Overview of Antiretrovirals for HIV Treatment
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Overview of Antiretrovirals for HIV Treatment Margaret Fikrig, MD July 20, 2020 133 AN AIDS TIMELINE: The 1st Decade RONALD REAGAN 1981-1989 GEORGE H.W. BUSH 1989-1993 ’82 ’85 ’87 AZT approved “AIDS” First HIV test SCIENCE/CLINICAL ’83 Virus isolated INTERNATIONAL 1981 1985 1986 1987 1988 1989 1990 134 AN AIDS TIMELINE: The 2nd Decade GEORGE H.W. BUSH 1989-1993 WILLIAMWILLIAM CLINTON CLINTON 1993 1993-2000-2000 92’ ddl/ddC 93’ d4t Dual NRTI’s HAART ’97: NEL, DLV, Combivir ’95: Saquinavir ’96: NVP, IDV, RIT ’92 AIDS ’96 HIV -’94 leading cause viral load ACTG SCIENCE/CLINICAL of death approved adults 25-44 076 for yrs old PMCT AIDS Deaths Red down 40% Ribbon due to Tony HAART Awards INTERNATIONAL 1991 1992 1993 1994 1995 1996 1997 1998 1999 135 An AIDS Timeline: The 3rd Decade GEORGE W. BUSH 2001-2008 BARACK H. OBAMA 2009 - Present ’00 ’01 ’03 ‘04 ’05 ‘06 ’07 ’08 ’11 ’12 ’13 Trizivir, Tenofovir Fuzeon Truvada TPV MVC ETV RPV Stribild Dolutegravir DRV Complera Kaletra Raltegravir Atripla SCIENCE/CLINICAL ’00 ’04 ’10 ’12 International 13th National PEPFAR: AIDS Int’l HIV/AIDS $15B for Conference AIDS Strategy Conf. HIV/AIDS Washington, over a in ACA passed DC Durban period of 5 South years Africa INTERNATIONAL 25 30 years years 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 136 An AIDS Timeline: The 3rd Decade BARACK H. OBAMA 2009 - 2017 DONALD J TRUMP 2017-PRESENT ’11 ’13 ‘14 ’15 ’12 ’16 ’17 ’18 ’19 Care RPV Stribild Dolutegravir Odefsey Continuum Doravirine Triumeq START Descovy Juluca USPSTF Complera Delstrigo Hope Act approved study recs PrEP, Dovato SCIENCE/CLINICAL Biktarvy Symtuza ’12 Ibalizumab International AIDS Conference Washington, DC INTERNATIONAL 30 40 years years 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 137 139 Chain Termination with NRTIs If zidovudine was the last nucleoside to be added, then the RT enzyme can no longer add new nucleosides (1) Thymidine added, chain (2) Zidovudine added, chain elongation can continue termination occurs THY ZDV OH N3 YES NO X P P P P P P OH RT enzyme OH RT enzyme NNRTIs Mechanisms of Action • Non-nucleoside reverse transcriptase inhibitors • Structurally diverse, hydrophobic molecules • Inhibit HIV-1 replication (not HIV-2) by binding to RT in a pocket adjacent to the catalytic site; results in the distortion of the key catalytic aspartic acid residues. • Efavirenz (EFV), Nevirapine (NVP), Etravirine (ETR), Rilpivirine (RPV) and Doravirine 141 Protease is an aspartic protease. Most PIs are synthetic 53 53 peptide like compounds 54 54 designed to mimic a natural 46 46 dipeptide cleavage site 82 82 84 84 20 20 63 63 10 24 2410 90 90 71 71 142 Integrase Strand Transfer Inhibitors (INSTI’s) a Linear PIC Viral DNA PIC Integrase enzyme HO-3-AC CA-3-OH INSTIs TG GT CD4+ T cell cytoplasm LTRs Nucleus 1 & 2 2-LTRs LTRs Integration Gap repair Lataillade & Kozal: AIDS Patient care & STDs, 2006 Entry Inhibitors • Fusion Inhibitors (FI): T20 - Fuzeon • Inhibits HIV-1 attachment/fusion by binding to gp41 and thus prevents HIV binding to T cell • CCR5 Inhibitor: Maraviroc • Inhibits HIV-1 entry through the CCR5 receptor R5 Viruses Dual Viruses X4 Viruses •Utilize the CCR5 co-receptor only •Can utilize both •Utilize the CXCR4 •Prevalent in early disease co-receptors co-receptor only •Emerge in later disease •Associated with accelerated CD4 T-cell decline CD4 T cell surface CXCR4 CCR5 145 Berger EA et al, Nature 1998;391:240 HIV-1 gp41 gp120 CD4 CCR5 T cell surface 146 HIV-1 HIV-1 RNA HIV-1 nucleocapsid T cell 147 How CCR5 antagonists binds to CCR5 causing a conformational change CD4 CCR5 CCR5 antagonist T cell surface 148 DHHS HIV Treatment Guidelines • Last updated December 18, 2019 • https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandad olescentgl.pdf 149 Goals of Treatment • Reduce HIV-related morbidity; prolong duration and quality of survival • Restore and/or preserve immunologic function • Maximally and durably suppress HIV viral load • Prevent HIV transmission 15 0 When to Start ART • Current recommendation: ART for all HIV infected patients is based on START study • START Study opened in March 2011, included 215 sites in 35 countries, enrolled 4685 patients with CD4 over 500. Half started ART immediately and half started when CD4<350. • Measured outcomes of AIDS events, non-AIDS events such as CVD, and death. • The trial was stopped early in March 2015 when analysis showed reduction of 53% in risk for serious illness or death and 70% risk reduction for AIDs defining illnesses. 