Download The Natural History of Untreated HIV

THE NATURAL HISTORY OF
UNTREATED HIV-1 INFECTION
PAUL ALLYN, MD
AFRICAN AMERICAN HIV UNIVERSITY
UNIVERSITY OF CALIFORNIA LOS ANGELES
AUGUST 28, 2014
OBJECTIVES
 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
OVERVIEW
Acute HIV-1 Infection
Primary Infection
Acute Retroviral Syndrome
Clinical Latency
Asymptomatic Disease
Early Symptomatic Disease
AIDS
Clinical AIDS
Advanced AIDS and Death
CDC STAGING SYSTEM
Stages based on CD4 cell count and symptoms.
WHO CLINICAL STAGING SYSTEM
Stage
Description
Stage 1
Asymptomatic or with persistent generalized lymphadenopathy, not AIDS.
Stage 2
Minor mucocutaneous manifestations and recurrent upper respiratory tract
infections, herpes zoster, mild weight loss (<10% of body weight).
Stage 3
Unexplained chronic diarrhea, prolonged fever, severe bacterial infections,
pulmonary tuberculosis, weight loss (>10% of body weight).
Stage 4
PCP 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.
TYPICAL COURSE OF HIV-1 INFECTION
Adapted from Pantaleo et al. NEJM 1993
THE VIRUS
Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th Ed. 2009.
TRANSMISSION
PRIMARY HIV INFECTION
 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/mm3 prior to infection)
 Initially asymptomatic
TYPICAL COURSE OF HIV-1 INFECTION
Adapted from Pantaleo et al. NEJM 1993.
ACUTE RETROVIRAL SYNDROME
 Timeframe: 1-6 weeks after exposure (peaks at 3
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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
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.
RASH OF ACUTE HIV
TYPICAL COURSE OF HIV-1 INFECTION
Adapted from Pantaleo et al. NEJM 1993.
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
PROBABILITY OF AIDS AT 3 YEARS ACCORDING TO CD4 CELL
COUNT AND VIRAL LOAD
Egger et al. Lancet 2002.
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.
WOMEN AND MEN: PROBABILITY OF SURVIVAL AT SAME CD4
COUNT
>200
Female
Male
<=200
Female
Male
Chaisson RE et al. NEJM 1995.
DOES EVERYONE DEVELOP AIDS IF LEFT
UNTREATED?
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
CLINICAL MANIFESTATIONS BY CD4 COUNT
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)
PSORIASIS
EOSINOPHILIC FOLLICULITIS
APHTHOUS ULCER
Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th Ed. 2009.
ORAL HAIRY LEUKOPLAKIA
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
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SHINGLES
THRUSH
TYPICAL COURSE OF HIV-1 INFECTION
AIDS
Adapted from Pantaleo et al. NEJM 1993.
AIDS
 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:
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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)
AIDS-DEFINING CONDITIONS
Multiple or recurrent bacterial
infections
Candidiasis
Invasive Cervical Cancer
Coccidiomycosis, disseminated or
extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis
Cytomegalovirus disease
Cytomegalovirus retinitis
HIV-related encephalopathy
Herpes simplex, chronic ulcers,
bronchitis, pneumonitis,
esophagitis
Histoplasmosis, disseminated or
extrapulmonary
Isosporiasis, chronic intestinal
Kaposi’s sarcoma
Lymphoid interstitial pneumonia
Burkitt’s lymphoma
Immunoblastic lymphoma
Primary CNS lymphoma
Mycobacterium aviumintracellulare 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
PNEUMOCYSTIS CARINII (JIROVECII)
PNEUMONIA
CT Chest PCP Pneumonia
(From Mandell 2009)
Normal CT Chest
(From radiopaedia.org)
CNS TOXOPLASMOSIS
Abnormal brain CT with toxoplasma ringenhancing lesion in an AIDS patient.
Mandell 2009
TOXOPLASMOSIS IN THE EYE
Normal retina
(from somerseye.com)
Toxo chorioretinitis
(Mandell 2009)
PULMONARY TUBERCULOSIS
CXR with TB
(From radiopaedia.org)
Normal CXR
(From radiopaedia.org)
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, Penicillium marneffei)
 Primary CNS lymphoma
 CMV Retinitis
 Wasting syndrome
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DISSEMINATED MAC
Enlarged painless lymph node.
Mandell 2009
PROGRESSIVE MULTIFOCAL
LEUKOENCEPHALOPATHY (PML)
Abnormal brain MRI in AIDS patient with PML.
CMV RETINITIS
Early disease with
involvement along
blood vessels.
Extensive disease with
retinal hemorrhage.
Normal retina
(from somerseye.com)
Mandell 2009
CD4+ LYMPHOCYTE COUNT AT TIME OF
DEVELOPMENT OF OPPORTUNISTIC ILLNESS
Herpes simplex
Herpes zoster
(shingles)
HIV Dementia
Candida
CMV
esophagitis
PCP Pneumonia
Toxoplasmosis
Disseminated
MAC
Moore RD and Chaisson RE. Ann Intern Med 1996.
TYPICAL COURSE OF HIV-1 INFECTION
AIDS
Adapted from Pantaleo et al. NEJM 1993.
AIDS DEATH
 Mean survival after reaching a CD4+ count of 200 is
38-40 months without treatment
 Mean survival after the development of clinicallydefined AIDS is 12-18 months (9 months in initial
San Francisco cohort)
 Opportunistic infections independently increase
risk of death
OVERALL TRENDS
CDC
CAUSE OF DEATH IN THE PRE-HAART ERA: MACS
1984-1995 (2119 HIV+ PATIENTS)
Unknown , 1.90%
Non-AIDS
Related, 5.70%
AIDS-Related,
92.40%
Overall Death Rate 9513 per 100,000 person
years (General population 267)
(Percentages are
approximate to show
general trend)
Adapted from Wada N et al. Am J Epidemiol 2013.
CAUSE OF DEATH IN THE HAART ERA:
MACS 1996-2008
Unknown ,
21.35%
Non-AIDS
Related, 21.35%
Overall Death Rate 2842 per 100,000 person
years (General population 463)
AIDS-Related,
57.30%
(Percentages are
approximate to show
general trend)
Adapted from Wada N et al. Am J Epidemiol 2013.
SUMMARY
 1-6 weeks (average 3 weeks) after primary infection 1/2 to 2/3 of
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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.
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/
QUESTIONS?