophageal, gastric and duodenal cancer, and gastric and duodenal ulcer and a randomly selected subcohort of ~2000 individuals within the China Kadoorie Biobank study of >0.5 million adults. We used a bead-based multiplex serology assay to measure antibodies against 19 pathogens (total 43 antigens) in baseline plasma samples. Associations between pathogens and antigen-specific antibodies with risks of site-specific cancers and ulcers were assessed using Cox regression fitted using the Prentice pseudo-partial likelihood. Seroprevalence varied for different pathogens, from 0.7% for Hepatitis C virus (HCV) to 99.8% for Epstein-Barr virus (EBV) in the subcohort. Compared to participants seronegative for the corresponding pathogen, Helicobacter pylori seropositivity was associated with a higher risk of non-cardia (adjusted hazard ratio [HR] 2.73 [95% CI: 2.09-3.58]) and cardia (1.67 [1.18-2.38]) gastric cancer and duodenal ulcer (2.71 [1.79-4.08]). HCV was associated with a higher risk of duodenal cancer (6.23 [1.52-25.62]) and Hepatitis B virus was associated with higher risk of duodenal ulcer (1.46 [1.04-2.05]). There were some associations of antibodies again some herpesviruses and human papillomaviruses with risks of gastrointestinal cancers and ulcers but these should be interpreted with caution. This first study of multiple pathogens with risk of gastrointestinal cancers and ulcers demonstrated that several pathogens are associated with risks of gastrointestinal cancers and ulcers. This will inform future investigations into the role of infection in the etiology of these diseases.

Helicobacter pylori multiplex serology and risk of non-cardia and cardia gastric cancer: a case-cohort study and meta-analysis.

BACKGROUND: Helicobacter pylori infection is a major cause of non-cardia gastric cancer (NCGC), but uncertainty remains about the associations between sero-positivity to different H. pylori antigens and risk of NCGC and cardia gastric cancer (CGC) in different populations. METHODS: A case-cohort study in China included ∼500 each of incident NCGC and CGC cases and ∼2000 subcohort participants. Sero-positivity to 12 H. pylori antigens was measured in baseline plasma samples using a multiplex assay. Hazard ratios (HRs) of NCGC and CGC for each marker were estimated using Cox regression. These were further meta-analysed with studies using same assay. RESULTS: In the subcohort, sero-positivity for 12 H. pylori antigens varied from 11.4% (HpaA) to 70.8% (CagA). Overall, 10 antigens showed significant associations with risk of NCGC (adjusted HRs: 1.33 to 4.15), and four antigens with CGC (HRs: 1.50 to 2.34). After simultaneous adjustment for other antigens, positive associations remained significant for NCGC (CagA, HP1564, HP0305) and CGC (CagA, HP1564, HyuA). Compared with CagA sero-positive only individuals, those who were positive for all three antigens had an adjusted HR of 5.59 (95% CI 4.68-6.66) for NCGC and 2.17 (95% CI 1.54-3.05) for CGC. In the meta-analysis of NCGC, the pooled relative risk for CagA was 2.96 (95% CI 2.58-3.41) [Europeans: 5.32 (95% CI 4.05-6.99); Asians: 2.41 (95% CI 2.05-2.83); Pheterogeneity<0.0001]. Similar pronounced population differences were also evident for GroEL, HP1564, HcpC and HP0305. In meta-analyses of CGC, two antigens (CagA, HP1564) were significantly associated with a higher risk in Asians but not Europeans. CONCLUSIONS: Sero-positivity to several H. pylori antigens was significantly associated with an increased risk of NCGC and CGC, with varying effects between Asian and European populations.

Sero-prevalence of 19 infectious pathogens and associated factors among middle-aged and elderly Chinese adults: a cross-sectional study.

