Download Document

Therapeutic
Options
New Options & New Challenges
James A Zachary MD
LSU Health Sciences Center
HIV Outpatient Clinic
11 April 2005
http://HIVManagement.org
http://HIVInfo.us
Objectives
• Review of principles of
antiretroviral therapy
• Review of antiretrovirals
• Newer agents
• Strategies for naïve and
experienced antiretroviral therapy
http://aidsinfo.nih.gov/
Principles of Therapy
• There is no latent stage of HIV
infection
• CD4 lymphocyte counts and HIV
viral load determinations are
critical to successful therapy
• Treatment should be individualized
Principles of Therapy
• There is no latent stage of HIV
infection
• CD4 lymphocyte counts and HIV viral
load determinations are critical to
successful therapy
• Treatment should be individualized
Lab Monitoring of Therapy
• CD4 lymphocytes = immunity
• HIV RNA PCR or HIV double-stranded
DNA = viral load
– equilibrium between viral replication vs
clearance of virus and inhibition of
replication
Principles of Therapy
• There is no latent stage of HIV
infection
• CD4 lymphocyte counts and HIV viral
load determinations are critical to
successful therapy
• Treatment should be individualized
Individualization of Therapy
• Clinical factors
• Laboratory factors
• Psychosocial factors
Individualization of Therapy
• Clinical factors: date of primary
infection, history of treatment (drugs,
intolerances, response), body weight,
kidney and liver disease, drug
interactions, absorption issues
• Laboratory factors
• Psychosocial factors
Individualization of Therapy
• Clinical factors
• Laboratory factors: CD4, viral load,
liver enzymes, Cr, hematologic
parameters (WBC, hemoglobin)
• Psychosocial factors
Individualization of Therapy
• Clinical factors
• Laboratory factors
• Psychosocial factors: support system,
mental health, adherence to medical
therapy in the past, access to care,
understanding of disease process,
relationship with medical providers, literacy
Principles of Therapy
• Combination therapy is always
utilized.
• It is important to consider resistance
issues.
• Antiretrovirals should be administered
at optimal dosing and dosing
frequencies.
Combination Therapy
DHHS Preferred Regimens
Potency
efavirenz +
(zidovudine or
tenofovir) +
lamivudine
lopinavir/r +
(zidovudine) +
lamivudine
++++
++++
Barrier
to
Resistance
Adherence
Issues
+++/+
CNS,
mito*
++/+
+++
Lipids,
mito*
++++
* Especially stavudine
Combination Therapy
DHHS NNRTI-Based Alternative Regimens
Potency
Adherence
Adverse
Effects
Barrier
to
Resistance
efavirenz +
emtricitabine +
(zidovudine or
tenofovir DF or
stavudine)
++++
++++
CNS,
mito*
++/+
efavirenz +
(lamivudine or
emtricitabine) +
(didanosine or
abacavir)
++++
++++
CNS,
mito*
++/+
Combination Therapy
DHHS NNRTI-Based Alternative Regimens
Adverse
Effects
Barrier
to
Resistance
Potency
Adherence
nevirapine –
based*
++++
+++/+
rash,
hepatitis*
++/+
efavirenz based
++++
++++
CNS
++/+
*April 72004: alternative regimen – women CD4<250 cells/mm3 or men CD4 < 400 cell/mm3
DHHS PI-Based Alternative Regimens
Potency
Barrier
to
Resistance
Adherence
Issues
+++/?
Atazanavir/R
++++
++++
food,
bilirubin
Fosamprenavir/R
++++
+++/+
rash
+++/?
