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December 5, 2007 Opportunistic Infections Robert Harrington, MD
I’d like to welcome everyone to the University of Washington I-TECH HIV/AIDS Clinical Seminar Series. We have with us today, Dr. Bob Harrington who is Associate Professor of Medicine at the University of Washington. He is currently associate professor of medicine at the University of Washington and medical director of the Harborview Medical Center HIV clinic (the Madison Clinic). His interests are in general infectious diseases, clinical HIV and the development of laboratory assays of HIV infectivity. He’s published over 40 manuscripts and book chapters on HIV and infectious diseases. Dr Harrington will be presenting on both December 5th and 13th. This will be the same presentation given to two different time zones. Before we begin, I’d like to ask all the sites to type in how many participants are at their sites.
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HIV-Associated Opportunistic Infections 2007
Robert D. Harrington, M.D. University of Washington
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1981 MMWR 1981
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1981 MMWR 1981
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HIV Infection: Pathogenesis
Anti-HIV T-cell response Sero-conversion Antibody response Typical Course Intermediate Stage AIDS CD4 Cell Count Plasma RNA Copies Viral set point 1,000 CD4 Cells 500 4-8 Weeks Up to 12 Years 2-3 Years A lot of important stuff happens here
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CD4 Count and Opportunistic Infections
CD4 Cell Count 1,000 Bacterial Pneumonia, TB, HSV, Cryptosporidiosis 500 CD4 Cells Thrush, lymphoma, KS 200 PCP 100 MAC, CMV, PML, PCNSL, Cryptococcus, Microsporidia, Toxo 4-8 Weeks Up to 12 Years 2-3 Years
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Opportunistic Infections and Geography
North America Common OIs PCP MAC Candida Regional Effects Southwest: Coccidiodomycosis Midwest: Histoplasmosis and Blastomycosis South: Blastomycosis and Toxoplasmosis
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Opportunistic Infections and Geography
PCP, TB Candida, MAC Cryptococcus Leishmaniasis The World PCP TB Candida Cryptococcus Penicilliosis Candida PCP MAC TB Bacteria Malaria Cryptococcus PCP TB Cryptococcus Isospora Cryptosporidiosis Microsporidia Holmes, CID, 03 Putong, SEA Trop Med, 02 Margues, Med Mycol, 2000 Amornkul, CID, 03
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Prophylaxis to Prevent Opportunistic Infections
Considerations for Prophylaxis Infection should be common and/or predictable Infection should be clinically significant Treatment (prophylaxis) should be effective, non-toxic and affordable
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Prophylaxis to Prevent Opportunistic Infections in the Developed World
Primary PCP CD4 < 200 MTb PPD > 5mm Toxo IgG+,CD4 < 100 MAC CD4 < 50 VZV Exposure with IgG- or no hstry S. pneumoniae HBV HAV Influenza Secondary PCP Toxo MAC CMV Cryptococcosis Histoplasmosis Coccidioidomycosis Salmonella species bacteremia Recurrent HSV Recurrent Candidiasis
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Prophylaxis to Prevent Opportunistic Infections in the Developing World
Primary prophylaxis: Secondary prophylaxis: for PCP and Cryptococcus WHO Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults. August, 2006
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TB prevention WHO recommendation:
Treat tuberculin skin test positive HIV-infected persons without active TB with 6 month regimen isoniazid preventive therapy (IPT) Difficulties: Lack of tuberculin skin testing People not screened Screen positive do not receive INH Screen positive started on INH do not complete regimen
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HIV-Associated and Opportunistic Infections
PCP MAC Cryptosporidiosis Microsporidiosis Bacterial respiratory infections Bacterial enteric infections Bartonellosis Coccidiodomycosis Paracoccidiomycosis Histoplasmosis Cryptococcus Toxoplasmosis Candida TB Aspergillosis CMV HSV VZV PML (JCV) HHV-8 HPV Penicilliosis Leshmaniasis
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HIV ASSOCIATED MALIGNANCIES
AIDS Defining Malignancies Kaposi’s sarcoma Primary CNS lymphoma (PCNSL) Non-Hodgkin’s lymphoma (NHL) Invasive cervical cancer
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HIV ASSOCIATED MALIGNANCIES
Increased Rates of Other Cancers in HIV Hodgkin’s disease Anal cancer Multiple myeloma Leukemia Lung cancer Head and neck tumors GI malignancies Genital cancers Hypernephroma Soft tissue tumors
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EFFECTS OF HAART ON OPPORTUNISTIC INFECTIONS
Declining incidence Reduced need for prophylaxis (primary and secondary) Spontaneous improvements and cure Immune reconstitution effects
