Download Primary Care of the HIV

Management of the Newly
Diagnosed HIV-infected Patient
Sarah Lewis MHS, PA-C
Case Presentation
• A 32 yo woman presents for care at your
clinic, referred from a public health clinic after
testing positive for HIV
• She presented for testing after discovering a
past boyfriend of hers is HIV+
• What questions do you have for her?
What does she know about HIV?
• Human Immunodeficiency Virus
• HIV is no longer a ‘death sentence’
– Diabetes mellitus can be a useful analogy
•
•
•
•
Chronic, incurable disease
Not immediately fatal
Eventually requires medications in most cases
Can usually be controlled with careful adherence, management, and
follow-up
• As with the care of persons with diabetes, working in a team and
providing continuing education is essential throughout the course of
the disease
• Patients educated about HIV and the potential for
resistance have better adherence to therapy1,2
1. Malow RW, et al. Alcohol Drug Abuse 1998;49:1021-4.
2. Tuldra A, et al. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999; Abstract 595.
HIV 101 for Patients
History of HIV
• retroviruses discovered in 1900 in animals only
• HIV related to primate retroviruses, that may
have crossed species into humans and undergone
mutations that became HIV as early as 1675??
• established in Africa as an epidemiologic disease
after 1930
• 1980 1st retroviruses found to affect T cells
• Gallo, Essex, & Montagnier pioneers of the cause
of AIDS
History of HIV
• 1981 1st descriptions of immunodeficiency disease
in previously healthy person in medical literature
• specific retrovirus, HIV-1 was not isolated until
1983
• HIV-2 (West Africa) is distinct from HIV-1
(Central Africa) by a longer clinical latency period
• although syndrome of AIDS was not reported until
1981, isolated cases were clearly reported in 1950s
& 1960s
History of HIV
• HIV antibodies found in blood sample from 1950s in
Central Africa suggesting emergence in 1930s;
• remained localized there until spreading to Africa and
then Haiti in late 1970s
• to US & Europe from Haiti & Africa
• first suspect US case 1968 15 y/o BM St. Louis w/
Kaposi’s & disseminated Chlamydial; blood samples +
for HIV
• HIV blood transmission documented 1982
• HIV testing 1985
• HIV drug Rx approved 1987
Primary HIV Infection (PHI)
a/k/a Acute HIV Infection
•
•
•
•
•
•
•
Pathogenesis
Clinical Presentation
Diagnosis
Epidemiology
PHI and the Natural History of HIV Disease
Treatment Options
Conclusions & Recommendations
Etiology: HIV Structure
• RNA retrovirus
• RNA into DNA an absolute must to multiply
• core, nucleocapsid
• double stranded RNA-genome at least nine genes
• protein & enzymes
– reverse transcriptase (RNA-to-DNA)
– polymerase (DNA-to DNA)
– ribonuclease (destroys old RNA)
– integrase (splices viral DNA into host DNA, now
permanent)
– protease (molecular scissor)
• spherical lipid bilayer viral envelope
Life Cycle of HIV
Sites of Action of antiretroviral
Medications
Day 0
Exposure to HIV at
mucosal surface (sex)
Day 0-2
Virus collected by
dendritic cells, carried
to lymph node
Day 4-11
HIV replicates in
CD4 cells, released
into blood
Day 11 on
Kahn JO, Walker BD. N Engl J
Med. 1998;339:33-39.
Virus spreads to
other organs
Primary HIV Infection: Pathogenesis
Plasma HIV RNA (copies/mL)
Symptoms
1,000,000
100,000
Plasma RNA Viral Load
10,000
1,000
CD4 Cell Count (cells/mm³)
10,000,000
1,000
100
CD4 Cell
Count
10
500
1
4-8 Weeks
Up to 12 Years
2-3 Years
How often do people with PHI seek
health care?
Swiss cohort
• 87% of seroconverters (20/23) in cohort study
had symptoms
• 95% of these patients had medical evaluation
• PHI considered in only 5 of 19 patients
PHI often leads to medical evaluation,
but is under-diagnosed!
Schacker T et al. Ann Int Med 1996;125:257-64.
How does HIV cause AIDS?
• HIV infects and
destroys an important
type of cell in the
body’s immune system
known as the T-helper
(TH) cell, also known as
the CD4 cell
How does HIV cause AIDS?
