ID Clinical Case Conference: July 10, 2006

1
ID Clinical Case Conference July 10, 2006

• Kevin P. High, MD, MSc
• Professor of Medicine
• Sections of Infectious Diseases,
  Hematology/Oncology and Molecular Medicine
• Wake Forest University Health Sciences

2
Case 1

• 62 yo AA male presented three years ago with
  pain in the right shoulder and fever
• Tap of the shoulder joint grew S. agglactiae
• Treated with several surgeries and beta-lactam
  antibiotics with resolution
• Three months later developed aggressive skin/soft
  tissue infection of the scrotum requiring I D
  and antibiotics

3
Case 1 contd

• June, 2005 presented with a thigh abscess no
  microbiology
• Third serious infection in a year prompted
  additional work-up including
• Mild renal insufficiency noted with mild anemia
  and protein of 11.9 . . . . .
• HIV (-)
• no protein on dipstick, but positive SSA . . . .
• Quantitative immunoglobulins sent and IgG 6.5
  grams (monoclonal spike, lambda)
• Bone Marrow Biopsy with 30 plasma cells
• Skeletal survey showed a ASx T11 compression Fx

4
Case 1 contd

• Dxd as having multiple myeloma and was treated
  with dexamethasone (40 mg/d 4 days/month),
  thalidomide (300 mg/d) and monthly Zometa with a
  nice response
• Contemplated autologous HSCT
• Now first-line therapy for MM based randomized
  trials that have shown survival benefit
• Pre-transplant LFTs normal, but routinely obtain
  hepatitis B panel
• Hep B Core Ab (), Hep B Surface Ab (-), Hep B
  Surface Ag ()

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Questions

• What additional information would you like?
• Is transplant now contraindicated?
• If so, why?
• If not, why not?

6
Additional Information

• Hep B E Ag (-), Hep B E Ab ()
• Hep B viral load
• 443 IU/mL (778 copies/mL)
• Hep A antibody ()
• Liver Biopsy
• Periportal fibrosis with infrequent septum
  formation

7
Questions

• What is the risk of Hepatitis B reactivation if
  he proceeds with HSCT?
• Is there a role for antiviral therapy?
• If so, which therapy?
• For how long?
• What about other immunomodulatory therapies?

8
Hepatitis B Reactivation During Anticancer
Therapy

• 350 million people worldwide with Chronic
  Hepatitis B
• Chemotherapy-induced reactivation first described
  in 1975 in 20 patients with lympho- and
  myelo-proliferative d/os (Wands, et al.
  Gastroenterology 197568105-112)
• Reactivation rates range from 25-60
• Lymphomas the most commonly described malignancy
  associated with reactivation of Hep B

Yeo and Johnson, Hepatology, 2006 43209-220
9
Patterns of Reactivation

• Increase in Surface Ag titer
• Increase in HepB DNA by gt 10-fold
• Most interesting
• Loss of Hep B Surface Ab and re-appearance of Hep
  B Surface Ag in previously (-) patients
• Appearance of Hep B Surface Ag in patients with
  Hep B Core Ab () only
• Occurs in about 4 with conventional chemo
• 14-50 of allogeneic HSCT recipients
• Only 3 of auto HSCT in this situation

10
Viral Replication During Chemotherapy Followed by
Hepatitis (sometimes with completion of
chemotherapy)
11
Yeo and Johnson, Hepatology 2006 43209-220.
12
Risk Factors for Reactivation

• Hep B E Ag positivity
• Pre-core and core promoter mutant strains
• Viral load gt 3 x 105 copies/mL
• Male Gender
• Younger age
• Specific chemotherapy used
• Corticosteroids
• Anthracyclines
• Anti-B cell and Anti-T cell chemotherapy
• Rituximab and Alemtuzumab

13
Rituximab-induced Reactivation in Hep B Surface
Ag Negative Subject
Sarrecchia, et al. J Infect Chemother
200511189-91
14
Prevention of Hep B Reactivation Using Antiviral
Therapy

• Lamivudine has most extensive experience
• Studied in at least 7 retrospective and 5
  prospective series at 100 mg/d
• Administered for the duration of chemotherapy and
  4-8 weeks beyond
• Longer (at least one year) in HSCT recipients
• Reduces the risk from 25-67 in placebo group to
  0-6 in the lamivudine group (Reviewed in Yeo and
  Johnson, Hepatology, 200643209-220)