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EFFECT OF HAART ON INCIDENCE OF OPPORTUNISTIC INFECTIONS
J.E. Kaplan et al. CID 2000;30:S5-S14 (Kovacks, NEJM, 2000)
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Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis
Primary Prophylaxis PCP When CD4 > 200 for 3 months MAC When CD4 > 100 for 3 months Toxo When CD4 > 200 for 3 months
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Secondary Prophylaxis or Maintenance Therapy
Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis Secondary Prophylaxis or Maintenance Therapy PCP When CD4 > 200 for 3 months CMV When CD4 > for 6 months MAC When CD4 > 100 for 6 months, no symptoms of MAC and after 12 months of MAC Rx Toxo When CD4 > 200 for 6 months and completed initial Toxo Rx Cryptococcus When CD4 > for 6 months and completed initial Crypto Rx
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Effect of HAART on Opportunistic Infections: Spontaneous Improvement/Cure
1 PML Survival and HAART: ASD 0.8 ART with PI 0.6 Survival Proportion 0.4 0.2 ART w/o PI No ART 6 12 18 24 Months after Diagnosis M.S. Dworkin et al. JID 1999;180:
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Other Infections Cured or Improved with HAART
Effect of HAART on Opportunistic Infections: Spontaneous Improvement/Cure Other Infections Cured or Improved with HAART Microsporidia Cryptosporidia Hepatitis B Molluscum Contagiosum Kaposi’s Sarcoma
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Case 1 A 42 year old man with HIV (CD4 89) presents with fever, headache, fatigue and recurrent molluscum contagiosum. Blood cultures are taken, his molluscum lesions are treated with liquid nitrogen, he is given Tylenol for his fevers and goes home. He returns several days later more lethargic with a worsening headache, a temperature of 39 degrees C and more molluscum lesions.
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Case 1 What questions do you have regarding his history and physical exam?
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Case 1 What questions do you have regarding his history and physical exam? Does he have any pulmonary symptoms? What is his TB exposure and testing history? Where has he lived? What animal and environmental exposures does he have? What is his toxoplasmosis serology? Has he had other infections in the past? Tell me more about these skin lesions. Can I see them?
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Case 1 Mandell, Atlas of Infectious Diseases
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Case 1 What diagnostic testing do you want?
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Case 1 What diagnostic testing do you want? Brain CT is negative
CSF analysis: opening pressure is 300 mm, WBC 0, protein 60, glucose 30, CRAG is negative, VDRL is negative, PCR for CMV, VZV, HSV and EBV are negative
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Case 1 Does he have meningitis? What is your differential diagnosis?
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Case 1 Does he have meningitis? What is your differential diagnosis?
Cryptococcal meningitis Bacterial meningitis (S. pneumoniae, H. influenza, N. meningitidis, L. monocytogenes) Tuberculous meningitis Other chronic meningitides (histoplamosis, blastomycosis, etc) Viral meningo-encephalitis (e.g., HSV, enteroviruses, other herpes viruses, rabies
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Case 1 What do you want to do next?
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Case 1 India Ink of CSF Mandell, Atlas of Infectious Diseases
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Case 1 Silver stain of CSF capsule Narrow base
Mandell, Atlas of Infectious Diseases
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Case 1 Why was the CSF CRAG negative? How are you going to treat him?
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Case 1 Why was the CSF CRAG negative? Antigen excess
How are you going to treat him? Initial therapy; AmphoB (0.7 mg/kg/d) with or without 5-FC for 2 weeks Followed by fluconazole at 400 mg/day for 10 weeks and then maintenance therapy with fluconazole at 200 mg/day. Relapse without suppressive therapy (or HAART) is 50 to 60% (Van der Horst, NEJM, 1997) (Saag, CID, 2000)
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Case 1 Anything else?
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Case 1 Anything else? High pressure associated with more symptoms (HA, meningismus, cranial nerve deficits) and higher antigen titers. Pressure > 350 is associated with early (first week) death Most experts recommend serial large volume spinal taps or spinal drains for patients with elevated CSF pressures (Graybill, CID, 2000)
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Case 1 How will you follow him?
