1. CHOLHUA , March 2015 Jean-Marc Fix, FSA, MAAA, VP, R&D
HIV?
CHOLHUA , March 2015
Jean-Marc Fix, FSA, MAAA, VP, R&D

2. Why not?
The End

3. Is a segment of the HIV-infected population insurable?
CHOLHUA , March 2015
Jean-Marc Fix, FSA, MAAA, VP, R&D

4. Agenda What is HIV infection? Evolution of HIV infection mortality
Evolution of HIV infection treatment
Segmentation of HIV-infected population
Mortality of the better segments
Underwriting skills
Unknowns and risk mitigation strategies

5. Face of a killer

6. Face of a killer

7. Face of a killer

8. Face of a killer

9. Face of a killer

10. A Close-up

11. Video- Infection
4’08”

12. Infectious pathway Men having sex with men Heterosexual
Intravenous drug user
Blood product (transfusion, hemophilia)
Occupational

13. Infectious pathway -Men
Source: HIV AIDS Surveillance vol 19 CDC

14. Infectious pathway -Women
Source: HIV AIDS Surveillance vol 19 CDC

15. Source: Gill et al, Clin Infect Dis 2010
What kills?
Depletion of CD4+ T helper cells
Loss of immune protection
AIDS defining diseases ~50% (1)
Liver disease (hepatitis co-infection)
Infection (non AIDS defining)
Cancer (non AIDS defining)
Cardiovascular
Drug overdose, accident, suicide
Source: Gill et al, Clin Infect Dis 2010

16. Together in Life and Death
What we remember
1985
AIDS Is Top Cause of Death for Young Adults in U.S. Disturbing report by federal agency
San Francisco Chronicle 2/1/95
Together in Life and Death
San Ramon pair die of AIDS 2 days apart… Ray, 58, and Peggy, 54, of San Ramon, died earlier this month after battling the disease for five years. They were buried Monday in the same grave. SFC 2/1/95
2001
1992
Hunting for the Hidden Killers: AIDS Time Magazine 7/4/83

17. Total: 33,4 millones (31,1 – 35,8 millones)
Número estimado de adultos y niños que vivían con el VIH en 2008
Europa oriental y Asia central
1,5 millones
[1,4 – 1,7 millones]
Europa occidental y central
[ – ]
América del Norte
1,4 millones
[1,2 – 1,6 millones]
Asia oriental
[ – 1,0 millones]
África del Norte y Oriente Medio
[ – ]
Caribe
[ – ]
Asia meridional y sudoriental
3,8 millones
[3,4 – 4,3 millones]
África subsahariana
22,4 millones
[20,8 – 24,1 millones]
América Latina
2,0 millones
[1,8 – 2,2 millones]
Oceanía
59 000
[ – ]
Total: 33,4 millones (31,1 – 35,8 millones)

18. HIV mortality

19. HIV deaths

20. What we should be hearing
Managing HIV as a Chronic Disease
South Afr j of HIV Med 2004
When AIDS became a chronic disease
West J Med 2000
HIV: Now a Manageable Chronic Disease
Pharmacy Times 2007
Comprehensive Clinical Care: Managing HIV as a Chronic Illness
AIDS Clinical Care Journalwatch retrieved July 2010

21. HIV mortality

22. Trends in Annual Age-Adjusted
Trends in Annual Age-Adjusted* Rate of Death Due to HIV Infection, United States, 1987−2010
Note: For comparison with data for 1999 and later years, data for 1987−1998 were modified to account
for ICD-10 rules instead of ICD-9 rules.
*Standard: age distribution of 2000 US population

23. Source: Pallella et al, J Acq Immune Def Syndr 2006
Advances in treatment
Source: Pallella et al, J Acq Immune Def Syndr 2006

24. HAART Highly Active Antiretroviral Treatment
Latest is triple cocktail, for ART naïve patients:
NNRTI + 2 NRTI: Atripla and Complera
Ritonavir boosted PI + 2 NRTI
INSTI + 2 NRTI
NRTI = nuclesos(t)ide reverse transcriptase inhibitor
NNRTI = non-nucleoside reverse trans. inhib.
PI = protease inhib.
INSTI = integrase strand transfer inhib.
Source: Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents DHHS as of 3/15

