1. HIV-Associated Opportunistic Infections 2010
February 11, 2010
HIV-Associated Opportunistic Infections 2010
Robert D. Harrington, MD

2. HIV-Associated Opportunistic Infections 2010
Robert D. Harrington, M.D.
University of Washington

3. MMWR 1981

4. CD4 Count and Opportunistic Infections
CD4 Cell Count
Bacterial Pneumonia, TB,
HSV, Cryptosporidiosis
1,000
Thrush, lymphoma, KS
500
PCP
200
100
MAC, CMV, PML, PCNSL,
Cryptococcus, Microsporidia
Toxo
4-8 Weeks
Up to 12 Years
2-3 Years

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

6. 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

7. 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

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

9. 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

10. 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

11. Prophylaxis to Prevent Opportunistic Infections in the Developed World
Primary Prophylaxis
PCP CD4 < 200 TMP/SMX
MTb PPD > 5mm INH
Toxo IgG+, CD4 < 100 TMP/SMX
MAC CD4 < 50 Azithromycin
VZV Vaccine
S. Pneumoniae Vaccine
HBV Vaccine
HAV Vaccine
Influenza Vaccine

12. Cotrimoxazole is beneficial in all pts with HIV infection regardless of CD4 count
Study in rural Uganda enrolled 509 HIV+ & 1522 HIV- individuals
All clients observed for 5 months after which HIV+ were given TMP-SMX (960mg) and followed up for 1.5yrs
Mermin et al. Lancet 2004 ; 364: 1428

13. Outcomes on Cotrimoxazole Prophylaxis
Mortality reduced by 46%, p=0.006
Malaria incidence reduced by 72% p<0.0001
Diarrhea incidence reduced by 35% p<0.0001
Clinic visits reduced by 15% p=0.04
Hospital admissions reduced by 21% p=0.04
Mermin et al. Lancet 2004 ; 364: 1428

14. Cotrimoxazole
WHO. Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults. 2006

15. WHO Guidelines 2008: Prophylaxis to Prevent Opportunistic Infections in the Resource-limited settings
Co-trimoxazole
WHO stage 2,3,4 or any stage with CD4 < 350
Tuberculosis
In settings where active TB can be excluded it may be appropriate to screen for latent TB with PPD and treat with INH for 6 months
Cryptococcus
In regions where cryptococcal disease is common it may be reasonable to prescribe azoles (fluconazole) for patients with stage 4 disease or CD4 < Rule out active disease first
Histoplasmosis & Penicilliosis
In areas endemic for these infections can consider using itraconazole (rather than fluconazole) to prevent cryptococcus, histoplasmosis and penicilliosis
Malaria
Co-trimoxazole daily
STDs
Regular routine testing and treatment or syndromic management where testing not available

16. WHO Guidelines 2008: Prophylaxis to Prevent Opportunistic Infections in the Resource-limited settings
Hepatitis B
If serologic testing available: For patients who are HbcAB negative – give series of 3 regular or DD vaccine with post vaccination AB testing
If serologic testing not available and prevalence of HBV is high – give series of 3 regular or DD vaccine
Pneumococcal vaccination
Consider in adults with stage 1 disease or CD4 > 500
Consider vaccination of children < 5 years who live with HIV infected persons
Influenza
When feasible – annual vaccination with inactivated flu vaccine

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

18. Case 1
A 32 yo HIV+, pregnant Ugandan woman who has been living in South Africa since she was 12 decides to return to Uganda to celebrate her mother’s 50th birthday.
A week after arriving she develops fever, myalgias, headache, mild dyspnea and diarrhea. She takes Tylenol for her fevers with little effect and then becomes lethargic over the next 12 hours prompting her family to bring her to the local clinic.
PMHx notable for HIV (untreated with CD4 of 189), thrush and 2 previous spontaneous abortions

19. Case 1
On exam she is obtunded but is arousable. VS: BP 100/60, HR 115, T 39.0, RR 14. Conjunctiva are pale, oral exam shows white plaques, lung exam reveals fine rales at the bases, CV RRR with 2/6 SEM, ABD is soft and non tender, skin is clear
What are some diagnostic possibilities?
Malaria
Meningitis (bacterial, cryptococcal > TB)
Bacteremia (Salmonella, S pneumonia, N. meningititis)
Pneumonia (bacterial, PCP)
Typhoid fever or enteritis

