hiv treatment guidelines: reviewing essentials for optimal care sponsored for cme credit by rush...

HIV Treatment Guidelines:Reviewing Essentials for Optimal Care

Sponsored for CME credit by Rush University Medical Center

Supported by an independent educational grant from Gilead Sciences Medical Affairs

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Educator

The Very Rev. Father Drew A. Kovach, MD, MDiv.The Very Rev. Father Drew A. Kovach, MD, MDiv.Director of HIV ServicesDirector of HIV Services

Kaiser Permanente HawaiiKaiser Permanente Hawaii

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Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.The Association of Nurses in AIDS Care (ANAC) is an approved provider of continuing education in nursing by the Virginia Nurses Association Continuing Education Approval Committee, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation.

The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UPN #012-999-07-206-L02-P). This slide kit is accredited for one hour of continuing education credit. The University of Florida College of Pharmacy will mail Statements of Continuing Education Credit within 30 working days after receiving evidence of successful completion of the course. Successful completion means that you must attend the entire program and complete an evaluation form.

Supported by an independent educational grant from Gilead Sciences Medical Affairs.

This program is accredited for case managers through the Commission for Case Manager Certification (CCMC). To have clock hours added to your certification file, please submit the verification of completion form provided by your host directly to CCMC.

Accreditation and Designation

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Faculty:CME Course Director

Harold A. Kessler, MDHarold A. Kessler, MDProfessor of Medicine and Immunology/MicrobiologyProfessor of Medicine and Immunology/Microbiology

Associate Director, Section of Infectious DiseasesAssociate Director, Section of Infectious DiseasesRush University Medical CenterRush University Medical Center

Chicago, IllinoisChicago, Illinois

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Faculty:Content Development and Training

Renslow D. Sherer, MDRenslow D. Sherer, MDClinical AssociateClinical Associate

Section of Infectious DiseaseSection of Infectious DiseaseThe University of ChicagoThe University of Chicago

Director, Infectious Disease UnitDirector, Infectious Disease UnitProject HOPEProject HOPE

Chicago, IllinoisChicago, Illinois

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Disclosure Information

● It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME

● Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months

● If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content

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Disclosure Information:CME Course Director

● Harold A. Kessler, MD

- Grants/Research Support

• Boehringer Ingelheim, Gilead Sciences, Merck, Tibotec, Theratechnologies

- Consultant

• Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Tibotec, Virco

- Speakers’ Bureau

• Bristol-Myers Squibb, GlaxoSmithKline, Merck, Tibotec, Virco

- Stock Shareholder

• Abbott Laboratories, GlaxoSmithKline, Merck

- Other Financial or Material Support: none

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Disclosure Information:Content Faculty

● Renslow D. Sherer, MD


• Abbott Laboratories, Johnson & Johnson, Pfizer

- Consultant

• Abbott Laboratories, GlaxoSmithKline, Tibotec


• Abbott Laboratories

- Stock Shareholder

• None

- Other Financial or Material Support

• None

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Disclosure Information:Medical Writer

● Peter Pinkowish


• None

- Consultant

• None


• None

- Stock Shareholder

• None


• None

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Disclosure Information:Educator

● Drew A. Kovach, MD, MDiv.


• None

- Consultant

• Gilead


• Gilead, BMS, Merck, Monogram Biosciences

- Stock Shareholder

• None


• None

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Opinions and Off-Label Discussions

The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions

or recommendations of Gilead Sciences Medical Affairs,Rush University Medical Center, University of Florida College of

Pharmacy, Association of Nurses in AIDS Care, orCommission for Case Manager Certification

The faculty may have included discussion on unlabeled usesof a commercial product or an investigational use of a

product not yet approved for this purpose

Please consult the full prescribing information before usingany medication mentioned in this program

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Program Evaluation

Your feedback is essential for measuringthe success of this CME/CE program

Completion of the program evaluation, included within your materials, and submission to the onsite program Host is required

CME/CE credits for this program cannot be providedwithout a completed evaluation

A post-activity brief online survey will be e-mailed to you in4 to 8 weeks to assess how your participation in this

educational activity has affected your practice of medicine

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Slide Handouts

● The enclosed slide handouts are provided for reference purposes only

● The faculty presenter may have customized the slides through reordering or deleting and thus the handouts may not exactly match the presentation

14

Learning Objectives (CME, CE, CPE)

● At the completion of this educational activity, participants should be able to:

- Explain the current recommendations on when to initiate antiretroviral therapy defined by the Department of Health and Human Services (DHHS) guidelines

- Describe the efficacy and safety data from key clinical trials on preferred initial antiretroviral regimens recommended by the DHHS guidelines

- Explain what constitutes treatment failure and review treatment considerations when a change in therapy is warranted

