Diane Solomon

2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors.

A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines. The groups goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screening guidelines incorporating longer screening intervals and co-testing. In addition to literature review, data from almost 1.4 million women in the Kaiser Permanente Northern California Medical Care Plan provided evidence on risk after abnormal tests. Where data were available, guidelines prescribed similar management for women with similar risks for CIN 3, AIS, and cancer. Most prior guidelines were reaffirmed. Examples of updates include: Human papillomavirus-negative atypical squamous cells of undetermined significance results are followed with co-testing at 3 years before return to routine screening and are not sufficient for exiting women from screening at age 65 years; women aged 21-24 years need less invasive management, especially for minor abnormalities; postcolposcopy management strategies incorporate co-testing; endocervical sampling reported as CIN 1 should be managed as CIN 1; unsatisfactory cytology should be repeated in most circumstances, even when HPV results from co-testing are known, while most cases of negative cytology with absent or insufficient endocervical cells or transformation zone component can be managed without intensive follow-up.

Reduced Prevalence of Oral Human Papillomavirus (HPV) 4 Years after Bivalent HPV Vaccination in a Randomized Clinical Trial in Costa Rica

Background Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination. Methods and Findings A total of 7,466 women 18–25 years old were randomized (1∶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CIu200a=u200a63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CIu200a=u200a63% to 79%) (p versus oral VEu200a=u200a0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses. Conclusions HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer. ClinicalTrials.gov, Registry number NCT00128661

Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials.

Objective To assess whether vaccination against human papillomavirus (HPV) increases the risk of miscarriage. Design Pooled analysis of two multicentre, phase three masked randomised controlled trials Setting Multicentre trials in several continents and in Costa Rica. Participants 26u2009130 women aged 15-25 at enrolment; 3599 pregnancies eligible for analysis. Interventions Participants were randomly assigned to receive three doses of bivalent HPV 16/18 VLP vaccine with AS04 adjuvant (n=13u2009075) or hepatitis A vaccine as control (n=13u2009055) over six months. Main outcome measures Miscarriage and other pregnancy outcomes. Results The estimated rate of miscarriage was 11.5% in pregnancies in women in the HPV arm and 10.2% in the control arm. The one sided P value for the primary analysis was 0.16; thus, overall, there was no significant increase in miscarriage among women assigned to the HPV vaccine arm. In secondary descriptive analyses, miscarriage rates were 14.7% in the HPV vaccine arm and 9.1% in the control arm in pregnancies that began within three months after nearest vaccination. Conclusion There is no evidence overall for an association between HPV vaccination and risk of miscarriage. Trial registration Clinical Trials NCT00128661 and NCT00122681.

Cervical-Cancer Screening with Human Papillomavirus and Cytologic Cotesting

For women 30 years of age or older (past the age at which new HPV infections peak), HPV and cytologic cotesting every 5 years is now an accepted alternative to cytologic testing alone every 3 years, since the risk of cervical cancer is very low in the years after a negative HPV test.

Determinants of seropositivity among HPV-16/18 DNA positive young women

BackgroundNot all women infected with HPV-16/18 have detectable levels of HPV-16/18 antibodies, those who seroconvert develop low antibody levels, and seroconversion occurs typically several months post-infection. We evaluated determinants of seropositivity among 646 women infected with HPV-16 and/or HPV-18.MethodsData are from the enrollment visit of the NCI-sponsored Costa Rica HPV Vaccine Trial. Sera were tested for HPV-16/18 antibodies by ELISA; cervical specimens were tested for HPV DNA using HC2 and SPF10/LiPA25. Odds ratios (OR) and 95% confidence intervals (CI) were computed.ResultsAmong HPV-16/18 DNA positives, seropositivity was 63.0% and 57.5%, respectively. Among HPV-16 DNA positives, seropositivity increased with lifetime number of sexual partners (p-trend = 0.01). Women with abnormal cytology and/or high viral load had a 1.63-2.79-fold increase in the detection of antibodies compared to women with normal cytology/low viral load. Current users of oral contraceptives had a 1.88-fold (95%CI, 1.14-3.09) increased detection of antibodies and current users of injectables had a 3.38-fold (95%CI, 1.39-8.23) increased detection compared to never users. Among HPV-18 DNA positive women, seropositivity was associated with current oral contraceptive use (OR 2.47; 95%CI 1.08-5.65).ConclusionsFactors associated with sustained HPV exposure (abnormal cytology, elevated HPV viral load, increasing lifetime partners) were predictive of HPV-16 seropositivity. Hormonal contraceptive use was associated with seropositivity suggesting an effect of hormones on immune responses to HPV. Patterns were less consistent for HPV-18. Follow up of incident HPV infections to evaluate seroconversion and their determinants is needed.

Antithrombotic therapies for stroke prevention

Aspirin is the most widely used antiplatelet agent, reducing nonfatal ischemic stroke by 22%. There is increasing evidence that the efficacy of aspirin may vary with the etiologic subtype of stroke. Although the cost and side effects have limited the use of ticlopidine, patients who are intolerant of aspirin and those experiencing transient ischemic attack or stroke during aspirin therapy should be given ticlopidine. Patients with atrial fibrillation have a five-fold increased risk of stroke and require prophylactic therapy with warfarin or aspirin. Aspirin is less effective than warfarin in preventing atrial fibrillation-associated stroke, but the higher risk of hemorrhagic complications and frequent monitoring associated with warfarin must be considered. Clinical and echocardiographic predictors of increased thromboembolic risk in atrial fibrillation patients have been identified and may direct the treatment choice.