• CD4 cells direct and
coordinate other cells in
the immune system to
battle infections
• When CD4 cells are
destroyed, the body loses
its ability to fight off
infections
HIV Infection is characterized by a steady
decline in the number of CD4 cells
Acute
Infection
Asymptomatic HIV Infection
AIDS
CD4 Cell Count
1,000
CD4 Cells
500
200
4-8 Weeks
Up to 12 Years
Time
2-3 Years
HIV Infection is characterized by a steady
decline in the number of CD4 cells
CD4 Cell Count (cells/mm³)
Acute
Infection
Asymptomatic HIV Infection
AIDS
1,000
CD4 cell count
500
200
high risk of opportunistic infections
4-8 Weeks
Up to 12 Years
Time
2-3 Years
How does HIV cause AIDS?
• Infections that develop as a
result of HIV-inflicted
damage to the immune
system are called
“opportunistic infections”
or “OIs”
• When someone with HIV
develops an opportunistic
infection, they are
diagnosed with AIDS
How does HIV cause AIDS?
• In the past, virtually
all patients diagnosed
with AIDS died within
a few years
• Now, with treatment,
many patients
diagnosed with AIDS
are surviving many
years with the disease
What is the “Viral Load”?
• The HIV viral load is
simply a measure of the
quantity of HIV in a
drop (mL) of a patient’s
blood, and it is usually
measured in copies/mL
• In general, the higher
the viral load, the faster
CD4 cells are destroyed
Clinical Approach to the Diagnosis of
Primary HIV Infection
• Exposure
• Signs & Symptoms
• Laboratory Testing
Exposure Risks (average, per episode,
involving HIV-infected source patient)
Percutaneous (blood)1
Mucocutaneous (blood)2
Receptive anal intercourse3
Insertive anal intercourse4
Receptive vaginal intercourse5
Insertive vaginal intercourse6
Receptive oral (male)7
Female-female orogenital8
IDU needle sharing9
Vertical (no prophylaxis)10
0.3%
0.09%
0.3 - 3%
0.06%
0.1 – 0.2%
0.03 – 0.14%
0.06%
4 case reports
0.67%
24%
Primary HIV Infection: Signs &
Symptoms
• 40-90% of patients will be symptomatic
• A mononucleosis-like illness of non-specific
signs and symptoms
• Signs and symptoms typically begin 1-4 weeks
post-exposure
• High index of suspicion is critical
Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.
Schacker T, et al. Ann Intern Med. 1996;125:257-264.
Primary HIV Infection:
Common Signs & Symptoms
fever
86
lethargy
74
myalgias
59
rash
57
headache
55
pharyngitis
N = 160 patients with PHI in
Geneva, Seattle, and Sydney
52
adenopathy
44
0
10
20
30
40
50
60
70
% of patients
Vanhems P et al. AIDS 2000; 14:0375-0381.
80
90
100
Primary HIV Infection:
Other Signs & Symptoms
aseptic meningitis
24
oral ulcers
15
genital ulcers
10
thrombocytopenia
45
leukopenia
40
transaminitis
21
0
20
40
60
% of patients
Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.
80
100
Primary HIV Infection
Rash
Mucosal Lesions
Trunk and face > limbs
Small pink macules
Oral ulcers, thrush
(Kahn, NEJM, 1998)
Oral Ulcers in Acute HIV Infection
From: Walker, B. 40th IDSA, Chicago 2002.
Genital Ulcer in Acute HIV Infection
From: Walker, B. 40th IDSA, Chicago 2002.
1 mil
HIV
RNA
100,000
+
_
10,000
Ab
P24 +
1,000
100
Exposure
Symptoms
10
0
20
30
Days
40
50
HIV-1 Antibodies
HIV RNA
Diagnostic Testing for PHI
Diagnostic Testing:
Viral Load
• More sensitive than HIV antibody or p24 Ag test3
• Positive one to three weeks before antibody test1
• Typically high level, e.g. greater than 50,000-100,000
copies/mL2,3
• False positives can occur
– Most false positives are low level (<10,000 copies/mL)
– HIV VL <10,000 copies/mL should probably be considered
“indeterminate”
1. Busch MP, Satten GA. Am J Med 1997;102:Suppl 5B:117-24.
2. Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.
3. Daar ES et al. Ann Intern Med. 2001;134:25-29.
Diagnostic Testing:
HIV Antibody
• The gold standard for diagnosis of HIV
infection when used with confirmatory
Western Blot
• Antibody conversion typically 22-27 days
following infection1
1. Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.
Why do we Care about Diagnosing
PHI?
