Welcome to I-TECH HIV/AIDS Clinical Seminar Series 17 June 2010 Opportunistic Infections H. Nina Kim, MD, MSc.

Welcome to I-TECH HIV/AIDS Clinical Seminar Series

17 June 2010

Opportunistic Infections

H. Nina Kim, MD, MSc

Case 1

43 yo man with HIV c/o bilateral R>L leg swelling and new lesion on his thigh. Has been feeling well, denies any fevers/nightsweats. ROS: Negative for cough/SOB, abd pain or change in stools.PMH:Stage 3 HIV, dx 1999

Nadir CD4 45 current 158 cells/mm3

Hx Pneumocystis pneumonia in 1999Hx oral candidiasisCurrent Meds:

Truvada 1 tab PO qDayKaletra 2 tabs PO BIDTMP-SMX 1 DS tab PO qDay

Physical Exam & Labs

T 37.9°C HR 100 BP 130/69, RR 18General – Fatigue-appearing man, no distress.HEENT – oral thrush.Chest – clear to auscultation.Cardiac – regular tachycardic, 2/6 systolic ejection

murmur.ABD – normal bowel tones, no organomegaly, non-

tender.Lymphatic – no adenopathy.Neuro – Alert, oriented x 4. O/W unremarkable.SKIN: …

LAB: CD4 158. HIV RNA <30. Chemistries WNL including liver function panel.

• “Face of AIDS”

– In 1981, emergence of KS among young gay men in New York, Los Angeles, San Francisco heralded start of AIDS epidemic

• AIDS initially called “Kaposi’s Sarcoma & Opportunistic Infections” (KSOI)

• Most common malignancy of AIDS patients– 20,000-fold higher risk to that of general population

– 70-fold higher risk to that of other immunosuppressed groups

Kaposi Sarcoma (KS)

• Neoplasm– Skin– Mucous membranes– Lymphatic system– Viscera (pulmonary, GI tract)

• Four variants– Classic KS (elderly men of E.Europe, Mediterranean descent)

– Endemic African KS

– Transplantation-related KS

– Epidemic HIV-associated KS

Kaposi Sarcoma (KS)

• Histopathology– Dilated vessels, vascular slits

– Spindle cells

– RBCs, hemosiderin deposits

– Inflammatory cells

• Vascular hyperplasia or true neoplastic growth?– Monoclonal cancer clonal outgrowth of spindle cells

Johns Hopkins Autopsy Resource Image Archive

Rabkin et. al. N Engl J Med 1997 Apr; 336:988-93.

• Novel herpes viral genome discovered in AIDS-KS tumor specimens in 1994

• Human herpes virus type 8 (HHV-8) or KSHV targets spindle cell

Chang et. al., Science 1994 Dec; 266:1865-9.

www.aids-images.ch

HHV-8

• Gamma herpesvirus.• Viral genes homologous to human genes• Tumorigenesis

– Kaposi sarcoma– Multicentric Castleman’s disease– Primary effusion (body cavity) lymphoma (also EBV-associated)

• Epidemiology (transmission, risk factors) still being worked out

• HHV-8 viremia– 0-52% of KS patients viremic at any given time– Portends development of KS in several studies– HHV-8 in PBMC (not plasma) correlates with KS severity

Casper, “HHV-8, KS & AIDS-associated Neoplasms.” Accessed www.hivinsite.com

Global distribution of HHV-8

www.aids-images.ch

Global distribution of KS

Cancer Research UK

www.info.cancerresearchuk.org/cancerstats

Malignancies in Uganda:1982-2000

Kaharuza et. al. Int Conf AIDS 2004 Jul; 15: Abstract C11879.