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Case 1 How will you follow him?
Cryptococcal antigen for monitoring therapy: Serum; No: no correlation between titer and outcome CSF; Yes: unchanged or rising titer is associated with failure and relapse. High dose steroids associated with increased mortality (Powderly, CID, 1994)
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Case 2 A 24 year old man with HIV (CD 68) is flown down from Alaska with fever, weight loss and fatigue starting 6 weeks ago but much worse over that last 4 days. He has declined HIV treatment. His PMH is notable only for thrush. He grew up in Indiana but has lived in Alaska all his adult life. He acquired HIV using IV drugs. He’s a fisherman. Physical exam reveals a cachectic male with a temperature of 40 degrees C. He has a papular skin rash, a tender oral ulcer and a palpable spleen. WBC is 1.3, Hct 24, plts 66,000. CXR demonstrates diffuse infiltrates and calcified lesions in the hilar region and in the LUQ.
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Case 2 What other things would you like to know about his history and exam?
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Case 2 What other things would you like to know about his history and exam? Does he still inject drugs? What is his TB exposure and testing history? Where has he lived and traveled besides Alaska and Indiana? What animal and environmental exposures does he have? Has he had other infections in the past? Has he ever had cancer? Can I see his CXR, skin and oral lesions?
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Case 2 (Mandell, Atlas of Infectious Disease)s
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Case 2 (Mandell, Atlas of Infectious Diseases) (
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Case 2 What is your differential diagnosis?
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Case 2 What is your differential diagnosis? Tuberculosis
Cryptococcosis Syphilis Histoplasmosis Blastomycosis MAC Leishmaniasis Parvovirus
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Case 2 What diagnostic tests do you want?
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Case 2 What diagnostic tests do you want? PPD RPR AFB blood culture
Fungal blood culture Bacterial blood culture Skin/ulcer biopsy CRAG Buffy coat preparation Histoplasmosis Ag
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Case 2 What diagnostic tests do you want? PPD negative (anergic)
RPR positive AFB blood culture done and pending Fungal blood culture done and pending Bacterial blood culture done and pending Skin/ulcer biopsy done CRAG negative Buffy coat preparation done Histoplasmosis Ag done and pending
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Case 2 Buffy Coat Preparation Intracellular yeast forms
(
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Case 2 Yeast phase, liver biopsy Mold phase Macroconidida Yeast forms
(Mandell, Atlas of Infectious Diseases)
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Histoplasmosis Among HIV+ patients
Illness severity related to intensity of exposure and immunity of host Most symptomatic HIV infected patients have CD4 < 100 (90%) Disease usually due to acute infection but may result from reactivation in some cases (Wheat, Medicine, 1990)
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Histoplasmosis Syndromes in HIV infected patients:
Disseminated infection (95%) – fever, weight loss, anemia, organomegaly Pneumonitis (50%) – most often presents with a diffuse reticular pattern on CXR CNS involvement (5-20%) – chronic meningitis, focal brain lesions Shock and ARDS in up to 20% Other sites: lymphnodes, mucosal lesions, gastrointestinal, ocular (Wheat, Medicine, 1990)
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Histoplasmosis Diagnosis
Histoplasma antigen (false + in blastomycosis, coccidioidomycosis, paracoccidioidomycosis) Urine 95% sensitive Serum 86% CSF 70% Alveolar lavage fluid 67% Culture; sensitivity 70 to 90%; takes 1 to 6 weeks to grow Fungal stain of tissue; sensitivity up to 70%, buffy coat stain positive in up to 45% (Wheat, Trends Microbiol, 2003)
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Case 2 What is your management plan?