• Public Health:
– Patients with PHI are likely to be highly infectious
– Diagnosis of HIV infection may lead to safer sex
• Personal Health
– 40% of patients with HIV not diagnosed until they
have AIDS
– Antiretroviral therapy (ART) during PHI may alter
the natural course of HIV disease
HIV Rapid
Tests
Public Health Need for Rapid HIV Tests
• High rates of non-return for test results
– In 2000, 31% did not return for results of HIVpositive conventional tests at publicly funded
sites
• Need for immediate information or referral for
treatment choices
– Perinatal settings
– Post-exposure treatment settings
• Screening in high-volume, high-prevalence
settings
Multispot
HIV-1/HIV-2
Uni-Gold
Recombigen
Reveal
G2
OraQuick
Advance
Multispot
HIV-1/HIV-2
Uni-Gold
Recombigen
Reveal
G2
OraQuick
Advance
Four FDA-approved Rapid HIV Tests
Sensitivity
(95% C.I.)
Specificity
(95% C.I.)
OraQuick Advance
- whole blood
- oral fluid
- plasma
99.6 (98.5 - 99.9)
99.3 (98.4 - 99.7)
99.6 (98.5 - 99.9)
100 (99.7-100)
99.8 (99.6 – 99.9)
99.9 (99.6 – 99.9)
Uni-Gold
Recombigen
- whole blood
- serum/plasma
100 (99.5 – 100)
100 (99.5 – 100)
99.7 (99.0 – 100)
99.8 (99.3 – 100)
Four FDA-approved Rapid HIV
Tests
Sensitivity
(95% C.I.)
Specificity
(95% C.I.)
Reveal G2
serum
plasma
99.8(99.2 – 100)
99.8(99.0 – 100)
99.1 (98.8 – 99.4)
98.6 (98.4 – 98.8)
Multispot
serum/plasma
HIV-2
100 (99.9 – 100)
100 (99.7 – 100)
99.9 (99.8 – 100)
Additional Rapid Tests
• FDA approved – May 2006
Sure Check
Stat Pak
Confirmatory Testing
• Confirmatory test is essential (not just EIA)
• For Western blot:
– Venipuncture for whole blood
– Oral fluid specimen
• Follow-up testing of persons with negative or
indeterminate Western blot results after 4 weeks
The Berlin Patient
• Treated soon after acute HIV infection with
didanosine, indinavir, and hydroxyurea
• Baseline VL 80,000-89,000 pre-treatment
• Treatment briefly interrupted twice in first 4
months of treatment
• Viral rebound during first interruption but not
the second
• VL remained undetectable after treatment was
stopped a third time
Lisziewicz J et al. NEJM 1999; 340: 1683-1684.
Unplanned Treatment Interruptions of ART
following Primary HIV Infection: “the Berlin
Patient”
ARV Rx Started Prior to HIV
Seroconversion
ddI + HU + IDV
No ARV Rx
Lisziewicz J et al. N Engl J Med 1999;340:1683.
Primary HIV Infection: Pathogenesis
Anti-HIV
T-cell response
Sero-conversion
Antibody response
Plasma HIV RNA (copies/mL)
1,000,000
100,000
Plasma RNA Viral Load
10,000
Viral set point
1,000
100
CD4 Cell
Count
10
Up to 12 Years
1,000
500
1
4-8 Weeks
CD4 count (cells/mm³)
10,000,000
2-3 Years
A lot of important stuff happens here
From Antigen-Presenting Cell (APC)
to CD4 Cell Destruction
APC
HIV
CD4 Cell
Activated CD4 Cell
HIV
Picture
Adapted from: Cohen DE, Walker BD.
Clin Infect Dis 2001;32:1756-68
Loss of HIV-specific Cytotoxic
T-Lymphocyte Response (CTL)
CD4
Cell
Activated CD4
Cell
Antigen-Presenting
Cells
Lymphokines
HIV
HIV
CD8 Cell
HIV-Infected
CD4
Picture
Mature CD8 CTL
Activated CD8 Pre CTL
Adapted from: Cohen DE, Walker BD.
Cellular Immune Response to Acute HIV
Infection
Acute
HIV
100
Weak CTL
Rapid Progression
HIV RNA
80
60
Moderate
CTL
40
20
Moderate
Progression
Strong CTL
Slow Progression
0
0
1
2
3
4
5Time6
7
8
6 months
Slide courtesy David Spach,
Hypothesis
Initiation of effective ART in the setting of
Primary HIV Infection may preserve
critical HIV-specific CD4 cells, allowing
for a potentially more robust CTL response
to HIV
Early ART with Structured
Treatment Interruptions: Theory
• ART administered during primary HIV infection
preserves HIV-specific CD4 cells
• Allows potential for robust HIV-directed CTL
response
• ART interrupted periodically to ‘prime’ the immune
system to recognize HIV, build CTL response
• ART is re-initiated before HIV inflicts too much
damage
• With subsequent treatment interruptions, improved
CTL response results in progressively lower viral set
point
• Ultimately, immune system may be able to exert
adequate control over HIV without ART
Structured Treatment Interruptions
Structured Treatment
Interruptions (STIs)
What’s the Evidence?
