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University of Science and Technology Beijing

Modern Tools to Understand the Epidemiology of Infectious Diseases. Lequan Min. University of Science and Technology Beijing. Outline. 1. Introduction. 2. Viral Infection/ Anti-Viral Infection Therapy/ Epidemic Spreading. 3. Modeling Viral Infection /Anti-Viral

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University of Science and Technology Beijing

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  1. Modern Tools to Understand the Epidemiology of Infectious Diseases Lequan Min University of Science and Technology Beijing

  2. Outline 1. Introduction 2. Viral Infection/ Anti-Viral Infection Therapy/ Epidemic Spreading 3. Modeling Viral Infection/Anti-Viral Infection Therapy/ Epidemic Spreading 4. Concluding Remarks

  3. Acknowledgements: Manythanks my colleagues Asoci. Prof. Yongmei Su at USTB, Pro. Yang Kuang at the Arizona State Univ., and my students Dr. Yu Zheng, Dr. Xiao Chen, Dr. Qun Zhang, Qilin Su, Quian Huang, Yao Hu and Pengfei Zhang for their very valuable co-operations, and Dr. Stefan F. Wieland at the Scripps Research Institute US for kindly providing the data for seven chimpanzees. This work is jointly supported by the 11TH 5- Year Plan Key Research Project of China (No.2008ZX10005-006) , and the NNSF of China (Nos. 61074192).

  4. 1. Introduction ● Virus infection and Epidemic Spreadingare major global health problems. ● Various viruses can infect almost any type of body tissues from brain to skin. ● Viral infections cannot be treated with antibiotics. In some cases the use of antibiotics makes the infection worse. Source:http//www.medterms.com/script/main/ art.asp?articlekey=11557

  5. 1. Introduction ●Two major viruses infected people in the world: ● 1966, B. S. Blumberg: Hepatitis B virus (HBV). ● 1983, F. Barré-Sinoussi and L. Montagnier Human immunodeficiency virus (HIV).

  6. HBV Structure & Antigens Dane particle A simpleied drawing of HBV particle and surface antigen

  7. HIV

  8. 1. Introduction herpes zoster virus infection chest-wall virus infection Varicella zoster Virus infection • Against SARS Over 5 hundred kind viruses are able to infect Human Beings .

  9. Why are there unknown reason infections? • Why do some virus infected people have recovered without therapy? • Why do some people appear very sensitive to viruses and become persistent infections? • Why do some anti-HBV/HIV infection therapy patients’ serum viruses have relapsed , and become worse after stopping treatments ?

  10. Whydo wild animals without any prevention have hardly become extinct by attacks of various infectious diseases? • Why do domestic animals more easily die by attacks of infectious diseases? • Why did Influenza during 1918-1919 killed nearly 50 million people, and no similar cases appear now day? • This talk will give some interpretations with some clinic/experimental evidences by modelling dynamics of viral infection and anti-viral infection therapy/epidemic spreading, and not going to address conclusive statements.

  11. 2.1 Epidemic Spreads • Black Death resulted in the deaths of an estimated 75 to 200 millionpeople during 1346-1353, killed 30–60% of Europe's total population. • Influenza pandemic during 1918-1919killed nearly 50 million people worldwide. • SARSpandemic in 2003. WHO: cumulative SARS cases worldwide total of 8,422. Death total of 919.

  12. HEPATITIS B : EPIDEMIOLOGY Prevalence of Chronic HBV Infection, Worldwide • Over 400 million people have chronic HBV infections • More Source: CDC and Prevention. MMWR 2008;57(RR-8):1-20.

  13. 2.2 HBV Infection and Anti-HBV Infection Therapy • 全球超过20亿的人曾感染过乙肝病毒。2 billion people have been infected with the hepatitis B virus (HBV) . • 超过2.4亿的人为慢性(终生)乙肝感染者。 More than 240 million have chronic (lifelong) HBV infections. • 每年有超过78万的人死于急慢性乙型肝炎。More than 780 000 people die every year due to the acute or chronic consequences of hepatitis B. • 慢性乙肝患者可以通过有效的治疗避免死亡。 Effective treatment of chronic HBV infection patient can aim to prevent the death from HBV disease. Source: WHO, Hepatitis B， 2014, (http://www.who.int)