15

A Brief History of Antiretroviral Therapy

● Early 80’s

- No antiretroviral therapy

● Late 80’s

- Zidovudine monotherapy

● Early 90’s

- Sequential NRTI monotherapy and dual-NRTI therapy

● Late 90’s

- The early HAART era

● Early 00’s

- Trials of treatment interruption

● Late 00’s

- Earlier initiation of therapy

- More potent, durable regimen combinations

- New classes of therapy

16

What’s New With the DHHS Guidelines

● What to start with

- Abacavir/lamivudine now a preferred NRTI (if negative for HLA-B*5701)

- Zidovudine/lamivudine changed to alternative NRTI

- Ritonavir-boosted saquinavir acceptable for initial therapy, but inferior to preferred or alternative PIs

- Options no longer recommended

• Nelfinavir

• Stavudine + lamivudine

• Abacavir/zidovudine/lamivudine

● Treatment interruption

- Long-term treatment interruption not recommended

Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

January 29, 2008 November 3, 2008● What to start with

- Abacavir/lamivudine now an alternate NRTI due to concerns about increased risk of myocardial infarction and virologic potency in patients with baseline HIV RNA >100,000 copiers/mL

- Ritonavir-boosted darunavir and once-daily lopinavir/r are now preferred PIs

- Use with caution

• Nevirapine + tenofovir DF + emtricitabine (or lamivudine)

- Options no longer recommended

• Unboosted atazanavir + didanosine + emtricitabine (or lamivudine)

● Resistance testing recommended for baseline HIV RNA 500-1000 copies/mL

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Program Overview

● When to start treatment

● Treatment goals


● Assessing treatment failure and when to change

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When to Start Treatment

Clinical CategoryCD4 Cell Count

(cells/mm3)Viral Load(copies/mL)

2008 DHHSGuidelines

2008 IAS-USAGuidelines

AIDS-defining illness or severe symptoms*

Any value Any value Treat

Asymptomatic <200 Any value Treat

200 to 350 Any value Treat

>350 >100,000 Consider treatment

>350 <100,000 Consider treatmentin some patients

Pregnant women Any value Any value Treat

HIV-associated nephropathy

Any value Any value Treat

HIV/HBV coinfection when HBV treatment is indicated

Any value Any value Treat Consider Treatment

Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008; Hammer SM, et al. JAMA. 2008;300:555-570.

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● Maintain higher CD4 count and prevent potentially irreversible damage to the immune system

● Decreased risk for HIV-associated complications

- Tuberculosis, non-Hodgkin’s lymphoma, Kaposi’s sarcoma, peripheral neuropathy, HPV-associated malignancies, and HIV-associated cognitive impairment

● Decreased risk of nonopportunistic conditions

- Cardiovascular disease, renal disease, liver disease, and non–AIDS-associated malignancies and infections

● Decreased risk of HIV transmission

Potential Benefits and Risksof Early Therapy

● Treatment-related side effects and toxicities

● Development of drug resistance due to incomplete viral suppression

- Loss of future treatment options

● Less time for patient adjustment to disease and treatment requirements

● Increased total time on medication

● Premature use of therapy before potentially better/safer future options are available

● Transmission of drug-resistant virus in patients who do not maintain full virologic suppression

Benefits Risks


20

NA-ACCORD:The Case for Earlier Initiation

● North American AIDS Cohort Collaboration on Research and Design

- 22 HIV research cohorts from United States and Canada

● Determine all-cause mortality in patients with CD4 between 351 to 500 cells/mm3

● Treatment arms

- Initiate treatment with CD4 between 351 to 500 cells/mm3

- Deferred treatment with CD4 between 351 to 500 cells/mm3

Baseline Characteristics

InitiateHAART(n=8358)

DeferHAART(n=5901)

Male (%) 83 75

Age (years) 40 38

HIV RNA (log10 copies/mL)

4.3 4.1

Median CD4 (cells/mm3) 421 432

HCV coinfection (%) 27 34

History of IDU (%) 16 21

Kitahata M, et al. 48th ICAAC. Washington, DC, 2008. Abstract H-869b.

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NA-ACCORD:Relative Hazard of All-Cause Mortality

Relative Hazard(95% CI) P Value

Deferral of HAART with CD4 between 351 to 500 cells/mm3

1.7(1.4, 2.1)

<0.001

Female sex 1.1(0.9, 1.5)

0.290

Older age (per 10 years) 1.6(1.5, 1.8)

<0.001

Baseline CD4 cell count per 100 cells/mm3

0.9(0.7, 1.0)

0.083

Kitahata M, et al. 48th ICAAC. Washington, DC, 2008. Abstract H-869b.

Rate of virologic suppression was similar between groups.HIV RNA was not an independent predictor of mortality.

