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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.