++++
Indinavir/r
++++
++++
nephrolithiasis,
lipids, fat
redistribution,
drug interactions,
bilirubin
nelfinavir
+++
+++
food, diarrhea
++
++
food, diarrhea,
fat, drug
interactions
+++
Saquinavir/R
++++
Antiretroviral Toxicity
• NRTI
– Mitochondrial: d4T, ddC, ddI
– Hematologic: AZT
• PI
– GI: nelfinavir, ritonavir, lopinavir
– Hepatic: indinavir, ritonavir atazanavir
– Lipodystrophy: lopinavir, indinavir, boosted
PIs
• NNRTI
– Rash: nevirapine, delavirdine
– Hepatic: nevirapine >> efavirenz
– CNS: efavirenz
Antiretrovirals with Hepatitis B Activity
• Tenofovir (TDF)
• Lamivudine (3TC)
• Emtricitabine (FTC)
Antiretrovirals Regimens to Avoid
• Monotherapy
• Dual therapy
• Triple nukes
– Abacavir + tenofovir + lamivudine
– Didanosine + tenofovir + lamivudine
– Tenofovir + 2NRTI
Antiretrovirals Regimens to Avoid
• Amprenavir oral solution
– Pregnant women
– Children < 4 years age
– Hepatic or renal dysfunction
– Concomitant metronidazole or disulfiram
• Amprenavir + fosamprenavir
• Amprenavir soln + ritonavir soln
Antiretrovirals Regimens to Avoid
• Atazanavir + indinavir:
hyperbilirubinemia
• Didanosine + stavudine: mito toxicity
• Didanosine + zalcitabine: mito toxicity
• Stavudine + zalcitabine: mito toxicity
• Efavirenz in first trimester of
pregnancy and women of childbearing
potential: teratogenicity
Antiretrovirals Regimens to Avoid
• Emtricitabine + lamivudine: duplicate
mechanism of action
• Lamivudine + zalcitabine: decreased
intracellular phosphorylation of both
drugs
• Nevirapine: increased toxicity
– Women CD4 > 250 cells/mm3
– Men CD4 > 400 cells/mm3
• NNRTI + didanosine + tenofovir: high failure
rate
Antiretrovirals Regimens to Avoid
• Hard gel saquinavir (Invirase) as the
sole PI: inadequate drug levels
• Zidovudine + stavudine: antagonistic
in vitro and in vivo
• Didanosine + tenofovir?: blunted CD4
increase
Principles of Therapy
• Combination therapy is always
utilized.
• It is important to consider resistance
issues.
• Antiretrovirals should be administered
at optimal dosing and dosing
frequencies.
HIV Resistance
• A virus is defined by its ability to
develop resistance!
• HIV resistance testing
– Initiation of therapy
• newly infected
• partner of someone on therapy
• recent vertical transmission
– Failing regimen: subtherapeutic drug
levels for whatever reason*
Complex of HIV-1 Reverse Transcriptase with an RNA-DNA Duplex
Clavel, F. et al. N Engl J Med 2004;350:1023-1035
HIV-1 Protease Dimer Binding with a Protease Inhibitor (Panel A)
and
A Drug-Sensitive (Wild-Type) Protease
Juxtaposed against a Drug-Resistant Protease (Panel B)
Clavel, F. et al. N Engl J Med 2004;350:1023-1035
HIV Resistance Testing
• Baseline?
• Lack of virologic suppression
• Must be done while patient is on
therapy
• Genotype vs phenotype
Principles of Therapy
• Combination therapy is always
utilized.
• It is important to consider resistance
issues.
• Antiretrovirals should always be
administered at optimal dosing and
dosing frequencies.
Optimized Dosing
• Adherence ~ dosing frequency, side
effects, possible side effects, refrigeration
requirements, meal dependence
• Clinical variables ~ body weight, potency
of drugs, bioavailability, penetration of
drugs into compartments, hepatic and renal
clearance, drug interactions, toxicities
Optimized Adherence
• Lower pill burden
• Combination formulations
– Combivir
– Trizivir
– Truvada
– Epzicom
• Protease inhibitor boosting
• Once-a-day and twice-a-day drugs
• Drugs with less toxicity
Combination Drugs
Combination
Components
Doses
Per day
Combivir
Trizivir
Epzicom
Truvada
ZDV + 3TC
ZDV + 3TC + ABC
ABC + 3TC
TDF + FTC
2
2
1
1
Protease Inhibitor Boosting
• Ritonavir inhibits hepatic
metabolism of most protease
inhibitors
• Decreases pill burden
• Decreases dosing frequency
• Decrease meal dependence
Protease Inhibitor Boosting
• Increased potential for non-PI
drug interactions
• Increases possibility of
hyperlipidemia and central fat
redistribution
Protease Inhibitor Boosting
• Once-a-day boosted PIs
– Fosamprenavir 1400 mg + ritonavir 200
mg
– Amprenavir 1600 mg + ritonavir 100 mg
– Hard gel cap saquinavir 1600 mg +
ritonavir 100-200 mg
– Atazanavir 2x150 mg + ritonavir 100 mg
Protease Inhibitor Boosting
• Twice-a-day PI boosting
– Amprenavir + ritonavir
– Hard gel caps or soft gel caps saquinavir
1000 mg bid + ritonavir 100 mg bid
– Fosamprenavir 700 mg bid + ritonavir
100 mg bid
– Indinavir 800 mg bid + ritonavir 100-200
mg bid
Once-A-Day NRTIs
•
•
•
•
•
Emtricitabine (FTC)
Tenofovir (TDF)
Didanosine EC (ddI)
Lamivudine (3TC)
Abacavir
Once-A-Day Menu 2005
• abacavir/lamivudine
• NNRTI
• tenofovir/emtricitabine
• Atazanavir/r
or lamivudine
• Fosamprenavir/r
• didanosine +
emtricitabine
• abacavir + didanosine
• abacavir + tenofovir
• abacavir + emtricitabine
Once-A-Day NNRTIs
• Efavirenz
• Nevirapine: slightly increased toxicity
(hepatic, rash)
Principles of Therapy
• Make changes in therapy cautiously
• Women and children should be
treated as aggressively as male
adults.