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NA-ACCORD: Survival Benefit When Initiating HAART With CD4 >500 Cells/mm3

● Determine impact of initiating HAART at CD4 >500 cells/mm3 on predicted survival

● Treatment arms

- Initiate treatment with CD4 >500 cells/mm3

- Deferred treatment when CD4 decreases to <500 cells/mm3

Baseline Characteristics

InitiateHAART(n=2616)

DeferHAART(n=6539)

Male (%) 82 83

Age (years) 40 38

HIV RNA (log10 copies/mL) 3.6 3.7

Median CD4 (cells/mm3) 660 664

HCV coinfection (%) 25 35

History of IDU (%) 14 21

HAART regimen (%) Unboosted PI Boosted PI NNRTI Other

517

3210

419

4010

Kitahata M, et al. 16th CROI. Montreal, 2009. Abstract 71.

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NA-ACCORD: Improved Survival AssociatedWith Initiating HAART With CD4 >500 Cells/mm3

Relative Hazard(95% CI) P Value

Deferral of HAART with CD4 >500 cells/mm3

1.6(1.3, 1.9)

<0.001

Female sex 1.2(0.9, 1.6)

0.117

Older age (per 10 years) 1.6(1.5, 1.7)

<0.001

Baseline CD4 cell count per 100 cells/mm3

1.0(1.0, 1.1)

0.696

As expected, both IDU and HCV coinfection were independent predictors of mortaility.HIV RNA was not an independent predictor of mortality.

Kitahata M, et al. 16th CROI. Montreal, 2009. Abstract 71.

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SMART Study: Benefits of Continuous Treatment of HIV Disease

● Open-label study

- CD4-guided intermittent therapy

• Stop: CD4 >350 cells/mm3

• Resume: CD4 <250 cells/mm3

- Continuous therapy

● Prematurely stopped January 2006

- 5.7% reduction in absolute risk of opportunistic disease and serious non-AIDS events (CVD, hepatic and renal diseases, non-AIDS cancers and death) with continuous versus intermittent therapy

SMART Study Group. J Infect Dis. 2008;197:1145-1155.

0

2

4

6

8

10

12

Rate of OD/Death

Overall <250

Latest CD4 (cells/mm3)250-349 350-499 >500

1.1Rat

e (p

er 1

00 p

erso

n-y

ears

)

Intermittent therapy (n=2720)Continuous therapy (n=2752)

3.4

1.3

9.7 9.8

2.9

4.1

0.8

2.5 2.2

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SMART Study: Retrospective ExploratoryAnalysis of Cardiovascular Disease Events

Phillips A, et al. 14th CROI. Los Angeles, 2007. Abstract 41.

CD4-GuidedIntermittent

Therapy(n=2742)

Continuous Therapy(n=2730)

RelativeHazard

(95% CI)

Number of events

Death from CVD Nonfatal clinical MI Nonfatal silent MI Nonfatal stroke CAD requiring surgery or invasive procedure

712118

22

41253

14

Clinical MI, silent MI, stroke, death from CVD, CAD requiring invasive procedure

48 31 1.57*(1.00-2.46)

Plus peripheral vascular disease, CHF, CAD requiring therapy

76 52 1.49†(1.04-2.11)

Plus death from unknown causes 84 54 1.58‡(1.12-2.22)

*P=0.05; †P=0.03; ‡P=0.009.

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D:A:D Study: Risk of MI Per Exposureto Individual NRTIs, PIs, and NNRTIs

NRTIs(Recent and Cumulative Exposure)

Adjusted for baseline demographics and cardiovascular risk factors and for latest measures of lipids, metabolic parameters, CD4 count, and HIV RNA level. P-Y FU: patient-years follow-up.Recent use: current or within the last 6 months.

Lundgren J, et al. 16th CROI. Montreal, 2009. Abstract 44LB.

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Rel

ativ

e R

isk

(95%

CI)

ZDV

Recent exposure (yes/no)Cumulative exposure(per year)

Number ofP-Y FU:

No. of MIs:

ddI d4T 3TC ABC TDF

138,109523

74,407331

95,320405

152,009554

53,300221

39,157139

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Rel

ativ

e R

isk

(95%

CI)

IDVNumber of

P-Y FU:No. of MIs:

NFV LPV/r SQV NVP EFV

68,469298

56,529197

37,136150

44,657221

61,655228

58,946221

PIs and NNRTIs(Cumulative Exposure)

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D:A:D Study:Conclusions

● Abacavir, didanosine, indinavir, and lopinavir/ritonavir were associated with an increased risk of MI

- For indinavir and lopinavir/r

• Risk increased with cumulative exposure

● No significant associations between exposure to other NRTIs including tenofovir DF, NRTIs, or the other PIs and the risk of MI

● Concomitant use of ritonavir did not appear to modify the effects of saquinavir or indinavir


28

Liver Disease is the Second Leading Cause of Death in HIV-Infected Patients (1999-2004)

● D:A:D study (n=23,441)

- Median follow-up: 3.5 years

● Baseline characteristics

- Nadir CD4: 200 cells/µL

- Previous AIDS: 26.5%

- HCV positive: 22.5%

- Active HBV infection: 6.8%

• Inactive HBV infection: 21.4%

- Receiving combination antiretroviral therapy: 88.7%

● Mortality

- Total: 5.3%

- Incidence: 1.62 per 100 person-years

- Median age: 44 years

Weber R, et al. Arch Intern Med. 2006;166:1632-1641.