OBJECTIVES: To systematically assess the sero-prevalence and associated factors of major infectious pathogens in China, where there are high incidence rates of certain infection-related cancers. DESIGN: Cross-sectional study. SETTING: 10 (5 urban, 5 rural) geographically diverse areas in China. PARTICIPANTS: A subcohort of 2000 participants from the China Kadoorie Biobank. PRIMARY MEASURES: Sero-prevalence of 19 pathogens using a custom-designed multiplex serology panel and associated factors. RESULTS: Of the 19 pathogens investigated, the mean number of sero-positive pathogens was 9.4 (SD 1.7), with 24.4% of participants being sero-positive for >10 pathogens. For individual pathogens, the sero-prevalence varied, being for example, 0.05% for HIV, 6.4% for human papillomavirus (HPV)-16, 53.5% for Helicobacter pylori (H. pylori) and 99.8% for Epstein-Barr virus . The sero-prevalence of human herpesviruses (HHV)-6, HHV-7 and HPV-16 was higher in women than men. Several pathogens showed a decreasing trend in sero-prevalence by birth cohort, including hepatitis B virus (HBV) (51.6% vs 38.7% in those born <1940 vs >1970), HPV-16 (11.4% vs 5.4%), HHV-2 (15.1% vs 8.1%), Chlamydia trachomatis (65.6% vs 28.8%) and Toxoplasma gondii (22.0% vs 9.0%). Across the 10 study areas, sero-prevalence varied twofold to fourfold for HBV (22.5% to 60.7%), HPV-16 (3.4% to 10.9%), H. pylori (16.2% to 71.1%) and C. trachomatis (32.5% to 66.5%). Participants with chronic liver diseases had >7-fold higher sero-positivity for HBV (OR=7.51; 95% CI 2.55 to 22.13). CONCLUSIONS: Among Chinese adults, previous and current infections with certain pathogens were common and varied by area, sex and birth cohort. These infections may contribute to the burden of certain cancers and other non-communicable chronic diseases.

On Bayesian modeling of censored data in JAGS.

BACKGROUND: Just Another Gibbs Sampling (JAGS) is a convenient tool to draw posterior samples using Markov Chain Monte Carlo for Bayesian modeling. However, the built-in function dinterval() for censored data misspecifies the default computation of deviance function, which limits likelihood-based Bayesian model comparison. RESULTS: To establish an automatic approach to specifying the correct deviance function in JAGS, we propose a simple and generic alternative modeling strategy for the analysis of censored outcomes. The two illustrative examples demonstrate that the alternative strategy not only properly draws posterior samples in JAGS, but also automatically delivers the correct deviance for model assessment. In the survival data application, our proposed method provides the correct value of mean deviance based on the exact likelihood function. In the drug safety data application, the deviance information criterion and penalized expected deviance for seven Bayesian models of censored data are simultaneously computed by our proposed approach and compared to examine the model performance. CONCLUSIONS: We propose an effective strategy to model censored data in the Bayesian modeling framework in JAGS with the correct deviance specification, which can simplify the calculation of popular Kullback-Leibler based measures for model selection. The proposed approach applies to a broad spectrum of censored data types, such as survival data, and facilitates different censored Bayesian model structures.

The relative and attributable risks of cardia and non-cardia gastric cancer associated with Helicobacter pylori infection in China: a case-cohort study.

BACKGROUND: Helicobacter pylori infection is a major cause of non-cardia gastric cancer (NCGC), but its causal role in cardia gastric cancer (CGC) is unclear. Moreover, the reported magnitude of association with NCGC varies considerably, leading to uncertainty about population-based H pylori screening and eradication strategies in high-risk settings, particularly in China, where approximately half of all global gastric cancer cases occur. Our aim was to assess the associations of H pylori infection, both overall and for individual infection biomarkers, with the risks of NCGC and CGC in Chinese adults. METHODS: A case-cohort study was done in adults from the prospective China Kadoorie Biobank study, aged 30-79 years from ten areas in China (Qingdao, Haikou, Harbin, Suzhou, Liuzhou, Henan, Sichuan, Hunan, Gansu, and Zhejiang), and included 500 incident NCGC cases, 437 incident CGC cases, and 500 subcohort participants who were cancer-free and alive within the first two years since enrolment in 2004-08. H pylori biomarkers were measured in stored baseline plasma samples using a sensitive immunoblot assay (HelicoBlot 2.1), with adapted criteria to define H pylori seropositivity. Cox regression was used to estimate adjusted hazard ratios (HRs) for NCGC and CGC associated with H pylori infection. These values were used to estimate the number of gastric cancer cases attributable to H pylori infection in China. FINDINGS: Of the 512 715 adults enrolled in the China Kadoorie Biobank between June, 2004, and July, 2008, 500 incident NCGC cases, 437 incident CGC cases, and 500 subcohort participants were selected for analysis. The seroprevalence of H pylori was 94·4% (95% CI 92·4-96·4) in NGCG, 92·2% (89·7-94·7) in CGC, and 75·6% (71·8-79·4) in subcohort participants. H pylori infection was associated with adjusted HRs of 5·94 (95% CI 3·25-10·86) for NCGC and 3·06 (1·54-6·10) for CGC. Among the seven individual infection biomarkers, cytotoxin-associated antigen had the highest HRs for both NCGC (HR 4·41, 95% CI 2·60-7·50) and CGC (2·94, 1·53-5·68). In this population, 78·5% of NCGC and 62·1% of CGC cases could be attributable to H pylori infection. H pylori infection accounted for an estimated 339 955 cases of gastric cancer in China in 2018. INTERPRETATION: Among Chinese adults, H pylori infection is common and is the cause of large numbers of gastric cancer cases. Population-based mass screening and the eradication of H pylori should be considered to reduce the burden of gastric cancer in high-risk settings. FUNDING: Cancer Research UK, Wellcome Trust, UK Medical Research Council, British Heart Foundation, Kadoorie Charitable Foundation, National Key Research and Development Program of China, and National Natural Science Foundation of China.

