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M01 S04 L07 ART Roxas
- 1. SHIP Telehealth Antiretroviral Agents Evalyn A. Roxas, MD, MPH ©, FPCP, FPSMID Infectious Diseases Specialist Cllinical Associate Professor,Sectionof InfectiousDiseases,UP-PGH AssistantProfessor,DepartmentofMedicalMicrobiology,UP-CPH September 13, 2018
- 2. Module 1- Lecture 7: ART Dosing and Side Effects
- 3. At the end of this session, the participants should be able… 1. To appreciate the importance of discovery of antiretroviral drugs 2. To understand the different types of antiretroviral drugs a. mechanism of action b. side effects c. dosing 3. To know the 2016 WHO guidelines on the use of antiretroviral drugs for treating and preventing HIV infection a. when to start b. what to start Objectives
- 4. Timeline of ARV Approvals 1987: Zidovudine1987: 1st NRTI Approved 1995: 1st PI 1996: 1st NNRTI 2003: 1st Fusion Inhibitor Entry inhibitors, Integrase inhibitors 1995: Lamivudine, Invirase® 1996: Nevirapine, Ritonavir, Indinavir 2003: T-20, Atazanavir, Emtricitabine, Fosamprenavir 2005: Tipranavir 2006: Darunavir 2007: Maraviroc 1991: Didanosine 1992: Zalcitabine 1994: Stavudine 1997: Delavirdine, Nelfinavir, Fortovase® 1998: Abacavir, Efavirenz 1999: Amprenavir 2000: Lopinavir/ritonavir 2001: Tenofovir
- 5. Currently, 51 DOH-designated treatment facilities offering anti-retroviral drugs in the Philippines. As of August 2017, a total of 22,413 PLHIV are currently enrolled on ART – 33% of the estimated total number of PLHIV (67,000) by the end of 2017. By 2022, the goal is to provide ART to 90% of PLHIV. www.doh.gov.ph
- 6. 1200 1000 800 600 400 200 0 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11+ 0 1/2 1/4 1/8 1/16 1/32 1/64 1/128 1/256 1/512 CD4+T-cells,cells/mL PlasmaViremia(DilutionalTiter) Clinical latency Opportunistic diseases Constitutional symptoms Death Acute HIV syndrome wide dissemination of virus seeding of lymphoid organs Primary infection Weeks Years Natural History of HIV Disease
- 7. HAART Improves Outcomes1 1Palella FJ et al. N Engl J Med 1998 March; 338:853-60.
- 8. What is the Goal of Treatment? Maximize Viral Suppression Restore and Preserve Immunological Function Improve Quality of Life Reduce HIV-related Morbidity and Mortality
- 10. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs) â—ĽAbacavir â—ĽDidanosine â—ĽEmtricitabine â—ĽLamivudine â—ĽStavudine â—ĽTenofovir â—ĽZalcitabine â—ĽZidovudine
- 11. NRTI Mechanism of Action â—ĽNRTIs mimic other nucleosides and are incorporated into the DNA strand â—ĽThey prevent the addition of the natural nucleosides into the DNA strand â—ĽNRTIs inhibit the viral reverse transcriptase enzyme â—ĽEnzyme responsible for transcribing viral RNA into double stranded DNA â—ĽThis halts the production of new virions Clinical Pharmacology 2007. Gold Standard, Inc.
- 12. 1 2 3 4
- 13. Zidovudine (AZT) • Zidovudine (ZDV), also known as azidothymidine (AZT) • Oldest ARV (1987) • Thymidine analogue • SE: headaches, fever, and nausea • Toxicities: rash, anemia, neutropenia, lactic acidosis, hepatotoxicity, cardiomyopathy, and myopathy • These conditions were found to be reversible upon reduction of AZT dosages • For lactic acidosis: usual symptoms are nonspecific – tired, muscle pain, abdominal pain • Lactic acidosis – medical emergency, stop meds, admit, check ABG and (if available) lactate level NRTIs
- 14. Lamivudine (3TC) • Originally developed for hepatitis B • Good activity against HIV at higher doses than that for Hepatitis B • Cytidine analogue • Well tolerated, allergies rare • Potential for lactic acidosis, but usually the last suspect • SE: nausea, diarrhea, headaches, feeling tired, and cough • Toxicities: liver disease, lactic acidosis, and worsening hepatitis B among those already infected • Can be taken with or without food • High level resistance is associated with the M184V/I mutation • Long-term use of lamivudine can trigger a resistant hepatitis B virus (YMDD) mutant. NRTIs
- 15. Tenofovir (TDF) • Tenofovir disoproxil fumarate (tenofovir DF) • Nucleotide analog reverse transcriptase • High barrier to resistance • Very good activity, drug of choice especially for HBV coinfection (with 3TC) • SE: nausea; occasional dizziness, diarrhea, headache • Toxicities: Lactic acidosis, liver toxicity, decreased bone mineral density • Potential to cause Fanconi-like syndrome – monitor creatinine; Avoid in renal failure • Low allergy potential • Can be taken with or without food. • Pregnancy category B drug • Passed through breast milk and could have serious side effects on a child who is breastfed. NRTIs
- 16. Emtricitabine (FTC) • Fixed-dose combination with tenofovir disoproxil (Truvada) or triple combination of emtricitabine, tenofovir and efavirenz (Sustiva) • Cytidine analogue • SE: unusual; diarrhea, headache, nausea, and rash. • More severe side effects: hepatotoxicity or a lactic acidosis. NRTIs
- 17. Stavudine (D4T) • Avoid as much as possible • Metabolic side effects, wasting • High potential for lactic acidosis NRTIs
- 18. â—ĽAdverse Effect â–Ş Mitochondrial toxicity â–Ş Increase the risk of lactic acidosis with hepatic steatosis â–Ş Increase transaminases â–Ş Lipid metabolism disorders â–Ş Lipodystrophy NRTI
- 19. 2-NRTI as part of Combination Regimen â—Ľ Most dual nucleoside regimens included one thymidine based drug, specifically zidovudine or stavudine. These drugs, when used along with lamivudine as two-NRTI backbones of potent combination regimens, have durable virologic potency for over five years â—Ľ Side effects of these agents however, may make it necessary to closely monitor for toxicities or to prescribe alternative NRTIs for selected patients.
