HIV Integrated Therapeutics 3 Spring 2023 Part 2 PDF

The Management of HIV Integrated Therapeutics 3 Spring 2023 – Part 2 Monika N. Daftary, PharmD, BCPS, AAHIVP Professor & Chair Howard University, College of Pharmacy 1 Objectives Identify and review goals of therapy Review the classification and mec...

The Management of HIV Integrated Therapeutics 3 Spring 2023 – Part 2 Monika N. Daftary, PharmD, BCPS, AAHIVP Professor & Chair Howard University, College of Pharmacy 1 Objectives Identify and review goals of therapy Review the classification and mechanism of action of antiretroviral drugs (NRTIs, NNRTIs, protease inhibitors, entry inhibitors, PK enhancers, PAIs and INSTIs) Major class specific and agent specific toxicities Identifying an appropriate regimen Identify and discuss current updates in the DHHS Guidelines Incorporate new information into clinical practice 2 Recap 3 Currently Available ARVs Nucleoside Reverse Transcriptase Inhibitors (Also Nucleotide) (NRTIs) Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Protease Inhibitors (PIs) Integrase Strand Transfer Inhibitors (INSTIs) Entry Inhibitors: -Fusion Inhibitors -CCR5 Antagonists -Post-Attachment Inhibitor -Attachment Inhibitor Pharmacokinetic Enhancers Capsid Inhibitor *Combination HIV Medicines 4  Current ARV Medications NRTI PI Fusion Inhibitor  Abacavir (ABC)  Atazanavir (ATV)  Enfuvirtide  Emtricitabine (FTC)  Darunavir (DRV) (ENF, T-20)  Lamivudine (3TC)  Fosamprenavir CCR5 Antagonist  Tenofovir DF (TDF) (FPV)  Maraviroc (MVC)  Tenofovir alafenamide (TAF)*  Lopinavir (LPV) PAI  Zidovudine (AZT, ZDV)  Saquinavir (SQV)  Ibalizumab (IBA) Didanosine (DDI)  Tipranavir (TPV)  Indinavir (IDV) AI Stavudine (D4T)  Nelfinavir (NFV) Fostemsavir NNRTI Integrase Inhibitor Pharmacokinetic (PK)  Efavirenz (EFV) (INSTI) Booster  Etravirine (ETR)  Dolutegravir (DTG)  Ritonavir (RTV)  Nevirapine (NVP)  Raltegravir (RAL)  Cobicistat (COBI)  Rilpivirine (RPV)  Cabotegravir (CAB) Capsid Inhibitor  Doravirine (DRV)  Bictegravir (BIC) Lenacapavir * TAF available only in co-formulations for HIV indication. Drug Therapy Selection 6 Initial ART Regimens: DHHS Categories Initial Regimens for Most People with HIV  Randomized controlled trials show optimal and durable virologic efficacy  Favorable tolerability and toxicity profiles  Easy to use Recommended Initial Regimens in Certain Clinical Situations  Effective but have potential disadvantages, limitations in certain patient populations, or less supporting data  May be the optimal regimen for individual patients Initial Treatment: Choosing Regimens Main categories:  1 INSTI + 2 NRTIs (Most preferred)  1 PK-boosted PI + 2 NRTIs  1 NNRTI + 2 NRTIs  1 NRTI + 1 INSTI (added in December 2019)  Regimens to Consider when ABC, TAF, and TDF Cannot be Used or Are Not Optimal: Combination of INSTI, boosted PI, or NNRTI + 2 NRTIs is preferred for most patients NRTI pair should include 3TC or FTC Few clinical end points to guide choices: recommendations based mostly on rates of HIV RNA suppression and severity of adverse effects Individualize regimen choice  Initial Therapy: Dual-NRTI Pairs  Once-daily dosing Tenofovir  In several single-pill regimen co-formulations  High virologic efficacy disoproxil/  Active against HBV Emtricitabine  Potential for renal and bone toxicity (Truvada)  Avoid in patients with renal insufficiency  Once-daily dosing Abacavir/  Co-formulated with DTG in a single-pill regimen  Use only for patients who are negative for HLA- Lamivudine B*5701 (risk of hypersensitivity reaction if positive) (Epzicom)  Possible risk of cardiovascular events; caution in patients with CV risk factors  Possible inferior efficacy if baseline HIV RNA >100,000 copies/mL  Initial Therapy: Dual-NRTI Pairs  Once-daily dosing Tenofovir  In