Oxygen metabolism after cardiac arrest: Patterns and associations with survival.

Aim: Whether changes in oxygen metabolism, as measured by oxygen consumption (VO2), carbon dioxide production (VCO2) and the respiratory exchange ratio (RER), are associated with survival after cardiac arrest is poorly understood. In this prospective observational study, we investigated the association between VO2, VCO2, and RER in the initial 12 and 24 h after return of spontaneous circulation (ROSC) and survival to hospital discharge. Methods: Adults with ROSC after cardiac arrest, admitted to the intensive care unit, requiring mechanical ventilation and treated with targeted temperature management were included. VO2 and VCO2 were measured continuously for 24 h after ROSC, using a noninvasive anesthesia monitor. Area under the curve for VO2, VCO2 & RER was calculated using all available values over 12 and 24 h after ROSC. Using logistic regression, we evaluated the relationship between these metabolic variables and survival to hospital discharge. Analyses were adjusted for temperature, vasopressors, and neuromuscular blockade. Results: Sixty four patients were included. Mean age was 64 ± 16 years, and 59% were women. There was no significant association between the area under the curve of VO2 or VCO2 and survival. A higher RER in the initial 12 h was associated with better survival (aOR = 3.97, 95% CI [1.01,15.6], p = 0.048). Survival was lower in those with median RER < 0.7 in the initial 12 h compared with those with a median RER ≥ 0.7 (25% vs 67%, p = 0.011). Conclusion: Higher RER in the initial 12 h was associated with survival after cardiac arrest. The etiology of unusually low RERs in this patient population remains unclear.

Thiamine as adjunctive therapy for diabetic ketoacidosis (DKAT) trial protocol and statistical analysis plan: a prospective, single-centre, double-blind, randomised, placebo-controlled clinical trial in the USA.

INTRODUCTION: Diabetic ketoacidosis (DKA) is a potentially life-threatening diabetic complication. Despite the high prevalence of DKA and the substantial associated healthcare burden, limited research on strategies to improve outcomes currently exists.Thiamine (vitamin B1) is a cofactor of pyruvate dehydrogenase, which plays a key role in aerobic glucose metabolism. Thiamine deficiency is common in patients with DKA, resulting in a shift to anaerobic metabolism and hyperlactatemia, which can prolong and complicate recovery. Therefore, we hypothesise that thiamine administration will improve aerobic metabolism and lead to faster resolution of acidemia in patients with DKA. METHODS AND ANALYSIS: In this single centre, double-blind, randomised, placebo-controlled, parallel group interventional trial, 100 patients admitted to the hospital with DKA will be randomised to receive either intravenous thiamine (200 mg in 50 mL 0.9% saline) or placebo (0.9% saline identical in appearance and volume) two times per day for 2 days. The primary outcome will be the change in bicarbonate level over 24 hours as compared between the two treatment groups. Additional secondary outcomes include the change over time in anion gap, lactate levels, oxygen consumption by circulating mononuclear cells, intensive care unit and hospital length-of-stay and hospital resource usage when comparing the two study arms. ETHICS AND DISSEMINATION: This trial was approved by the Committee on Clinical Investigations, the institutional review board of Beth Israel Deaconess Medical Center (protocol number 2018P000475). Findings will be disseminated through peer-reviewed publications and professional conference presentations. TRIAL REGISTRATION NUMBER: NCT03717896; clinicaltrials.gov.

Effects of Exercise Testing and Cardiac Rehabilitation in Patients with Coronary Heart Disease on Fear and Self-Efficacy of Exercise: A Pilot Study.

