Transcript Challenging Cases in HIV Implications of Anemia

Challenging Cases in HIV
Implications of Anemia
David H. Henry, MD
Clinical Professor of Medicine
Pennsylvania Hospital
Joan Karnell Cancer Center
Philadelphia, PA
Case Discussion #1
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A 37-year-old female, HIV positive for five years.
CD4 350 cells/mm3, viral load undetectable (<50 copies/mL)
Current Therapy: Combivir® + Sustiva®
She has a two-month history of weakness
Denies GI/GU bleeding
Menstrual cycle normal
Physical examination is unremarkable
Stool Hemoccult negative
Case Discussion #1
• Lab results
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Hemoglobin 7.6 g/dL
MCV 92
RDW 10%
WBC 6.8
Platelets 440
Peripheral smear, NCNC RBC, and reticulocytes 0.2%
Creatinine 0.9 mg/dL
Ferritin 440 ng/mL
B12 340 pg/mL
Folate 10 nmol/L
EPO level 600 mU/mL
Case Discussion #1
• Clinical evaluation
– Underproductive anemia mechanism with normal MCV
– Normal creatinine, B12, folate, and ferritin
– Reticulocytes are very low consistent with bone
marrow, severely depressed
Anemia Work-up
Reticulocyte count
Underproductive (<5%)
Overdestructive (>10%)
………………………………………..
110 ….. B12, folate deficiency, MDS
MCV
90 ….. ACD, CRF, drugs……….
70 ….. Fe deficiency, thalassemia…
Case Discussion #1
• What is your diagnosis of this patient?
 Anemia of chronic disease secondary to HIV
 Treatment-related anemia
 Anemia due to blood loss (GI/GU bleeding)
Case Discussion #1
• What is your diagnosis of this patient?
– AZT-related anemia
• AZT-related anemia comes in two forms:
─ MCV normal
» Severe anemia and severe EPO elevation
(bone marrow failure)
─ MCV increased
» Mild anemia and mild EPO elevation
• AZT-related anemia of profound type
─ Frequently happens in patients who have been on AZT
for some time, as in this patient
─ Patients have normal MCV
Case Discussion #1
• What therapy would you consider for this patient?
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Discontinuation of AZT therapy
Begin EPO therapy (epoetin alfa)
Change HIV therapy to non-AZT-containing regimen
Discontinue AZT-therapy and begin EPO therapy
Change HIV therapy and begin EPO therapy
• Recommendation
– Discontinuation of AZT usually results in complete
recovery
– Not responsive to EPO therapy (EPO > 500 mU/mL)
Case Discussion #2
• A 47-year-old male, IV drug user
• Complaining of weakness, low-grade fevers, and night
sweats
• Denies GI or GU bleeding
• History of shingles, but no other opportunistic infections
• Physical examination reveals temperature 99.6º F
• Few enlarged cervical axillary lymph nodes and positive
thrush
• Stool Hemoccult negative
Case Discussion #2
• Lab results:
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Hemoglobin 9.1 g/dL
WBC 3.7
Platelets 560
Reticulocyte 0.9%
MCV 89
Creatinine 1.2 mg/dL
Chest x-ray negative
Urinalysis and urine culture unremarkable
Blood culture sent, the patient agrees to HIV testing, which is
positive
Case Discussion #2
• Baseline labs:
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CD4 80 cells/mm3
Viral load over 100,000 copies/mL
Ferritin 620 ng/mL
B12 400 pg/mL
Folate 9 nmol/L
EPO level 30 mU/mL
• Patient agrees to start HAART and HIV resistance testing
is sent
– Four weeks later, blood cultures return positive for MAI
(Mycobacterium avium-intracellulare)
Case Discussion #2
• Clinical evaluation
– Underproductive anemia with normal MCV
– Folate, B12, ferritin, and creatinine normal
– EPO level inadequate for a degree of anemia at
30 mU/mL
– No HIV medications started as of yet
Case Discussion #2
• What is your diagnosis of this patient?
 Anemia of chronic disease secondary to HIV
 Anemia associated with opportunistic bone marrow
infection
 Anemia due to blood loss (GI/GU bleeding)
 Anemia due to nutritional deficiency
• Diagnosis
– Anemia of chronic disease secondary to HIV,
untreated, and development of MAI systemic infection
Case Discussion #2
• What therapy would you consider for this patient?
