1. HIV/AIDS M3 lecture Angela Remington, MD MS Fellow Infectious Diseases Updated 2005

2. Introduction AIDS first recognized 1981 AIDS first recognized 1981 HIV RNA retrovirus discovered 1983 HIV RNA retrovirus discovered 1983 2 nd leading cause of disease burden worldwide 2 nd leading cause of disease burden worldwide Leading cause of death in Africa Leading cause of death in Africa Approx 1 million people currently diagnosed in America Approx 1 million people currently diagnosed in America

3. Transmission of HIV Blood, semen, breast milk, saliva Blood, semen, breast milk, saliva Sexual, parenteral, vertical Sexual, parenteral, vertical Risk of contracting infection dependent on Risk of contracting infection dependent on –Viral load –Integrity of the exposed site –Type of body fluid –Volume of body fluid

4. Transmission of HIV Risk after a single exposure Risk after a single exposure –>90% blood or blood products –14% vertical –0.5-1% injection drug use –0.2-0.5% genital mucous membrane –<0.1% non-genital mucous membrane

5. MTCT of HIV Developing countries 40% Developing countries 40% On Zidovudine alone 7% On Zidovudine alone 7% Zidovudine with C-section 2% Zidovudine with C-section 2% HAART <1% if viral load <50 copies HAART <1% if viral load <50 copies 80% of those infected vertically are infected close to the time of delivery 80% of those infected vertically are infected close to the time of delivery

6. Transmission Risk of transmission is now 1/10,000,000 with each unit of blood Risk of transmission is now 1/10,000,000 with each unit of blood 100 confirmed cases from healthcare exposure 100 confirmed cases from healthcare exposure Risk with needle stick 0.32% Risk with needle stick 0.32% Risk with mucous membrane exposure 0.03% Risk with mucous membrane exposure 0.03%

7. global Estimated 42 million people living with HIV/AIDS in 2002 Estimated 42 million people living with HIV/AIDS in 2002 5 million new infections per year 5 million new infections per year 3 million deaths per year 3 million deaths per year Parts of Africa 25-40% of adults are infected Parts of Africa 25-40% of adults are infected 85% heterosexual transmission worldwide 85% heterosexual transmission worldwide

8. The Virus Glycoproteins (gp 120, gp41) Glycoproteins (gp 120, gp41) 2 copies of ssRNA, viral enzymes 2 copies of ssRNA, viral enzymes Attachment with gp 120 to CD4 receptor Attachment with gp 120 to CD4 receptor Fusion mediated by gp 41 Fusion mediated by gp 41 Inside cell RNA transcribed to DNA by RT Inside cell RNA transcribed to DNA by RT DNA incorporated into cell genome DNA incorporated into cell genome DNA is copied and translated to viral enzymes, proteases DNA is copied and translated to viral enzymes, proteases New infectious virus buds from host cell to repeat process New infectious virus buds from host cell to repeat process

9. Immunology Gradual reduction in number of circulating CD4 cells inversely correlated with the viral load Gradual reduction in number of circulating CD4 cells inversely correlated with the viral load Any depletion in numbers of CD4 cells renders the body susceptible to opportunistic infections Any depletion in numbers of CD4 cells renders the body susceptible to opportunistic infections Lymphatic tissue (spleen, lymph nodes, tonsils/adenoids) main reservoir of HIV Lymphatic tissue (spleen, lymph nodes, tonsils/adenoids) main reservoir of HIV

10. Primary Infection 70-80% symptomatic, 3-12 weeks after exposure 70-80% symptomatic, 3-12 weeks after exposure Fever, rash, cervical lymphadenopathy, aseptic meningitis, encephalitis, myelitis, polyneuritis Fever, rash, cervical lymphadenopathy, aseptic meningitis, encephalitis, myelitis, polyneuritis Surge in viral RNA copies to >1 million Surge in viral RNA copies to >1 million Fall in CD4 count to 300-400 Fall in CD4 count to 300-400 Recovery in 7-14 days Recovery in 7-14 days

11. Seroconversion 3-12 weeks, median 8 weeks 3-12 weeks, median 8 weeks Level of viral load post seroconversion correlates with risk of progression of disease Level of viral load post seroconversion correlates with risk of progression of disease Differential for this syndrome: EBV, CMV, Strep pharyngitis, toxoplasmosis, secondary syphilis Differential for this syndrome: EBV, CMV, Strep pharyngitis, toxoplasmosis, secondary syphilis

12. Asymptomatic phase Remain well with no evidence of HIV disease except for generalized lymphadenopathy Remain well with no evidence of HIV disease except for generalized lymphadenopathy Fall of CD4 count by about 50-150 cells per year Fall of CD4 count by about 50-150 cells per year

13. Symptomatic phase Mild impairment of immune system Mild impairment of immune system Chronic weight loss Chronic weight loss Fever Fever Diarrhea Diarrhea Mild candida infections Mild candida infections Recurrent herpes infections Recurrent herpes infections Pelvic inflammatory disease Pelvic inflammatory disease Bacillary angiomatosis Bacillary angiomatosis Cervical dysplasia Cervical dysplasia

