Paul Allyn, MDAfrican American HIV University

University of California Los AngelesAugust 26, 2015

THE NATURAL HISTORY OF UNTREATED HIV-1

INFECTION

OBJECTIVESTo illustrate the natural

progression of HIV-1 if left untreated

To highlight common clinical manifestations of HIV by CD4 count

To discuss exceptions to this overall trend

AIDS

Clinical AIDS Advanced AIDS and Death

Clinical LatencyAsymptomatic Disease Early Symptomatic

Disease

Acute HIV-1 InfectionPrimary Infection Acute Retroviral

Syndrome

BROAD OVERVIEW

CDC STAGING SYSTEM

Stages based on CD4 cell count and symptoms.

WHO CLINICAL STAGING SYSTEMStage 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 INFECTION

Adapted from Pantaleo et al. NEJM 1993

THE VIRUS

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

TRANSMISSION

PRIMARY HIV INFECTIONTimeframe: 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 INFECTION

Adapted from Pantaleo et al. NEJM 1993.

ACUTE RETROVIRAL SYNDROMETimeframe: 1-6 weeks after exposure

(peaks at 3 weeks)High viral load, low CD4 count Mononucleosis-like illness in 1/2 -2/3 of patientsSymptoms typically resolve within 10-15

daysUp to 50% patients asymptomatic

ACUTE RETROVIRAL SYNDROMESymptoms 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 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, 7 th Ed. 2009.

WOMEN VERSUS MEN: PROBABILITY OF SURVIVAL AT SAME CD4 COUNT

Chaisson RE et al. NEJM 1995.

>200

<=200

Female

Male

Female

Male

Does everyone develop AIDS if not treated?

SPECIAL CIRCUMSTANCESLong-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 countsAble to contain viral replication

CLINICAL MANIFESTATIONS BY CD4 COUNT

CD4+ COUNT >500Patients with CD4+ counts > 500 generally

asymptomaticMay have mild or moderate lymphadenopathy

(persistent generalized lymphadenopathy)Recurrent herpes infections may be present as

wellMay have exacerbation of skin conditions:

PsoriasisEosinophilic folliculitisAphthous ulcersHairy Leukoplakia (benign white plaques on tongue)

APHTHOUS ULCER

Mandell 2009

HAIRY LEUKOPLAKIA

CD4+ COUNT 200-500Most patients with CD4+ counts between 200 and 500

cells remain asymptomatic or have mild disease. May have:Worsening of chronic skin conditionsRecurrent herpes simplex or varicella-zoster virus

(shingles)Vaginal or oropharyngeal candidiasis (thrush)Recurrent diarrhea Intermittent feverWeight lossMuscle aches, joint aches, headache, and fatigue commonly

reportedCommon to have bacterial sinusitis, bronchitis, pneumonia

THRUSH

TYPICAL COURSE OF HIV INFECTION

Adapted from Pantaleo et al. NEJM 1993.

AIDS

AIDSPatients with CD4+ Cells <200 are classified as

having AIDS by 1993 CDC definitionCertain 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)

AIDS-DEFINING CONDITIONS

Multiple or recurrent bacterial infections

Candidiasis Invasive Cervical Cancer

Coccidioidomycosis, 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 MAI, 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

Mandell 2009Abnormal brain CT with toxoplasma ring-enhancing

lesion in an AIDS patient.

TOXOPLASMOSIS IN THE EYE

Normal retina (from somerseye.com)

Toxo chorioretinitisfrom Mandell 2009

END-STAGE AIDSPatients with CD4+ cells < 50 have end-stage

immunodeficiencyAt risk for additional opportunistic illnesses:

Disseminated Mycobacterium avium complex (MAC)Progressive multifocal leukoencephalopathy (PML)Cryptococcal meningitisOther disseminated fungal infections

(coccidiomycosis, histoplasmosis, aspergillosis, Penicillium marneffei)

Primary CNS lymphomaCMV RetinitisWasting syndrome

DISSEMINATED MAC

Enlarged painless lymph node.

Mandell 2009

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Abnormal brain MRI AIDS patient with PML.

CMV RETINITIS

Normal retina (from somerseye.com)Early disease with

involvement along blood vessels.

Extensive disease with retinal hemorrhage.

Mandell 2009

CD4+ LYMPHOCYTE COUNT AT TIME OF DEVELOPMENT OF OPPORTUNISTIC ILLNESS

Moore RD and Chaisson RE. Ann Intern Med 1996.

Herpes simplex

Herpes zoster (shingles)

Candida esophagitis

PCP PneumoniaToxoplasmosis

CMV

Disseminated MAC

HIV Dementia

TYPICAL COURSE OF HIV INFECTION

Adapted from Pantaleo et al. NEJM 1993.

AIDS

AIDS DEATHMean survival after reaching a CD4+ count

of 200 is 38-40 months without treatmentMean 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

OVERALL TRENDS

CDC

CAUSE OF DEATH IN THE PRE-HAART ERA: MACS 1984-1995 (2119 HIV+ PATIENTS)

AIDS-Related; 92.40%

Non-AIDS Related; 5.70%

Unknown ; 1.90%

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)

CAUSE OF DEATH IN THE HAART ERA: MACS 1996-2008

Overall Death Rate 2842 per 100,000 person years (General population 463)

AIDS-Related; 57.30%

Non-AIDS Related; 21.35%

Unknown ; 21.35%

Adapted from Wada N et al. Am J Epidemiol 2013.

(Percentages are approximate to show general trend)

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.

KEY RESOURCESMandell, 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/hivWHO: http://www.who.int/hiv/en/

QUESTIONS?