Challenging Cases in HIV Implications of Anemia

1. Challenging Cases in HIVImplications of Anemia David H. Henry, MD Clinical Professor of Medicine Pennsylvania Hospital Joan Karnell Cancer Center Philadelphia, PA

2. 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

3. 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

4. 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

5. Reticulocyte count Underproductive (<5%) Overdestructive (>10%) ……………………………………….. 110 ….. B12, folate deficiency, MDS MCV 90 ….. ACD, CRF, drugs………. 70 ….. Fe deficiency, thalassemia… Anemia Work-up

6. 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)

7. 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

8. 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)

9. 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

10. 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

11. 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)

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. Prevalence and Implications of Anemia in the Patient with HIV

20. n = 154 Patients (%) n = 36 n = 22 n = 12 n = 6 Hemoglobin level (g/dL) Distribution of Hb in Anemic HIV Patients Nadler JP et al. 5th IWADRL in HIV, Paris 2003

21. Distribution of Hb by Gender Nadler JP et al. 5th IWADRL in HIV, Paris 2003

22. 39% 31% 19% 12% *Anemia was defined as <12 g/dL for women and < 13 g/dL for men Prevalence of Anemia* by Race/Gender Levine AM et al., J Acquir Immune Defic Syndr 2001:26:28-35 Semba R et al., Clin Infect Dis 2002;34:260-266

23. Baseline Hb by CD4+ Strata Nadler JP et al. 5th IWADRL in HIV, Paris 2003

24. Baseline Hb by VL Strata Nadler JP et al. 5th IWADRL in HIV, Paris 2003

25. Prevalence of Anemia According to Treatment Regimen Nadler JP et al. 5th IWADRL in HIV, Paris 2003

26. 64% 54% 52% 47% 46% 35% 1.5% 1.2% 0.6% * 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 Prevalence of Anemia* During HAART Levine AM et al., J Acquir Immune Defic Syndr 2001:26:28-35 Semba R et al., Clin Infect Dis 2002;34:260-266

27. 9 ‡ (N = 501) 8 7 6 † Overall odds ratio for HIV progression 5 4 3 2 1 0 Cases* Controls Female cases Controls Male cases Controls 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 Creagh T, et al. IAS 2001; Poster 1049

28. 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

29. 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

30. 100 90 Normal (n = 2716)Hb >14 g/dL for menand >12 g/dL for women 80 Proportion alive (%) 70 Mild (n = 3917)Hb 8-14 g/dL for menand 8-12 g/dL for women Severe (n = 92)Hb <8 g/dL formen and women 60 50 P < .001 40 12 36 0 6 18 24 30 Months after recruitment Progression to Death for Patients According to Baseline Hb in EuroSIDA: Multivariate Analysis • Mocroft A, et al. AIDS. 1999;13:943-950

31. 70 60 Recovery P = .0001 for all CD4 categories (log rank) 50 No recovery 40 Median survival (months) 30 20 10 0 0-49 50-99 100-149 150-199 ≥200 CD4 count (cells/mL) 0.39 (0.32-0.49) 0.43 (0.32-0.59) 0.37 (0.24-0.57) 0.27 (0.17-0.45) 0.39 (0.30-0.50) Risk ratio (99% CI) Recovery From Anemia Is Associated With Improved Survival (N = 3203) Sullivan PS, et al. Blood. 1998;91:301-308

32. N=24 treatment-naïve, HIV-infected patients Hb ( x g/dL) CD4 cell count ( x 102 cells/µL) Change From Baseline Viral load ( xlog10RNA copies/mL) 0 3 6 9 12 15 18 21 24 Time on HAART (months) Progression of Hb During HAART Servais J, et al. JAIDS. 2001;28:221-225

33. Association Between Anemia Treatments and Death Rates • Moore R. JAIDS. 1998;19:29

34. 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

35. 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)

36. 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