14. AIDS CD4 <200 CD4 <200 –Pneumocystis pneumonia –Esophageal Candidiasis –Mucocutaneous herpes simplex –Miliary/extrapulmonary TB –Cryptosporidium –HIV-associated wasting –Microsporidium –Peripheral neuropathy

15. AIDS CD <100 CD <100 –Cerebral toxoplasmosis –Non-Hodgkin’s lymphoma –Cryptococcal meningitis –HIV-associated dementia –Primary CNS Lymphoma –Progressive multifocal leukoencephalopathy

16. AIDS CD4<50 CD4<50 –CMV retinitis, gastroenteritis –Disseminated Mycobacterium avium complex

17. Diagnosis Antibody test, ELISA Antibody test, ELISA Western blot Western blot HIV RNA viral load HIV RNA viral load

18. Skin and Oral disease Seborrheic dermatitis Seborrheic dermatitis Xeroderma Xeroderma Itchy folliculitis Itchy folliculitis Scabies Scabies Tinea Tinea Herpes zoster Herpes zoster Papillomavirus Papillomavirus Oral and vaginal candidiasis Oral and vaginal candidiasis Oral hairy leukoplakia Oral hairy leukoplakia Aphthous ulcers Aphthous ulcers Herpes simplex Herpes simplex Gingivitis Gingivitis Kaposi’s sarcoma Kaposi’s sarcoma Molluscum contagiosum Molluscum contagiosum Bacillary angiomatosis Bacillary angiomatosis

22. GI disease Esophageal candidiasis Esophageal candidiasis Large bowel disease (bloody diarrhea) Large bowel disease (bloody diarrhea) –C. diff –CMV Small bowel disease (watery diarrhea) Small bowel disease (watery diarrhea) –Cryptosporidium –Microsporidium –Giardia –MAC –CMV

23. Pulmonary Disease Pneumocystis pneumonia Pneumocystis pneumonia Bacterial pneumonia Bacterial pneumonia Nocardia Nocardia

24. Pneumocystis pneumonia Most common AIDS presenting illness Most common AIDS presenting illness Reactivation of infection (original airborne transmission, asymptomatic, early age) Reactivation of infection (original airborne transmission, asymptomatic, early age) Inversely correlated with CD4 count Inversely correlated with CD4 count 40% of patients with CD4 <100 and not prophalaxed will have pneumonia annually 40% of patients with CD4 <100 and not prophalaxed will have pneumonia annually Prophalaxis started at CD4 <200, trimethoprim/sulfa, dapsone, atovaquone, pentamidine Prophalaxis started at CD4 <200, trimethoprim/sulfa, dapsone, atovaquone, pentamidine

25. Pneumocystis pneumonia 2-3 week history of SOB and dry cough 2-3 week history of SOB and dry cough Hypoxemia Hypoxemia Perihilar ground glass appearance on CXR Perihilar ground glass appearance on CXR Silver stain of organism in sputum Silver stain of organism in sputum High dose trimethaprim/sulfa, steroid if hypoxic High dose trimethaprim/sulfa, steroid if hypoxic

26. Nervous system disease Toxo Toxo Crypto Crypto PML PML CMV retinitis CMV retinitis Dementia Dementia Peripheral neuropathy Peripheral neuropathy

27. Management Treatment recommended when symptomatic or CD4 count below 200 Treatment recommended when symptomatic or CD4 count below 200 Earlier if high viral load, rapidly falling CD4 count, hepatitis C co-infection Earlier if high viral load, rapidly falling CD4 count, hepatitis C co-infection

28. antiretrovirals Nucleoside reverse transcriptase inhibitors Nucleoside reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors Protease inhibitors Protease inhibitors Fusion inhibitors Fusion inhibitors R5/X4 inhibitors R5/X4 inhibitors

29. NRTIs ddC ddC ddI ddI 3TC 3TC ZDV ZDV d4T d4T Abacavir Abacavir FTC FTC

30. NNRTIs Nevirapine Nevirapine Efavirenz Efavirenz Delavirdine Delavirdine

31. PIs Indinavir Indinavir Saquinavir Saquinavir Ritonavir Ritonavir Nelfinavir Nelfinavir Lopinavir/ritonavir Lopinavir/ritonavir Amprenavir Amprenavir Fosamprenavir Fosamprenavir Tipranavir Tipranavir Atazanavir Atazanavir

32. Others T-20 T-20 Tenofovir Tenofovir R5/X4 under development R5/X4 under development

33. Side effects NRTIs: mitochondrial dysfunction NRTIs: mitochondrial dysfunction ddC, ddI, d4T: neuropathy ddC, ddI, d4T: neuropathy d4T, ddI: hepatic steatosis, lactic acidosis d4T, ddI: hepatic steatosis, lactic acidosis ddI: pancreatitis ddI: pancreatitis ZDV: anemia ZDV: anemia d4T: fat atrophy d4T: fat atrophy Abacavir: hypersensitivity reaction Abacavir: hypersensitivity reaction Tenofovir: renal failure Tenofovir: renal failure NNRTIs: rash, liver toxicity NNRTIs: rash, liver toxicity PIs: fat redistribution, insulin resistance, hyperlipidemia PIs: fat redistribution, insulin resistance, hyperlipidemia Indiavir: renal stones Indiavir: renal stones Nelfinavir: diarrhea Nelfinavir: diarrhea