HIV/AIDS

1. HIV/AIDS Wayne A. Duffus, MD, PhD SC DHEC, Medical Director HIV/STD Division Clinical Assistant Professor Infectious Diseases, USC School of Medicine

2. The Life Cycle of HIV-1 Structural Protein andEnzyme Precursors Viral RNA ViralDNA ViralRNA 1. Bindingand infection 2. Reversetranscriptionand integrationof viral DNA 3. Transcriptionand translation 4. Modificationand assembly 5. Budding andfinal assembly

3. HIV Positive • Patient must have a confirmed positive blood, urine, saliva test • Can last 7 – 10 years, or longer • Person may appear completely healthy • Can unknowingly infect another person • Causes changes in CD4 count and HIV viral load

4. The Pathogenesis of HIV-1 Infection: Compartments Colon, Duodenum and Rectum Chromaffin Cells Brain Macrophages and Glial Cells Lymphocytes in Blood,Semen and Vaginal Fluid Lymph Nodes Thymus Gland Bone Marrow Lung Alveolar Macrophages Skin Langerhans’ Cells

5. AIDS • Positive HIV test and CD4 count <200, or positive test and has certain infections • Terminal stage of disease • Highly infectious • Could appear completely healthy

6. CD4+ T Cell Count • The cell type in the body that HIV infects and destroys • Tells us how strong the immune system is • Normal levels are 500 – 1500 • Below 200, patient has AIDS • Associated with certain diseases when low

7. CD4 (T Cell) Count Natural History of Untreated HIV-1 Infection 1000 800 600 400 200 0 Early Opportunistic Infections CD4Cells + Late Opportunistic Infections 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Infection Time in Years

8. CD4 (T cell) Count • Used to determine when to start HAART (<350) • Followed constantly while on therapy • Should increase if therapy effective • Trend reversed if not compliant with meds

9. HIV RNA Viral Load • Measures the amount of HIV virus RNA present in the body • Normal = 0 • Infected > 0, could be as high as 750K • Used in determining when to start HAART (>100,000 copies/ml) and response to therapy

10. HIV Viral Load • Followed constantly while on therapy • Should decrease if therapy effective • When <400 copies, we say undetectable • Undetectable does not mean uninfected

11. Relating Disease Progression to Plasma HIV RNA Level Viral Load Death 1,000 10,000 100,000 .

12. The Variable Course of HIV-1 Infection Typical Progressor Rapid Progressor Primary HIVInfection Primary HIVInfection Clinical Latency AIDS AIDS CD4 Level CD4 Level Viral Replication Viral Replication A B months years months years Nonprogressor Primary HIVInfection Clinical Latency CD4 Level Viral Replication ? C months years Reprinted with permission from Haynes. In: DeVita et al, eds. AIDS: Etiology, Treatment and Prevention. 4th ed. Lippincott-Raven Publishers; 1997:89-99.

13. Primary HIV Infection • Period from initial infection with HIV to complete sero-conversion • Window Period • Acute Retroviral Syndrome

14. Window Period • Time during which a recently infected person will have a negative HIV test • Up to 6 months • Associated with very high HIV viral load • Can be associated with symptoms • Condom use required • Retesting necessary

15. Acute Retroviral Syndrome • HIV ELISA may be negative during acute retroviral syndrome • Requires a high index of suspicion • May have fever, fatigue, rash, pharyngitis as most common symptoms • Duration usually <2 weeks, but … • Diff dx: infectious mononucleosis, secondary syphilis, acute hepatitis A or B, roseola or other viral exanthems, toxoplasmosis

16. Fever 80 – 90% Fatigue 70 – 90% Rash 40 – 80% Headache 32 – 70% Lymphadenopathy 40 – 70% Pharyngitis 50 – 70% Thrombocytopenia Arthralgia 5 – 70% Myalgia 50 – 70% Night sweats 50% GI symptoms 30 – 60% Aseptic meningitis 24% Oral/genital ulcers 5 – 20% Lymphopenia Acute Retroviral Syndrome

19. Opportunistic Infections (O.I.s’) • Occur only when immuno-suppressed • Increases with decreasing CD4 count • Available medications for prophylaxis • Examples • PCP, Toxoplasmosis, MAC, etc • Increase chance of complications and death

20. Candida of esophagus, trachea, or lungs Invasive cervical ca Extrapulmonary coccidioidomycosis Extrapulmonary cryptococcocus Cryptosporidiosis (>1 month) CMV retinitis Extrapulmonary histoplasmosis HIV associated dimentia HIV wasting Kaposi’s Sarcoma Certain lymphomas Disseminated Mycobacterium avium-complex Tuberculosis Pneumocystis carinii pneumonia (PCP) Recurrent bacterial pneumonia Progressive multifocal leukoencephalopathy Recurrent Salmonellosis Toxoplasmosis AIDS Defining Conditions

21. Natural History of HIV-1 Infection Oral hairy leukoplakia Thrush Pneumocystis carinii pneumonia Tuberculosis Atypical herpes simplex virus disease Coccidioidomycosis Histoplasmosis CD4, cells/mm3 Cryptococcosis Toxoplasmosis Cytomagalovirus disease Cryptosporidioisis Mycobacterium aviumcomplex disease Months Years after onset of HIV infection

