1

Opportunistic infections in
HIV-infected patients
 Introduction (1)
2

 The acquired immunodeficiency syndrome (AIDS) is

characterized by:
 the gradual erosion of immune competence and
 the development of opportunistic infections (OIs)

 The average rate of decline of CD4+ lymphocyte cells

(CD4 slope) is
 approximately 40 to 80 cells/µL/year in the absence
of antiretroviral therapy
 An accelerated decline in the CD4+ count occurs at 1.5
to 2 years
 Introduction (2)
3

 The CD4+ count:

 dictates the need for OI prophylaxis
 Influences the differential diagnosis of the OI
 is an independent indicator of prognosis.

 For these reasons, the CD4+ count has become a

primary surrogate marker of immune suppression and
antiretroviral activity.
4

GMI
 The effect of opportunistic infections on viral load
and survival
5

 Acute Ols up regulate HIV replication,

 resulting in higher HIV-1 RNA concentrations in the
plasma and lymphoid tissues of HIV-infected patients
 This enhanced replication is presumably caused by
antigen-mediated activation ofHIV-1 replication in
latently infected cells.
 Changes in the natural history of opportunistic
infections (1)
6

 Ols result from long-standing immunosuppression from

HIV infection
 Ironically, HAART therapy also has been associated
with a worsening or an unmasking of occult Ols in
patients with advanced AIDS
 When antiretroviral therapy strengthens the immune
system, inflammatory symptoms in response to
infection are more clinically pronounced.
 This syndrome has been referred to as immune
reconstitution inflammatory syndrome (IRIS).
 Changes in the natural history of opportunistic
infections (2)
7

 The initiation of HAART typically results in an

increase in CD4 + lymphocytes and a decrease in HIV-
1 RNA to undetectable levels.
 This initial increase in CD4 + T cells after start of
therapy involves an increase in memory T cells with
low proliferation and a decrease in functional or
effector cells.
 As a result, opportunistic infections that are present in
tissues are allowed to proliferate once the immune
system is recovering, allowing IRIS to occur.
 Prevention of OIs (1)
8

 General strategies to prevent opportunistic

infections are:
 Reduction of exposure;
 Immunization;
 Chemoprophylaxis (primary/secondary);
 Starting HAART; and
 Balanced nutrition and positive living.
 Prevention of OIs (2)
9

 Reduction of Exposure: Prevent Risk Factors

 Unsafe Sex
 Intravenous drug use (IVDU)
 Environmental and occupational exposure
 Pet-related
 Food and water hygiene
 Travel-related care
 Prevention of OIs (3)
10

 Primary prophylaxis
 Primary prophylaxis is defined as therapy that is
initiated before the appearance of an OIs in high-risk
asymptomatic persons to prevent the initial occurrence
of an infection.
 Prevention of OIs (4)
11

 Secondary prophylaxis or chronic suppressive

therapy
 Secondary prophylaxis is used to prevent recurrence of
an OI once the patient has developed signs and
symptoms of active infection.
 In some cases, secondary prophylaxis regimens can be
discontinued after patients achieve a certain CD4+
level.
12

Management of common OIs

 Pneumocystis Jiroveci Pneumonia (PCP)
13

 Caused by Pneumocystis jiroveci (fungus??)

 The taxonomic classification of pneumocystis as a
genus of protozoan organisms was questioned for
several years.
 Now they are recognized as fungi based on ribosomal
RNA and other gene sequence homologies, the
composition of their cell walls, and the structure of
key enzymes
 Organism was transmitted early in life by the
respiratory-aerosol route, with 75 percent of humans
infected by the age of four years
 DX…PCP
14

 The clinical features of PCP in AIDS patients differ from those of

non-AIDS patients in that:
 a more subtle onset, with mild fever, a non productive cough,

tachypnea, and dyspnea,

 clinical tests:

 The two most common abnormal laboratory values associated with

PCP in HIV-infected patients are

 a CD4 count below 200 cells/mm 3 and
 an elevated lactate dehydrogenase level>500 mg/dL but not specific