20. Case 1 What diagnostic testing do you want:
CBC and chemistries: Hct 28, WBC 6, plts 90K, glucose 70, creat 1.4
Blood cultures for bacteria, AFB and fungi: done and pending
CRAG: negative
CSF exam: RBC 0, WBC 8 (all lymphs), glucose 60, protein 30, CRAG negative, Gram’s stain negative
CXR - normal
Blood smear

21. Case 1
(Malaria.org.za)

22. Malaria: Epidemiology
300 to 500 million cases per year
1 million deaths per year
80% in African children
Geographic overlap with HIV epidemic

23. Malaria: Epidemiology
Overlapping geography, although:
Malaria mostly rural
HIV mostly urban
WHO, 2006

24. HIV/Malaria Interaction
Modeling suggests that HIV leads to additional 3 million cases of malaria and additional 65,000 malarial deaths (Korenromp, Emer Inf Dis, 2005)
Malaria is associated with increased in HIV RNA: increase of 0.25 log with asymptomatic infection and 0.89 log with symptomatic malaria (Kubin, Lancet, 2005)

25. HIV/Malaria Interactions
(Slutsker, Curr Opin Infec Dis, 2007)

26. Case 1
Why did this patient become so ill?

27. HIV/Malaria: Clinical Presentation
Severity Risks
Residence in a malaria endemic region?
Yes: Adults mostly immune, disease primarily in children < 5
No: Population not immune – more severe disease
Pregnancy
Even if residing in endemic region – reduced immunity

28. HIV/Malaria: Clinical Presentation
Severity Risks
HIV status
Increased frequency of malaria (clinical and subclinical)
Increased severity - especially in those with CD4 < 200
Higher parasite densities and more clinical symptoms with lower CD4 counts
(Grimwade, AIDS, 2004) (Patnaik, JID, 2005)
(Cohen, CID, 2005) (Whitworth, Lancet, 2000)

29. HIV/Malaria: Clinical Presentation
Prospective cohort study in Chris Hani Baragwanath Hosptial in Soweto, SA
N=336; 33% HIV+, 33% non-immune
Risks for severe disease: HIV+ status, high parasite load, and high WBC
HIV patients:
Risk of severe disease higher in those with CD4 < 200
Risk of severe disease higher only in non-immune patients (OR 4.15)
More atypical symptoms (GI and respiratory)
(Cohen, CID, 2005)

30. HIV/Malaria: Clinical Presentation
Clinical Signs and Symptoms
Non-immune patients
Fever (q48 for all but P. malariae, q72), chills, myalgia, headache, vomiting, diarrhea, splenomegaly, thrombocytopenia, pulmonary and renal dysfunction,
Severe disease: acidosis, hypoglycemia, DIC, shock, cerebral malaria (40% mortality in Africa)

31. HIV/Malaria: Diagnosis
Blood smear
Antigen detection methods
PCR
Non-immune patients may have symptoms prior to detectible parasitemia – need to perform serial testing

32. HIV/Malaria: Prevention
How might her infection have been averted?
If she hadn’t gone home!
Chemo-prophylaxis
Insecticide treated nets

33. HIV/Malaria: Prevention
Prospective cohort study of 1035 patients that were given TMP/SMX (TS) or TS + ARV or TS + ARV + ITN (interventions added to population over time)
Compared with baseline malaria incidence rate of 50.8/100py
TS = 9/100py
TS/ARV = 3.5/100py
TS/ARV/ITN = 2.1/100py
(Mermin, Lancet, 2006)

