Lecture 15 - Antivirals

‭Antivirals vs. Antibiotics‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭ iruses are parasitic‬ V ‭Viruses are reliant on host cell to reproduce‬ ‭Decreased ability to be selectively toxic‬ ‭Antivirals are less effective than antibiotics‬ ‭Non-HIV Viral Infections: Herpes Viruses‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭ erpes simplex:‬‭HSV 1 and HSV 2 (ex. cold sores)‬ H ‭Varicella-zoster (ex. chicken pox)‬ ‭Herpes-zoster (ex. shingles)‬ ‭Cytomegalovirus (CMV)‬ ‭Treatment of Herpes‬‭Viruses‬ ‭Prototype‬ ‭‬ A ● ‭ cy‬‭clovir‬‭(Zovirax)‬ ‭●‬ ‭Famci‬‭clovir‬‭, valacy‬‭clovir‬ ‭Primary Indication‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭ SV1 & HSV2‬ H ‭Varicella-zoster‬ ‭Herpes-zoster‬ ‭CMV (minimal)‬ ‭Acyclovir‬ ‭MOA‬ ‭●‬ ‭Inhibition of viral replication by suppression of viral DNA‬ ‭○‬ ‭Inhibits DNA polymerase and blocks DNA strand growth‬ ‭●‬ ‭Prodrug‬ ‭●‬ ‭Administration: Oral (tx or prophylactic), topical, IV‬ ‭Pharmacokinetics‬ ‭●‬ ‭Renal elimination‬ ‭ dverse Effects‬ A ‭Topical‬ ‭●‬ ‭Burning, stinging at site of application‬ ‭●‬ ‭No systemic absorption‬ ‭Oral‬ ‭●‬ ‭N/V/D, headache, vertigo‬ ‭IV‬ ‭‬ P ● ‭ hlebitis (inflammation at infusion site)‬ ‭●‬ ‭Nephrotoxicity: Reversible‬ ‭○‬ ‭Increased risk in dehydrated patients/kidney impairment‬ ‭Oseltamivir (Tamiflu)‬ ‭MOA‬ ‭●‬ I‭ nhibits neuraminidase impacts viral replication‬ ‭●‬ ‭Prodrug‬‭; must be hydrolyzed‬ ‭Indications‬ ‭●‬ ‭Seasonal‬‭influenza‬‭(tx and prophylactic)‬ ‭●‬ ‭Influenza A (tx and prophylactic)‬ ‭Administration‬ ‭●‬ ‭Oral‬‭; initiate treatment within 48 hours of symptom‬‭onset‬ ‭Pharmacokinetics‬ ‭●‬ ‭Hepatic metabolism‬ ‭●‬ ‭Renal excretion‬ ‭Adverse Effects‬ ‭●‬ ‭GI: N/V/D‬ ‭●‬ ‭Neuropsychiatric‬‭effects: Confusion, delirium, hallucination‬ ‭●‬ ‭Hypersensitivity reaction:‬‭SJS‬ ‭Nirmatrelvir and Ritonavir (Paxlovid)‬ ‭ OA‬ M ‭Nirmatrelvir‬ ‭●‬ ‭Inhibits protease preventing processing of polyprotein precursors‬ ‭●‬ ‭Leads to inhibition of viral replication‬ ‭Ritonavir‬ ‭●‬ ‭Pharmacokinetic‬‭enhancer‬‭; no activity against virus‬ ‭●‬ ‭Inhibits metabolism of nirmatrelvir, resulting in increased nirmatrelvir plasma‬ ‭concentration‬ ‭Indications‬ ‭●‬ ‭Mild to moderate‬‭COVID-19‬ ‭●‬ ‭Non-hospitalized patients with risk of progression to severe illness‬ ‭Administration‬ ‭●‬ ‭Oral‬‭; initiate within 5 days of symptom onset‬ ‭Pharmacokinetics‬ ‭●‬ ‭P450 inhibitor (CYP3A)‬ ‭●‬ ‭Ritonavir 98-99%‬‭protein-bound‬ ‭●‬ ‭Renal excretion‬ ‭ dverse Effects‬ A ‭Hepatic Effects‬ ‭●‬ ‭Hepatitis‬ ‭●‬ ‭Elevation of transaminases‬ ‭Hypersensitivity Reactions‬ ‭●‬ ‭SJS‬ ‭●‬ ‭Anaphylaxis‬ ‭Drugs for HIV Infection‬ ‭HIV Statistics‬ ‭In the U.S.‬ ‭●‬ ‭1.1 million are HIV-positive‬ ‭●‬ ‭658,000 have died since 1981‬ ‭Globally‬ ‭●‬ ‭38 million people are currently living with HIV/AIDS‬ ‭●‬ ‭1.7 million children are HIV-positive‬ ‭HIV vs. AIDS‬ ‭Human Immunodeficiency Virus (HIV)‬ ‭●‬ ‭Infecting virus‬ ‭Acquired Immunodeficiency Syndrome (AIDS)‬ ‭●‬ ‭Syndrome that develops years after infection‬ ‭●‬ ‭Characterized by HIV-positive status and either:‬ ‭○‬ ‭CDT 4 cell count: < 200 cells/mL or…‬ ‭○‬ ‭AIDS deficiency illness, such as:‬ ‭‬ P ■ ‭ neumocystis pneumonia‬ ‭■‬ ‭Kaposi’s sarcoma‬ ‭■‬ ‭Tuberculosis‬ ‭HIV Transmission‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭ exual transmission‬ S ‭Transfusion‬ ‭Sharing needles‬ ‭Accidental needle stick/occupational‬ ‭exposure‬ ‭ ‬ ‭Pregnancy‬ ● ‭●‬ ‭Maternal/child transmission during‬ ‭breastfeeding‬ ‭Pathophysiologic Overview: HIV‬ ‭1.