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Case 2 What is your management plan? Mild disease: Itraconazole
Moderate to severe disease: Liposomal AmB for .5 to 2 weeks followed by itraconazole (200 mg bid; measure levels) or high dose fluconazole (800 mg/day) - for 10 weeks Maintenance: Itraconazole > fluconazole (more relapses with fluconazole) CNS disease: Ampho B followed by fluconazole To monitor disease - can measure Ag levels at 1 and 3 months (Wheat, CID, 2000) (Johnson, Ann Int Med, 2002) (Wheat, CID, 2007)
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Case 3 27 year-old Mexican woman with RLQ pain
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Case 3 3 months prior to presentation: returned to Seattle after 1 year stay in Mexico 2 weeks prior to presentation: TAB/IUD placement 4 days prior to presentation: IUD expelled and patient complaining of RLQ pain. On exam RLQ tenderness to deep palpation Continued RLQ pain but no f/c/ns, n/v, diarrhea, weight loss
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Case 3 HIV history Dx 4/00 during pregnancy. CD4 1365/45%, VRL 22,000 copies/ml at diagnosis. Briefly on NVP/Combivir -> hepatotoxicity, followed by AZT intrapartum. No ARVs since, no OIs. Current CD4 147/11%, VRL 178,000 copies/ml.
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Case 3 Medications: Bactrim DS Social History
Lives with partner, 4 year old daughter (both well) Sexually active with single partner, 100% condom use. No animal exposures. No tob/EtOH/drugs.
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Case 3 General: well appearing
VS: T=37.1, BP=116/77, HR 111, RR 16, 168 lbs (8 lb loss over past month) AB: normoactive BS, soft, non-distended, tender to deep palpation in RLQ with radiation to RUQ and epigastrum. No HSM or masses palpated. Pelvic (3 days prior by gynecologist): normal Abdominal imaging is performed:
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Case 3: Abdominal CT Scan
Multiple enlarged and necrotic lymph nodes in the RLQ mesentery. Ileal and cecal wall thickening.
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Case 3: Abdominal CT Scan
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Case 3, continued What is your differential diagnosis?
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Case 3, continued What is your differential diagnosis?
Inflammatory bowel disease Bacterial colitis (Salmonella, Campylobacter, Yersinia) Parasitic infection (Amebiasis, Cryptosporidia, others) Intra-abdominal bacterial abscess (from appendicitis or diverticular disease) TB
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Case 3 What diagnostic tests do you want?
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Case 3 What diagnostic tests do you want? Stool culture
Stool examination for O&P PPD AFB blood culture Bacterial blood culture Colonoscopy
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Case 3 What diagnostic tests do you want? Stool culture Negative
Stool examination for O&P Negative PPD Negative (anergic) AFB blood culture Done and pending Bacterial blood culture Negative Colonoscopy Done
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Case 3: Colonoscopy Dept. of Medicine, Div. of Gastroenterology
Photos courtesy of Steve Rulyak, MD 2.5 cm ulceration with heaped up borders terminal ileum 1 cm deep ulcer with heaped up borders cecum Scattered apthous ulcerations overlying nodular mucosa
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Case 3: Histopathology Caseating granulomas with rare AFB
Multiple necrotizing granulomas with multinucleated Giant cells AFB stain negative Photos courtesy of Heike Deubner, MD HMC Dept. of Pathology
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Pathogenesis and Natural History
Effect of HIV on TB TB acquisition Progressive, primary infection 10% (up to 37%) LTBI 90% Reactivation TB 10% annual risk, 30% lifetime Early HIV disease Disease similar to HIV negative pts Late HIV disease At least 50% EPTB
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TB/HIV Co-infection: Clinical Presentation
Presentation depends on immune status Extra-pulmonary disease in 40 to 80% CNS TB develops in 5 to 10% of HIV+ patients (< 2% of HIV- patients) Bacteremia occurs in 26 to 42%
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TB/HIV Co-infection: Clinical Presentation
Late HIV (CD4 < 200) Early HIV PTB:EPTB 50: :20 Presentation Resembles primary TB Resembles reactivation CXR LNs Common Rare Lower lobes Common Rare Cavitation Rare Common Anergy Common Rare Smear + Less common Common Adverse drug reactions Common Rare Relapse Common Rare
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Pathogenesis and Natural History
Atypical presentations of TB are common Kenya: acute pneumonia – 9% are TB Malawi: cough for < 3 weeks – 35% are TB Tanzania: fever in HIV+ patients – 23% are TB Kenya: diarrhea in HIV+ patients – 13% are TB Cote d’Ivoire and Congo: autopsy series – 38 to 47% COD is TB (< 50% diagnosed with TB ante-mortem) Corbett, Lancet, 2006
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Back to the case….. AFB stain: 1+ AFB
hsp65 PCR: Mycobacterium tuberculosis complex Culture: 2+ AFB -> sensitive to INH, RIF, EMB, STREP but resistant to PZA What organism is this?