34. HIV/Malaria: Prevention
Malaria Prevention in HIV+ Pregnant Women
Clinical situation
Recommendaion
All pregnant women at risk for malaria
Insectiside treated nets (ITN)
Not on ARVs
TMP/SMX - no
Start IPT (SP X 3)
TMP/SMX – yes
No IPT, start TMP/SMX 4 wks after IPT
Will get SD NVP only
Give IPT or TMP/SMX
Will get short course AZT
Give IPT or TMP/SMX and follow Hgb
Will get NVP based HAART and is < 32 wks
No IPT, start TMP/SMX 4 wks after IPT and ARVs 2 wks later
Will get NVP based HAART and is > 32 wks
No IPT, start HAART immediately – then TMP/SMX
Already on TMP/SMX and or HAART
No IPT, continue TMP/SMX
(Brentlinger, Behrens, Micek, Lancet ID, 2006)

35. HIV/Malaria: Treatment
Dictated by
Malaria species
Clinical status
Regional drug susceptibilities

36. HIV/Malaria: Treatment
P,O study of SP therapy for malaria in patients presenting to clinic at Siaya District Hospital, Kenya ( )
N=508, 130 HIV-, 256 HIV+ with CD4 > 200 and 122 HIV+ with CD4 < All treated with SP (1500/75)
MV analysis looking at treatment failure at 28 days. Compared to HIV- patients: HIV+ patients with anemia had a significantly higher failure rate (20.5% Vs 7.7% - HR of 3.4)

37. HIV/Malaria: Treatment

38. HIV/Malaria: Treatment

39. HIV/Malaria: Treatment

40. HIV/Malaria: Treatment

41. HIV/Malaria: Treatment/Drug Interactions
(Khoo, AIDS, 2005)

42. HIV/Malaria: Treatment/Drug Interactions
Quinine is extensively metabolized by CYP 3A4. Quinine exposure may be increased in patients on PIs (RTV) and decreased in patients on NNRTI (EFV, NVP, ETV)
Lumefantrine and halofantrine are extensively metabolized by CYP 3A4 and halofantrine can prolong the QT interval. Using either drug in patients on PIs should be avoided. NNRTI use would be expected to decrease exposure to these drugs
(Khoo, AIDS, 2005)

43. Case 2
A 32 yo HIV+ male with a CD4 of 12 presents with fever, headache and confusion for 2 days. He complained to his partner of blurred vision from his R eye 1 day PTA.
PMHx is notable for thrush, esophageal candida, wasting syndrome, chronic HBV and HCV, several episodes of zoster (the most recent a month ago) and active IVDU

44. Case 2
On exam he is obtunded but arousable. T 39, HR 110, BP 110/70, RR 14. R pupil reacts poorly to light. No meningismus. Lungs are clear, CV: RRR, 2/6 SEM at the base of the heart, no gallops, Abd: quiet BT, mild RUQ tenderness, Skin: multiple injection tracks, scars at sites of previous skin abscesses and zoster outbreaks.

45. Case 2 What diagnoses are you considering ABE with emboli
Toxoplasmosis
Cryptococcal meningitis
Bacterial meningitis
CMV
VZV

46. Case 2 What diagnostic testing do you want BC: done and pending
CRAG: negative
CMV PCR from plasma: 100 copies
CSF exam: RBC 2, WBC 15 (lymphs), protein 60, glucose 50, Gram’s stain negative, CRAG negative, PCR for CMV negative, EBV 80 copies, HSV negative, VZV 110 copies

47. Case 2
Brain MRI (

48. Case 2
Dilated Eye Exam

49. Case 2
Diagnosis?
VZV encephalitis and RPHRN

50. Varicella-zoster virus
Organism: Varicella-zoster virus, a member of the herpes virus family.
Epidemiology:
In the pre-vaccine era over 90% of US adults were sero-positive for VZV.
Risk of developing zoster in HIV infected individuals is 17 times that of non-infected patients (~30/1000 py in HIV+ men Vs 2/1000 py in HIV- men).
Recurrent attacks in HIV+ patients: ~20-30%.
(Rogues, JID, 1993)
(Veenstra, AIDS, 1995)

51. VZV Clinical Syndromes
Cutaneous
Ophthalmic
Central Nervous System
Other (hepatitis, gastritis, pancreatitis, pneumonitis, Guillain-Barre syndrome)

