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HIV/AIDS. Wayne A. Duffus, MD, PhD SC DHEC, Medical Director HIV/STD Division Clinical Assistant Professor Infectious Diseases, USC School of Medicine. The Life Cycle of HIV-1. Structural Protein and Enzyme Precursors. Viral RNA. Viral DNA. Viral RNA. 1. Binding and infection.

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hiv aids

HIV/AIDS

Wayne A. Duffus, MD, PhD

SC DHEC, Medical Director HIV/STD Division

Clinical Assistant Professor

Infectious Diseases, USC School of Medicine

the life cycle of hiv 1
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

hiv positive
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
the pathogenesis of hiv 1 infection compartments
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

slide5
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
cd4 t cell count
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
cd4 t cell count1
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

cd4 t cell count2
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
hiv rna viral load
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
hiv viral load
HIV Viral Load
  • Followed constantly while on therapy
  • Should decrease if therapy effective
  • When <400 copies, we say undetectable
  • Undetectable does not mean uninfected
the variable course of hiv 1 infection
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.

primary hiv infection
Primary HIV Infection
  • Period from initial infection with HIV to complete sero-conversion
    • Window Period
    • Acute Retroviral Syndrome
window period
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
acute retroviral syndrome
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
acute retroviral syndrome1
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
opportunistic infections o i s
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
aids defining conditions
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
natural history of hiv 1 infection
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

hiv complications at cd4 500mm 3
HIV- Complications at CD4>500mm3
  • Infectious
    • Acute retroviral syndrome
    • Candida vaginitis
  • Other
    • Generalized LAD
    • Guillain-Barre (very rare)
    • Vague constitutional symptoms
hiv complications at cd4 200 500mm 3
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)
oropharyngeal candidasis
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)
oral hairy leukoplakia
Oral Hairy Leukoplakia
  • Caused by EBV
  • No treatment required
kaposi s sarcoma
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)
hiv complications at cd4 200mm 3
HIV- Complications at CD4 < 200mm3
  • Infectious
    • PCP
    • Histoplasmosis (other endemic fungi)
    • Miliary TB
    • PML
  • Non-Infectious
    • Wasting
    • Peripheral neuropathy
    • Cardiomyopathy
    • Dementia
pneumocystis carinii pneumonia
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
histoplasma
Histoplasma
  • Mississippi River Delta
  • Rarer in SC
  • Wide spectrum of illness from acute sepsis like syndrome to acute pneumonia to cutaneous involvement
progressive multifocal leukoencephalopathy pml
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%).
progressive multifocal leukoencephalopathy pml1
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.
hiv complications at cd4 100mm 3
HIV- Complications at CD4 < 100mm3
  • Infectious
    • Disseminated HSV
    • Toxoplasmosis
    • Candida esophagitis
    • Cryptosporidiosis, microsporidiosis, isospora
    • Cryptococcal disease
cryptococcal meningitis
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.
cryptococcal meningitis1
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.
cryptococcal meningitis2
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.
toxoplasmic encephalitis
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.
toxoplasmic encephalitis1
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.
hiv complications at cd4 50mm 3
HIV- Complications at CD4 < 50mm3
  • Infectious
    • Disseminated CMV/Retinitis
    • Disseminated MAC
  • Non-Infectious
    • CNS Lymphoma
disseminated mac
Disseminated MAC
  • Usually a sub-acute/chronic illness characterized by fevers, weight loss, diarrhea, night sweats, wasting
  • CD4<50
primary cns lymphoma
Primary CNS Lymphoma
  • B-cell malignancies, high-grade (73%).
  • Occurs in extremely immunocompromised hosts (CD4 < 50 cells/mm3), unlike systemic NHL.
  • Common signs include focal neuro deficits (38-78%), altered sensorium (57%), seizures (21%), cranial nerve defects (13%).
primary cns lymphoma1
Primary CNS Lymphoma
  • 50% of patients will have single lesions, usually in the gray matter. Toxo lesions are usually multiple, smaller and associated with basal ganglia but the two entities cannot be distinguished by imaging alone.
primary cns lymphoma2
Primary CNS Lymphoma
  • Diagnosis is based on clinical presentation, neuroimaging, CSF studies, and brain biopsy.
  • CSF PCR for EBV is sensitive (66-99%) and specific (60-99%).
  • Treatment is radiation +/- chemotherapy.
  • Response is related to stage of disease and control of HIV.
summary of ois for which prevention is recommended
Primary Prophylaxis

Pneumocystisjiroveci pneumonia (PCP)*

Tuberculosis*

Toxoplasmosis*

Mycobacterium avium complex (MAC)*

Varicella-zoster*

S pneumoniae infections†

Hepatitis A and B†

Influenza†

Summary of OIs for Which Prevention Is Recommended

* Standard of care

† Generally recommended

summary of ois for which prevention is recommended1
Summary of OIs for Which Prevention Is Recommended

Secondary Prophylaxis

  • Pneumocystis jiroveci pneumonia (PCP)*
  • Toxoplasmosis*
  • Mycobacterium avium complex (MAC)*
  • Cryptococcosis*
  • Histoplasmosis*
  • Coccidioidomycosis*
  • Cytomegalovirus*
  • Salmonella bacteremia†

* Standard of care

† Generally recommended

ois for which prevention is not routinely indicated
Primary Prophylaxis

Bacteria (neutropenia)†

Cryptococcosis†

Histoplasmosis†

Cytomegalovirus†

Secondary Prophylaxis

Herpes simplex virus§

Candida §

OIs for Which Prevention Is Not Routinely Indicated

§ Recommended only if subsequent episodes are frequent or severe

† Evidence for efficacy but not routinely indicated

indications for possible discontinuation of primary and secondary prophylaxis

Agent

Recommendation(only for patients on effective ART)

