1. P AUL A LLYN, MD A FRICAN A MERICAN HIV U NIVERSITY U NIVERSITY OF C ALIFORNIA L OS A NGELES A UGUST 28, 2014

2. To illustrate the natural progression of untreated HIV-1 To highlight common clinical manifestations of HIV during this progression To discuss exceptions to this overall trend

3. AIDS Clinical AIDSAdvanced AIDS and Death Clinical Latency Asymptomatic DiseaseEarly Symptomatic Disease Acute HIV-1 Infection Primary InfectionAcute Retroviral Syndrome

4. Stages based on CD4 cell count and symptoms.

5. StageDescription Stage 1Asymptomatic or with persistent generalized lymphadenopathy, not AIDS. Stage 2Minor mucocutaneous manifestations and recurrent upper respiratory tract infections, herpes zoster, mild weight loss (<10% of body weight). Stage 3Unexplained chronic diarrhea, prolonged fever, severe bacterial infections, pulmonary tuberculosis, weight loss (>10% of body weight). Stage 4PCP pneumonia, toxoplasmosis of the brain, esophageal candidiasis, Kaposi’s sarcoma, CMV, extrapulmonary TB, lymphoma, disseminated MAC, wasting syndrome, encephalopathy. Stages defined clinically, designed for resource-poor areas.

6. Adapted from Pantaleo et al. NEJM 1993

7. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7 th Ed. 2009.

9. Timeframe: 0 weeks (immediately after transmission) Characterized by: High viral load (high concentration of HIV RNA in the blood) Declining CD4+ lymphocyte count (average about 1000 cells/mm 3 prior to infection) Initially asymptomatic

10. Adapted from Pantaleo et al. NEJM 1993.

11. Timeframe: 1-6 weeks after exposure (peaks at 3 weeks) High viral load, low CD4 count Mononucleosis-like illness in 1/2 -2/3 of patients Symptoms typically resolve within 10-15 days Up to 50% patients asymptomatic

12. Symptoms variable in those who have them: Fever (96%) Enlarged lymph nodes (74%) Sore throat/Pharyngitis (70%) Rash (70%) Muscle or joint aches (54%) Low blood counts, platelets, and white cells (45%, 38%) Diarrhea (32%) Headache (32%) Nausea/Vomiting (27%) Hair loss (alopecia) Mood changes (depression, irritability) Data from Niu MT et al. JID 1993.

14. Adapted from Pantaleo et al. NEJM 1993.

15. After acute infection, most patients remain asymptomatic for years Immune system develops antibodies to suppress the virus and the viral load stabilizes (viral set point) Over time, there is typically a gradual decline in CD4+ lymphocytes (on average 50-75 cells per year) Median time from infection to development of AIDS is approximately 8-10 years Some may develop AIDS in <5 years (approximately 20%) Few will remain asymptomatic without evidence of immunosuppression for more than 10 years (<5%) Many factors impact prognosis, but HIV-1 RNA levels (viral load) combined with CD4+ cell counts are the best predictor of disease progression to AIDS and death from AIDS

16. Egger et al. Lancet 2002.

17. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7 th Ed. 2009.

18. Chaisson RE et al. NEJM 1995. >200 <=200 Female Male Female Male

20. Long-term nonprogressors: Remain asymptomatic without treatment or evidence of immunologic decline for many years 2 Groups: 1. Those with detectable viral load but adequate CD4+ cells to protect them from opportunistic disease (though these gradually decline over time) 2. Elite Controllers: Small group, have undetectable viral loads and maintain normal CD4+ lymphocyte counts Able to contain viral replication

22. Patients with CD4+ counts > 500 generally asymptomatic May have mild or moderate lymphadenopathy (persistent generalized lymphadenopathy) Recurrent herpes infections may be present as well May have exacerbation of skin conditions: Psoriasis Eosinophilic folliculitis Aphthous ulcers Hairy Leukoplakia (benign white plaques on tongue)

25. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7 th Ed. 2009.

