HIV Pharmacology 101ish - 202ish: New HIV Clinicians Workshop Parya Saberi, PharmD, MAS The Medical Management of HIV/AIDS December 2012 Objectives What are commonly used ARVs and where do they work in the HIV lifecycle? What are commonly used ARV doses, adverse effects, and special considerations? How do you combine ARVs in 1 st line preferred regimens? The Story of Azidothymidine ARV Timeline 1964: synthesized to inhibit cancerous cells, but did not show positive effects 1985: IV AZT tested for 1 st time on human subject 1986: concluded that there was less mortality with AZT 1987: 1 st drug FDA approved for HIV treatment at 400mg q4hrs 1994: FDA approved for prevention of vertical transmission 1
FDA-approved ARVs HIV Life-cycle Nucleoside Reverse Transcriptase Inhibitors Protease Inhibitors Abacavir (ABC) Didanosine (ddi and ddi EC) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4t) Tenofovir (TDF) Zalcitabine (ddc) withdrawn from market Zidovudine (ZDV) 3TC/ABC 3TC/ABC/ZDV 3TC/ZDV FTC/TDF Non- nucleoside Reverse Transcriptase Inhibitors Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP and NVP XR) Rilpivirine (RPV) Integrase Inhibitor Raltegravir (RAL) Amprenavir (APV) Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (Fos- APV) Indinavir (IDV) Lopinavir/ritonavir (LPV/r) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV ) Tipranavir (TPV) Fusion Inhibitor EnfuvirNde (ENF) CCR5 co- receptor antagonist Maraviroc (MVC) MulNple Class CombinaNons EFV/FTC/TDF RPV/FTC/TDF ELV/COBI/FTC/TDF Fusion inhibitors Co- receptor inhibitors Reverse transcriptase inhibitors Integrase inhibitors Protease inhibitors Maraviroc Need Trofile prior to use Dose: Standard (w/ TPV/r, NVP, RAL, NRTIs, ): 300mg PO BID With potent CYP3A inhibitors (except TPV/r) (w/ or w/o potent CYP3A inducers): 150mg PO BID With potent CYP3A inducers (except NVP): 600mg PO BID AEs: hepatotoxicity, rash Selzentry (Maraviroc) Take 1 tablet (150mg) orally twice daily with or without food 2
Enfuvirtide Injection site reaction Symptoms: pain, pruritus, erythema, warmth Incidence: 98% Patient education: Sterile technique (alcohol swab and gloves) Solution at room temp before injection Rotate injection site Avoid injection into site with little sub-q fat Massage area after injection Wear loose clothes around injection site May need warm compresses Nucleoside Reverse Transcriptase Inhibitors Generic Name Brand Name Abbreviation Dose Food Requirements zidovudine Retrovir AZT 300mg BID No restrictions didanosine Videx EC ddi >60kg: 400mg QD <60kg: 250mg QD stavudine Zerit d4t >60kg: 40mg BID <60kg: 30mg BID Empty stomach No restrictions lamivudine Epivir 3TC 150mg BID or 300mg QD No restrictions Fixed-dose Combos Brand Name NRTI Combination Oral Dose Combivir AZT (300mg)/ 3TC (150mg) One tab BID Trizivir AZT (300mg)/ 3TC (150mg)/ ABC (300mg) One tab BID Truvada TDF (300mg)/ FTC (200mg) One tab QD Epzicom ABC (600mg)/ 3TC (300mg) One tab QD abacavir Ziagen ABC 300mg BID or 600mg QD No restrictions tenofovir Viread TDF 300mg QD No restrictions emtricitabine Emtriva FTC 200mg QD No restrictions Atripla Complera TDF (300mg)/ FTC (200mg)/ EFV (600mg) TDF (300mg)/ FTC (200mg)/ RPV (25mg) One tab QD One tab QD Stribild TDF (300mg)/ FTC (200mg)/ COBI (150mg)/ ELV (150mg) One tab QD 3
