Therapeutic Options

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Therapeutic Options

• New Options New Challenges
• James A Zachary MDLSU Health Sciences CenterHIV
  Outpatient Clinic11 April 2005

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http//HIVManagement.org
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http//HIVInfo.us
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Objectives

• Review of principles of antiretroviral therapy
• Review of antiretrovirals
• Newer agents
• Strategies for naïve and experienced
  antiretroviral therapy

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http//aidsinfo.nih.gov/
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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

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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

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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

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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

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Individualization of Therapy

• Clinical factors
• Laboratory factors
• Psychosocial factors

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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

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Individualization of Therapy

• Clinical factors
• Laboratory factors CD4, viral load, liver
  enzymes, Cr, hematologic parameters (WBC,
  hemoglobin)
• Psychosocial factors

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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

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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.

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Combination Therapy
DHHS Preferred Regimens DHHS Preferred Regimens DHHS Preferred Regimens DHHS Preferred Regimens DHHS Preferred Regimens DHHS Preferred Regimens
Potency Adherence Issues Issues Barrier to Resistance
efavirenz (zidovudine or tenofovir) lamivudine / / CNS, mito /
lopinavir/r (zidovudine) lamivudine Lipids, mito
Especially stavudine
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Combination Therapy
DHHS NNRTI-Based Alternative Regimens DHHS NNRTI-Based Alternative Regimens DHHS NNRTI-Based Alternative Regimens DHHS NNRTI-Based Alternative Regimens DHHS NNRTI-Based Alternative Regimens DHHS NNRTI-Based Alternative Regimens
Potency Adherence Adverse Effects Adverse Effects Barrier to Resistance
efavirenz emtricitabine (zidovudine or tenofovir DF or stavudine) CNS, mito /
efavirenz (lamivudine or emtricitabine) (didanosine or abacavir) CNS, mito /
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Combination Therapy
DHHS NNRTI-Based Alternative Regimens DHHS NNRTI-Based Alternative Regimens DHHS NNRTI-Based Alternative Regimens DHHS NNRTI-Based Alternative Regimens DHHS NNRTI-Based Alternative Regimens DHHS NNRTI-Based Alternative Regimens
Potency Adherence Adverse Effects Adverse Effects Barrier to Resistance
nevirapine based / / rash, hepatitis /
efavirenz -based CNS /
April 72004 alternative regimen women CD4lt250
cells/mm3 or men CD4 lt 400 cell/mm3
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DHHS PI-Based Alternative Regimens DHHS PI-Based Alternative Regimens DHHS PI-Based Alternative Regimens DHHS PI-Based Alternative Regimens DHHS PI-Based Alternative Regimens DHHS PI-Based Alternative Regimens
Potency Adherence Issues Issues Barrier to Resistance
Atazanavir/R food, bilirubin /? /?
Fosamprenavir/R / rash /? /?
Indinavir/r nephrolithiasis, lipids, fat redistribution, drug interactions, bilirubin
nelfinavir food, diarrhea
Saquinavir/R food, diarrhea, fat, drug interactions
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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 gtgt efavirenz
• CNS efavirenz

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Antiretrovirals with Hepatitis B Activity

• Tenofovir (TDF)
• Lamivudine (3TC)
• Emtricitabine (FTC)

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Antiretrovirals Regimens to Avoid

• Monotherapy
• Dual therapy
• Triple nukes
• Abacavir tenofovir lamivudine
• Didanosine tenofovir lamivudine
• Tenofovir 2NRTI

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Antiretrovirals Regimens to Avoid

• Amprenavir oral solution
• Pregnant women
• Children lt 4 years age
• Hepatic or renal dysfunction
• Concomitant metronidazole or disulfiram
• Amprenavir fosamprenavir
• Amprenavir soln ritonavir soln

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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

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Antiretrovirals Regimens to Avoid

• Emtricitabine lamivudine duplicate mechanism
  of action
• Lamivudine zalcitabine decreased intracellular
  phosphorylation of both drugs
• Nevirapine increased toxicity
• Women CD4 gt 250 cells/mm3
• Men CD4 gt 400 cells/mm3
• NNRTI didanosine tenofovir high failure rate

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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

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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.

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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

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Complex of HIV-1 Reverse Transcriptase with an
RNA-DNA Duplex
Clavel, F. et al. N Engl J Med 20043501023-1035
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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 20043501023-1035
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HIV Resistance Testing

• Baseline?
• Lack of virologic suppression
• Must be done while patient is on therapy
• Genotype vs phenotype

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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.