0

10

20

30

40

AIDS Liver-RelatedDiseases

CVD

Cause of Death (n=1246)

Pat

ien

ts (

%)

31.1%

14.5%

11.0%

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Independent Predictorsof Liver-Related Death

Latest CD4 Cell Count (cells/µL)<50

50-99

100-199

200-349

350-499

>500

HIV Acquisition via IDU

Hepatitis C StatusNegative

Positive

Hepatitis B StatusNegative

Positive

Weber R, et al. Arch Intern Med. 2006;166:1632-1641.

0.2 1.0 10 100

Relative Rate of Death

16.06

11.54

7.14

3.95

1.67

2.01

6.66

3.73

Multivariate analysis.Not shown: Age per 5 years (1.32).

30

HOPS Cohort: Early Initiation of HAART Decreases Risk of Toxicities

● Prospective, dynamic cohort (>8000 patients)

- 8-year follow-up

● Incidence of nucleoside analogue-associated toxicities was significantly reduced when HAART was initiated at progressively higher CD4 cell counts

● These data suggest that a delay in initiating HAART increases the risk of toxicities

Lichtenstein KA, et al. JAIDS. 2008;47:27-35.

Peripheral Neuropathy

(n=1969)Anemia(n=1398)

RenalInsufficiency

(n=1152)

Number of incident cases

294 70 79

Hazard Ratio (95% CI)

Pre-HAART CD4cell count (cells/mm3)

0-199* 1.43†(1.05-1.93)

1.34(0.77-2.32)

2.23‡(1.22-4.06)

>350* 0.88(0.64-1.21)

0.63(0.33-1.21)

1.01(0.52-1.94)

Multivariate analysis.*Referent to CD4 cell count 200 to 349 cells/mm3.†P=0.022.‡P=0.009.

31

Program Overview


● Treatment goals



32

Treatment Goals

● Primary goals

- Reduce HIV-related morbidity and prolong survival

- Improve quality of life

- Restore and preserve immunologic function

- Maximally and durably suppress viral load

- Prevent vertical HIV transmission


33

Maximal Viral Suppressionin Initial Therapy

● Use two, preferably three, active drugs from multiple drug classes

● HIV RNA <50 copies/mL usually occurs within the first 12 to 24 weeks of therapy

● Predictors of virologic success

- High potency of antiretroviral regimen

- Excellent adherence to treatment regimen

- Low baseline HIV RNA level

- Higher baseline CD4 cell count

- Rapid reduction in HIV RNA level in response to treatment

• >1 log10 copies/mL in 1 to 4 monthsAvailable at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

34

Strategies to Achieve Treatment Goals

● Selection of initial combination regimen tailored to the patient

- Efficacy, pill burden, potential side effects

● Pretreatment drug resistance testing

● Improve potential for adherence

- Simplify medication regimens

- Address patient factors (eg, active substance abuse, depression)

- Discuss health system issues (eg, interruptions in medication access

- Inadequate treatment education and support


35

Prevalence ofTransmitted Drug Resistance

0

5

10

15

20

Any Class NRTI NNRTI PI

Res

ista

nce

(%

)

Europe 2002/2003 (n=1083)

USA 2005 (n=240)

USA adolescents 2005 (n=55)

9%

17%18%

11%

15%

5%

7%

4%5%

4%

2% 3%

Wensing AM, et al. J Infect Dis. 2005;192:958-966.Wensing AM, et al. 16th IAC, 2006. Abstract TuAB0101.Ross L, et al. 46th ICAAC, 2006. Abstract H-993.Viani R, et al. J Infect Dis. 2006;194:1505-1509.

36

Drug Resistance Testing

● Recommended for all HIV-infected individuals entering care, regardless of whether therapy will be initiated

- If therapy is deferred, consider repeating testing at the time of antiretroviral therapy initiation

- Genotypic assay is preferred for treatment-naïve patients

● Recommend genotypic testing

- All pregnant women prior to initiation of therapy

- Those entering pregnancy with detectable HIV RNA levels while on therapy

● Recommended when HIV RNA 500 to 1000 copies/mL

- Amplification of the virus may not be reliable


37

HLA-B*5701 Screening

● Recommended before starting abacavir-containing regimen

- Reduce the risk of hypersensitivity reaction

● HLA-B*5701 positive

- Avoid abacavir

- Record as abacavir allergy in patient’s medical record

● If HLA-B*5701 screening is not readily available

- Reasonable to initiate abacavir with appropriate clinical counseling and monitoring for any signs of hypersensitivity reaction

Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.Hammer SM, et al. JAMA. 2008;300:555-570.