• Primary HIV infection should be
treated within the first 6 months.
Changes in Therapy
Many variables should considered be at the time alteration of treatment
• Adherence issues
• Genotypic and phenotypic resistance
and cross-resistance issues
• Pharmacokinetic issues
• Toxicity issues
• Availability
• Strategic planning for patient and
lifestyle
Principles of Therapy
• Make changes in therapy cautiously
• Women and children should be
treated as aggressively as male
adults.
• Primary HIV infection should be
treated within the first 6 months.
Principles of Therapy
• Make changes in therapy cautiously
• Women and children should be
treated as aggressively as male
adults.
• Primary HIV infection should be
treated within the first 6 months.
Principles of Therapy
• HIV infected persons should always
be considered infectious
• Expert consultation just as in other
areas of medicine may be helpful.
Principles of Therapy
• HIV infected persons should always
be considered infectious
• Expert consultation just as in other
areas of medicine may be helpful.
Case 1
• 22 year old with new dx
HIV presents to ED with
PCP, oral thrush, weight
loss of 15 lbs/3 mos, O2
sat 90% on RA
• CD4 41
• HIV VL > 750,000
copies/cc
• WBC 2.4, AGC 1200, hgb
12.5, MCV 88
• LDH 450, AST 55, ALT
45, alb 3.1, INR 1.1
Case 1
• PCP treated with
SMX/TMP
• Oral thrush
responds to
nystatin S&S
• Pt presents to clinic
Case 1
• Complete H&P especially psychosocial
issues, estimated date of infection, route of
transmission, risk factors, sexual
preference
• Complete lab baseline including hepatitis A,
B, C serology, toxoplasma gondii IgG,
serum testosterone, repeat CD4, RPR,
IPPD
Case 1
• History
– Heterosexual
– Literacy poor
– No support system
– Lost job while in hospital –
bordering on being homeless
– Smokes 1.5 ppd
– Drinks alcohol daily
Case 1
• Physical
– BMI 18
– Minimal oral thrush
– Perianal ulcers
Case 1
• Lab results:
– CD4 75
– Hep B surface Ag reactive
– HCV-Ab – nonreactive
– HAV-IgG-Ab +
– PPD - nonreactive
– CXR – clear
– Baseline genotype: pansensitive
– Perianal ulcer: HSV II
Case 1
• Problem list
–
–
–
–
–
–
–
–
–
–
AIDS CD4 75 HIV viral load high – not on ARVs
S/P PCP doing well - resolving
Mild oral candidiasis
Likely chronic hepatitis B
Mild anemia and leukopenia
Illiteracy
Poor support system
Borderline homelessness
Depression – multiple new diagnosis
Tobacco use
Case 1
• AIDS CD4 75 HIV viral load high – not
on ARVs
Plan?
Case 1
Plan
• AIDS CD4 75 HIV viral load high – not
on ARVs
– Hold ARV therapy for now
– Educate thoroughly
– Test adherence
– Address other pressing psychosocial
issues
Case 1
Plan
• Mild oral candidiasis
– Fluconazole?