 Initiation of HAART
 MAI therapy
 Consideration of EPO therapy
 All of the above
• Recommendation
– Initiation of HAART
– MAI therapy
– Consideration of EPO therapy
Case Discussion #3
• A 36-year-old male, HIV positive for 10 years
• History of PCP at diagnosis
• HAART second-line therapy: Truvada® + Reyataz® + Norvir®
• CD4 275 cells/mm3
• Viral load 800 copies/mL
• He is complaining of rectal irritation and fatigue for two
months. Denies GI or GU bleeding
• On physical exam, no lymphadenopathy and no
hepatosplenomegaly
• There is a 2-cm perianal mass with positive stool Hemoccult
– Biopsy of anal mass is positive for anal squamous cell carcinoma
Case Discussion #3
• Lab results
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Hemoglobin 8 g/dL
MCV 70
RDW 18%
WBC 4.7
Platelets 120
Reticulocytes 0.9%
EPO level 300 mU/mL
Ferritin 9 ng/mL
B12 400 pg/mL
Folate 7 nmol/L
Case Discussion #3
• What is your diagnosis of this patient?
 Anemia of chronic disease secondary to HIV
 Treatment-related anemia
 Anemia associated with iron deficiency due to blood
loss (GI/GU bleeding)
Diagnosis
– The patient has iron deficiency anemia due to occult
GI bleeding from his anal carcinoma
Case Discussion #3
• What therapy would you consider for this patient?
• Recommendation
– Treatment would consist of p.o./IV iron (some question
about oral iron absorption in patients with inflammation)
– The patient would also require chemoradiation therapy
due to his anal cancer
– Initiation of EPO therapy
Prevalence and Implications of Anemia
in the Patient with HIV
Distribution of Hb in
Anemic HIV Patients
70%
n = 154
Patients (%)
60%
50%
40%
30%
20%
n = 36
n = 22
10%
n = 12
n=6
0%
8.0-8.9
9.0-9.9
10.0-10.9
11.0-11.9
12.0-12.5
Hemoglobin level (g/dL)
Nadler JP et al. 5th IWADRL in HIV, Paris 2003
Distribution of Hb by Gender
Nadler JP et al. 5th IWADRL in HIV, Paris 2003
Prevalence of Anemia* by Race/Gender
39%
40%
35%
31%
30%
25%
19%
20%
12%
15%
African American
Caucasian
10%
5%
0%
Women
Men
*Anemia was defined as <12 g/dL for women and < 13 g/dL for men
Levine AM et al., J Acquir Immune Defic Syndr 2001:26:28-35
Semba R et al., Clin Infect Dis 2002;34:260-266
Baseline Hb by CD4+ Strata
Nadler JP et al. 5th IWADRL in HIV, Paris 2003
Baseline Hb by VL Strata
Nadler JP et al. 5th IWADRL in HIV, Paris 2003
Prevalence of Anemia
According to Treatment Regimen
Nadler JP et al. 5th IWADRL in HIV, Paris 2003
Prevalence of Anemia* During HAART
70%
64%
60%
47%
54%
52%
50%
40%
46%
35%
No anemia
Mild anemia
Severe anemia
30%
20%
10%
1.5%
1.2%
0.6%
0%
Start
6 Months
12 Months
* No anemia: > 12 g/dL women; >14 g/dL men
Mild anemia: 8-12 g/dL women; 8-14 g/dL men
Severe anemia: <8 g/dL for both women and men
Levine AM et al., J Acquir Immune Defic Syndr 2001:26:28-35
Semba R et al., Clin Infect Dis 2002;34:260-266
Association of Anemia and HIV Disease
Progression in Patients Receiving HAART
Overall odds ratio for
HIV progression
9
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(N = 501)
8
7
6
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5
4
3
2
1
0
Cases* Controls
Female Controls
cases
Male Controls
cases
*Case definition = patients with 2 Hb levels < 11 g/dL; 21% met the case definition
†P < .0001
‡P = .001
Creagh T, et al. IAS 2001; Poster 1049
Drugs that Commonly Cause Anemia
in HIV-Infected Patients
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Antiretrovirals
– Zalcitabine
– AZT-containing therapy (Retrovir®,Combivir®, Trizivir®)
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Antifungal Agents
– Flucytosine
