Prevention, diagnosis, and treatment of key

Opportunistic Infections in HIV Infection

Theodoros KelesidisUCLA CARE Center

The Late Phase of HIV-1

PCR=polymerase chain reaction; bDNA=branched DNA.Adapted with permission from Saag. In: DeVita et al, eds. AIDS: Etiology, Treatment and Prevention.4th ed. Lippincott-Raven Publishers; 1997:203-213.

Plasma viral titer by PCR or bDNA assayPlasma viral titer by culture or p24 antigen

Number of CD4 cells

106

105

104

103

102

101

1400

1200

1000

800

600

400

200

Pla

sma

Vir

emia C

D4

+ Co

un

t

1 2 9 10Time (Years)

+

Risk of Death Associated with ADEs Adjusted Hazard Ratio

Herpes simplex 0.97Mycobacterial disease 5.07Toxoplasmosis 5.10Cryptococcosis 9.00

PML 9.56Non-Hodgkin’s lymphoma 19.31

Mocroft A, and ART Cohort Collaboration CROI 2007# 80.

33 YO with chest pain, fever and productive cough worsening over 3d

Candidiasis • Oropharyngeal candidiasis is the most

common opportunistic infection in persons infected with HIV

• is usually associated with significant immunosuppression (CD4 counts <200 cells/microL)

• Topical therapy for the initial episode of oropharyngeal candidiasis in HIV-infected patients with mild disease.

• For patients with recurrent infection, moderate to severe disease, or in those with advanced immunosuppression (CD4 <100 cells/microL) (200 mg loading dose, followed by 100 to 200 mg daily for 7 to 14 days after clinical improvement)

37 YO HIV + male CD4 76 as of six months ago, now has DOE, fever, dry cough, and pleuritic chest pain.

His symptoms have been progressing over the last month despite 10 days of Levaquin.

38C 120/70,HR120, pulse ox is 69% on room air. Ill appearing, in mild respiratory distress

Pneumocystis• We now refer to the organism that causes human

disease as pneumocystis jirovecii • In ‘80’s AIDS defining illness for 2/3rds of patients• Ugandan study found 38.6% of 83 pts admitted

with pneumonia had PCP on BAL• Presentation:

– Gradual onset dyspnea, fever, nonproductive cough, unremarkable lung exam, tachycardia

– CXR: Diffuse bilateral interstitial infiltrates, is a leading cause of pneumothorax.

– Cavitation, adenopathy and effusion should prompt search for other pathogens

Diagnosis of PCP

• hypoxemia, elevated LDH nonspecific

• induced sputum • BAL • Specific dx should be sought in

those with mod-severe disease

Treatment

• TMP/SMZ treatment of choice• Steroids ASAP but at least within 72 hours if

pO2<70 or Aa gradient >35 mm/Hg• Pentamidine is second choice for moderate to

severe disease• Discontinue prophylaxis in patients who have

responded to ARVs with a CD4 cell >200 sustained for longer than 3 months

39 yo engineer from Belize with right sided weakness, tremor, expressive aphasia, and generalized seizure. Found to be HIV positive, CD4= 32. No history of IVDU.

Toxoplasmosis

• Most common cause of intracerebral lesions in persons with HIV.

• 15-30% of US population is seropositive• 50-75% in some European countries. • Without prophylaxis 30% of seropositive with

CD4<50 will develop CNS disease.• 95% of persons with Toxoplasmosis are

antibody positive.

Toxoplasmosis

• Presentation: headache, fever, confusion, focal deficits, and seizures

• Differential: CNS lymphoma, abscess, cryptococcoma, tuberculoma

DIAGNOSIS

– CT or MRI with contrast are not specific,

– Serum and CSF IgG/IgM

– CSF PCR is specific 96-100%, but sensitivity 50%

Toxoplasmosis-Treatment

• Pyr + sulfadiazine + leucovorin• Preferred alternative Pyr+ clinda + leucovorin• TMP-SMX which is inexpensive and readily

available in developing countries may be suitable first line therapy for acute TE

Toxoplasmosis treatment

• Acute therapy for 6 weeks, until resolution of contrast enhancement

• Adjunctive steroids for mass effect and edema• Chronic Maintenance therapy until CD4>200 x

6 months – Sulfadiazine 2-4 gm + Pyr 25-50 +leucovorin 10-25

Primary Prophylaxis

• CD4<100 and Toxoplasma IgG +• Discontinue ppx when CD4>200 > 3 months• TMP-SMZ SS or DS qd• Alternatives

– Dapsone + Pyrimethamine q week + Folinic acid q week

– Mepron +/_ Pyrimethamine – ? Azithromycin

28YO M, HIV status unknown, brought in by his wife with headache, vomiting and confusion worsening over 9 days.

39.4C, combative, without obvious focal findings.

CT with contrast increased intracranial pressure.