38

Program Overview


● Treatment goals



39

DHHS Guidelines Recommendations for Treatment-Naïve Patients

NNRTI PI Dual NRTI

Preferred Efavirenz1 Atazanavir + ritonavir qd2 Emtricitabine/tenofovir DF

Darunavir + ritonavir qd

Fosamprenavir + ritonavir bid

Lopinavir/ritonavir qd or bid3

Alternative Nevirapine4 Atazanavir5 Abacavir/lamivudine6

Fosamprenavir Zidovudine/lamivudine

Fosamprenavir + ritonavir qd Didanosine + emtricitabine

Saquinavir + ritonavir Didanosine + lamivudine1Do not use during 1st trimester of pregnancy or in those with high pregnancy potential. Use with caution in patients with unstable psychiatric disease.2Do not use in patients who require high-dose (>20 mg omeprazole equivalent/day) proton-pump inhibitors (PPIs). Use with caution in patients on PIIs on any dose, H2 blockers, or antacids.3Do not use lopinavir/r once-daily in pregnant women. 4Do not use in patients with severe hepatic impairment (Child-Pugh score B or C) and in women with CD4 cell count >250 cells/mm3 or in men with CD4 cell count >400 cells/mm3.5Do not use in combination with tenofovir DF or didanosine/lamivudine.6Do not use in patients who test positive for HLA-B*5701. Use with caution in patients with baseline HIV RNA >100K copies/mL and in patients at high risk for cardiovascular disease.


Select 1 NNRTI or 1 PI Plus a Dual NRTI

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IAS-USA Guidelines Recommendations for Treatment-Naïve Patients

NNRTI PI Dual NRTI

Preferred Efavirenz Lopinavir + ritonavir Emtricitabine/tenofovir DF1

Atazanavir + ritonavir Abacavir/lamivudine2

(if test negative for HLA-B*5701)

Fosamprenavir + ritonavir

Darunavir + ritonavir

Saquinavir + ritonavir

Alternative Nevirapine Zidovudine/lamivudine

Didanosine + emtricitabine

Didanosine + lamivudine

Select 1 NNRTI or 1 PI Plus a Dual NRTI

1A baseline urinalysis and estimation of creatinine clearance or glomerular filtration rate for assessment of renal function are recommended. All patients receiving tenofovir should be observed for development of renal dysfunction. Lamivudine can be substituted for emtricitabine.2Emtricitabine can be substituted for lamivudine.

Hammer SM, et al. JAMA. 2008;300:555-570.

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Factors to ConsiderWhen Selecting an Initial Regimen

● Comorbidity or conditions

● Adherence potential

● Dosing convenience and frequency, food and fluid considerations

● Potential adverse events

● Potential drug interactions

● Pregnancy potential

● Results of genotypic drug testing

● Gender and pretreatment CD4 cell count if considering nevirapine


42

DHHS Guidelines Recommendations:Dual NRTI Components

● Preferred

- Emtricitabine/tenofovir DF*

● Alternative

- Abacavir/lamivudine* (if negative for HLA-B*5701)

- Zidovudine/lamivudine*

- Didanosine + lamivudine or emtricitabine

*Emtricitabine may be used in place of lamivudine or visa versa.


43

D:A:D Study: Risk of MI Per Exposureto Individual NRTIs, PIs, and NNRTIs

NRTIs(Recent and Cumulative Exposure)

Adjusted for baseline demographics and cardiovascular risk factors and for latest measures of lipids, metabolic parameters, CD4 count, and HIV RNA level. P-Y FU: patient-years follow-up.Recent use: current or within the last 6 months.


0.6

0.8

1

1.2

1.4

1.6

1.8

2

Rel

ativ

e R

isk

(95%

CI)

ZDV

Recent exposure (yes/no)Cumulative exposure(per year)

Number ofP-Y FU:

No. of MIs:

ddI d4T 3TC ABC TDF

138,109523

74,407331

95,320405

152,009554

53,300221

39,157139

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Rel

ativ

e R

isk

(95%

CI)

IDVNumber of

P-Y FU:No. of MIs:

NFV LPV/r SQV NVP EFV

68,469298

56,529197

37,136150

44,657221

61,655228

58,946221

PIs and NNRTIs(Cumulative Exposure)

44

D:A:D Study:Conclusions

● Abacavir, didanosine, indinavir, and lopinavir/ritonavir were associated with an increased risk of MI

- For indinavir and lopinavir/r

• Risk increased with cumulative exposure

● No significant associations between exposure to other NRTIs including tenofovir DF, NRTIs, or the other PIs and the risk of MI

● Concomitant use of ritonavir did not appear to modify the effects of saquinavir or indinavir


45

Abacavir and CVD Risk:Summary of Key Studies/Analyses

StudyDesign

EventAssessment

Effect of Abacavir Found

on CVD Risk

D:A:D (n=33,347) Prospective,observational cohort

Prospective,predefined

Yes

French Hospital Database (n=289 cases; 884 controls)

Case control in observational cohort

Prospective (validated

retrospectively)

Yes(1st year of exposure)

SMART (n=2752) Randomized control trial, observational analysis

Prospective, predefined

Yes

STEAL (n=357) Randomized control trial Prospective Yes

GSK analysis (n=14,174) Randomized controltrials (n=54)

Retrospective, database search

No

ACTG 5001/ ALLRT (n=3205)

Randomized controltrials (n=5)

Retrospective No

Reiss P. 16th CROI. Montreal, 2009. Abstract 152.

46

DHHS Guidelines Recommendations:NNRTI or PI Components

● Preferred

- Efavirenz*

- Atazanavir + ritonavir

- Darunavir + ritonavir

- Fosamprenavir + ritonavir bid

- Lopinavir/ritonavir qd or bid

● Alternative- Nevirapine (females and males with CD4 <250 and <400 cells/mm3,

respectively)

- Atazanavir (add ritonavir 100 mg/day if used with tenofovir DF)

- Fosamprenavir, fosamprenavir + ritonavir qd

- Saquinavir + ritonavir *Except during 1st trimester of pregnancy or in women with high pregnancy potential.Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

47

Antiretroviral Agents Not Recommended as Initial Therapy

Reasons for Not Recommending as Initial Therapy

Darunavir unboosted Usage without ritonavir has not been studied

Delavirdine Inferior virologic efficacy, tid dosing

Didanosine + tenofovir DF High rate of early virologic failureRapid selection of resistant mutationsPotential for immunologic non-response/CD4 decline

Enfuvirtide No clinical trial data in treatment-naïve patientsRequires bid subcutaneous dosing

Etravirine Insufficient data in treatment-naïve patients

Indinavir + ritonavir tid dosing with meal restriction, fluid requirement, high incidence of nephrolithiasis (when used with ritonavir)

Maraviroc Insufficient data in treatment-naïve patients

Nelfinavir Inferior virologic efficacy

Raltegravir Insufficient data in treatment-naïve patients

Ritonavir as sole PI High pill burden, gastrointestinal intolerance

Saquinavir High pill burden, inferior virologic efficacy

Stavudine + lamivudine Significant toxicities

Tipranavir + ritonavir Lack of data in treatment-naïve patients

Zidovudine/lamivudine/abacavir Inferior virologic efficacy


48

Antiretroviral Regimens That Should Not Be Offered At Any Time

Rationale Exception

Monotherapy with NRTI or NNRTI

Rapid development of resistanceInferior efficacy versus regimens with >3 antiretrovirals

Prevention of perinatal transmission in pregnant women with HIV RNA <1000 copies/mL prior to therapy, although combination is generally preferred

Dual-NRTI regimens

Rapid development of resistanceInferior efficacy versus regimens with >3 antiretrovirals

Triple-NRTI regimens

High rate of early virologic non- response with ABC/TDF/3TC or TDF/ddI/3TCOther triple-NRTI regimens have not been evaluated

Abacavir/zidovudine/lamivudinePossibly tenofovir DF + zidovudine/ lamivudine


49

Antiretroviral Components That Should Not Be Offered At Any Time

Rationale Exception

Atazanavir + indinavir

Potential additive hyperbilirubinemia No exception

Didanosine + stavudine

High incidence of toxicitiesSerious, even fatal cases of lactic acidosis with hepatic steatosis + pancreatitis in pregnant women

When no other antiretroviral options are available and potential benefits outweigh the risks

2 NNRTI combinations

High incidence of adverse events, drug interaction (reduced efavirenz levels)

No exception

Emtricitabine + lamivudine

Similar resistance profileNo potential benefit

No exception

Nelfinavir in pregnant women

Ethyl methanesulfonate, known animal carcinogen, mutagen, and teratogen

No exception

Stavudine + zidovudine

Antagonistic effect on HIV No exception


50

Program Overview


● Treatment goals



51

Antiretroviral Treatment Failure

● Often associated with virologic failure, immunologic failure, and/or clinical progression

● Factors associated with an increased risk of treatment failure

- Baseline patient factors

- Incomplete medication adherence and missed clinic appointments

- Drug adverse events and toxicity

- Suboptimal pharmacokinetics

- Suboptimal potency


52

Switching Treatments on One or More Occasions Becomes Necessary

0

5

10

15

20

25

30

35

40

Pat

ien

ts (

%)

Mocroft A, et al. AIDS Res Hum Retroviruses. 2005;21:527-536.

Failure Toxicities Choice Other Unknown

7.8%

17.9%

30.2%30.4%

13.7%

Reason for Changing First HAART (1999-2003)

n=1198 HIV/HCV-coinfected patients; overall rate for stopping: 31.1%.

53

Assessing Causes ofTreatment Failure

● Review medical history

- HIV RNA and CD4 cell count change over time

- Occurrence of HIV-related clinical events

- Treatment history

- Results of prior resistance testing

- Adherence issues

- Tolerability of medications

- Concomitant medications and comorbidities

● Assess for signs of clinical progression


54

Assessment of Treatment Failure

● Initial assessment

- Adherence

- Medication intolerance

- Pharmacokinetic issues

- Suspected drug resistance

● Further evaluation

- Incomplete virologic response

• HIV RNA >400 copies/mL after 24 weeks

• HIV RNA >50 copies/mL after 48 weeks

- Virologic rebound

• Repeated detection of HIV RNA above the assay limit of detection


55

Assessment of Virologic Failure

● No consensus on the optimal time to change therapy for virologic failure

- Aggressive approach

• Change for any repeated, detectable viremia after suppression to HIV RNA <50 copies/mL

- Other approaches

• Change after detectable viremia >1000 copies/mL

- Ongoing replication promotes selection of drug resistance and may limit future options

● Assess degree of drug resistance and consider prior treatment history and prior resistance results


56

General Approaches to the Management of Virologic Failure

● Goal is to re-establish maximal virologic suppression to a HIV RNA level of <50 copies/mL

● Identify fully active agents

- Add at least two, and preferably three, fully active agents on the basis of drug history, resistance testing, or new mechanistic class

- Drug potency and viral susceptibility are more important than the number of drugs prescribed

- Adding a single, fully active antiretroviral drug is not recommended

• Risk rapid development of resistance

● Discontinuing or briefly interrupting therapy is not recommended

- Increases risk of clinical progression


57

Program Evaluation

Your feedback is essential for measuringthe success of this CME/CE program

Completion of the program evaluation, included within your materials, and submission to the onsite program Host is required

CME/CE credits for this program cannot be providedwithout a completed evaluation

A post-activity brief online survey will be e-mailed to you in4 to 8 weeks to assess how your participation in this

educational activity has affected your practice of medicine

58

Outcomes Measurement Reminder

● CME providers are required to assess “changes in learners competence, performance or patient outcomes achieved as a result of their participation in a CME sponsored educational activity”

● As a result of this requirement you will receive via e-mail a short 1-page survey 1 to 3 months after completing this course

- We consider the survey to be an additional component of your overall participation in this educational activity and would urge you to reflect on what you learned in the activity and then complete this survey

● Please be certain that you have correctly written your e-mail address on the CME evaluation form that you complete at the end of today’s activity

Comprehensive Care of HIV Patients

● My Approach

● The Art of Medicine and application of Science to the individual when treating HIV patients

CONCEPTS OF WHOLENESS & WELLNESS – MY BIAS

● Whole people

- Body

- Mind

- Spirit

● Whole lives

● Levels of Healing

● Life being livable not just being alive

● A good life

HIV/AIDS

● The most comprehensive chronic disease

● Impacts all aspects of a person’s life

- Social

- Economic

- Physical

- Emotional

- Spiritual

With an uncertain future…

Holistic Approach

● Mind, Body, Spirit – The “trinity” of man

● 3 Spheres

● Dis-ease, distress or pain in any one affects the other two

● Managing whole people to make people whole

Treat the Whole Person

● Not just treating numbers or lab values

● Not just treating with pills

● Not just treating only the symptoms

● Not just treating stereotypes

● Not just treating to make ourselves feel better

● Not just treating the mind and the body

Quality & Quantity of Life

Access the Patient and Ourselves

● Meeting people “on the road” where they are, not where we think they should be

● Admit our own bias and prejudice and frustration

● Admit that how we feel will affect how we treat

EMOTIONAL ISSUES OF HIV

Emotional Issues of HIV

● “Heart ache” vs. Chest Pain

● “Who is on your back” vs. Back Pain

● “Worn out” vs. Fatigue

● Relationship

- With yourself

- With others

- With God


● Partner Issues (past, present, future)

- One partner positive, the other negative

- Both positive

- No partner

● Parents and Family Issues (past, present, future)

● Friends and co-worker Issues (past, present, future)


● Financial Issues (past, present, future)

● Job Issues

- Feeling of self-worth, “pulling your own weight”

- Identity

- Common ground with others. “What do you do?”