27. Most patients with CD4+ counts between 200 and 500 cells remain asymptomatic or have mild disease. May have: Worsening of chronic skin conditions Recurrent herpes simplex or varicella-zoster virus (shingles) Vaginal or oropharyngeal candidiasis (thrush) Recurrent diarrhea Intermittent fever Weight loss Muscle aches, joint aches, headache, and fatigue commonly reported Common to have bacterial sinusitis, bronchitis, pneumonia

30. Adapted from Pantaleo et al. NEJM 1993. AIDS

31. Patients with CD4+ Cells <200 are classified as having AIDS by 1993 CDC definition Certain opportunistic infections seen at this stage are indicative of AIDS, including: Pneumocystis carinii (jirovecii) pneumonia (PCP) Toxoplasmosis Cryptosporidiosis Esophageal candidiasis Tuberculosis Increased risk of certain cancers: Invasive cervical cancer in women Rectal or anal carcinoma in men Hematologic abnormalities (ITP, anemia, neutropenia) HIV-associated nephropathy (kidney disease)

32. Multiple or recurrent bacterial infections CandidiasisInvasive Cervical Cancer Coccidiomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonaryCryptosporidiosis Cytomegalovirus diseaseCytomegalovirus retinitisHIV-related encephalopathy Herpes simplex, chronic ulcers, bronchitis, pneumonitis, esophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal Kaposi’s sarcomaLymphoid interstitial pneumoniaBurkitt’s lymphoma Immunoblastic lymphomaPrimary CNS lymphomaMycobacterium avium- intracellulare complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site Pneumocystis carinii (jirovecii) pneumonia Recurrent pneumonia Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Wasting syndrome of HIV infection CNS toxoplasmosis

33. CT Chest PCP Pneumonia (From Mandell 2009) Normal CT Chest (From radiopaedia.org)

34. Mandell 2009 Abnormal brain CT with toxoplasma ring- enhancing lesion in an AIDS patient.

35. Normal retina (from somerseye.com) Toxo chorioretinitis (Mandell 2009)

36. CXR with TB (From radiopaedia.org) Normal CXR (From radiopaedia.org)

37. Patients with CD4+ cells < 50 have end-stage immunodeficiency At risk for additional opportunistic illnesses: Disseminated Mycobacterium avium complex (MAC) Progressive multifocal leukoencephalopathy (PML) Cryptococcal meningitis Other disseminated fungal infections (coccidiomycosis, histoplasmosis, aspergillosis, Penicillium marneffei) Primary CNS lymphoma CMV Retinitis Wasting syndrome

38. Enlarged painless lymph node. Mandell 2009

39. Abnormal brain MRI in AIDS patient with PML.

40. Normal retina (from somerseye.com) Early disease with involvement along blood vessels. Extensive disease with retinal hemorrhage. Mandell 2009

41. Moore RD and Chaisson RE. Ann Intern Med 1996. Herpes simplex Herpes zoster (shingles) Candida esophagitis PCP Pneumonia Toxoplasmosis CMV Disseminated MAC HIV Dementia

42. Adapted from Pantaleo et al. NEJM 1993. AIDS

43. Mean survival after reaching a CD4+ count of 200 is 38-40 months without treatment Mean survival after the development of clinically- defined AIDS is 12-18 months (9 months in initial San Francisco cohort) Opportunistic infections independently increase risk of death

44. CDC

45. Overall Death Rate 9513 per 100,000 person years (General population 267) Adapted from Wada N et al. Am J Epidemiol 2013. (Percentages are approximate to show general trend)

46. Overall Death Rate 2842 per 100,000 person years (General population 463) Adapted from Wada N et al. Am J Epidemiol 2013. (Percentages are approximate to show general trend)

47. 1-6 weeks (average 3 weeks) after primary infection 1/2 to 2/3 of patients develop an acute mononucleosis-like illness called the acute retroviral syndrome that lasts 10-15 days. Following the acute infection, patients enter a period of clinical latency where they may remain mostly asymptomatic for up to 8-10 years on average, though this duration varies considerably. Disease progression can be predicted by baseline viral load and CD4+ cell count. Over time most patients (except for nonprogressors) will have declining CD4+ cells with increasing risk of developing symptoms. When CD4+ cells fall below 200 or with specific opportunistic infections, patients are defined as having AIDS. Risk of death increases dramatically when patients develop clinical symptoms of AIDS. HAART dramatically reduces this risk.

48. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 7 th Edition. Churchill Livingstone. 2009. Vergis EN and Mellors JW. Natural History of HIV-1 Infection. Infectious Disease Clinics of North America 2000. CDC: www.cdc.gov/hiv WHO: http://www.who.int/hiv/en/