How vague is vague? How informative is informative? Reference analysis for Bayesian meta-analysis.

Meta-analysis provides important insights for evidence-based medicine by synthesizing evidence from multiple studies which address the same research question. Within the Bayesian framework, meta-analysis is frequently expressed by a Bayesian normal-normal hierarchical model (NNHM). Recently, several publications have discussed the choice of the prior distribution for the between-study heterogeneity in the Bayesian NNHM and used several "vague" priors. However, no approach exists to quantify the informativeness of such priors, and thus, we develop a principled reference analysis framework for the Bayesian NNHM acting at the posterior level. The posterior reference analysis (post-RA) is based on two posterior benchmarks: one induced by the improper reference prior, which is minimally informative for the data, and the other induced by a highly anticonservative proper prior. This approach applies the Hellinger distance to quantify the informativeness of a heterogeneity prior of interest by comparing the corresponding marginal posteriors with both posterior benchmarks. The post-RA is implemented in the freely accessible R package ra4bayesmeta and is applied to two medical case studies. Our findings show that anticonservative heterogeneity priors produce platykurtic posteriors compared with the reference posterior, and they produce shorter 95% credible intervals (CrI) and optimistic inference compared with the reference prior. Conservative heterogeneity priors produce leptokurtic posteriors, longer 95% CrI and cautious inference. The novel post-RA framework could support numerous Bayesian meta-analyses in many research fields, as it determines how informative a heterogeneity prior is for the actual data as compared with the minimally informative reference prior.

Extending Bayesian back-calculation to estimate age and time specific HIV incidence.

CD4-based multi-state back-calculation methods are key for monitoring the HIV epidemic, providing estimates of HIV incidence and diagnosis rates by disentangling their inter-related contribution to the observed surveillance data. This paper, extends existing approaches to age-specific settings, permitting the joint estimation of age- and time-specific incidence and diagnosis rates and the derivation of other epidemiological quantities of interest. This allows the identification of specific age-groups at higher risk of infection, which is crucial in directing public health interventions. We investigate, through simulation studies, the suitability of various bivariate splines for the non-parametric modelling of the latent age- and time-specific incidence and illustrate our method on routinely collected data from the HIV epidemic among gay and bisexual men in England and Wales.

Fraction and incidence of liver cancer attributable to hepatitis B and C viruses worldwide.