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Case 3: Microbiology Final diagnosis: ileocecal tuberculosis
secondary to Mycobacterium bovis
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Case 3, continued Who wants to treat her TB?
Who wants to treat her HIV? What issues are you worried about?
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TB/HIV Co-infection: Principles of Treatment
Treatment generally the same as in HIV- patients (4 drugs for 2 months and 2 drugs for 4 months) Sub-optimal response (culture + after 2 months) – give 9 months, skeletal TB – 6 to 9 months, CNS TB – 9 to 12 months If using regimens without INH or a rifamycin - duration should be 12 to 15 months
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Principles of Treatment: Importance of Rifamycin
Treatment with NON rifamycin-containing regimens is associated with: • Higher relapse rates • Higher mortality Wallis, et al. (1996) Tuber Lung Dis 77:516-23 Hawken, et al. (1993) Lancet 342:332-38 Perriens, et al. (1991) AM Rev Resp Dis 144:750-55 Korwnromp, et al. (2003) CID 37:101-12
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Principles of Treatment
Be wary of drug interactions between the rifamycins and HIV medications Do not use TB treatment regimens that are dosed weekly (e.g. INH-rifapentine) or even twice weekly in patients with CD4 counts < 100 Consider measuring drugs levels if there is concern for malabsorption or increased elimination of TB therapies
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Principles of Treatment
Malabsorption More common in patients with late HIV infection (low CD4) and with GI symptoms Rifampin and ethambutol are most prone to malabsorbtion Rifabutin is less subject to malabsorption than rifampin (Pearlman, CID, 2005)
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Principles of Treatment
Drug Interactions: The P450 system Isoform CYP 3A is affected and/or involved in the metabolism of rifamycins, NNRTI and PIs Rifamycins: Induce CYP 3A Rifampin > rifapentine > rifabutin Rifampin is not metabolized by CYP 3A (level not affected by other drugs that influence CYP 3A) Rifabutin is metabolized by CYP 3A (level is affected by other drugs that also affect CYP 3A)
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Principles of Treatment
Drug Interactions: The P450 system NNRTIs (efavirenz and nevirapine) Induce CYP 3A Protease Inhibitors (many) Inhibit CYP 3A
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Principles of Treatment
Drug Interactions: Rifamycins and PIs PI Rifabutin Rifampin ATZ 400/d QOD No AMP 1200 BID QD (300 3x/wk) No IDV 1000 q8hr QD (300 3x/wk) No LPV/r 3 caps BID QD (150 3x/wk) QD +R* NLF 1250 BID QD (300 3x/wk) No (*Extra RTV 300 BID)
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Principles of Treatment
Drug Interactions: Rifamycins and PIs PI Rifabutin Rifampin SQV/RTV 400/400 BID 150 QOD (150 3x/wk) QD IDV/RTV 800/200 BID 150 QOD (150 3x/wk) No ATZ/RTV 300/100 QD 150 QOD (150 3x/wk) No data APV/RTV 600/100 BID 150 QOD (150 3x/wk) No data TPV/RTV 500/200 BID 150 QOD (150 3x/wk) No data DRV/RTV 600/100 BID 150 QOD (150 3x/wk) No data
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Principles of Treatment
Drug Interactions: Rifamycins and NNRTIs NNRTI Rifabutin Rifampin EFV 600 QD QD (600 3x/wk) QD NVP 200 BID QD QD DLV No No Web site for more complete table showing dosages:
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Case, continued Back to our case
Would you treat her HIV first, her TB first, both simultaneously?
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CDC/ATS/IDSA Recommend:
Treatment and Outcome CDC/ATS/IDSA Recommend: If initiating both anti-tuberculous and HIV treatment, don’t start both simultaneously. TB therapy usually started 4 to 8 weeks prior to HAART
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WHO: Treatment HIV-TB Pulmonary TB Extrapulmonary TB Start TB therapy
HAART as soon as TB Rx tolerated, Between 2 to 8 weeks (2 weeks if CD4 < 50!) CD4 < 200 Start TB therapy HAART after intensive phase of TB Rx (HAART earlier if severely immunocompromised) CD Start TB therapy Monitor CD4 count and start HAART when indicated CD4 > 350 CD4 not available TB therapy Improving, no OIs HAART when TB Rx complete
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Case, continued Back to our case Who thinks she’s going to do well?