Clinical Features of KS

• Wide spectrum of disease

• Skin lesions– Brown, red, violaceous– Macules, papules, plaques, nodules

• Differential Dx:– Bacillary angiomatosis– Pyogenic granuloma– Cutaneous manifestation of lymphoma– Angiosarcoma

• Visceral involvement– GI tract (asymptomatic, abd pain, diarrhea, bleeding)– Pulmonary (asymptomatic, SOB, cough) poor prognosis

Courtesy of Dr. Virginia Broudy

Courtesy of Dr. Virginia Broudy

www.hab.hrsa.govwww.idimages.org

www.hivwebstudy.com

Staging of KS00 11

TumorTumor Confined to: Confined to: Skin/mucosa and/orSkin/mucosa and/or Lymph nodes and/orLymph nodes and/or Minimal oral diseaseMinimal oral disease

Tumor-associated Tumor-associated edema or ulcerationedema or ulceration

Extensive oral KS Extensive oral KS Pulm or GI KSPulm or GI KS Other non-nodal Other non-nodal

visceraviscera

Immune statusImmune status CD4 >/= 200CD4 >/= 200 CD4 < 200CD4 < 200

Systemic illnessSystemic illness No hx OI, thrushNo hx OI, thrush No B* symptomsNo B* symptoms Karnofsky status > 70Karnofsky status > 70

Hx OI, thrushHx OI, thrush B* symptomsB* symptoms Karnofsky status < 70Karnofsky status < 70 Other HIV diseaseOther HIV disease

* >2 weeks of unexplained fever, night sweats, involuntary weight loss >10%, diarrhea

AIDS Clinical Trial Group

Krown et. al. J Clin Oncol 1997 Sep;15:3085-92.

Survival with KS in HAART era

Palmieri, et. al. HIV Medicine 2006 July; 7: 291-3.

Treatment of KS

• No universally effective therapy– Palliative.– Main indications are visceral disease, lymphedema & if KS

bothers pt (e.g. symptomatic foot disease, facial lesions)– Tailor to individual patient

• HAART

• Local therapy– Radiation, cryotherapy, topical retinoids, intralesional chemo

• Systemic chemotherapy– Liposomal anthracyclines (Doxil) – highest remission rates

(60-80%)– Paclitaxel – partial remission seen in up to 60%

• IFN-alfa – Response up to 40%

Antman, et. al. N Engl J Med 2000 Apr; 342: 1027-38.

KS & HAART

AZT introduced

Dual ART

HAART introduced

SEER Stat Database, www.seer.cancer.gov

Decline in incidence in US Decline in incidence in US and Europe in era of HAARTand Europe in era of HAART

One case series: 80% early One case series: 80% early stage lesions responded x 3-stage lesions responded x 3-6 mo HAART6 mo HAART

Madison Clinic data (HAART Madison Clinic data (HAART era): 37% KS improvement era): 37% KS improvement with 36 mo follow-upwith 36 mo follow-up

Certain ARVs more effective Certain ARVs more effective vs. KS?vs. KS?

Tx slide

Case series n=9 patients with KS flareCase series n=9 patients with KS flare Onset of flare – mean of 5 weeks into HAART (range, 3-7 wks)Onset of flare – mean of 5 weeks into HAART (range, 3-7 wks) Eruption of new lesions, increased edema/prominence of KSEruption of new lesions, increased edema/prominence of KS

Case of fatal KS-associated IRIS in a patient who presented with Case of fatal KS-associated IRIS in a patient who presented with respiratory failure (negative BAL, steroid-responsive)respiratory failure (negative BAL, steroid-responsive)

KS & Immune Reconstitution Inflammatory Syndrome

• Immune Reconstitution Inflammatory Syndrome (IRIS)– Exuberant immune-mediated

inflammatory response to antigenic triggers with start of HAART

– Primary disorder = Immune perturbation not infection

– Growing list of associated infectious & rheumatologic diseases

Leidner, et. al. AIDS Patient Care STDs 2005 Oct;19: 635-44.

Crane, et. al. Int J STD & AIDS 2005 Jan;16: 80-2.

AIDS-associatedKaposi Sarcoma

• Incidence high in pre-HAART era, now reduced but still common, esp. among MSM

• KS prevalence mirrors prevalence of HHV-8 infection

• Chronic disease without a cure, marked by slow often partial remission

• Visceral disease, esp pulmonary involvement, associated with poor prognosis

• HAART is probably key to KS treatment & should be initiated in all KS pts

Case 2

47 yo journalist with stage 3 HIV with CD4 102 on HAART presents with fever, chills, diffuse abdominal pain, cough, bloody diarrhea. He returned from a recent trip to SE Asia. His exam is notable for HR 123 BP 90/45 RR 25 O2 Sat 93% on 3 L NC, petechial rash on trunk and scattered wheezing in all lung fields. CXR shows bilateral interstitial infiltrates.

