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Challenging Cases in HIVImplications of Anemia
David H. Henry, MDClinical Professor of Medicine
Pennsylvania Hospital Joan Karnell Cancer Center
Philadelphia, PA
Case Discussion #1
• 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– 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? 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:– 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:– 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– 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
Nadler JP et al. 5th IWADRL in HIV, Paris 2003
0%
10%
20%
30%
40%
50%
60%
70%
8.0-8.9 9.0-9.9 10.0-10.9 11.0-11.9 12.0-12.5
Hemoglobin level (g/dL)
Pat
ient
s (
%)
n = 6n = 12
n = 22
n = 36
n = 154
Distribution of Hb by Gender
Nadler JP et al. 5th IWADRL in HIV, Paris 2003
Prevalence of Anemia* by Race/Gender
Levine AM et al., J Acquir Immune Defic Syndr 2001:26:28-35Semba R et al., Clin Infect Dis 2002;34:260-266
0%
5%
10%
15%
20%
25%
30%
35%
40%
Women Men
African American
Caucasian
39%
19%
31%
12%
*Anemia was defined as <12 g/dL for women and < 13 g/dL for men
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
Levine AM et al., J Acquir Immune Defic Syndr 2001:26:28-35Semba R et al., Clin Infect Dis 2002;34:260-266
0%
10%
20%
30%
40%
50%
60%
70%
Start 6 Months 12 Months
No anemia
Mild anemia
Severe anemia
64%
47%54%
0.6%
35%
46%
52%
1.2%1.5%
* 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
Creagh T, et al. IAS 2001; Poster 1049
Association of Anemia and HIV Disease Progression in Patients Receiving HAART
*Case definition = patients with 2 Hb levels < 11 g/dL; 21% met the case definition†P < .0001‡P = .001
0
1
2
3
4
5
6
7
8
9
Cases* Controls Female cases
Controls Male cases
Controls
Ove
rall
odds
rat
io f
or
HIV
pro
gres
sion
†
‡
(N = 501)
Drugs that Commonly Cause Anemia in HIV-Infected Patients
• Antiretrovirals– Zalcitabine– AZT-containing therapy (Retrovir®,Combivir®, Trizivir®)
• Antifungal Agents– Flucytosine– Amphotericin
• Anti-Pneumocystis Carinii Agents– Sulfonamides– Trimethoprim– Pyrimethamine– Pentamidine
• Antineoplastic Agents– Cyclophosphamide, doxorubicin, methotrexate, paclitaxel, vinblastine
• 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– Hb < 10 g/dL 8.62 (95% CI:5.52, 13.3)
– Hb 10-11 g/dL 7.31 (95% CI:4.52, 11.7)
– Hb 11-12 g/dL 3.93 (95% CI:2.44, 6.35)
– Hb > 12 g/dL Reference group
Moore R et al. CROI 2004, Abstract K5
Progression to Death for Patients According to Baseline Hb in EuroSIDA: Multivariate Analysis
Mocroft A, et al. AIDS. 1999;13:943-950
Months after recruitment
100
0 6 12 18 24 30 36
90
80
70
60
50
40
Pro
port
ion
aliv
e (%
)
P < .001
Normal (n = 2716)Hb >14 g/dL for men
and >12 g/dL for women
Mild (n = 3917)Hb 8-14 g/dL for men
and 8-12 g/dL for women
Severe (n = 92)Hb <8 g/dL for
men and women
Recovery From Anemia Is Associated With Improved Survival (N = 3203)
Sullivan PS, et al. Blood. 1998;91:301-308
0
10
20
30
40
50
60
70
Recovery
No recovery
0-49
Med
ian
surv
ival
(m
onth
s)
CD4 count (cells/mL)
50-99 100-149 150-199 ≥200
Risk ratio (99% CI)
0.39(0.30-0.50)
0.43(0.32-0.59)
0.37(0.24-0.57)
0.27(0.17-0.45)
0.39(0.32-0.49)
P = .0001 for all CD4 categories (log rank)
Progression of Hb During HAART
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2 N=24 treatment-naïve, HIV-infected patients
Time on HAART (months)
0 3 6 9 12 15 18 21 24
Cha
nge
Fro
m B
asel
ine
Viral load( x log10RNA copies/mL)
Hb( x g/dL)
CD4 cell count( x 102 cells/µL)
Servais J, et al. JAIDS. 2001;28:221-225
Association Between Anemia Treatments and Death Rates
Death Rate: Cox Proportional Hazards Model
Treatment RH P value
All Patients(n = 2348)
Epoetin alfa 0.57 .002
Transfusion 1.32 .003
Patients with Anemia(n = 498)
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– 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– 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