Challenging Cases in HIVImplications of Anemia

Douglas T. Dieterich, MDProfessor of Medicine, Liver DiseasesDirector, Continuing Medical Education

Department of MedicineMount 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

Sulkowski MS et al. CROI 2005; Abstract P-172

• n = 51

• Median (IQR) time between bxs, 2.84 yrs (2.05–3.41)

• 28% with more than 2 stage progression

45%

23%

10%14%

8%

0

20

40

60

0 1 2 3 or 4 5 or 6

Fibrosis stage at second biopsy

Pat

ient

s (%

)

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

Hb Decrease by W eek 4

3.14

1.96

0

1

2

3

AZT No AZT

Hb

loss

(g/

dL)

RBV Dose Reduction by W eek 4

52%

20%

0%

20%

40%

60%

AZT No AZT

Pat

ient

s w

ith R

BV

dec

reas

e

Alvarez D et al. CROI 2005; Abstract P-192

Dieterich D, et al. CROI 2004

Hematologic Response

*P < .001 vs. BL†P < .001 for epoetin alfa vs. SOC‡P = .503 vs. BL

101Baseline 2 3 4 8 12 16

11

12

13

14

*

 

‡

13.7 ± 0.4

Epoetin alfa (n = 30)

SOC (n = 22) †

Hb

(g/d

L)

Time (weeks)

11.7 ± 0.3

Hematologic Response: AZT vs. No AZT

*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

101Baseline 2 3 4 8 12 16

11

12

13

14

‡

 

13.8 ± 0.513.6 ± 0.7

12.3 ± 0.5

11.0 ± 0.4

*

Hb

(g/d

L)

Time (weeks)

Epoetin alfa + No AZT

Epoetin alfa + AZT

SOC + No AZT

SOC + AZT

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)

0

20

40

60

100

80

0 20 40 60 80 100

Cumulative ribavirin dose

Cum

ulat

ive

pegi

nter

fero

n-al

fa-2

a (4

0KD

) do

se

● SVR ● No SVR

SVR Rates According to Exposure

Genotype 1 recipients of peginterferon alfa-2a (40KD) plus ribavirin

39%

SV

R r

ate

(%)

≥ 80/80/80exposure

0

10

20

30

40

50

11%

< 80/80/80exposure*

62

29%

Allpatients

n = 176 114

*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• 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 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)

Levine AM, et al, J AIDS 26:28-35, 2001

Black White Hispanic

Pe

rce

nt (

%)

0

25

50

<12 <10 <8

Hb (g/dL)

P < .001

NS

P<.001

Relationship Between HAART and Anemia in HIV Infected Women

1575 Women, Free of Anemia at Baseline

Levine AM, et al, Blood 98:501a, 2001

Factors Associated withDevelopment 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

Factors Associated with Reduced Risk of Anemia

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

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

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

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 – Platelets 68,000

– AST/ALT 34/43 – Bilirubin 1.3 INR 1.6

• HCV RNA negative

• HBV DNA negative

• Does not drink or smoke

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