Therapeutic Options New Options & New Challenges James A Zachary MD LSU Health Sciences Center HIV Outpatient Clinic 11 April 2005

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

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 PotencyAdherence Issues Barrier to Resistance efavirenz + (zidovudine or tenofovir) + lamivudine /+ CNS, mito* ++/+ lopinavir/r + (zidovudine) + lamivudine Lipids, mito* ++++ * Especially stavudine

Combination Therapy DHHS NNRTI-Based Alternative Regimens PotencyAdherence 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 PotencyAdherence Adverse Effects Barrier to Resistance nevirapine – based* /+ rash, hepatitis* ++/+ efavirenz - based ++++ CNS ++/+ *April 72004: alternative regimen – women CD4<250 cells/mm 3 or men CD4 < 400 cell/mm 3

DHHS PI-Based Alternative Regimens PotencyAdherenceIssues 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 +++

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/mm 3 –Men CD4 > 400 cells/mm 3 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: Complex of HIV-1 Reverse Transcriptase with an RNA-DNA Duplex

Clavel, F. et al. N Engl J Med 2004;350: 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 CombinationComponentsDoses Per day CombivirZDV + 3TC2 TrizivirZDV + 3TC + ABC2 EpzicomABC + 3TC1 TruvadaTDF + FTC1

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 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 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 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, O 2 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 weekVLCD4AST 150, , 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 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.