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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

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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

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Combination Drugs
Combination Components Doses Per day
Combivir ZDV 3TC 2
Trizivir ZDV 3TC ABC 2
Epzicom ABC 3TC 1
Truvada TDF FTC 1
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Protease Inhibitor Boosting

• Ritonavir inhibits hepatic metabolism of most
  protease inhibitors
• Decreases pill burden
• Decreases dosing frequency
• Decrease meal dependence

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Protease Inhibitor Boosting

• Increased potential for non-PI drug interactions
• Increases possibility of hyperlipidemia and
  central fat redistribution

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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

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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

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Once-A-Day NRTIs

• Emtricitabine (FTC)
• Tenofovir (TDF)
• Didanosine EC (ddI)
• Lamivudine (3TC)
• Abacavir

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Once-A-Day Menu 2005

• abacavir/lamivudine
• tenofovir/emtricitabine or lamivudine
• didanosine emtricitabine
• abacavir didanosine
• abacavir tenofovir
• abacavir emtricitabine

• NNRTI
• Atazanavir/r
• Fosamprenavir/r

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Once-A-Day NNRTIs

• Efavirenz
• Nevirapine slightly increased toxicity (hepatic,
  rash)

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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.

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Changes in TherapyMany 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

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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.

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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.

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Principles of Therapy

• HIV infected persons should always be considered
  infectious
• Expert consultation just as in other areas of
  medicine may be helpful.

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Principles of Therapy

• HIV infected persons should always be considered
  infectious
• Expert consultation just as in other areas of
  medicine may be helpful.

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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 gt 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

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Case 1

• PCP treated with SMX/TMP
• Oral thrush responds to nystatin SS
• Pt presents to clinic

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Case 1

• Complete HP 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

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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

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Case 1

• Physical
• BMI 18
• Minimal oral thrush
• Perianal ulcers

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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

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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

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Case 1

• AIDS CD4 75 HIV viral load high not on
  ARVsPlan?

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Case 1Plan

• AIDS CD4 75 HIV viral load high not on ARVs
• Hold ARV therapy for now
• Educate thoroughly
• Test adherence
• Address other pressing psychosocial issues

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Case 1Plan

• Mild oral candidiasis
• Fluconazole?
• Likely chronic hepatitis B
• Consideration for ARV therapy
• Mild anemia and leukopenia
• Consideration for ARV therapy

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Case 1Plan

• Illiteracy
• Poor support system
• Borderline homelessness
• Depression multiple new diagnosis

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Case 1Plan

• Illiteracy case management
• Poor support system
• Borderline homelessness
• Depression multiple new diagnosis

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Case 1Plan

• Illiteracy case management
• Poor support system case management
• Borderline homelessness
• Depression multiple new diagnosis

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Case 1Plan

• Illiteracy case management
• Poor support system case management
• Borderline homelessness residential living
  situation
• Depression multiple new diagnosis

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Case 1Plan

• Illiteracy case management
• Poor support system case management
• Borderline homelessness residential living
  situation
• Depression multiple new diagnosis mental
  health referral, support group, adjustment period

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Case 1Plan

• Initiation of antiretroviral therapy
• NNRTI-based
• PI-based

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Case 1Plan

• 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

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Case 1Plan

• 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

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Case 1Plan

• NRTI selection
• Emtricitabine
• Tenofovir
• Lamivudine
• Abacavir
• Truvada
• Trizivir
• Epzicom

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Case 1Plan

• 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

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Case 1Plan

• NRTI selection
• Truvada
• Tenofovir emtricitabine or once-a-day lamivudine

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Case 1Plan

• 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

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Case 1Plan

• Followed closely at weekly or biweekly intervals
  until viral load is lt400 copies/cc
• Would check ultrasensitive VL after two VL lt400
  copies/cc
• Follow liver enzymes closely

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Case 1
VL
time
week VL CD4 AST
1 50,500 45 45
2 5000 50 90
4 1500 48 100
6 1500 60 110
8 1700 61 90
12 3000 75 100
16 76,000 80 110
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Case 1

• Options
• Change meds to NNRTI-based regimen
• Do resistance testing
• Other evaluations

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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

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Case 1Plan

• Hold medications
• Tackle psychosocial issues
• Educate, educate, educate
• Case management intensification
• Restart with weekly follow-up when the chaos calms

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Case 2

• 55 y/o Caucasian male with AIDS s/p CMV retinitis
• Allergy delavirdine, sulfa
• PMH CAD, HTN
• Tobacco use
• CD4 450 VL lt400
• Meds lopinavir/ritonavir, stavudine, lamivudine,
  atorvastatin, benazepril

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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

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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

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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

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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 VLlt400
• 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.