 Polymerase chain reaction (PCR) is an alternative method for

diagnosing PCP.
 PCR is highly sensitive and specific for detecting Pneumocystis;

 however, PCR cannot reliably distinguish colonization from disease

 PCP
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 Chest radiographs
 one of bilateral diffuse interstitial pneumonitis
 atypical patterns, such as: pleural effusion, cavities,
pneumatoceles, and nodules
 Early predictors of mortality from PCP at hospital
admission
 Increasing patient age, subsequent episode of PCP,
low hemoglobin, low partial pressure of oxygen
breathing room air, the presence of medical
comorbidity, and pulmonary Kussmaul respiration
 PCP - treatment
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 Patients with reasonably good gas exchange (i.e.,

Pao; >70 mm Hg) but with signs of clinical
deterioration most often are admitted to the hospital
and given:
 oxygen by nasal cannula
 started on IV TMP-SMX (15-20 mg l kg/day TMP,
75-100 mg l kg/day SMX) for 21 days
 standard regimen is two double-strength tablets
three times per day
 PCP - treatment
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 Adverse effects of TMP-SMX include:

 an erythematous, maculopapular, morbilliform rash,
 less commonly, severe urticaria, exfoliative dermatitis,
and Stevens- Johnson syndrome
 GI intolerance: nausea, vomiting, abdominal pain
 Hematologic side effects: leukopenia, anemia, and
thrombocytopenia.
 Neurologic toxicities, hyperkalemia, and hepatitis also
may occur.
 PCP - treatment
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 Alternatives To Trimethoprim-sulfamethoxazole
 IV pentamidine isethionate
 The mechanism of action is unknown, but it may be related to
interference with oxidative phosphorylation, inhibition of nucleic acid
biosynthesis, or interference with dihydrofolate reductase.
 Mote toxic than Trimethoprim-sulfamethoxazole
 Adverse effects:
 Most common: nephrotoxicity, dysglycemia, hepatotoxicity,
hyperkalemia, and hyperamylasemia
 Less common: thrombocytopenia, orthostatic hypotension,
ventricular tachycardia, leukopenia, nausea, vomiting
 Pentamidine 4 mg/kg IV once daily infused over at
least 60 minutes; may reduce the dose to 3 mg/kg IV
 PCP - treatment
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 Atovaquone suspension, 750 mg twice a day (BID), is

available for treatment of mild to moderate PCP
 Atovaquone interrupts protozoan pyrimidine synthesis
 demonstrates activity against P. carinii and Toxoplasma gondii
 Adverse effects include: rash, fever, elevated LFTs, and emesis.
 Atovaquone is safer, but less effective, than TMP-SMX in
patients with mild to moderate PCP
 When compared with IV pentamidine in the treatment of mild to
moderate PCp, atovaquone and pentamidine were equally
efficacious; however, pentamidine was significantly more toxic
 Concomitant administration of fatty foods with atovaquone
doubles the absorption
 PCP - treatment
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 An oral regimen of dapsone plus TMP

 Dapsone- TMP (100 mg/day + 20 mg/kg/day )can be
used to treat mild to moderate PCP in patients
intolerant of TMP-SMX
 Dapsone is associated with hematologic toxicities
including: hemolytic anemia,
methemoglobinemia, neutropenia, and
thrombocytopenia.
 PCP - treatment
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 Clindamycin (600 mg IV every 6 hours or 600 mg

orally three times a day [TID]) + 30 mg/day of
primaquine base.
 Although skin rashes are common with this
combination, these often subside with continued
therapy.
 Some patients experience toxicities (fever, rash,
granulocytopenia, and methemoglobinemia) requiring
discontinuation
 Safe for pregnancy (category B)
 PCP - treatment
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 Initiation of Corticosteroids
 Corticosteroids have an important role in the
management of patients with acute PCP who are
clinically ill and have a low Po2, <70 mm Hg)
 Many patients who are started on PCP therapy
have an acute period of clinical deterioration,
 which may be associated with an acute
inflammatory reaction to the rapid killing of
Pneumocystis
 PCP - treatment
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 The recommended dosing of prednisone is 40 mg given