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Treatment and Outcome Thailand Survival
Retrospective study of 1103 HIV+ patients with TB 411 received HAART Risk factors for death No HAART Delay of HAART > 6 months MDR TB Gastrointestinal TB (Manosuthi, J Acquir Immune Defic Syndr 2006;43:42-46)
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Treatment and Outcome San Francisco
Retrospective study of 700 patients with TB 264 (38%) HIV+ Mean duration of Rx 10.2 months (HIV+) 8.4 months (HIV-) 17% of HIV+ and 37% of HIV- standard 6 mos of Rx Relapse rates 9.3/100 person-yrs (HIV+) Vs 1.0/100 person-yrs (HIV-) More relapse in HIV+ pts Rx with standard Rx (HR 4.33) and with intermittent Rx (HR 4.12) (Nahid, Am J Respir Crit Care Med 2007)
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326 S. African miners treated for TB in 1995
Treatment and Outcome Sonnenberg, Lancet, 2001 326 S. African miners treated for TB in 1995 326 TB patients 151 HIV+ 175 HIV- 1. HR recurrence 2.4 2. More re-infection 3. Death HIV+ 28% HIV- 4% 41 recurrences 24 recurrences 8 relapse 17 relapse 13 re-infection 1 re-infection 20 ? 6 ?
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Back to the case… Started 4 drug TB regimen (RIPE) with rifabutin in place of rifampin Completed 8 weeks then developed multiple drug allergies/intolerances Rifabutin: fever, rash -> failed desensitization with recurrent rash, fever, anaphylactoid reaction INH: hepatitis, RUQ pain Levofloxacin, Moxifloxacin: rash, tremor
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Case, continued Started new regimen of cycloserine, EMB, STREP
Completed 4 months above regimen without incident (6 months total) Subsequent CT scan showed near complete resolution of adenitis
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Case, continued Started on HAART: ATV/r, Truvada
CD4 77/3%, VRL > 1 million copies/ml Two weeks after initiation HAART -> L-sided flank/abdominal pain after incident at work. Exam with LUQ tenderness. Naprosyn prescribed and symptoms resolved. Presently doing well on HAART with complete viral suppression.
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TB and HIV Co-infection, 2007
Conclusions TB and HIV are a couple of bad actors that have an bad influence on one another Africa is bearing the brunt of these co-epidemics HAART is decreasing the incidence of and mortality due to TB but is also expanding the pool of patients especially vulnerable to TB Atypical (primary and extrapulmonary) presentations of TB predominate in HIV-TB co-infected persons Response to anti-tuberculous is excellent as long as you use daily dosing and watch out for drug interactions IRS due to HAART is a significant problem that clinicians should recognize and may require steroid therapy
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Case 4 A 38 year old man presented to the ED with dysuria, hematuria and abd pain for 2 weeks Laboratory studies, an abd/pelvic CT were performed – diagnosed with a UTI and sent home on ciprofloxacin Read of CT the next day- abnormal bladder wall thickening and surrounding soft tissue stranding He returned to the ED 1 week later with lower abdominal pain and swelling of his R thigh, scrotum and penis.
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Case 4 He denied fevers, chills, nausea, vomiting, weight loss, night sweats PMH “Told I had HIV” in ’94 Episode of submandibular swelling early ’05 PPD+ s/p INH therapy for latent TB Social history From Ethiopia to US ’93 Went back one year earlier. While there he waded in the Blue Nile….
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Case 4
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Case 4 While in Ethiopia had a fever, was diagnosed with malaria and treated with an unknown drug. PE: 37.2, NAD Abdomen: soft, diffusely tender, especially in the suprapubic area, no rebound or guarding, edema of the penis, scrotum and R thigh
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Case 4 WBC 4,500 (840 eosinophils) , HCT 40, PLT 224, UA unremarkable, blood and urine cultures sent Patient was admitted and started on broad spectrum antibiotics and given praziquantel. Ultrasound: bilateral hydronephrosis and very thickened scrotal skin (~2 cm), testicles nl, CT…
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Case 4 “It’s like necrotizing fasciitis, but from the inside out!”
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Case 4 Diagnoses? Recommendations?
