December 5, 2007 Opportunistic Infections Robert Harrington, MD
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Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series
December 5, 2007
Opportunistic Infections
Robert Harrington, MD
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HIV-Associated Opportunistic Infections 2007
Robert D. Harrington, M.D.
University of Washington
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1981MMWR 1981
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1981
MMWR 1981
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1
10
100
1,000
10,000
100,000
1,000,000
10,000,000
Pla
sma
HIV
RN
A
Plasma RNA Copies
CD4 Cells
4-8 Weeks Up to 12 Years 2-3 Years
CD
4 Cell C
ount
1,000
500
Intermediate Stage AIDS
HIV Infection: Pathogenesis
Typical Course
Viral set point
Anti-HIVT-cell response
Sero-conversionAntibody response
A lot of important stuff happens here
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1
10
100
1,000
10,000
100,000
1,000,000
10,000,000
Pla
sma
HIV
RN
A
MAC, CMV, PML, PCNSL, Cryptococcus, Microsporidia, Toxo
PCP
CD4 Cells
4-8 Weeks Up to 12 Years 2-3 Years
CD4 Cell Count
1,000
500
CD4 Count and Opportunistic Infections
200
100
Bacterial Pneumonia, TB, HSV, Cryptosporidiosis
Thrush, lymphoma, KS
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Opportunistic Infections and Geography
Common OIs• PCP• MAC• Candida
Regional Effects• Southwest:
– Coccidiodomycosis
• Midwest:– Histoplasmosis and
Blastomycosis
• South: – Blastomycosis and
Toxoplasmosis
North America
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Opportunistic Infections and Geography
The World
TBBacteriaMalariaCryptococcus
CandidaPCPMAC
Holmes, CID, 03Putong, SEA Trop Med, 02Margues, Med Mycol, 2000Amornkul, CID, 03
PCPTBCandidaCryptococcusPenicilliosis
PCPTBCryptococcusIsosporaCryptosporidiosisMicrosporidia
PCP, TBCandida, MACCryptococcusLeishmaniasis
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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
PrimaryPCP CD4 < 200
MTb PPD > 5mm
Toxo IgG+,CD4 < 100
MAC CD4 < 50
VZV Exposure with IgG- or no hstry
S. pneumoniae
HBV
HAV
Influenza
SecondaryPCP
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
WHO Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults. August, 2006
Primary prophylaxis:
Secondary prophylaxis: for PCP and Cryptococcus
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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
• Hodgkin’s disease• Anal cancer• Multiple myeloma• Leukemia• Lung cancer
• Head and neck tumors• GI malignancies• Genital cancers• Hypernephroma• Soft tissue tumors
Increased Rates of Other Cancers in HIV
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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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Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis
Secondary Prophylaxis or Maintenance TherapyPCP When CD4 > 200 for 3 monthsCMV When CD4 > 100-150 for 6 monthsMAC 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 > 100-200 for 6 months and completed initial Crypto Rx
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Effect of HAART on Opportunistic Infections: Spontaneous Improvement/Cure
0
0.2
0.4
0.6
0.8
1
0 6 12 18 24Months after Diagnosis
Su
rviv
al P
rop
orti
on
M.S. Dworkin et al. JID 1999;180:621-625
No ARTART w/o PI
ART with PI
PML Survival and HAART: ASD 1990-97
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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
Narrow base
capsule
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)
(www.aids-images.ch)
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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
(www.accessmedicine.com)
Buffy Coat Preparation
Intracellular yeast forms
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Case 2
Mold phaseYeast phase, liver biopsy
Yeast forms Macroconidida(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
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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
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Case 3: Histopathology
Photos courtesy of Heike Deubner, MDHMC Dept. of Pathology
Caseating granulomas with rare AFB
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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 diseaseDisease similar to HIV negative pts
Late HIV diseaseAt 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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Late HIV (CD4 < 200) Early HIV
PTB:EPTB 50:50 80:20Presentation Resembles primary TB Resembles
reactivationCXR
LNs Common RareLower lobes Common RareCavitation Rare Common