STIs During PHI: Evidence From
an Animal Model
• ART with STIs (3 weeks on/3 weeks off)
compared to standard ART in macaques acutely
infected with SIV and with chronic infection
• In acutely-infected macaques, viral rebound rate
decreased significantly during subsequent
treatment interruptions
• Virologic control in these animals was associated
with vigorous SIV-specific CD8-mediated
immunity
Lori F et al. 40th ICAAC, September 2000, abstract L-17.
STIs During PHI: Evidence of
Improved Virologic Control
• Trial involving 14 patients diagnosed with PHI
• All patients initiated combination ART during
PHI, prior to seroconversion, and had full viral
suppression for at least 8 months before STIs
implemented
• All ARVs were discontinued simultaneously
• Therapy re-instituted if VL persistently (>3
weeks) over 5,000 copies/mL or if VL at any time
over 50,000 copies/mL
Walker B. State of the Art Lecture and Summary. 8th CROI, Session
STIs During PHI: Evidence of
Improved Virologic Control
• Initial success: 8/14 patients were able to
discontinue ART following one or more STIs,
maintaining a VL less than 500 copies/mL
• However, all but 3 of these patients
subsequently lost virologic control
Walker B. State of the Art Lecture and Summary. 8th CROI, Session
STIs during Chronic Infection
• Results variable but less encouraging
• No consistent improvement in virologic
control
• Significant proportion fail to regain CD4 count
prior to treatment interruptions
• May nonetheless prove useful for other reasons
Potential Benefits of Treatment during
PHI
•
•
•
•
Suppress initial burst of viremia
? alter viral set-point
Decrease viral evolution
Preserve CD4 lymphocytes (both absolute
number and HIV-specific)
• Potentially decrease risk of transmission
• Possibly allow for therapy to be stopped
Potential Risks of Treatment during
PHI
• Drug toxicity
• Costs of possible lifelong therapy
• Starting therapy in patients who may never had
needed it
• Early development of resistance
• Limited evidence to date of clinical benefit
Treatment of PHI:
Recommendations
• Patients should be informed of the risks,
benefits, and uncertainties
• For treatment, consider two nucleoside
analogues plus a protease inhibitor or an
NNRTI (consider US treatment guidelines)
• STI strategies remain experimental
• Consider referrals to studies when possible
Primary HIV Infection:
Conclusions
• PHI is under-diagnosed
• May represent a critical opportunity to intervene
• A high index of suspicion, recognition of key signs &
symptoms, and lab testing are required for the
diagnosis
• ART may provide opportunity for improved longterm virologic control of HIV
• Ongoing studies should clarify the potential role of
treatment during PHI, including Structured Treatment
Interruptions
Case Presentation continued
• How is she coping with the diagnosis?
Common responses:
- “I’ve tried not to think about it, ever since I found out”
- “I’ve watched so many friends die, and now I’m next”
- “My friends tell me it’s not that big a deal”
- “I’ve been researching this on the internet and I have a
10-page list of questions for you”
Case Presentation continued
• Ask about sources of social support
– Friends, family
– Community organizations
• Offer counseling
How and when did she
contract HIV?
• What are her risk factors for acquiring HIV?
– She has been an injection drug user for the past 10
years
– She also admits to unprotected sex with drug use
– She does not know when she might have
contracted HIV, but her last HIV test was negative
about one year ago
• Risk factor identification can guide counseling
and prevention
Why do we care about when she
contracted her HIV?
• Resistance
– Increasing transmission of drug-resistant HIV strains
– Resistance testing generally indicated for patients infected
within the past 2-3 years, even if antiretroviral therapy is not
being considered in the near future (ability of currently
available resistance assays to detect resistance wanes with
time)
• Primary HIV Infection (PHI)
– Loss of HIV-specific CD4 cells occurs immediately after PHI
– Some evidence that early treatment of PHI may favorably
influence subsequent course of disease1,2
1. Lisziewicz J et al. N Engl J Med 1999;340:1683.
2. Walker BD. Nature 2000;407:313-4.
Time Trends in Primary HIV-1
Genotypic Drug Resistance Among
Recently Infected Persons
% of resistant isolates
25
NRTI any
NNRTI any
PI any primary
two classes
three classes
20
15
10
5
0
1996-97
1998-99
JAMA. 2002 Jul 10;288(2):181-8.
