1. Implementing GRADE… Canadian Clinical Preventive Guidelines for Newly Arriving Immigrants and Refugees for Primary Care Practitioners Dr. Kevin Pottie Centre for Global Health, Institute of Population Health, University of Ottawa Website: http://www.ccirh.uottawa.ca http://www.ccirh.uottawa.ca

2. Canadian Collaboration for Immigrant and Refugee Health (CCIRH) 43 Delphi Participants-selected topics 23 Interdisciplinary Expert Review Teams 10 Panel Members: Kevin Pottie (co-chair), Peter Tugwell (co- chair), John Feightner, Vivian Welch, Chris Greenaway, Laurence Kirmayer, Helena Swinkels, Meb Rashid, Lavanya Narasiah, Noni MacDonald Collaborating Partners: Public Health Agency of Canada, Citizenship and Immigrant Canada, Edmonton Multicultural Health Broker, Calgary Refugee Program, Champlain Regional Health, CIHR. Collaborating Partners: Public Health Agency of Canada, Citizenship and Immigrant Canada, Edmonton Multicultural Health Broker, Calgary Refugee Program, Champlain Regional Health, CIHR.

3. Objective: Develop evidence-based clinical preventive guidelines for immigrants and refugees new to Canada for primary care practitioners. Infectious Diseases Hepatitis B Hepatitis C HIV Intestinal Parasites Malaria MMR/DPTP-HIB Tuberculosis Varicella (Chicken Pox) Mental Health Depression Child Maltreatment Intimate Partner Violence Post Traumatic Stress Disorder Other Chronic Disease Cancer of the Cervix Unmet Contraceptive Needs Diabetes Dental Caries/Peridontal disease Iron Deficiency Anemia Pregnancy Care Vision Disorders

4. Development Process CCIRH Planning Committee (GRADE) Delphi consensus to select priority conditions Expert Consensus Meeting (May 2006) (GRADE as part of CCIRH methods) Systematic Evidence Reviews: 6-12 months PICO Question refinement and development of GRADE DNP documents GRADE meeting to make recommendations

5. CCIRH 14 Step Methods Process Logic model and key questions approach (U.S. and Can Task Forces with GRADE-Related Questions: values and preferences, clinically important outcomes, cost) Search strategies and summary of findings tables and equity considerations (Cochrane Collaboration) Review appraisals (NICE; AGREE, EPOC) Quality assessment and recommendation development (GRADE)

6. Making Recommendations (GRADE Approach) Determine GRADE PICO Question. Determine most important desirable and undesirable effects (SoF table) Rate quality of evidence (type of evidence, quality, directness, consistency, effect size) Determine recommendation (yes/no) and summarize basis for recommendation

7. PICO Question Should Canadian primary care practitioners routinely vaccinate female immigrants and refugees against human papillomavirus (HPV) to reduce morbidity and mortality from cervical cancer?

8. Outcome No. of studies Design (RCT or Obs) Limitation s (ie study quality) (-1 or -2) Consisten cy (-1) Directness (-1 or -2) Imprecise or sparse data (-1) Reporting bias (-1) GRADE Quality High grade cervical lesion 5 (36266)RCT No limitations -1*DirectNo Moderate Any cervical intraepithel ial neoplasia 5 (24613)RCT No limitations DirectNo Moderate >1 serious adverse event 6 (39609)RCT No limitations DirectNo Moderate *Consistency is downgraded since there was statistically significant heterogeneity in the per protocol analysis which disappeared in the intention to treat analysis. *Results are graded as “direct” since there are no plausible biological or cultural reasons why the relative efficacy of the HPV vaccine for the prevention of cervical cancer is likely to be different. Rambout et al. 2007 CMAJ GRADE QUALITY: CCIRH SUMMARY: HPV vaccination for prevention of cervical caner

9. Summary of Findings Table: Prophylactic HPV vaccination against cervical cancer Patients or population: Women 15-25 years Settings: not previously infected with HPV Intervention: HPV vaccination Comparison: Placebo or ‘no HPV vaccination’ SOURCES: Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized trials. Rambout et al. 2007 CMAJ OutcomesIllustrative comparative risks* (95% CI) Relative effect (95% CI) (Odds ratio) Number of particip ants (studies) Quality of the evidence (GRADE) Comments Assume d riskCorresponding risk Placebo or no vaccina tion Vaccination High Grade Cervical Lesion 15 per 1000 0.0078 (8 per 1000) 95% CI: (0.0065 – 0.0095) 0.52 (0.43-0.63) 36266 (5 studies) moderateNNT 139 (117 to 180) Persistent HPV infection – 6 months 40 per 1000 0.0092 (9 per 1000) 95% CI: (0.0074 – 0.011) 0.22 (0.18-0.27) 14207 (3 studies) moderateNNT 32 (30 to 34) ≥ 1 serious adverse event** 22 per 1000 0.022 (22 per 1000) 95% CI: (0.020- 0.026) 1.00 (0.87-1.14) 39609 (6 studies) moderateTwo trials did not report allocation concealment *The basis for the assumed risk is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the intervention group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio GRADE: GRADE Working Group grades of evidence (see explanations) ** serious adverse events: bronchospasm, gastroenteritis, headache, hypertension, pain at injection site or impaired joint movement in injected limb.

10. Cervical Cancer: Vaccination Recommend vaccination to 9-26 year old females against Human Papillomavirus (HPV) to reduce invasive changes related to cervical cancer.