High-quality data on liver cancers by probable cause are scarce in many regions of the world. The United Nations recently set a goal of eliminating viral hepatitis as a major public health threat by 2030. We aimed to estimate the number of new cases of cancers attributable to hepatitis B virus (HBV) and hepatitis C virus (HCV) at a global, regional and country level, and by development status. We used data on the prevalence of HBV and HCV in hepatocellular carcinoma from a systematic review including 119,000 cases in 260 studies covering 50 countries. A statistical model was constructed to extrapolate empirical data to countries without prevalence data. Country-specific numbers of liver cancer cases attributable to HBV and HCV were calculated using data from GLOBOCAN 2012. Globally, 770,000 cases of liver cancer occurred worldwide in 2012, of which 56% (95% CI: 52-60) were attributable to HBV and 20% (95% CI: 18-22) to HCV. Currently, HBV causes approximately two out of three cases of liver cancer in less developed countries but one in four cases in more developed countries and shows a much higher degree of geographical aggregation in Eastern Asia and sub-Saharan Africa than HCV. These estimates help set priorities for liver cancer prevention. High-coverage HBV vaccination will be transformational in HBV-endemic countries but the prevention of HCV transmission and the treatment of chronic carriers of both viruses requires new scalable solutions.

New cancer cases in France in 2015 attributable to infectious agents: a systematic review and meta-analysis.

To provide an assessment of the burden of cancer in France in 2015 attributable to infectious agents. A systematic literature review in French representative cancer cases series was undertaken of the prevalence of infectious agents with the major associated cancer types. PubMed was searched for original studies published up to September 2016; random-effects meta-analyses were performed. Cancer incidence data were obtained from the French Cancer Registries Network, thereby allowing the calculation of national incidence estimates. The number of new cancer cases attributable to infectious agents was calculated using population-attributable fractions according to published methods. Of the 352,000 new cancer cases in France in 2015, 14,336 (4.1% of all new cancer cases) were attributable to infectious agents. The largest contributors were human papillomavirus (HPV) and Helicobacter pylori, responsible for 6333 and 4406 new cancer cases (1.8 and 1.3% of all new cancer cases) respectively. Infectious agents caused a non-negligible number of new cancer cases in France in 2015. Most of these cancers were preventable. The expansion of vaccination (i.e., for hepatitis B virus and HPV) and screen-and-treat programs (for HPV and hepatitis C virus, and possibly for H. pylori) could greatly reduce this cancer burden.

Multicentric randomised study of Helicobacter pylori eradication and pepsinogen testing for prevention of gastric cancer mortality: the GISTAR study.

INTRODUCTION: Population-based eradication of Helicobacter pylori has been suggested to be cost-effective and is recommended by international guidelines. However, the potential adverse effects of widespread antibiotic use that this would entail have not been sufficiently studied. An alternative way to decrease gastric cancer mortality is by non-invasive search for precancerous lesions, in particular gastric atrophy; pepsinogen tests are the best currently available alternative. The primary objective of GISTAR is to determine whether H pylori eradication combined with pepsinogen testing reduces mortality from gastric cancer among 40-64-year-old individuals. The secondary objectives include evaluation of H pylori eradication effectiveness in gastric cancer prevention in patients with precancerous lesions and evaluation of the potential adverse events, including effects on microbiome. METHODS AND ANALYSIS: Individuals are recruited from general population (50% men) in areas with high gastric cancer risk in Europe and undergo detailed lifestyle and medical history questionnaire before being randomly allocated to intervention or control groups. The intervention group undergoes H pylori testing and is offered eradication therapy if positive; in addition, pepsinogen levels are detected in plasma and those with decreased levels are referred for upper endoscopy. All participants are offered faecal occult blood testing as an incentive for study participation. Effectiveness of eradication and the spectrum of adverse events are evaluated in study subpopulations. A 35% difference in gastric cancer mortality between the groups is expected to be detectable at 90% power after 15 years if 30 000 individuals are recruited. Biological materials are biobanked for the main and ancillary studies. The study procedure and assumptions will be tested during the pilot phase. ETHICS AND DISSEMINATION: The study was approved by the respective ethics committees. An independent Data Safety and Monitoring Board has been established. The findings will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT02047994.

Cervical cancer screening in rural Bhutan with the careHPV test on self-collected samples: an ongoing cross-sectional, population-based study (REACH-Bhutan).