2000-01
Past Medical History
• Injection drug use (crystal methamphetamine)
for past 5 years; no history of treatment
• No other recreational drug use, no EtOH
• Smoker: 2 PPD for past 10 years
• Depression
• Allergic rhinitis
• No established primary care provider for past 5
years
Medications
• Diphenhydramine (Benadryl)
• Ibuprofen (Motrin) prn
• St. John’s Wort
Social History
• Single, no children
• Born & raised in Idaho but has lived in Eastern
Washington for past 8 years; no other travel
• Estranged from family but many friends
• Works as a waitress
Review of systems
• Intermittent vaginal labial pain for two weeks
• Otherwise negative ROS
Physical exam
• Afebrile, vital signs normal, weight 110 lbs
• PE unremarkable except for shallow vulvar
ulcers
Photo courtesy Beth Schenck, MD
What tests would you order?
•
•
•
•
•
•
•
CD4, viral load
CBC w/ differential
Comprehensive metabolic panel
Toxoplasmosis, CMV IgG, RPR
Hepatitis panel (hepatitis A, B, C)
HSV culture from labial region (or HSV serology?)
Screening for other sexually transmitted infections
(STIs): oral, rectal, urethral GC and urethral CT
Any interventions?
• 10 day course of acyclovir (400mg po tid)
• Counseling re: safer sex, needle sharing
• Follow up
– Social work/case management
– Substance abuse treatment, if interested
• She isn’t!
– Consider psychiatry/counseling
– Nutritionist
– Return approximately 2 weeks for counseling and
follow-up lab results
Lab results
•
•
•
•
•
•
•
•
CBC, electrolyte panel unremarkable
AST=45, ALT=92, other LFTs normal
Absolute CD4=220 cells/mm³ (16%)
HIV viral load=108,000 copies/mL
HAV Ab+
HBsAb-, HBcAb-, HBsAgHCV AbToxo Ab+, CMV Ab+, RPR-
Follow-up appointment
• She returns in two weeks for follow-up
• Receiving counseling but still “pretty down”
about the diagnosis
• Still using crystal methamphetamine, though
less
• How do you explain the CD4 and VL results to
her?
HIV Infection is characterized by a steady
decline in the number of CD4 cells
Acute
Infection
Asymptomatic HIV Infection
AIDS
CD4 Cell Count
1,000
CD4 Cells
500
200
4-8 Weeks
Up to 12 Years
Time
2-3 Years
HIV Infection is characterized by a steady
decline in the number of CD4 cells
CD4 Cell Count (cells/mm³)
Acute
Infection
Asymptomatic HIV Infection
AIDS
1,000
CD4 cell count
500
200
high risk of opportunistic infections
4-8 Weeks
Up to 12 Years
Time
2-3 Years
CD4 Count, Viral Load, and Clinical Course
Primary
Infection
Seroconversion
10,000,000
AIDS
Plasma HIV RNA
1,000,000
100,000
10,000
Viral Load
1,000
1,000
CD4 Cells
100
CD4 Cell Count
Intermediate Stage
500
10
1
4-8 Weeks
Up to 12 Years
2-3 Years
What about HIV treatment?
• She would like to start “the cocktail” she’s heard
about for HIV
• Should she initiate treatment?
– Considerable variation in day-to-day CD4 and VL counts
– Co-incident infections often result in lower CD4 and higher
VL
– Repeat measurements indicated to establish true baseline
How do you explain her elevated
transaminases?
• Up to 19% of HIV+ individuals with
chronic hepatitis C have negative HCV Ab
titers1
• HCV RNA PCR (viral load) testing is
indicated if chronic hepatitis C suspected
1. George, et al. JAIDS 2002;31:154-162
Case Presentation continued
• You order repeat CD4 count and viral load as
well as hepatitis C viral load and an HIV
resistance assay
• Results
–
–
–
–
HCV VL=1,688,340 copies/mL
CD4 count=280 cells/mm3
HIV VL=88,000 copies/mL
Resistance assay does not reveal any resistance
Case Presentation continued
• She returns to clinic two weeks later
• You review the results with her
• She is anxious to start HIV medications
• Should you start her on antiretroviral therapy?
When Should Patients with HIV be Treated
with Antiretroviral Therapy (ART)?
• Benefits
– reduced morbidity &
mortality
– immune system recovery
• Drawbacks
– toxicities
– lifestyle changes
– potential for developing
resistance
Initiation of ART: Key
Considerations
• Symptoms & opportunistic infections
• CD4 count
• HIV viral load
• Anticipated adherence - patient ‘readiness’
(cells/mm³)
Mellors et al. Ann Intern Med 1997;126:946.