  14. Approved HBV treatments Interferon: • Interferon alfa-2b – 1991 • Peginterferon alfa-2a (Peg-INF)– 2005 Nucleoside Analogues (NA): • Lamivudine (LAM)– 1998 • Adefovir (ADV)– 2002 • Entecavir – 2005 • Telbivudine (LTD)– 2006 • Tenofovir (TDF) – 2008

  15. 资料来源: EASL Guidelines 2009/ 1年疗效统计 Source: EASL Guidelines 2009/ outcomes for one YEAR’s therapy

  16. Antiviral resistance increases over time 80 60 40% 40 Incidence of resistance (%) 25% 24% 20 18% 12% 11% 5% 2% 0.4% 0.8% 0.1% 0% 0.3% 0 Resistance to NAs…is it just a matter of time?? Slide 25

  17. An HBV infected patient with almost normal ALT treated by LVD 106 copies/ml was the lowest limit of detection • Source: Nowak M. J. et. al. Proc. Natl. Acad．Sci. USA 93, 1996: 4398-4402. Serum HBV Relapsed immediately after stopping 168 days’ treatment with drug lamivudine.

  18. An Int. Anti-HBV Infection Therapy Trail.

  19. 169 HBeAg positive patients received EVT treatment

  20. PEG-IFN alpha, tenofovir (TDF), entecavir (ETN) had been selected as the first-line therapy to initial treatment in naive Chronic HBV infected patients. • In China, some Traditional Chinese Medicine (TCM) have also accepted as one choice to HBV infection therapy. • In particular to the patients who failed for NA treatments. • Source: EASL Clinical Practice Guidelines: management of chronic HBV infection, J. Hepatal 2012: 57: 167-185

  21. Monotone Traditional Chinese Medicine (TCM) treatment. • TCM + NA combination treatment.

  22. Long-term personalized TCM treatment to suppress HBV 1000 copies/ml was the lowest limit of detection L. Min, Y. Ye, Proc. of The 3rd Int. Conf. On Bioinformatics and Biomedical Engineering (iCBBE 2009)

  23. Traditional Chinese medicines (TCM) personalized therapy for HBeAg (+) chronic hepatitis B Chinese patient with suboptimal response to NA. Y. Ye & L. Min, Poster presented in 5th Ditan Int. Conf. Infecytious Disease; Int. J. Infectious Diseases, 15 Suppl. 2011, S76.

  24. TCM + NA anti-HBV infection personalized combination therapy for a chronic HBV patient with almost normal ALT • X. Chen, L. Min, Y. Ye, Q. Zhang, Oral presentation addressed in 5th Ditan Int. Conf. Infecytious Disease; Int. J. Infectious Diseases, 15 Suppl. 2011, S28; Computer Eng. & Appl. (in Chinese), 48(24), 2012:20-27.

  25. TCM Treatments • Evidences show that traditional Chinese medicine (TCM) may regulate chronic hepatitis B (CHB) patients’ immune functions. • ChiCTR-TRC-10001263 was a double-bind randomized placebo-controlled trial. • Two kinds of TCMs were used in the trial: Tiaoganjianpihuoxue grain (TCM1) and Tiaoganjieduhuashi grain (TCM2).

  26. A total of 560 CHB Chinese patients with HBeAg-positive were randomly assigned, in 1:1 ratio, two groups: experimental group (EXG) and controlled group (CTG), and each group are further divided into 3 subgroups. • CTG received 10 mg of ADV + placebo for TCM orally daily for 48 weeks. • Roughly speaking, EXG received TCM1 or TCM2 +placebo for ADV orally daily for the first 24 weeks, and then switched to TCM2 + ADV for additional 24 weeks.

  27. Results: ●28 /31 patients in EXG /CTG achieved complete response. ● 42 /55 in EXG / CTG responded poorly. • The TCMs + AD therapy resulted significantly in increased proportion of patients achieving HBeAg loss in EXG two subgroups than the two CTG subgroups. • The other virologic and biochemical responses of CG and EG had not significant differences at week 48.

