Yumi Lee, PharmD, BCPS NYSCHP- Royal Counties September 14,
2011
Slide 2
Identify the CD4 cell parameters where initiation of therapy is
appropriate Recognize the advantages and disadvantages of early
versus deferred therapy Identify the preferred regimens as per
treatment guidelines Understand the benefits and detriments of
recommended treatment regimens
Slide 3
1981- Beginning of HIV/AIDS epidemic Outbreak of rare cancer
and pneumonia in homosexuals (Kaposis sarcoma and PCP) Blood sample
of African man who died of mysterious illness in 1959 later
confirmed to be HIV 1984- Patient zero Canadian flight attendant
died of AIDS 8,000 confirmed cases in US and 3,700 deaths 1987-
Treatment arrives FDA approved Zidovudine (Retrovir ) 100,000
150,000 cases of HIV and AIDS
Slide 4
1992- Combination therapy arrives Addition of Zalcitabine
(Hivid ) marks beginning of combination therapy 1996- Protease
inhibitors arrive Triple therapy introduced 2000s- More
antiretrovirals released 4.9 million people newly infected in 2005
40.3 million people worldwide living with HIV/AIDS 2006- Origins of
HIV discovered Simian form of HIV (SIV) entered humans by monkey
bites or ingesting monkey meat and brains
Goals of Antiretroviral Therapy (ART) Durable suppression of
HIV viral load Restoration of immune function Prevention of HIV
transmission Prevention of drug resistance Improvement in quality
of life
Slide 8
What is the recommended CD4 threshold?
Slide 9
CD4 (cells/mm 3 )Recommendation 500Panel divided Clinical
Conditions Favoring Initiation of Therapy Regardless of CD4 History
of AIDS-defining illness Certain acute opportunistic infections
Pregnancy HIV-associated nephropathy Hepatitis B co-infection when
HBV treatment is indicated CD4 count decline >100 cells/mm 3 per
year HIV RNA >100,000 copies/mL DHHS: US Department of Health
and Human Services * Panel divided: 55% strongly recommend and 45%
moderately recommend 50% favor initiating therapy at this stage;
50% view initiating therapy at this stage at optional
http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
Slide 10
Immediate arm: ART immediately after randomization Deferred
arm: CD4 250 and 350 as on and off switch Primary endpoints
Opportunistic infection (OI) or death from any cause Fatal or
nonfatal OI Serious non-AIDS events Fatal and non-fatal OI plus
serious non-AIDS events Emery S, et al. J Infect Dis.
2008;197:1133-1144. HIV-infected with CD4 >350 (n=5472)
Immediate Continuous Arm (n=2752; 249 not on ART) Deferred
Intermittent Arm (n=2270; 228 not on ART)
Slide 11
Subgroup analysis investigated optimal threshold for initiating
ART (n= 477) Immediate group experienced substantially fewer events
compared with deferred group Event n, (Rate per 100 person yrs)
Deferred Arm (n=228) Immediate Arm (n=249)HR95% CI P- value OI/
Death 15 (4.8)5 (1.3)3.51.3-9.6.02 OI only 11 (3.5)4
(1.1)3.31.0-10.3.04 Serious non-AIDS events 12 (3.9)2
(0.5)7.01.6-31.4.01 Composite* 21 (7.0)6 (1.6)4.21.7-10.4.002 Emery
S, et al. J Infect Dis. 2008;197:1133-1144. *Fatal and nonfatal OI
plus serious non-AIDS events. (OI= opportunistic infection)
Slide 12
Established in 2006, examining 22 HIV research cohorts
(n=17,517) Two analyses comparing Initiation of ART in CD4 >350
500 vs. CD4 350 (n=8,362) Initiation of ART in CD4 >500 vs. CD4
500 (n=9,155) Adjusted for lead-time bias allowed ART to be
initiated within 1.5 yrs after baseline CD4 Primary outcome: All
cause mortality *Cohort study not randomized trial* Kitahata MM, et
al. N Engl J Med. 2009;360:1815-1826.
Slide 13
www.clinicaloptions.com/HIV
Slide 14
Analysis of 15 cohorts from US and Europe (n=24,444) The Lancet
2009;373:1352-1363. www.clinicaloptions.com/HIV
www.clinicaloptions.com/HIV
Slide 15
Arguments in FavorArguments Against Cohort data showing
survival benefit Available data do not definitively establish
benefit of ART in all patients with CD4 >500 Untreated HIV
infection may be associated with higher risk of non-AIDS conditions
Benefits of earlier initiation may be outweighed by: Risks of short
or long term drug-related adverse events Risk of non-adherence in
asymptomatic patients Potential for development of drug resistance
Availability of newer regimens with improved efficacy, convenience,
and tolerability Growing evidence that treatment reduces HIV
transmission DHHS. Available at:
http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
Slide 16
Randomize trial underway Follow up period for 4 5 years Study
endpoints: Fatal AIDS or non-fatal serious AIDS events
(cardiovascular, liver, renal, and cancer), and all-cause mortality
Treatment-naive patients with CD4+ cell count > 500 cells/mm (N
= 4000) Immediate Treatment Deferred Treatment to CD4 350 cells/mm
3 ClinicalTrials.gov. NCT00867048.
Preferred regimens: those with optimal and durable efficacy,
favorable tolerability and toxicity profile, and ease of use NNRTI
basedEfavirenz * + Tenofovir/Emtricitabine Boosted PI
basedAtazanavir/R + Tenofovir/Emtricitabine Darunavir/R +
Tenofovir/Emtricitabine INSTI basedRaltegravir +
Tenofovir/Emtricitabine *Should not be used in first trimester of
pregnancy or women in child-bearing age Should not be used in
patients who require >20mg omeprazole equivalent per day US
Department of Health and Human Services guidelines. 2009.
