ncrc-arvs-initial-therapy.pptx

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ARVs for Initial Therapy: Characteristics and Adverse Effects

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Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents January 2020 ARVs for Initial Therapy: Characteristics and Adverse Effects About This Presentation These slides were developed using the Guidelines updated in December 2019 The intended audience is clinicians involved in the care of patients with HIV. Because the field of HIV care is rapidly changing, users are cautioned that the information in this presentation may become out of date quickly. It is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. January 2020 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Developed by the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC) https://AIDSInfo.nih.gov January 2020 ARVs for Initial Therapy: Characteristics and Adverse Effects, Outline ARV classes and agents – advantages and disadvantages ARV adverse effects (AE) January 2020 Available ARV Classes and Medications NRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir DF (TDF) Tenofovir alafenamide (TAF) Zidovudine (AZT, ZDV) NNRTI Delavirdine (DLV) Doravirine (DOR) Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP) Rilpivirine (RPV) Integrase Inhibitor (INSTI) Bictegravir (BIC) Dolutegravir (DTG) Elvitegravir (EVG) Raltegravir (RAL) PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Saquinavir (SQV) Tipranavir (TPV) Fusion Inhibitor Enfuvirtide (ENF, T-20) CCR5 Antagonist Maraviroc (MVC) Entry Inhibitor Fostemsavir (FOS) Ibalizumab (IBA) Pharmacokinetic (PK) Booster Ritonavir (RTV, /r) Cobicistat (COBI, /c) January 2020 Commonly-used ARV Medications NRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir DF (TDF) Tenofovir alafenamide (TAF) Zidovudine (AZT, ZDV) NNRTI Delavirdine (DLV) Doravirine (DOR) Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP) Rilpivirine (RPV) Integrase Inhibitor (INSTI) Bictegravir (BIC) Dolutegravir (DTG) Elvitegravir (EVG) Raltegravir (RAL) PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Saquinavir (SQV) Tipranavir (TPV) Fusion Inhibitor Enfuvirtide (ENF, T-20) CCR5 Antagonist Maraviroc (MVC) Entry Inhibitor Fostemsavir (FOS) Ibalizumab (IBA) Pharmacokinetic (PK) Booster Ritonavir (RTV, /r) Cobicistat (COBI, /c) January 2020 HIV Life Cycle and Targets for ARVs Graphic: aidsinfo.nih.gov January 2020 ARV Components in Initial Therapy: NRTI Pairs ADVANTAGES Established backbone of combination therapy Minimal drug interactions DISADVANTAGES Lactic acidosis and hepatic steatosis reported with most NRTIs (rare) January 2020 Graphic: aidsinfo.nih.gov Initial Therapy: Dual-NRTI Pairs (1) ABC/3TC Once-daily dosing Coformulated with DTG in a single-pill regimen Use only for patients who are negative for HLA-B*5701 (risk of hypersensitivity reaction if positive) Possible risk of cardiovascular events; caution in patients with CV risk factors Possible inferior efficacy if baseline HIV RNA >100,000 copies/mL and used with EFV, ATV/r, or RAL Should not be used for treatment of HBV January 2020 Initial Therapy: Dual-NRTI Pairs (2) TDF/FTC, TDF/3TC Once-daily dosing In several single-pill regimen coformulations Active against HBV Potential for renal and bone toxicity (more than with TAF); exacerbated by PK boosters Avoid if renal disease or osteoporosis Lower lipid levels (vs ABC and TAF) TAF/FTC Once-daily dosing In several single-pill regimen coformulations Active against HBV Renal and bone toxicity; less common than with TDF/FTC Approved for eGFR ≥30 mL/min Excess weight gain (vs ABC and TDF) in some studies January 2020 ARV Components in Initial Therapy: INSTIs ADVANTAGES DTG, BIC: higher barrier to resistance than RAL, EVG Low rates of AEs Few drug-drug interactions (not true of EVG/COBI) Single-pill combination regimens available with BIC, DTG, EVG/COBI DISADVANTAGES RAL, EVG: lower genetic barrier to resistance than DTG, BIC, PIs COBI: many drug-drug interactions DTG: higher rates of infant neural tube defects if DTG exposure at conception; no info on BIC Greater weight gain (especially with TAF) Graphic: aidsinfo.nih.gov January 2020 ARV Components in Initial Therapy: PIs ADVANTAGES High genetic barrier to resistance PI resistance uncommon with failure of boosted PIs Single-pill combination regimen available with DRV DISADVANTAGES Metabolic complications (less likely with DRV and ATV than with older