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Case 4 Differential diagnosis: Schistosoma haematobium Filiariasis
Genitourinary tuberculosis Cancer (KS, lymphoma) Not necrotizing fasciitis
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Case 4 Hospital Course Thick and thin smears negative, including time appropriate smears for filiariasis Urine O+P x 6 neg Filariasis Ab neg RPR neg Multiple blood and urine cultures negative Patient discharged with outpatient follow-up
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Case 4 Subsequent Course
One week later: cystoscopy: multiple sub-mucosal growths, diffuse leukoplakia Soon after: presented to ED with leg and groin pain. Sent home, then admitted with difficulty urinating. PE: edema from chest to abdomen to R leg CD4 32, VL 52K Developed a fever, lactate rose to 9.3, transferred to the ICU
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Case 4 Subsequent Course A diagnostic procedure was performed
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Case 4 Skin biopsy: lymphoma
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Non-Hodgkin’s Lymphomas
HIV ASSOCIATED NHL Non-Hodgkin’s Lymphomas AIDS defining illnesses, times more common in HIV+ people, #2 after KS Over 90% are of B-cell origin, many associated with EBV and HHV-8 WHO classes I: NHL that occurs in immunocompetent people: Burkitt’s, DLBCL II: NHL specific to HIV+ people: plasmablastic lymphoma and PEL III: Lymphomas that occur in other immunocompromised groups: PTLPD
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Non-Hodgkin’s Lymphomas
HIV ASSOCIATED NHL Non-Hodgkin’s Lymphomas Risk factors Low CD4, high HIV RNA, older age and male gender Effect of HAART Lower incidence of PCNSL Controversial effect of incidence of other NHL: NHL now represents higher % of ADI but overall rate of disease is flat or slightly decreased
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Non-Hodgkin’s Lymphomas
HIV ASSOCIATED NHL Non-Hodgkin’s Lymphomas Clinically 90% of NHL are either DLBCL or Burkitt’s Usually presents with advanced stage, B symptoms and extra-nodal involvement (BM, CNS, head and neck, soft tissue) PCNSL - immunoblastic, EBV+ 90%, CD4 < 50 PEL – represent 5% of NHL; malignant effusions without nodal disease, HHV-8+, most are EBV +
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Non-Hodgkin’s Lymphomas
HIV ASSOCIATED NHL Non-Hodgkin’s Lymphomas Treatments and outcomes Pre-HAART era: 10% survival at 2 years HAART era CHOP and HAART (Ratner, 2001) Response rates up to 48% EPOCH followed by HAART (Little, 2003) 74% complete response, >100 CD4 cells- 88% alive at 56m, < % alive at 56m Critical finding- Able to give full dose therapy in majority 60% survival > 4 yrs Rituxamab (anti-CD 20) (AIDS Malignancy Consortium Phase III) Non-significant difference between regimens Of the 16 that died of infections, 15 received R-CHOP Of those 15, however, 9 had CD4 counts <5
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Non-Hodgkin’s Lymphomas
HIV ASSOCIATED NHL Non-Hodgkin’s Lymphomas Treatments and outcomes PEL: CR 40%, median survival 6 months PCNSL: whole brain XRT + steroids: median survival > 1.5 years (compared with 2-3 mos, pre-HAART)
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HIV ASSOCIATED NHL Treatment and Outcomes
Outcomes much better with HAART: approaching that of HIV negative patients Bower, Curr Opin Inf Dis, 2006.
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HIV ASSOCIATED NHL Treatment and Outcomes But, poor outcomes
persist for those with 1) poor immune function: CD4 < 50 2) Poor performance status 3) AIDS OI Weiss, Cancer, 2006.
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Recommendations Be aware of unusual (extra-nodal) presentations
Initiate HAART at diagnosis (avoid AZT) Start PCP prophylaxis at the same time regardless of CD4 count G-CSF and erythropoietin as needed EPOCH/CHOP +/- Rituxamab Prophylactic intrathecal chemotherapy
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Next session: December 13th, 2007 Dr. Bob Harrington M.D.
See for local times Listserv: Thank you for attending the session. We will answers to the questions that we were unable to get to today to the Distance Learning listserv. If you have additional questions, please them to the listserv. That listserv is: Please contact if you would like to get on this listserv. Please be sure to fill out site coordinator and participant evaluations and return to Anya, we greatly appreciate your feedback.
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Next session: December 13th, 2007 Dr. Bob Harrington M.D.
See for local times This will appear on the virtual classroom in between sessions.
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