Human Immunodeficiency Virus 2007 What every physician should know

1. Human Immunodeficiency Virus 2007What 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

2. Objectives • 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!

3. 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

7. Pathogenesis of HIV:Cellular Life Cycle

8. Sexual intercourse IDU Maternal-fetal Risk of transmission after occupational exposure with HIV-contaminated needle = ~0.3% ~3% HCV ~30% HBV Pathogenesis of HIV:Transmission

9. Pathogenesis of HIV:Natural History

10. Walensky, et al. J Infect Dis 2006; 194: 11-19.

11. Survival from age 25 years Median survival= 35+ years Lohse, N. et. al. Ann Intern Med 2007;146:87-95

15. Adults and children estimated to be living with HIV as of end 2005 Eastern Europe & Central Asia 1.6 million [990 000 – 2.3 million] Western & Central Europe 720 000 [570 000 – 890 000] North America 1.2 million [650 000 – 1.8 million] East Asia 870 000 [440 000 – 1.4 million] North Africa & Middle East 510 000 [230 000 – 1.4 million] Caribbean 300 000 [200 000 – 510 000] South & South-East Asia 7.4 million [4.5 – 11.0 million] Sub-Saharan Africa 25.8 million [23.8 – 28.9 million] Latin America 1.8 million [1.4 – 2.4 million] Oceania 74 000 [45 000 – 120 000] Total: 40.3 (36.7 – 45.3) million

16. Acute HIV Infection:Signs and Symptoms • Occasional (<50%) • Oral ulcers • Thrombocytopenia • Leukopenia • Diarrhea • Headache • Nausea • Elevated ALT or AST • Aseptic meningitis Common • Fever 96% • Adenopathy 74% • Sore throat 70% • Rash 70% • Myalgia 54% Cough is not part of acute HIV infection

17. HIV Serology is Negative during Acute HIV Infection Symptoms p24 Antigen HIV RNA HIV ELISA Negative Western blot 0 1 2 3 4 5 6 7 8 9 10 Weeks Since Infection Recombinant peptide ELISA Viral lysate ELISA

18. 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)

19. 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

20. 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

21. Treatment of HIV Infection • 21 FDA-approved antiretrovirals • Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs) • Non-nucleoside RTIs (NNRTIs) • Protease inhibitors (PIs) • Fusion inhibitor

22. Treatment of HIV Infection • 21 FDA-approved antiretrovirals • Nucleoside(-tide) Reverse Transcriptase Inhibitors (NRTIs) • Non-nucleoside RTIs (NNRTIs) • Protease inhibitors (PIs) • Fusion inhibitor

23. “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 Nucleoside(-tide*) Reverse Transcriptase Inhibitors

24. “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 Non-Nucleoside Reverse Transcriptase Inhibitors

25. Treatment of HIV Infection • 21 FDA-approved antiretrovirals • Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs) • Non-nucleoside RTIs (NNRTIs) • Protease inhibitors (PIs) • Fusion inhibitor

26. “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 Protease Inhibitors

27. Treatment of HIV Infection • 21 FDA-approved antiretrovirals • Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs) • Non-nucleoside RTIs (NNRTIs) • Protease inhibitors (PIs) • Fusion inhibitor

28. Inhibits viral fusion with CD4 T-lymphocyte membrane Large molecule Intramuscular injection Approved for salvage therapy only Enfurvitide (T-20) Fusion Inhibitor

29. Estimated Timeline for New Antiretrovirals CXCR4 inhibitors Entry inhibitor (anti-gp120, CCR5) GS-9137 Maturation inhibitor MK-0518 TNX-355 Integrase inhibitor PA-457 Maraviroc Etravirine TMC278 PI Brecanavir NNRTI Vicriviroc Apricitabine NRTI

30. 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

31. 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

32. 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

33. 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)

34. 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

35. Antiretroviral Drug ToxicitiesLate 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

36. 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!

37. 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!