OBJECTIVES: The Bhutanese Screening Programme recommends a Pap smear every 3 years for women aged 25-65 years, and coverage ranges from 20% to 60%, being especially challenging in rural settings. The 'REACH-Bhutan' study was conducted to assess the feasibility and outcomes of a novel approach to cervical cancer screening in rural Bhutan. DESIGN: Cross-sectional, population-based study of cervical cancer screening based on the careHPV test on self-collected samples. SETTING: Women were recruited in rural primary healthcare centres, that is, Basic Health Units (BHU), across Bhutan. PARTICIPANTS: Overall, 3648 women aged 30-60 were invited from 15 BHUs differing in accessibility, size and ethnic composition of the population. INTERVENTIONS: Participants provided a self-collected cervicovaginal sample and were interviewed. Samples were tested using careHPV in Thimphu (the Bhutanese capital) referral laboratory. MAIN OUTCOME MEASURES: Screening participation by geographic area, centre, age and travelling time. Previous screening history and careHPV positivity by selected characteristics of the participants. RESULTS: In April/May 2016, 2590 women (median age: 41) were enrolled. Study participation was 71% and significantly heterogeneous by BHU (range: 31%-96%). Participation decreased with increase in age (81% in women aged 30-39 years; 59% in ≥50 years) and travelling time (90% in women living <30 min from the BHU vs 62% among those >6 hours away). 50% of participants reported no previous screening, with the proportion of never-screened women varying significantly by BHU (range: 2%-72%). 265 women (10%; 95% CI 9% to 11%) were careHPV positive, with a significant variation by BHU (range: 5%-19%) and number of sexual partners (prevalence ratio for ≥3 vs 0-1, 1.55; 95% CI 1.05 to 2.27). CONCLUSIONS: Community-based cervical cancer screening by testing self-collected samples for human papillomavirus (HPV) can achieve high coverage in rural Bhutan. However, solutions to bring self-collection, HPV testing and precancer treatment closer to the remotest villages are needed.

Worldwide burden of cancer attributable to HPV by site, country and HPV type.

HPV is the cause of almost all cervical cancer and is responsible for a substantial fraction of other anogenital cancers and oropharyngeal cancers. Understanding the HPV-attributable cancer burden can boost programs of HPV vaccination and HPV-based cervical screening. Attributable fractions (AFs) and the relative contributions of different HPV types were derived from published studies reporting on the prevalence of transforming HPV infection in cancer tissue. Maps of age-standardized incidence rates of HPV-attributable cancers by country from GLOBOCAN 2012 data are shown separately for the cervix, other anogenital tract and head and neck cancers. The relative contribution of HPV16/18 and HPV6/11/16/18/31/33/45/52/58 was also estimated. 4.5% of all cancers worldwide (630,000 new cancer cases per year) are attributable to HPV: 8.6% in women and 0.8% in men. AF in women ranges from <3% in Australia/New Zealand and the USA to >20% in India and sub-Saharan Africa. Cervix accounts for 83% of HPV-attributable cancer, two-thirds of which occur in less developed countries. Other HPV-attributable anogenital cancer includes 8,500 vulva; 12,000 vagina; 35,000 anus (half occurring in men) and 13,000 penis. In the head and neck, HPV-attributable cancers represent 38,000 cases of which 21,000 are oropharyngeal cancers occurring in more developed countries. The relative contributions of HPV16/18 and HPV6/11/16/18/31/33/45/52/58 are 73% and 90%, respectively. Universal access to vaccination is the key to avoiding most cases of HPV-attributable cancer. The preponderant burden of HPV16/18 and the possibility of cross-protection emphasize the importance of the introduction of more affordable vaccines in less developed countries.

Hepatitis C virus seroprevalence in the general female population of 9 countries in Europe, Asia and Africa.

BACKGROUND: New oral treatments with very high cure rates have the potential to revolutionize global management of hepatitis C virus (HCV), but population-based data on HCV infection are missing in many low and middle-income countries (LMIC). METHODS: Between 2004 and 2009, dried blood spots were collected from age-stratified female population samples of 9 countries: China, Mongolia, Poland, Guinea, Nepal, Pakistan, Algeria, Georgia and Iran. HCV antibodies were detected by a multiplex serology assay using bead-based technology. RESULTS: Crude HCV prevalence ranged from 17.4% in Mongolia to 0.0% in Iran. In a pooled model adjusted by age and country, in which associations with risk factors were not statistically heterogeneous across countries, the only significant determinants of HCV positivity were age (prevalence ratio for ≥45 versus <35 years = 2.84, 95%CI 2.18-3.71) and parity (parous versus nulliparous = 1.73, 95%CI 1.02-2.93). Statistically significant increases in HCV positivity by age, but not parity, were seen in each of the three countries with the highest number of HCV infections: Mongolia, Pakistan, China. There were no associations with sexual partners nor HPV infection. HCV prevalence in women aged ≥45 years correlated well with recent estimates of female HCV-related liver cancer incidence, with the slight exception of Pakistan, which showed a higher HCV prevalence (5.2%) than expected. CONCLUSIONS: HCV prevalence varies enormously in women worldwide. Medical interventions/hospitalizations linked to childbirth may have represented a route of HCV transmission, but not sexual intercourse. Combining dried blood spot collection with high-throughput HCV assays can facilitate seroepidemiological studies in LMIC where data is otherwise scarce.

