Vikrant V. Sahasrabuddhe

Prevalence and distribution of HPV genotypes among HIV-infected women in Zambia.

We screened 145 HIV-infected non-pregnant women at a tertiary care centre in Lusaka, Zambia. Liquid-based cytology and human papillomavirus (HPV) genotyping with PGMY09/11 biotinylated primers (Roche Linear Array® HPV genotyping test) maximised sensitivity of cytology and HPV assessments. Among high-risk (HR) types, HPV 52 (37.2%), 58 (24.1%) and 53 (20.7%) were more common overall than HPV 16 (17.2%) and 18 (13.1%) in women with high-grade squamous intraepithelial lesions or squamous cell carcinoma (SCC) on cytology. High-risk HPV types were more likely to be present in women with CD4+ cell counts <200 μ l−1 (odds ratios (OR): 4.9, 95% confidence intervals (CI): 1.4–16.7, P=0.01) and in women with high-grade or severe cervical cytological abnormalities (OR: 8.0, 95% CI: 1.7–37.4, P=0.008). Human papillomavirus diversity in high-grade lesions and SCC on cytology suggests that HPV 16- and 18-based vaccines may not be adequately polyvalent to induce protective immunity in this population.

Evolution and Taxonomic Classification of Human Papillomavirus 16 (HPV16)-Related Variant Genomes: HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67

Background Human papillomavirus 16 (HPV16) species group (alpha-9) of the Alphapapillomavirus genus contains HPV16, HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. These HPVs account for 75% of invasive cervical cancers worldwide. Viral variants of these HPVs differ in evolutionary history and pathogenicity. Moreover, a comprehensive nomenclature system for HPV variants is lacking, limiting comparisons between studies. Methods DNA from cervical samples previously characterized for HPV type were obtained from multiple geographic regions to screen for novel variants. The complete 8 kb genomes of 120 variants representing the major and minor lineages of the HPV16-related alpha-9 HPV types were sequenced to capture maximum viral heterogeneity. Viral evolution was characterized by constructing phylogenic trees based on complete genomes using multiple algorithms. Maximal and viral region specific divergence was calculated by global and pairwise alignments. Variant lineages were classified and named using an alphanumeric system; the prototype genome was assigned to the A lineage for all types. Results The range of genome-genome sequence heterogeneity varied from 0.6% for HPV35 to 2.2% for HPV52 and included 1.4% for HPV31, 1.1% for HPV33, 1.7% for HPV58 and 1.1% for HPV67. Nucleotide differences of approximately 1.0% - 10.0% and 0.5%–1.0% of the complete genomes were used to define variant lineages and sublineages, respectively. Each gene/region differs in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) /noncoding region 2 (NCR2) >upstream regulatory region (URR)> E6/E7 > E2/L2 > E1/L1. Conclusions These data define maximum viral genomic heterogeneity of HPV16-related alpha-9 HPV variants. The proposed nomenclature system facilitates the comparison of variants across epidemiological studies. Sequence diversity and phylogenies of this clinically important group of HPVs provides the basis for further studies of discrete viral evolution, epidemiology, pathogenesis and preventative/therapeutic interventions.

Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma

BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated. METHODS We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health-AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided. RESULTS Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users. CONCLUSIONS Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.

Implementation of 'see-and-treat' cervical cancer prevention services linked to HIV care in Zambia.

Greater than 80% of the worlds new cases and deaths due to cervical cancer occur in the developing world [1]. No more than 5% of women in these settings are screened for cervical cancer even once in their lifetimes [2]. Earlier attempts to establish population-based cervical cancer prevention programs using cytology screening in resource-limited settings have inevitably fallen short or failed [3–5]. Although many of the reasons for failure can be attributed to lack of resources and trained manpower, the multiple visit requirements of cytology-based screening programs jeopardizes success and sustainability.

Advancing Cervical Cancer Prevention Initiatives in Resource-Constrained Settings: Insights from the Cervical Cancer Prevention Program in Zambia

Groesbeck Parham and colleagues describe their Cervical Cancer Prevention Program in Zambia, which has provided services to over 58,000 women over the past five years, and share lessons learned from the programs implementation and integration with existing HIV/AIDS programs.

The impact of antiretroviral therapy on HPV and cervical intraepithelial neoplasia: current evidence and directions for future research

Increasing numbers of human immunodeficiency virus (HIV)-infected women are now accessing life-prolonging highly active antiretroviral therapy (HAART) in developing countries. There is a need for better understanding of interactions of human papillomavirus (HPV) and HIV, especially in the context of increasing life expectancy due to HAART. The data regarding the impact of HAART on reducing the incidence and progression and facilitating the regression of HPV infection and cervical abnormalities is largely inconsistent. Published studies differ in their study designs (prospective or retrospective cohorts or record linkage studies), screening and diagnostic protocols, duration and type of HAART use, recruitment and referral strategies, and definitions of screening test and disease positivity. Due to the ethical and resource limitations in conducting randomized trials of the impact of HAART on incidence of HPV, CIN, and cervical cancer among HIV-infected women, it is important to consider innovative study designs, including quasi-experimental trials and operations research in sentinel populations to answer the critical research questions in this area.