● Living with a chronic potentially fatal disease, in otherwise young healthy people, with an uncertain future

● “Pill Burden”

- Number (PI vs. NNRTI regimens)

- Timing (complex regimens)

- Constant reminder

Looking Good, Feeling BadThe disconnect…


● The “Follow-up” Burden

- Frequent labs and other tests

- Frequent office visits

- Multiple sources of treatment and care

- Refilling prescriptions


● The Burden of not feeling “normal”

- Effects of the disease

- Effects of the treatments

- We ask our patients to “get used to” not feeling well and to tolerate “side effects”

● The Burden of not looking “normal”

- Lipodystrophy and wasting syndrome


● No end to the therapy in sight

● The uncertain future

- of successful therapy?

- of long term side effects from the therapy?


● HIV vs. Cancer Model

- Cyclic vs. Continuous chemotherapy

- How long will the remission last?

- What do I do if and when “it comes back?”

- Do I even want to treat it?

- Will you help me with the pain?

The Result of Emotional Issues of HIV

● ANXIETY and DEPRESSION

- “The Twins” Never separate

- All individual with HIV will become clinically depressed; early, middle or late but it will come!

- Patient & doctor need to recognize it

- Tools: Anxiety and depression inventories (Beck, Hamilton etc.)

The Treatment of the Emotional Issues of HIV

● Treat or Refer; But Do Something!

● Anti-anxiety agents

● Antidepressants

● Psychotherapy

- Individual

- Group

The Treatment of the Emotional Issues of HIV

● Behavioral Therapies

- Hypnosis

- Biofeedback

- Jacobson Progressive Relaxation

- Cognitive Behavioral Management

SPIRITUAL ISSUES OF HIV

What Is Spirituality?

It is NOT Religion!

Religion

● Rituals

● Rules

● Collective

● Control

● Mind

● Belief

● Vehicle to things spiritual

● Think “from the outside in”

Spirituality

● Experience

● Imagination

● Freedom

● Soul

● Personal

● Think “from the inside out”

WHAT THEN IS IT?

● It is core

● It is essence

● It is inspiration

● IT IS LIFE

Soul as in Sol.

Sol as in Sun.

Sun as in Light.

Spiritual Sources

● The patient

● The provider

● The partner/spouse

● The family

● The community of faith

● The cosmos

● The God or Creator

Spiritual Issues of HIV

● Purpose of life

● Beyond ourselves

● “Hole” in the heart

● Guilt and Judgment

● Suffering

● Relationships with people and with God

Spiritual Issues of HIV

● Guilt about lifestyle choices

● “Judgmental” churches

● No support for gay, lesbian, bisexual, & transgender people

● No support of same sex relationships

● Guilt and judgment about having HIV

The Result of Spiritual Issues of HIV

● Feeling abandoned by God

● Feeling a sense of condemnation

● Feeling alienated from “religious people”

● Feeling helpless and hopeless

● Feeling worthless

● Feeling sad

● Feeling bad

Treatment of Spiritual Issues of HIV

● Treat or Refer; But Do Something!

● Acknowledge that these issues are real

● Pastoral care to find Spiritual peace

● Tolerant, inclusive congregations

● The Sacraments (Religious “Actions”)

- The Mass, Divine Liturgy, Communion

- Confession: Forgiveness & Absolution

- Anointing with Prayers for Healing

● Prayer and Meditation

Treatment of Spiritual Issues of HIV

● Inspirational books and articles

● Inspirational writings by people living with HIV

● Websites

● Spiritual support groups

● My Prescription for Spiritual Wellness

Prescription for Spiritual Wellness

● Meaning in life involves finding the greatness hidden inside of us.

● Purpose in life is determined by how we use this greatness.

● Faith is to believe that greatness can be embedded within the frailty of our own fallibility.


● Serenity involves using our goodness to pursue meaning until moments of greatness reveal themselves to us.

● Courage is to recognize moments of greatness when they occur, despite personal cost.

● Dissonance lingers in the state of unvisited expectations of greatness.


● Grace is to understand that our greatness does not belong to us, simply because it is inside of us.

● Perspective is gained with understanding that greatness does not extinguish or diminish with passing of time or opportunity.


● Wisdom is approached when we understand that we do not have the latitude to choose which greatness is ours or how large our greatness is.

● Simplicity involves not trying to make someone else’s greatness our own.

● Power in life is revealed when we recognize greatness hidden inside of every being.


● Joy resides in appreciation of the greatness of others.

● Love is discovered when we help another find their greatness and to accept their help in finding ours.

● Peace in life occurs when we recognize that regardless of whether we discover our greatness we are still loved by our Creator/God.

All Issues Of HIV Has To Be Managed

● Spiritual

● Emotional

● Physical

- Making people whole requires a holistic approach

- Wellness

- Wholeness

- Holiness

In their words…

David Taylor

Tom Connor

Linda Jordan

Joel Arce, Luis Arce, Angel Glover, Steve Koceja and

Noel Arce

Daniel Waters

Diana Hindrew

All God’s Blessings

Thank you

hiv treatment guidelines: reviewing essentials for optimal care sponsored for cme credit by rush...

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