Lamivudine FDA approved for treatment of HIV & HBV Salt of almost all regimens Epivir Take 1 tablet (150mg) orally twice (lamivudine, 3TC) daily with or without food Epivir Take 1 tablet (300mg) orally once (lamivudine, 3TC) daily with or without food Emtricitabine Fluorinated analog of 3TC Emtriva (emtricitabine, FTC) Take 1 capsule (200mg) orally once daily with or without food Tenofovir Renal insufficiency Risk factors: underlying renal disease, concurrent nephrotoxins, age, race, other comorbidities, low CD4+, high VL, unknown Monitor phosphorus, Scr, electrolytes, U/A Decrease in BMD Used for treatment of HBV Viread (tenofovir, TDF) Take one tablet (300mg) orally once daily with or without food Abacavir Pop Quiz #1 ABC hypersensitivity reaction (BLACK BOX WARNING) 3-9% incidence; ~9d onset (within hours of rechallenge) Symptoms: Fever, rash, GI effects, respiratory symptoms May lead to anaphylaxis, organ failure, & death ABC should be d/c ed & NEVER EVER rechallenged Recommend HLA-b5701 testing prior to use Dose does not need to be adjusted for renal impairment Ziagen (abacavir, ABC) Take 1 tablet (300mg) orally twice daily with or without food or Take 2 tablets (600mg) orally once daily Which NRTI combination(s) are redundant and/ or should be avoided? 1. Truvada/3TC 2. Epzicom/TDF 3. Truvada/ABC 4. Trizivir/TDF 5. d4t/ddi 6. Combivir/ABC 4
Pop Quiz #2 Which statement is incorrect? 1. Use ABC without dose adjustment if CrCl<50 2. Use TDF if HLA-b5701 is positive 3. Use FTC or 3TC in almost all regimens 4. Use TDF & FTC/3TC if patient is HIV/HBV coinfected 5. None of the above Non-nucleoside Reverse Transcriptase Inhibitors Generic Name Brand Name Abbreviation Dose Food Requirements delavirdine Rescriptor DLV 400mg TID No food restrictions efavirenz Sustiva EFV 600mg QD Initially HS; preferably on empty stomach etravirine Intelence ETR 200mg BID Take w/food nevirapine Viramune NVP 200mg QD x2wks; then 200mg BID No food restrictions rilpivirine Edurant RPV 25mg QD Take w/meal Efavirenz CNS AEs Drowsiness, abnormal dreams, dizziness Most symptoms after 2-4 wks Incidence >50% Counseling: preferably take & on empty stomach Rash Pregnancy category D Inducer of CYP3A4 Sustiva (efavirenz, EFV) Take 1 tablet (600mg) orally once at bedtime on an empty stomach Etravirine Do not use w/ r/tpv, r/fos-apv, r/atv, unboosted PIs, NNRTIs AE: Rash Check genotypic susceptibility score prior to use Inducer of CYP3A4 Intelence (etravirine, ETR) Take 1 tablet (200mg) orally twice daily with a meal 5
Rilpivirine Use w/ caution if VL>100,000 c/ml PPIs contraindicated H2 blockers 12 hrs before or 4 hrs after RPV Meal: at least 400 kcals (w/ 13g of fat) AEs: rash, depression, headache, insomnia CYP3A inducers & inhibitors affect RPV clearance but RPV unlikely to affect drugs metabolized by CYP3A Edurant (rilpivirine, RPV) Take 1 tablet (25mg) orally daily with a meal Pop Quiz #3 Which of the following statement(s) is incorrect? 1. RPV can be used w/ PPIs without any problems 2. EFV should be taken with high fat meals & early in the morning 3. RPV should be taken on an empty stomach 4. NNRTIs have very few drug-drug interactions 5. NNRTIs are unlikely to cause rash 6. All of the above Raltegravir Used for tx-experienced & tx-naïve patients AE: rash, headache, CK, myositis, rhabdomyolysis Few drug-drug interactions With rifampin, dose to 800mg bid Isentress (Raltegravir, RAL) Take 1 tablet (400mg) orally twice daily with or without food 6