- 20. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) â—ĽDelavirdine â—ĽEfavirenz â—ĽNevirapine
- 21. Mechanism of Action â—ĽNNRTIs also inhibit the viral reverse transcriptase enzyme but have a different mechanism of action compared to NRTIs â—ĽNNRTIs bind directly to the reverse transcriptase enzyme Viral RNA double stranded DNA
- 22. 1 2 3 4
- 23. Nevirapine • Older NNRTI • High hepatotoxicity risk for Male with CD4<400 or Female CD4<250 • SE: rash, headache, nausea, feeling tired, and liver problems • Toxicities: severe skin rash to Steven Johnsons Syndrome • DO NOT USE with Anti-tuberculous drugs (levels become subtherapeutic) • Low barrier for resistance (K103N) • Safe for use during pregnancy NNRTI
- 24. Efavirenz • Newer NNRTI • Generally well tolerated • Can cause vivid dreams, avoid in patients with suicidal ideation • Low potential to cause rash and SJS • Can be used with Anti-Koch’s • TERATOGENIC, do not use in pregnant women NNRTI
- 25. NNRTI ◼HIV-2 is intrinsically resistant to most NNRTIs ◼AE ▪ GI ▪ Skin rash – rarely, Stevens -Johnson syndrome ▪ Numerous interactions with other drugs due to their metabolism by the CYP450 system
- 27. PI Mechanism of Action â—ĽProtease - enzyme is responsible for cleaving (cutting up) larger polyproteins into structural proteins and reverse transcriptase enzyme â—ĽProtease is needed to form a fully mature, functional virus that is able to replicate and produce more virus â—ĽProtease inhibitors prevent this enzyme from doing its job in the later steps of the viral life cycle Clinical Pharmacology 2007. Gold Standard, Inc.
- 29. Lopinavir-ritonavir • Combination PI (ritonavir for boosting) • Common side effects: diarrhea (improves with time), metabolic (lipid abnormalities, wasting) • Serious: pancreatitis • High barrier to mutation • Expensive • Lots of drug interactions: rifampicin, PPI’s, statins • Safe for pregnant • Special precaution: structural heart disease,IHD, or cardiomyopathies
- 30. â—ĽAE â–Ş Redistribution and accumulation of body fat â–Ş Central obesity â–Ş Dorsocervical fat enlargement â–Ş Facial and peripheralwasting â–Ş Breast enlargement â–Ş Cushingoid appearance â–Ş Inc in triglycerides and LDL â–Ş Glucose intolerance, insulin resistance
- 31. NNRTI vs. PI Based Regimens Pro Con NNRTI- based •Low pill burden •Spare PI class •Low barrier for developing drug resistance (K103N) PI- based •Potency •High barrier to developing resistance •Long-term metabolic consequences: dyslipidemia, insulin resistance, abnormal lipoaccumulation
- 32. Fusion Inhibitors Enfuvirtide - N/A; MOA: disrupts the HIV-1 molecular machinery at the final stage of fusion with the target cell, preventing uninfected cells from becoming infected â—ĽAE â–Ş Local injection site reactions â–Ş Hypersensitivity reactions â–Ş Eosinophilia
- 34. CCR5 inhibitors Maraviroc -N/A â—Ľ First in new class of agents â—Ľ binds to the CCR5 receptor on the membrane of human cells such as CD4 cells. This binding prevents the interaction of HIV-1 gp120 and human CCR5 which is necessary for entry into the cell. â—Ľ does not prevent HIV-1 entry into CXCR4-tropic or dual-tropic cells.
