What have the rotavirus vaccine trials taught us

What have the rotavirus vaccine trials taught us about the epidemiology, outcomes and cost of intussusception? Barclay Stewart, MD Msc. PH

Rotavirus ✤ Reoviridae (DS RNA virus) ✤ 5 sub-species, human infection with A, B, C ✤ Rotavirus A has several serotypes, similar to influenza ✤ ✤ ✤ Glycoprotein VP 7 defines G serotypes Protease VP 4 defines P serotypes Fecal-oral transmission, replicated in intestinal epithelium ✤ Progeny release from cell by lysis

Rotavirus epidemiology ✤ Cause of 60% of diarrheal disease in children (90% of those by rotavirus A) ✤ Essentially all children under five have been infected at some point ✤ Infection begets immunity, less severe episodes after repeated infection, rarely pathologic adults ✤ Globally ✤ ✤ ✤ 2 million hospitalizations 450, 000 deaths in children under five, 85% in LMICs US ✤ 2. 7 million cases ✤ 60, 000 hospitalizations ✤ 40 deaths

Distribution of rotavirus 10 k 20 k 30 k 40 k 50 k 60 k 70 k

Rotavirus vaccines ✤ Rotashield (Wyeth), Lanzhou (LIBP), Rota. Vac (Bharat Int. /PATH), Rota. Teq (Merck) and Rotarix (GSK) ✤ ✤ Oral, attenuated live virus of various G/P serotypes and reassortments Like polio and typhoid OALV vaccines, intussusception a theoretical risk

Rotavirus and intussusception ✤ ✤ Trials in US, Venezuela, Finland consistently demonstrated a 80 100% efficacy in preventing severe rotavirus A diarrhea Rotashield licensed in 1998 in US ✤ ✤ 9 months later, 500, 000 vaccinations in 4 million of that US birth cohort had received at least one dose Passive surveillance described 15 cases of intussusception. . . October 1998 Vaccine available August 1998 Licensed in US July 1999 15 cases of IS July 1999 Vaccine suspended August 1999 98 cases of IS October 1999 Vaccine withdrawn

Rotashield and intussusception ✤ Wyeth’s pre-license RCT IS rate (no significant statistical evidence) ✤ ✤ ✤ Vaccinated: 50 per 100, 000 Controls: 20 per 100, 000 Original post-implementation trial data presented to ACIP estimated: ✤ Population-attributable risk of IS to be 1 in 2, 500 to 1 in 3, 300 ✤ ✤ ✤ RR of 21. 7 in the 3 rd to 21 st day following vaccination Equates to around 4, 600 to 9, 400 cases in US after complete implementation Corroborated by CDC and HMO cohort study Kramarz P, France EK, Destefano F, et al. : Population-based study of rotavirus vaccination and intussusception. Pediatr Infect Dis J 2001, 20: 410 -416. Simonsen L, Morens DM, Elixahauser A, et al. : Effect of rotavirus vaccination programme on trends in admission of infants to hospital for intussusception. Lancet 2001, 358: 1224 -1229.

But wait. . . ✤ Though there is an initial increase in IS after vaccination, Wyeth and the CDC found a compensatory DECREASE in IS more than 3 weeks form vaccination 1 Temporary increase ✤ OR of hospital admission ✤ ✤ Increased risk of IS <3 wks after vaccination: 4. 6 Log 10 OR 0 >3 wks after vaccination: 0. 3 Decreased risk of IS 1 Compensatory decrease Patel MM, Haber P, Baggs J, Zuber P, Bines JE, Parashar UD. Intussusception and rotavirus vaccination: a review of the available evidence. Expert Rev Vaccines 2009; 8: 1555 -1564

Vaccinated and non-vaccinated IS ✤ ✤ 3% decrease in IS over 1 year in US And - intussusception in the 19972000 birth cohort decreased from 87 per 100, 000 to 12 per 100, 000 Low rate of rotavirus in US compared to LMICs ‘Real losers are the infants in the developing world. ’ Dr Roger Glass Murphy, B. Reappraisal of the Association of Intussusception with the Licensed Live Rotavirus Vaccine Challenges Initial Conclusions. J Royal Soc of Trop Med and Hygiene. 2002.