Elvitegravir (used in EVG/COBI/TDF/FTC only) Alternative regimen if ARV-naïve & CrCl>70mL/min EVG Metabolized by CYP3A COBI CYP3A inhibitor (boosts EVG); use w/ caution w/ CYP3A substrates Inhibits Cr tubular secretion Scr & CrCL w/o glomerular function baseline estimated CrCl, U. glucose, U. protein, & phos D/c if CrCl decreases to <50mL/min Co-administration w/ other ARVs not recommended 7
Protease Inhibitors Generic Name Brand Name Abbreviation Dose (unboosted) Dose (boosted) atazanavir Reyataz ATV 400 mg QD 300 mg QD + RTV 100 mg QD darunavir Prezista DRV - 800 mg QD + RTV 100mg QD 600 mg BID + RTV 100 mg BID fosamprenavir Lexiva fos-apv 1400 mg BID 700 mg BID + RTV 100 mg BID 1400 mg QD + RTV 200 mg QD indinavir Crixivan IDV 800 mg q8h 800 mg BID + RTV 100-200mg BID lopinavir/ ritonavir Kaletra LPV/r - 2 tabs BID PI-naïve: 4 tabs QD Food Requirements With food With food No food restrictions Empty stomach/light snack; w/ 48oz of fluid If boosted: can take w/food With food nelfinavir Viracept NFV 1250 mg BID - With food ritonavir Norvir RTV - 100-200mg QD-BID to boost PIs saquinavir Invirase SQV - 1000 mg BID + RTV 100 mg BID tipranavir Aptivus TPV - 500 mg BID + RTV 200 mg BID With food With food With food Reasons to Boost Taking advantage of a drug-drug interaction Low-dose CYP-450 inhibitors (e.g., RTV or COBI) lead to: drug concentrations and exposure frequency of dosing Use of lower doses of PI Elimination of food restriction Atazanavir Darunavir Little effect on lipids Dosed QD Indirect hyperbilirubinemia Preferred PI in pregnancy Drug-drug interactions Acid reducing agents Reyataz (atazanavir, ATV) Norvir (ritonavir, RTV) Take 1 capsule (300mg) orally once daily with norvir Take 1 tablet (100mg) orally once daily with atazanavir No DRV mutations: 800mg DRV + 100mg RTV QD 1 DRV mutations: 600mg DRV + 100mg RTV BID Precaution: sulfa allergy (unknown x-sensitivity) Many drug-drug interactions Prezista (Darunavir, DRV) Norvir (ritonavir, RTV) Take 2 tablets (2 x 400mg) orally once daily with ritonavir Or Take 1 tablet (800mg) orally once daily with ritonavir Take 1 tablet (100mg) orally once daily 8
Lopinavir/ritonavir Pop Quiz #4 Co-formulated LPV + RTV Many drug-drug interactions Preferred PI in pregnancy AE: dyslipidemia, GI intolerance (D/N/V) Kaletra (lopinavir/ ritonavir, LPV/RTV) Take 2 tablets (2x 200/50mg) orally twice daily Which of the following statement(s) is incorrect? 1. DRV/r (QD) & ATV/r are associated with less diarrhea compared to LPV/r 2. DRV/r & LPV/r can be used with acid reducing agents w/ o problems 3. You should always be aware of drug-drug interactions when using PIs 4. DRV & ATV are the only two PIs that have QD dosing 5. DRV/r & ATV/r impact triglycerides less than LPV/r Preferred Regimens EFV DRV/r TDF/FTC ATV/r RAL Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2012. http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf 9