  28. Outcomes of the complete-response patients’ therapy efficacy in experimental group (EXG) and control (CTG) group. • Source: L. Min, X. Chen, Y. Ye et al., Evidence-Based Complementary and Alternative Medicine Volume 2013, http://dx.doi.org/10.1155/2013/767290

  29. Outcomes of the poor-response patients’ therapy efficacy in experimental group (EXG) and control (CTG) group • Source: L. Min, X. Chen, Y. Ye et al., Evidence-Based Complementary and Alternative Medicine Volume 2013, http://dx.doi.org/10.1155/2013/767290

  30. Seven chimpanzees were inoculated 1 to 1010 genome equivalents (GE) of HBV DNA. HBV DNA of five chimpanzees was lower than undetectable levels at or before week 39. Two chimpanzees inoculated with a dosage of 10 GE of HBV DNA, suffered prolonged or persistent infection. HBV DNA peaks of some animals with 1-1010 inoculated HBV are almost the same!!! Suppressed HBV loads were relapsed and then suppressed in 4 animals S. F. Weiland 13th ISVHLD, March, 20-24, 2009, Washington

  31. 2010全球新增HIV感染者人数约2.7百万. • About 2.7 million people have been infected newly with HIV in 2010 . • 2010全球约有1.8百万人死于 HIV. • About 1.87 million people deaths from HIV in 2010 . • 2010全球约有0.8% - 3千4百万人感染HIV. • About 0.8% --34 million people have been infected by HIV estimated in 2010 . • Source: WHO, Progress Report 2011 (http://www.who.int)

  32. Antiretroviral (ART) medicines • Abacavir (ABC) Didanosine (DDI) Emtricitabine (FTC) • Lamivudine (3TC) Stavudine (D4T) Zidovudine (AZT) • Tenofovir (TDF) Efavirenz (EFV) Nevirapine (NVP) Tripranvir (TPV) Atazanavir (ATV) Durunavir (DRV) Fosamprenavir (f-APV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV)

  33. Antiretroviral (ART) medicines • ● *ART 治疗可使10-30% 的初治患者在治疗前4-8周内伴有免疫恢复 • ● ART treatments may make 10–30% of the people be associated with immune recovery usually within the first 4–8 weeks. • ● ART 治疗可显著地延长HIV 感染者的寿命 • ● ART treatments can significantly prolong the • life of HIV infected patients. • *Source: WHO : Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection Progress

  34. Antiretroviral (ART) Treatment Sourece: Clinical Trial Datasets GART Study, http://hivdb.stanford.edu/pages/clinicalStudyData/GART.html.

  35. The first and only man to be cured of HIV infection is Timothy Ray Brown treated for his HIV infection with a normal anti-HIV drug regimen. • When he developed leukemia, he underwent twice bone marrow transplants. • His HIV became imeidately undetectable after the first bone marrow transplants. • Five years later, Brown remains HIV free. • Sourcehttp://www.webmd.com/hiv-aids/features/hiv-cure-in-reach

  36. It is a long way to against HIV • An HIV infected baby from Mississippi received treatment medications just 30 hours after birth. • Another HIV infected baby from California was treated when she was only 4 hours old. • The California baby is still HIV-negative almost a year after birth. • The Mississippi baby tested HIV-free for more than 2 years, but is now HIV-positive again. • http://www.webmd.com/hiv-aids/features/hiv-cure-in-reach

  37. 3.1. 乙肝病毒(HBV)感染/抗HBV感 染治疗动力学模型 3.1.1 Modelling anti-HBV Infection Therapy without Immune Response

  38. Basic virus infection model (基本病毒感染模型) Virus infection model Anti-virus infection therapy model (1) • Source: Nowak M. J. et. al. Proc. Natl. Acad．Sci. USA 93, 1996: 4398-4402

  39. x, y, v 分别表示未感染的细胞个数， 感染的细胞个数，游离病毒(HBV)个数. • λ — 未感染细胞的产生速率。 • dx —未感染细胞的死亡速率。 • βvx — 未感染细胞被游离病毒感染的速率。 • ay — 感染细胞的死亡速率。 • ky — 感染细胞产生病毒的速率。 • uv — 游离病毒被清除的速率。 ● Without immune responds. ● Describe non-symptom infections♂

  40. 模型有两个常数解（平衡点）：Two constant solution (equilibrium points) • Q1----- 康复平衡点（代表宿主痊愈） • host's disease-free (virus free steady- • state) . • Q2 ----- 带毒平衡点（代表宿主持续感染） • host's persistent infection (endemic • steady-state).