Bronchoscopy was performed. BAL revealed the following:

What is your diagnosis?

Disseminated Strongyloidiasis

• Endemic in tropical or subtropical regions (SE Asia)

• Strongyloides cause a systemic dissemination (hyperinfection syndrome) with high mortality in some patients, generally immunosuppressed (HIV+, chemo, steroids)

• Intestinal invasion may result in gram negative sepsis

• Trivia: what other conditions/meds predispose?

Case 335 yo man with stage 3 HIV comes in c/o 3 weeks of HA, sleepiness and double vision.

PMH:

HIV dx 1990 – last CD4 50 in 2009

Hx depression with psychotic features

Chronic hepatitis B

Soc Hx:

Immigrated from Somalia in 2008.

Case 3Exam: T 38.0 BP 140/85 HR 65 RR 14

GEN: Drowsy, thin man in no acute distress.

Mental status: Opens eyes spontaneously, attends and able to answer questions appropriately, oriented to self, place and year. Obeys commands.

NECK: No stiffness.

NEURO: Cranial nerves II-XII intact & symmetric. Gait is wide-based. No focal impairment in sensory/motor exam.

What would you do next?

Lumbar puncture

• Opening pressure 55 cm H2O

• CSF WBC 153 (lymphocyte predominant)

• CSF glucose 35

• CSF protein 87

CT head with contrast: No focal abnormalities.

Tuberculous vs Cryptococcal Meningitis

Cohen, CROI 2009, Abstract #791.

Lumbar puncture

• Opening pressure 55 cm H2O

• CSF WBC 153 (lymphocyte predominant)

• CSF glucose 35

• CSF protein 87

CSF Cryptococcal Antigen 1:512.

Primary Induction Therapy for Cryptococcal Meningitis

• Amphoterocin B deoxycholate 0.7-1.0 mg/kg or liposomal AmB 3-4 mg/kg or ABLC 5 mg/kg per day IV plus flucytosine (5-FC) 100 mg/kg/day x 2 weeks minimum

OR• AmBd, liposomal AmB, ABLC plus fluconazole 800 mg x 2

wks minimum OR• Fluconazole ≥800 mg/day (1200 mg/day favored) plus 5FC

100 mg/kg/day x 6 weeks OR• Fluconazole 800-2000 mg/day; ≥1200 mg/day favored x

10-12 weeks if used alone

Use of itraconazole is discouraged.

2010 Infectious Disease Society of America Guidelines

RCT of Combination High-dose Fluconazole + 5FC vs Fluconazole alone

Nussbaum, Clin Infect Dis Feb 2010; 50:338-44.

Primary Outcome: Early fungicidal activitySecondary outcomes: 2-week, 10-week Mortality

Primary Outcome: Early fungicidal activitySecondary outcomes: 2-week, 10-week Mortality

Nussbaum, Clin Infect Dis Feb 2010; 50:338-44.

Case 335 yo man with stage 3 HIV comes in c/o 3 weeks of HA, sleepiness and double vision.

PMH:

HIV dx 1990 – last CD4 50 in 2009

Hx depression with psychotic features

Chronic hepatitis B

Soc Hx:

Immigrated from Somalia in 2008.

Medications:Efavirenz 600 mg PO qHSTDF + FTC 1 tab PO qDay

Cryptococcal Meningitis & IRIS

• Incidence 47 cases per 100 person-years

• Median interval from HAART initiation to dx IRIS: 63 days (range, 12-129)

• Headache is most common symptom; neck stiffness, photophobia, fever, focal neuro deficit less common

• Papilledema & decreased LOC may be more common w/ CM-IRIS

• OP higher at IRIS c/w first CM dx: median 46 vs 20 cm H2O

• % PMN CSF higher in CM-IRIS; CrAg titers lower

Sungkanuparph, Clin Infect Dis September 2009; 49:931-4.

How soon can we start HAART in patients with Cryptococcal meningitis?

Makadzange, Clin Infect Dis June 2010; 50:1532-38.