BACKGROUND: Exercise fear and low exercise self-efficacy are common in patients attending cardiac rehabilitation (CR). This study tested whether exercise prescription methods influence exercise fear and exercise self-efficacy. We hypothesized that the use of graded exercise testing (GXT) with a target heart rate range exercise prescription, relative to standard exercise prescription using rating of perceived exertion (RPE), would produce greater reductions in exercise fear and increase self-efficacy during CR. METHOD: Patients in CR (N = 32) were randomized to an exercise prescription using either RPE or a target heart rate range. Exercise fear and self-efficacy were assessed with questionnaires at three time points: baseline; after the GXT in target heart rate range group; and at session 6 for the RPE group and CR completion. Items were scored on a five-point Likert-type scale with higher mean scores reflecting higher fear of exercise and higher self-efficacy. To analyze mean differences, a mixed effects analysis was run. RESULTS: There were no significant changes in exercise self-efficacy between baseline and discharge from CR; these were not statistically significant (mean differences baseline - 0.63; end - 0.27 (p = 0.13)). Similarly, there was no change in fear between groups (baseline 0.30; end 0.51 (p = 0.37)). CONCLUSION: Patients in the RPE and target heart rate groups had non-significant changes in exercise self-efficacy over the course of CR. Contrary to our hypothesis, the use of GXT and target heart rate range did not reduce fear, and we noted sustained or increases in fear of exercise among patients with elevated baseline fear. A more targeted psychological intervention seems warranted to reduce exercise fear and self-efficacy in CR.

Semi-supervised exercise training program more effective for individuals with postural orthostatic tachycardia syndrome in randomized controlled trial.

PURPOSE: Exercise like any medication requires the correct dose; to be effective the appropriate frequency, duration, and intensity are necessary. This study aimed to assess if a semi-supervised exercise training (ET) program would be more effective at improving aerobic fitness (VO2PEAK), exercise tolerance, and symptoms in individuals with postural orthostatic tachycardia syndrome (POTS) compared to the standard of care (SOC). METHODS: Subjects were randomized to either the ET or SOC groups (n 26 vs. 23; age 33 ± 11 vs. 37 ± 10 years; VO2PEAK 66 ± 15 vs. 62 ± 15% predicted, ET vs. SOC respectively, p > 0.05). Composite Autonomic Symptom Score (COMPASS 31), 10 min stand test, and cardiopulmonary exercise test were performed at baseline and following 12 weeks. The ET group received an exercise consultation and eight semi-supervised in-person or virtual exercise sessions. RESULTS: The ET group demonstrated a greater improvement in VO2PEAK, higher or longer tolerance for baseline peak workload, and more often had a delayed symptom onset with exercise than the SOC group (ΔVO2PEAK 3.4 vs. - 0.2 mL/min/kg, p < 0.0001, ΔWorkload 19 ± 17 vs. 0 ± 10 W; Workload time 63 ± 29 vs. 22 ± 30 s; onset-delay 80% vs. 30%, p < 0.05). Individuals in the ET group reported a significant improvement in orthostatic intolerance domain score (p = 0.02), but there was not a significant difference in the improvement in total COMPASS score (- 11.38 vs. - 6.49, p = 0.09). CONCLUSION: Exercise training was more effective with greater improvements in aerobic fitness, orthostatic symptoms, and exercise tolerance for individuals with POTS when intensity and progression were personalized and delivered with minimal supervision compared to the SOC.

Comparison of Ratings of Perceived Exertion and Target Heart Rate-Based Exercise Prescription in Cardiac Rehabilitation: A RANDOMIZED CONTROLLED PILOT STUDY.