orally BID for 5 days, then 40 mg/day for 5 days, and
then 20 mg/day for 11 days, for a total of 21 days.
 Since Prednisone is not available in Ethiopia,
Prednisolone is administered as 60 mg qd x7 days, 40 mg
qd x7 days then 20 mg ad x7 days (total for 21 days)
 More common side effects of short-term corticosteroids
include:
 ulcerative esophagitis, increased appetite, weight gain,
sodium and fluid retention, headache, and elevated
LFTs.
 PCP - prophylaxis
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 Indications to start
Primary prophylaxis

CD4 < 350

WHO Stage III and IV disease

Diagnosis of tuberculosis on HIV positive

Malaria endemic area

 Secondary prophylaxis

Treatment for clinical PCP

 Duration of prophylaxis

 Till CD4 is > 350 for three months

 PCP prophylaxis regimen
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 Preferred:
 Cotrimoxazole 1 DS QD

 Cotrimoxazole 1 SS QD

 Alternatives:

 Cotrimoxazole 1 DS Three times weekly

 Atovaquone1500 mg PO daily with food

 Dapsone 100 mg PO daily or 50 mg PO BID

 Atovaquone 1500 mg + pyrimethamine 25 mg +

leucovorin 10 mg) PO daily with food

 Toxoplasma Gondii Encephalitis
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 T. gondii is a parasitic protozoan that can infect

people
 It is spread by environmental factors, such as the
consumption of raw or undercooked meats and
contact with cat feces
 T. gondii is at risk for developing clinical disease,
particularly at CD4 + counts less than 100 cells/μL
 Toxo…
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1.Primary infection, due to

 eating undercooked meat containing tissue cysts or
 ingesting oocysts that have been shed in cat feces and sporulated in the
environment
2. Re-activation of latent tissue cysts disease in individuals who cannot
produce detectable antibodies
 CNS is most common clinical presentation: headache,
confusion, lethargy, low - grade fever, seizures (~25%),
hemiparesis and speech abnormalities
 CT scan or MRI of the brain will typically show multiple

contrast-enhancing lesions in the grey matter of the cortex or

basal ganglia
 Toxo…
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Diagnosis
 HIV-infected patients with TE are almost uniformly

seropositive for anti-toxoplasma immunoglobulin

G (IgG) antibodies.
 identification of one or more mass lesions by CT or

MRI, and detection of the organism in a clinical

sample
 On imaging studies, lesions are usually ring-enhancing
and have a predilection for the basal ganglia
 Primary Prophylaxis..TOXO

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 Toxoplasma-seropositive patients who have CD4

counts <100 cells/μL should receive prophylaxis
 Patients receiving trimethoprim-sulfamethoxazole
(TMP-SMX) or atovaquone for PCP prophylaxis
require no additional medications;
 patients receiving dapsone should have
pyrimethamine plus leucovorin added to the
regimen or
 be switched to TMP-SMX or atovaquone
 Toxoplasma Gondii Encephalitis
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 The double-strength-tablet daily dose of TMP-SMX, which is the

preferred regimen for PCP prophylaxis, is also effective against TE
and is recommended.
 TMP-SMX, one double-strength tablet three times weekly, is an
alternative
 Secondary prophylaxis:
 pyrimethamine plus clindamycin.
 However, only the combination of pyrimethamine plus sulfadiazine
provides protection against PCP as well.
 sulfadiazine-pyrimethamine is more effective than clindamycin -
pyrimethamine or pyrimethamine alone
 The use of atovaquone with or without pyrimethamine is also effective
as prophylaxis for both Toxoplasma and PCP, but is significantly more
expensive
 Toxoplasma Gondii Encephalitis
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 Treatment
 Acute Therapy
 sulfadiazine 4 g/day in three or four daily divided doses and
pyrimethamine as a single 200-mg loading dose, followed by
50 to 75 mg/day as a single daily dose plus leucovorin 10 to
25 mg orally every day
 Alternative therapy includes pyrimethamine plus
leucovorin with clindamycin 600 to 900 mg IV every 6
hours or 600 mg orally every 6 hours for at least 6 weeks.
 does not prevent PCP, therefore additional PCP prophylaxis
must be administered when it is used
 Toxoplasma Gondii Encephalitis
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 pyrimethamine-sulfadiazine was superior to

