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HIV Update 2013Ellen M. Tedaldi, M.D.Professor of Medicine
Director, Temple Comprehensive HIV Program
Objectives for today
Epidemiology-local
Screening and Diagnosis
Evaluation of the HIV+ patient
Treatment updates
Ophthalmology connections
HIV/AIDS in Philadelphia
•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
Demographics of HIV in Philadelphia
HIV IN AFRICA and SELECTED US SITES
Mortality by Race and PayerDisparities
Figure 2. Mortality Over Time By PayerHIV Outpatient Study (HOPS) 1996-2007 Figure 1. Mortality Over Time By Race
HIV Outpatient Study (HOPS) 1996-2007
Palella, AIDS, 2011
Communities in Crisis: Is There a Generalized HIV Epidemic in Impoverished Urban Areas of the United States?
Denning P, IAC July 2010
Objectives for today
Epidemiology-local
Screening and Diagnosis
Evaluation of the HIV+ patient
Treatment updates
Ophthalmology connections
Screening/diagnosis
2011 PA law changed-no written consent
2013 USPSTF- All adults 15-65 to be tested for HIV
Rapid testing in ER, L&D, anywhere
HIV Testing
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 2-4 weeks
Now rapid testing (Alere) same
© 2010 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
Reactivity of FDA approved assays for HIV-1 compared to WB
The Future of HIV Testing.Branson, Bernard
JAIDS Journal of Acquired Immune Deficiency Syndromes. 55 Supplement 2, The HIV Epidemic in the United States: A Time for Action:S102-S105, December 15, 2010.DOI: 10.1097/QAI.0b013e3181fbca44
FIGURE 2 . Reactivity of FDA-approved assays for HIV-1 compared with Western blot.
© 2010 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
The Future of HIV Testing.Branson, Bernard
JAIDS Journal of Acquired Immune Deficiency Syndromes. 55 Supplement 2, The HIV Epidemic in the United States: A Time for Action:S102-S105, December 15, 2010.DOI: 10.1097/QAI.0b013e3181fbca44
FIGURE 3 . Proposed diagnostic algorithm for HIV diagnosis. *Denotes if Ag/Ab combo test is used.
HIV PATHOGENESIS
Time course of HIV Infection
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
December 2009AETC National Resource Center,
www.aidsetc.org
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 2012www.aidsetc.org 16
Objectives for today
Epidemiology-local
Screening and Diagnosis
Evaluation of the HIV+ patient
Treatment updates
Ophthalmology connections
Initial Evaluation of HIV+ Patient
HistoryPhysical:
attention to skin, lymphadenopathy, liver, neuro
Women: baseline PAP and GC/Chlamydia
Men: GC/Chlamydia
Other factors:◦Disclosure◦Support system◦Partner status◦Psych history and
current status
Laboratory Testing
CBCChemistryHepatitis B and C
and A testingRPRCMVLipid ProfileToxoplasma
Antibody
Confirm ELISA/ Western Blot
CD4+ cell count“Viral Load” or
HIV RNA PCR “copies”
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 www.aidsetc.org 20
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 www.aidsetc.org21
Differences in viral Load: Women v. Men:Regression Model Adjusted for Race, Country and History of AIDS
-0.05
0.00
0.05
0.10
0.15
0.20
0.25
50 100 150 200 250
Adapted from Beatriz Grinsztejn et al. CROI 2008; abstract 672.
Exact Screening CD4+ Lymphocytes (mm3)
Mal
e-F
em
ale
Mea
n V
iral
Lo
ad
Dif
fere
nce
(L
og
10 C
op
ies/
mL
)
Drug Resistance Testing
•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.
Vaccinations:
InfluenzaPneumovax* 13, 23 PPD * 5 mm, Hepatitis BHepatitis ATetanus/TdapHPV
AVOID: MMR, Varicella, Herpes Zoster, and live vaccines * although have been evaluated
Eye screening
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??
Time course of HIV Infection
When to Start?
CD4+ =200
CD4 = 350
CD4 = 500
When to Start ARTExact CD4 count at which to initiate therapy
not known, but evidence points to starting at higher counts
Current recommendation: ART for allART for treatment and prevention
February 2013 www.aidsetc.org 28
START Design
HIV-infected participants with CD4+ cell counts > 500 cells/mm3
Early ART Group
Immediately initiate ART
N=450 at 70 sites for pilot phaseN=2,000 (est.) for definitive study
Deferred ART Group
Defer ART until CD4+ <350 cells/mm3 or symptoms
develop
N=450 at 70 sites for pilot phaseN=2,000 (est.) for definitive study
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 www.aidsetc.org 30
Potential Benefits of Early Therapy
◦ Untreated HIV may be associated with development of AIDS and non-AIDS-defining conditions
Earlier ART may prevent HIV-related end-organ damage; deferred ART may not reliably repair damage acquired earlier ◦Increasing evidence of direct HIV effects on
various end organs and indirect effects via HIV-associated inflammation
◦End-organ damage occurs at all stages of infection
February 2013 www.aidsetc.org 31
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 www.aidsetc.org 32
Potential Benefits of Early Therapy (3)
Prevention of sexual and bloodborne transmission of HIV
Prevention of mother-to-child transmission of HIV
March 2012 www.aidsetc.org 33
A New Paradigm:
Time in YearsInfection
CD4+cells
1000
800
600
400
200
0
Early Opportunistic Infections
Late Opportunistic Infections
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Ongoing Morbidity from HIV
The Broader Spectrum of HIV Disease
Considerations for Initial Regimen of Highly Active Antiretroviral Therapy (HAART)
Initial Treatment
Underlying Conditions
DiabetesHepatitis
CV Disease
LifestyleDosing
Pill Burden
Drug Interactions
Toxicity
Short TermLong Term
Initial Assessment: PATHSAssess for
Psychological statusAssess for
Adherence barriersAssess for
Treatment readiness
Assess for Health Literacy
Assess for Support system
Principles of Highly Active Antiretroviral Therapy (HAART)
Therapy is foreverAdherence must be over 90%Retention in care is critical for long term
success.
RNA
Reversetranscriptase
Protease
DNA
Nucleus
Protease inhibitorsReverse transcriptase inhibitors:NRTI (nucleosides, nucleotides)
NNRTI
EntryInhibitors:
Fusion, CD4, CCR5CXCR4
Targets of HIV Therapy
HIV
Integrase Inhibitors
CD4+ T-Cell
HAART: Highly Active Antiretroviral Therapy
Classes of ART
Nucleoside Reverse Transcriptase Inhibitors
Non-nucleoside Reverse Transcriptase Inhibitors
Protease Inhibitors
Fusion Inhibitors
Integrase inhibitors
Current ARV Medications
NRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT, ZDV)
NNRTI Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP) Rilpivirine (RPV)
PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV)
Integrase Inhibitor (II) Raltegravir (RAL) Elvitegravir* (EVG)Dolutegravir
Fusion Inhibitor Enfuvirtide (ENF, T-20)
CCR5 Antagonist Maraviroc (MVC)
February 2013 www.aidsetc.org 40
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
The visual preferred therapies
NNRTI
Integrase
Protease
Viral Load TestingType of test ordered:
real time PCRLower limit of
detection is 20 copiesGenerally don’t
measure this or CD4 in acute hospital setting or with intercurrent illness or within 2 weeks of vaccinationViral Load and Progression of
Disease
Goal of Therapy
Actually < 20 copies
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 suppressionClinical progression:
◦ Occurrence of HIV-related events (after ≥3 months on therapy; excludes immune reconstitution syndromes)
October 2011 www.aidsetc.org 45
The Success Story
Mortality and HAART Use Over Time -- All HOPS Patients Updated as of 2Q2013
0
10
20
30
40
50
60
70
80
90
100
0
2
4
6
8
10
12
14
16
% o
f Pat
ient
s on
HA
AR
T
Dea
ths
per
100
Per
son
Yea
rs
Quarter
Death Per 100 Person Years
%Patients o n H AART
End of observation defined as the earlier of status change date and last contact + 365 days .
8/14/13 Cerner Corporation
HIV treatment cascade
Predictors of Inadequate Adherence
Regimen complexity and pill burdenLow literacy levelActive drug use or alcoholism StigmaMental illness (especially depression)Cognitive impairmentLack of patient education Medication adverse effectsTreatment fatigue
November 2008AETC National Resource Center, www.aidsetc.org
Predictors of Good Adherence
Emotional and practical supports
Convenience of regimen
Understanding of the importance of adherence
Belief in efficacy of medications
November 2008AETC National Resource Center,
www.aidsetc.org
•Feeling comfortable taking medicationsin front of others•Keeping clinic appointments•Severity of symptoms or illness
Prevention of Opportunistic Infections
CD4 < 200 cells/mm3
Pneumocystis juroveci
Toxoplasmosis
CD4 < 50 cells/mm3
Mycobacterium avium
Health Maintenance Screening: Lipids
Women: over age 45 with risks for CV disease (USPSTF)
Women with HIV qualify◦Low HDL◦High LDL◦High hsCRP
Mulligan, Clin Inf Dis 2010
AGES 14-24
Immune Reconstitution Inflammatory Syndrome (IRIS)
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
Case Definition:• A paradoxical deterioration in clinical status afterinitiating highly active antiretroviral therapy(HAART) attributable to the recovery of theimmune response to latent or subclinical infectiousor non-infectious processes Other Nomenclature• Immune reconstitution inflammatory syndrome(IRIS)• Immune restoration/restitution/recovery disease• Immune rebound illness• HAART attacks
54
Antiretroviral Therapy Improves Qualitative and Quantitative Immune Defects
Immune suppression/deficiency
HIV replication
Immune activation
Qualitative/functional immune
defects
Response to recall antigens
Quantitative immune defects
CD4 counts
Impaired pathogen-specific immunity
OI
HAART
HIV replication
Immune activation
Qualitative/functional immune
defects
Reversal of anergy
Lymphocyte proliferative capacity
Quantitative immune defects
Redistribution, death (HIV-, activation-induced),
production (peripheral expansion and thymic)
Improved pathogen-specific
immunity
Immune Reconstitution
Improved immune control
Migueles, Buenos Aires 2003
Clinical factors Associated with IRIS
Male SexLower CD4 cell count/ percentage at ART initiationHigher HIV RNA at ART initiationLower CD4:CD8 ration at ART initiation More rapid initial fall in HIV RNA on ARTAntiretroviral 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
Adapted from Deeks SG, et al. BMJ. 2009;338:a3172. Operskalski EA. Curr HIV/AIDS Rep. 2011;8:12-22.
Increased comorbidities
Low CD4+ T-cell nadir
Coinfections (hepatitis, CMV,
EBV, and HPV)
Cumulative cART
exposure
Aging
Lifestyle (smoking, etc)
Persistent inflammation
HIV Disease Contributes to Non-AIDS Events
www.aidsetc.org 57
ART-Associated Adverse Effects
Lactic acidosis/hepatic steatosis
Hepatotoxicity Insulin resistance,
diabetes mellitus Fat maldistribution Hyperlipidemia Cardiovascular and
cerebrovascular effects Increased bleeding in
hemophiliacs Osteonecrosis,
osteopenia, osteoporosis Rash
December 2009
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 2312a2Young, CID, 2011
Traditional Factors Are the Biggest Contributor to CHD in HIV Population
*Component of metabolic syndrome.†Precise contribution unclear.
CHD risk
Emerging factors:Lp(a), CRP, IMT, and endothelial function Diabetes
Lipids*
Family historyAbdominal obesity*
Hypertension*
Cigarette smoking
Hyperglycemia
Insulin resistance*
Inactivity, diet
HIV infection†
Age
Sex
HAART†
Immune activation
High levels of D-Dimer, CRP, IL-6
Smoking rates
Etc…..
HIV and Hepatitis CChallenges 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)
Objectives for today
Epidemiology-local
Screening and Diagnosis
Evaluation of the HIV+ patient
Treatment updates
Ophthalmology connections
CMV and IRIS
Retrospective studies: CMV associated IRIS was common 18%
Prospective studies: 63% in those with prior CMV disease
Immune recovery vitritisImmune recovery uveitis
Secondary to residual CMV antigens or proteins
Ocular OI :CMV retinitis and others
Other ocular OISyphiliticH zosterMolluscumToxoInfectiousHSVPneumocystisCryptococcal
CMVRelated to low CD4
< 50Genetics related to
IL-10 signaling may be related to risk
CMV Retinitis and Immune Recovery
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
Four Prevention Opportunities
YEARS
Treatment Of HIVReduced Infectivity
INFECTED
YEARS
UNEXPOSED
Behavioral,Structural
StructuralCircumcisio
nCondoms
STDs
Cohen et al, JCI, 2008Cohen IAS 2008
HOURS
VaccinesART PrEP
Microbicides
EXPOSED (precoital/coital)
72h
VaccinesART PEP
EXPOSED (postcoital)
Pre-exposure Prophylaxis
PREP studiesUsing antivirals to
prevent HIV in uninfected
HPTN 052
1763 discordant heterosexual couples
9 countries, 13 sites
Immediate ART350-550cells/uL
Deferred ART CD4 <250AZT+3TC+EFV
Endpoints: i) HIV Transmission to partners ii) OIs and clinical Events iii) ART toxicity
Randomization
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
HIV 2012
Focus on testing, linkage and retentionNew models for preventionTreatment: more once a day regimensManaging immune reconstitutionNon-HIV complications predominate