PURPOSE: Although ratings of perceived exertion (RPE) are widely used to guide exercise intensity in cardiac rehabilitation (CR), it is unclear whether target heart rate ranges (THRRs) can be implemented in CR programs that predominantly use RPE and what impact this has on changes in exercise capacity. METHODS: We conducted a three-group pilot randomized control trial (#NCT03925493) comparing RPE of 3-4 on the 10-point modified Borg scale, 60-80% of heart rate reserve (HRR) with heart rate (HR) monitored by telemetry, or 60-80% of HRR with a personal HR monitor (HRM) for high-fidelity adherence to THRR. Primary outcomes were protocol fidelity and feasibility. Secondary outcomes included exercise HR, RPE, and changes in functional exercise capacity. RESULTS: Of 48 participants randomized, four patients dropped out, 20 stopped prematurely (COVID-19 pandemic), and 24 completed the protocol. Adherence to THRR was high regardless of HRM, and patients attended a median (IQR) of 33 (23, 36) sessions with no difference between groups. After randomization, HR increased by 1 ± 6, 6 ± 5, and 10 ± 9 bpm ( P = .02); RPE (average score 3.0 ± 0.05) was unchanged, and functional exercise capacity increased by 1.0 ± 1.0, 1.9 ± 1.5, 2.0 ± 1.3 workload METs (effect size between groups, ηp2 = 0.11, P = .20) for the RPE, THRR, and THRR + HRM groups, respectively. CONCLUSIONS: We successfully implemented THRR in an all-RPE CR program without needing an HRM. Patients randomized to THRR had higher exercise HR but similar RPE ratings. The THRR may be preferable to RPE in CR populations for cardiorespiratory fitness gains, but this needs confirmation in an adequately powered trial.

Exercise Prescription Methods and Attitudes in Cardiac Rehabilitation: A NATIONAL SURVEY.

PURPOSE: High-quality exercise training improves outcomes in cardiac rehabilitation (CR), but little is known about how most programs prescribe exercise. Thus, the aim was to describe how current CR programs prescribe exercise. METHODS: We conducted a 33-item anonymous survey of CR program directors registered with the American Association of Cardiovascular and Pulmonary Rehabilitation. We assessed the time, mode, and intensity of exercise prescribed, as well as attitudes about maximal exercise testing and exercise prescription. Results were summarized using descriptive statistics. Open-ended responses were coded and quantitated thematically. RESULTS: Of 1470 program directors, 246 (16.7%) completed the survey. In a typical session of CR, a median of 5, 35, 10, and 5 min was spent on warm-up, aerobic exercise, resistance training, and cooldown, respectively. The primary aerobic modality was the treadmill (55%) or seated dual-action step machine (40%). Maximal exercise testing and high-intensity interval training (HIIT) were infrequently reported (17 and 8% of patients, respectively). The most common method to prescribe exercise intensity was ratings of perceived exertion followed by resting heart rate +20-30 bpm, although 55 unique formulas for establishing a target heart rate or range (THRR) were reported. Moreover, variation in exercise prescription between staff members in the same program was reported in 40% of programs. Program directors reported both strongly favorable and unfavorable opinions toward maximal exercise testing, HIIT, and use of THRR. CONCLUSIONS: Cardiac rehabilitation program directors reported generally consistent exercise time and modes, but widely divergent methods and opinions toward prescribing exercise intensity. Our results suggest a need to better study and standardize exercise intensity in CR.

Model-based impact and cost-effectiveness of cervical cancer prevention in sub-Saharan Africa.

Using population and epidemiologic data for 48 countries in sub-Saharan Africa, we used a model-based approach to estimate cervical cancer cases and deaths averted, disability-adjusted life years (DALYs) averted and incremental cost-effectiveness ratios (I$ (international dollar) per DALY averted) for human papillomavirus (HPV) vaccination of pre-adolescent girls. Additional epidemiologic data from Uganda and South Africa informed estimates of cancer risk reduction and cost-effectiveness ratios associated with pre-adolescent female vaccination followed by screening of women over age 30. Assuming 70% vaccination coverage, over 670,000 cervical cancer cases would be prevented among women in five consecutive birth cohorts vaccinated as young adolescents; over 90% of cases averted were projected to occur in countries eligible for GAVI Alliance support. There were large variations in health benefits across countries attributable to differential cancer rates, population size, and population age structure. More than half of DALYs averted in sub-Saharan Africa were in Nigeria, Tanzania, Uganda, the Democratic Republic of the Congo, Ethiopia, and Mozambique. When the cost per vaccinated girl was I$5 ($0.55 per dose), HPV vaccination was cost-saving in 38 sub-Saharan African countries, and cost I$300 per DALY averted or less in the remaining countries. At this vaccine price, pre-adolescent HPV vaccination followed by screening three times per lifetime in adulthood cost I$300 per year of life saved (YLS) in Uganda (per capita GDP I$1,140) and I$1,000 per YLS in South Africa (per capita GDP I$9,480). In nearly all countries assessed, HPV vaccination of pre-adolescent girls could be very cost-effective if the cost per vaccinated girl is less than I$25-I$50, reflecting a vaccine price being offered to the GAVI Alliance. In-country decision makers will need to consider many other factors, such as affordability, acceptability, feasibility, and competing health priorities, when making decisions about cervical cancer prevention. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Sub-Saharan Africa Region" Vaccine Volume 31, Supplement 5, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