The debate ✤ ✤ ✤ Though there is a risk of IS, this was dwarfed by the cost and death of rotavirus disease globally Vaccine trials had to enroll more than 50, 000 subjects per trial to capture risk of IS, so this wasn’t well evaluated Merck and GSK pushed on with Rotarix and Rota. Tec ✤ Intussusception was not seen in early phase trials

Early trial/implementation results ✤ Mexico first country to adopt vaccination in 2006 ✤ ✤ Nicaragua ✤ ✤ 65% reduction in diarrhea-deaths in under 5’s 40% reduction in severe infections and 50% reduction in ED visits United States ✤ Estimated 86% reduction in diarrhea-related hospitalizations

Rotarix and Rota. Teq ✤ Pooled analysis of 41 trials of 186, 263 infants ✤ HICs ✤ ✤ LMICs ✤ ✤ Prevents 86% of severe diarrhea cases (RR 0. 14, 95% CI 0. 07 to 0. 26) Prevents 63% of severe diarrhea cases (RR 0. 37, 95% CI 0. 18 to 0. 75) Intussusception (no difference than in placebo from 2 mos to 2 yrs) ✤ ✤ ✤ Rotarix: 58 cases in 97, 246 vaccinations Rota. Teq: 34 cases in 81, 459 vaccinations WHO recommended routine national use in 2009 - only 28 countries have incorporated RVV

What can we learn? ✤ Parallel trials in LMICs and HICs and extensive study in US give opportunity to describe differences in intussusception with regard to: ✤ ✤ ✤ How common is intussusception, does it vary by location or national income How often are kids able to avoid operation with radiologic reduction? What is the cost of caring for intussusception?

What have we learned? ✤ Relatively little! ✤ No standardization of intussusception definition or reporting despite it being a ‘requirement’ of rotavirus vaccine trials ✤ Data often controlled by manufacturers ✤ Very little cost data associated with monitoring

Search strategy ✤ ✤ Built to retrieve reports of intussusception and epidemiology, outcomes, cost since the first rotavirus vaccine trial end date in 1997 "Intussusception"[Mesh] AND ("Epidemiology"[Mesh] OR "Incidence"[Mesh] OR "Morbidity"[Mesh] OR "Mortality"[Mesh] OR “Cost of Illness”[Mesh] OR "Costs and Cost Analysis"[Mesh] OR (“Radiologic reduction”[Tiab] OR “Hydrostatic reduction”[Tiab] OR “Pneumatic reduction”[Tiab]) OR (“Operative”[Tiab] OR “Nonoperative”[Tiab]) OR "Outcome Assessment (Health Care)"[Mesh]) AND ("1997/01/01"[PDAT] : "2013/12/31"[PDAT])

Results of search 613 reports returned with search 76 reports gave primary epi, outcome or data 27 reports with incidence data 59 reports with outcome data 3 reports with cost data

Incidence Placebo HIC LMIC Rotarix Rota. Teq (RR; 95 CI) 55 per 100, 000 57 per 100, 000 37 per 100, 000 (0. 87; 0. 52 to 1. 46) (0. 67; 0. 34 to 1. 31) 66 per 100, 000 None reported in 27 per 100, 000 3, 294 infants from 2 (1. 49; 0. 06 to 36. 6) trials

Results of search 613 reports returned with search 76 reports gave primary epi, outcome or data 27 reports with incidence data 59 reports with outcome data 3 reports with cost data

Unfortunately. . . ✤ Significant heterogeneity in inclusion and exclusion, i. e. : ✤ ✤ ✤ Infants receiving other study vaccines (pneumococcal) Infants receiving concomitant oral poliovirus vaccine Surveillance different across studies and countries within WHO Regions ✤ May be significant variation within smaller locales, socioeconomic groups, etc. ✤ Not all trials powered to detect intussusception ✤ Some trials stopped early

Incidence post-RV trials Author Location Incidence Bissantz Buettcher Eng Espuny Gay Greenberg Jo Lloyd-Johnsen Nakagomi Nelson Nogochi Parashar Reijnen Takeuchi Tan Webby Weilb Germany Switzerland USA Spain UK Israel South Korea Australia Japan Hong Kong Japan USA Netherlands Japan Singapore Australia Germany 27 38 33 8 120 200 236 27 185 89 158 37 110 190 29 65 16 92 62 Mean 91 Low- and Middle-Income Countries Author Bahl Bines Carneiro Chen Chouikha Edino Giak Khumjul Location Incidence India Vietnam Tanzania Taiwan Tunisia Niger Malaysia Thailanad 41 302 68 77 62 74 18 11 Incidence (per 100, 000) High-Income Countries 82 HICs LMICs