Switch from cytology-based to human papillomavirus test-based cervical screening: Implications for colposcopy

Human papillomavirus (HPV) testing is more sensitive than cytology; some cervical cancer prevention programs will switch from cytology to carcinogenic HPV test‐based screening. The objective of our study is to evaluate the clinical implications of a switch to HPV test‐based screening on performance and workload of colposcopy. Women in the population‐based, 7‐year Guanacaste cohort study were screened at enrollment using cytology. We also took another specimen for HPV DNA testing and collected magnified cervical photographic images (cervigrams). A final case diagnosis (≥cervical intraepithelial neoplasia [CIN] grade 3, CIN2,

Thalamic ataxia syndrome

We identified 10 patients with contralateral ataxia and hemisensory loss following unilateral thalamic lesions. Seven patients had ischemic infarcts, and three had hemorrhages. Hemiparesis, when present, was only a transient finding, whereas ataxia, dysmetria, dysdiadochokinesia, rebound, and hemisensory loss persisted. Two patients had cerebellar outflow tremor. Another developed a severe Déjerine-Roussy pain syndrome. Four patients had lesions of the dominant hemisphere, and two had visual field deficits. None had mutism, aphasia, or astasia. On radiographic evaluation, all patients had lesions in the mid to posterior thalamus, a localization consistent with a lesion of the dentatorubrothalamic and ascending sensory pathways into the thalamus. The thalamic ataxia syndrome has a distinct localizing value that is distinguishable from the ataxic hemiparesis syndrome. Strokes occurring in the ventral lateral and posterior nuclei of the thalamus produce the clinical picture of contralateral cerebellar dysfunction and sensory loss with only transient weakness.

Letter to the Editor of Lancet

The evidence is clear. HPV virus like particle (VLP) vaccines are highly effective in preventing persistent HPV infection and related cervical disease in girls and women naive to the relevant HPV type(s). However, what remains unclear is the public health benefit (PHB) to be derived from vaccination of mid adult women 24-45: the age cohort considered in the study by Munoz et al1. Heres why: n nIn the trial, the vaccine efficacy (VE) in the per-protocol population was 90% for disease or infection related to HPV 6, 11, 16, and 18. VE is the appropriate metric to answer the focused question of whether the vaccine is able to prevent infection and disease in women naive to the relevant HPV type. However this is not the best metric to evaluate the PHB of vaccination. To assess PHB, a different cohort, disease endpoint and metric may be considered. n n nCohort: Analysis of PHB should use the intention-to-treat population rather than the per-protocol cohort that excludes women with pre-existing infections and women who do not complete the full course of vaccination. (VE in the intention to treat population was only 31% in the Munoz study). It also should evaluate the generalizability of results from the cohort to the target population. n n nEndpoint: Newly-detected infections that persist for 6 months may be a reasonable surrogate endpoint for evaluating VE, however PHB should be based on the reduction in an endpoint close to the disease targeted for prevention (i.e. CIN2+, or better yet CIN3+, as surrogates for cancer risk). In the Munoz study, virtually all the endpoints were either persistent infection or CIN1 (which the authors admit is considered a manifestation of productive HPV infection). The number of cases of CIN2+ is not reported. n n nMetric: A relative ratio of disease reduction as measured by VE, does not account for the incidence of disease (attack rate) in the unvaccinated population in contrast to an absolute rate reduction of disease (e.g. how many cases averted per 1,000 women vaccinated). To illustrate the importance of attack rate in assessing PHB, consider these examples: a vaccine with only 50% VE against a disease that would affect 20% of the population will prevent 100 events per 1,000 vaccinated, while a vaccine with 90% VE against a disease that would strike 1.0% of the population will prevent only 9 events per 1,000 vaccinated. n n n nRecent data provide evidence that new HPV infections in older, sexually-experienced women carry only a low risk of developing into CIN2+. 2 In the Munoz study, 25 “cases” of persistent HPV-16 and/or HPV-18 persistent infection or disease (largely CIN1) were averted in almost 4000 person-years of follow-up. If 10% of these infections would have been expected to develop into CIN2 or worse, then the extrapolated PHB of vaccinating women 24-45 would be prevention of 1.33 cases of CIN2+/1000 women over two years. n nHPV vaccination is expensive. It is clear that targeting young women prior to sexual debut will provide the greatest benefit from HPV vaccination for a given cost. The peak of CIN2/3 occurs in women in their late-20s and early 30s---HPV vaccination must precede the acquisition of those causal HPV infections that occurred 5-10 years earlier.3 PHB and cost-effectiveness, not just VE, should be considered before establishing vaccination recommendations.1 Muñoz N, Manalastas R, Pitisultithum P, et al. Safety, immunogenicity, and effi cacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24–45 years: a randomised, double-blind trial. Lancet 2009; 373: 1949–57. 2 Dunne E. ACIP considerations: vaccination of women 27-45 years. Quadrivalent HPV vaccine. Presented at the Meeting of the Advisory Committee on Immunization Practices (ACIP); Atlanta,GA, USA; June 25, 2008.