Transcript What the Primary Care Physician Should Know About HIV

HIV Update and Review for the
Primary Care Physician
Scott Hendrickson D.O.
Assistant Professor
Department of Internal Medicine
Oklahoma State University
Center for Health Sciences
Overview
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Epidemiology
Testing
Primary HIV infection
Manifestations of HIV
Opportunistic infections
Antiretroviral therapy
New therapies
Who is Today’s HIV Patient?
• HIV patients today are living longer, and new
treatment considerations are emerging
• Patients frequently present with comorbid
conditions, such as hepatitis C (HCV) coinfection,
mental illness, and substance abuse 1-4
• The major causes of death in today’s patient are
non-opportunistic illnesses, especially hepatic,
pulmonary, cardiovascular, and renal
complications 5
1. Sulkowski M. Curr Infect Dis Rep. 2001;3:469-476. 2. Centers for Disease Control and Prevention.
http://www.cdc.gov/hiv/pubs/facts/HIV-HCV_Coinfection.htm. Accessed September 23, 2004. 3. Kimmel PL, et al. Ann Intern
Med. et al. 2003;139:214-226. 4. Bing EG, et al. Arch Gen Psychiatry. 2001;58:721-728. 5. Pallela F, et al. 11th Conference on
Retroviruses and Opportunistic Infections, 2004; Poster 872.
85,000
Newly diagnosed AIDS cases
75,000
Deaths
Persons living with AIDS
400,000
1993 Definition
implementation
350,000
65,000
300,000
55,000
250,000
45,000
200,000
35,000
150,000
25,000
100,000
15,000
50,000
5,000
0
0
1986
1988
1990
1992
1994
Year
1996
1998
2000
2002
No. of persons living with AIDS
No. of cases and no. of deaths
AIDS Cases, Deaths, and Persons Living with
AIDS by Year, 1985-2002–United States
Proportion of AIDS Cases and Population, by
Race/Ethnicity 2002—United States
AIDS cases
N* = 42,651
1%
<1%
17%
31%
US Population
N* = 288,368,706
4%
<1%
13%
13%
69%
51%
White, not Hispanic
Black, not Hispanic
Hispanic
Asian/Pacific Islander
American Indian/
Alaska Native
Note. Exclude persons from US dependencies, possessions, and associated nations.
*Includes 44 persons of unknown race or multiple races.
% of AIDS Cases
Reported Through 2001
Cumulative AIDS Cases Through
2001 – Exposure Category by State
100
90
80
70
60
50
40
30
20
10
0
9
10
9
11
6
9
9
10
25
64
68
MS
MO
46
USA
MSM
http://www.statehealthfacts.kff.org/
IDU
MSM + IDU
7
13
8
10
11
14
59
58
OK
TX
Heterosexual
HIV Testing
• Suspect the Dx of and test for HIV in the
following clinical settings
– Pneumococcal pneumonia in a person under the
age of 55 with no comorbid conditions
– New Hep B or Hep C
– New TB Dx
– Shingles in the adult
– Thrush in the adult
HIV Testing
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Thrombocytopenia
Fever of unknown origin
Unexplained weight loss
Diffuse lymphadenopathy
Persons in high risk categories presenting
with S/Sx of Primary HIV infection
Primary HIV Infection
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Acute retroviral syndrome
Occurs 2-4 weeks after infection
Mono-type syndrome
Immunology
– Very high viral load
– Rapidly falling CD4 count
Primary HIV Infection:
Common Signs & Symptoms
fever
86
lethargy
74
myalgias
59
rash
57
headache
55
pharyngitis
52
adenopathy
N = 160 patients with PHI in
Geneva, Seattle and Sydney
44
0
10
20
30
40
50
60
70
% of patients
Vanhems P et al. AIDS 2000; 14:0375-0381.