15 1 15 2 153 New rec for screening for DM •2.3 In conditions associated with an altered relationship between A1C and glycemia, such as sickle cell disease, pregnancy (second and third trimesters and the postpartum period), glucose-6- phosphate dehydrogenase deficiency, HIV, hemodialysis, recent blood loss or transfusion, or erythropoietin therapy, only plasma blood glucose criteria should be used to diagnose diabetes. B Prior guidelines used A1c q 3-6 mos if abnormal, and q12 mos if normal. 154 155 Initial Treatment: Choosing Regimens • Recommended regimens have comparable efficacies, but vary in pill burden, drug side effects, drug interactions, and propensity to select for resistance if adherence is suboptimal. • Regimens are tailored for the individual based on: – Pretreatment HIV RNA level – Pretreatment CD4 count – HIV genotypic drug resistance testing – HLA-B 5701 status – Anticipated adherence – Patient comorbidities • CVD, hyperlipidemia, renal disease, osteopenia, psychiatric illness • Pregnancy or its potential • Coinfection with Hep B, Hep C, tuberculosis, cryptococcus – Regimen-Specific Considerations • Regimen’s barrier to resistance • Potential adverse drug effects • Potential drug interactions • Convenience- pill burden, dosing frequency, food requirements 15 6 DHHS Guidelines last updated December, 2019 aidsinfo.nih.gov DHHS Guidelines: Preferred Initial ART 157 DHHS Guidelines – First line ART INSTI Integrase Inhibitors + Nucleoside Reverse Transcriptase OR Boosted Inhibitors 2 NRTI PI/r Protease + Inhibitors OR + Non Nucleoside NNRTI Reverse Transcriptase Inhibitors 158 DHHS Guidelines last updated December,2019 aidsinfo.nih.gov First Line Approved STR Triumeq Biktarvy DTG/ABC/3TC BIC/TAF/FTC • If patient is HBV co-infected Use TDF/FTC or TAF/FTC • Check HLA B*5701 before the use of Abacavir • Dolutegravir should not be used in first trimester of pregnancy (Risk for Neural Tubal Defect 0.3%vs. 0.1%) 159 DHHS Guidelines last updated December,2019 aidsinfo.nih.gov DOVATO: ART of 2 • If patient is HBV co-infectedDovato Need to Use TDF/FTC or TAF/FTC • 3TC/DTG should not be3TC/DTG used for HIV VL >500, 000 copies, if starting before GT or HBV testing is back • Dolutegravir should not be used in first trimester of pregnancy 160 DHHS Guidelines last updated December,2019 aidsinfo.nih.gov DHHS Guidelines last updated December, 2019 aidsinfo.nih.gov DHHS Guidelines: Preferred Initial ART 161 Backbone Drugs (2NRTI’s) • Abacavir/lamivudine- ABC/3TC- Epzicom – Pro: Less renal and bone toxicity than TDF/FTC – Con: -- Requires HLA B5701 testing due to hypersensitivity reaction – Has been linked with increased cardiovascular events in some studies – Less effective than TDF/FTC when initial VL>100,000 (not true with dolutegravir) – Not used when CrCl<50 as 3TC must be dose adjusted – Cannot be used in patients with Hep B co-infection • Tenofovir/emtricitabine- TDF/FTC- Truvada – Pro: -Effective in HBV co-infected patients. -More favorable lipid effects than ABC or TAF – Con: -Renal toxicity including proximal tubulopathy and AKI -Decreases BMD Not used with CrCl<50 as FTC must be dose adjusted • Tenofovir alafenamide/FTC- Descovy – Pro- Effective in HBV co-infected patients - Less renal and bone toxicity than TDF -Can be used with CrCl down to 30 Con- LDL, HDL and TG increase more than with TDF - Associated with weight gain when switched from TDF 162 Integrase Strand Transfer Inhibitors (INSTI’s) • Raltegravir – RAL- (Isentress) – Pro: - Longest experience (2007). – No food requirement – No CYP3A4 interactions – Con: - Twice daily dosing of 400mg tablet, 400mg – or two 600mg tablets daily » ( FDA approved May 2017) – Lower genetic barrier to resistance than DTG – Increased CK, myopathy and rhabdomyolosis reported * – Absorption reduced by cation containing substances (Al, Ca, Fe, Mg, Zn) * – Rare depression and SI in patients with pre-existing issues* – Insomnia * – Increased weight gain when used with TAF than with other antiretrovirals* 163 INSTI’s • Dolutegravir- DTG (Tivicay) – Pro: - Once daily – Higher barrier to resistance than EVG or RAL – Comes coformulated with ABC/3TC (Triumeq) – Comes coformulated with RPV (Juluca) – No food requirement – No CYP3A4 interactions. – Con: - Inhibits renal tubular secretion of Cr and can increase serum Cr without affecting GFR -Increases metformin levels two fold. -Increased risk of neural tube defect 164 INSTI’S CONTINUED • Bictegravir – Pro: - Once daily – Comes co-formulated with TAF/FTC – Higher barrier to resistance than EVG,RAL, similar to DTG Con: -diarrhea, headache, fatigue, weight gain 165 166 167 168 169 12/2019 DHHS guidelines: Alternate Regimens in certain clinical situations 170 Genvoya • TAF/FTC/Elvitegravir/cobicistat • Cons: – Cobi is a strong cytochrome P (CYP) 3A4 inhibitor so it has more drug interactions – ELV has a lower barrier to resistance than dolutegravir or bictegravir – Cobi inhibits tubular secretion of Cr and can increase serum Cr without affecting GFR – Should be taken with food STRIBILD-