pyrimethamine-clindamycin in effectiveness.
 pyrimethamine-clindamycin led to fewer discontinuations
than pyrimethamine-sulfadiazine (11% vs. 30%,
respectively)
 Trimethoprim-sulfamethoxazole may be considered a
treatment option,
 particularly
in patients who cannot take an oral regimen
because the only widely available parenteral sulfonamide is
the sulfamethoxazole component of TMP-SMX.
 Toxoplasma Gondii Encephalitis
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 1st line regimen in the Ethiopian context :

 Co-trimoxazole 2DS or 4SS po bid, for 28 days,
followed by 1DS or 2SS po bid for 3 months in adults.
 In children, 10mg of trimethoprim + 50mg of
sulfamethoxazole/kg per dose every 12 hours for 28 days
followed by maintainance therapy at 50% reduced dosage
for three months.
 Toxoplasma Gondii Encephalitis
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 TIP
 The water solubility of sulfadiazine is less than that of
other sulfonamides; therefore, hydration (2-3 L l day)
is needed to prevent crystalline nephropathy; and
aggressive hydration and alkalinization can be used in
cases of crystal formation.
 HIV associated Cryptococcal meningitis
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 Most HIV-associated cryptococcal infections are

caused by Cryptococcus neoformans, but
 occasionally Cryptococcus gattii is the etiology
 Most cases are observed in patients who have CD4
T lymphocyte (CD4) cell counts <100 cells/μL
 HIV associated Cryptococcal meningitis..
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 The initial portal of entry is the lungs, where the

organism is normally contained by an intact immune
system.
 The most common symptoms are: fever and headache.
 Less frequent signs and symptoms: nausea and vomiting,
meningismus, photophobia, and altered mental status.
 Focal neurologic deficits and seizures are observed in less
than 10% of patients.
 CSF glucose is decreased, whereas CSF proteins are usually
elevated.
 CSF cryptococcal antigen titer and CSF culture are
frequently positive.
 HIV associated Cryptococcal meningitis
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 Factors associated with a poor prognosis.

 Altered mental status at baseline,
 high CSF cryptococcal antigen titer,
 an elevated initial CSF opening pressure of greater
than 20 cm H20
 HIV associated Cryptococcal meningitis
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 Treatment
 Induction therapy: amphotericin B, 0.7 mg/kg/day
IV; plus flucytosine (100 mglkg/day) given orally in
four divided doses as for 14 days.
 Consolidation therapy: oral fluconazole 400 mg/day
for 8 weeks or until CSF cultures are sterile can be
initiated.
 suppressive therapy: fluconazole 200 mg daily
continued indefinitely unless immune reconstitution
occurs with HAART.
 HIV associated Cryptococcal meningitis
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 Option A. (preferred in Ethiopian situation)

 Induction phase ( 2 weeks)
 Fluconazole 600 mg po bid daily alone (In children
12mg/kg/day in two divided doses):
 Consolidation phase (8 weeks)
 Fluconazole 800 mg/day, in children 12mg/kg/day)
 Maintenance treatment (or secondary prophylaxis)-
Fluconazole 200 mg daily( in children 6mg/kg/day)
 HIV associated Cryptococcal meningitis
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 Discontinuation of secondary prophylaxis :

 Maintenance treatment for at least one year and have a
CD4 cell count of greater than or equal to 200
cells/mm3 (two measurements six months apart).
 Enteric infections
41