Model-based impact and cost-effectiveness of cervical cancer prevention in the Extended Middle East and North Africa (EMENA).

To date, no studies have evaluated the cost-effectiveness of human papillomavirus (HPV) vaccination in countries in the Extended Middle East and North Africa (EMENA) region. We synthesized population and epidemiologic data for 20 EMENA countries using a model-based approach to estimate averted cervical cancer cases and deaths, disability-adjusted life years (DALYs) and cost-effectiveness ratios (I$ [international dollars] per DALY averted) associated with HPV vaccination of pre-adolescent girls. We utilized additional epidemiologic data from Algeria, Lebanon, and Turkey to evaluate select cervical cancer screening strategies either alone or in combination with vaccination. Results showed that pre-adolescent vaccination of five consecutive birth cohorts at 70% coverage has the potential to prevent over 180,000 cervical cancer cases. Cases averted varied by country, largely due to differences in cancer burden and population size; 69% of cases averted occurred in the three GAVI-eligible countries in EMENA. Despite the low cervical cancer incidence in EMENA, we found that HPV vaccination was cost-effective using a threshold of each country's gross domestic product per capita (a common metric for evaluating cost-effectiveness) in all but five countries at a cost per vaccinated girl of I$25 ($5 per dose). However, cost-effectiveness diminished with increasing vaccine cost; at a cost of I$200 per vaccinated girl, HPV vaccination was cost-effective in only five countries. When the cost per vaccinated girl exceeded I$50 in Lebanon and Turkey and I$150 in Algeria, screening alone was most attractive. We identified opportunities to improve upon current national screening guidelines, involving less frequent screening every 3-5 years. While pre-adolescent HPV vaccination promises to be a cost-effective strategy in most EMENA countries at low costs, decision makers will need to consider many other factors, such as affordability, acceptability, feasibility, and competing health priorities, when making decisions about cervical cancer prevention. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Extended Middle East and North Africa Region" Vaccine Volume 31, Supplement 6, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

Health and economic impact of human papillomavirus 16 and 18 vaccination of preadolescent girls and cervical cancer screening of adult women in Peru / Repercusiones sanitarias y económicas de la vacunación de niñas preadolescentes contra los tipos 16 y 18 del virus del papiloma humano y el tamizaje del cáncer cervicouterino en las mujeres adultas en el Perú

OBJECTIVE: To estimate the benefits, cost-effectiveness (i.e., value for money), and required financial costs (e.g., affordability) of adding human papillomavirus (HPV) vaccination to Peru's cervical cancer screening program. METHODS: Evidence (e.g., coverage, delivery costs) from an HPV vaccination demonstration project conducted in Peru was combined with epidemiological data in an empirically calibrated mathematical model to assess screening (HPV DNA testing three to five times per lifetime) and HPV vaccination under different cost, coverage, and efficacy assumptions. Model outcomes included lifetime risk of cancer reduction, cancer cases averted, lives saved, average life expectancy gains, short-term financial costs, and discounted long-term economic costs. RESULTS: Status quo low levels of screening (e.g., cytologic screening at 10.0% coverage) reduced lifetime risk of cervical cancer by 11.9%, compared to not screening. Adding vaccination of preadolescent girls at a coverage achieved in the demonstration program (82.0%) produced an additional 46.1% reduction, and would cost less than US$ 500 per year of life saved (YLS) at ~US$ 7/dose or ~US$ 1 300 at ~US$ 20/dose. One year of vaccination was estimated to cost ~US$ 5 million at ~US$ 5/dose or ~US$ 16 million at ~US$ 20/dose, including programmatic costs. Enhanced screening in adult women combined with preadolescent vaccination had incremental cost-effectiveness ratios lower than Peru's 2005 per capita gross domestic product (GDP; US$ 2 852, in 2009 US$), and would be considered cost-effective. CONCLUSIONS: Preadolescent HPV vaccination, followed by enhanced HPV DNA screening in adult women, could prevent two out of three cervical cancer deaths. Several strategies would be considered "good value" for resources invested, provided vaccine prices are low. While financial costs imply substantial immediate investments, the high-value payoff should motivate creative mechanisms for financing and scale-up of delivery programs.