Preventable fractions of cervical cancer via effective screening in six Baltic, central, and eastern European countries 2017-40: a population-based study.

BACKGROUND: Cervical cancer incidence remains high in several Baltic, central, and eastern European (BCEE) countries, mainly as a result of a historical absence of effective screening programmes. As a catalyst for action, we aimed to estimate the number of women who could be spared from cervical cancer across six countries in the region during the next 25 years, if effective screening interventions were introduced. METHODS: In this population-based study, we applied age-period-cohort models with spline functions within a Bayesian framework to incidence data from six BCEE countries (Estonia, Latvia, Lithuania, Belarus, Bulgaria, and Russia) to develop projections of the future number of new cases of cervical cancer from 2017 to 2040 based on two future scenarios: continued absence of screening (scenario A) versus the introduction of effective screening from 2017 onwards (scenario B). The timespan of available data varied from 16 years in Bulgaria to 40 years in Estonia. Projected rates up to 2040 were obtained in scenario A by extrapolating cohort-specific trends, a marker of changing risk of human papillomavirus (HPV) infection, assuming a continued absence of effective screening in future years. Scenario B added the effect of gradual introduction of screening in each country, under the assumption period effects would be equivalent to the decreasing trend by calendar year seen in Denmark (our comparator country) since the progressive regional introduction of screening from the late 1960s. FINDINGS: According to scenario A, projected incidence rates will continue to increase substantially in many BCEE countries. Very high age-standardised rates of cervical cancer are predicted in Lithuania, Latvia, Belarus, and Estonia (up to 88 cases per 100 000). According to scenario B, the beneficial effects of effective screening will increase progressively over time, leading to a 50-60% reduction of the projected incidence rates by around 2040, resulting in the prevention of cervical cancer in 1500 women in Estonia and more than 150 000 women in Russia. The immediate launch of effective screening programmes could prevent almost 180 000 new cervical cancer diagnoses in a 25-year period in the six BCEE countries studied. INTERPRETATION: Based on our findings, there is a clear need to begin cervical screening in these six countries as soon as possible to reduce the high and increasing incidence of cervical cancer over the next decades. FUNDING: None.

Global burden of cancers attributable to infections in 2012: a synthetic analysis.

BACKGROUND: Infections with certain viruses, bacteria, and parasites are strong risk factors for specific cancers. As new cancer statistics and epidemiological findings have accumulated in the past 5 years, we aimed to assess the causal involvement of the main carcinogenic agents in different cancer types for the year 2012. METHODS: We considered ten infectious agents classified as carcinogenic to human beings by the International Agency for Research on Cancer. We calculated the number of new cancer cases in 2012 attributable to infections by country, by combining cancer incidence estimates (from GLOBOCAN 2012) with estimates of attributable fraction (AF) for the infectious agents. AF estimates were calculated from the prevalence of infection in cancer cases and the relative risk for the infection (for some sites). Estimates of infection prevalence, relative risk, and corresponding 95% CIs for AF were obtained from systematic reviews and pooled analyses. FINDINGS: Of 14 million new cancer cases in 2012, 2·2 million (15·4%) were attributable to carcinogenic infections. The most important infectious agents worldwide were Helicobacter pylori (770 000 cases), human papillomavirus (640 000), hepatitis B virus (420 000), hepatitis C virus (170 000), and Epstein-Barr virus (120 000). Kaposi's sarcoma was the second largest contributor to the cancer burden in sub-Saharan Africa. The AFs for infection varied by country and development status-from less than 5% in the USA, Canada, Australia, New Zealand, and some countries in western and northern Europe to more than 50% in some countries in sub-Saharan Africa. INTERPRETATION: A large potential exists for reducing the burden of cancer caused by infections. Socioeconomic development is associated with a decrease in infection-associated cancers; however, to reduce the incidence of these cancers without delay, population-based vaccination and screen-and-treat programmes should be made accessible and available. FUNDING: Fondation de France.

