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
2
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
7
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
8
Disclosure Information:Content Faculty
● Renslow D. Sherer, MD
- Grants/Research Support
• Abbott Laboratories, Johnson & Johnson, Pfizer
- Consultant
• Abbott Laboratories, GlaxoSmithKline, Tibotec
- Speakers’ Bureau
• Abbott Laboratories
- Stock Shareholder
• None
- Other Financial or Material Support
• None
9
Disclosure Information:Medical Writer
● Peter Pinkowish
- Grants/Research Support
• None
- Consultant
• None
- Speakers’ Bureau
• None
- Stock Shareholder
• None
- Other Financial or Material Support
• None
10
Disclosure Information:Educator
● Drew A. Kovach, MD, MDiv.
- Grants/Research Support
• None
- Consultant
• Gilead
- Speakers’ Bureau
• Gilead, BMS, Merck, Monogram Biosciences
- Stock Shareholder
• None
- Other Financial or Material Support
• None
11
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
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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
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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
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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
● What to start with
● 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
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
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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
Lundgren J, et al. 16th CROI. Montreal, 2009. Abstract 44LB.
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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).
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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.
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Program Overview
● When to start treatment
● Treatment goals
● What to start with
● Assessing treatment failure and when to change
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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
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
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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.
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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
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
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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
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
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
● When to start treatment
● Treatment goals
● What to start with
● Assessing treatment failure and when to change
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.
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
Select 1 NNRTI or 1 PI Plus a Dual NRTI
40
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.
41
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
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
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.
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
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.
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)
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
Lundgren J, et al. 16th CROI. Montreal, 2009. Abstract 44LB.
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.
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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
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
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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
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
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
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
50
Program Overview
● When to start treatment
● Treatment goals
● What to start with
● Assessing treatment failure and when to change
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
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.
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
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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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
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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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
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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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
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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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
Emotional Issues of HIV
● 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)
Emotional Issues of HIV
● Financial Issues (past, present, future)
● Job Issues
- Feeling of self-worth, “pulling your own weight”
- Identity
- Common ground with others. “What do you do?”
Emotional Issues of HIV
● 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…
Emotional Issues of HIV
● The “Follow-up” Burden
- Frequent labs and other tests
- Frequent office visits
- Multiple sources of treatment and care
- Refilling prescriptions
Emotional Issues of HIV
● 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
Emotional Issues of HIV
● No end to the therapy in sight
● The uncertain future
- of successful therapy?
- of long term side effects from the therapy?
Emotional Issues of HIV
● 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.
Prescription for Spiritual Wellness
● 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.
Prescription for Spiritual Wellness
● 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.
Prescription for Spiritual Wellness
● 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.
Prescription for Spiritual Wellness
● 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