US incidence Characteristic n Incidence (per 100, 000) RR (95% CI) 3, 463 33. 6 -     Male 2, 097 39. 8 1. 5 (1. 4– 1. 6)     Female 1, 366 27. 1 Reference     White, non-Hispanic 799 27. 0 Reference     Black, non-Hispanic 356 37. 0 1. 4 (1. 2– 1. 6)     Hispanic 881 45. 4 1. 7 (1. 5– 1. 9) 73 20. 1 0. 7 (0. 6– 1. 0) 43 4. 3 Reference     6– 14 207 11. 6 2. 7 (1. 9– 3. 7)     15– 24 795 40. 1 9. 2 (6. 8– 12. 6)     25– 32 860 54. 3 12. 5 (9. 2– 17. 0)     33– 52 1, 557 39. 3 9. 1 (6. 7– 12. 3)     Northeast 562 36. 0 1. 3 (1. 2– 1. 5)     Midwest 623 26. 7 Reference     South 1, 264 34. 4 1. 3 (1. 2– 1. 4)     West 1, 014 37. 2 1. 4 (1. 3– 1. 5) Total Gender Ethnicity     Asian or Pacific Islander     Other 202 Age groups, wk     1– 5 Region of country PNW? ? Tate, J. Trends in Intussusception Hospitalizations Among US Infants, 1993– 2004: Implications for Monitoring the Safety of the New Rotavirus Vaccination Program. University of Washington. Pediatrics. 2007

US incidence Tate, J. Trends in Intussusception Hospitalizations Among US Infants, 1993– 2004: Implications for Monitoring the Safety of the New Rotavirus Vaccination Program. University of Washington. Pediatrics. 2007

US incidence Tate, J. Trends in Intussusception Hospitalizations Among US Infants, 1993– 2004: Implications for Monitoring the Safety of the New Rotavirus Vaccination Program. University of Washington. Pediatrics. 2007

US incidence Tate, J. Trends in Intussusception Hospitalizations Among US Infants, 1993– 2004: Implications for Monitoring the Safety of the New Rotavirus Vaccination Program. University of Washington. Pediatrics. 2007

IS in Africa ✤ Data from 10 African countries Steele, D. Workshop on intussusception in African countries – Meeting report. Vaccine. 2012

IS in India Bhowmick, K. Retrospective Surveillance for Intussusception in Children Aged Less than Five Years in a South Indian Tertiary-care Hospital. J Health Pop Nut. 2009.

IS in Singapore Boudville, I. The Epidemiology of Paediatric Intussusception in Singapore: 1997 to 2004. Ann Acad Med Singapore 2006; 35: 674 -9

IS in Thailand Khumjul, C. Incidence of intussusception among children 0– 5 years of age in Thailand, 2001– 2006. Vaccine. 2009.

IS in Germany Khol, L. Intussusception-associated hospitalisations in Southern Germany. Eur J Ped. 2010

IS in Japan Nakagomi, T. A high incidence of intussusception in Japan as studied in a sentinel hospital over a 25 -year period (1978 -2002). 2008.

IS in Israel Greenberg, D. Intussusception in Children in Southern Israel: Disparity between 2 Populations. Ped Inf Dis. 2008

IS in Chile O’Ryan, M. Two year review of intestinal intussusception in six large public hospitals of Santiago, Chile. Ped Inf Dis J. 2003.

IS in Denmark Fischer, T. Intussusception in Early Childhood: A Cohort Study of 1. 7 Million Children. 2004.

Results of search 613 reports returned with search 76 reports gave primary epi, outcome or data 27 reports with incidence data 59 reports with outcome data 3 reports with cost data

Outcomes globally Radiologic reduction (%) Mortality (%) HICs 27 - 88 <1 LMICs 0 - 75 8 - 25 Data extracted from the reports that described radiologic reduction and/or mortality from the systematic search strategy

Outcomes in US Jen, H. The impact of hospital type and experience on the operative utilization in pediatric intussusception: a nationwide study. J Ped Surg. 2009

Hospital type and experience matters in US Children's hospitals 748 (61) n (%) Length of stay [IQR] Total charge [IQR] Non–children's hospitals 473 (39) 2 [1, 4] 3 [2, 4] p-value <0. 005 $8, 007 [$4, 185, $13, 937] $8, 969 [$4, 781, $14, 511] Complications (%) 37 (5. 0) 27 (5. 7) Mortality (%) 3 (0. 4) 0 (0. 0) Radiologic reduction 292 (39%) 121 (26%) Radiologic reduction failures requiring surgery 45 (6. 0%) 30 (6. 3%) Immediate operations 411 (55%) 322 (68%) Treatment <0. 001 Jen, H. The impact of hospital type and experience on the operative utilization in pediatric intussusception: a nationwide study. J Ped Surg. 2009