Slide 21
WHY?WHY NOT? Long track record Unbeaten clinical trial
Convenience Forgiving missed doses CNS adverse events Teratogenic
in 1 st trimester Low genetic barrier to resistance Lower CD4
increase than other drug classes
Slide 22
WHY?WHY NOT? Long track record Greater CD4 increase vs.
Efavirenz Boosted Atazanavir as good as Efavirenz with less
resistance risk at failure Preferred in pregnancy GI adverse
effects Greater pill burden Lipid elevation Lipohypertrophy
Increased tenofovir renal toxicity?
Slide 23
WHY?WHY NOT? Very well tolerated As effective as EFV with
better tolerability No lipid effects Not known to be teratogenic
Rapid virologic suppression Greater CD4 increase vs EFV No
long-term data Twice daily dosing Resistance risk at virologic
failure similar to EFV
Slide 24
Alternative regimens: those that are effective and tolerable
but have potential disadvantages compared with preferred regimens;
an alternative regimen may be the preferred regimen for some
patients NNRTI basedEfavirenz + (Abacavir or Zidovudine) +
Lamivudine Nevirapine * + Zidovudine/Lamivudine Boosted PI
basedAtazanavir/R + (Abacavir or Zidovudine) + Lamivudine
Fosamprenavir/R + [(Abacavir or Zidovudine) + Lamivudine] or
Tenofovir/Emtricitabine Lopinavir/R ~ + [(Abacavir or Zidovudine) +
Lamivudine] or Tenofovir/Emtricitabine Saquinavir/R +
Tenofovir/Emtricitabine US Department of Health and Human Services
guidelines. 2009. *Should not be used in females with CD4 >250
and males with CD4 >400 Associated with increased MI risk ~
LPV/r + ZDV/3TC recommended in pregnancy
Slide 25
Acceptable regimens: those that may be selected for some
patients but are less satisfactory than preferred of alternative
regimens NNRTI basedEfavirenz + Didanosine + (Lamivudine or
Emtricitabine) Unboosted PI basedAtazanavir + (Abacavir or
Zidovudine) + Lamivudine US Department of Health and Human Services
guidelines. 2009. Regimens that may be acceptable but more data are
needed CCR5 antagonist basedMaraviroc * + Zidovudine + Lamivudine
INSTI basedRaltegravir + (Abacavir + Zidovudine) + Lamivudine
Boosted PI basedDarunavir/R + (Abacavir + Zidovudine) + Lamivudine
Saquinavir/R + (Abacavir + Zidovudine) + Lamivudine *CCR5 tropism
assay necessary
Slide 26
What standard tests should be preformed?
Slide 27
Tests administered to all patients Tests administered to
selected patients HIV RNA CD4 cell count Viral resistance test
Complete blood count Blood chemistry profile Liver enzymes
Bilirubin Blood urea nitrogen Creatinine Urinalysis Fasting blood
glucose Fasting serum lipids Screening for syphilis Hepatitis A, B,
C Coinfection screening Tuberculosis Toxoplasma gondii Cervical Pap
smear (women) Pregnancy (women) HLA-B*5701 Tropism assay
Slide 28
Resistance testing recommended for all antiretroviral-naive
patients, regardless of infection duration *Test source patient
especially if treated with antiretroviral drugs. 1.)DHHS
guidelines. January 12, 2009. 2) Hirsch MS, et al. Clin Infect Dis.
2008;47:266-285. 3) EACS Guidelines Version 3. DHHS 1 IAS-USA 2
European 3 Primary/acuteRecommend Post-exposure prophylaxis --
Recommend* Chronic, tx naveRecommend FailureRecommend
PregancyRecommend Pediatric--Recommend
Slide 29
Genotype vs. Phenotype GenotypePhenotype Basis of testDetects
drug resistance mutations present in viral genes Measures ability
of virus to grow in different concentrations of ART
InterpretationRequires knowledge of mutations selected by
individual ART and potential for cross- resistance conferred by
certain mutations Visual interpretation by bars indicating
susceptibility to individual agents SensitivityEnhanced sensitivity
for detecting mixtures of wild- type and resistance virus Results
reflect susceptibility of dominant viral species Availability of
results1-2 weeks2-3 weeks Relative costLower costHigher cost
Slide 30
Initiation of Antiretroviral Therapy: Patient Case
Slide 31
HIV Screening MS is a 33-yr-old woman visiting you, her new
primary care physician. As you take her medical history, she
mentions that she had an abnormal Pap smear a few yrs ago. You ask
her if she has ever been tested for HIV. She says no and also says
that she is confident that she has not acquired HIV. Is there a
basis for you to encourage her to be tested at this time? A. Yes,
she is in a high-risk group B. Yes, all adults up to 64 yrs of age
should be tested C. No, I do not think that she needs testing
www.clinicaloptions.com/hiv
Slide 32
HIV Screening B. Yes, all adults up to 64 yrs of age should be
tested CDC recommends HIV screening for all patients: 13-64 years
old unless local prevalence has been documented to be