Likely diagnoses include?

a. Cryptococcal meningitis

b. Tuberculous meningitis

c. Cocci meningitis

d. Lymphomatous meningitis

e. Bacterial meningitis

Cryptococcosis• PreHAART occurred in 6-10% of

persons with AIDS in US, Europe & Australia

• 7/1000 AIDS pts in 2000 in US

• Cause of 20-45% of cases of community acquired meningitis in South Africa, moving ahead of tuberculous meningitis

Cryptococcosis• Meningitis or meningoencephalitis is

the most common manifestation• Presents with progressive

headache, fever, AMS worsening over several weeks may have symptoms of increased ICP.

• Meningismus, papillaedema, cranial nerve palsies not uncommon

Diagnosis• High organism load in HIV, so India ink usually

positive in AIDS, (sensitivity 75-85%)• Cryptococcal antigen high sensitivity 95% and

specificity for diagnosis but little utility in assessing response to therapy

• 75% with meningitis also have ++ blood cultures• opening pressure >200mm Hg in 75% • CSF lymphocytic pleocytosis• elevated protein, low glucose• cultures grow in 48-72 hours

Use of Lumbar punctures• CT first, always check the opening pressure with

each LP• Repeat LP for signs of increased ICP (HA, AMS,

visual or hearing loss), may require lumbar drain• Daily LPs to achieve a closing pressure <20 or

50% of the opening pressure• If not improving or new symptoms repeat LP

Treatment Guidelines• Preferred induction regimen: 2 weeks of

– AmB + flucytosine – Consolidation if CSF culture neg – Fluconazole 400 mg/day x 8 weeks

• Maintenance – Fluconazole 200 qd until CD4>200 x 6

months

• Combination fluconazole and 5-FC, in small studies had response rates of 60–80%, comparable to ampB-based regimens

SM• 59 YO Lebanese male admitted 9/30 with

new onset seizures• PMH

– pancytopenia with negative work up – PE word finding difficulty, flattening of

R nasolabial fold• R hand decreased grip strength, decreased

strength biceps• CT showed L frontal enhancing

lesion with mass effect and a small R cerebellar enhancing lesion

• CT of chest and abdomen showed 2.3 x 1.8 cm mass at the root of the mesentary along the superior mesenteric vessels

What tests do you want?

• HIV1/2 serology• Toxoplasma serology• ppd• Blood cultures

Mycobacterium avium complex (MAC)

• Most common bacterial OI in the developed world

• 10-20% of persons with AIDS• independent predictor of mortality• Acquired through inhalation or

ingestion, spreads through lymphatics• Fevers, night sweats, weight loss, • Labs: anemia, elevated alkaline

phosphatase

Prophylaxis and treatment

• Prophylaxis: Start CD4<50 Stop CD4>100 x 3 months

• Azithromycin 1200 q week • Combination therapy is essential resistance seen in

46% after 16 weeks on Clarithromycin alone• Clarithromycin + Ethambutol +/- Rifabutin or• 12 months of treatment and• CD4>100 x more than 6 months

Fever in patient with CD4<50• 34 YO with fever to 102, weight loss,

heartburn and diarrhea, no cough, no visual changes, no headache, no marked adenopathy.

• Labs: Hct 29, LDH 255, LFTS normal• stool studies show a few red blood cells• Chest x-ray unremarkable

Fever in patient with CD4<50

Mycobacterium avium complex

Cytomegalovirus

Cryptococcus

M. tuberculosis

Lymphoma

Endemic mycoses

Epidemiology-CMV

• Developed world 40-70% healthy adults infected.• In persons with HIV especially IVDU and MSM,

close to 100% are also seropositive for CMV• Autopsy studies show up to 90% of persons dying

with HIV in preHAART era had CMV disease• 40% developed sight threatening disease after

CD4 dropped to <50• CMV retinitis Remains the most common cause of

visual loss in developed countries

Cytomegalovirus

Reactivation when CD4<100

• 85% retinitis• 17% GI tract esophagitis,

gastritis, duodenitis, colitis• 1% encephalitis,

polyneuritis, polyradiculopathy• ?% pneumonitis

CMV Treatment• Ganciclovir- IV, PO or intravitreal

• Foscarnet- IV, intravitreal

• Cidofovir- IV

• +/-Prophylaxis if CD4<50• Preemptive therapy for viremia?• Treatment of symptomatic disease with induction followed by

maintenance therapy• In the absence of immune reconstitution drug resistance

emerges with serial accumulation of mutations

Summary of prophylaxis

Infection Preferred drug Indications

Pneumocystis carinii pneumonia

Trimethoprim-sulfamethoxazole (double-strength tablet daily)

CD4 count <200 cells/microL; thrush; unexplained fever for more than two weeks; history of PCP

Toxoplasmosis

Trimethoprim-sulfamethoxazole (double-strength tablet daily)

CD4 count <100 cells/microL and Toxoplasma sero-positive

Mycobacterium avium complex

Azithromycin (1200 mg weekly)

CD4 count <50 cells/microL

Take home messages• OIs are the most common presentations of

AIDS/HIV• Usually occur when CD4 < 200• Most important: PCP, MAC, Cryptococcus,

Toxoplasma, CMV • Candida infection is the most common OI and

MAC is the most common bacterial OI• Life Threatening: PCP, Cryptococcus• Prophylaxis if CD4 <200: bactrim, azithromycin