80
90
100
1 mil
HIV
RNA
100,000
+
_
10,000
Ab
1,000
100
Exposure
Symptoms
10
0
20
30
Days
40
50
HIV-1 Antibodies
HIV RNA
PHI: Diagnostic Testing
Rapid HIV testing
Manifestations of HIV
HIV Seroconversion-macular rash
Persistent generalized lymphadenopathy
Seborrheic dermatitis
Herpes zoster
Tuberculosis
Oral candidiasis
Kaposi’s Sarcoma
HIV Wasting Syndrome
Bacillary angiomatosis
HIV-associated psoriasis
Secondary syphilis
Secondary syphilis
Opportunistic Infections
• Pneumocystis pneumonia
• Disseminated mycobacterium avium
complex
• Toxoplasmosis encephalitis
• Crypotococcal meningitis
• Disseminated histoplasmosis
• Cytomegalovirus infections
Pneumocystis jiroveci pneumonia
• Pneumocystis is a fungi
that produces pneumonia in
immunosuppressed patients
• Wide range of severity
• It is the most frequent form
of presentation of AIDS
• Usually CD4 count less
than 200 cells/mm3
• Diagnosis: clinical, induced
sputum, BAL
Treatment
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TMP/SMX for 21 days
Pentamidine
TMP plus dapsone
Clindamycin plus primaquine
Atovaquone
Trimetrexate plus leucovorin
Corticosteroids : pO2 < 70 mm/Hg or A-a gradient
> 35 mm Hg
PCP Prophylaxis
• CD4+ T cell count < 200 ; H/O oral candidiasis;
Unexplained fever > 2 weeks; Previous episode of
PCP
• TMP/SMX DS 1 tablet po daily
• Dapsone 50 mg po b.i.d. or 100 mg daily
• Atovaquone 1500 mg po daily
• Pentamidine aerosol 300 mg monthly
Disseminated Mycobacterium
avium
• Usually late in the
course of AIDS (CD4
<50)
• Persistent fevers, night
sweats, fatigue, weight
loss, and anorexia
• Hepatosplenomegaly,
lymphadenopathy, and
(rarely) jaundice
• Anemia, leukopenia,
elevated alkaline
phosphatase levels are
common
Mycobacterium avium complex
• Improved survival with 3 drugs vs 2:
– CLR 500 mg po bid (AZ 500 mg daily)
– EMB 15 mg/kg po qd
– RBT 300 mg po qd (adjust for ART)
• Failure to response/relapse
– Susceptibility testing
– Ciprofloxacin 500-750 mg po bid or
levofloxacin 500 mg qd
– Amikacin 10-15 mg/kg IV qd
Acquisition of
Toxoplasma gondii
• Cat Feces
• Undercooked Red
Meat
DHS/HIV/PP
Toxoplasmosis
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Presentation as encephalopathy
Gradual to acute onset
CD4 count <200
Ring enhancing lesions on CT/MRI
Toxoplasmosis
• Standard therapy is pyrimethamine plus
sulfadiazine
• Sulfadiazine may not be available
• Pyrimethamine 200 mg load the 50 mg daily plus
clindamycin 600 mg qid plus leucovorin 10 mg
daily.
• SMX/TMP (based on 5 mg/kg TMP) bid
• If no clinical/radiographic improvement in 2 weeks
or clinical decline in one week: BIOPSY
Cryptococcal meningitis
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Fever and Headache
25% of patients present with nuchal rigidity
Cryptococcal antigen on the CSF
CD4 <200
Treatment is with IV AmphoB until the CSF is
cleared of antigen or the maximal total dose is
given
• Minimum of 8 weeks of consolidation therapy
with fluconasol 400mg daily
• Fluconasol 200mg daily suppressive therapy
Antiretroviral Drugs
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Nucleoside reverse transcriptase inhibitors
Nonnucleoside RTI’s
Protease inhibitors
Integrase Inhibitors (T20)
~20 different aproved drugs or combination
drugs
• Compact regimens have evolved
– 2 pills once daily
HIV Replication Cycle and Sites of Drug Activity
NRTIs
NNRTIs
Attachment Inhibitors
Protease Inhibitors
Nucleus Cellular DNA
HIV Virions
Reverse
Integrase
Transcriptase
Protease
Capsid
proteins
and viral
RNA
CD4
Receptor
Viral RNA
Unintegrated
double stranded
Viral DNA
Integrated
viral DNA
CCR5
or
CXCR4
co-receptor
2
1
Attachment
New HIV
particles
Reverse
Transcription
3
Viral
mRNA
4
gag-pol
polyprotein
5
6
Assembly and
Release
Adapted:Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:9-11
Uncoating
Integration Transcription
Translation
Goals of Antiretroviral Therapy
& Tools to Achieve Goals
• Improvement of quality of
life
• Reduction of HIV-related
morbidity and mortality
• Restoration and/or
preservation of
immunologic function
• Maximal and durable
suppression of viral load
• Selection of ARV regimen
• Preservation of future
treatment options
• Rational sequencing of
therapy
• Maximizing adherence
• Use of resistance testing in
selected clinical settings
Before Initiating ART
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Confirm HIV results
Complete H&P
CBC, chemistry profile
CD4 cell count