PIs) GI intolerance Higher potential for drug interactions (CYP450), especially with RTV Graphic: aidsinfo.nih.gov January 2020 ARV Components in Initial Therapy: NNRTIs ADVANTAGES Long half-lives Less metabolic toxicity (dyslipidemia, insulin resistance) vs. some PIs Single-pill combination regimens available with DOR, EFV, and RPV DISADVANTAGES Low genetic barrier to resistance High rates of NNRTI resistance if virologic failure Cross-resistance among most NNRTIs EFV: high rate of CNS adverse effects RPV: lower efficacy if HIV RNA >100,000 or CD4 <200 Rash; hepatotoxicity CYP450 drug interactions Graphic: aidsinfo.nih.gov January 2020 Adverse Effects Important to anticipate and overcome ART toxicities in order to achieve ART success over a lifetime Consider potential adverse effects when selecting ARV regimen; also consider overlapping toxicities of patient’s other medications, drug-drug interactions, patient’s comorbidities, and previous history of ARV intolerance January 2020 Adverse Effects: NRTI Class Effects Lactic acidosis and hepatic steatosis (with older NRTIs; not likely with 3TC, FTC, ABC, TAF, TDF) Lipodystrophy (with older NRTIS, especially d4T, AZT; not likely with 3TC, FTC, ABC, TAF, TDF) January 2020 Adverse Effects: Individual NRTIs (1) Emtricitabine (FTC) Minimal toxicity Hyperpigmentation In HBV coinfection, exacerbation of HBV if discontinued Lamivudine (3TC) Minimal toxicity In HBV coinfection, exacerbation of HBV if discontinued January 2020 Adverse Effects: Individual NRTIs (3) Abacavir (ABC) Hypersensitivity reaction (contraindicated if HLA-B*5701 positive) Rash Possible increased risk of MI Tenofovir alafenamide (TAF) Tenofovir disoproxyl fumarate (TDF) Renal impairment* (increased Cr, proteinuria, metabolic acidosis, other) Decrease in bone-mineral density* In HBV coinfection, exacerbation of HBV if discontinued Headache GI intolerance Weight gain (TAF) * Less likely with TAF vs TDF January 2020 Adverse Effects: INSTI Class Effects Rash, hypersensitivity reaction Insomnia, depression Possible weight gain January 2020 Adverse Effects: Individual INSTIs Raltegravir (RAL) Nausea Headache Diarrhea CPK elevation, myopathy, rhabdomyolysis Bictegravir (BIC) and Dolutegravir (DTG) Headache Insomnia DTG: increased Cr* Weight gain Elvitegravir/cobicistat (EVG/c) Increased Cr* Increased risk of TDF-related nephrotoxicity Nausea, diarrhea Weight gain * Inhibition of Cr secretion; no effect on glomerular function January 2020 Adverse Effects: PI Class Effects Hyperlipidemia (boosted PIs) Lipodystrophy (not likely with ATV or DRV) Hepatotoxicity GI intolerance Possibility of increased bleeding risk for hemophiliacs Drug-drug interactions January 2020 Adverse Effects: Individual PIs Atazanavir (ATV) Hyperbilirubinemia PR prolongation Nephrolithiasis, cholelithiasis CKD Darunavir (DRV) Rash Liver toxicity Possible increased risk of cardiovascular events January 2020 Adverse Effects: Pharmacokinetic Boosters Both PK boosters: GI intolerance Increased risk of renal toxicity if given with TDF Increased lipids if given with PIs Ritonavir (RTV, /r) Hyperglycemia Hepatitis Cobicistat (COBI, /c) Increased serum Cr (inhibition of Cr secretion; no effect on glomerular function)  January 2020 Adverse Effects: NNRTI Class Effects Rash, including Stevens-Johnson syndrome Hepatotoxicity (especially NVP) Drug-drug interactions January 2020 Adverse Effects: Individual NNRTIs Efavirenz (EFV) Neuropsychiatric Dyslipidemia QTc prolongation Doravirine (DOR) Sleep disturbance, dizziness Depression Etravirine (ETR) Nausea Rilpivirine (RPV) Depression, insomnia QTc prolongation Increased serum Cr (inhibition of Cr secretion; no effect on glomerular function) January 2020 Adverse Effects: Individual Entry Inhibitors Maraviroc (MVC) Rash Abdominal pain Cough Hepatotoxicity Musculoskeletal symptoms Orthostatic hypotension, especially if severe renal disease Enfuvirtide (ENF, T-20) Injection-site reactions Hypersensitivity reaction Increased risk of bacterial pneumonia Ibalizumab (IBA) Diarrhea Rash Increased creatinine Fostemsavir (FOS) Nausea, diarrhea QTc prolongation January 2020 Websites to Access the Guidelines AETC National Coordinating Resource Center https://aidsetc.org AIDSInfo https://aidsinfo.nih.gov January 2020 About This Slide Set This presentation was prepared by Susa Coffey, MD, for the AETC National Resource Center in January 2020. Visit the AETC NCRC website for the most current version. https://aidsetc.org