Cervical Cancer Prevention in Low- and Middle-Income Countries: Feasible, Affordable, Essential

The annual worldwide burden of the preventable disease cervical cancer is more than 530,000 new cases and 275,000 deaths, with the majority occurring in low- and middle-income countries (LMIC), where cervical cancer screening and early treatment are uncommon. Widely used in high-income countries, Pap smear (cytology based) screening is expensive and challenging for implementation in LMICs, where lower-cost, effective alternatives such as visual inspection with acetic acid (VIA) and rapid human papillomavirus (HPV)-based screening tests offer promise for scaling up prevention services. Integrating HPV screening with VIA in “screen-and-treat-or-refer” programs offers the dual benefits of HPV screening to maximize detection and using VIA to triage for advanced lesions/cancer, as well as a pelvic exam to address other gynecologic issues. A major issue in LMICs is coinfection with human immunodeficiency virus (HIV) and HPV, which further increases the risk for cervical cancer and marks a population with perhaps the greatest need of cervical cancer prevention. Public–private partnerships to enhance the availability of cervical cancer prevention services within HIV/AIDS care delivery platforms through initiatives such as Pink Ribbon Red Ribbon present an historic opportunity to expand cervical cancer screening in LMICs. Cancer Prev Res; 5(1); 11–17. ©2011 AACR.

Human Papillomavirus Genotype Attribution and Estimation of Preventable Fraction of Anal Intraepithelial Neoplasia Cases Among HIV-Infected Men Who Have Sex With Men

BACKGROUND The prevention of human papillomavirus (HPV)-induced anal cancer in high-risk populations such as human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) remains an urgent priority, given rising incidence rates despite widespread antiretroviral therapy use. METHODS HPV genotypes and anal disease prevalence, by cytology and histopathologic findings, were evaluated among 363 HIV-infected MSM. We modeled fractions of high-grade anal intraepithelial neoplasia (HGAIN) attributable to individual carcinogenic HPV genotypes and estimated the range of the proportion of HGAIN cases potentially preventable by prophylactic HPV vaccines. RESULTS HPV16 was the most common genotype overall (26.4% of cases) and among HGAIN cases (55%). Prevalence of multiple (≥ 2) carcinogenic HPV genotypes increased from 30.9% in cases of AIN grade <1 to 76.3% in cases of AIN grade 3 (P(trend) < .001). The fractions of HGAIN cases attributable to carcinogenic HPV16/18 targeted by currently licensed bivalent and quadrivalent HPV vaccines ranged from 12% to 61.5%, and the fractions attributable to carcinogenic HPV16/18/31/33/45/52/58 targeted by an investigational nonavalent HPV vaccine ranged from 39% to 89.4%. CONCLUSIONS Our analytical framework allows estimation of HGAIN cases attributable to individual HPV genotypes in the context of multiple concurrent HPV infections, which are very common among HIV-infected MSM. Our results suggest that licensed and investigational HPV prophylactic vaccines have the potential to prevent a substantial proportion of HGAIN cases in this population.

Comparison of visual inspection with acetic acid and cervical cytology to detect high-grade cervical neoplasia among HIV-infected women in India.

Human immunodeficiency virus (HIV)‐infected women in India and other developing country settings are living longer on antiretroviral therapy, yet their risk for human papillomavirus (HPV)‐induced cervical cancer remains unabated because of lack of cost‐effective and accurate secondary prevention methods. Visual inspection after application of dilute acetic acid on the cervix (VIA) has not been adequately studied against the current standard: conventional cervical cytology (Pap smears) among HIV‐infected women. We evaluated 303 nonpregnant HIV‐infected women in Pune, India, by simultaneous and independent screening with VIA and cervical cytology with disease ascertainment by colposcopy and histopathology. At the cervical intraepithelial neoplasia (CIN2+) disease threshold, the sensitivity, specificity and positive and negative predictive value estimates of VIA were 80, 82.6, 47.6 and 95.4% respectively, compared to 60.5, 59.6, 22.4 and 88.7% for the atypical squamous cells of undetermined significance or severe (ASCUS+) cutoff on cytology, 60.5, 64.6, 24.8 and 89.4% for the low‐grade squamous intraepithelial cells or severe (LSIL+) cutoff on cytology and 20.9, 96.0, 50.0 and 86.3% for high‐grade squamous intraepithelial lesion or severe (HSIL+) cutoff on cytology. A similar pattern of results was found for women with the presence of carcinogenic HPV‐positive CIN2+ disease, as well as for women with CD4+ cell counts <200 and <350 μL−1. Overall, VIA performed better than cytology in this study with biologically rigorous endpoints and without verification bias, suggesting that VIA is a practical and useful alternative or adjunctive screening test for HIV‐infected women. Implementing VIA‐based screening within HIV/acquired immunodeficiency syndrome care programs may provide an easy and practical means of complementing the highly anticipated low‐cost HPV‐based rapid screening tests in the near future, thereby contributing to improve program effectiveness of screening.

The risk of hepatocellular carcinoma among individuals with acquired immunodeficiency syndrome in the United States

Hepatocellular carcinoma (HCC) is a concern among individuals with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS).