3. •Rate of HIV 5x
national average
•Heterosexuals
55% of new
infections
•New infections
•15% 13-24
y/o
•51% 25-45
y/o
•34% > 45
y/o
HIV/AIDS in Philadelphia
10.
Rapid testing (similar
to ELISA) need
confirmation with
Western Blot
Traditional HIV Test
has ELISA/Western
Blot
Temple: HIV antigen:
+p 24 “4th generation
assay-positive with 24 weeks
Now rapid testing
(Alere) same
HIV Testing
15. Acute Retroviral Syndrome:
Common Signs and Symptoms
Fever
Lymphadenopathy
Pharyngitis
Rash
Myalgia or arthralgia
Diarrhea
Headache
Nausea and vomiting
Hepatosplenomegaly
Weight loss
Thrush
Neurological symptoms
AETC National Resource Center,
December 2009
www.aidsetc.org
16. Goals of Treatment
Reduce
HIV-related morbidity;
prolong duration and quality of
survival
Restore and/or preserve immunologic
function
Maximally and durably suppress HIV
viral load
Prevent HIV transmission
March 2012
16
www.aidsetc
.org
19.
CBC
Chemistry
Hepatitis B and C
and A testing
RPR
CMV
Lipid Profile
Toxoplasma
Antibody
Confirm ELISA/
Western Blot
CD4+ cell count
“Viral Load” or
HIV RNA PCR
“copies”
Laboratory Testing
20. Use of CD4 Cell Levels to
Guide Therapy Decisions
CD4 count
◦ The major indicator of immune function
◦ Most recent CD4 count is best predictor of
disease progression
◦ A key factor in decision to start ART or OI prophylaxis
◦ Important in determining response to ART
Adequate response: CD4 increase 50-150 cells/µL per year
CD4 monitoring
◦ Check at baseline (x 2) and at least every 3-6 months*
* May consider every 6-12 months in clinically stable patients
with sustained HIV RNA suppression and CD4 status well above
threshold for opportunistic infection risk.
March 2012
20
www.aidsetc.org
21. Use of HIV RNA Levels to
Guide Therapy Decisions (2)
RNA monitoring
◦ Check at baseline (x 2)
◦ Immediately before initiating ART
◦ 2-4 weeks (not more than 8 weeks) after start or
change of ART, then every 4-8 weeks until suppressed
to <200 copies/mL
◦ Every 3-4 months with stable patients; may consider
every 6 months for stable adherent patients with VL
suppression >2-3 years
◦ Isolated “blips” may occur (transient low-level RNA,
typically <400 copies/mL), are not thought to predict
virologic failure
ACTG defines virologic failure as confirmed HIV RNA >200
copies/mL
March 2012
21
www.aidsetc.org
22. Differences in viral Load: Women v. Men:
Regression Model Adjusted for Race, Country
and History of AIDS
0.25
Male-Female Mean Viral Load
Difference (Log10 Copies/mL)
0.20
0.15
0.10
0.05
0.00
50
100
150
200
-0.05
Exact Screening CD4+ Lymphocytes (mm3)
Adapted from Beatriz Grinsztejn et al. CROI 2008; abstract 672.
250
23. •Genotype &
Phenotype
•Generally need at
least 1000 copies of
virus to do test
•Done at baseline on
all
•Reliable when
patient on HIV med
for virologic failure.
Drug Resistance Testing
25.
If CD4 under 200 cells/mm3, eye exam to
evaluate for CMV, HIV retinopathy.
If CMV present, role of measuring CMV
viral load and prophylaxis with
valganciclovir for patients at high risk??
Eye screening
28. When to Start ART
Exact CD4 count at which to initiate therapy
not known, but evidence points to starting
at higher counts
Current recommendation: ART for all
ART for treatment and prevention
February 2013
28
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c.or
g
29.
30. Consider Deferral of ART
Clinical or personal factors may support
deferral of ART
◦ If CD4 count is low, deferral should be considered
only in unusual situations, and with close follow-up
When there are significant barriers to
adherence
If co morbidities complicate or prohibit ART
“Elite controllers” and long-term
nonprogressors
March 2012
30
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c.or
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31. Potential Benefits of Early
Therapy
◦ Untreated HIV may be associated with
development of AIDS and non-AIDSdefining conditions
Earlier ART may prevent HIV-related endorgan damage; deferred ART may not
reliably repair damage acquired earlier
◦ Increasing evidence of direct HIV effects on
various end organs and indirect effects via HIVassociated inflammation
◦ End-organ damage occurs at all stages of infection
February 2013
31
ww
w.ai
dset
c.or
g
32. Potential Benefits of Early
Therapy
Potential decrease in risk of many
complications, including:
◦
◦
◦
◦
◦
◦
HIV-associated nephropathy
Liver disease progression from hepatitis B or C
Cardiovascular disease
Malignancies (AIDS defining and non-AIDS defining)
Neurocognitive decline
Blunted immunological response owing to ART
initiation at older age
◦ Persistent T-cell activation and inflammation
February 2013
32
ww
w.ai
dset
c.or
g
33. Potential Benefits of Early
Therapy (3)
Prevention of sexual and bloodborne
transmission of HIV
Prevention of mother-to-child transmission
of HIV
March 2012
33
ww
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dset
c.or
g
34. A New Paradigm:
The Broader Spectrum of HIV Disease
Ongoing Morbidity from HIV
1000
800
600
CD4+
cells
400
Early Opportunistic Infections
Late Opportunistic Infections
200
0
1
Infection
2
3
4
5
6
7
8
9 10 11 12 13 14
Time in Years
35. Considerations for Initial Regimen of
Highly Active Antiretroviral Therapy
(HAART)
Underlying
Conditions
Lifestyle
Dosing
Pill Burden
Diabetes
Hepatitis
CV Disease
Drug
Interactions
Initial
Treatment
Toxicity
Short Term
Long Term
36. Initial Assessment: PATHS
Assess for
Psychological
status
Assess for
Adherence barriers
Assess for
Treatment
readiness
Assess for Health
Literacy
Assess for Support
system
37. Therapy is forever
Adherence must be over 90%
Retention in care is critical for long term
success.
