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Challenging Cases in HIV Implications of Anemia David H. Henry, MD Clinical 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 70% n = 154 Patients (%) 60% 50% 40% 30% 20% n = 36 n = 22 10% n = 12 n=6 0% 8.0-8.9 9.0-9.9 10.0-10.9 11.0-11.9 12.0-12.5 Hemoglobin level (g/dL) Nadler JP et al. 5th IWADRL in HIV, Paris 2003 Distribution of Hb by Gender Nadler JP et al. 5th IWADRL in HIV, Paris 2003 Prevalence of Anemia* by Race/Gender 39% 40% 35% 31% 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 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 70% 64% 60% 47% 54% 52% 50% 40% 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 Association of Anemia and HIV Disease Progression in Patients Receiving HAART Overall odds ratio for HIV progression 9 ‡ (N = 501) 8 7 6 † 5 4 3 2 1 0 Cases* Controls Female Controls cases Male Controls cases *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 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 Hb 10-11 g/dL Hb 11-12 g/dL Hb > 12 g/dL 8.62 (95% CI:5.52, 13.3) 7.31 (95% CI:4.52, 11.7) 3.93 (95% CI:2.44, 6.35) Reference group Moore R et al. CROI 2004, Abstract K5 Progression to Death for Patients According to Baseline Hb in EuroSIDA: Multivariate Analysis 100 Proportion alive (%) 90 Normal (n = 2716) Hb >14 g/dL for men and >12 g/dL for women 80 70 60 Severe (n = 92) 50 Hb <8 g/dL for men and women Mild (n = 3917) Hb 8-14 g/dL for men and 8-12 g/dL for women P < .001 40 0 6 12 18 24 30 36 Months after recruitment Mocroft A, et al. AIDS. 1999;13:943-950 Recovery From Anemia Is Associated With Improved Survival (N = 3203) Median survival (months) 70 60 Recovery P = .0001 for all CD4 categories (log rank) 50 No recovery 40 30 20 10 0 Risk ratio (99% CI) 0-49 0.39 (0.32-0.49) 50-99 100-149 150-199 CD4 count (cells/mL) 0.43 (0.32-0.59) 0.37 (0.24-0.57) 0.27 (0.17-0.45) ≥200 0.39 (0.30-0.50) Sullivan PS, et al. Blood. 1998;91:301-308 Progression of Hb During HAART N=24 treatment-naïve, HIV-infected patients 2 Hb Change From Baseline 1.5 ( x g/dL) 1 0.5 CD4 cell count ( x 102 cells/µL) 0 -0.5 -1 Viral load ( x log10RNA copies/mL) -1.5 -2 0 3 6 9 12 15 18 21 24 Time on HAART (months) Servais J, et al. JAIDS. 2001;28:221-225 Association Between Anemia Treatments and Death Rates Death Rate: Cox Proportional Hazards Model All Patients (n = 2348) Patients with Anemia (n = 498) Treatment RH P value Epoetin alfa 0.57 .002 Transfusion 1.32 .003 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