Plasma HIV RNA measurement
Consider resistance testing
Assess “readiness” for treatment and
adherence
Before Initiating ART:
Additional Tests
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RPR or VDRL
PPD
Chest X ray
Hepatitis A,B,C
serology
• Toxoplasma IgG
• Fasting glucose and
lipids
• Gynecologic exam
with pap smear
• Testing for chlamydia
and gonorrhea
• Ophthalmology exam
(CD4+ T cell count
<100 cells/µL)
Indications for ART in the
Chronically HIV-Infected
Patient
Treat all (regardless of viral load):
• Symptomatic (AIDS, severe symptoms)
• Asymptomatic, CD4 count <200 cells/µL
Considerations in Initiating
ART: Chronically HIV-Infected
Patient, Asymptomatic
• Strong evidence of decreased mortality and
morbidity with ART if CD4 <200 cells/µL or
symptomatic
• Theoretical benefit of treatment at higher CD4
• Few data establish clinical benefit for treatment if
CD4 >200 cells/µL; optimal point to initiate ART is
unknown
• Individualize treatment decisions
Benefits and Risks of
Deferred Therapy
BENEFITS
• Avoid negative effects on
quality of life
• Avoid drug-related toxicity
• Preserve future drug options
• Delay development of drug
resistance
• Decrease total time on
medications
RISKS
• Possibility of irreversible
immune system depletion
• Increased possibility of
progression to AIDS
• Possible increased risk of
HIV transmission
Current Antiretroviral Medications
PI
NRTI
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Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Zidovudine
Zalcitabine
Tenofovir
ABC
DDI
FTC
3TC
D4T
ZDV
DDC
TDF
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Amprenavir
Atazanavir
Fosamprenavir FPV
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
– soft gel
– hard gel
APV
ATV
IDV
LPV
NFV
RTV
SQV
SGC
HGC
NNRTI
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Delavirdine
Efavirenz
Nevirapine
DLV
EFV
NVP
Fusion Inhibitor
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Enfuvirtide
T-20
Initial Treatment:
Preferred Regimens
NNRTI-Based
Efavirenz*
+ (lamivudine or emtricitabine)
+ (zidovudine or tenofovir)
# pills
/day
2-5
PI-Based
Lopinavir/ritonavir (Kaletra)
+ (lamivudine or emtricitabine)
+ zidovudine
*Avoid in pregnant women and women with pregnancy potential.
8-10
Metabolic Complications
Dysregulation
Lipid
of
abnormalities
glucose
metabolism
Mitochondrial
Toxicity
Body fat
redistribution
• One syndrome or several?
• One etiology or multifactorial?
Bone
ARV-Associated Adverse Effects:
Fat Maldistribution
Lipodystrophy:
• No uniform definition
• Mechanism not understood
– peripheral fat wasting more associated with NRTIs
(especially stavudine)
– central fat accumulation perhaps more associated with
PIs
• May be associated with dyslipidemia, insulin resistance,
lactic acidosis
• Treatment: switching to other agents may slow progression;
insufficient data to guide specific therapy
Lipodystrophy
ARV-Associated Adverse
Effects: Lactic Acidosis/
Hepatic Steatosis
• Possibly due to mitochondrial toxicity
• Associated with NRTIs (especially d4T, ddI,
ZDV)
• Clinical presentation variable: have high index
of suspicion
• Lactate >2-5 mmol/dL plus symptoms
• Treatment: discontinue ARVs, supportive care
ARV-Associated Adverse
Effects: Lactic Acidosis/
Hepatic Steatosis (continued)
• Rare, but high mortality*
* Pregnant women may be at increased risk for
lactic acidosis and liver damage when treated
with stavudine + didanosine. This
combination should be avoided in pregnant
women, if possible.
New HIV therapies
HIV Entry Mechanism
2. Co-receptor
interaction
Chemokine
HIV
Receptor
Inhibitors
gp41
3a. Anchorage
gp120
1. CD4
Attachment
HIV
CXCR4
CCR5
CD4
CD4
attachment
inhibitors
3c. Fusion
Complete
gp41
Cell
HIV
Fusion
Inhibitors
HIV 3b. coil-coil
interaction
Pitfalls and unanswered questions in current
HIV vaccine development
Pitfalls
• Natural immune response to HIV infection is <5% effective
• Promising animal vaccine approaches with homologous
sequences have completely failed (eg, SIV 239)
• Naturally controlled infections do not protect against pathogenic
superinfection
• Enormous clade and sequence variability
Unanswered questions
• How do we deal with sequence variability?
• What are the true surrogates for protective immunity?
• How do we elicit antibodies with neutralizing activity?
• How do we elicit persistent immune responses?
Desrosiers R. 11th CROI, San Francisco 2
Questions?