Outcomes from Africa n (%) Contrast enema 96 (10) Ultrasound 114 (11) Surgery 689 (69) Unknown 90 (9) Treatment Air/contrast reduction Surgical reduction or resection Spontaneous/unknown 56 (6) 899 (90) 45 (5) Steele, D. Workshop on intussusception in African countries – Meeting report. Vaccine. 2012

Bowel resection risk in US Risk factor Odds ratio 95% CI p-value Pediatric hospital 0. 20 0. 10– 0. 41 <0. 001 Age >4 y 1. 67 0. 80– 3. 49 0. 176 Female 0. 93 0. 51– 1. 67 0. 796 Medicaid primary 1. 61 0. 92– 2. 82 0. 093 Severe disease 21. 23 9. 01– 50. 01 <0. 001 Transfer from another facility 1. 71 0. 68– 4. 30 0. 253 Coexisting condition 4. 83 2. 27– 10. 30 <0. 001 Chronic comorbidity 2. 39 0. 74– 7. 72 0. 145 Mc. Ateer, J. Pediatric Specialist Care Is Associated with a Lower Risk of Bowel Resection in Children with Intussusception: A Population-Based Analysis. J ACS. Aug 2013.

Results of search 613 reports returned with search 76 reports gave primary epi, outcome or data 27 reports with incidence data 59 reports with outcome data 3 reports with cost data

Cost in US with diagnostic approach Outcomes CE US/c. CE Male 209 129 Female 157 98 Perforation (per 100, 000) 760 471 Laparotomy (per 100, 000) 25, 173 24, 488 Male 11, 044 11, 649 Female 11, 008 11, 626 Male 77. 8 Female 77. 8 Radiation-induced malignancy (per 100, 000) Cost (2008 US dollars) Effectiveness (QALYs) Bucher, T. Intussusception in children: cost-effectiveness of ultrasound vs diagnostic contrast enema. J Ped Surg. 2011

Cost in US Hospital costs (USD) Total charges (USD) Median IQR All children 2, 865 933 - 11, 043 7, 110 1, 811 - 31, 950 Non-operatively managed 2, 490 455 - 7, 618 6, 350 1, 431 - 12, 192 Rice-Townsend, S. Variation in practice patterns and resource utilization surrounding management of intussusception at freestanding Children's Hospitals. J Ped Surg. 2013

Cost in Taiwan % Median age (months) Length of stay; Hospital charges days (% increase) USD (% increase) 24 Sex Male 61 Female 39 Treatment Non-operatively managed 69 2. 4 (ref) 185 (ref) Operatively managed 31 6. 2 (258) 1, 243 (672) Ho, WL. Intussusception in Taiwanese children: analysis of incidence, length of hospitalization and hospital costs in different age groups. J Formos Med Assoc. 2005

Conclusions ✤ ✤ Rotarix and Rota. Teq are associated with a TEMPORARY INCREASE in IS after vaccination and a SUSTAINED DECREASE in IS through childhood Rotavirus is more common in LMICs, IS is not necessarily more common ✤ ✤ ✤ Vaccines less efficacious in LMICs, though absolute reduction greater than in HICs Vaccines seem to decrease IS more in LMICs Globally ✤ ✤ Median age seems to be different in US than rest of published studies ✤ Ultrasound widely used and accurate for diagnosis ✤ LMICs don’t have resources to perform radiologic reduction, operative rates much high ✤ ✤ More common in males LMICs have higher mortality rates Essentially no cost data available for estimating IS impact on health system (or change with wide-spread vaccination)

Post-vaccination O/P Murphy, B. Reappraisal of the Association of Intussusception with the Licensed Live Rotavirus Vaccine Challenges Initial Conclusions. J Royal Soc of Trop Med and Hygiene. 2002.

Ultrasound works in many places Sensitivity Specificity France 100 China 100 - Taiwan 100 - Canada 100 88 Korea 100 USA 100 93 Netherlands 98. 5 100 Australia 100 95 Vietnam 97. 5 99 Data extracted from studies presenting the diagnostic accuracy of ultrasound for IS