15
Specific Issues in HSCT

• Hep B immune donor into Hep B S Ag () recipient
  can lead to cure
• Hep B S Ag() donor into Hep B naïve recipient
  leads to high incidence of hapatitis and up to
  1/6 subjects dying from fulminant hepatic failure
  (Blood 1995863236-40)
• Hep B Reactivation occurs in 50 overall (allo gt
  auto)
• Late hepatitis an issue due to re-constitution of
  immunity

16
Lamivudine Resistance and Withdrawal Hepatitis
After HSCT

• Resistance to lamivudine occurs during
  prophylaxis in about 40 of subjects, but
  clinical disease occurs rarely (0-6)
• Withdrawal Hepatitis
• Occurs in up to 13 with lamivudine w/d
• Associated with high pre-chemotherapy viral load
  (Gut 2005541597-1603)

17
Adefovir?Very Little Data
Cortelezzi, et al. J Clin Virol 200635467-9.
18
Hepatitis B Reactivation After Other
Immunomodulatory Therapy

• Multiple recent reports of Hep B reactivation in
  patients receiving anti-TNF Ab Therapy
• Infliximab for Crohns Dz (World J Gastro,
  200612974-6 and Gut,2004531363-65)
• Infliximab and MTX for RA (Ann Rheum Dis,
  200362686-7)
• Infliximab for Spondyloarthropathy (Ann Rheum
  Dis, 200564788-9)

19
Anti-TNF Therapy in Hep BPrevention of
Reactivation with Lamivudine
Roux, et al. Rheumatology 2006 ePub ahead of
printing
20
Anti-TNF Therapy in Hep CLack of Significant
Effect
Roux, et al. Rheumatology 2006 ePub ahead of
printing
21
Our patient

• Recommended to proceed with HSCT (autologous)
  with lamivudine prophylaxis
• Continue lamivudine for at least one year post
  transplant
• Follow with monthly viral load and LFTs

22
Cases 2, 3, 4, 5

• 72 yo man with HTN and a history of chicken pox
  and no prior zoster
• 68 yo woman with DM, CHF, a history of chicken
  pox and zoster 2 years ago
• 45 yo woman with a history of chicken pox and HIV
  positive
• 75 yo man with no significant illnesses and no
  known history of chicken pox
• Who should get zoster vaccine?

23
Electron Micrograph of Varicella Zoster Virus
Arvin AM, Gershon AA, editors. Varicella-zoster
virus virology and clinical management.
Cambridge, UK Cambridge University Press 2000.
24
VZV Spreads From Skin to Establish Latency in
Dorsal Root Ganglion
Descending noradrenergic andserotoninergic
inhibitory fibers
Ascendingspinothalamic fibers
Skin or mucousmembrane
Dorsal-rootganglion
Antegrade Spread
VZVvaricella-zoster virus. Modified from Kost R
et al. N Engl J Med. 199633532-42.
25
Schematic of VZV Latency and Reactivation
http//merck.micromedex.com/images/bhg/BHG01D10F02
.gif
26
Herpes Zoster Rash
Photo provided courtesy of Dr. Kenneth Schmader,
Associate Professor of Medicine Geriatrics,
Duke University School of Medicine.
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Incidence of Herpes ZosterIncreases With Age
Rate per 100,000 person-years
Age (years)
Donahue J et al. Arch Intern Med.
19951551605-1609.
28
Age-related Activity of VZV
Weller. N Engl J Med. 1983309362.
29
Will zoster incidence increase and/or age of
onset decrease with widespread use of the
varicella vaccine?
Vaccine 2002 202500-2507
30
Duration of Pain Associated With PHN Increases
With Age
100
gt1 yr
6 - 12 mo
80
1 - 6 mo
lt1 mo
60
Percent of patients reporting pain
40
20
0
0-19
20-29
30-39
40-49
50-59
60-69
70
Age (years)
Kost R et al. N Engl J Med. 199635532-42.
Note this study was from a pain clinic (?
referral bias accounting for very high
percentages)
31
Severity of Acute Herpes Zoster is a Major Risk
Factor for PHN in Adults 50 Years of Age
1.0
0.9
0.8
0.7
0.6
Severe or incapacitating pain and ?47 lesions
Patients reporting pain ()
0.5
No or mild acute pain and lt47 lesions
0.4
0.3
0.2
0.2
0
15
30
45
60
75
90
105
120
135
150
165
180
0
Study day
PHNpostherpetic neuralgia. Modified from Whitley
R et al. J Infect Dis. 19991799-15.
32
Sources of Neuropathic Pain
Bennett G. Hosp Prac (Off Ed). 19983395-98101-1
04107-110.
33
Shingles Vaccine Approved by FDA June, 2006

