1. 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.

2. HIV-Associated Opportunistic Infections 2007
Robert D. Harrington, M.D.
University of Washington

3. 1981
MMWR 1981

4. 1981
MMWR 1981

5. 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

6. 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

7. Opportunistic Infections and Geography
North America
Common OIs
PCP
MAC
Candida
Regional Effects
Southwest:
Coccidiodomycosis
Midwest:
Histoplasmosis and Blastomycosis
South:
Blastomycosis and Toxoplasmosis

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. HIV ASSOCIATED MALIGNANCIES
AIDS Defining Malignancies
Kaposi’s sarcoma
Primary CNS lymphoma (PCNSL)
Non-Hodgkin’s lymphoma (NHL)
Invasive cervical cancer

15. 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

16. EFFECTS OF HAART ON OPPORTUNISTIC INFECTIONS
Declining incidence
Reduced need for prophylaxis (primary and secondary)
Spontaneous improvements and cure
Immune reconstitution effects

17. EFFECT OF HAART ON INCIDENCE OF OPPORTUNISTIC INFECTIONS
J.E. Kaplan et al. CID 2000;30:S5-S14
(Kovacks, NEJM, 2000)

18. 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

19. 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

20. Effect of HAART on Opportunistic Infections: Spontaneous Improvement/Cure1
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:

21. 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

22. 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.

23. Case 1
What questions do you have regarding his history and physical exam?

24. 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?

25. Case 1
Mandell, Atlas of Infectious Diseases

26. Case 1
What diagnostic testing do you want?

27. 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

28. Case 1
Does he have meningitis?
What is your differential diagnosis?

29. 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

30. Case 1
What do you want to do next?

31. Case 1
India Ink of CSF
Mandell, Atlas of Infectious Diseases

32. Case 1 Silver stain of CSF capsule Narrow base
Mandell, Atlas of Infectious Diseases

33. Case 1
Why was the CSF CRAG negative?
How are you going to treat him?

34. 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)

35. Case 1
Anything else?

36. 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)

37. Case 1
How will you follow him?

38. 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)

39. 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.

40. Case 2
What other things would you like to know about his history and exam?

41. 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?

42. Case 2
(Mandell, Atlas of Infectious Disease)s

43. Case 2
(Mandell, Atlas of Infectious Diseases) (

44. Case 2
What is your differential diagnosis?

45. Case 2 What is your differential diagnosis? Tuberculosis
Cryptococcosis
Syphilis
Histoplasmosis
Blastomycosis
MAC
Leishmaniasis
Parvovirus

46. Case 2
What diagnostic tests do you want?

47. 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

48. 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

49. Case 2 Buffy Coat Preparation Intracellular yeast forms(

50. Case 2 Yeast phase, liver biopsy Mold phase Macroconidida Yeast forms
(Mandell, Atlas of Infectious Diseases)

51. 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)

52. 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)

53. 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)

54. Case 2
What is your management plan?

55. 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)

56. Case 3
27 year-old Mexican woman with RLQ pain

57. 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

58. 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.

59. 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.

60. 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:

61. Case 3: Abdominal CT Scan
Multiple enlarged and necrotic lymph nodes in the RLQ mesentery. Ileal and cecal wall thickening.

62. Case 3: Abdominal CT Scan

63. Case 3, continued
What is your differential diagnosis?

64. 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

65. Case 3
What diagnostic tests do you want?

66. Case 3 What diagnostic tests do you want? Stool culture
Stool examination for O&P
PPD
AFB blood culture
Bacterial blood culture
Colonoscopy

67. 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

68. 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

69. 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

70. 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

71. 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%

72. 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

73. 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

74. 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?

75. Case 3: Microbiology Final diagnosis: ileocecal tuberculosis
secondary to Mycobacterium bovis

76. Case 3, continued Who wants to treat her TB?
Who wants to treat her HIV?
What issues are you worried about?

77. 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

78. 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

79. 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

80. 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)

81. 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)

82. Principles of Treatment
Drug Interactions: The P450 system
NNRTIs (efavirenz and nevirapine)
Induce CYP 3A
Protease Inhibitors (many)
Inhibit CYP 3A

83. 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)

84. 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

85. 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:

86. Case, continued Back to our case
Would you treat her HIV first, her TB first, both simultaneously?

87. 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

88. 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

89. Case, continued
Back to our case
Who thinks she’s going to do well?

90. 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)

91. 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)

92. 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 ?

93. 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

94. 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

95. 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.

96. 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

97. 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.

98. 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….

99. Case 4

100. 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

101. 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…

102. Case 4
“It’s like necrotizing fasciitis, but from the inside out!”

103. Case 4
Diagnoses?
Recommendations?

104. Case 4 Differential diagnosis: Schistosoma haematobium Filiariasis
Genitourinary tuberculosis
Cancer (KS, lymphoma)
Not necrotizing fasciitis

105. 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

106. 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

107. Case 4
Subsequent Course
A diagnostic procedure was performed

108. Case 4
Skin biopsy: lymphoma

109. 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

110. 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

111. 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 +

112. 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

113. 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)

114. HIV ASSOCIATED NHL Treatment and Outcomes
Outcomes much better with HAART:
approaching that of HIV negative patients
Bower, Curr Opin Inf Dis, 2006.

115. 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.

116. 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

117. Next session: December 13th, 2007 Dr. Bob Harrington M.D.
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118. Next session: December 13th, 2007 Dr. Bob Harrington M.D.
See for local times
This will appear on the virtual classroom in between sessions.