HIV / AIDS
&
Opportunistic Infections
www.hivma.org
Learning Objectives
• HIV – the basics
• Epidemiology and screening
• New diagnosis and prognosis
• Antiretrovirals
• Opportunistic infections – clinical cases
Human Retroviruses
HTLV-1
HTLV-2
HIV-1
HIV-2
Adult T-cell Leukemia, HAM/TSP
Possible association with HAM/TSP
Extremely slow progression to AIDS
HIV-1 Group M
HIV-1 Group N
HIV-2
HIV-1 Group O
SIV (Chimpanzee)
SIV (Sooty Mangabey)
HIV Infection
White Blood Cells
Lymphocytes
T - Lymphocytes
CD4+ T – Lymphocytes
(Helper)
CD4+ T – Lymphocytes
CCR5+ (Memory)
T-Cell Panel
• % CD3
• % CD4
• % CD8
63
4
55
• Normal CD4%
• Normal CD4
>30%
>450
• AIDS
• CD3, Abs
• CD4, Abs
• CD8, Abs
569
38
494
–
–
–
–
CD4 < 200
CD4% < 14%
OI
Malignancy
• Kaposi
• NHL
• Cervical cancer
Who Should Be Tested?
• Routine HIV screening for all individuals ages
13-64 in all health-care settings.
• At least annual screening for high risk patients:
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–
–
–
Injection drug use (sex partners)
Persons who exchange sex for money/drugs
MSM and sex partners of HIV infected persons
Heterosexuals (sex partner) with >1 sex partner since
last HIV test
• Repeat test before new sexual relationship.
HIV Test
• Routine HIV ELISA (HIV-1/O/2)
- Positive  Western Blot
• Rapid HIV ELISA
- Negative  Routine HIV ELISA
- Positive  Western Blot
• Window Period:
- Routine HIV ELISA ~3 weeks
- HIV Quantitative PCR ~7 days
Initial Evaluation of New HIV
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HIV ELISA / WB
CD4 count
HIV Viral Load
CBC w/ diff
Comprehensive Chemistry
Lipid profile
Genotype resistance test
Hepatitis A, B, C serologies
RPR
Toxoplasma serology
Testing for GC/Chlamydia
TST or IGRA
HLA-B*5701
Urinalysis
Thrush
Genital & peri-anal lesions
Pap smear
Anal Pap smear (MSM)
Lymphadenopathy
Skin:
KS lesions
folliculitis
psoriasis
Neurologic:
peripheral neuropathy
neurosyphilis
HAND / neuropsych testing
Ophthalmologic (CD4 < 50)
Prognosis
3-yr probability of AIDS = AIDS defining illness or death, not CD4<200
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
Natural Course of HIV Infection
Primary
Infection
Seroconversion
Intermediate Stage
AIDS
Plasma HIV RNA
1,000,000
100,000
Plasma RNA Copies
10,000
CD4 Cell Count
10,000,000
1,000
1,000
CD4 Cells
100
200
10
1
4-8 Weeks
Up to 12 Years
2-3 Years
Opportunistic Infections – CD4 < 200
Oral candidiasis
Pneumocystis pneumonia
Opportunistic Infections – CD4 < 100
Candida esophagitis
Toxoplasma encephalitis
Opportunistic Infections – CD4 < 50
Disseminated cryptococcosis
Kaposi sarcoma
Opportunistic Infections – CD4 < 50
CMV Retinitis
Molluscum contagiosum
Many other…
Disseminated Mycobacterium avium
Progressive multifocal leukoencephalopathy
Cryptosporidiosis & other protozoa
AIDS Defining Illnesses
Candidiasis
Esophageal
Tracheal, bronchial
Cervical Cancer, invasive
Coccidioides – disseminated
Chronic diarrhea (>1 month)
Cryptosporidia or Isospora
Cryptococcus – extrapulmonary
CMV
Retinitis
Other (not liver, spleen, LN)
HSV
Chronic ulcer (>1 month)
Pulmonary, esophageal
Histoplasma – disseminated
HIV encephalopathy
Kaposi’s sarcoma
Lymphoma (NHL)
Burkitt’s
Immunoblastic
Primary CNS
Mycobacterium
TB – any
Other – disseminated/extrapulmonary
Pneumonia
Pneumocystis
Recurrent bacterial (within 1 yr)
PML
NT Salmonella septicemia, recurrent
Toxoplasmic encephalitis
Wasting syndrome - HIV
MMWR 1992; 41 (RR17)
When to Start HAART?
