Prevention, diagnosis, and
treatment of key Opportunistic
Infections in HIV Infection
Theodoros Kelesidis
UCLA
The Late Phase of HIV-1
1400
Plasma viral titer by PCR or bDNA assay
Plasma viral titer by culture or p24 antigen
+
Number of CD4
cells
106
1200
1000
104
800
103
600
102
400
101
200
1
2
9
CD4+ Count
Plasma Viremia
105
10
Time (Years)
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.
Risk of Death Associated with ADEs
Adjusted Hazard Ratio
Herpes simplex
0.97
Mycobacterial disease
5.07
Toxoplasmosis
5.10
Cryptococcosis
9.00
PML
9.56
Non-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 ampBbased 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
Trimethoprimsulfamethoxazole
(double-strength tablet
daily)
CD4 count <200
cells/microL; thrush;
unexplained fever for
more than two weeks;
history of PCP
Toxoplasmosis
Mycobacterium avium
complex
Trimethoprimsulfamethoxazole
(double-strength tablet
daily)
Azithromycin (1200 mg
weekly)
CD4 count <100
cells/microL and
Toxoplasma seropositive
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