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

Welcome to I-TECH HIV/AIDS Clinical Seminar Series

February 11, 2010HIV-Associated Opportunistic Infections 2010

Robert D. Harrington, MD

HIV-Associated Opportunistic Infections 2010

Robert D. Harrington, M.D.

University of Washington

MMWR 1981

MAC, CMV, PML, PCNSL, Cryptococcus, MicrosporidiaToxo

PCP

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

Opportunistic Infections and Geography

Common OIs• PCP• MAC• Candida

Regional Effects• Southwest:

– Coccidiodomycosis

• Midwest:– Histoplasmosis and

Blastomycosis

• South: – Blastomycosis and

Toxoplasmosis

North America

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

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

HIV ASSOCIATED MALIGNANCIES

AIDS Defining Malignancies

• Kaposi’s sarcoma

• Primary CNS lymphoma (PCNSL)

• Non-Hodgkin’s lymphoma (NHL)

• Invasive cervical cancer

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

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

Prophylaxis to Prevent Opportunistic Infections in the Developed World

Primary ProphylaxisPCP 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

Cotrimoxazole is beneficial in all pts with HIV infection regardless of CD4 count

Mermin et al. Lancet 2004 ; 364: 1428

• 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

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

Cotrimoxazole

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

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 < 100. 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

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 testingIf 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 > 500Consider vaccination of children < 5 years who live with HIV infected persons

Influenza When feasible – annual vaccination with inactivated flu vaccine

EFFECTS OF HAART ON OPPORTUNISTIC INFECTIONS

• Declining incidence

• Reduced need for prophylaxis (primary and secondary)

• Spontaneous improvements and cure

• Immune reconstitution effects

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

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

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

Case 1

(Malaria.org.za)

Malaria: Epidemiology

• 300 to 500 million cases per year

• 1 million deaths per year – 80% in African children

• Geographic overlap with HIV epidemic

Malaria: Epidemiology

WHO, 2006

Overlapping geography, although:Malaria mostly ruralHIV mostly urban

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)

HIV/Malaria Interactions

(Slutsker, Curr Opin Infec Dis, 2007)

Case 1

Why did this patient become so ill?

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


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)


• 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)


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)

HIV/Malaria: Diagnosis

• Blood smear

• Antigen detection methods

• PCR

• Non-immune patients may have symptoms prior to detectible parasitemia – need to perform serial testing

HIV/Malaria: Prevention

• How might her infection have been averted?

– If she hadn’t gone home!– Chemo-prophylaxis– Insecticide treated nets


• 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)


Malaria Prevention in HIV+ Pregnant WomenClinical 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)

HIV/Malaria: Treatment

• Dictated by– Malaria species– Clinical status– Regional drug susceptibilities


• P,O study of SP therapy for malaria in patients presenting to clinic at Siaya District Hospital, Kenya (2002-04)

• N=508, 130 HIV-, 256 HIV+ with CD4 > 200 and 122 HIV+ with CD4 < 200. 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)


http://www.cdc.gov/malaria/pdf/treatmenttable.pdf







HIV/Malaria: Treatment/Drug Interactions

(Khoo, AIDS, 2005)

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)

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

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.

Case 2

• What diagnoses are you considering– ABE with emboli– Toxoplasmosis – Cryptococcal meningitis– Bacterial meningitis– CMV– VZV

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

Case 2

(www.medscape.com)

Brain MRI

Case 2

Dilated Eye Exam

Case 2

Diagnosis?

• VZV encephalitis and RPHRN

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)

VZV Clinical Syndromes

• Cutaneous

• Ophthalmic

• Central Nervous System

• Other (hepatitis, gastritis, pancreatitis, pneumonitis, Guillain-Barre syndrome)

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)(WWW.knol.google.com)

VZV Ophthalmic Disease• 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(Bayu, CID, 1997)(Chern, Int Ophthal Clin, 1998)(Ormerod, CID, 1998)(Batisse, AIDS, 1996)

ARN

RPHRN

(www.retinalphysician.com and www.nature.com)

http://www.retinalphysician.com/

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)(www.medscape.com)

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

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?

Case 3

(aidscience.org)

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

Case 3

• Toxoplasmosis• Primary CNS lymphoma• Tuberculomas• Cryptococcomas and other dimorphic fungi (histo, cocci, blasto)• Nocardia• Syphilis• Bacterial brain abscesses• Metastatic tumors• CVA with edema

Differential Diagnosis?

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

Case 3

Mass lesion(s) on CT or MRI

Toxoplasma serology?

Multiple or Single lesions?

Empiric Toxoplasmatherapy

Positive

Biopsy

CSF EBV PCR

Treat for lymphoma?*

Continue Toxoplasma Rx

Improvement in 2 wks

Negative

Multiple Single

No improvementin 2 wks

Negative Positive

*Use PET or SPECT

Case 3

(aidscience.org)

Final Answer: Sometimes its both

Toxoplasma gondii

• Organism– 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.

Toxoplasma gondii

• Clinical presentation/syndrome– CD4 < 100. 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.

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

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

Case 4

• Differential diagnosis and diagnostic tests?

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

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

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

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 70 - 90%• Brain biopsy

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

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!

Welcome to I-TECH HIV/AIDS Clinical Seminar SeriesEmail: [email protected]

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

Documents

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