OBJETIVO: Calcular los beneficios, la rentabilidad (relación costo-efectividad), y los costos financieros (asequibilidad) de añadir la vacunación contra el virus del papiloma humano (VPH) al programa de tamizaje del cáncer cervicouterino en el Perú. MÉTODOS: Se combinaron los datos probatorios (por ejemplo, cobertura, costos de prestación) de un proyecto piloto de vacunación contra el VPH llevado a cabo en el Perú con datos epidemiológicos, en un modelo matemático calibrado empíricamente para evaluar el tamizaje (prueba de ADN del VPH tres a cinco veces durante toda la vida) y la vacunación contra el VPH, según diferentes supuestos de costo, cobertura y eficacia. Los resultados del modelo incluían la reducción del riesgo de cáncer durante toda la vida, los casos de cáncer evitados, las vidas salvadas, los incrementos de la esperanza media de vida, los costos financieros a corto plazo y los costos económicos a largo plazo actualizados. RESULTADOS: Los bajos niveles de tamizaje actuales (cobertura del tamizaje citológico de 10,0 %) redujeron en 11,9 % el riesgo de cáncer cervicouterino durante toda la vida en comparación con la ausencia de tamizaje. La adición de la vacunación de las niñas preadolescentes con la cobertura alcanzada en el programa piloto (82,0 %) produjo una reducción adicional de 46,1 % y costaría menos de US$ 500 por cada año de vida salvado a US$ 7 la dosis, o de US$ 1 300 a US$ 20 la dosis. Se calculó que el costo de las vacunaciones de un año era aproximadamente de US$ 5 millones a unos US$ 5 la dosis o de aproximadamente US$ 16 millones a unos US$ 20 la dosis, incluidos los costos programáticos. La mejora del tamizaje en las mujeres adultas combinada con la vacunación de las preadolescentes mostraba cocientes de rentabilidad incremental inferiores al producto interno bruto per cápita del Perú en el año 2005 (PIB US$ 2 852, en dólares del 2009), y se consideraría rentable. CONCLUSIONES: La vacunación de las preadolescentes contra el VPH, junto con la mejora del tamizaje mediante la prueba de ADN del VPH en las mujeres adultas, podría prevenir dos de cada tres muertes debidas a cáncer cervicouterino. Varias estrategias se considerarían rentables en relación con los recursos invertidos, a condición de que el precio de la vacuna sea bajo. Aunque los costos financieros implican inversiones inmediatas sustanciales, el valor elevado de los beneficios debe motivar la elaboración de mecanismos creativos para financiar y extender los programas de prestación de servicios.

Health and economic impact of HPV 16/18 vaccination and cervical cancer screening in Eastern Africa.