52. VZV Cutaneous Disease Zoster
Single dermatomal (throacic 40-50%, trigeminal 20-25%)
Multi-dermatomal
Disseminated (3 or more continguous dermatomes or 20 lesions outside a snigle dermatome)
Chronic: ulcerative, crusted and hyperkeratoic lesions that persist for months
(Wright, Clin Derm, 1997)
(Cohen, Clin Exp Derm, 1989)
(Castanet, Dermatology, 1996) (

53. VZV Ophthalmic Disease
ARN
10-17% of zoster involves V1 and 50-89% of these cases report ocular complications (usually keratitis)
ARN: anterior uveitis and peripheral retinal necrosis
CD4 < 200, dcreased acuity and pain
60-90% have antecedent zoster
RPHRN
More common than ARN, CD4 5-83
Usually bilateral
Rapidly progressive multi-focal lesions with early fovea disease and retinal detachments (70%)…minimal inflammation
70-82% have antecedent zoster
RPHRN
(Bayu, CID, 1997)
(Chern, Int Ophthal Clin, 1998)
(Ormerod, CID, 1998)
(Batisse, AIDS, 1996)
( and

54. VZV CNS Disease Accounts for 2-4% of CNS disease PHN (9-14%)
Encephalitis
Fever, HA, behavior change and focal deficits, usually 2-3 weeks post rash
Rapid onset of CNS symptoms with appearance of necrotizing and demyelinating lesions – WGM junction
Large/medium vessels – ischemia/hemorrhage
Small vessel with ischemia and demyelination
Ventricultis
CSF: elevated protein and lymphocytic pleocytosis
Meningitis (with or without zoster)
Myelitis
Typically weeks after zoster
(Gray, Brain, 1994)
(Kleinschmidt-DeMasters, Hum Pathol, 1996)
(Weaver, Neurology, 1999)
(DeLa Blanchardiere, Scan J Inf Dis, 2000)
(Lionnet, CID, 1996) (

55. VZV: Diagnosis and Treatment
Diagnosis: Fluorescent antibody assay of cells scraped from the base of a lesion. Culture is less sensitive that FA and can take weeks to grow. PCR.
Treatment:
Zoster: acyclovir, Val-acyclovir, famciclovir
ARN: IV acyclovir (or foscarnet)
RPHRN: IV foscarnet and ganciclovir and intravitreal ganciclovir and/or foscarnet
Encephalitis: foscarnet and IV acyclovir
Acyclovir-resistant VZV: foscarnet
Prevention
Vaccination (to prevent varicella) for individual with CD4 > 200
Zoster vaccination – under investigation
Post exposure: VZIG and vaccination > acyclovir

56. Case 3
A 47 year old sexually active Cuban male was brought to the ED by one of his girlfriends with confusion. He denied all symptoms and denied being HIV infected
Exam revealed a temperature of 38.3, HR 99, BP 110/70, RR 12. He had thrush and slight R facial droop, mild R UE weakness and an unsteady gait
CD4 count was 9, HIVRNA is > 1 million . He tested negative for antibodies to toxoplasmosis.
What other tests results would you like?

57. Case 3
(aidscience.org)

58. Case 3 CSF Analysis Cell count: 15 wbc (all lymphocytes), 0 rbc
Glucose: 50 (serum 80)
Protein: 30
VDRL: negative
CRAG: negative
Fungal, Gram’s and AFB stains: negative
PCR for HSV, CMV, VZV: negative
PCR for EBV: positive

59. Case 3 Differential Diagnosis? Toxoplasmosis Primary CNS lymphoma
Tuberculomas
Cryptococcomas and other dimorphic fungi (histo, cocci, blasto)
Nocardia
Syphilis
Bacterial brain abscesses
Metastatic tumors
CVA with edema

60. Case 3 PCNSL occurs in up to 2% of AIDS patients
Thallium SPECT and PET scans are useful for differentiating toxoplasmosis from PCNSL. Sensitivity > 90%, specificity? (false + with tuberculomas, cryptococcomas and other omas)
PCR for EBV in CSF: sensitivity 85 to 97%, specificity much lower, PPV 29-50% (Corcoran, J Clin Virol, 2008;42,433-36)
Combination of PCR and SPECT scans may make the diagnosis and obviate the need for biopsy - No