several single-pill regimen co-formulations  High virologic efficacy Alafenamide/  Active against HBV Emtricitabine  Renal and bone toxicity is less common than with (Descovy) TDF/FTC  Approved for eGFR ≥30 mL/min  In some combinations, use supported by bioequivalence/bioavailability studies or randomized switch studies  No randomized comparisons with ABC/3TC  Initial Regimens for Most People with HIV For people who do not have a history of long-acting cabotegravir use as PrEP, the following regimens are recommended: INSTI + 2 NRTIs Bictegravir-tenofovir alafenamide-emtricitabine (Biktarvy) Dolutegravir-abacavir-lamivudine—only for individuals who are HLA-B*5701 negative and without chronic HBV coinfection (Triumeq) Dolutegravir plus (tenofovir alafenamide or tenofovir DF) plus (emtricitabine or lamivudine) (Tivicay plus Descovy or Truvada) Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the people with HIV. September 21, 2022. 11  Initial Regimens for Most People with HIV For people who do not have a history of long-acting cabotegravir use as PrEP, the following regimens are recommended: INSTI + 1 NRTI Dolutegravir-lamivudine —except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom antiretroviral therapy is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available (Dovato) Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the people with HIV. September 21, 2022. 12  Initial Regimens for Most People with HIV For people with HIV and a history of using long-acting cabotegravir as PrEP, integrase genotypic drug resistance testing should be done before the start of antiretroviral therapy. If treatment is begun prior to the results of genotypic testing, the following regimen is recommended: Boosted PI + 2 NRTIs Darunavir (boosted with cobicistat or ritonavir) plus (tenofovir alafenamide or tenofovir DF) plus (emtricitabine or lamivudine)—pending the results of the genotype test Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the people with HIV. September 21, 2022. 13 Initial ART Regimens Biktarvy Triumeq Dovato Truvada + Descovy + Boosted PI Tivicay Tivicay + 2 NRTIs 14  Recommended Initial Regimens in Certain Clinical Situations INSTIs + 2 NRTIs Elvitegravir-cobicistat-tenofovir alafenamide- emtricitabine Elvitegravir-cobicistat-tenofovir DF-emtricitabine Raltegravir plus tenofovir DF-emtricitabine Raltegravir plus tenofovir alafenamide- emtricitabine Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the people with HIV. September 21, 2022. 15  Recommended Initial Regimens in Certain Clinical Situations Boosted PI plus 2 NRTIs: (in general, boosted Darunavir is preferred over boosted Atazanavir): Darunavir plus ritonavir plus (tenofovir alafenamide or tenofovir DF) plus (emtricitabine or lamivudine) Darunavir-cobicistat plus (tenofovir alafenamide or tenofovir DF) plus (emtricitabine or lamivudine) Atazanavir plus ritonavir plus (tenofovir alafenamide or tenofovir DF) plus (emtricitabine or lamivudine) Atazanavir-cobicistat plus (tenofovir alafenamide or tenofovir DF) plus (emtricitabine or lamivudine) Darunavir plus ritonavir plus abacavir-lamivudine—if HLA-B*5701 negative (BII) Darunavir-cobicistat plus abacavir-lamivudine—if HLA-B*5701 negative (BII) Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the people with HIV. September 21, 2022. 16  Recommended Initial Regimens in Certain Clinical Situations NNRTI + 2 RTIs Doravirine-tenofovir DF-lamivudine Doravirine plus tenofovir alafenamide-emtricitabine Efavirenz (600 mg)-tenofovir DF-emtricitabine Efavirenz (400 mg)-tenofovir DF-emtricitabine Efavirenz (600 mg) plus tenofovir alafenamide-emtricitabine Rilpivirine-tenofovir DF-emtricitabine—if HIV RNA 200 cells/mm3 Rilpivirine-tenofovir alafenamide-emtricitabine—if HIV RNA 200 cells/mm3 Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the people with HIV. September 21, 2022. 