Eastern Africa has the world's highest cervical cancer incidence and mortality rates. We used epidemiologic data from Kenya, Mozambique, Tanzania, Uganda, and Zimbabwe to develop models of HPV-related infection and disease. For each country, we assessed HPV vaccination of girls before age 12 followed by screening with HPV DNA testing once, twice, or three times per lifetime (at ages 35, 40, 45). For women over age 30, we assessed only screening (with HPV DNA testing up to three times per lifetime or VIA at age 35). Assuming no waning immunity, mean reduction in lifetime cancer risk associated with vaccination ranged from 36 to 45%, and vaccination followed by screening once per lifetime at age 35 with HPV DNA testing ranged from 43 to 51%. For both younger and older women, the most effective screening strategy was HPV DNA testing three times per lifetime. Provided the cost per vaccinated girl was less than I$10 (I$2 per dose), vaccination had an incremental cost-effectiveness ratio [I$ (international dollars)/year of life saved (YLS)] less than the country-specific per capita GDP, a commonly cited heuristic for "very cost-effective" interventions. If the cost per vaccinated girl was between I$10 (I$2 per dose) and I$25 (I$5 per dose), vaccination followed by HPV DNA testing would save the most lives and would be considered good value for public health dollars. These results should be used to catalyze design and evaluation of HPV vaccine delivery and screening programs, and contribute to a dialogue on financing HPV vaccination in poor countries.

Health and economic impact of human papillomavirus 16 and 18 vaccination of preadolescent girls and cervical cancer screening of adult women in Peru.

OBJECTIVE: To estimate the benefits, cost-effectiveness (i.e., value for money), and required financial costs (e.g., affordability) of adding human papillomavirus (HPV) vaccination to Peru's cervical cancer screening program. METHODS: Evidence (e.g., coverage, delivery costs) from an HPV vaccination demonstration project conducted in Peru was combined with epidemiological data in an empirically calibrated mathematical model to assess screening (HPV DNA testing three to five times per lifetime) and HPV vaccination under different cost, coverage, and efficacy assumptions. Model outcomes included lifetime risk of cancer reduction, cancer cases averted, lives saved, average life expectancy gains, short-term financial costs, and discounted long-term economic costs. RESULTS: Status quo low levels of screening (e.g., cytologic screening at 10.0% coverage) reduced lifetime risk of cervical cancer by 11.9%, compared to not screening. Adding vaccination of preadolescent girls at a coverage achieved in the demonstration program (82.0%) produced an additional 46.1% reduction, and would cost less than US$ 500 per year of life saved (YLS) at ~US$ 7/dose or ~US$ 1 300 at ~US$ 20/dose. One year of vaccination was estimated to cost ~US$ 5 million at ~US$ 5/dose or ~US$ 16 million at ~US$ 20/dose, including programmatic costs. Enhanced screening in adult women combined with preadolescent vaccination had incremental cost-effectiveness ratios lower than Peru's 2005 per capita gross domestic product (GDP; US$ 2 852, in 2009 US$), and would be considered cost-effective. CONCLUSIONS: Preadolescent HPV vaccination, followed by enhanced HPV DNA screening in adult women, could prevent two out of three cervical cancer deaths. Several strategies would be considered "good value" for resources invested, provided vaccine prices are low. While financial costs imply substantial immediate investments, the high-value payoff should motivate creative mechanisms for financing and scale-up of delivery programs.

Cost-effectiveness of human papillomavirus vaccination and screening in Spain.

BACKGROUND: In Spain, prophylactic vaccination against human papillomavirus (HPV) types 16 and 18 is being offered free-of-charge to one birth cohort of girls aged 11-14. Screening is opportunistic (annual/biannual) contributing to social and geographical disparities. METHODS: A multi-HPV-type microsimulation model was calibrated to epidemiologic data from Spain utilising likelihood-based methods to assess the health and economic impact of adding HPV vaccination to cervical cancer screening. Strategies included (1) screening alone of women over age 25, varying frequency (every 1-5 years) and test (cytology, HPV DNA testing); (2) HPV vaccination of 11-year-old girls combined with screening. Outcomes included lifetime cancer risk, life expectancy, lifetime costs, number of clinical procedures and incremental cost-effectiveness ratios. RESULTS: After the introduction of HPV vaccination, screening will need to continue, and strategies that incorporated HPV testing are more effective and cost-effective than those with cytology alone. For vaccinated girls, 5-year organised cytology with HPV testing as triage from ages 30 to 65 costs 24,350€ per year of life saved (YLS), assuming life-long vaccine immunity against HPV-16/18 by 3 doses with 90% coverage. Unvaccinated girls would benefit from organised cytology screening with HPV testing as triage; 5-year screening from ages 30 to 65 costs 16,060€/YLS and 4-year screening from ages 30 to 85 costs 38,250€/YLS. Interventions would be cost-effective depending on the cost-effectiveness threshold and the vaccine price. CONCLUSIONS: In Spain, inequitable coverage and overuse of cytology make screening programmes inefficient. If high vaccination coverage among pre-adolescent girls is achieved, organised cytology screening with HPV triage starting at ages 30 to at least 65 every 4-5 years represents the best balance between costs and benefits.