PCP

Primary: CD4 >200 cells/µL for 3 months

Secondary: CD4 >200 cells/µL for 3 months

Toxo

Primary: CD4 >200 cells/µL for 3 months

Secondary: CD4 >200 cells/µL for 6 months + initial toxo treatment + asymptomatic

MAC

Primary: CD4 >100 cells/µL for 3 months

Secondary: CD4 >100 cells/µL for 6 months + 12 months MAC treatment + asymptomatic

Indications for Possible Discontinuation of Primary and Secondary Prophylaxis
highly active anti retroviral therapy haart
Highly Active Anti-Retroviral Therapy(HAART)
  • Collective name given to the HIV medications that patients are on
  • Medications must be taken daily
  • Take all or not at all, each day
  • Missing medications can cause problems
current antiretroviral medications
NRTI

Abacavir ABC

Didanosine DDI

Emtricitabine FTC

Lamivudine 3TC

Stavudine D4T

Tenofovir TDF

Zidovudine ZDV

NNRTI

Delavirdine DLV

Efavirenz EFV

Nevirapine NVP

Fusion Inhibitor

Enfuvirtide T-20

PI

Amprenavir APV

Atazanavir ATV

Darunavir DRV

Fosamprenavir FPV

Indinavir IDV

Lopinavir LPV

Nelfinavir NFV

Ritonavir RTV

Saquinavir SQV

hard gel HGC

tablet INV

Tipranavir TPV

CCR5 Coreceptor Antagonist

Maraviroc MVC

Integrase Inhibitor

RaltegravirRAL

Current Antiretroviral Medications
initial treatment preferred components

Efavirenz*

  • Atazanavir + ritonavir
  • Fosamprenavir + ritonavir (BID)
  • Lopinavir/ritonavir (BID)
Initial Treatment: Preferred Components

*Avoid in pregnant women and women with significant pregnancy potential.

**Emtricitabine can be used in place of lamivudine and vice versa.

NNRTI Option

NRTI Options

  • Tenofovir + emtricitabine**
  • Zidovudine + lamivudine**

OR

+

PI Options

optimal time to start will change over time as more data emerge
Optimal Time to Start Will Change Over Time as More Data Emerge

Factors Favoring

Later Initiation

Factors Favoring

Earlier Initiation

Long-term toxicities

- more prevalent

- more serious

Drug development

stalls

More drugs

Better drugs

Better management

of toxicities

Unprecedented progress has been made, but there is much to be done

Drug development and enlightened clinical investigation must continue

leading causes of death in people aged 25 44 years in the us 1983 1998
Leading Causes of Death in People Aged 25-44 Years in the US (1983-1998)

40

Unintentional injuries

30

Cancer

Deaths per 100,000 Population

20

Heart disease

Suicide

HIV infection

10

Homicide

Liver disease

Stroke

Diabetes

0

1988

1984

1990

1986

1992

1994

1996

1998

Year

Gallant J. Planning for Long-Term Success in HIV Management. Satellite Symposium to the

First IAS Conference on HIV Pathogenesis and Treatment, July 8 – 11, 2001.

metabolic and morphologic complications associated with hiv
Metabolic

Glucose disorders

insulin resistance

impaired glucose tolerance

hyperglycemia

frank diabetes

Lipid elevations

increased triglycerides

increased cholesterol

Hyperlactatemia

lactic acidosis

Bone disease

osteopenia

osteoporosis

avascular necrosis

Morphologic

Fat accumulation

abdominal obesity

buffalo hump

lipomatosis

breast enlargement

gynecomastia

Fat loss

appendices

face

buttocks

Metabolic and morphologic complications associated with HIV
slide79

Relative Amounts of HIV

in Various Body Fluids

Low/Not

Detectable

High

Moderate

breast milk

urine

saliva

feces

sweat

tears

blood/ serum

semen

body cavity fluids

vaginal fluid

Modes of Transmission:

perinatal, parenteral, sex

hiv transmission factors
HIV Transmission Factors
  • AIDS
  • STD
  • Genital lesions
  • Frequency of unprotected sex
  • Circumcision
  • Viral load
when does transmission occur
When does transmission occur?
  • Antenatal ∼20%
  • Intrapartum ∼80%
  • Breastfeeding ∼14%*

*above baseline

Lancet 340(8819):585

zdv effective when begun late wade nejm 11 98
ZDV

No treatment

Antenatal

Intrapartum

Postpartum

<48 Hrs

>72 Hrs

Transmission

26%

6.1%

∼5%

10%

18%

ZDV effective when begun lateWade NEJM 11/98
redefine health
Redefine Health
  • Health is NOT just the absence of disease
  • Biopsychosocial model AND …
    • Drugs
    • Housing
    • Support system
    • Finances
    • Violences
    • Criminal justice issues
  • Life priorities of HIV+ IDUs
    • Only 37% ranked HIV as most important
    • Top priorities: housing, money, safety from violence
redefine success
Redefine Success
  • Success is NOT just:
    • Undetectable viral load
    • Abstinence from drug use
  • Success also includes:
    • Making it to appointments
    • Preventative care (PAP smears, vaccinations, PCP/MAC prophylaxis, PPD)
    • Less, safer, more controlled drug use
    • Improvement in non-medical areas (housing, support system, criminal activity, etc.)
why adopt a different definition of success
Why Adopt a Different Definition of Success?
  • Recognizes that success is not only about taking one’s medications
  • Actively engages patients in health care and treatment
  • Values the health impacts of “non-medical” interventions (e.g. controlled drug use, stable housing, social supports)
  • Improve patients self-efficacy
  • Provides more opportunities for success