Hiv eye update 2013

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


Epidemiology-local



Treatment updates


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


Epidemiology-local



Treatment updates


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


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


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


Potential Benefits of Early Therapy (3)

Prevention of sexual and bloodborne transmission of HIV

Prevention of mother-to-child transmission of HIV


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)


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.


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)


Epidemiology-local



Treatment updates


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

Hiv eye update 2013

Education

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