Human Immunodeficiency Virus 2007
What every physician should know
Clinical Management Course
February 15th 2007
Todd Hulgan, MD, MPH
Assistant Professor
Dept. of Medicine, Division of Infectious Diseases
Center for Health Services Research
AIDS Clinical Trials Center
Vanderbilt University School of Medicine
Objectives
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Timeline of HIV
HIV Pathogenesis
Epidemiology of HIV Infection
Clinical Manifestations
 Acute HIV Infection
 Opportunistic Infections
• Treatment of HIV
• Complications of HIV Treatment
• Watch for highlighted text!
The Lingo
• “HAART”: Highly-active antiretroviral therapy; at least 3
drugs from at least 2 drug classes
• “CD4 nadir”: lowest CD4+ T lymphocyte count
• “Viral load”: plasma HIV-RNA concentration (copies/mL);
determined by PCR
• “Undetectable”: a viral load below the limit of assay
detection (once <400 copies/mL; now <50); goal of therapy.
• “Genotype”: genetic sequence of gag-pol region of HIV
genome that includes reverse transcriptase and protease;
mutations in these regions confer drug resistance
• “OI”: opportunistic infection
Pathogenesis of HIV:
Cellular Life Cycle
Pathogenesis of HIV:
Transmission
1. Sexual intercourse
2. IDU
3. Maternal-fetal
• Risk of transmission after
occupational exposure
with HIV-contaminated
needle = ~0.3%
 ~3% HCV
 ~30% HBV
Pathogenesis of HIV:
Natural History
Walensky, et al. J Infect Dis 2006; 194: 11-19.
Survival from age 25 years
Lohse, N. et. al. Ann Intern Med 2007;146:87-95
Median survival=
35+ years
Adults and children estimated to be living
with HIV as of end 2005
Western & Central Eastern Europe
& Central Asia
Europe
720 000
North America
1.2 million
[650 000 – 1.8 million]
Caribbean
1.6 million
[570 000 – 890 000] [990 000 – 2.3 million] East Asia
North Africa & Middle East
300 000
[200 000 – 510 000]
Latin America
1.8 million
[1.4 – 2.4 million]
510 000
[230 000 – 1.4 million]
Sub-Saharan Africa
25.8 million
[23.8 – 28.9 million]
870 000
[440 000 – 1.4 million]
South & South-East Asia
7.4 million
[4.5 – 11.0 million]
Oceania
74 000
[45 000 – 120 000]
Total: 40.3 (36.7 – 45.3) million
00003-E-‹#› – December 2005
Acute HIV Infection:
Signs and Symptoms
Common
• Fever
• Adenopathy
• Sore throat
• Rash
• Myalgia
Occasional (<50%)
96%
74%
70%
70%
54%
Cough is not part of
acute HIV infection
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Oral ulcers
Thrombocytopenia
Leukopenia
Diarrhea
Headache
Nausea
Elevated ALT or AST
Aseptic meningitis
HIV Serology is Negative during Acute
HIV Infection
Symptoms
p24 Antigen
HIV RNA
HIV ELISA
0
Negative Western blot
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Weeks Since Infection
Recombinant peptide ELISA
Viral lysate ELISA
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Things that should make you think of
undiagnosed chronic HIV…
• Anyone in risk group
 Unprotected intercourse/multiple partners
 Any prior or current IDU
• Herpes zoster (shingles) in an otherwise
healthy young or middle-aged person
• Candidiasis- oropharyngeal or recurrent
vaginal
• Tuberculosis
• “Spontaneous” pneumothorax without
apparent risk factors (PCPblebs)
Opportunistic Infections
• Pneumocystis jiroveci pneumonia (PCP)
 Risk increased with CD4 <200 cells/mm3
 Present with subacute onset dyspnea
 Hypoxemia
 Bilateral interstitial infiltrates
 Diagnose by bronchoscopy and GMS stain
 Treat with high-dose TMP-SMX  corticosteroids
Opportunistic Infections
• Mycobacterium avium complex (MAC)
 CD4 <50
 Fever, malaise, anorexia/wasting, pancytopenia, GI symptoms
• Cryptococcal meningitis
 CD4 <100-200
 Severe HA, fever, may have few inflammatory cells in CSF; may
have high opening pressure
 Clinical benefit from repeated LPs while on treatment
• Cerebral Toxoplasmosis
 CD4 <50-100
 Presents as CNS mass lesion- HA, seizure, focal neuro deficits
Treatment of HIV Infection
• 21 FDA-approved
antiretrovirals
 Nucleoside/tide Reverse
Transcriptase Inhibitors (NRTIs)
 Non-nucleoside RTIs (NNRTIs)
 Protease inhibitors (PIs)
 Fusion inhibitor
Treatment of HIV Infection
• 21 FDA-approved
antiretrovirals
 Nucleoside(-tide) Reverse
Transcriptase Inhibitors (NRTIs)
 Non-nucleoside RTIs (NNRTIs)
 Protease inhibitors (PIs)
 Fusion inhibitor
Nucleoside(-tide*) Reverse
Transcriptase Inhibitors
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“Nucleoside analogues”, “Nucs”, NRTIs
Few acute side effects
Long-term side effects
“Backbone” of most regimens
Less potent vs. NNRTIs and PIs
Generally require multiple resistance
mutations
• Various co-formulations decrease pill
burden
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Zidovudine
Lamivudine
Stavudine
Didanosine
Zalcitabine
Abacavir
Emtricitabine
*Tenofovir
Non-Nucleoside Reverse
Transcriptase Inhibitors
• “Non-nucs”, NNRTIs
• As potent as PIs
• Common adverse reactions and