• Same virus as varicella vaccine, but at higher
  potency
• Has been studied in over 38,000 patients 60
  years of age
• Excluded immunocompromised patients
• Patients offered appropriate viral therapy and
  standard-of-care pain medications
• Primary endpoint
• Burden of illness of herpes zoster (pain and
  discomfort)
• Secondary endpoint
• Incidence of PHN (pain more than 90 days after
  rash onset)

Oxman et al. NEJM. 20053522271-84
34
Burden of Illness is a Compilation of Worst Pain
Scores Over Time (like an AUC)
10
9
8
7
6
5
Worst pain score
4
3
2
1
0
0
10
30
40
50
60
70
20
Days since rash onset
AUCarea under the curve. Adapted from Oxman M et
al. N Engl J Med. 20053522271-2284.
35
Effect of Zoster Vaccine on Burden of Illness in
Herpes Zoster

The Burden of Illness Score is incorporates the
incidence, severity, and duration of the pain and
discomfort associated with herpes zoster. Each
subject with zoster rated their worst pain on a
Pain Inventory. The rating was used to
calculate a severity-of-illness score (ranging
from 1 to 1813 in this study) defined as the AUC
of zoster pain plotted against time during the
182-day observation period after rash onset. The
BOI Score was the mean severity-of-illness score
for the treatment group. plt0.001 Adapted from
Table 2 in Oxman et al. NEJM. 20053522271-84
36
Effect of Zoster Vaccine on Incidence of Herpes
Zoster

Adapted from Table 2 in Oxman et al. NEJM.
20053522271-84
37
Effect of Zoster Vaccine on PHN

p lt 0.001 Adapted from Table 3 in Oxman et al.
NEJM. 20053522271-84
38
Kaplan-Meier Estimates of the Effect of Zoster
Vaccine on Cumulative Incidence of Postherpetic
Neuralgia and Herpes Zoster
Oxman et al. NEJM. 20053522271-84
39
Serious Adverse Events Among All Subjects
Adapted from Table 4 in Oxman et al. NEJM.
20053522271-84
40
Adverse Events Substudy

Adapted from Table 4 in Oxman et al. NEJM.
20053522271-84 Events occurring from the day of
vaccination through Day 42 Difference in risk
between vaccine and placebo groups was
statistically significant (plt0.05)
41
Shingles Prevention Study Summary

• Efficacy
• Decreased incidence zoster by 51.3 (plt0.001)
• Decreased incidence PHN by 66.5 (plt0.001)
• Reduced zoster morbidity by 61.1 (plt0.001)
• Safety
• Systemic side effects similar to placebo
• Injection site reactions were well tolerated

Oxman et al. NEJM. 20053522271-84
42
Do Not Use Varicella Vaccine to Prevent Shingles!

• Results of Oxman study do not imply a
  recommendation to use varicella vaccine for
  prevention of herpes zoster or PHN in older
  adults.
• Varicella virus vaccine is indicated for
  vaccination against varicella, not zoster, in
  individuals 12 months of age and older.

Physicians Desk Reference 2005. Montvale, NJ.
Thomson PDR 2005
43
Cases 2, 3, 4, 5

• 72 yo man with HTN and a history of chicken pox
  and no prior zoster
• 68 yo woman with DM, CHF, a history of chicken
  pox and zoster 2 years ago
• 45 yo woman with a history of chicken pox and HIV
  positive
• 75 yo man with no significant illnesses and no
  known history of chicken pox

Yes
NO(?)
NO
Yes