When Should ART be Initiated?
An analysis of prospective studies
• 13 cohort studies from Europe & North America
• 12,574 patients initiating ART
–
–
–
–
–
Median age 38; mostly men
Median baseline CD4 count 250; VL 74,000
Median month of ART initiation: 12/1997
Mostly protease inhibitor (PI)-based regimens
24,310 person-years of follow-up
Egger et al. Lancet 2002; 360:119-30.
Findings: effect of
baseline CD4
count and VL on
response to ART
Years from starting HAART
Egger et al. Lancet 2002; 360:119-30.
Findings: Effect of risk factor for HIV
acquisition and age on clinical progression
Egger et al. Lancet 2002; 360:119-30.
Conclusions
• CD4 count at initiation of ART carried
strongest prognostic significance,
corroborating findings from other studies1-4
• Age, infection via IDU, history of AIDSrelated illness also appeared to affect durability
of clinical response to ART
1. Chen RY et al. 8th CROI, Chicago 2001
2. Hogg RS et al. JAMA. 2001;286:2568-2577
3. Sterling et al, 9th CROI, Seattle 2002
4. Palella et al, 9th CROI, Seattle 2002
Caveats
• High VL (>100,000 copies/mL) also carried
prognostic significance, but
– few patients initiated on efavirenz or ritonavir-boosted
regimens
– other recent studies have not demonstrated a clear
correlation between baseline viral load and efficacy of
ART1,2
• Observational study: other potential confounding
factors could have affected results
– However, randomized controlled trial very unlikely
1. Philips AN et al. JAMA 2001;286:2560-2567.
2. Hogg RS et al. JAMA 2001;286:2568-2577.
Implications for Clinical Practice
• Ideally, initiate ART before CD4 count drops below
200 cells/mm³ and before clinical symptoms develop
• A benefit for treatment before CD4 count falls below
350 may exist, but the small risk of clinical
progression if therapy is deferred must be balanced
against drawbacks of ART
• If CD4 already less than 200 or clinical progression
has occurred, ART is clearly indicated as soon as
patient is ready to start
Implications for Clinical Practice:
Significance of Baseline Viral Load
• Initiation of ART before VL >100,000 may allow for more
therapeutic options and greater clinical success
• However, highly potent efavirenz (Sustiva)- or lopinavirritonavir (Kaletra)- based regimens may be equally
effective in patients with high baseline viral loads1-3
• VL a marker for rate of CD4 decline: consider more
frequent monitoring in patients with high VL?
1. XIV International AIDS Conference, July 2002. Abstract TuOrB1189
2. Arribas JR et al. AIDS 2002;16(11):1554-6.
3. Walmsley S et al. NEJM 2002 346(26):2039-46.
When Should ART be Initiated?
DHHS Guidelines
Clinical Category
CD4 count Viral Load
Recommendation
Symptomatic (AIDS,
severe Sx)
Any value
Any value
Treat
Asymptomatic, AIDS
< 200/mm3 Any value
Treat
Asymptomatic
> 200/mm3 Any value
but < 350
Treatment should
generally be offered
Asymptomatic
> 350/mm3 > 55,000
copies/mL
Asymptomatic
> 350/mm3 < 55,000
copies/mL
Some experts would
recommend initiating
treatment
Many experts would
defer therapy and
observe
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and
Adolescents, October 6, 2005.
Impact of CD4 and Viral Load on
Initiation of ART: Summary
• The optimal time to initiate therapy is:
–
–
–
–
unclear
before CD4 drops below 200 cells/mm3
perhaps when CD4 drops below 350 cells/mm3
determined more by CD4 count than by viral load
• Viral load
– predicts the slope of CD4 decline
– may help determine whether to start closer to CD4
count of 200 cells/mm3 or 350 cells/mm3
Back to the Case
• 31 yo woman with asymptomatic HIV infection
• CD4=280 cells/mm3
• Viral load=88,000 copies/mL
• Should she initiate antiretroviral therapy?
When Should ART be Initiated?
DHHS Guidelines
Clinical Category
CD4 count Viral Load
Recommendation
Symptomatic (AIDS,
severe Sx)
Any value
Any value
Treat
Asymptomatic, AIDS
< 200/mm3 Any value
Treat
Asymptomatic
> 200/mm3 Any value
but < 350
Treatment should
generally be offered
Asymptomatic
> 350/mm3 > 55,000
copies/mL
Asymptomatic
> 350/mm3 < 55,000
copies/mL
Some experts would
recommend initiating
treatment
Many experts would
defer therapy and
observe
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and
Adolescents, March 23, 2004.