resistance sites
• Long half-life
• Resistance can be rapid and is
class-wide
• Efavirenz
• Nevirapine
• Delavirdine
Treatment of HIV Infection
• 21 FDA-approved
antiretrovirals
 Nucleoside/tide Reverse
Transcriptase Inhibitors (NRTIs)
 Non-nucleoside RTIs (NNRTIs)
 Protease inhibitors (PIs)
 Fusion inhibitor
Protease Inhibitors
• “PIs”
• Generally most potent antiretroviral
activity
• Distinct short and long-term toxicities
• Large pill burden
• Often “boosted” with low doses of
ritonavir
• Usually require multiple resistance
mutations
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Indinavir
Ritonavir
Saquinavir
Amprenavir
Nelfinavir
Lopinavir/ritonavir
Atazanavir
Fosamprenavir
Tipranavir
Darunavir
Treatment of HIV Infection
• 21 FDA-approved
antiretrovirals
 Nucleoside/tide Reverse
Transcriptase Inhibitors (NRTIs)
 Non-nucleoside RTIs (NNRTIs)
 Protease inhibitors (PIs)
 Fusion inhibitor
Fusion Inhibitor
• Inhibits viral fusion with CD4
• Enfurvitide (T-20)
T-lymphocyte membrane
• Large molecule
• Intramuscular injection
• Approved for salvage
therapy only
Refining Antiretroviral Regimens
Estimated Timeline for
New Antiretrovirals
CXCR4
inhibitors
Entry inhibitor
(anti-gp120, CCR5)
GS-9137
MK-0518
Maraviroc
2006
2007
Etravirine
Maturation inhibitor
TNX-355
Integrase inhibitor
PA-457
2008
2009
2010
TMC278
PI
Brecanavir
NNRTI
Vicriviroc
Apricitabine
NRTI
clinicaloptions.com/hiv
Measures of Treatment Effect
• CD4 T-lymphocytes
 Target of HIV
 Absolute count (and %) important
 Normal = 800-1200 cells/mm3
 <200 cells/mm3 = ↑ risk for opportunistic infections
 Qualitative dysfunction even with higher absolute
levels (e.g. TB, VZV, candidiasis)
 Monitored every 3-4 months while on treatment
Measures of Treatment Effect
• HIV RNA by PCR
 “Viral load”
 Reported as “copies” of viral RNA
 Measures actively replicating virus
 Goal of treatment = “undetectable”
• <50 copies
 Monitored monthly after starting treatment,
then every 3-4 months
Measures of Treatment Effect
• HIV Genotypic Resistance Test
 Identifies mutations in the viral genome (gag and pol)
 Certain mutations decrease the effectiveness of
medications (i.e. makes the virus “resistant”)
 Important mutations are known for each medication
 Complicated lab report
 Used when patient has detectable virus on treatment
(“failing” treatment), pregnancy, recent infection,
occasionally in treatment naïve patients
 “Phenotypic” assays also available
Antiretroviral Drug Toxicities:
Early Side Effects
• Nausea with almost all drugs
• Diarrhea with most PIs
• Rash
 NNRTIs; abacavir
 Stevens-Johnson/TEN can occur
• Hepatitis
 NNRTIs
 Fulminate hepatitis can occur
• Hyperlactatemia/lactic acidosis
 NRTIs (esp. d-drugs: d4T, ddI)
Antiretroviral Drug Toxicities:
Unique Side Effects
• “d” drugs- didanosine (ddI), stavudine (d4T), zalcitibine (ddC)
 Peripheral neuropathy (ddI+d4T>>ddI or d4T)
 Lactic acidosis
 Pancreatitis (ddI>d4T)
• Abacavir
 Hypersensitivity
• Efavirenz
 CNS toxicity: dizziness; “vivid” dreams
• Zidovudine (AZT)
 Anemia; macrocytosis (↑MCV)
• Indinavir
 Nephrolithiasis
• Indinavir and atazanavir
 Benign hyperbilirubinemia
Antiretroviral Drug Toxicities
Late Metabolic Side Effects
• Dyslipidemia:
 Approximately 20% of patients on PI’s will have
elevated total cholesterol/LDL/triglycerides and/or
decreased HDL
 Increased incidence of atherosclerosis/cardiovascular
disease?
• Yes, but minimal vs. traditional risk factors, benefit of HAART
• Diabetes:
 Approximately 5% of patients receiving PI’s will develop
diabetes, more develop insulin resistance
• Lipodystrophy
Stopping Antiretroviral Medications
• A patient with HIV is admitted for symptoms that could be
related to drug toxicity…so what do you do?
 If stopping medications, all should be stopped together, except…
 NNRTIs (NVP, EFV) should be stopped several days (5-7?) before
other medications
• Long half-life (>48 hrs!)
• If stopped simultaneously, other drugs are metabolized first, leaving
NNRTI “monotherapy” and development of class resistance is possible
• If concerned about possible toxicity, always better to stop…
 can restart later if needed…
• except abacavir!
 Contact the ID/HIV fellow/attending on call if you have questions!
Conclusions
• HIV mortality has decreased significantly in US and Europe
• HIV care in developed countries shifted to pharmacology,
adherence, toxicity and co-morbidity management
• Opportunistic infections still important
 Often presenting illness at the time of HIV diagnosis
• Non-opportunistic complications of increasing importance
 Hepatitis C co-infection an increasing problem
• Liver disease a leading cause of death among HIV+ in US
 Malignancy
• Increased rates of many not-traditionally-AIDS-related malignancies
 Drug toxicity; cardiovascular disease
• Always call your friendly neighborhood ID/HIV specialist if
you have questions!