– Amphotericin
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Anti-Pneumocystis Carinii Agents
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Sulfonamides
Trimethoprim
Pyrimethamine
Pentamidine
Antineoplastic Agents
– Cyclophosphamide, doxorubicin, methotrexate, paclitaxel, vinblastine
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Immune Response Modifiers
– IFN-α
Volberding P et al., Clinical Infectious Diseases 2004;38:1454-1463
Hb as a Prognostic Factor for
AIDS-Defining Illness (ADI)
• Incidence rate ratio (IRR) events/100 person-years
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Hb < 10 g/dL
Hb 10-11 g/dL
Hb 11-12 g/dL
Hb > 12 g/dL
8.62 (95% CI:5.52, 13.3)
7.31 (95% CI:4.52, 11.7)
3.93 (95% CI:2.44, 6.35)
Reference group
Moore R et al. CROI 2004, Abstract K5
Progression to Death for Patients According to
Baseline Hb in EuroSIDA: Multivariate Analysis
100
Proportion alive (%)
90
Normal (n = 2716)
Hb >14 g/dL for men
and >12 g/dL for women
80
70
60
Severe (n = 92)
50
Hb <8 g/dL for
men and women
Mild (n = 3917)
Hb 8-14 g/dL for men
and 8-12 g/dL for women
P < .001
40
0
6
12
18
24
30
36
Months after recruitment
Mocroft A, et al. AIDS. 1999;13:943-950
Recovery From Anemia Is Associated With
Improved Survival (N = 3203)
Median survival (months)
70
60
Recovery
P = .0001 for all CD4 categories (log rank)
50
No recovery
40
30
20
10
0
Risk ratio
(99% CI)
0-49
0.39
(0.32-0.49)
50-99
100-149
150-199
CD4 count (cells/mL)
0.43
(0.32-0.59)
0.37
(0.24-0.57)
0.27
(0.17-0.45)
≥200
0.39
(0.30-0.50)
Sullivan PS, et al. Blood. 1998;91:301-308
Progression of Hb During HAART
N=24 treatment-naïve, HIV-infected patients
2
Hb
Change From Baseline
1.5
( x g/dL)
1
0.5
CD4 cell count
( x 102 cells/µL)
0
-0.5
-1
Viral load
( x log10RNA copies/mL)
-1.5
-2
0
3
6
9
12
15
18
21
24
Time on HAART (months)
Servais J, et al. JAIDS. 2001;28:221-225
Association Between Anemia Treatments
and Death Rates
Death Rate: Cox Proportional Hazards Model
All Patients
(n = 2348)
Patients with
Anemia
(n = 498)
Treatment
RH
P value
Epoetin alfa
0.57
.002
Transfusion
1.32
.003
Epoetin alfa
0.68
.045
Transfusion
1.50
.002
Moore R. JAIDS. 1998;19:29
Treatment of HIV and
Treatment-related Anemia
• Epoetin alfa
– Initiate Treatment
– Symptomatic vs asymptomatic
– Hb < 11 g/dL
– EPO < 500 mU/ml
– 40,000 Units QW or 10,000 Units TIW
• Allow at least 4 weeks to assess dose response
– ± Iron supplementation as indicated*
– If no response at 4 weeks
• Increase from 10,000 Units TIW to 20,000 Units TIW
• Increase from 40,000 Units QW to 60,000 Units QW
– Optimal Hb: ≥13 g/dL men, ≥12 g/dL women
– Maintain Hb by titrating dose or increasing dosing interval
*Ferritin <100ng/mL, transferrin saturation <20%
Volberding P et al., Clinical Infectious Diseases 2004;38:1454-1463
Treatment of HIV and
Treatment-related Anemia
• Anemia is a not uncommon complication in HIV
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Treatment-related toxicity (AZT-based therapy)
HIV disease
Opportunistic bone marrow infections
Nutritional deficiencies
Vitamin B12, iron or folate deficiencies
Blood loss
• Symptoms of anemia can significantly impact a patient’s
QOL and physical functioning (fatigue, sleeplessness,
cognitive function)
Treatment of HIV and
Treatment-related Anemia
• Anemia risk factors
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Female
African American
AZT-based therapy
High HIV-RNA levels
Low CD4 counts
• Treatment of anemia
– Symptomatic, Hb < 11 g/dL, EPO < 500 mU/mL
– Epoetin alfa (40,000 Units QW)
– RBC Transfusions