Therapeutic Options
New Options & New Challenges
James A Zachary MDLSU Health Sciences Center
HIV Outpatient Clinic11 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 Adherence IssuesBarrier
to Resistance
efavirenz + (zidovudine or tenofovir) + lamivudine
++++ +++/+ CNS, mito* ++/+
lopinavir/r + (zidovudine) + lamivudine ++++ +++ Lipids,
mito* ++++
* Especially stavudine
Combination Therapy
DHHS NNRTI-Based Alternative Regimens
Potency AdherenceAdverse 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
Potency AdherenceAdverse Effects
Barrier to
Resistance
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 Adherence IssuesBarrier
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
+++
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*
Clavel, F. et al. N Engl J Med 2004;350:1023-1035
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)
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 ZDV + 3TC 2
Trizivir ZDV + 3TC + ABC 2
Epzicom ABC + 3TC 1
Truvada TDF + FTC 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
• NNRTI • Atazanavir/r• Fosamprenavir/r
• abacavir/lamivudine • tenofovir/emtricitabine
or lamivudine• 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 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
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 ARVsPlan?
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
Case 1Plan
• Mild oral candidiasis– Fluconazole?
• Likely chronic hepatitis B– Consideration for ARV therapy
• Mild anemia and leukopenia– Consideration for ARV therapy
Case 1Plan
• Illiteracy
• Poor support system
• Borderline homelessness
• Depression – multiple new diagnosis
Case 1Plan
• Illiteracy: case management
• Poor support system
• Borderline homelessness
• Depression – multiple new diagnosis
Case 1Plan
• Illiteracy: case management
• Poor support system: case management
• Borderline homelessness
• Depression – multiple new diagnosis
Case 1Plan
• Illiteracy: case management
• Poor support system: case management
• Borderline homelessness: residential living situation
• Depression – multiple new diagnosis
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
Case 1Plan
• Initiation of antiretroviral therapy
–NNRTI-based
–PI-based
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
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
Case 1Plan
• NRTI selection– Emtricitabine– Tenofovir– Lamivudine– Abacavir– Truvada– Trizivir– Epzicom
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
Case 1Plan
• NRTI selection– Truvada– Tenofovir + emtricitabine or once-a-day
lamivudine
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
Case 1Plan
• 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
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
VL
time
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 1Plan
• 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.