Cost-effectiveness analysis of cervical cancer prevention based on a rapid human papillomavirus screening test in a high-risk region of China.

This study assessed the cost-effectiveness of a new, rapid human papillomavirus (HPV)-DNA screening test for cervical cancer prevention in the high-risk region of Shanxi, China. Using micro-costing methods, we estimated the resources needed to implement preventive strategies using cervical cytology or HPV-DNA testing, including the Hybrid Capture 2 (hc2) test (QIAGEN Corp., Gaithersburg, MD) and the rapid HPV-DNA careHPV test (QIAGEN). Data were used in a previously published model and empirically calibrated to country-specific epidemiological data. Strategies differed by initial test, targeted age, frequency of screening, number of clinic visits required (1, 2 or 3) and service delivery setting (national, county and township levels). Outcomes included lifetime risk of cancer, years of life saved (YLS), lifetime costs and incremental cost-effectiveness ratios (cost per YLS). For all screening frequencies, the most efficient strategy used 2-visit rapid HPV-DNA testing at the county level, including screening and diagnostics in the first visit, and treatment in the second visit. Screening at ages 35, 40 and 45 reduced cancer risk by 50% among women compliant with all 3 screening rounds, and was US$ 150 per YLS, compared with this same strategy applied twice per lifetime. This would be considered very cost-effective evaluated against China's per-capita gross domestic product (US$ 1,702). By enhancing the linkage between screening and treatment through a reduced number of visits, rapid HPV-DNA testing 3 times per lifetime is more effective than traditional cytology, and is likely to be cost-effective in high-risk regions of China.

Benefits, cost requirements and cost-effectiveness of the HPV16,18 vaccine for cervical cancer prevention in developing countries: policy implications.

Approximately 70% of cases of cervical cancer worldwide are caused by genotypes 16 and 18 of human papillomavirus (HPV), which is sexually transmitted. With the availability of an effective vaccine against these HPV types, there is real hope for reducing the global burden of cervical cancer in developing countries. Stakeholders faced with decisions about where to invest money to improve health must consider the burden of disease caused by cervical cancer relative to other priorities and the comparative benefits of different interventions. We conducted a series of analyses to obtain information for agencies drafting immunisation policy recommendations, financing coordination mechanisms, and country decision-makers on the benefits, cost requirements and cost-effectiveness of the HPV16,18 vaccine. We found that making an HPV16,18 vaccine accessible to 70% of young adolescent girls in 72 of the poorest countries, China, Thailand, and all of Latin America and the Caribbean, could prevent the future deaths of more than four million women vaccinated over the next decade. Provided the cost per vaccinated girl is less than $10-$25, adolescent HPV16,18 vaccination would be cost-effective even in relatively poor countries. Concerns about financial costs and affordability highlight the need for lowering vaccine prices, cost-efficient mechanisms for delivery of vaccinations to adolescents, and creative sources of financing.

Exploring the cost-effectiveness of HPV vaccination in Vietnam: insights for evidence-based cervical cancer prevention policy.