• Likely chronic hepatitis B
– Consideration for ARV therapy
• Mild anemia and leukopenia
– Consideration for ARV therapy
Case 1
Plan
•
•
•
•
Illiteracy
Poor support system
Borderline homelessness
Depression – multiple new diagnosis
Case 1
Plan
•
•
•
•
Illiteracy: case management
Poor support system
Borderline homelessness
Depression – multiple new diagnosis
Case 1
Plan
• Illiteracy: case management
• Poor support system: case
management
• Borderline homelessness
• Depression – multiple new diagnosis
Case 1
Plan
• Illiteracy: case management
• Poor support system: case
management
• Borderline homelessness: residential
living situation
• Depression – multiple new diagnosis
Case 1
Plan
• Illiteracy: case management
• Poor support system: case management
• Borderline homelessness: residential living
situation
• Depression – multiple new diagnosis:
mental health referral, support group,
adjustment period
Case 1
Plan
• Initiation of antiretroviral therapy
–NNRTI-based
–PI-based
Case 1
Plan
• PI-based therapy was chosen
– Pros
• Late presentation: low CD4 and high VL
• Degree of longterm adherence is unknown
– Cons
• Possibly higher pill burden and frequency
• Possible GI side effects including hepatitis,
fat redistribution, lipids
Case 1
Plan
• PI-based therapy was chosen
– Atazanavir 150 mg 2 once a day +
ritonavir 100 mg once day
– Fosamprenavir 700 mg 2 once a day +
ritonavir 100 mg 2 once a day
– Kaletra 3 caps bid
Case 1
Plan
• NRTI selection
– Emtricitabine
– Tenofovir
– Lamivudine
– Abacavir
– Truvada
– Trizivir
– Epzicom
Case 1
Plan
• NRTI selection
–
–
–
–
–
Emtricitabine: active against hep B
Tenofovir: active against hep B
Lamivudine: active against hep B
Truvada: both components active against hep B
Trizivir: triple NRTI with lamivudine active
against hep B
– Epzicom: double NRTI with lamivudine active
against hep B
Case 1
Plan
• NRTI selection
– Truvada
– Tenofovir + emtricitabine or once-a-day
lamivudine
Case 1
Plan
• Fosamprenavir 700 mg 2 once a day
• Ritonavir 100 mg 2 once a day
• Truvada once a day or tenofovir 300
mg once a day + emtricitabine 200 mg
once a day
Case 1
Plan
• Followed closely at weekly or biweekly
intervals until viral load is <400
copies/cc
• Would check ultrasensitive VL after
two VL <400 copies/cc
• Follow liver enzymes closely
Case 1
VL
time
week
1
2
4
6
8
12
16
VL
50,500
5000
1500
1500
1700
3000
76,000
CD4
45
50
48
60
61
75
80
AST
45
90
100
110
90
100
110
Case 1
• Options
– Change meds to NNRTI-based regimen
– Do resistance testing
– Other evaluations
Case 1
• Options
– Change meds to NNRTI-based regimen
– Do resistance testing
– Other evaluations
• Adherence evaluation
–
–
–
–
Re-evaluate psychosocial issues carefully
Patient reported adherence
Pill counts
Pharmacy reported adherence
Case 1
Plan
•
•
•
•
•
Hold medications
Tackle psychosocial issues
Educate, educate, educate
Case management intensification
Restart with weekly follow-up when
the chaos calms
Case 2
• 55 y/o Caucasian male with AIDS s/p CMV
retinitis
• Allergy: delavirdine, sulfa
• PMH: CAD, HTN
• Tobacco use
• CD4 450 VL <400
• Meds: lopinavir/ritonavir, stavudine,
lamivudine, atorvastatin, benazepril
Case 2
• History: legs burning at night and
calves painful with exercise
• Physical: BMI 24, mild facial
lipoatrophy, dec ankle jerks bil, barely
palpable DP and PT pulses
• Lab: cholesterol 281 trig 450 HDL 20
Case 2
•
•
•
•
•
•
•
•
Increase atorvastatin and add gemfibrozil
Indinavir/ritonavir + ZDV + 3TC
Atazanavir + d4T + 3TC
Fosamprenavir + ABC + 3TC
Efavirenz + ABC + 3TC
Efavirenz + ddI + tenofovir
Efavirenz + ABC + TDF
Efavirenz + d4T + 3TC
Case 2
•
•
•
•
•
•
•
•
Increase atorvastatin and add gemfibrozil
Indinavir/ritonavir + ZDV + 3TC
Atazanavir + d4T + 3TC
Fosamprenavir + ABC + 3TC
Efavirenz + ABC + 3TC
Efavirenz + ddI + tenofovir
Efavirenz + ABC + TDF
Efavirenz + d4T + 3TC
Secrets To Successful Viral
Load Suppression
• Start ARVs only when indicated and appropriate for
the client
• Adherence, adherence, adherence!
• See the patient at a minimum of 2 weeks after
initiation of any regimen and q2-4 weeks thereafter
until VL<400
• Communication: call the patient often during first 14
days!
• Addiction, illiteracy, low function, chaos, and ARVs do
not mix. A multidisciplinary approach is optimal.
• Encouragement!
• Form a relationship with your patient.