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HIV-Associated Opportunistic Infections 2010

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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

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

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

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 (

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 (

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 (

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

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