Using mathematical models of cervical cancer for the northern and southern regions of Vietnam, we assessed the cost-effectiveness of cervical cancer prevention strategies and the tradeoffs between a national and region-based policy in Vietnam. With 70% vaccination and screening coverage, lifetime risk of cancer was reduced by 20.4-76.1% with vaccination of pre-adolescent girls and/or screening of older women. Only when the cost per vaccinated girl was low (i.e., I$100), screening alone was most cost-effective. When optimal policies differed between regions, implementing a national strategy resulted in health and economic inefficiencies. HPV vaccination appears to be an attractive cervical cancer prevention strategy for Vietnam, provided high coverage can be achieved in young pre-adolescent girls, cost per vaccinated girl is

Health and economic outcomes of HPV 16,18 vaccination in 72 GAVI-eligible countries.

The risk of dying from cervical cancer is disproportionately borne by women in developing countries. Two new vaccines are highly effective in preventing HPV 16,18 infection, responsible for approximately 70% of cervical cancer, in girls not previously infected. The GAVI Alliance (GAVI) provides technical assistance and financial support for immunization in the world's poorest countries. Using population-based and epidemiologic data for 72 GAVI-eligible countries we estimate averted cervical cancer cases and deaths, disability-adjusted years of life (DALYs) averted and incremental cost-effectiveness ratios (I$/DALY averted) associated with HPV 16,18 vaccination of young adolescent girls. In addition to vaccine coverage and efficacy, relative and absolute cancer reduction depended on underlying incidence, proportion attributable to HPV types 16 and 18, population age-structure and competing mortality. With 70% coverage, mean reduction in the lifetime risk of cancer is below 40% in some countries (e.g., Nigeria, Ghana) and above 50% in others (e.g., India, Uganda, Kenya). At I$10 per vaccinated girl (approximately $2.00 per dose assuming three doses, plus wastage, administration, program support) vaccination was cost-effective in all countries using a per capita GDP threshold; for 49 of 72 countries, the cost per DALY averted was less than I$100 and for 59 countries, it was less than I$200. Taking into account country-specific assumptions (per capita GNI, DPT3 coverage, percentage of girls who are enrolled in fifth grade) for the year of introduction, percent coverage achieved in the first year, and years to maximum coverage, a 10-year modeled scenario prevented the future deaths of approximately 2 million women vaccinated as adolescents. Despite favorable cost-effectiveness, assessment of financial costs raised concerns about affordability; as the cost per vaccinated girl was increased from I$10 to I$25 (approximately $2 to $5 per dose), the financial costs for the 10-year scenario increased from >US$ 900 million to US$ 2.25 billion. Provided high coverage of young adolescent girls is feasible, and vaccine costs are lowered, HPV 16,18 vaccination could be very cost-effective even in the poorest countries, and provide comparable value for resources to other new vaccines such as rotavirus.

Cost-effectiveness of HPV 16, 18 vaccination in Brazil.

We use an empirically calibrated model to estimate the cost-effectiveness of cervical cancer prevention in Brazil, a country with a high cervical cancer burden. Assuming 70% coverage, HPV 16, 18 vaccination of adolescent girls is expected to reduce the lifetime risk of cancer by approximately 42.7% (range, 33.2-53.5%); screening three times per lifetime is expected to reduce risk by 21.9-30.7% depending on the screening test, and a combined approach of vaccination and screening is expected to reduce cancer risk by a mean of 60.8% (range, 52.8-70.1%). In Brazil; provided the cost per vaccinated woman is less than I$ 25, implying a per dose cost of approximately I$ 5, vaccination before age 12, followed by screening three times per lifetime between ages 35 and 45, would be considered very cost-effective using the country's per capita gross domestic product as a cost-effectiveness threshold. Assuming a coverage rate of 70%, this strategy would be expected to prevent approximately 100,000 cases of invasive cervical cancer over a 5-year period. Vaccination strategies identified as cost-effective may be unaffordable in countries with similar socioeconomic profiles as Brazil without assistance; these results can provide guidance to the global community by identifying health investments of highest priority and with the greatest promise.