Challenging Cases in HIV Implications of Anemia

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Challenging Cases in HIVImplications 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

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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

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Case Discussion 1

• Baseline labs
• Hb 11.5 g/dL
• HIV-RNA lt 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

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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

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Ishak Fibrosis Stage on Second Biopsy Among
Persons with Little or No Fibrosis on First
Biopsy
Sulkowski MS et al. CROI 2005 Abstract P-172
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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 dont 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

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Zidovudine Impact on HCV Treatment
Alvarez D et al. CROI 2005 Abstract P-192
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Hematologic Response
Mean Hb (g/dL)
P lt .001 vs. BL P lt .001 for epoetin alfa vs.
SOC P .503 vs. BL
Dieterich D, et al. CROI 2004
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Hematologic Response AZT vs. No AZT
Mean Hb (g/dL)
P lt .090 for epoetin alfa-treated patients
receiving AZT vs. not receiving AZTP lt .001 for
epoetin alfa-treated patients receiving AZT vs.
SOC patients receiving AZTP .001 for epoetin
alfa-treated patients not receiving AZT vs. SOC
patients not receiving AZT
Dieterich D, et al. CROI 2004
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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)

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SVR Rates According to Exposure
Patients violated the rule if ? 1 of the three
targets were not achieved
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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
2004381454-1463
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Signs and Symptoms of Anemia

• CNS
• 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

• Immune System
• 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
2004381454-1463
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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 lt 6.5 g/dL
WHO World Health Organization
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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
2004381454-1463
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Risk Factors Currently Associated with Anemia in
HIV Infection

• History of clinical AIDS
• CD4 Cell count of lt 200 cells/µL
• Plasma virus load
• Women
• African American
• Zidovudine use
• Increasing age (gt 50 years)
• Lower body mass index
• History of bacterial pneumonia
• Oral candidiasis
• History of fever

Volberding P et al., Clinical Infectious Diseases
2004381454-1463
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Percent Anemic by Ethnicity(N 2056 HIV Women)
Levine AM, et al, J AIDS 2628-35, 2001
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Relationship Between HAART and Anemia in HIV
Infected Women
1575 Women, Free of Anemia at Baseline
Levine AM, et al, Blood 98501a, 2001
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Prevalence of Anemia by Race/Gender
Levine AM et al., J Acquir Immune Defic Syndr
20012628-35 Semba R et al., Clin Infect Dis
200234260-266
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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-a

Volberding P et al., Clinical Infectious Diseases
2004381454-1463
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Prevalence of Anemia During HAART
Levine AM et al., J Acquir Immune Defic Syndr
20012628-35 Semba R et al., Clin Infect Dis
200234260-266
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Treatment of HIV and Treatment-related Anemia

• Epoetin alfa
• Initiate Treatment
• Symptomatic vs asymptomatic
• Hb lt 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 lt100ng/mL, transferrin saturation lt20
Volberding P et al., Clinical Infectious Diseases
2004381454-1463
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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

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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 Platelets 68,000
• AST/ALT 34/43 Bilirubin 1.3 INR 1.6
• HCV RNA negative
• HBV DNA negative
• Does not drink or smoke

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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

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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 42177-182 June 2006