Human Immunodeficiency Virus 2007What every physician should know
Clinical Management Course
February 15th 2007
Todd Hulgan, MD, MPHAssistant Professor
Dept. of Medicine, Division of Infectious DiseasesCenter for Health Services Research
AIDS Clinical Trials CenterVanderbilt University School of Medicine
Objectives• Timeline of HIV• HIV Pathogenesis• Epidemiology of HIV Infection • Clinical Manifestations
Acute HIV InfectionOpportunistic 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.
Lohse, N. et. al. Ann Intern Med 2007;146:87-95
Survival from age 25 years
Median survival= 35+ years
00003-E-15 – December 2005
Adults and children estimated to be living Adults and children estimated to be living with HIV as of end 2005with HIV as of end 2005
Total: 40.3 (36.7 – 45.3) million
Western & Central Europe
720 000720 000[570 000 – 890 000][570 000 – 890 000]
North Africa & Middle East510 000510 000
[230 000 – 1.4 million][230 000 – 1.4 million]
Sub-Saharan Africa25.8 million25.8 million
[23.8 – 28.9 million][23.8 – 28.9 million]
Eastern Europe & Central Asia1.6 million 1.6 million
[990 000 – 2.3 million][990 000 – 2.3 million]
South & South-East Asia7.4 million7.4 million[4.5 – 11.0 million][4.5 – 11.0 million]
Oceania74 00074 000
[45 000 – 120 000][45 000 – 120 000]
North America1.2 million1.2 million
[650 000 – 1.8 million][650 000 – 1.8 million]
Caribbean300 000300 000
[200 000 – 510 000][200 000 – 510 000]
Latin America1.8 million1.8 million
[1.4 – 2.4 million][1.4 – 2.4 million]
East Asia870 000870 000
[440 000 – 1.4 million][440 000 – 1.4 million]
Acute HIV Infection:Signs and Symptoms
Common• Fever 96%• Adenopathy 74%• Sore throat 70%• Rash 70%• Myalgia 54%
Occasional (<50%)• Oral ulcers• Thrombocytopenia• Leukopenia• Diarrhea• Headache• Nausea• Elevated ALT or AST• Aseptic meningitis
Cough is not part of acute HIV infection
HIV Serology is Negative during Acute HIV Infection
0 1 2 3 4 5 6 7 8 9 10
Symptoms
p24 AntigenHIV RNA
HIV ELISA
Weeks Since InfectionRecombinant peptide ELISA
Viral lysate ELISA
Negative Western blot
Things that should make you think of undiagnosed chronic HIV…
• Anyone in risk groupUnprotected intercourse/multiple partnersAny 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 (PCPblebs)
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
• “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
• 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
• 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 T-lymphocyte membrane
• Large molecule• Intramuscular injection• Approved for salvage
therapy only
• Enfurvitide (T-20)
clinicaloptions.com/hiv
Refining Antiretroviral Regimens
Estimated Timeline for New Antiretrovirals
PA-457
PI
NNRTI
NRTI
Maturation inhibitor
Maraviroc
GS-9137
TMC278Etravirine
Apricitabine
Brecanavir
Integrase inhibitor
Entry inhibitor (anti-gp120, CCR5)
CXCR4 inhibitors
2006 2007 2008 2009 2010
MK-0518 TNX-355
Vicriviroc
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 RNAMeasures actively replicating virusGoal 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!