DHHS Guidelines 2011 (http://aidsinfo.nih.gov)
Antiretrovirals
• Nucleoside RTI:
Abacavir
Didanosine / ddI
Emtricitabine / FTC
Lamivudine / 3TC
Stavudine / d4T
Tenofovir
Zidovudine / AZT
• Protease Inhibitors:
(Ziagen)
(Videx)
(Emtriva)
(Epivir)
(Zerit)
(Viread)
(Retrovir)
• Non-Nucleoside RTI:
Efavirenz
Nevirapine
Etravirine
Rilpivirine
(Sustiva)
(Viramune)
(Intelence)
(Edurant)
• Entry/Fusion Inhibitor:
Enfuvirtide / T20 (Fuzeon)
Maraviroc
(Selzentry)
Atazanavir
Darunavir
Fosamprenavir
Inidinavir
Lopinavir/Ritonavir
Nelfinavir
Ritonavir
Tipranavir
(Reyataz)
(Prezista)
(Lexiva)
(Crixivan)
(Kaletra)
(Viracept)
(Norvir)
(Aptivus)
• Integrase Inhibitor:
Raltegravir
(Isentress)
• Combinations:
Atripla (Tenofovir + FTC + Sustiva)
Combivir (AZT + 3TC)
Epzicom (Abacavir + 3TC)
Trizivir (AZT + Abacavir + 3TC)
Truvada (Tenofovir + FTC)
HIV Replicative Cycle
ART Basics
• General concepts:
– Need 3 active agents: (2 NRTI) + (NNRTI or PI or Integrase inhibitor)
– Treatment is life-long. Discontinuing ART results in viral rebound.
• Goal of therapy
– HIV VL < 50 = “undetectable viral load”
• ART Resistance
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Baseline resistance
Suboptimal medication adherence (90-95% compliance)
Suboptimal pharmacokinetics
Suboptimal potency of the regimen
Resistant strains are “archived” = permanent
• Common initial regimens:
Atripla (Tenofovir + FTC + Sustiva) - QD
Truvada + Reyataz + Norvir - QD
Truvada + Isentress - BID
Combivir + Kaletra - BID
Can We Eradicate Infection?
Nature Medicine 2003; 9:853-860
Common adverse reactions
• Rash
– Any antiretroviral
– Mild to severe (SJS)
– First 2 months
• Nausea/Vomiting
– Any antiretroviral
– R/O hepatitis
– Symptomatic management
• Diarrhea
– Any, but usually PIs
– Symptomatic management
• Renal failure
– Tenofovir (Truvada/Atripla)
– First several months
• CNS/Psychiatric
– Efavirenz (Sustiva/Atripla)
– First several weeks
• Drug-Drug Interaction
– New prescriptions
• Fluticasone, Statins
• PPIs
– OTC
• St. John’s Wort
When Should You Stop HAART?
• Patient clearly non-compliant (active drug abuse) –
not “stopping” and actually “starting”
• Severe drug reaction:
Abacavir hypersensitivity reaction – fever, rash, GI, and/or pulmonary
symptoms within 6 weeks of initiation, association with HLA-B*5701.
Lactic acidosis (ddI/d4T>AZT) – malaise, myalgias, non-specific
symptoms or critically ill, pancreatitis/hepatitis, elevated serum
lactate and acidemia.
NNRTI hypersensitivity – occurs within 6 weeks of initiation, hepatitis
(fulminant hepatic failure) and/or rash (Stevens-Johnson).
Nevirapine hepatotoxicity risk factors: pregnancy, HBV/HCV, CD4 >
250 [F] or CD4 > 400 [M].