61. Case 3 Mass lesion(s) on CT or MRI Toxoplasma serology?
Negative
Positive
Multiple or Single lesions?
Multiple
Single
Empiric Toxoplasma
therapy
CSF EBV PCR
Negative
Positive
Improvement in 2 wks
No improvement
in 2 wks
Treat for lymphoma?*
Continue Toxoplasma Rx
Biopsy
*Use PET or SPECT

62. Case 3
Final Answer: Sometimes its both
(aidscience.org)

63. Toxoplasma gondii Organism Epidemiology and route of infection
Toxoplasma gondii, a protozoa
Epidemiology and route of infection
By age 50, sero-prevalence rate is 15% in USA compared with 90 to 100% in France and developing nations
Ingestion of oocysts or tissue cysts leads to the release of organisms which mature into tachyzoites, disseminate and then persist in the CNS or other tissues
Immunosuppression allows for the development of trophozoites from the tissue cysts leading to disease.

64. Toxoplasma gondii Clinical presentation/syndrome Diagnosis
CD4 < Encephalitis; fever, mental status changes, headache, seizures and focal neurological signs.
Diagnosis
Serology (ELISA) is positive is over 95% of patients? (reported range 22-95)
MRI or CT shows multiple enhancing lesions in the grey-white matter junction, white matter or basal ganglia
Definitive diagnosis requires brain biopsy; a presumptive diagnosis can be made given a characteristic presentation and response to anti-Toxoplasma therapy.

65. Toxoplasma gondii Treatment
Pyrimethamine plus sulfadiazine plus leukovorin or
Pyrimethamine plus clindamycin plus leukovorin or
High dose TMP/SMX (Torre, AAC;42,1346-9)
Other regimens active against Toxoplasma
Atovaquone plus pyrimethamine plus leucovorin
Atovaquone plus sulfadiazine
Azithromycin plus pyrimethamine

66. Case 4
A 46 yo Native American female with advanced HIV (CD4 44), not on HAART presents with incoordination of her R hand, an unsteady gait and slurred speech
Exam reveals and thin woman, alert and oriented, BP 90/60, HR 90, RR12, temperature 37. She has a slight R facial droop, R hand weakness and dysmetria and an unsteady gait due to mild R leg weakness

67. Case 4
Differential diagnosis and diagnostic tests?

68. PML and HIV PML Caused by JC virus (a polyoma virus)
85% of adults have serologic evidence for infection
Most are asymptomatically infected as children
Latent in kidney, traffics in lymphocytes and may be latent in brain

69. PML and HIV
Clinically
Typically presents with focal CNS signs. Preference for
Occipital lobes (hemianopia)
Frontal and parietal lobes (hemiparesis)
Cerebellum (ataxia and dysmetria)
Seizure in 20%
Insidious progression over weeks to months

70. PML and HIV Clinically PML IRIS Onset after HAART
Typical clinical presentation
Atypical MR - edema and mass effect, significant enhancement
Less JCV by PCR
May have better outcome

71. PML and HIV
Diagnosis
Typical MR findings - patchy white matter lesions (hyperintense on T2 and flair), 10-15% enhance with gadolinium
CSF JCV PCR positive in %
Brain biopsy

72. PML and HIV Treatment HAART
> 60% response rate (20-30% improve)
Worse outcomes for those with CD4 < 150
Serotonergic receptor 5HT2a may be used by JCV: anecdotal reports of 5HT2a binding agents having benefits (olanzapine, mirtazapine, respiradone)
Steroids for PML IRIS

73. Summary
Opportunistic infections are predictable based on a patients immune status and environment
Disseminated and atypical presentations are the rule with extreme immune suppression
Prophylaxis against certain OIs is indicated if the OI is common and the prophylaxis is affordable, effective and well tolerated
HAART alone is treatment enough for certain OIs and can eliminate the need for prophylaxis
The timing of HAART relative to OI therapy is controversial but should probably be early…..except with cryptococcus and watch out for IRIS!

74. Next session: February 25, 2010
Next session: February 25, 2010
Immune Reconstitution Inflammatory Syndrome, Part 3