 Enteric infections can be caused by fungal, viral,

bacterial, or protozoan pathogens
 Clinical manifestations caused by GI infections
appear with a decline in the CD4+count
 Most patients present with a change in bowel habits,
predominantly diarrhea (acute or persistent)
 Viral Infections
42

 More common among HIV patients are CMV and HSV

infections.
 CMV is a double-stranded DNA virus in the herpes virus
family that can cause disseminated or localized end-organ
disease
 Common when CD4 T lymphocyte cell (CD4) counts <50 cells/mm3
 CMV usually involves the colon (colitis) , and the common
presentation are diarrhea, Esophagitis, dementia
 Tissue biopsy is preferred for a definitive diagnosis
 CMV infection of the pancreas, liver, gallbladder, and
biliary tree also has been described, retinitis lesions,
 CMV..
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 DX:- CMV viremia can be detected by PCR,

antigen assays
 PCR are not recommended for diagnosis of CMV
end-organ disease because of their poor positive
predictive value.
 A negative serum or plasma PCR assay also does
not rule out CMV end-organ disease
 Treating Disease OF CMV
44

 Intravitreal injections of ganciclovir (2 mg/injection) or foscarnet (2.4

mg/injection) for 1–4 doses over a period of 7–10 days to provide higher
intraocular levels of drug and faster control of the infection until steady state
intraocular ganciclovir concentrations are achieved plus
 Valganciclovir 900 mg PO BID for 14–21 days, then 900 mg once daily

Alternative Therapy
 Intravitreal injections as listed above plus one of the following systemic

therapy:
 Ganciclovir 5 mg/kg IV q12h for 14–21 days, then 5 mg/kg IV daily OR

 Ganciclovir 5 mg/kg IV q12h for 14–21 days, then valganciclovir 900 mg PO

daily , or
 Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h for 14–21 days, then 90–120

mg/kg IV q24h (AI), or

 Note: This regimen should be avoided in patients with sulfa allergy

because of cross hypersensitivity with probenecid

 CMV…
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 Adverse effects of ganciclovir/valganciclovir

include anemia, neutropenia, thrombocytopenia,
nausea, diarrhea, and renal dysfunction.
 Ganciclovir-related neutropenia often can be
reversed with hematopoietic growth factors.
 Adverse effects of foscarnet include nephrotoxicity,
and electrolyte abnormalities; seizures and anemia
 Herpes zoster
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 There is a high incidence of zoster in association with

HIV infection
 More than 90% of adults have serologic evidence of
infection with varicella-zoster virus
 Presentation is similar to immunocompetent patient,
duration may be longer and the risk of disseminated
infection is greater in HIV infected individuals
 Lesions are painful, pruritic, grouped and can be
pustular on an erythematous base
47
48
 Herpes zoster treatment
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 Dermatomal
 Acyclovir p.o. 800 mg 5X day for at least 7 days
(until lesions crust) or acyclovir IV 10 mg/kg/day
tid
 Disseminated
 Acyclovir 30-36 mg/kg/day IV at least 7 days
 Esophageal disease
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 most commonly caused by Candida, but can also

be caused by CMV; HSV;
 Symptoms include dysphagia, odynophagia, and
thrush (with Candida infections).
 Oral ulcers are common with HSV; rare with
Candida, and uncommon with CMV
 Pain is usually diffuse in Candida infections and
more focused with HSV; CMv;.
 Fever is primarily associated with CMV
 Esophageal disease
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 Oropharyngeal candidiasis - treatment

 Oral fluconazole (100 mg once daily)
 local antifungal therapy

 Miconazole Gel
 "swish and swallow" nystatin suspension, one
teaspoon four or five times daily
 Clotrimazole four or five times daily)
 Esophageal disease
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 Esophageal candidiasis – tretment

 14 to 21 days of fluconazole at higher doses (up to
400 mg PO or IV daily).
 Alternate therapies include:

 amphotericin B IV 0.3 - 0.6 mg/kg/day ,

 itraconazole 200mg daily with food,
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