Initiation of Antiretroviral Therapy:
Key Considerations
• Symptoms & opportunistic infections
• CD4 count
• HIV viral load
• Anticipated Adherence - patient ‘readiness’
Adherence
“Drugs don’t work if people don’t
take them.”
- C. Everett Koop
Virologic Control falls sharply with
diminished adherence
Patients with HIV RNA
<400 copies/mL, %
100
80
60
40
20
0
>95
90-95
80–90
70-80
<70
PI adherence, % (electronic bottle caps)
Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.
Predictors of Poor Adherence
•
•
•
•
•
•
•
Active alcohol or substance abuse1,2,6
Work outside the home for pay1
Depressed mood1
Lack of perceived efficacy of ART3
Lack of advanced disease4
Concern over side effects4
Regimen complexity5
1. Chesney MA. 37th ICAAC, 1997; Toronto. Abstract 281.
2. Cheever LW, Curr Infect Dis Rep 1999 Oct;1(4):401-407.
3. Horne R, et al. 39th ICAAC, 1999; San Francisco. Abstract 588.
4. Wenger N, et al. 6th CROI, 1999, Abstract 98.
5. Stone VE, et al. JAIDS 2001; 28:124-131
6. Howard AA et al. AIDS 2002;16:2175-82.
Factors Associated with Higher
Levels of Adherence
•
•
•
•
•
Twice-daily or once-daily regimens1,4
Belief in own ability to adhere to regimen1
Not living alone2
Dependent on a significant other for support2
History of opportunistic infection or advanced
HIV disease3
1. Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117-125.
2. Morse EV et al, Soc Sci Med 1991;32:1161-1167.
3. Singh N, et al, AIDS Care 1996;8:261-269.
4. Stone VE, et al. JAIDS 2001; 28:124-131
Factors Associated with Higher
Levels of Adherence
• Belief in efficacy of antiretroviral therapy
• Belief that non-adherence will lead to viral
resistance
Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.
Mental Health Issues
• She refuses to see a psychiatrist, but is open to
depression treatment by you
– Should she continue her St. John’s Wort?
• St. John’s Wort has significant interactions
with many antiretroviral agents
• Efficacy in major depression questionable
Case Presentation continued
• You substitute paroxetine (Paxil) for St. John’s
Wort
• She returns in a month; her depression is improving
• She is still using crystal methamphetamine
• Would you start her on antiretroviral therapy?
• What is your estimate of her ability to adhere to
treatment?
Clinicians’ Estimates of Adherence
Not Much Better Than Random
Bangsberg
Paterson
Haubrich
Steiner
Bosely
Charney
Caron
Gilbert
Blowey
Mushlin
2001
2000
1999
1995
1995
1967
1978
1980
1997
1977
JAIDS
Annals Int Med
AIDS
Arch Int Med
Eur Resp J
Pediatrics
Clin Pharmacol
Can Med Assoc J
Ped Nephrology
Arch Int Med
Slide courtesy David Bangsberg, MD
ART
ART
ART
AZT
Inhaled terbutaline
Penicillin
Antacids
Digoxin
Cyclosporin
Hypertensive
What about her hepatitis C?
• HIV accelerates the course of hepatitis C, but variable
rates of progression still seen
• Avoiding alcohol, other insults to the liver is critical
• Co-infection with HIV also reduces the response rate
to treatment for hepatitis C – but treatment can be
helpful, even curative, and deserves consideration
• For her, probably best to focus on HIV first, but
discussing the possibility of future treatment and a
Hepatology consultation is a good idea
Case Presentation continued
• You start her on a regimen of AZT (zidovudine;
Retrovir) + 3TC (lamivudine; Epivir) +
efavirenz (Sustiva)*
* Note: efavirenz is a potential teratogen and should not be used in
pregnant women or women with high potential to become pregnant
“Preferred” regimens for
treatment-naïve patients
• efavirenz/tenofovir/emtricitabine
• ritonavir-boosted atazanavir +
tenofovir/emtricitabine
• ritonavir-boosted darunavir +
tenofovir/emtricitabine
• raltegravir + tenofovir/emtricitabine.