Principles of Highly Active
Antiretroviral Therapy (HAART)
38. Targets of HIV Therapy
Integrase Inhibitors
Entry
Inhibitors:
Fusion, CD4, CCR5
CXCR4
Nucleus
RNA
Protease
HIV
Reverse
transcriptase
DNA
CD4+ T-Cell
Reverse transcriptase inhibitors:
NRTI (nucleosides, nucleotides)
NNRTI
Protease inhibitors
39. Classes of ART
Nucleoside Reverse
Transcriptase Inhibitors
Non-nucleoside Reverse
Transcriptase Inhibitors
Protease Inhibitors
Fusion Inhibitors
Integrase inhibitors
HAART: Highly Active
Antiretroviral Therapy
41. Initial Regimens: Preferred
NNRTI based
EFV/TDF/FTC1,2
PI based
ATV/r + TDF/FTC²
DRV/r (QD) + TDF/FTC²
II based
RAL + TDF/FTC²
Pregnant women LPV/r (BID) + ZDV/3TC²
1. EFV should not be used during the first trimester of pregnancy or in
women trying to conceive or not using effective and consistent
contraception.
2. 3TC can be used in place of FTC and vice versa. TDF should be used
with caution in patients with renal insufficiency.
March 2012
www.aidsetc.org
41
43. Viral Load Testing
Viral Load and Progression of
Disease
Type of test ordered:
real time PCR
Lower limit of
detection is 20 copies
Generally don’t
measure this or CD4
in acute hospital
setting or with
intercurrent illness or
within 2 weeks of
vaccination
45. Treatment-Experienced
Patients:
ART Failure
Virologic failure:
◦ HIV RNA >400 copies/mL after 24 weeks, >50
copies/mL after 48 weeks, or >400 copies/mL after
viral suppression
Immunologic failure:
◦ Failure to achieve and maintain adequate CD4
increase despite virologic suppression
Clinical progression:
◦ Occurrence of HIV-related events (after ≥3 months
on therapy; excludes immune reconstitution
syndromes)
October 2011
www.aidsetc.org
45
46. Mortality and HAART Use Over Time -- All HOPS Patients
Updated as of 2Q2013
16
100
90
80
12
70
10
8
D eath P er 10 0 P ers on Y ea rs
% P atie nts o n H A AR T
60
50
40
6
30
4
20
2
10
0
0
Quarter
End of observation defined as the earlier of status change date and last contact + 365 days .
8/14/13 Cerner Corporation
The Success Story
% of Patients on HAART
Deaths per 100 Person Years
14
48. Predictors of Inadequate
Adherence
Regimen complexity and pill burden
Low literacy level
Active drug use or alcoholism
Stigma
Mental illness (especially depression)
Cognitive impairment
Lack of patient education
Medication adverse effects
Treatment fatigue
November 2008
AETC National Resource
Center, www.aidsetc.org
49.
Emotional and
practical supports
Convenience of
regimen
Understanding of
the importance of
adherence
Belief in efficacy of
medications
•Feeling comfortable taking medications
in front of others
•Keeping clinic appointments
•Severity of symptoms or illness
Predictors of Good Adherence
November 2008
AETC National Resource Center,
www.aidsetc.org
51.
Women: over age
45 with risks for CV
disease (USPSTF)
AGES 14-24
Women with HIV
qualify
◦ Low HDL
◦ High LDL
◦ High hsCRP
Health Maintenance Screening:
Lipids
Mulligan, Clin Inf Dis 2010
52.