‬ H ‭ IV infects and kills off CD4 T‬ ‭lymphocytes‬ ‭2.‬ ‭Decreased CD4 T-cells → decreased‬ ‭immunity‬ ‭3.‬ ‭Increased risk for opportunistic infections and neoplasms‬ ‭HIV Replication Rate‬ ‭Initial Phase‬ ‭●‬ ‭Replication is massive due to high number of available CD4 T-cells (1-10 billion‬ ‭virions/day)‬ ‭●‬ ‭Immune response does not happen immediately‬ ‭●‬ ‭Patients may experience‬‭acute retroviral syndrome‬‭and can be acutely ill‬ ‭Second Stage‬ ‭●‬ ‭Host immune system responds‬ ‭●‬ ‭HIV plasma level declines‬ ‭●‬ ‭Patient may be asymptomatic for 10 years‬ ‭Last Stage (AIDS)‬ ‭●‬ ‭CD4 T-cell count is very low‬ ‭●‬ ‭Vulnerable to opportunistic infections‬ ‭Opportunistic Infections‬ ‭ ‬ I‭ nfections arising from organisms that don’t generally cause serious disease‬ ● ‭●‬ ‭HIV-positive individuals are highly susceptible due to decreased immunity‬ ‭●‬ R ‭ isk for opportunistic infection is highest‬ ‭among individuals with a CD4 T-cell count‬ ‭< 200 cells/mL‬ ‭●‬ ‭Antiretroviral therapy has greatly reduced‬ ‭incidence and mortality related to‬ ‭opportunistic infections‬ ‭Pharmacological Tx for HIV‬ ‭●‬ A ‭ ntiretroviral therapy (ART): Refers to a‬ ‭combination of drugs‬ ‭●‬ ‭Reduced the number of HIV-related deaths‬ ‭significantly in the U.S.‬ ‭●‬ ‭Treatment is very expensive and maoy be lifelong‬ ‭●‬ ‭So effective that HIV levels are almost undetectable‬ ‭Types of Antiretroviral Therapy‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭ everse transcriptase inhibitors‬ R ‭Integrase strand transfer inhibitors (INSTIs)‬ ‭Protease inhibitors (PIs)‬ ‭Fusion inhibitors‬ ‭Chemokine receptor agonists (CCR5)‬ ‭Post-attachment inhibitors‬ ‭Reverse Transcriptase Inhibitors‬ ‭●‬ N ‭ ucleoside/nucleotide reverse transcriptase‬ ‭inhibitors (NRTIs)‬ ‭●‬ ‭Non-nucleoside reverse transcriptase‬ ‭inhibitors (NNRTIs)‬ ‭ ucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)‬ N ‭General Characteristics‬ ‭●‬ ‭Active against‬‭HIV-1/HIV-2‬ ‭●‬ ‭Analogs of naturally occurring nucleotides/nucleosides‬ ‭○‬ ‭Thymine, guanine, adenine, cytosine‬ ‭●‬ ‭Adverse effects are associated with mitochondrial toxicity‬ ‭○‬ ‭Lactic acidosis‬ ‭○‬ ‭Hepatomegaly‬ ‭Prototype‬ ‭●‬ ‭Abacavir (Ziagen) “ABC”‬ ‭●‬ Z ‭ idovudine (Retrovir or AZT) was formally the first line NRTI but no longer‬ ‭recommended in the U.S.