17  Recommended Initial Regimens in Certain Clinical Situations Regimens to Consider when Abacavir, Tenofovir alafenamide, and Tenofovir DF Cannot be Used or Are Not Optimal Dolutegravir-lamivudine (AI), except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom antiretroviral therapy is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available Darunavir plus ritonavir once daily plus raltegravir twice daily (CI)—if HIV RNA 200 cells/mm3 Darunavir plus ritonavir once daily plus lamivudine (CI) Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. What to start: initial combination regimens for the people with HIV. September 21, 2022. 18  Selecting Initial ART Regimen: Factors to Consider Patient  HIV RNA; CD4 count Characteristics  HIV resistance test results  HLA-B*5701 status  Patient preferences  Anticipated adherence Comorbidities or  Cardiovascular disease, hyperlipidemia, renal Other Conditions disease, osteoporosis, psychiatric illness, others  Pregnancy or pregnancy potential  Coinfections: HCV, HBV, TB Regimen  Genetic barrier to resistance Characteristics  Potential adverse effects  Drug interactions with other medications  Convenience (pill #, dosing frequency, fixed- dose combinations, food requirements)  Cost Selecting Initial ART Regimen: Selected Clinical Scenarios CD4 100,000 Do not use: higher rate of virologic failure  RPV-based ART  ABC/3TC + EFV or ATV/r  DRV/r + RAL HLA-B*5701 positive Do not use ABC: risk of abacavir hypersensitivity Must treat before Avoid NNRTI-based regimens and DTG/3TC. Avoid ABC. resistance test Recommended ART Regimens: BIC/TAF/FTC results are known DTG plus (TAF or TDF) plus (3TC or FTC) (DRV/r or DRV/c) plus (TAF or TDF) plus (3TC or FTC)  Selecting Initial ART Regimen: Selected Clinical Scenarios One-pill regimen  DTG/ABC/3TC (only if HLA-B*5701 negative)  EFV/TDF/FTC  EVG/COBI/TAF/FTC  EVG/COBI/TDF/FTC  RPV/TAF/FTC (if HIV RNA 200 cells/µL)  RPV/TDF/FTC (if HIV RNA 200 cells/µL)  **not full list** Food effects Should be taken with food:  ATV/r or ATV/c  DRV/r or DRV/c  EVG/c/TAF/FTC  EVG/c/TDF/FTC  RPV/TAF/FTC  RPV/TDF/FTC Should be taken on empty stomach: EFV  Selecting Initial ART Regimen: Selected Clinical Scenarios Chronic kidney  Avoid TDF unless the patient has ESRD. disease (eGFR Use ABC or TAF.  ABC not associated with renal dysfunction 30 mL/min  Options when ABC or TAF cannot be used: -DTG plus 3TC -DRV/r plus 3TC -DRV/r plus RAL (if CD4 cell count >200 -cells/mm3 and HIV RNA 100,000 copies/mL, do not use with EFV or ATV/r) Psychiatric  Consider avoiding EFV and RPV: can illness exacerbate psychiatric symptoms; may be associated with suicidality High cardiac  Consider avoiding ABC and LPV/r: increased CV risk in some studies risk  BIC-, DOR-, DTG-, RAL-, or RPV-based regimens may be considered for those with high cardiac risk.  Selecting Initial ART Regimen: Selected Clinical Scenarios HAD  Avoid EFV-based regimens if possible  Favor DTG- or DRV-based regimens. Medication-  Opioid withdrawal may occur when EFV is assisted initiated in patients who are on a stable dose of methadone. treatment for  Clinical monitoring is recommended, as opioid medications used to treat opioid dependence dependence may need to be adjusted in some patients. Cardiac QTc  Consider avoiding EFV- or RPV-based regimens if patient is taking other medications with known risk interval of Torsades de Pointes, or in patients at higher risk prolongation of Torsades de Pointes.  