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!