‬ ‭MOA‬ ‭●‬ I‭ nhibits HIV replication by suppressing synthesis of viral DNA‬ ‭●‬ ‭Converts to its active form intracellularly‬ ‭●‬ ‭Once incorporated into the DNA, it terminates the addition of the strand‬ ‭Therapeutic Benefits‬ ‭●‬ ‭Decreases viral load‬ ‭●‬ ‭Increases CD4 T-cell count‬ ‭●‬ ‭Delays onset of disease symptoms‬ ‭●‬ ‭Reduces symptom severity‬ ‭Adverse Effects‬ ‭●‬ ‭Fatigue/headache‬ ‭●‬ ‭Lactic acidosis‬‭(black box warning)‬ ‭○‬ ‭Nausea, fatigue, malaise, anorexia, hyperventilation‬ ‭●‬ ‭Hepatomegaly‬ ‭●‬ ‭Hypersensitivity reaction (5-8%)‬ ‭○‬ ‭Fever, rash, myalgia, GI disturbances, respiratory symptoms (early signs)‬ ‭Drug Interactions‬ ‭●‬ ‭Alcohol:‬‭ABC competes with the same enzyme needed‬‭to metabolize alcohol‬ ‭●‬ ‭Many potential drug-drug interactions‬ ‭ on-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)‬ N ‭Difference from NRTIs‬ ‭●‬ ‭No structural relationship with naturally occurring nucleosides‬ ‭●‬ ‭Bind to the active center of reverse transcriptase to cause direct inhibition of binding of‬ ‭nucleosides in DNA formation‬ ‭●‬ ‭Does not undergo active conversion in the cells‬ ‭●‬ ‭Only active against HIV-1‬ ‭Prototype‬ ‭●‬ ‭Efavirenz (Sustiva)‬ ‭MOA‬ ‭●‬ B ‭ inds directly with HIV reverse transcriptase (enzyme)‬ ‭●‬ ‭Then suppresses enzyme activity and replication‬ ‭Efavirenz Adverse Effects‬ ‭●‬ ‭CNS symptoms‬‭(most common)‬ ‭○‬ ‭Dizziness‬ ‭○‬ ‭Insomnia‬ ‭○‬ ‭Nightmares‬ ‭●‬ ‭Rash (common)‬ ‭○‬ ‭Mild-severe‬ ‭○‬ ‭Severe rash (may evolve into SJS)‬ ‭●‬ ‭Metabolized by P450‬‭enzymes‬ ‭●‬ ‭Teratogenicity‬ ‭○‬ ‭Avoid in pregnancy‬ ‭○‬ ‭Use two forms of birth control‬ ‭Protease Inhibitors (PIs)‬ ‭General Characteristics‬ ‭●‬ ‭Effective against HIV-1 and HIV-2‬ ‭●‬ ‭Most effective when used in‬‭combination with NRTIs‬ ‭MOA‬ ‭●‬ I‭ nhibits protease enzymes needed to complete the final step in HIV maturation‬ ‭●‬ ‭All PIs are‬‭substrates of cytochrome P450 enzymes‬ ‭●‬ ‭Can act as inhibitors, inducers, or both‬ ‭Adverse Effects‬ ‭●‬ ‭Hyperglycemia‬ ‭○‬ ‭New onset diabetes‬ ‭○‬ ‭Exacerbation of existing diabetes‬ ‭●‬ ‭Fat redistribution (‬‭lipodystrophy‬‭)‬ ‭●‬ ‭Hyperlipidemia‬ ‭●‬ ‭↑ bleeding in pts with hemophilia‬ ‭●‬ ‭↓ cardiac conductivity‬ ‭●‬ ‭↑ serum transaminases‬ ‭Prototype: Darunavir (Prezista)‬ ‭●‬ ‭Taken with ritonavir‬‭to boost its effects‬ ‭MOA‬ ‭●‬ B ‭ inds to active site of HIV protease and prevents the enzyme from cleaving HIV‬ ‭polyproteins‬ ‭○‬ ‭Prevents HIV maturation‬ ‭ ‬ ‭Immature HIV are not infectious‬ ○ ‭ ‬ ‭Few HIV strains are resistant‬ ● ‭Pharmacokinetics‬ ‭●‬ ‭Substrate and inhibitor of CYP3A4‬ ‭●‬ ‭Inducer of CYP2C9‬ ‭Adverse Reactions‬ ‭●‬ ‭Hyperlipidemia‬ ‭●‬ ‭Hyperglycemia‬‭(less frequently)‬ ‭●‬ ‭Rash‬ ‭●‬ ‭N/V/D, headache‬ ‭Drug Interactions‬ ‭●‬ ‭Many potential interactions‬ ‭●‬ ‭Drugs metabolized by CYP3A4 and CYP2C9‬ ‭●‬ ‭Inducers of CYP3A4 can accelerate metabolism of darunavir, leading to subtherapeutic‬ ‭levels‬ ‭Drug Treatment as Prevention‬ ‭Pre-Exposure Prophylaxis (PrEP)‬ ‭●‬ ‭Large RCT trial completed in 2009‬ ‭●‬ ‭Used after single-exposure (oral/vaginal/anal intercourse, contaminated needles,‬ ‭occupational needle-stick, splash)‬ ‭●‬ ‭Must be initiated immediately to be most effective (< 72 hours) and taken for 28 days‬ ‭●‬ ‭Treatment determined by type of exposure‬ ‭○‬ ‭Non-occupational (nPEP)‬ ‭○‬ ‭Occupational PEP‬ ‭Prototype: Tenofovir/Emtricitabine (Truvada)‬ ‭●‬ ‭Currently limited to those who have a high-risk for HIV exposure/acquisition‬ ‭●‬ ‭Reduces HIV acquisition in HIV-negative people by 44-73%‬