HIV-Associated Dyslipidemia
Fat Accumulation
HIV Lipohypertrophy
Increase abdominal fat
Dorsocervical fat pad
Metabolic Changes
Increased Triglycerides
Increased LDL
Decreased HDL
Insulin resistance
Case #1
• 31 M with history of HIV presents with
fevers and progressive DOE x 3 weeks.
• He reports he was diagnosed with HIV
about 10 years ago when he developed
shingles. He never followed-up and has
never been on HAART.
• He does not know his last CD4 count or
viral load.
Case #1
ROS:
Physical Exam:
20 lbs weight loss x1 year
Night sweats for past month
Diarrhea
101.80F 94 110/60 16
Pulse Ox 92%
SH:
Acquired by MSM
Born & raised in Ohio
Moved to AZ 2 yrs ago
Visits homeless shelters
GEN – appears comfortable
OP – thrush
LUNGS – diffuse crackles
ABD – soft, non-tender
SKIN – no lesions
MS – alert & oriented
CXR
Laboratory Results
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CD3
CD4
CD8
CD3, Abs
CD4, Abs
CD8, Abs
HIV VL
87
9
75
610
64
530
500K
Differential Diagnosis?
Differential Diagnosis
Pneumonia in HIV
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CAP – Pneumococcus, Influenza
Pneumocystis
TB
Coccidioides
Histoplasma
Cryptococcus
Diagnostic Tests
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Nasal Influenza swab - negative
Blood cultures - negative
Urine S.pneumonia antigen - negative
Sputum culture - normal flora
Sputum AFB smear - negative x3
Sputum fungal smear - negative
Induced sputum PCP DFA - negative
Serum Cryptococcal antigen - negative
Coccidioides ELISA - negative
Pneumocystis jiroveci
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Subtle – symptoms for weeks to months
90% with CD4 < 200 or CD4% < 15%
CXR findings variable – possibly negative
Negative CXR – role of HRCT
Diagnosis:
– Induced Sputum DFA 50-90%
– BAL DFA 90-99%
– Transbronchial Bx 95+%
Therapy
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PaO2 < 70 mmHg
A-a > 35 mmHg
Corticosteroids
IV TMP/SMX
IV Pentamidine
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PO TMP/SMX
Clinda + Primaquine
TMP/Dapsone
Atovaquone
- Clinical deterioration common within 3-5d of initiation of
therapy, particularly in those not receiving corticosteroids.
- Treatment failure if no improvement or worsening after at
least 4-8d of therapy.
Prophylaxis
TMP/SMX, Dapsone, Atovaquone, Aero
Pentamidine
Stop prophylaxis when CD4 > 200 x 3 months
20 Prophylaxis:
- Requires QD TMP/SMX, not QMWF
10 Prophylaxis:
- CD4 < 200, or CD4% < 14%
- History of thrush
- AIDS defining illness
Pneumonia in HIV
• S.pneumoniae remains most common cause. Other
organisms = H.influenza, S.aureus, P.aeruginosa.
• Give Pneumovax and revaccinate when CD4 > 200.
• Pulmonary TB in HIV patients with CD4 > 350 similar to
that in non-HIV infected individuals.
• Pulmonary TB in AIDS patients – typically no cavitation,
appears more like consolidation or diffuse infiltrates.
• TB in HIV patients – at higher risk of extrapulmonary
disease at all CD4 counts.
• AIDS patients and HIV patients with unknown CD4 count
presenting with pneumonia  Respiratory Isolation.
Coccidioides
• Common cause of pneumonia in Arizona
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CD4 < 250, past history NOT a risk factor
Radiographs – diffuse or focal infiltrates
Serologic tests ~60% sensitivity
Diagnosis – fungal culture, smear ~40%
Disseminated disease frequent:
lymph nodes, meningitis, skin
Case #2
• 42 M with history of IVDA presents with
complaints of intermittent fever, HA, and
increasing lethargy over the past 4 weeks.
• He is subsequently found to be HIV + with
a CD4 count of 23.
• He reports having been in and out of jail
on several occasions.
• Poor historian, appears confused.
MRI Brain
Differential Diagnosis?
