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THE Natural History of Untreated HIV-1 Infection

THE Natural History of Untreated HIV-1 Infection. Paul Allyn, MD African American HIV University University of California Los Angeles August 13, 2013. Objectives. To provide an overview of HIV-1 progression from viral transmission to AIDS-related death in UNTREATED HIV. . Overview.

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THE Natural History of Untreated HIV-1 Infection

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  1. THE Natural History of Untreated HIV-1 Infection Paul Allyn, MD African American HIV University University of California Los Angeles August 13, 2013

  2. Objectives • To provide an overview of HIV-1 progression from viral transmission to AIDS-related death in UNTREATED HIV.

  3. Overview

  4. Overview of Untreated HIV-1 Infection • Transmission of HIV-1 virus results in primary infection. • Acute retroviral syndrome develops 1-6 weeks later. • HIV often diagnosed several years after initial infection because the acute infection is self-limited, nonspecific, and often mild. • The acute retroviral syndrome is followed by a period of latency where patients remain relatively asymptomatic for a period of many years. • This period is typically defined by a gradual loss of CD4+ T cells. • Eventually patients may develop early symptoms with declining T cells. • Most patients continue to progress to clinically-defined AIDS and eventually death.

  5. CDC Staging System Stages based on CD4 cell count and symptoms.

  6. WHO Clinical Staging System Stages defined clinically, designed for resource-poor areas.

  7. Typical Course of HIV Infection Adapted from Pantaleo et al. NEJM 1993

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

  9. Transmission

  10. Primary HIV Infection • Timeframe: 0 weeks (after transmission) • Characterized by: • High viral load (high concentration of HIV RNA in the blood) • Declining CD4+ lymphocyte count (average about 1000 cells/mm3 prior to infection) • Initially asymptomatic

  11. Typical Course of HIV Infection Adapted from Pantaleo et al. NEJM 1993.

  12. Acute Retroviral Syndrome • 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

  13. Acute Retroviral Syndrome • 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. Rash of Acute HIV

  15. Aphthous Ulcer Mandell 2009

  16. Typical Course of HIV Infection Adapted from Pantaleo et al. NEJM 1993.

  17. Clinical Latency (asymptomatic Infection) • 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

  18. Probability of AIDS at 3 Years According to CD4 Cell Count and Viral Load Egger et al. Lancet 2002.

  19. PROBABILITY of Developing AIDS Based on CD4+ Lymphocyte Count and Viral Load Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th Ed. 2009.

  20. Women Versus Men: Probability of Survival at Same CD4 Count >200 Female Male <=200 Female Male Chaisson RE et al. NEJM 1995.

  21. Special Circumstances • 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. CD4+ Count >500 • 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)

  23. Hairy Leukoplakia

  24. CD4+ Count 200-500 • 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

  25. Thrush

  26. Typical Course of HIV Infection AIDS Adapted from Pantaleo et al. NEJM 1993.

  27. AIDS • Patients with CD4+ Cells <200 are classified as having AIDS by 1993 CDC definition • Certain opportunistic infections seen at this stage and 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)

  28. AIDS-Defining Conditions

  29. Pneumocystis Carinii (Jirovecii) Pneumonia CT Chest PCP Pneumonia (From Mandell 2009) Normal CT Chest (From radiopaedia.org)

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

  31. Toxoplasmosis in the Eye Normal retina (from somerseye.com) Toxochorioretinitis from Mandell 2009

  32. End-Stage AIDS • 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, Penicilliummarneffei) • Primary CNS lymphoma • CMV Retinitis • Wasting syndrome

  33. Disseminated MAC Enlarged painless lymph node. Mandell 2009

  34. Progressive Multifocal Leukoencephalopathy Abnormal brain MRI AIDS patient with PML.

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

  36. CD4+ Lymphocyte Count at Time of Development of Opportunistic Illness Herpes simplex Herpes zoster (shingles) HIV Dementia Candida esophagitis CMV PCP Pneumonia Disseminated MAC Toxoplasmosis Moore RD and Chaisson RE. Ann Intern Med 1996.

  37. Typical Course of HIV Infection AIDS Adapted from Pantaleo et al. NEJM 1993.

  38. AIDS Death • 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

  39. Overall Trends CDC

  40. Cause of Death in the Pre-HAART Era: MACS 1984-1995 (2119 HIV+ Patients) (Percentages are approximate to show general trend) Overall Death Rate 9513 per 100,000 person years (General population 267) Adapted from Wada N et al. Am J Epidemiol 2013.

  41. Cause of Death in the HAART Era: MACS 1996-2008 (Percentages are approximate to show general trend) Overall Death Rate 2842 per 100,000 person years (General population 463) Adapted from Wada N et al. Am J Epidemiol 2013.

  42. Summary • 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.

  43. Key Resources • Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 7th 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/

  44. Questions?

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