  41. 基本病毒复制数: Basic reproduce number: • I.R0< 1，则 Q1 是大范围吸引的. • If R 0< 1， then Q1is globally attractive. II. R 0 >1, 则 Q2 是大范围吸引的. • 如果 • If R 0 > 1， then Q2is globally attractive. Source: P. D. Leenheer, H. L. Smith, SIAM J. Appl. Math. 63, 2003, 1313-1327.

  42. 基本病毒复制数:Basic reproduce number: Theoretical suggestionsI. 具有R 0< 1的无症状病毒感染者，即使感染大量病毒也能自愈 ● Non-symptom infected individual with R0< 1 will recover eventually even infected a large amount virus. II. 具有R0 >1的无症状病毒感染者，即使感染1个病毒也成为持续带毒者. ●Non-symptom infected individual with R 0> 1 will become persistent infection even infected one virus.

  43. ● R0中的λ/d 项表示患者肝细胞的总数量。 Term λ/d in R0 represents the total number of cells of the patients liver. ● 这意味着肝脏大的患者比肝脏小的感染者更容易持续带毒。 This implies that an individual with larger liver will more easily become persistent infection than the one with smaller liver. ● R0的实际意义有异议的. The practical meaning of R0 is questionable . Source: L Min, Y Su , Y Kuang, Rocky Mountain J. Math. 8, 2008, 1573-1585.

  44. 3.1.1 Modelling anti-HBV Infection Therapy without Immune Response An amended Basic Virus Indection Model (4) Virus basic reproductive number R0= βk/auR0= (1 – m)(1 – n) βk/au Independent on the total number of liver cells. (4) Source: L. Min, Y. Su, Kuang Y, Rocky Mountain J. Math. 8, 2008, 1573-1585.

  45. Theorem 1 (L. Min, Y. Su & Y. Kuang 2008, Y. Zheng, L. Min, Y. Ji & Y. Kuang 2010) If R0= βk/au≤ 1. Then Q1 is globally attractive. Non-symptom infected individual with R0= βk/au< 1 will recover eventually even infected a large amount virus. Since R0 is independent on λ/d, our model gives a more reasonable description than that of Nowak et al’s basic virus infection Model. • Source: L Min, Y Su, Y Kuang, Rocky Mountain J. Math. 8(5):1573-1585, 2008. • Y Zheng, L Min, Y. Ji, et al., J. Systems Science and Complexity. 23: 1221–1230, Source: Y Zheng, L Min, Y. Ji, et al., J. Systems Science and Complexity. 23: 1221–1230, 2010.

  46. Theorem 2 (Y. Zheng, L. Min, Y. Ji & Y. Kuang 2010) If R0= βk/au> 1. Then Q2 is globally attractive. Non-symptom infected individual with R0 = βk/au> 1 will become persistent infection even infected one virus. Since R0 is independent on λ/d, our model gives a more reasonable description than that of Nowak et al.’s basic virus infection Model. • Source: L Min, Y Su, Y Kuang, Rocky Mountain J. Math. 8(5):1573-1585, 2008. • Y Zheng, L Min, Y. Ji, et al., J. Systems Science and Complexity. 23: 1221–1230, Source: Y Zheng, L Min, Y. Ji, et al., J. Systems Science and Complexity. 23: 1221–1230, 2010.

  47. ● 对于R0= βk/au ≤ 1 的无症状感染者 即使感染大量病毒，也将最终痊愈。 ● 对于R0= βk/au > 1 的无症状感染者 即使感染微量（1个）病毒，也会成为 持续带毒者. Source: L Min, Y Su, Y Kuang, Rocky Mountain J. Math. 8(5):1573-1585, 2008. Y Zheng, L Min, Y. Ji, et al., J. Systems Science and Complexity. 23: 1221–1230, 2010.

  48. ● We introduce some approaches to determine parameters in (4). ● Select m = n = 0 after stopping the 168 day’s treatment. ● Numerical simulation is in good agreement with the patient’s HBV DNA loads. Fig. Modeling (solid line) LVD anti-HBV infection therapy and virus rebounded after stopping treatment at 168th day (circles) reported by Nowak et al. 1996.模拟Nowak et al.等1966报道的 一个肝功ALT正常患者拉米夫定抗HBV感染治疗（1-168天）和停药(168天后)反弹. Source: Y Zheng, L Min, Y. Ji, et al., J. Systems Science and Complexity. 23: 1221–1230, 2010.

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