11. Basis of Recommendation Balance of benefits and harms: Net benefits. For HPV vaccination, the number needed to vaccinate (NNT) – i.e. vaccinate – to prevent invasive changes is 139 (117 to 180) in studies with a 15-48 month duration (relative risk 0.52, 95% CI: 0.43 to 0.63). The expected NNT in immigrant and refugee women is expected to be more favourable since there is higher mortality from cervical cancer in foreign-born women than Canadian-born (3.4 vs 2.5 per 100,000 women) and higher prevalence of HPV infection in developing countries. Anaphylaxis occurs in less than 1 in 100,000 doses. Quality of evidence: moderate Values and preferences: The Committee attributed more value to preventing cervical cancer and less value to current uncertainty of impact on mortality.

12. HEPATITIS B: SCREENING Screen adults and children from intermediate and high Hepatitis B endemic countries with HBCore AB and HBsAg to decrease disease severity and transmission and mortality from Hepatocarcinoma. Basis of Recommendation Balance of benefits and harms: Net benefit: The number needed to screen to prevent one death due to hepatocellular carcinoma (HCC) is 2058 (95% CI: 1462 to 4412), corresponding to a relative risk reduction of 38% (95% CI: 17% to 52%). The expected NNS in refugees and immigrants is expected to be more favourable due to higher prevalence of hepatitis B for immigrants and refugees, ranging from 1-10% compared to <0.5% for North Americans. Toxicity depends on treatment decisions. Quality of evidence: moderate Values and preferences: The Committee attributed more value to preventing death due to hepatocellular carcinoma and less value to burden of screening and side effects of treatment

13. GRADE Challenges and Response Quality of evidence- focus on effectiveness of intervention (rare RCT for prevention) Whose values and preferences? How to evaluate explicitly? YES/No vs. Strong/Weak recommendation Response: CMAJ- positive peer review; debate on how to present basis of recommendation

14. Thank You

15. Pregnancy: Women’s Health Immigrants and refugees have an elevated risk for social isolation which is associated with maternal physical and mental morbidity. Research recommendation to develop and study interventions for social isolation.

16. Basis of Recommendation Balance of benefits and harms: Risk of causing harm with a social intervention to reduce social isolation and no evidence to demonstrate effectiveness. Perceived lack of social support is higher amongst immigrant and refugee women than Canadian-born women (15.4% compared to 7.2%). Therefore, we approved a research recommendation to develop and study interventions for pregnant women and social isolation. Quality of evidence: very low Values and preferences: The Committee attributed more value to the large uncertainty of benefits without a studied intervention.

17. Clinical Considerations Immigrant and refugee women account for over half of the total births in Canada. Reports suggest a higher risk status in some newly arrived pregnant women for maternal mortality. Although no clinical action recommendation made to address social isolation, pregnant women may benefit from other established antenatal screening: diabetes, depression, HIV, Hepatitis B, Hepatitis C, syphilis, iron deficiency, hemoglobinopathies, rubella and varicella susceptibility. Being alert for risks of unprotected/ unregulated work environments and sexual abuse (specifically in forced migrants) may also be beneficial.

18. Vision Screen all adults for visual impairment to reduce vision loss and related morbidity. Vision < 6/12, refer to optometrist or ophthalmologist for comprehensive ophthalmic evaluation

19. Basis of Recommendation Balance of benefits and harms: Net benefits. Refractory error is correctible with spectacles for 83% of people, corresponding to a number needed to treat of 5 people. Effects of screening are likely to be important for immigrants and refugees since there is a higher burden of uncorrected visual impairment in developing countries (e.g. blindness prevalence is 1% in Africa compares to 0.3% in the Americas). Harms are minimal, and may include out of pocket costs. Quality of evidence: very low Values and preferences: The Committee attributed more value to the importance of ensuring adequate visual acuity for daily functioning and employment and less value to the concern of screening and cost of spectacles. Clinical Considerations: Even modest visual impairment (visual acuity <6/12) is associated with significant morbidity. Special considerations exist for doing vision screening kids<8 years of age. Referral for assessment is also warranted for other risk factors for blinding eye disease including diabetes, age>65; blacks over 40; and a family history of glaucoma.

20. Tuberculosis (TB) in Adults Screen all refugees from high TB incidence countries, between the ages of 21 and 50 years, as soon as possible after their arrival in Canada with a TST. Screen all other adult immigrants if they have risk factors that increase the risk of developing active TB with a TST. Treat for latent TB infection in those found to be positive, after ruling out active TB.

21. Recommendations for Preventing Tuberculosis (TB) in Immigrants and Refugees Children Screen children and adolescents ≤ 20 years from high TB incidence countries (smear positive pulmonary TB ≥ 15/100,000 population) as soon as possible after their arrival in Canada, with a Tuberculin Skin Test (TST) and treat for latent TB infection if found to be positive, after ruling out active TB.

22. Basis of Recommendation The recommendation is based on the balance between the potential benefit of treatment (lifetime risk of infection which is influenced primarily by age, presence of medical factors that increase the risk of development of active TB, immigration class, and to a lesser degree the effect of time since arrival) versus the potential harm of hepatotoxicity and the poor efficacy of INH in many settings due to sub-optimal uptake of screening and treatment. Assuming 70% adherence, children from high TB incidence countries [number needed to treat (NNT) 20-26 and number needed to harm (NNH) 134-268] and those with risk factors for development of active TB were the groups judged most likely to benefit from chemoprophylaxis (NNT 2-20, NNH- variable).

23. What are the health problems? What are the clinically important outcomes: desirable and undesirable effects? Diversity of Effectiveness: How do immigrants and refugees differ from the Canadian population? Is it important? What actions might be most feasible for primary care practitioners? -users’ views- Does doing this cost more than that? (societal values) Will immigrants accept it? (values and preferences) Is it useful for practitioners