Differential Diagnosis
CNS Lesions in HIV
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Toxoplasma Encephalitis
Primary CNS Lymphoma
Bacterial brain abscess
Progressive Multifocal Leukoencephalopathy
TB
Cryptococcus
CMV Encephalitis
Chagas disease
Diagnostic Tests
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Blood cultures - negative
Serum Cryptococcal antigen - negative
Toxoplasma IgG positive, IgM negative
LP: 8 WBC (90%L), 64 G, 60 P
– Toxoplasma DNA PCR negative
– CMV and JC virus PCRs negative
– TB PCR negative
– Cryptococcal antigen negative
Toxoplasma Encephalitis
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80% have CD4 < 100
95+% Toxoplasma IgG+
~30% single lesion
CSF PCR sensitivity 50%
Definitive dx = brain bx
• Therapy – 6 wks
Pyrimethamine/Sulfadiazine
Pyrimethamine/Clindamycin
• 10 Prophylaxis (CD4 < 100)
DS TMP/SMX QD
Pyrimethamine/Dapsone
Adapted from http://www.cdc.gov
Cryptococcal Meningitis
• Majority of cases occur in patients with CD4 < 50.
• Classic meningeal symptoms/signs (neck stiffness &
photophobia) infrequent.
• Disseminated disease common: pulmonary, blood, skin.
• Elevated opening pressure > 75% (> 20cm H2O).
• Cryptococcal antigen 90+% sensitive (serum & CSF).
• Treatment:
Ampho B +/- Flucytosine x 2wks  Fluconazole
Repeated LP for symptomatic elevated ICP
Case #3
• 29M diagnosed with AIDS ~2 months ago
(Thrush), started on HAART 6 weeks ago.
• Presents with acute onset of fever, cough,
pleuritic chest pain, and dyspnea.
• He looks well despite Temp 102.60F.
Exam only notable for L sided bronchial
breath sounds.
• CD4 count 29  146.
CXR
CT Chest
Laboratory Studies
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Blood cultures
Fungal BC
Mycobacterial BC
Serum Cryptococcal Ag
Urine Histoplasma Ag
RPR
• LDH 188
• WBC 12.9 (88%N)
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BAL Bacterial Cx BAL Fungal Cx BAL Mycobacterial Cx BAL PCP DFA BAL Viral Cx BAL Cytology:
WBC/RBC, benign bronchial cells
• Transbronchial Bx:
Bronchial mucosa - crush artifact
Diagnosis?
• Lymph node biopsy reveals caseating
granulomata with rare acid fast organisms
• LN Mycobacterial culture - MAC
Disseminated MAC
• Occurs in advanced AIDS, CD4 < 50.
• Vast majority – fevers, weight loss, night sweats, severe
anemia (Hct < 25%).
• Organ involvement: spleen, LN, liver, intestines, and
bone marrow. Lung involvement rare (< 10%).
• Diagnosis:
– Blood culture – single 90-95%, two 99%.
– May take 2-6 weeks to grow.
• Treatment: Clarithromycin + Ethambutol +/- Rifabutin
• 10 Prophylaxis (CD4 < 50): Azithromycin 1200mg Qwk
Immune Reconstitution
Inflammatory Syndrome
• Paradoxical worsening of
clinical or laboratory
parameters despite rising
CD4 counts and declining
viral loads.
• Inflammatory reaction to
a subclinical infection.
• Estimated to occur in 1025% of those initiating
ART (weeks to months).
CID 2004; 38:1159-66
Summary
• HIV
– HIV-1/0/2 strains. CD4 T-cell, CCR5 > CXCR4. LN damage.
• Epidemiology and screening
– About 50,000 new cases / yr. MSM > heterosexual > IVDA.
– HIV EIA  HIV WB. Check VL for acute retroviral syndrome.
• New diagnosis and prognosis
– Screen for other STIs. Baseline genotype resistance testing.
• Antiretrovirals
– Indications: CD4 < 350, AIDS, HIVAN, HBV trmt, pregnancy
– Need 3 active agents, strict compliance, lifelong treatment
• Opportunistic infections
– Primary Prophylaxis: PJP, Toxoplasma, MAC
– Cryptococcus, CMV, Cryptosporidia
– IRIS – unmasking versus paradoxical