Pros & Cons of Preferred Regimens TDF/FTC/EFV: Pros: 1 tablet QD (co-formulated) Comparator regimen in most RCTs Cons Low genetic barrier to resistance & cross-resistance to other NNRTIs Renal & bone AEs + CNS & rash AEs + dyslipidemia Pregnancy category D Empty stomach & at bedtime Drug-drug interactions TDF/FTC/RAL: Pros: Low drug interaction potential Rapid decline in HIV VL No food requirements Few AEs Cons: BID Low genetic barrier to resistance CK, myopathy, & skin reactions Pros & Cons of Preferred Regimens TDF/FTC/ATV/r: Pros: QD (3 tablets) lipid & metabolic AEs vs other PIs Good GI tolerability Higher genetic barrier to resistance Cons: Hyperbilirubinemia, nephrolithiasis Food requirements Drug-drug interactions TDF/FTC/DRV/r: Pros: QD (4 tablets) Higher genetic barrier to resistance Good GI tolerability lipid & metabolic AEs vs other PIs Cons: Rash Food requirements Drug-drug interactions Alternative Regimens RPV LPV/r TDF/FTC Fos-APV/r EVG/COBI RPV EFV ATV/r LPV/r ABC/3TC DRV/r Fos-APV/r RAL Factors to consider when selecting a regimen Drug resistance testing History of ARV use & prior drug resistance tests Comorbidities (CVD, liver/renal disease, GERD, etc.) Drug AEs Drug-drug interactions Pregnancy (or pregnancy potential) Labs (renal/hepatic function, HLA-b5701, CD4+, VL, coreceptor tropism, lipids, etc.) Patient s adherence potential Convenience (pill burden, dosing frequency, food requirements, etc.) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2012. http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf 10
Case #1 You are going to start ARVs for your 30 y/o White HIV+ female patient. She has a positive HLA-b5701 test, is hoping to become pregnant in the coming year, and is extremely worried about changes in her appearance due to ARV adverse effects. Her baseline VL=178K and CD4 + =458. Which regimen(s) would you consider? Epzicom (ABC/3TC) + r/drv (once-daily) Truvada (TDF/FTC) + r/atv Atripla (TDF/FTC/EFV) Complera (TDF/FTC/RPV) Truvada (TDF/FTC) + r/drv Quick Case #2a Your patient is 38 y/o African American male with H of HIV, hyperlipidemia, and GERD. He is taking famotidine (20mg PO BID). He has never been on ARVs before. Labs are as follows: HLA-b5701: negative Genotype: 103N (resistance to EFV) 1/11/2011 6/18/2011 11/19/2011 3/29/2012 8/10/2012 CD4 (ABS) 855 849 697 625 530 HIV Viral L 101711 (H) 110963 (H) 125065 (H) 11/19/20011 CHOL 250 TRIG 138 HDL 42 LDL CALC 180 (H) Quick Case #2a Quick Case #2b Which 1st line ARV regimen(s) may be appropriate? Atripla (EFV/TDF/FTC) Truvada (TDF/FTC) + DRV/r (once-daily) Truvada (TDF/FTC) + ATV/r Complera (TDF/FTC/RPV) Truvada + LPV/r Patient was started on Truvada/ATV/r. His VL is undetectable within 3 months & his CD4+ cell count is 690 cells/mm 3. However, his GERD worsens & now he require omeprazole 40mg QD. Which regimen(s) would you change him to now? Atripla (EFV/TDF/FTC) Truvada (TDF/FTC) + DRV/r (once-daily) Truvada (TDF/FTC) + LPV/r Complera (TDF/FTC/RPV) Truvada (TDF/FTC) + RAL 11
Quick Case #3 A 56 y/o White male has H significant for depression (suicidal ideation), HTN, and HLP. He is currently taking atorvastatin (10mg QD) & citalopram (20mg QD). His labs are as follows: estimated CrCl= 40mL/min, LDL= 140, TG= 168. His chart indicates allergy ( LFT elevation ) from ABC in 2001. Which regimen(s) would you consider for him? Stribild (TDF/FTC/COBI/EVG) Atripla (TDF/FTC/EFV) Truvada (TDF/FTC) + RAL Truvada (TDF/FTC) + LPV/r Truvada (TDF/FTC) + ATV/r Truvada (TDF/FTC) + DRV/r Complera (TDF/FTC/RPV) Epzicom (ABC/3TC) + ATV/r InSTI 12