Selecting Initial ART Regimen: Selected Clinical Scenarios Hyperlipidemia Associated with Dyslipidemia: PI/r or PI/c EFV EVG/c Can consider: BIC, DOR, DTG, RAL, and RPV have fewer lipid effects. Pregnancy If already on effective ART, should continue If not on ART, should start as soon as possible: should follow most recent guidelines: 2 NRTIs + INSTI (select) 2 NRTIs+ Boosted PI Patients of childbearing See above. potential who are planning to become pregnant or who are sexually active and not using effective contraception Selecting Initial ART Regimen: Selected Clinical Scenarios HBV  Use TDF or TAF with FTC or 3TC, whenever possible: use 2 NRTIs with activity against both HIV and HBV  If TDF and TAF are contraindicated: treat HBV with FTC or 3TC + entecavir + suppressive ART regimen HCV  Consult current recommendations TB  TAF and BIC are not recommended with any rifamycin- containing regimen.  If rifampin is used:  EFV: no dosage adjustment needed  RAL: increase RAL to 800 mg BID  DTG: 50 mg BID (only if no significant INSTI mutations)  The following are not recommended: PI/c or PI/r, BIC, EVG, DOR, RPV, or TAF.  If PI-based regimen: use rifabutin in place of rifampin Selecting Initial ART Regimen: Selected Clinical Scenarios Concern for  For many people with HIV, gaining weight after starting ART is part of a “return to health.” weight gain  However, some ARV regimens are associated with greater weight gain than others, suggesting that particular drugs may contribute to weight gain.  Initiation of INSTI-containing regimens, particularly BIC and DTG, has been associated with greater weight gain than NNRTI- or boosted PI-regimens.  Greater weight gain has been observed with initiation of TAF than TDF or with a switch from TDF to TAF.  ARV-associated weight gain appears to disproportionately affect women and Black and Hispanic people. Antiretroviral Drugs Not Recommended The following ARV drugs are no longer recommended for use because of suboptimal antiviral potency, unacceptable toxicities, high pill burden, or pharmacologic concerns: - delavirdine (DLV) -didanosine (ddI) -indinavir (IDV) -nelfinavir (NFV) -stavudine (d4T) 28 Antiretroviral Regimen Not recommended  Monotherapy with any antiretroviral  Dual-NRTI therapy  3-NRTI regimen (except ABC + 3TC + ZDV or possibly TDF + 3TC + ZDV) 29 Antiretroviral Components: Not Recommended  Atazanavir plus Indinavir  Cobicistat plus Ritonavir as Pharmacokinetic Enhancers  Didanosine plus Stavudine  Didanosine plus Tenofovir Disoproxil Fumarate  Two Non-Nucleoside Reverse Transcriptase Inhibitor Combinations  Emtricitabine + Lamivudine 30 Antiretroviral Components: Not Recommended  NVP initiation in women with CD4 counts of >250 cells/µL or in men with CD4 counts of >400 cells/µL  ETR + unboosted PI  ETR + RTV-boosted FPV or TPV  Unboosted DRV, SQV, TPV  Stavudine + Zidovudine  Tenofovir Alafenamide plus Tenofovir Disoproxil Fumarate 31 HAART-Associated Adverse Clinical Events Lactic Acidosis/Hepatic Steatosis Hyperglycemia/Diabetes Mellitus Fat Maldistribution Hyperlipidemia Increased bleeding episodes with hemophilia Osteopenia and Osteoporosis Rash 32 Clinical Pearls: NRTIs All NRTIs Lactic Acidosis and hepatomegaly with steatosis Increase LFTs, N, V, D, HA HBV Coverage except Abacavir Acute HBV exacerbation can occur if certain NRTIs stopped Others Abcavir: HLA-B*5701, medication card, do not rechallenge, CVD issue Emtricitabine: hyperpigmentation of palms/soles (see next slide) TDF vs TAF: TDF – renal issues, Fanconi Syndrome, decrease BMD Zidovudine: hematologic toxicity, myopathy Didanosine and Stavudine: pancreatitis, peripheral neuropathy 33 Hyperpigmentation of the Palms with Emtriva 34 Clinical Pearls: NNRTIs All NNRTIs Hepatotoxicity, rash Substrates of CYP3A4 and other isoenzymes Inducers: Efavirenz and Etravirine Cannot use with strong Inducers: Rilpivirine and Doravirine Efavirenz Psychiatric symptoms, CNS effects, can affect lipids Rilpivirine Depression Not be used with HIV RNA >100,000 and/or CD4