- 36. Antiretroviral Drugs Slow HIV Replication Integrase Inhibitors Block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell.
- 37. Integrase Inhibitors â—ĽRaltegravir â—ĽElvitegravir â—ĽUseful in salvage therapy for patients whose virus has mutated and acquired resistance to other drugs
- 38. Highly Active Antiretroviral Therapy (HAART)
- 40. Selecting a Regimen • Potency • Tolerability • Drug-drug interactions • Co-morbidities • Lifestyle (dosing convenience, etc) • Adherence • Pre-treatment CD4 cell count • Gender
- 44. 2002- WHO first published guidelines on the use of antiretroviral therapy (ART) for HIV infection among adults and adolescents 2006 -updates of the guidelines introduced the concept of a public health approach, with simplified and harmonized ART regimens 2013 - first revision by WHO into consolidated guidelines that address the use of ARV drugs for HIV treatment and prevention across all age groups and populations, based on the HIV service continuum. 2016- updates the 2013 consolidated guidelines on the use of antiretroviral drugs following an extensive review of evidence and consultations in mid-2015 • strong evidence has emerged to show that using ART earlier results in better clinical outcomes for people living with HIV compared with delayed treatment. • newer class of drugs – integrase inhibitors – is becoming more affordable for low- and middle-income countries. • Most countries have moved or are moving to provide lifelong ART regardless of CD4 cell count to all pregnant and breastfeeding women, and many are moving to implement viral load testing as the preferred means of monitoring people who are taking ART.
- 45. New recommendations • Provide lifelong ART to all children, adolescents and adults, including all pregnant and breastfeeding women living with HIV, regardless of CD4 cell count. • WHO has also expanded earlier recommendations to offer PrEP to selected people at substantial risk of acquiring HIV. • Alternative first-line treatment regimens are recommended, including an integrase inhibitor as an option in resource-limited settings and reduced dosage of a key recommended first-line drug, efavirenz, to improve tolerability and reduce costs.
- 50. 1. HAART improves outcomes (death) The goals of treatment are a. maximize viral suppression b. restore and preserve immunologic function c. reduce HIV related morbidity and mortality d. improve quality of life 2. Different types of antiretroviral drugs a. NRTI b. NNRTI c. PI d. Fusion inhibitor e. CCR5 inhibitors f. Integrase inhibitors Summary
- 51. 3. 2016 WHO guidelines on ART Strong evidence has emerged to show that using ART earlier results in better clinical outcomes for people living with HIV compared with delayed treatment. Newer class of drugs – integrase inhibitors – is becoming more affordable for low- and middle-income countries. Most countries have moved or are moving to provide lifelong ART regardless of CD4 cell count to all pregnant and breastfeeding women, and many are moving to implement viral load testing as the preferred means of monitoring people who are taking ART. Summary
- 52. 3. 2016 WHO guidelines on ART Most countries have moved or are moving to provide lifelong ART regardless of CD4 cell count to all pregnant and breastfeeding women, and many are moving to implement viral load testing as the preferred means of monitoring people who are taking ART. Summary
- 53. End
Editor's Notes
- 1. Adsorption - virus binds to the host cell. Penetration - virus injects its genome into host cell. 2. Virus fuses with cell membrane and empties contents into cell (RNA/DNA + reverse transcriptase) 3. Reverse transcriptase copies the viral RNA into DNA 4. Viral Genome Replication - viral genome replicates using the host's cellular machinery. (DNA moves into nucleus of host cell and inserts itself into host DNA) 5. Assembly - viral components and enzymes are produced and begin to assemble. (Viral DNA instructs cell to build new virus proteins and RNA) 6-7. Maturation - viral components assemble and viruses fully develop. (Proteins are assembled into new viruses) Release - newly produced viruses are expelled from the host cell.
- NRTI, NNRTI Integrase inhibitors Protease and maturation inhibitors Fusion inhibitors
- studies
- NRTI, NNRTI Integrase inhibitors Protease and maturation inhibitors Fusion inhibitors
- Inducers – nevirapine Inhibitors – delavirdine Mixed inducers/inhibitors - efavirenz
- Dorsocervical fat enlrgement – buffalo hump
- Active only against HIV 1 Enfuvirtide is indicated for the treatment of HIV-1 infection, in combination therapy with other antiretrovirals, in patients where all other treatments have failed.
- (SelzentryTM) Approved August 6th, 2007
- The first integrase inhibitor approved by the U.S. Food and Drug Administration (FDA) was raltegravir (brand name Isentress), approved on October 12, 2007 Since integrase inhibitors target a distinct step in the retroviral life cycle, they may be taken in combination with other types of HIV drugs to minimize adaptation by the virus. They are also useful in salvage therapy for patients whose virus has mutated and acquired resistance to other drugs.