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Challenging Cases in HIV
Implications of Anemia
Douglas T. Dieterich, MD
Professor of Medicine, Liver Diseases
Director, Continuing Medical Education
Department of Medicine
Mount Sinai School of Medicine
New York, NY
Case Discussion #1
• 37-year-old Caucasian woman with HIV for about 10
years on AZT/3TC, NVP
• HCV diagnosed 5 years ago
• HCV-RNA 5.2 million IU genotype 1a
• Liver biopsy done 6 months ago reveals grade 3, stage
2/4 fibrosis
• She finally consents to treatment of her HCV
Case Discussion #1
• Baseline labs:
–
–
–
–
–
–
Hb 11.5 g/dL
HIV-RNA < 50 copies/mL
CD4 444 cells/mm3
ALT/AST 56/87
Bilirubin 1.2 mg/dL
INR 1.2
• She was instructed in birth control methods and began
oral contraceptives
• Abdominal ultrasound: course echotexture c/w
hepatocellular disease
• No other medications in stable relationship
• Cleared by psychiatry
Case Discussion #1
• Do you have to start HCV treatment now?
 Yes
 No
• Recommendation
– Yes, you need to start HCV treatment!
• Clinical data shows that progression of liver disease is very
rapid, even in well treated HIV patients
Ishak Fibrosis Stage on Second Biopsy Among
Persons with Little or No Fibrosis on First Biopsy
60
Patients (%)
45%
40
• n = 51
• Median (IQR) time between bxs, 2.84 yrs (2.05–3.41)
• 28% with more than 2 stage progression
23%
20
10%
14%
8%
0
0
1
2
3 or 4
Fibrosis stage at second biopsy
5 or 6
Sulkowski MS et al. CROI 2005; Abstract P-172
Case Discussion #1
• If you start HCV treatment, do you need to
change her antiretroviral regimen to avoid
AZT-based therapy?
 Yes
 No
• Recommendation
– No, you don’t need to stop the AZT to treat the HCV
• DHHS treatment guidelines suggest avoiding the
combination of ribavirin and AZT, if possible
• Clinical data shows that there will be more anemia in
patients who take AZT-based therapy
─ Clinical data demonstrate that EPO therapy can normalize Hb
even if the patients are taking AZT-based therapy
Zidovudine: Impact on HCV Treatment
RBV Dose Reduction
by Week 4
Hb Decrease by Week 4
3.14
Hb loss (g/dL)
1.96
2
1
0
Patients with RBV decrease
60%
3
52%
40%
20%
20%
0%
AZT
No AZT
AZT
No AZT
Alvarez D et al. CROI 2005; Abstract P-192
Hematologic Response
Epoetin alfa (n = 30)
14
†
SOC (n = 22)
13.7 ± 0.4
*
Hb (g/dL)
13
12
‡
11.7 ± 0.3
11
Mean Hb (g/dL)
10
Baseline 1 2 3 4
8
12
16
Time (weeks)
*P < .001 vs. BL
†P < .001 for epoetin alfa vs. SOC
‡P = .503 vs. BL
Dieterich D, et al. CROI 2004
Hematologic Response: AZT vs. No AZT
Hb (g/dL)
14
Epoetin alfa + No AZT
SOC + No AZT
Epoetin alfa + AZT
SOC + AZT
*
‡
13.8 ± 0.5
13.6 ± 0.7
13
12.3 ± 0.5
12
11.0 ± 0.4
11
10
Mean Hb (g/dL)
Baseline
1
2
3
4
8
12
16
Time (weeks)
*P < .090 for epoetin alfa-treated patients receiving AZT vs. not receiving AZT
†P < .001 for epoetin alfa-treated patients receiving AZT vs. SOC patients receiving AZT
‡P = .001 for epoetin alfa-treated patients not receiving AZT vs. SOC patients not receiving AZT
Dieterich D, et al. CROI 2004
Results: Treatment Factors
Predictive of an SVR
• The relationship between
various treatment factors and
SVR rates were examined
• Cumulative peginterferon-alfa-2a
(40KD) dose was strongly
correlated with cumulative
ribavirin dose (r = 0.87)
• Ribavirin dose also correlated
with ribavirin treatment duration
(r = 0.98)
Cumulative peginterferon-alfa-2a
(40KD) dose
● SVR
● No SVR
100
80
60
40
20
0
0
20
40
60
80
Cumulative ribavirin dose
100
SVR Rates According to Exposure
Genotype 1 recipients of
peginterferon alfa-2a (40KD) plus ribavirin
50
39%
SVR rate (%)
40
29%
30
20
11%
10
0
n=
176
62
All
patients
< 80/80/80
exposure*
114
≥ 80/80/80
exposure
*Patients violated the rule if  1 of the three targets were not achieved
Common Symptoms of Anemia
•
•
•
•
•
•
•
•
•
•
•
•
Fatigue
Weakness
Shortness of breath
Dizziness or fainting
Pale skin, including decreased pinkness of the lips, gums, lining on
the eyelids, nail beds and palms
Rapid heart beat (tachycardia)
Feeling cold
Sadness or depression
Decreased sexual function
Difficulty sleeping
Decreased appetite
Impaired cognitive function