25. Video-Treatment
4’09”

26. Advances in treatment

27. Action path of treatment

28. Action path of treatment

29. (1): Marsden and Zack J Antimicrob Chemo 2009
HIV reservoirs
CD4+ memory T-cell
Can stay inactive and virus dormant for many years
Under current therapy: 60+ years to clear the virus (1)
(1): Marsden and Zack J Antimicrob Chemo 2009

30. Variables for mortality
Age
Gender
Smoking
Income
CD4+ cell count
Viral load
Time since infection
Response to treatment
Quality of follow-up
Infection source

31. Source: Pallella et al NEJM 1998
Mortality by therapy
When:
Where: 8 cities in US
Who:12% IDU, 12% Females, MSM decreasing to 65%
Severity: All had CD4+ cell counts below 100/mm3
Significant treatment change in 1996
Source: Pallella et al NEJM 1998

32. Mortality by therapy RR death or morbidity None vs. Monotherapy 1.5
None vs. combo
2.9
None vs. combo with protease inhibitor
4.5
Source: Pallella et al NEJM 1998

33. Source: Bashkaran et al, JAMA 2008
Mortality evolution
When:
Where: 23 cohorts in Europe, Australia, Canada
Who:18% IDU, 22% Females, MSM 57%
Severity: Since seroconversion
Follow-up: median 6.3 (range 1 day to 23.8 years)
Source: Bashkaran et al, JAMA 2008

34. Source: Bashkaran et al, JAMA 2008
Mortality evolution
Deaths
Pre 1996
Expected 56 28 33 39 41 37
Observed
1332
481
231
212
188
127
Obs/Exp 24 17
7.0
5.5
4.6
3.4
Source: Bashkaran et al, JAMA 2008

35. Source: Bashkaran et al, JAMA 2008
Mortality evolution
Source: Bashkaran et al, JAMA 2008

36. Source: Bashkaran et al, JAMA 2008
Mortality evolution
Source: Bashkaran et al, JAMA 2008

37. Source: adapted from Table 4, Bashkaran et al, JAMA 2008
Mortality by age
Ratio observed to expected mortality by age, 15 year after seroconversion
Age at seroconversion
15-24
3720%
736%
25-34
2225%
375%
35-44
3728%
150%
45+ na
192%
Source: adapted from Table 4, Bashkaran et al, JAMA 2008

38. Source: Lewden et al, J Acq Immune Def Syndr 2007
Mortality by segment
7 year post cART France, first treated with PI
Overall: SMR 7.0
Men 4.8
Women 13.0
HCV status
Positive: 13.9
Negative: 4.4
HIV transmission
IV drugs 16.3
Other 5.5
Source: Lewden et al, J Acq Immune Def Syndr 2007

39. Source: Lewden et al, J Acq Immune Def Syndr 2007
Mortality by segment
CD4+ count
cells/mm3
SMR
500+
2.5
3.5
5.6
<200
30.3
Source: Lewden et al, J Acq Immune Def Syndr 2007

40. Source: Lewden et al, J Acq Immune Def Syndr 2007
Mortality by segment
Source: Lewden et al, J Acq Immune Def Syndr 2007

41. Mortality by age, CD4+ count and viral load
Monte Carlo simulation model
Includes HIV resistance evolution with treatment
Calibrated from a US cohort (CHORUS, less IDU, less non-white)
Validated against VA study (more IDU, more non-white)
Source: Braithwaite et al, Am J of Med 2005

42. Source: Braithwaite et al, Am J of Med 2005
Modeling flowchart
Source: Braithwaite et al, Am J of Med 2005

43. Source: from Braithwaite et al, Am J of Med 2005
Mortality Age 30
Age
CD4+ (cells/mm^3)
Viral load /ml
Median survival
Mort Mult (men) 30
800
10,000
31.30
400%
100,000
23.70 x
1,000,000
17.20
500
26.80
21.20
14.60
200
21.90
18.10
12.20
Source: from Braithwaite et al, Am J of Med 2005