New onset or worsening of
symptoms of an infection or
inflammatory condition after
initiation of antiretroviral
therapy
Symptoms not explained by a
newly acquired infection, the
predicted course of a previously
diagnosed infection or adverse
effects of drug therapy
A decrease in HIV RNA by at
least 1 log10
Risk higher with lower CD4
count at initiation of HAART
Immune Reconstitution
Inflammatory Syndrome (IRIS)
53. Case Definition:
• A paradoxical deterioration in clinical status after
initiating highly active antiretroviral therapy
(HAART) attributable to the recovery of the
immune response to latent or subclinical infectious
or non-infectious processes
Other Nomenclature
• Immune reconstitution inflammatory syndrome
(IRIS)
• Immune restoration/restitution/recovery disease
• Immune rebound illness
• HAART attacks
Immune Reconstitution
54. Antiretroviral Therapy Improves
Qualitative and Quantitative Immune
Defects
Immune suppression/deficiency
HIV
replication
Immune
activation
Qualitative/functio
nal immune defects
Quantitative
immune defects
Response to recall
antigens
CD4 counts
Impaired
pathogen
-specific
immunity
OI
Immune Reconstitution
HAART
HIV
replication
Immune
activation
Qualitative/function
al immune defects
Quantitative immune
defects
Reversal of anergy
Redistribution, death (HIV-,
activation-induced),
production (peripheral
expansion and thymic)
Lymphocyte
proliferative capacity
Improved
pathogenspecific
immunity
Improved
immune
control
54
Migueles, Buenos Aires 2003
55. Clinical factors Associated with
IRIS
Male Sex
Lower CD4 cell count/ percentage at ART
initiation
Higher HIV RNA at ART initiation
Lower CD4:CD8 ration at ART initiation
More rapid initial fall in HIV RNA on ART
Antiretroviral naïve at time of OI diagnosis
Shorter interval between OI therapy initiation
and ART initiation
†Derived
from cohorts where IRIS due to multiple pathogens were reported (i.e.
cohorts which examined only TB-IRIS were excluded
56. HIV Disease Contributes to NonAIDS Events
Low CD4+
T-cell nadir
Coinfections
(hepatitis, CMV,
EBV, and HPV)
Persistent
inflammation
Increased
comorbidities
Cumulative
cART
exposure
Lifestyle
(smoking, etc)
Aging
Adapted from Deeks SG, et al. BMJ. 2009;338:a3172. Operskalski EA. Curr HIV/AIDS Rep. 2011;8:12-22.
58. HIV and Bone Disease
Continuous ART
associated with
greater bone loss1
Certain ART with
higher risk e.g.
tenofovir
Vitamin D
deficiency
Increased
fractures2
1Grund
B, et al. ICAAC/IDSA 2008. Abstract 2312a
2Young, CID, 2011
59. Traditional Factors Are the Biggest
Contributor to CHD in HIV
Population
Family history
Inactivity, diet
Abdominal obesity*
Sex
Age
Cigarette smoking
CHD risk
Lipids*
Hypertension*
HIV
infection†
Hyperglycemia
HAART†
Emerging factors:
Lp(a), CRP, IMT, and
endothelial function
*Component of metabolic syndrome.
†Precise contribution unclear.
Insulin resistance*
Diabetes
60.
High levels of DDimer, CRP, IL-6
Smoking rates
Etc…..
Immune activation
61. HIV and Hepatitis C
Challenges of
therapy in co
infection
Accelerated course
of HCV when have
HIV
Increased risk of
hepatotoxicity with
ART
Impact on
mortality/morbidity
Interactions with
ART and new HCV
RX (DAA)
63. Retrospective studies: CMV associated
IRIS was common 18%
Prospective studies: 63% in those with
prior CMV disease
Immune recovery vitritis
Immune recovery uveitis
Secondary to residual CMV antigens or
proteins
CMV and IRIS
64. Other ocular OI
Syphilitic
H zoster
Molluscum
Toxo
Infectious
HSV
Pneumocystis
Cryptococcal
CMV
Related to low CD4
< 50
Genetics related to
IL-10 signaling may
be related to risk
Ocular OI :CMV retinitis and
others
65. Guidelines:
-for CD4< 50 and +
CMV PCR with
retinal lesions
consider
valganciclovir with
initiation of HAART
Continue x 3-6
months during
period of risk
CMV Retinitis and Immune
Recovery
66. Four Prevention OpportunitiesCohen et al, JCI, 2008
Cohen IAS 2008
UNEXPOSED
EXPOSED
EXPOSED
INFECTED
(precoital/coital) (postcoital)
Behavioral,
Structural
Structural
Circumcision
Condoms
STDs
YEARS
Vaccines
ART PrEP
Microbicides
HOURS
Vaccines
ART PEP
72h
Treatment Of HIV
Reduced Infectivity
YEARS
68. HPTN 052
1763 discordant heterosexual couples
9 countries, 13 sites
Randomization
Immediate ART
350-550cells/uL
AZT+3TC+EFV
Deferred ART
CD4 <250
Endpoints: i) HIV Transmission to partners
ii) OIs and clinical Events
iii) ART toxicity
69. HPTN 052: use of ART in
serodiscordant couples
Heterosexual
couples : treat
HIV+ partner
above 350 cells
compared delay
ART until <350
Reduction in HIV infection in
those treated immediately
70.
Focus on testing, linkage and retention
New models for prevention
Treatment: more once a day regimens
Managing immune reconstitution
Non-HIV complications predominate
HIV 2012