Effect of HIV Infection on Human Papillomavirus Types Causing Invasive Cervical Cancer in Africa.

OBJECTIVES: HIV infection is known to worsen the outcome of cervical human papillomavirus (HPV) infection and may do so differentially by HPV type. DESIGN: Twenty-one studies were included in a meta-analysis of invasive cervical cancers (ICC) among women infected with HIV in Africa. METHOD: Type-specific HPV DNA prevalence was compared with data from a similar meta-analysis of HIV-negative ICC using prevalence ratios (PR). RESULTS: HPV detection was similar in 770 HIV-positive (91.2%) and 3846 HIV-negative (89.6%) ICC, but HIV-positive ICC harbored significantly more multiple HPV infections (PR = 1.75, 95% confidence intervals: 1.18 to 2.58), which were significantly more prevalent in ICC tested from cells than from biopsies. HPV16 was the most frequently detected type in HIV-positive ICC (42.5%), followed by HPV18 (22.2%), HPV45 (14.4%), and HPV35 (7.1%). Nevertheless, HIV-positive ICC were significantly less frequently infected with HPV16 than HIV-negative ICC (PR = 0.88, 95% confidence intervals: 0.79 to 0.99). Other high-risk types were significantly more prevalent in HIV-positive ICC, but only for HPV18 was there a significantly higher prevalence of both single and multiple infections in HIV-positive ICC. Increases for other high-risk types were primarily accounted for by multiple infections. The proportion of HPV-positive ICC estimated attributable to HPV16/18 (71.8% in HIV positive, 73.4% in HIV negative) or HPV16/18/31/33/45/52/58 (88.8%, 89.5%) was not affected by HIV. CONCLUSIONS: HIV alters the relative carcinogenicity of HPV types, but prophylactic HPV16/18 vaccines may nevertheless prevent a similar proportion of ICC, irrespective of HIV infection.

Methylation Levels of CADM1, MAL, and MIR124-2 in Cervical Scrapes for Triage of HIV-Infected, High-Risk HPV-Positive Women in Kenya.

OBJECTIVES: To evaluate the value of cervical cell methylation markers in screening HIV-infected women also positive for high-risk human papillomavirus (hrHPV). DESIGN: Cross-sectional and prospective. METHODS: Two hundred forty-eight HIV-infected hrHPV-positive women enrolled in a cervical cancer screening study in Nairobi, Kenya, had colposcopy-directed biopsy and histological diagnoses. Exfoliated cervical cells were used to measure methylation levels of the CADM1, MAL, and MIR124-2 genes using quantitative methylation-specific polymerase chain reaction. Methylation levels were summarized as cycle threshold (Ct) ratios compared with the ß-actin gene. Median Ct ratios were compared across histological diagnoses, with 95% confidence intervals calculated by bootstrapping. Methylation levels at 6 months were assessed in 128 women who remained hrHPV positive. RESULTS: All 3 methylation markers showed significantly (P < 0.001) raised median Ct ratios in women with cervical intraepithelial neoplasia (CIN) grade 3 compared with women with a normal cervix. When markers were combined into a single test, the area under the receiver operating characteristic curve for prediction of CIN2 or worse (CIN2+) was 0.80. When the test was calibrated to have similar specificity, sensitivity of the combined tri-marker test for CIN2+ was comparable with cytology [atypical squamous cells of undetermined significance or worse] (89% and 95%, respectively) and superior to visual inspection with acetic acid (85% vs 70%) and HPV16/18 genotyping (65% vs 40%). Among women with no CIN2+ at baseline and persistent hrHPV at 6-month follow-up, MAL-m1 and MIR124-2 Ct ratios increased significantly. CONCLUSIONS: Methylation markers in combination with HPV testing may offer a full molecular screening strategy to the many HIV-infected women who are also hrHPV positive.