44. Source: from Braithwaite et al, Am J of Med 2005
Mortality Age 40
Age
CD4+ (cells/mm^3)
Viral load /ml
Median survival
Mort Mult (men) 40
800
10,000
28.00
250%
100,000
22.60
425%
1,000,000
15.20 x
500
24.40
350%
18.90
14.00
200
19.70
15.50
10.90
Source: from Braithwaite et al, Am J of Med 2005

45. Source: from Braithwaite et al, Am J of Med 2005
Mortality Age 50
Age
CD4+ (cells/mm^3)
Viral load /ml
Median survival
Mort Mult (men) 50
800
10,000
22.30
200%
100,000
20.30
250%
1,000,000
14.30 x
500
21.10
225%
17.70
325%
12.90
200
16.50
375%
14.60
500%
10.20
Source: from Braithwaite et al, Am J of Med 2005

46. HAART treatment consequences
Dyslipidemia
Insulin resistance/diabetes
Endothelial dysfunction
Altered fat distribution
More AMI in HIV +
Source: Triant et al, J Clin Endocrinol Metab 2007

47. HAART treatment consequences
HIV +
HIV -
Ratio
Heart Attack Rates per 1000 PY
18-34
4.65
0.88
528%
35-44
10.13
3.34
303%
45-54
18.74
7.56
248%
55-64
33.39
14.78
226%
65-74
77.68
24.47
317%
75-84
43.63
36.47
120%
Source: Triant et al, J Clin Endocrinol Metab 2007

48. Data limitations- the bad news
Atherosclerotic cardiovascular conditions take a long time to manifest themselves

49. Underwriting skill-the good news
Cardiovascular risk: our best skill set and treating physician are now well aware of the risk
Hepatitis co-infection (Hep. B &C)
IDU
We CAN identify the best risks

50. Coronary heart disease risk in HIV
% increase in risk
HIV+ 1
HIV+ 2
HIV – (7)
Age - per year 9% 6%
6-9%
Sex – M vs F
N/A
110% %
Diabetes – Yes vs No
260%
90% %
Smoking – Yes vs No
140%
290%
70-290%
Hypertension –Yes vs No
30%
80%
80-90%
Tot Chol - per 1mmol/L
26%
25-33%
HDL chol. - per 1mmol/L
-28%
-52%
Source: Schambelan et al, Circulation 2008

51. The best Age: older is better Behavior: no drugs, how HIV acquired
Income: higher is better
HIV characteristics: CD4+ cell count and viral load
Treatment: timing, quality, response, follow-up, adherence
Documentation: available and plentiful

52. Unknowns and risk mitigation strategies
Full underwriting
Shorter term or shorter term equivalent coverage?
Limit the face amount
Reinsure

53. Potential Treatment Venues
Don’t get infected
Kill the virus
Prevent entry of the virus in the cell
Prevent normal virus intracellular processes
Prevent viability of cell produced virus
Kill infected active cells
Kill infected latent cells
Prevent CD4+ cell depletion

54. Kill the Virus Immune response boosters: cytokines, interferon,
monoclonal antibodies,
vaccine,
gene therapy

55. Prevent Virus Entry Prevent entry of the virus Block access on T cell
CD4
CCR5
CXCR4
Block connectors from virus
Block fusion
Cleave connectors: abzyme

56. Prevent Normal Virus Process
Viral decay accelerator
Innate antiretroviral factor

57. Prevent viability of cell produced virus
Maturation inhibitors
Env targeted cytotoxin (Berger 6/10)
Gag cleavage (Adamson, 8/09)
CA-CA interaction (ibid.)
Zinc finger inhibitors

58. Maybe one day Kill infected active cells Kill infected latent cells
Prevent CD4+ cell depletion
Gene therapy
Vaccine

59. Updates
Better understanding of CD4 cell death due to HIV infection of nearby cells and drug blocking that death and an existing drug blocking that effect (Doitsh, Nature 2013)
In monkeys, gene therapy ups the natural defenses against HIV (Gardner, Nature 2015)

60. Questions?