22. HIV- Complications at CD4>500mm3 • Infectious • Acute retroviral syndrome • Candida vaginitis • Other • Generalized LAD • Guillain-Barre (very rare) • Vague constitutional symptoms

23. HIV- Complications at CD4 200-500mm3 • Infectious • Pneumococcal pneumonia • TB • Herpes zoster • Kaposis sarcoma • Oral hairy leukoplakia (OHL) • Oropharyngeal candidiasis (thrush) • Non-Infectious • Cervical Ca • Lymphomas • ITP (Immune thrombocytopenic purpura)

24. Oropharyngeal Candidasis • Thrush limited to oropharynx • Esophagitis more serious usually CD4<100 • Odynophagia • Chest pain • Other causes of esophagitis • CMV (usually CD4<50) • Idiopathic ulceration (CD4<50)

26. Candidal esophagitis

27. Oral Hairy Leukoplakia • Caused by EBV • No treatment required

29. Kaposi’s Sarcoma • Clinical manifestations variable in HIV • Usually cutaneous or oral but visceral involvement also occurs (GI, respiratory tract) • Causative organism human herpes virus 8 (HHV-8)

31. Presentation of Kaposi's sarcoma

32. Presentation of Kaposi's sarcoma

33. HIV- Complications at CD4 < 200mm3 • Infectious • PCP • Histoplasmosis (other endemic fungi) • Miliary TB • PML • Non-Infectious • Wasting • Peripheral neuropathy • Cardiomyopathy • Dementia

34. Pneumocystis carinii pneumonia • Variable presentations • Pneumocystiscarinii changed to Pneumocystisjiroveci • 20-40% in patients not on HIV rx • Usually subacute presentation of dry cough, dyspnea • CXR typically reveals interstitial infiltrates • May have lobar consolidation • Pneumothorax in severe cases • Treatment/ prophylaxis

35. Pneumocystis jiroveckii (carinii) pneumonia

36. Diagnosis of Pneumocystis carinii

37. Histoplasma • Mississippi River Delta • Rarer in SC • Wide spectrum of illness from acute sepsis like syndrome to acute pneumonia to cutaneous involvement

38. Oral lesions of disseminated Histoplasma capsulatum infection

39. Progressive Multifocal Leukoencephalopathy (PML) • Clinical disease occurs in patients with advanced disease and onset may be insidious, over several weeks. • Clinical signs and symptoms include hemi-paresis (43%), cognitive defects (22%), speech deficits (28%),visual deficits (16%), sensory deficits (14%), and seizures (5%).

40. Progressive Multifocal Leukoencephalopathy (PML) • Clinical hallmark of disease is patient with focal neurologic defect, white matter disease and no mass effect. Lesions do not enhance on imaging • PML is a demyelinating disease of the central nervous system caused by infection of oligodendrocytes by JCV, a papovavirus.

41. Progressive Multifocal Leukoencephalopathy

42. Progressive Multifocal Leukoencephalopathy

43. HIV- Complications at CD4 < 100mm3 • Infectious • Disseminated HSV • Toxoplasmosis • Candida esophagitis • Cryptosporidiosis, microsporidiosis, isospora • Cryptococcal disease

44. Cryptococcal Meningitis • C. neoformans is an encapsulated yeast, inhaled into the small airways where it usually causes sub-clinical disease; dissemination to the CNS is not related to pulmonary response. • C. neoformans produces no toxins and evokes little inflammatory response. The main virulence factor is the capsule.

45. Cryptococcal Meningitis • Clinical manifestations: • headache (70-90%), fever (60-80%), malaise (76%), stiff neck (20-30%), photophobia (6-18%), seizures (5-10%) nausea. • Average duration of symptoms is 30 days. • Predictors of poor outcomes are altered mental status, increased opening pressure, WBC<20 cells/mm3.

46. Cryptococcal Meningitis • Diagnosis made by CSF examination with india ink (74-88%), Crypto Ag serum/CSF (99%), CSF culture. • Level of Crypto Ag is not indicative of severity of disease or a marker of response to therapy. Serum Crypto Ag can rule out clinical disease in HIV positive but not negative patients.

47. Cryptococcus neoformans

48. Toxoplasmic Encephalitis • Clinical presentation includes focal neurologic deficit (50-89%), seizures (15-20%), fever (56%), generalized cerebral dysfunction, neuropsychiatric abnormalities. • Diagnosis is often presumptive based on characteristic lesions, clinical course, risk strata and positive serology.

49. Toxoplasmic Encephalitis • Presumptive diagnosis is considered confirmed by tissue sample or response to TOXO therapy in appropriate time frame. • Patients should show clinical response -- neuro deficits, not necessarily fever or headache -- by day 5 (50%), day 7 (70%), and day 14 (90%). In contrast, patients with CNS lymphoma all had worsening of signs or symptoms by day 10 of therapy.

50. Cerebral toxoplasmosis