Antiretroviral Therapy: Optimal Response
ART Initiated
CD4 count (cells/mm3)
Viral Load (copies/mL)
1000000
Viral Load
100000
10000
1000
100
50
50
10
0
1
2
3
Time (months)
4
5
6
7
8
Antiretroviral Therapy: Optimal Response
ART Initiated
200
Viral Load
100000
CD4 Count
150
10000
100
1000
50
100
50
50
10
0
0
1
2
3
4
Time (months)
5
6
7
8
CD4 count (cells/mm3)
Viral Load (copies/mL)
1000000
Health Care Maintenance
• Vaccines
–
–
–
–
Hepatitis A, hepatitis B (if not immune)
Pneumococcal
Influenza
Tetanus
• Pap smears
– Every 6 months initially, then yearly if negative
– If ASCUS or more significant abnormality
colposcopy per latest guidelines (do not triage by
HPV status)
Health Care Maintenance
• Breast, prostate, colorectal cancer screening
– Same as for HIV-negative patients
• Cholesterol screening
– Protease inhibitors, efavirenz, some NRTIs
associated with dyslipidemia
– Check baseline lipids before treatment and
periodically after initiation of treatment
– Higher rates of CAD among HIV-infected
patients starting to be seen
Health Care Maintenance
• PPD
– Treatment of LTBI warranted for:
• ≥5mm of induration on PPD, or
• Recent contact with someone with active TB
– LTBI treatment:
• INH + pyridoxine x 9 months
• Rifampin + pyrazinamide x 2 months is NO LONGER
RECOMMENDED
• STI screening
– Annual anal/pharyngeal/urethral screening for GC, urethral
chlamydia recommended for MSM
– Annual RPR
– More frequent STI screening may be appropriate for some
patients
Where is she now?
• She achieves an undetectable viral load in four
months; CD4 count rises to 410 cells/mm3
• Pap smear negative, vaccinations initiated
• What would you focus on next?
• Main health issues besides HIV:
– Hepatitis C
– Crystal methamphetamine use
– Smoking
Pulmonary Manifestations
• Pneumocystis carinii (actually a fungus)
– prophylaxis w/ Bactrim-DS if CD4+ < 200
•
•
•
•
•
CMV
M. tuberculosis (4% of HIV)
Histoplasma
Staphylococcus
various tumors
Pneumocystis Carinii (PCP)
Mucocutaneous Manifestations
• may present early
• viral exanthem of seroconversion: erythematous,
fine maculopapular rash
• face trunk & arms
• pruritis, fever, malaise, night sweats, fatigue, pharyngitis wt.
loss, N/V/D/HA, lymphadenopathy
• allergic, infectious, neoplastic
• viral: HSV, VZ, EBV, HPV (genital warts)
Oral Hairy Leukoplakia
• white-grey, thickened, raised lesions, vertical folds
or “hairs” that form on tongue & buccal mucosa
• sides of tongue typical; cannot be scraped off like
candida
18 y/o WM c/o of rectal bleeding; high
school jock, popular;
dx genital warts; HIV +
33 y/o WM w/ AIDS X 2 yrs.
c/o “hemorrhoids acting up”
dx rectal carcinoma
Extensive vulvar
condylomata
acuminata
Cervical intraepithelial
neoplasia
Herpes Simplex Virus
• painful vesicles on red base; rupture & crust
• become large, ulcerative, necrotic
• genitalia, digits, perianal or perioral
Lesions of Genital Herpes
Herpes Zoster (Shingles)
involving the face & eye
Herpes Zoster (Shingles)
Staphylococcus aureus
• folliculitis, furuncles or bullous impetigo
Fungal Skin Infections
• Candida, Cryptococcus, or Histoplasma
Kaposi’s Sarcoma
others: squamous cell carcinoma, basal cell carcinoma, cutaneous lymphomas
Neurologic Manifestations
•
•
•
•
•
•
•
•
•
•
viral encephalitis (numerous agents)
meninigitis (numerous agents)
parasitic cerebral toxoplasmosis
lymphoma
neurosyphilis
AIDS dementia
spinal myelopathy or myelitis
zoster
radiculopathy
polyneuropathy
Ocular Manifestations
• AIDS retinopathy: immune or CMV
• CMV retinitis
AIDS and Cytomegalovirus (CMV) Retinitis
T4 Cell Count <50/cu.mm
National HIV/AIDS Clinician’s
Consultation Center
• Warmline: Offers treating clinicians
upto-the-minute HIV clinical and drug
information and individualized, expert case
consultation
• Monday – Friday 6am to 5 pm PST
• 1-800-933-3413
• Warmline is a free service to health care
providers
Useful references
• NIH AIDS info (incredible site)
http://www.aidsinfo.nih.gov/Default.aspx
• John Hopkins AIDS Service
http://www.hopkins-aids.edu
• National Clinicians’ Postexposure Prophylaxis
Hotline (PEPline) 1-888-448-4911
www.ucsf.edu/hivcntr
• National HIV Telephone Consultation Service
1-800-933-3413
• Hepatitis Hotline 1-888-443-7232