Anergy Common RareSmear + Less common CommonAdverse drug reactions Common RareRelapse Common Rare
TB/HIV Co-infection: Clinical Presentation
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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 77:516-23Hawken, et al. (1993) Lancet 342:332-38Perriens, et al. (1991) AM Rev Resp Dis 144:750-55Korwnromp, 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 RifampinATZ 400/d 150 QOD No
AMP 1200 BID 150 QD (300 3x/wk) No
IDV 1000 q8hr 150 QD (300 3x/wk) No
LPV/r 3 caps BID 150 QD (150 3x/wk) 600 QD +R*
NLF 1250 BID 150 QD (300 3x/wk) No
(*Extra RTV 300 BID)
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Principles of Treatment
Drug Interactions: Rifamycins and PIs
PI Rifabutin RifampinSQV/RTV 400/400 BID 150 QOD (150 3x/wk) 600 QDIDV/RTV 800/200 BID 150 QOD (150 3x/wk) NoATZ/RTV 300/100 QD 150 QOD (150 3x/wk) No dataAPV/RTV 600/100 BID 150 QOD (150 3x/wk) No dataTPV/RTV 500/200 BID 150 QOD (150 3x/wk) No dataDRV/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 450 QD (600 3x/wk) 600 QD
NVP 200 BID 300 QD 600 QD
DLV No No
Web site for more complete table showing dosages:www.cdc.gov/nchstp/tb/TB_HIV_Drugs/TOC.htm
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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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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
Start TB therapyHAART as soon as TB Rx tolerated,Between 2 to 8 weeks (2 weeks if CD4 < 50!)
Start TB therapyHAART after intensive phase of TB Rx(HAART earlier if severely immunocompromised)
Start TB therapyMonitor CD4 count and start HAART when indicated
TB therapy Improving, no OIs HAART when TB Rxcomplete
CD4 not available
CD4 < 200
CD4 200-350
CD4 > 350
HIV-TB
Extrapulmonary TBPulmonary TB
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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• 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
Survival
(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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Treatment and OutcomeSonnenberg, Lancet, 2001
326 S. African miners treated for TB in 1995
326 TB patients
151 HIV+ 175 HIV-
41 recurrences 24 recurrences
8 relapse
13 re-infection
20 ?
17 relapse
1 re-infection
6 ?
1. HR recurrence 2.42. More re-infection3. Death HIV+ 28% HIV- 4%
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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
1. Rifabutin: fever, rash -> failed desensitization with recurrent rash, fever, anaphylactoid reaction
2. INH: hepatitis, RUQ pain
3. 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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“It’s like necrotizing fasciitis, but from the inside out!”
Case 4
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Case 4
Diagnoses?
Recommendations?
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Case 4
• Schistosoma haematobium
• Filiariasis
• Genitourinary tuberculosis
• Cancer (KS, lymphoma)
• Not necrotizing fasciitis
Differential diagnosis:
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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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HIV ASSOCIATED NHL
Non-Hodgkin’s Lymphomas• AIDS defining illnesses, 60-200 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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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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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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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, <100- 16% 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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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
Bower, Curr Opin Inf Dis, 2006.
Outcomes much better with HAART: approaching that of HIV negative patients
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HIV ASSOCIATED NHL
Treatment and Outcomes
Weiss, Cancer, 2006.
But, poor outcomespersist for those with 1) poor immune function: CD4 < 502) Poor performance status3) AIDS OI
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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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Thank you!Next session: December 13th, 2007
Dr. Bob Harrington M.D.See http://globalhivlearning.org for local timesListserv: [email protected]
Email: [email protected]
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Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series
Next session: December 13th, 2007
Dr. Bob Harrington M.D.See http://globalhivlearning.org for local times