Volberding P et al., Clinical Infectious Diseases 2004;38:1454-1463
Signs and Symptoms of Anemia
CNS
•
•
•
•
Immune System
Debilitating fatigue
Dizziness, vertigo
Depression, sadness
Impaired cognitive function
Gastrointestinal System
• Anorexia
• Nausea
Vascular System
• Low skin temperature
• Pallor of skin, mucous
membranes, and
conjunctivae
• Impaired T-cell and
macrophage function
Cardiorespiratory System
• Exertional dyspnea
• Tachycardia, palpitations
• Cardiac enlargement,
hypertrophy
• Increased pulse pressure,
systolic ejection murmur
• Risk of life-threatening
cardiac failure
Genital Tract
• Menstrual problems
• Loss of libido
Volberding P et al., Clinical Infectious Diseases 2004;38:1454-1463
WHO Criteria for Assessment of
Therapy-Induced Toxicity: Anemia
Severity of Anemia
Hb Range
Grade 0
≥ 11.0 g/dL
Grade 1
9.5-10.9 g/dL
Grade 2
8.0-9.4 g/dL
Grade 3
6.5-7.9 g/dL
Grade 4
< 6.5 g/dL
WHO = World Health Organization
HIV-related Anemia
• Lower than normal levels of Hb
– Normal Hb
• Female: 12 to 16 g/dL
• Males: 14 to 18 g/dL
• Causes of anemia
– Decreased RBC production
• infection, medication (AZT-containing), HIV disease itself
– Increased RBC destruction/loss (i.e. hemolysis)
• Blood loss (bleeding ulcer, menstrual cycle)
– Ineffective RBC production
• Nutritional deficiency: vitamin B12, folic acid
Volberding P et al., Clinical Infectious Diseases 2004;38:1454-1463
Risk Factors Currently Associated with
Anemia in HIV Infection
• History of clinical AIDS
•
•
•
•
CD4 Cell count of < 200 cells/µL
Plasma virus load
Women
African American
• Zidovudine use
• Increasing age (> 50 years)
• Lower body mass index
• History of bacterial pneumonia
• Oral candidiasis
• History of fever
Volberding P et al., Clinical Infectious Diseases 2004;38:1454-1463
Percent Anemic by Ethnicity
(N = 2056 HIV+ Women)
Percent (%)
50
P < .001
Black
White
Hispanic
25
P<.001
NS
0
<12
<10
<8
Hb (g/dL)
Levine AM, et al, J AIDS 26:28-35, 2001
Relationship Between HAART and Anemia
in HIV Infected Women
1575 Women, Free of Anemia at Baseline
Factors Associated with
Development of Anemia
Factors Associated with Reduced
Risk of Anemia
OR
P value
Black
1.9
<.01
Low CD4 cells
2.9
<.01
High HIV-RNA
1.7
.02
Low MCV
17.1
<.01
AIDS
1.7
.02
AZT, 6 mos
2.2
<.01
HAART ≥ 18 mos
OR = .33
P < .01
Levine AM, et al, Blood 98:501a, 2001
Prevalence of Anemia* by Race/Gender
39%
40%
31%
35%
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
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
Prevalence of Anemia* During HAART
70%
64%
60%
47%
50%
40%
54%
52%
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
Treatment of HIV and
Treatment-related Anemia
• Epoetin alfa
– Initiate Treatment
– Symptomatic vs asymptomatic
– Hb < 11 g/dL
– 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
Case Discussion #2
• 43 year old Caucasian MSM with HIV for 12 years
• Multiple HIV regimens
– AZT/3TC
– ddI/d4T, IDV for 6 years
• Last 3 years on FTC/TDF, EFV
• CD4 180 cells/mm3
• HIV RNA 72 copies/mL
Case Discussion #2
• Noticed that his feet were swelling and his waist size had
increased by 2 inches
• Abdominal U/S:
– Moderate ascites
– Irregular liver consistent with cirrhosis
– Large spleen and esophageal varices
• Lab showed at this point
– Hb 10.5 g/dL
– AST/ALT 34/43
• HCV RNA negative
• HBV DNA negative
• Does not drink or smoke
– Platelets 68,000
– Bilirubin 1.3 INR 1.6
Case Discussion #2
• What is etiology of this cirrhosis?
• What is the etiology of his anemia?
– Cirrhosis commonly causes anemia and is
treatable with EPO
• What do we do now?
– EGD for varices and possible banding
– EPO for anemia
– Diuretics for edema and ascites
– Transplant list
Severe Liver Disease with Prolonged
Exposure to Antiretroviral Drugs
• There are many possible etiologies for liver disease in
HIV+ individuals
• Cryptogenic liver disease defined as no HBV, HCV or
EtOH as risk factors
• Cryptogenic liver disease was rare (0.5%), mean time
with HIV was 15 years, all on ARVs
• 60% had F3 or F4 on biopsy
• Only independent predictor was prolonged ddI exposure
Maida, I et al JAIDS 42:177-182 June 2006